Anti-tissue factor antibody-drug conjugate and application thereof in cancer treatment

Abstract

The present invention provides methods and compositions for treating cancer, such as advanced cervical cancer, in a subject, for example by administering an antibody-drug conjugate that binds to tissue factor (TF). The invention also provides articles of manufacture and compositions comprising the antibody-drug conjugates that bind to TF for the treatment of cancer, such as advanced cervical cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 580,877, filed on November 2, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to anti-tissue factor (TF) antibody-drug conjugates and methods for using the same in treating cancer (such as advanced cervical cancer). Background Art

[0004] Tissue factor (TF), also known as thromboplastin, factor III or CD142, is a protein present in subendothelial tissue, platelets and leukocytes, and is necessary for the formation of thrombin from the zymogen prothrombin. The formation of thrombin ultimately leads to blood coagulation. TF enables cells to initiate the coagulation cascade, and it plays the role of a high-affinity receptor for coagulation factor VII (FVII), a serine protease. The resulting complex provides a catalytic event that is responsible for initiating the coagulation protease cascade by specific limited proteolysis. Different from other cofactors that circulate as non-functional precursors of these protease cascades, TF is an efficient initiator that is fully functional when expressed on the cell surface.

[0005] TF is a cell surface receptor for the serine protease factor VIIa (FVIIa). The binding of FVIIa to TF starts a signal transduction process within the cell, which plays a role in angiogenesis. Angiogenesis is a normal process in growth and development and wound healing, but it is also a basic step in the transformation of tumors from a dormant state to a malignant state. When cancer cells acquire the ability to produce proteins involved in angiogenesis (i.e., angiogenic growth factors), these proteins are released by the tumor into nearby tissues, thereby stimulating new blood vessels to sprout from existing healthy blood vessels toward the tumor and enter the tumor. Once new blood vessels enter the tumor, the tumor can rapidly expand its size and invade local tissues and organs. Through new blood vessels, cancer cells can further escape into the circulatory system and remain in other organs to form new tumors, also known as metastatic tumors.

[0006] Expression of TF has been observed in many types of cancer, including cervical cancer, and is associated with more aggressive disease. In addition, human TF also exists in a soluble alternatively spliced ​​form, asHTF. AsHTF was recently found to promote tumor growth (Hobbs et al., 2007, Thrombosis Res. 120(2): S13-S21).

[0007] Cervical cancer constitutes a serious medical problem worldwide, with an estimated 500,000 new cases and 250,000 deaths each year. See Tewari et al., 2014, N Engl J Med., 370: 734-743. In the European Union, approximately 34,000 new cases of cervical cancer and 13,000 deaths occur each year. See Hillemanns et al., 2016, Oncol. Res. Treat. 39: 501-506. The main types of cervical cancer are squamous cell carcinoma and adenocarcinoma. Long-term infection with human papillomavirus (HPV) types 16 and 18 causes most cases of cervical cancer. The standard of first-line treatment for cervical cancer is platinum + taxane-based therapy. Bevacizumab is an anti-VEGF antibody that has been approved by the U.S. Food and Drug Administration for use in combination with chemotherapy to treat cervical cancer, and has improved overall survival in clinical trials. First-line (1L) treatment for advanced cervical cancer consists of a combination of bevacizumab and paclitaxel + platinum (such as cisplatin or carboplatin) or paclitaxel + topotecan. Although the objective response rate (ORR) is 48% and the median overall survival (OS) is about 18 months, unfortunately, almost all patients relapse after receiving this 1L treatment. See Tewari et al., 2014, N Engl J Med., 370: 734-743. For second-line (2L) treatment, there is no approved treatment, and patients are usually treated with single-agent therapy, including but not limited to: pemetrexed, topotecan, docetaxel, albumin-bound paclitaxel, vinorelbine, and bevacizumab used in some cases. A meta-analysis of single-agent therapy showed only a moderate response rate of 10.9% (i.e., 60 responders in 552 patients) and a median overall survival (OS) of about 7 months.See, e.g., Burotto et al., 2015, Oncologist 20:725-726; Candelaria et al., 2009, Int. J. Gynecol. Cancer. 19:1632-1637; Coronel et al., 2009, Med. Oncol. 26:210-214; Fiorica et al., 2009, Gynecol. Oncol. 115:285-289; Garcia et al., 2007, Am. J. Clin. Oncol. 30-428-431; Goncalves et al., 2008, Gynecol. Oncol. 108:42-46; Homesley et al., 2008, Int. J. Clin. Oncol. 13:62-65; McLachlan et al., 2017, Clin. Oncol. (R. Co ll.Radiol.)29:153-160; Miller et al., 2008, Gynecol. Oncol.110:65-70; Monk et al., 2009, J. Clin. Oncol.27:1069-1074; Muggia et al., 2004, Gynecol. Oncol.92:639-643; Rose et al., 2006, Gynecol. Oncol.102:210-213; Santin et al., 2011, Gynecol. Oncol.122:495-500; Schilder et al., 2005, Gynecol. Oncol.96:103-107; and Torfs et al., 2012, Eur. J. Cancer.48:1332-1340. The five-year relative survival rate for stage IV cervical cancer is only 15%, indicating a high need for improved cervical cancer treatments.

[0008] The present invention meets this need by providing highly specific and potent anti-TF antibody-drug conjugates, particularly for the treatment of cervical cancer.

[0009] All references cited herein, including patent applications, patent publications, and scientific literature, are hereby incorporated by reference in their entirety to the same extent as if each individual reference were specifically and individually indicated to be incorporated by reference. Summary of the invention

[0010] Provided herein is a method for treating cervical cancer in a subject, comprising administering to the subject an antibody-drug conjugate that binds to tissue factor (TF). In some aspects, provided herein is a method for treating cervical cancer in a subject, comprising administering to the subject an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof coupled to monomethyl auristatin or a functional analog thereof (e.g., a functional peptide analog) or a functional derivative thereof, and wherein the antibody-drug conjugate is administered at a dose ranging from about 1.5 mg / kg to about 2.1 mg / kg. In another embodiment, the dose is about 2.0 mg / kg. In some of any embodiments herein, the antibody-drug conjugate is administered approximately once every 1 week, 2 weeks, 3 weeks, or 4 weeks. In some of any embodiments herein, the antibody-drug conjugate is administered approximately once every 3 weeks. In some of any embodiments herein, the subject has previously been treated with one or more therapeutic agents and has not responded to the treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate. In some of any embodiments herein, the subject has previously been treated with one or more therapeutic agents and relapsed after the treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate. In some of any embodiments herein, the subject has previously been treated with one or more therapeutic agents and has experienced disease progression during the treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate. In some of any embodiments herein, one or more therapeutic agents include platinum-based therapeutic agents. In some of any embodiments herein, one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxorubicin liposomes (doxil), cetuximab (cetuximab), pembrolizumab (pembrolizumab), nivolumab (nivolumab) and bevacizumab (bevacizumab). In some of any embodiments herein, the subject has experienced disease progression during or after treatment with: a) paclitaxel and cisplatin, b) paclitaxel and carboplatin, or c) paclitaxel and topotecan. In some of any embodiments herein, the subject has been treated with bevacizumab. In some of any embodiments herein, the subject is not eligible for bevacizumab treatment. In some of any embodiments herein, the subject is not a candidate for curative therapy. In some of any embodiments herein, curative therapy includes radiation therapy and / or evisceration. In some of any embodiments herein, the subject has not responded to treatment with no more than two prior systemic treatment regimens. In some of any embodiments herein, the subject has relapsed after treatment with no more than two prior systemic treatment regimens.In some of any embodiments herein, the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma. In some of any embodiments herein, the cervical cancer is advanced cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer. In some of any embodiments herein, the cervical cancer is recurrent cervical cancer. In some of any embodiments herein, the monomethyl auristatin is monomethyl auristatin E (MMAE). In some of any embodiments herein, the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof. In some of any embodiments herein, the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:.

[0011] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0012] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0013] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0014] Wherein the light chain variable region comprises:

[0015] (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0016] (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0017] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 5; wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme.

[0018] In some of any embodiments herein, the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence that is at least about 85%, at least about 90%, or at least about 95% identical to the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence that is at least about 85%, at least about 90%, or at least about 95% identical to the amino acid sequence of SEQ ID NO: 8. In some of any embodiments herein, the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8. In some of any embodiments herein, the anti-TF antibody of the antibody-drug conjugate is tisotumab. In some of any embodiments herein, the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and monomethyl auristatin. In another embodiment, the linker is a cleavable peptide linker. In another embodiment, the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein:

[0019] a)MC is:

[0020]

[0021] b) vc is the dipeptide valine-citrulline, and

[0022] c) PAB is:

[0023]

[0024] In some of any of the embodiments herein, the linker is linked to a thiol residue of an anti-TF antibody, which is obtained by partial reduction or full reduction of the anti-TF antibody or antigen-binding fragment thereof. In another embodiment, the linker is linked to MMAE, wherein the antibody-drug conjugate has the following structure:

[0025]

[0026] wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or an antigen-binding fragment thereof. In another embodiment, the average value of p in the antibody-drug conjugate population is about 4. In some of any embodiments herein, the antibody-drug conjugate is tisotumab vedotin. In some of any embodiments herein, the route of administration of the antibody-drug conjugate is intravenous (e.g., intravenous infusion). In some of any embodiments herein, 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 of any embodiments herein, one or more therapeutic effects in the subject are improved relative to baseline after administration of the antibody-drug conjugate. In another embodiment, one or more therapeutic effects are selected from the group consisting of the size of a tumor derived from cervical cancer, an objective response rate, a duration of response, a duration of response, progression-free survival, and overall survival. In some of any embodiments herein, the size of a tumor derived from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of a tumor derived from cervical cancer before administration of the antibody-drug conjugate. In some of any embodiments herein, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In some of any embodiments herein, the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate. In some of any embodiments herein, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.In some of the embodiments herein, after administration of the antibody-drug conjugate, the duration of the 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. In some of the embodiments herein, the subject has one or more adverse events, and further receives other therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some of the embodiments herein, the subject is at risk of developing one or more adverse events, and further receives other therapeutic agents to prevent or reduce the severity of one or more adverse events. In some of the embodiments herein, one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general physical health deterioration. In some of any embodiments herein, one or more adverse events are grade 3 or higher adverse events. In some of any embodiments herein, one or more adverse events are serious adverse events. In some of any embodiments herein, one or more adverse events are conjunctivitis and / or keratitis, and the other medicaments are preservative-free lubricating eye drops, ocular vasoconstrictors, and / or steroid eye drops. In some of any embodiments herein, the antibody-drug conjugate is administered as a monotherapy. In some of any embodiments herein, the subject is a human. In some of any embodiments herein, the antibody-drug conjugate is in a pharmaceutical composition comprising an antibody-drug conjugate and a pharmaceutically acceptable carrier.

[0027] Also provided herein are articles of manufacture comprising an antibody-drug conjugate that binds to TF. In some aspects, provided herein are articles of manufacture comprising: a) a medicament comprising an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog thereof (e.g., a functional peptide analog) or a functional derivative thereof; and b) a package insert comprising instructions for administering the medicament comprising the antibody-drug conjugate in a method of treating cervical cancer in a subject according to some of any embodiments herein. In another embodiment, the medicament comprising the antibody-drug conjugate is in a container selected from the group consisting of a vial, a syringe, and an infusion bag. In another embodiment, the container comprises the antibody-drug conjugate at a dose of about 4 mg to about 500 mg. In another embodiment, the container comprises the antibody-drug conjugate at a dose of about 20 mg to about 60 mg. In another embodiment, the container comprises the antibody-drug conjugate at a dose of about 40 mg. In yet another embodiment, the container comprises the antibody-drug conjugate at a dose of 40 mg. In yet another embodiment, the container comprises an antibody-drug conjugate at a concentration of about 5 mg / mL to about 15 mg / mL. In some of any embodiments herein, the drug comprising the antibody-drug conjugate is a lyophilized powder. In another embodiment, the lyophilized powder is reconstituted with a suitable diluent to a final concentration of about 5 mg / mL to about 15 mg / mL. In some of any embodiments herein, the drug comprising the antibody-drug conjugate is administered by intravenous infusion or injection. In another embodiment, the drug comprising the antibody-drug conjugate is administered by intravenous infusion. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The patent or application file contains at least one drawing printed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0029] Figure 1 is a graph showing the mechanism of action (MOA) of the antibody-drug conjugate tesotumomab vedotin.

[0030] Figure 2 is a diagram showing the design of a dose escalation study with tisotumomab vedotin in the treatment of cancer patients. q3w means that the treatment cycle is a cycle every 3 weeks.

[0031] Figure 3 is a graph showing the most common treatment-related adverse reactions (AEs) in ≥4 patients overall following treatment with tetuzumab vedotin at all doses tested. N=27 represents 27 patients.

[0032] Figure 4A and 4Bis a graph showing A) mean plasma tesotumomab vedotin concentrations and B) mean plasma free MMAE concentrations over time during Cycle 1 and Cycle 2 for all dose groups.

[0033] Figure 5 Graph showing the best percent change in tumor size from baseline in 27 patients. (i) Patient 1 had cervical cancer and was treated with 2.2 mg / kg of tesotumomab vedotin. (ii) Patient 2 had cervical cancer and was treated with 1.2 mg / kg of tesotumomab vedotin. Baseline was defined as the most recent available assessment performed before the first treatment with tesotumomab vedotin.

[0034] Figure 6 is a computed tomography (CT) scan of lung metastases of patient 2. The patient had cervical cancer and was treated with 1.2 mg / kg of tesotumomab vedotin.

[0035] Figure 7 is a graph showing the most common adverse events (AEs) in 34 cervical cancer patients treated.

[0036] Figure 8 is a graph showing the best percent change in target lesions from baseline. a Two patients dropped out before CT scanning and are therefore not shown in the figure. b Denotes PD due to new lesions on the same scan. Baseline was defined as the latest available assessment performed before the first treatment with tezomib vedotin.

[0037] Fig. 9 is a graph showing the best percent change in target lesions from baseline. a Indicates patients with best PR response who have nodal disease and refractory non-target lesions. b Denotes patients with best PD response who had nodal disease, refractory non-target lesions, and new lesions. Baseline was defined as the latest available assessment before the first treatment with tezomib vedotin.

[0038] Fig.10 is a graph showing time and duration of reaction. a Responses defined as unconfirmed + confirmed responses.

[0039] Fig.11 is a diagram showing the design of a Phase II study of treatment with tesotumomab vedotin in patients with previously treated recurrent or metastatic cancer who have received at least one prior systemic therapy. aIndicates infusion of 2.0 mg / kg of tesotumomab vedotin on day 1 of each cycle until disease progression. Each treatment cycle is 3 weeks (Q3W). b CT or MRI scans were performed every 6 weeks (±7 days) during the first 30 weeks of treatment and every 12 weeks (±7 days) thereafter, regardless of whether treatment was delayed. c Indicates optional. DETAILED DESCRIPTION

[0040] I. Definitions

[0041] In order to better understand the present invention, some terms are first defined. As used in this application, unless otherwise described herein, each of the following terms shall have the following meanings. Additional definitions are described throughout the application.

[0042] The term "and / or" as used herein should be considered to specifically disclose each of the two features or components, with or without the other. Thus, the term "and / or" as used in, for example, the phrase "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in, for example, the phrase "A, B, and / or C" is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0043] It is to be understood that aspects and embodiments of the present invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same common meaning as understood by those of ordinary skill in the art to which the present disclosure belongs. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and Oxford Dictionary of Biochemistry and Molecular Biology, revised, 2000, Oxford University Press, provide a common dictionary of many terms used in the present disclosure to the skilled person.

[0045] Units, prefixes and symbols are expressed in the form accepted by their International System of Units (SI). Numerical ranges include numerical values ​​that limit the range. The titles provided herein are not limitations of the various aspects of the present disclosure, and the various aspects or embodiments of the present disclosure can be understood with reference to the specification as a whole. Therefore, the terms defined below are fully defined with reference to the full text of the specification.

[0046] The terms "tissue factor", "TF", "CD142", "tissue factor antigen", "TF antigen" and "CD142 antigen" are used interchangeably herein and, unless otherwise indicated, include any variants, isoforms and species homologs of human tissue factor expressed naturally by cells or on cells transfected with tissue factor genes. The tissue factor may be the sequence of GenBank Accession No. NP_001984.

[0047] The term "immunoglobulin" refers to a class of structurally related proteins consisting of two pairs of polypeptide chains: a pair of light (L) low molecular weight chains and a pair of heavy (H) chains, all four of which are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, for example, Chapter 7 of Fundamental Immunology (Paul, W., ed., 2nd ed., Raven Press, New York (1989)). In brief, each heavy chain generally comprises a heavy chain variable region (abbreviated herein as V H or VH) and the heavy chain constant region (C H The heavy chain constant region usually contains three domains: H 1. C H2 and C H 3. Each light chain generally comprises a light chain variable region (abbreviated herein as V L or VL) and the light chain constant region (C L or CL). The light chain constant region usually contains a domain C L . V H and V L The V domains can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in sequence and / or in the form of structurally defined loops), also called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). H and V L It is usually composed of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mot. Biol.. 195, 901-917 (1987)). Generally, the numbering of amino acid residues in this region is carried out by the method described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, National Institutes of Health, Public Health, Bethesda, Maryland (1991) (the phrases herein, variable domain residue numbering as in or according to Kabat, refer to this numbering system for the heavy chain variable domain or the light chain variable domain). Using this numbering system, the actual linear amino acid sequence of the peptide may contain fewer or additional amino acid sequences corresponding to shortening or insertion of the variable domain FR or CDR. For example, the heavy chain variable domain may contain V H Single amino acid insertion after residue 52 of CDR2 (residue 52a according to Kabat) and insertion residue after residue 82 of heavy chain FR (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues can be determined for a given antibody by aligning regions of antibody sequence homology with a "standard" Kabat numbering sequence. Immunoglobulins can be derived from any conventionally known isotype, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art, including but not limited to human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (such as IgM or IgG1) encoded by the heavy chain constant region gene.

[0048] In the context of the present invention, the term "antibody" (Ab) refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of any of them, which has the ability to specifically bind to an antigen under typical physiological conditions, and its half-life is very 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, about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 or more days, etc., or any other relevant functionally defined time period (e.g., sufficient to induce, promote, enhance and / or regulate the physiological response associated with the binding of the antibody to the antigen and / or sufficient for the antibody to produce effector activity). The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with the antigen. The constant region of the antibody (Ab) can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system (such as C1q), which is the first component in the classical pathway of complement activation. As mentioned above, unless otherwise specified or clearly contradictory to the context, the term antibody herein includes antibody fragments (such as antigen-binding fragments) that retain the ability to specifically bind to an antigen. It is known that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antigen-binding fragments encompassed by the term "antibody" include: (i) Fab' or Fab fragments, which are fragments of V L 、V H , C L and C H 1 domain, or the monovalent antibody described in WO2007059782 (Genmab A / S); (ii) F(ab')2 fragment, which is a bivalent fragment containing two Fab fragments connected by a disulfide bridge at the hinge region; (iii) Fd fragment, which is essentially composed of V H and C H 1 domain; (iv) Fv fragment, which is essentially composed of the V L and V H (v) dAb fragment (Ward et al., Nature 341, 544-546 (1989)), which is essentially composed of V H (vi) camelid antibodies or nanobodies (Revets et al., Expert Opin Biol Ther. 2005 Jan; 5(1): 111-24) and (vii) isolated complementarity determining regions (CDRs). In addition, although the two domains V and V of the Fv fragment are L and V HThey are encoded by different genes, but can be connected into a protein chain using synthetic linkers through recombinant methods. L and V H The domains are paired to form monovalent molecules (called single-chain antibodies or single-chain Fv (scFv); see, for example, Bird et al., Science 242, 423-426 (1988) and Huston et al., PNAS USA 85, 5879-5883 (1988)). Unless otherwise specified or the context clearly indicates, such single-chain antibodies are encompassed within the term antibody. Although such antigen-binding fragments are generally included in the meaning of antibodies, they are collectively and independently unique features of the present invention, exhibiting different biological properties and utilities. These and other useful antibody fragments in the context of the present invention are further discussed herein. It should also be understood that, unless otherwise specified, the term "antibody" also includes polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides such as chimeric antibodies and humanized antibodies provided by any known technology, such as enzyme cleavage, peptide synthesis and recombinant technology, and antibody fragments (such as antigen-binding fragments) that retain the ability to specifically bind to antibodies. The antibodies produced can have any isotype. In the absence of explicit indication, the term "antibody" also includes antigen-binding fragments or antigen-binding portions of any of the above-mentioned immunoglobulins, unless the context indicates otherwise.

[0049] An "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds to TF is substantially free of antibodies that specifically bind to antigens other than TF). However, an isolated antibody that specifically binds to TF may have cross-reactivity with other antigens (e.g., TF molecules from different species). In addition, the isolated antibody may be substantially free of other cellular material and / or chemical substances. In one embodiment, the antibody includes a conjugate linked to another agent (e.g., a small molecule drug). In some embodiments, the anti-TF antibody includes a conjugate of an anti-TF antibody and a small molecule drug (e.g., MMAE or MMAF).

[0050] The term "monoclonal antibody" (mAb) refers to a non-naturally occurring preparation of antibody molecules having a single molecular composition, i.e., antibody molecules whose primary sequences are substantially identical and which exhibit a single binding specificity and affinity for a particular epitope. A monoclonal antibody is an example of an isolated antibody. Monoclonal antibodies can be produced by hybridoma, recombination, transgenic or other techniques known to those skilled in the art.

[0051] "HuMAb" refers to antibodies in which both FR and CDR in the variable region are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or somatic mutations in vivo). However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (such as a mouse) have been grafted onto human framework sequences. The terms "human antibody" and "fully human antibody" are used synonymously.

[0052] "Humanized antibody" refers to an antibody in which some, most or all of the amino acids outside the CDR of a non-human antibody are replaced by corresponding amino acids derived from human immunoglobulin. In one embodiment of the humanized form of the antibody, some, most or all of the amino acids outside the CDR have been replaced by amino acids from human immunoglobulin, while some, most or all of the amino acids within one or more CDRs remain unchanged. A small amount of addition, deletion, insertion, substitution or modification of amino acids is allowed as long as they do not eliminate the ability of the antibody to bind to a specific antigen. "Humanized antibody" retains antigenic specificity similar to the original antibody. In some embodiments, the CDR of a humanized antibody contains CDRs from non-human mammalian antibodies. In other embodiments, the CDR of a humanized antibody contains CDRs from engineered synthetic antibodies.

[0053] "Chimeric antibodies" refer to antibodies in which the variable regions are derived from one species and the constant regions are derived from another species, for example, antibodies in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.

[0054] "Anti-antigen antibody" refers to an antibody that specifically binds to an antigen. For example, an anti-TF antibody specifically binds to TF.

[0055] An "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen to which the intact 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 antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with one antigen-binding site, and a residual "Fc" fragment, the name of which reflects its ability to crystallize readily. Pepsin treatment produces a F(ab')2 fragment that has two antigen-binding sites and is still able to cross-link antigen.

[0056] When used in this article, the term "hypervariable region", "HVR" or "HV" refers to the region of the antibody variable domain with hypervariability in the loop form defined in sequence and / or structure. Typically, an antibody comprises 6 HVRs, 3 in VH (H1, H2, H3) and 3 in VL (L1, L2, L3). In natural antibodies, H3 and L3 of the 6 HVRs show the most diversity, and H3 in particular is considered to play a unique role in conferring fine specificity to antibodies. See, for example, Xu et al., Immunity 13: 37-45 (2000); Johnson and Wu, Methods in Molecular Biology 248: 1-25 (Lo ed., Human Press, Totowa, NJ, 2003)). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0057] Many HVR descriptions are used and covered herein. The Kabat complementarity determining region (CDR) HVR is based on sequence variability and is the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., NIH, Public Health, Bethesda, Maryland (1991)). Chothia HVR refers to the position of the structural loop (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987)). "Contact" HVR is based on analysis of variable complex crystal structures. The residues from each of these HVRs are marked as follows.

[0058]

[0059] As used herein, the term "binding" or "specific binding" in the context of antibody binding to a predetermined antigen is generally a specific binding affinity corresponding to about 10 when measured, for example, by surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using the antigen as a ligand and the antibody as an analyte. -7 M or less, for example, about 10 -8 M or less, for example, about 10 -9 M or smaller, about 10 -10 M or less, or about 10 -11 M or smaller, or even smaller K DThe binding affinity of the antigen to the target antigen is at least 10 times lower, such as at least 100 times lower, such as at least 1,000 times lower, such as at least 10,000 times lower, such as at least 100,000 times lower, and at least 100,000 times lower than its binding affinity to a non-specific antigen other than the predetermined antigen or a closely related antigen (such as BSA, casein). D The amount of affinity lower depends on the antibody's K D Therefore, when the antibody K D When very low (ie, the antibody is highly specific), the amount by which the affinity for the antigen is lower than the affinity for the non-specific antigen may be at least 10,000 times.

[0060] The term “k d ”(sec -1 ) refers to the dissociation rate constant for a specific antibody-antigen interaction. The value is also referred to as k off value.

[0061] The term “k a ”(M -1 ×sec -1 ) refers to the association rate constant for a specific antibody-antigen interaction.

[0062] The term "K D ” (M) refers to the dissociation equilibrium constant for a specific antibody-antigen interaction.

[0063] The term "K A ”(M -1 ) refers to the binding equilibrium constant for a specific antibody-antigen interaction, expressed as k a Divide by k d And get.

[0064] The term "ADC" refers to an antibody-drug conjugate, which in the context of the present invention refers to an anti-TF antibody conjugated to another moiety as described in this application, such as MMAE or MMAF.

[0065] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0066] The abbreviation "PAB" refers to a self-immolative spacer group:

[0067]

[0068] The abbreviation "MC" refers to the extending group maleimidocaproyl:

[0069]

[0070] The term "Ab-MC-vc-PAB-MMAE" refers to an antibody conjugated to the drug MMAE via a MC-vc-PAB linker.

[0071] "Cancer" refers to a large and diverse group of diseases characterized by the uncontrolled growth of abnormal cells in the body. "Cancer" or "cancerous tissue" can include tumors. Uncontrolled cell division and growth lead to the formation of malignant tumors, which invade adjacent tissues and may also metastasize to distant sites in the body via the lymphatic system or bloodstream. After metastasis, the distant tumor can be said to have "derived from" the pre-metastatic tumor. For example, a tumor that "derives from" cervical cancer means a tumor that is a result of cervical cancer that has metastasized.

[0072] "Treatment" or "therapy" of a subject refers to any type of intervention or procedure performed on a subject, or administration of an active agent to a subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing or preventing the onset, progression, development, severity or recurrence of symptoms, complications, conditions or biochemical markers associated with a disease. In some embodiments, the disease is cancer.

[0073] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates, such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" and "individual" are used interchangeably herein.

[0074] "Effective amount" or "therapeutically effective amount" or "therapeutically effective dose" refers to an amount that, at a dosage and for a necessary time period, is capable of achieving a desired therapeutic outcome. Such desired therapeutic outcomes include protecting a subject from the onset of disease or promoting regression of disease, as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of impairment or disability due to affliction with the disease. The ability of a therapeutic agent to promote regression of disease can be evaluated using a variety of methods known to those skilled in the art, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays. The therapeutically effective amount of an anti-TF antibody-drug conjugate may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the anti-TF antibody-drug conjugate to elicit a desired response in the individual. In a therapeutically effective amount, the therapeutically beneficial effects of the anti-TF antibody-drug conjugate outweigh any toxic or deleterious effects.

[0075] A therapeutically effective amount of a drug (e.g., an anti-TF antibody-drug conjugate) includes a "prophylactically effective amount," which is any amount of a drug that, when administered alone or in combination with an anti-cancer agent to a subject at risk for developing cancer (e.g., a subject with a pre-malignant condition) or suffering from the recurrence of cancer, inhibits the development or recurrence of the cancer. In some embodiments, a prophylactically effective amount completely prevents the development or recurrence of the cancer. "Inhibiting" the development or recurrence of cancer means reducing the likelihood that the cancer will develop or recur, or completely preventing the development or recurrence of the cancer.

[0076] As used herein, "subtherapeutic dose" refers to a dose of a therapeutic compound (eg, an antibody-drug conjugate) that is less than the usual or typical dose of the therapeutic compound when administered alone to treat a hyperproliferative disease (eg, cancer).

[0077] For example, an "anticancer agent" promotes the regression of cancer in a subject. In some embodiments, a therapeutically effective amount of a drug promotes the regression of cancer to the point of eliminating the cancer. "Promoting cancer regression" means that the administration of an effective amount of a drug alone or in combination with an anticancer agent can result in a reduction in tumor growth or size, tumor necrosis, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease-free periods, or the prevention of impairment or disability due to the affliction of the disease. In addition, the terms "effective" and "effectiveness" with respect to treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote the regression of cancer in a patient. Physiological safety refers to toxicity or other adverse physiological reactions (adverse reactions) at the cellular, organ and / or organism level caused by administration.

[0078] For example, for the treatment of tumors, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, or at least about 100% in treated subjects (e.g., one or more treated subjects) relative to untreated subjects (e.g., one or more untreated subjects).

[0079] In other embodiments of the present disclosure, tumor regression can be observed and persists for a period of at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days. Despite these ultimate measures of therapeutic effectiveness, evaluation of immunotherapeutic drugs must also consider "immune-related response patterns."

[0080] A "sustained response" refers to a persistent effect in reducing tumor growth after treatment has stopped. For example, the tumor size can remain the same or smaller than it was at the beginning of the dosing period. In some embodiments, the duration of a sustained response is at least the same as the duration of treatment, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the duration of treatment.

[0081] 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% in the sum of the longest diameters of the target lesions (SLD) relative to the baseline SLD; "stable disease" or "SD" means that the target lesions have neither shrunk sufficiently to meet the PR criteria nor increased sufficiently to meet the PD criteria relative to the smallest SLD since the start of treatment.

[0082] As used herein, "progression-free survival" or "PFS" refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival can include the time a patient experiences a complete response or a partial response, as well as the time a patient experiences stable disease.

[0083] As used herein, "overall response rate" or "ORR" refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0084] As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group of individuals who are likely to survive after a specific period of time.

[0085] The term "weight-based dose" as used herein refers to a dose given to a patient calculated based on the patient's weight. For example, if a patient weighing 60 kg requires 2 mg / kg of an anti-TF antibody-drug conjugate, an appropriate amount of anti-TF antibody-drug conjugate (i.e., 120 mg) can be calculated and administered.

[0086] The term "flat dose" as used with respect to the methods and dosages of the present disclosure refers to a dose that is administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, a flat dose is not given in the form of a mg / kg dose, but rather in the form of an absolute amount of an agent (e.g., an anti-TF antibody-drug conjugate). For example, a 60 kg person and a 100 kg person would receive the same dose of an antibody-drug conjugate (e.g., 240 mg of an anti-TF antibody-drug conjugate).

[0087] The phrase "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically with the other ingredients contained in the formulation and / or with the mammal to be treated therewith.

[0088] As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, pamoates (i.e., 4.4'-methylene-bis(2-hydroxy-3 -naphthoate), alkali metal (such as sodium and potassium) salts, alkaline earth metal (such as magnesium) salts, and ammonium salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In cases where multiple charged atoms are part of a pharmaceutically acceptable salt, there may be multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0089] "Administering" refers to physically introducing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration of the anti-TF antibody-drug conjugate include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). As used herein, the phrase "parenteral administration" refers to forms of administration other than enteral and topical administration, usually by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. The therapeutic agent may be administered by non-parenteral routes or orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical administration. Administration may also be performed, for example, once, multiple times and / or over one or more extended periods of time.

[0090] The terms "baseline" or "baseline value" used interchangeably herein may refer to an assessment or characterization of symptoms prior to administration of a therapy (antibody-drug conjugate described herein) or at the start of administration of a therapy. A baseline value may be compared to a reference value to determine a reduction or improvement in symptoms of a TF-related disease (such as cervical cancer) contemplated herein. The terms "reference" or "reference value" used interchangeably herein may refer to an assessment or characterization of symptoms after administration of a therapy (antibody-drug conjugate described herein). A reference value may be determined one or more times during a dosing regimen or treatment cycle or at the completion of a dosing regimen or treatment cycle. A "reference value" may be an absolute value; a relative value; a value with an upper and / or lower limit; a range of values; an average value; a median value; a mean; or a value compared to a baseline value.

[0091] Similarly, a "baseline value" can be an absolute value; a relative value; a value with an upper and / or lower limit; a range of values; an average value; a median value; a mean value; or a value compared to a reference value. Reference values ​​and / or baseline values ​​can be obtained from one individual, two different individuals, or a group of individuals (e.g., a group of two, three, four, five or more individuals).

[0092] The term "monotherapy" as used herein means that the antibody drug conjugate is the only anticancer agent administered to a subject during a treatment cycle. However, other therapeutic agents may also be administered to a subject. For example, an anti-inflammatory or other agent may be administered to a subject with cancer during a monotherapy period to treat symptoms associated with the cancer, but not the underlying cancer itself, including, for example, inflammation, pain, weight loss, and general discomfort.

[0093] As used herein, "adverse event" (AE) is any unfavorable and usually unexpected or undesirable sign (including abnormal laboratory findings), symptom or disease associated with the use of a drug therapy. A drug therapy can have one or more associated AEs, and each AE can have the same or different levels of severity. Reference to a method that can "modify adverse events" refers to a treatment regimen that reduces the incidence and / or severity of one or more AEs associated with the use of a different treatment regimen.

[0094] As used herein, a “serious adverse event” or “SAE” is an adverse event that meets one of the following criteria:

[0095] ● Is fatal or life-threatening (“life-threatening” as used in the definition of a serious adverse event refers to an event in which the patient is at risk of death at the time of the event; it does not refer to an event that hypothetically could have resulted in death if it were more severe.

[0096] ● Causes persistent or severe disability / incapacity

[0097] ●Constitutes congenital anomaly / birth defect

[0098] ● Is medically important, defined as an event that could harm the patient or may require medical or surgical intervention to prevent one of the above outcomes. Medical and scientific judgment must be exercised in determining whether an AE is “medically important”

[0099] ● Hospitalization is required or an extension of an existing hospitalization is required, except for the following: 1) routine treatment or monitoring of the underlying disease, not accompanied by any worsening of the disease; 2) elected or pre-planned treatment of a pre-existing condition that is not related to the indication being studied and has not worsened since the signing of the informed consent, and in the absence of any deterioration in the patient's general condition for social reasons and suspension of care.

[0100] The use of alternatives (eg, "or") should be understood to refer to one, both, or any combination of the alternatives. As used herein, the indefinite articles "a" or "an" should be understood to refer to "one or more" of any cited or listed components.

[0101] The term "about" or "substantially comprising" refers to a value or composition within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which will depend on how the value or composition is measured or determined, i.e., the limits of the measurement system. For example, "about" or "substantially comprising" can be expressed as within 1 standard deviation or greater than 1 standard deviation as practiced in the art. Alternatively, "about" or "substantially comprising" can represent a range of up to 20%. In addition, particularly with respect to biological systems or processes, these terms can represent up to an order of magnitude or up to 5 times a value. When a specific value or composition is provided in the present application and claims, unless otherwise stated, it should be assumed that the meaning of "about" or "substantially comprising" is within an acceptable error range for that specific value or composition.

[0102] As used herein, the terms "about once a week," "about once every two weeks," "about once every three weeks," or any other similar dosing interval terms refer to approximate numbers. "About once a week" may include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "About once every two weeks" may include every 14 days ± 2 days, i.e., every 12 days to every 16 days. "About once every three weeks" may include every 21 days ± 3 days, i.e., every 18 days to every 24 days. For example, similar approximations apply to about once every four weeks, about once every five weeks, about once every six weeks, and about once every twelve weeks.

[0103] As described herein, any concentration range, percentage range, ratio range or integer range should be understood to include any integer value within the range, including fractional values ​​thereof (such as tenths and hundredths of integers) where appropriate, unless otherwise specified.

[0104] Various aspects of the disclosure are described in further detail in the following subsections.

[0105] II. Antibody-drug conjugates

[0106] The present invention provides anti-TF antibody-drug conjugates useful for treating cancer in a subject. In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer is advanced cervical cancer (such as stage 3 cervical cancer 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 recurrent, recurrent and / or metastatic cervical cancer.

[0107] A. TF antibody

[0108] Typically, the antibodies of the present disclosure immunospecifically bind to TF and exert cytostatic and cytotoxic effects on malignant cells such as cervical cancer cells. The antibodies of the present disclosure are preferably monoclonal, and may be multispecific, human, humanized or chimeric antibodies, single-chain antibodies, Fab fragments, F(ab') fragments, fragments produced by Fab expression libraries, and TF binding fragments of any of the above. The immunoglobulin molecules of the present disclosure may be immunoglobulin molecules of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass.

[0109] In certain embodiments of the present disclosure, the antibodies are human antigen-binding fragments described herein, including but not limited to Fab, Fab' and F(ab')2, Fd, single-chain Fv (scFv), single-chain antibodies, disulfide-linked Fv (sdFv), and V-containing fragments. L or V H The antigen-binding fragments, including single-chain antibodies, may comprise the variable region alone or in combination with all or part of the following: hinge region, CH1, CH2, CH3 and CL domains. The present disclosure also includes antigen-binding fragments comprising any combination of the variable region and hinge region, CH1, CH2, CH3 and CL domains. Preferably, the antibody or antigen-binding fragment thereof is human, murine (such as mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camelid, horse or chicken.

[0110] The antibodies disclosed herein may be monospecific, bispecific, trispecific or more multispecific. Multispecific antibodies may be specific for different epitopes of TF, or may be specific for both TF and a heterologous protein. See, e.g., PCT Publications WO 93 / 17715; WO 92 / 08802; WO 91 / 00360; WO 92 / 05793; Tutt et al., 1991, J. Immunol. 147: 60 69; U.S. Pat. No. 4,474,893; U.S. Pat. No. 4,714,681; U.S. Pat. No. 4,925,648; U.S. Pat. No. 5,573,920; U.S. Pat. No. 5,601,819; Kostelny et al., 1992, J. Immunol. 148: 15471553.

[0111] Antibodies disclosed herein can be described or specified according to the specific CDRs they contain. The precise amino acid sequence boundaries of a given CDR or FR can be easily determined using any of a number of known schemes, including Kabat et al., (1991), Sequences of Proteins of Immunological Interest, 5th ed., NIH, Public Health, Bethesda, Maryland ("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 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); 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 (the "IMGT" numbering scheme); Honegger A and Plückthun A, Yetanother numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool, J Mol Biol, 2001 Jun 8;309(3):657-70, (the "Aho" numbering scheme); and Martin et al., Modeling antibody hypervariable loops: a combined algorithm, PNAS, 1989, 86(23):9268-9272, (the "AbM" numbering scheme). The boundaries of a given CDR may vary, depending on the scheme used for identification.In some embodiments, the "CDR" or "complementarity determining region" or individually designated CDR (such as CDR-H1, CDR-H2, CDR-H3) of a given antibody or region thereof (such as its variable region) should be understood to encompass the (or specific) CDRs defined by any of the above schemes. For example, when stating that a specific CDR (such as CDR-H3) contains a given V. H or V L When referring to the amino acid sequence of a corresponding CDR in a variable region amino acid sequence, it is understood that the CDR has the sequence of a corresponding CDR (e.g., CDR-H3) in the variable region, as defined by any of the above schemes. A scheme for identifying one or more specific CDRs can be specified, such as CDRs defined by the Kabat, Chothia, AbM, or IMGT methods.

[0112] The CDR sequences of the anti-TF antibodies of the anti-TF antibody-drug conjugates provided herein are according to the IMGT numbering scheme described in Lefranc, MP et al., Dev. Comp. Immunol., 2003, 27, 55-77.

[0113] In certain embodiments, the antibodies of the present disclosure comprise one or more CDRs of antibody 011. See WO 2011 / 157741 and WO 2010 / 066803. The present disclosure encompasses antibodies or derivatives thereof comprising a heavy or light chain variable domain, the variable domain comprising: (a) a set of three CDRs, wherein the CDR set is from monoclonal antibody 011, and (b) a set of four framework regions, wherein the framework region set is different from the framework region set in monoclonal antibody 011, and wherein the antibody or derivative thereof immunospecifically binds to TF. In certain embodiments, the anti-TF antibody is 011. Antibody 011 is also known as tisotumab.

[0114] In one aspect, anti-TF antibodies that compete with tesotumomab for binding to TF are provided.Anti-TF antibodies that bind to the same epitope as tesotumomab are also provided.

[0115] In one aspect, provided herein is an anti-TF antibody comprising 1, 2, 3, 4, 5 or 6 CDR sequences of tesotumomab.

[0116] In one aspect, provided herein is an anti-TF antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and / or wherein the light chain variable region comprises: (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; wherein the CDRs of the anti-TF antibody are defined by the IMGT numbering scheme.

[0117] The anti-TF antibodies described herein may comprise any suitable framework variable domain sequence, as long as the antibody retains the ability to bind to TF (such as human TF). As used herein, the heavy chain framework region is referred to as "HC-FR1-FR4" and the light chain framework region is referred to as "LC-FR1-FR4". In some embodiments, the anti-TF antibody comprises the heavy chain variable domain framework sequences of SEQ ID NOs: 9, 10, 11, and 12 (HC-FR1, HC-FR2, HC-FR3, and HC-FR4, respectively). In some embodiments, the anti-TF antibody comprises the light chain variable domain framework sequences of SEQ ID NOs: 13, 14, 15, and 16 (LC-FR1, LC-FR2, LC-FR3, and LC-FR4, respectively).

[0118] In one embodiment, an anti-TF antibody comprises a heavy chain variable domain comprising a framework sequence and a hypervariable region, wherein the framework sequence comprises the HC-FR1-HC-FR4 amino acid sequences of SEQ ID NO: 9 (HC-FR1), SEQ ID NO: 10 (HC-FR2), SEQ ID NO: 11 (HC-FR3) and SEQ ID NO: 12 (HC-FR4), respectively; CDR-H1 comprises the amino acid sequence of SEQ ID NO: 1; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2; and CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3.

[0119] In one embodiment, the anti-TF antibody comprises a light chain variable domain comprising a framework sequence and a hypervariable region, wherein the framework sequence comprises the LC-FR1-LC-FR4 amino acid sequences of SEQ ID NO: 13 (LC-FR1), SEQ ID NO: 14 (LC-FR2), SEQ ID NO: 15 (LC-FR3) and SEQ ID NO: 16 (LC-FR4), respectively; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.

[0120] In some embodiments of the anti-TF antibodies described herein, the heavy chain variable domain comprises the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSSISGSGDYTYYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSPWGYYLDSWGQGTLVTVSS (SEQ ID NO:7), and the light chain variable domain comprises the amino acid sequence DIQMTQSPPSLSASAGDRVTITCRASQGISSRLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO:8).

[0121] In some embodiments of the anti-TF antibodies described herein, the heavy chain CDR sequence comprises the following:

[0122] a) CDR-H1 (GTFFSNYA (SEQ ID NO: 1));

[0123] b) CDR-H2 (ISGSGDYT (SEQ ID NO: 2)); and

[0124] c) CDR-H3 (ARSPWGYYLDS (SEQ ID NO: 3)).

[0125] In some embodiments of the anti-TF antibodies described herein, the heavy chain FR sequence comprises the following:

[0126] a) HC-FR1(EVQLLESGGGLVQPGGSLRLSCAAS(SEQ ID NO:9));

[0127] b) HC-FR2 (MSWVRQAPGKGLEWVSS (SEQ ID NO: 10));

[0128] c) HC-FR3 (YYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO: 11)); and

[0129] d) HC-FR4 (WGQGTLVTVSS (SEQ ID NO: 12)).

[0130] In some embodiments of the anti-TF antibodies described herein, the light chain CDR sequence comprises the following:

[0131] a) CDR-L1 (QGISSR (SEQ ID NO: 4));

[0132] b) CDR-L2 (AAS (SEQ ID NO: 5)); and

[0133] c) CDR-L3 (QQYNSYPYT (SEQ ID NO: 6)).

[0134] In some embodiments of the anti-TF antibodies described herein, the light chain FR sequence comprises the following:

[0135] a) LC-FR1(DIQMTQSPPSLSASAGDRVTITCRAS(SEQ ID NO:13));

[0136] b) LC-FR2(LAWYQQKPEKAPKSLIY(SEQ ID NO:14));

[0137] c) LC-FR3(SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:15)); and

[0138] d) LC-FR4 (FGQGTKLEIK (SEQ ID NO: 16)).

[0139] In some embodiments, provided herein is an anti-TF antibody that binds to TF (such as human TF), wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody comprises:

[0140] (a) a heavy chain variable domain comprising:

[0141] (1) HC-FR1 comprising the amino acid sequence of SEQ ID NO: 9;

[0142] (2) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0143] (3) HC-FR2 comprising the amino acid sequence of SEQ ID NO: 10;

[0144] (4) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2;

[0145] (5) HC-FR3 comprising the amino acid sequence of SEQ ID NO: 11;

[0146] (6) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0147] (7) HC-FR4 comprising the amino acid sequence of SEQ ID NO: 12;

[0148] and / or

[0149] (b) a light chain variable domain comprising:

[0150] (1) LC-FR1 comprising the amino acid sequence of SEQ ID NO: 13;

[0151] (2) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0152] (3) LC-FR2 comprising the amino acid sequence of SEQ ID NO: 14;

[0153] (4) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5;

[0154] (5) LC-FR3 comprising the amino acid sequence of SEQ ID NO: 15;

[0155] (6) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and

[0156] (7) LC-FR4 comprising the amino acid sequence of SEQ ID NO: 16;

[0157] In one aspect, provided herein is an anti-TF antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7, or comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8. In one aspect, provided herein is an anti-TF antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7, and comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8.

[0158] In some embodiments, provided herein are anti-TF antibodies comprising a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In certain embodiments, the heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7 contains substitutions (such as conservative substitutions), insertions or deletions relative to the reference sequence and retains the ability to bind to TF (such as 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 substitution, insertion or deletion (e.g., 1, 2, 3, 4 or 5 amino acids) occurs in a region outside of the CDR (e.g., in the FR). In some embodiments, the anti-TF antibody comprises a heavy chain variable domain sequence of SEQ ID NO:7, including post-translational modifications of the sequence. In a specific embodiment, the heavy chain variable domain comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:3.

[0159] In some embodiments, provided herein are anti-TF antibodies comprising a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8 contains substitutions (such as conservative substitutions), insertions or deletions relative to the reference sequence and retains the ability to bind to TF (such as 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 substitution, insertion or deletion (e.g., 1, 2, 3, 4 or 5 amino acids) occurs in a region outside of the CDR (e.g., in the FR). In some embodiments, the anti-TF antibody comprises a light chain variable domain sequence of SEQ ID NO: 8, including post-translational modifications of the sequence. In a specific embodiment, the light chain variable domain comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0160] In some embodiments, the anti-TF antibody comprises the heavy chain variable domain of any of the embodiments provided above and the light chain variable domain of any of the embodiments provided above. In one embodiment, the antibody comprises the heavy chain variable domain sequence of SEQ ID NO: 7 and the light chain variable domain sequence of SEQ ID NO: 8, including post-translational modifications of these sequences.

[0161] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate comprises: i) a heavy chain CDR1 as set forth in SEQ ID NO:1, a heavy chain CDR2 as set forth in SEQ ID NO:2, and a heavy chain CDR3 as set forth in SEQ ID NO:3; and ii) a light chain CDR1 as set forth in SEQ ID NO:4, a light chain CDR2 as set forth in SEQ ID NO:5, and a light chain CDR3 as set forth in SEQ ID NO:6; wherein the CDRs of the anti-TF antibody of the antibody-drug conjugate are defined by the IMGT numbering scheme.

[0162] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate comprises: i) an amino acid sequence that is at least 85% identical to the heavy chain variable region of SEQ ID NO:7, and ii) an amino acid sequence that is at least 85% identical to the light chain variable region of SEQ ID NO:8.

[0163] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate is a monoclonal antibody.

[0164] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate is tesotumomab, also known as antibody 011, as described in WO 2011 / 157741 and WO 2010 / 066803.

[0165] The antibodies of the invention may also be described or specified according to their binding affinity for TF. Preferred binding affinities include dissociation constants or Kd less than 5x10 -2 M, 10 -2 M, 5x10 -3 M, 10 -3 M, 5x10 -4 M, 10 -4 M, 5x10 -5 M, 10 -5 M, 5x10 -6 M, 10 -6 M, 5x10 -7 M, 10 -7 M, 5x10 -8 M, 10 -8 M, 5x10 -9 M, 10 -9 M, 5x10 -10 M, 10 -10 M, 5x10 -11 M, 10 -11 M, 5x10 -12 M, 10 -12 M, 5x10 -13 M, 10 -13 M, 5x10 -14 M, 10 -14 M, 5x10 -15 M or 10 -15 The binding affinity of M.

[0166] There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated α, δ, ε, γ, and μ, respectively. γ and α classes are further divided into subclasses, for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in a variety of polymorphic variants called allotypes (reviewed in Jefferis and Lefranc 2009 mAbs Vol 1 Issue 4 1-7), any of which are suitable for use in some embodiments herein. Common allotype variants in the population are variants labeled by the letters a, f, n, z, or a combination thereof. In any embodiment herein, the antibody may include a heavy chain Fc region comprising a human IgG Fc region. In other embodiments, the human IgG Fc region comprises human IgG1.

[0167] Antibodies also include modified derivatives, i.e., modified by covalent attachment of any type of molecule to the antibody such that the covalent attachment does not prevent the antibody from binding to TF or exerting a cytostatic or cytotoxic effect on HD cells. For example, but not limited to, antibody derivatives include antibodies that have been modified, for example, by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, attachment to cellular ligands or other proteins, etc. Any of a variety of chemical modifications may be performed by known techniques, including, but not limited to: specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. In addition, the derivative may contain one or more non-classical amino acids.

[0168] B. Antibody-drug conjugate structure

[0169] In some aspects, the anti-TF antibody-drug conjugates described herein include a linker between an anti-TF antibody or antigen-binding fragment thereof described herein and a cytostatic or cytotoxic drug. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a cleavable linker.

[0170] In some embodiments, the linker is a cleavable peptide linker comprising maleimidocaproyl (MC), a dipeptide valine-citrulline (vc), and p-aminobenzylcarbamate (PAB). In some embodiments, the cleavable peptide linker has the formula: MC-vc-PAB-, wherein:

[0171] a)MC is:

[0172]

[0173] b) vc is the dipeptide valine-citrulline, and

[0174] c) PAB is:

[0175]

[0176] In some embodiments, the linker is a cleavable peptide linker comprising a maleimidocaproyl group (MC). In some embodiments, the cleavable peptide linker has the formula: MC-, wherein:

[0177] a)MC is:

[0178]

[0179] In some embodiments, the linker is linked to a thiol residue of an anti-TF antibody or an antigen-binding fragment thereof, which is obtained by partial reduction or full reduction of the anti-TF antibody or an antigen-binding fragment thereof. In some embodiments, the linker is linked to a thiol residue of an anti-TF antibody or an antigen-binding fragment thereof, which is obtained by partial reduction of the anti-TF antibody or an antigen-binding fragment thereof. In some embodiments, the linker is linked to a thiol residue of an anti-TF antibody or an antigen-binding fragment thereof, which is obtained by full reduction of the anti-TF antibody or an antigen-binding fragment thereof.

[0180] In some aspects, the anti-TF antibody-drug conjugates described herein include a linker described herein between an anti-TF antibody or antigen-binding fragment thereof described herein and a cytostatic or cytotoxic drug. Auristatins are known 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 have anticancer (see U.S. Pat. No. 5,663,149) and antifungal activity (see Pettit et al., (1998) Antimicrob. Agents and Chemother. 42:2961-2965). For example, auristatin E can react with p-acetylbenzoic acid or benzoylvaleric acid to generate AEB and AEVB, respectively. Other typical auristatin derivatives include AFP, MMAF (monomethyl auristatin F), and MMAE (monomethyl auristatin E). Suitable auristatins and auristatin analogs, derivatives and prodrugs, and suitable linkers for conjugating auristatins to antibodies are described, for example, in U.S. Pat. No. 5,635,483, U.S. Pat. No. 5,780,588 and U.S. Pat. No. 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 cytostatic or cytotoxic drug is auristatin or a functional analog thereof (such as a functional peptide thereof) or a functional derivative thereof. In some embodiments, the auristatin is monomethyl auristatin or a functional analogue (such as a functional peptide) or a functional derivative thereof.

[0181] In some embodiments, the auristatin is monomethyl auristatin E (MMAE):

[0182]

[0183] The wavy line indicates the linker attachment site.

[0184] In some embodiments, the auristatin is monomethyl auristatin F (MMAF):

[0185]

[0186] The wavy line indicates the linker attachment site.

[0187] In some embodiments, the cleavable peptide linker has the formula: MC-vc-PAB-, and is linked to MMAE. The resulting linker-Auristatin MC-vc-PAB-MMAE is also referred to as vcMMAE. The vcMMAE drug linker moiety and coupling methods are disclosed in WO2004010957, US7659241, US7829531 and US7851437. When vcMMAE is linked to the anti-TF antibody or antigen-binding fragment thereof described herein, the resulting structure is:

[0188]

[0189] Wherein, p represents a number from 1 to 8, for example, p can be 3-5, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or antigen-binding fragment thereof as described herein. In one embodiment, the average value of p in the antibody-drug conjugate population is about 4. In some embodiments, p is measured by hydrophobic interaction chromatography (HIC), for example, based on enhanced hydrophobicity to separate the drug-loaded material, wherein the least hydrophobic unconjugated form is eluted first, and the most hydrophobic 8 drug forms are eluted last, and the peak area percentage represents the relative distribution of the antibody-drug conjugate material 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 reverse phase high performance liquid chromatography (RP-HPLC), for example, first performing a reduction reaction to completely dissociate the heavy and light chains of the ADC, and then separating the light and heavy chains and their corresponding drug-loaded forms on a RP column, wherein the percentage peak is derived from the integration of the light and heavy chain peaks, combined with the drug load assigned to each peak, to calculate the weighted average of the drug-to-antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0190] In some embodiments, the cleavable peptide linker has the formula: MC-vc-PAB-, and is linked to MMAF. The resulting linker-Auristatin MC-vc-PAB-MMAF is also referred to as vcMMAF. In another embodiment, the non-cleavable linker MC is linked to MMAF. The resulting linker-Auristatin MC-MMAF is also referred to as mcMMAF. vcMMAF and mcMMAF drug linker moieties and coupling methods are disclosed in WO2005081711 and US7498298. When vcMMAF or mcMMAF is linked to an anti-TF antibody or antigen-binding fragment thereof described herein, the resulting structure is:

[0191]

[0192]

[0193] Wherein, p represents a number from 1 to 8, for example, p can be 3-5, S represents a sulfhydryl residue of an anti-TF antibody, and Ab or mAb represents an anti-TF antibody or antigen-binding fragment thereof as described herein. In one embodiment, the average value of p in the antibody-drug conjugate population is about 4. In some embodiments, p is measured by hydrophobic interaction chromatography (HIC), for example, to separate the drug-loaded material based on enhanced hydrophobicity, where the least hydrophobic unconjugated form is eluted first, and the most hydrophobic 8 drug forms are eluted last, and the peak area percentage represents the relative distribution of the antibody-drug conjugate material 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 reverse phase high performance liquid chromatography (RP-HPLC), for example, first performing a reduction reaction to completely dissociate the heavy and light chains of the ADC, and then separating the light and heavy chains and their corresponding drug-loaded forms on a RP column, wherein the percentage peak is derived from the integration of the light and heavy chain peaks, combined with the drug load assigned to each peak, to calculate the weighted average of the drug-to-antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0194] In one embodiment, the antibody-drug conjugate is tesotumomab vedotin.

[0195] C. Nucleic Acids, Host Cells, and Manufacturing Methods

[0196] In some aspects, nucleic acids encoding anti-TF antibodies or antigen-binding fragments thereof described herein are also provided herein. Vectors comprising nucleic acids encoding anti-TF antibodies or antigen-binding fragments thereof described herein are also provided herein. Host cells expressing nucleic acids encoding anti-TF antibodies or antigen-binding fragments thereof described herein are also provided herein. Host cells comprising vectors comprising nucleic acids encoding anti-TF antibodies or antigen-binding fragments thereof described herein are also provided herein. Methods for making anti-TF antibodies or antigen-binding fragments thereof are described in U.S. Pat. No. 9,168,314.

[0197] The anti-TF antibodies described herein can be prepared by well-known recombinant techniques using well-known expression vector systems and host cells. In one embodiment, the antibodies are prepared in CHO cells using a GS expression vector system, such as Dela Cruz Edmunds et al., 2006, Molecular Biotechnology 34; 179-190, EP216846, U.S. Pat. No. 5,981,216, WO 87 / 04462, EP323997, U.S. Pat. No. 5,591,639, U.S. Pat. No. 5,658,759, EP338841, U.S. Pat. No. 5,879,936, and U.S. Pat. No. 5,891,693.

[0198] After the antibody is isolated and purified from the cell culture medium using techniques well known in the art, it is conjugated to an auristatin via a linker as described in US Pat. No. 9,168,314.

[0199] The monoclonal anti-TF antibodies described herein can be made, for example, by the hybridoma method first described by Kohler et al., Nature, 256, 495 (1975), or can be made by recombinant DNA methods. Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, by Clackson et al., Nature 352: 624-628 (1991) and Marks et al., J. Mol. Biol. 222: 3581 (1991). Monoclonal antibodies can be obtained from any suitable source. Thus, for example, monoclonal antibodies can be obtained from hybridomas prepared from murine spleen B cells obtained from mice immunized with an antigen of interest, for example, in the form of cells expressing the antigen on the surface or nucleic acid encoding the antigen of interest. Monoclonal antibodies can also be obtained from hybridomas derived from antibody-expressing cells of immunized humans or non-human mammals (such as rats, dogs, primates, etc.).

[0200] In one embodiment, the antibodies of the present invention are human antibodies. Transgenic or transchromosomal mice carrying a portion of the human immune system rather than the mouse system can be used to generate human monoclonal antibodies against tissue factor. Such transgenic and transchromosomal mice include mice referred to herein as HuMAb mice and KM mice, respectively, which are collectively referred to herein as "transgenic mice."

[0201] The HuMAb mouse contains a human immunoglobulin gene miniloci encoding unrearranged human heavy chain (μ and γ) and kappa light chain immunoglobulin sequences, as well as targeted mutations that inactivate the endogenous μ and kappa chain loci (Lonberg, N. et al., Nature, 368, 856-859 (1994)). Thus, the mice exhibit reduced expression of mouse IgM or κ, and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to produce high affinity human IgG, κ monoclonal antibodies (Lonberg, N. et al., (1994), supra; reviewed 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 preparation of HuMAb mice is described in detail in 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. Pat. No. 5,545,806, U.S. Pat. No. 5,569,825, U.S. Pat. No. 5,625,126, U.S. Pat. No. 5,633,425, U.S. Pat. No. 5,789,650, U.S. Pat. No. 5,877,397, U.S. Pat. No. 5,661,016, U.S. Pat. No. 5,814,318, U.S. Pat. No. 5,874,299, U.S. Pat. No. 5,770,429, U.S. Pat. No. 5,545,807, WO 98 / 24884, WO 94 / 25585, WO 93 / 1227, WO 92 / 22645 / WO 92 / 03918, and WO 01 / 09187.

[0202] The HCo7 mouse has a JKD disruption in its endogenous light chain (kappa) gene (as described in Chen et al., EMBO J. 12:821-830 (1993)), a CMD disruption in its endogenous heavy chain gene (as described in Example 1 of WO 01 / 14424), a KCo5 human kappa light chain transgene (as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)), and an HCo7 human heavy chain transgene (as described in U.S. Pat. No. 5,770,429).

[0203] The HCo12 mouse has a JKD disruption in its endogenous light chain (kappa) gene (as described in Chen et al., EMBO J. 12:821-830 (1993)), a CMD disruption in its endogenous heavy chain gene (as described in Example 1 of WO 01 / 14424), a KCo5 human kappa light chain transgene (as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)), and a HCo12 human heavy chain transgene (as described in Example 2 of WO 01 / 14424).

[0204] The HCo17 transgenic mouse strain (see also US2010 / 0077497) was generated by co-injection of an 80 kb insert of pHC2 (Taylor et al., (1994) Int. Immunol., 6:579-591), a Kb insert of pVX6, and a -460 kb yeast artificial chromosome fragment of the yIgH24 chromosome. This strain was designated (HCo17) 25950. The (HCo17) 25950 strain was then bred with mice containing a CMD mutation (as described in Example 1 of PCT Publication WO 01109187), a JKD mutation (Chen et al., (1993) EMBO J. 12:811-820), and a (KC05) 9272 transgene (Fishwild et al., (1996) Nature Biotechnology, 14:845-851). The resulting mice express human immunoglobulin heavy chain and kappa light chain transgenes in a background homozygous to disrupt the endogenous mouse heavy chain and kappa light chain loci.

[0205] The HCo20 transgenic mouse strain is the result of co-injection of the minilocus 30 heavy chain transgene pHC2, the YAC yIgH10 containing the germline variable region (Vh), and the minilocus construct pVx6 (as described in WO09097006). The (HCo20) strain was then bred with mice containing the CMD mutation (as described in Example 1 of PCT Publication WO 01 / 09187), the JKD mutation (Chen et al., (1993) EMBO J. 12:811-820), and the (KC05)9272 transgene (Fishwild et al., (1996) Nature Biotechnology, 14:845-851). The resulting mice express human 10 immunoglobulin heavy chain and kappa light chain transgenes in a background homozygous to disrupt the endogenous mouse heavy chain and kappa light chain loci.

[0206] To generate HuMab mice with the beneficial effects of the Balb / c strain, HuMab mice were crossed with KC05[MIK](Balb) mice generated by backcrossing the KC05 strain and wild-type Balb / c mice (e.g., Fishwild et al., (1996) Nature Biotechnology, 14:845-851) to generate mice as described in WO09097006. This cross Balb / c heterozygote was used to create the HCo12, HCo17, and HCo20 strains.

[0207] In the KM mouse strain, the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al., EMBO J. 12: 811-820 (1993), and the endogenous mouse heavy chain gene has been homozygously disrupted as described in Example 1 of WO 01 / 09187. This mouse strain carries the human kappa light chain transgene KCo5, as described in Fishwild et al., Nature Biotechnology, 14: 845-851 (1996). This mouse strain also carries a human heavy chain transchromosome consisting of chromosome 14 fragment hCF (SC20), as described in WO 02 / 43478.

[0208] Splenocytes from these transgenic mice can be used to produce hybridomas, which can secrete human monoclonal antibodies according to well-known techniques. It is also possible to produce another non-human mammal or plant that is transgenic for the immunoglobulin heavy chain and light chain sequence of interest, and thus produce antibodies in a recyclable form, thereby transgenicly producing human monoclonal antibodies or polyclonal antibodies of the present invention or antibodies of the present invention derived from other species. Related to transgenic production in mammals, antibodies can be produced and recovered in the milk of goats, cattle or other mammals. See, for example, U.S. Patent No. 5,827,690, U.S. Patent No. 5,756,687, U.S. Patent No. 5,750,172 and U.S. Patent No. 5,741,957.

[0209] In addition, human antibodies of the invention or antibodies of the invention from other species can be produced by display technology using techniques well known in the art, including but not limited to phage display, retroviral display, ribosome display and other technologies, and the resulting molecules can be further matured, such as affinity maturation, because such techniques are well known in the art (see, for example, 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 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. Pat. No. 5,733,743). If non-human antibodies are produced using display technology, such antibodies can be humanized.

[0210] III. Treatment Methods

[0211] A. Cervical cancer

[0212] Despite advances in screening, diagnosis, prevention, and treatment, cervical cancer remains one of the leading causes of cancer-related deaths in women. It accounts for approximately 4% of all newly diagnosed cancer cases 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 sixteenth most common cancer in the European Union. Depending on the stage at which it first appears, cervical cancer will recur in 25-61% of women. See Tempfer et al., 2016, Oncol. Res. Treat. 39: 525-533. In most cases, recurrent disease is diagnosed within 2 years of initial treatment and may 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, however, the five-year relative survival rate for stage IV cervical cancer is only 15%, indicating a high need for improved cervical cancer treatments.

[0213] The present invention provides methods for treating cervical cancer with the antibody-drug conjugates described herein. In a preferred aspect, the antibody-drug conjugate is tisotumab vedotin. In one aspect, the antibody-drug conjugates described herein are used in a method for treating cervical cancer in a subject. In some embodiments, the subject has not previously been treated for cervical cancer. In some embodiments, the subject has previously been treated for at least one cervical cancer. In some embodiments, the subject has previously been treated with bevacizumab. In some embodiments, the subject is not eligible for bevacizumab treatment. In some embodiments, the subject is not a candidate for curative therapy. In some embodiments, the curative therapy is radiation therapy and / or evisceration therapy. In some embodiments, the curative therapy is radiation therapy. In some embodiments, the curative therapy is evisceration therapy. In specific embodiments, the subject is human.

[0214] In some embodiments of the methods or uses provided herein, the cervical cancer is an adenocarcinoma, an adenosquamous carcinoma, a squamous cell carcinoma, a small cell carcinoma, a neuroendocrine tumor, a glassy cell carcinoma, or a vestibular gland carcinoma. In some embodiments, the cervical cancer is an adenocarcinoma, an adenosquamous carcinoma, or a squamous cell carcinoma. In some embodiments, the cervical cancer is an adenocarcinoma. In some embodiments, the cervical cancer is an adenocarcinoma. In some embodiments, the cervical cancer is an adenosquamous carcinoma. In some embodiments, the cervical cancer is a 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 the cervical cancer cells express TF. In some embodiments, the percentage of cells expressing TF is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing TF is determined using flow cytometry. In some embodiments, the percentage of cells expressing TF is determined using enzyme-linked immunosorbent assay (ELISA).

[0215] In some embodiments of the methods or uses provided herein, cervical cancer is 0, 1, 2, 3 or 4 stage cervical cancer. In some embodiments, cervical cancer is 0, 1A, 1B, 2A, 2B, 3A, 3B, 4A or 4B stage cervical cancer. In some embodiments, cervical cancer is staged by the International Federation of Gynecology and Obstetrics (FIGO) staging system. In some embodiments, staging is based on clinical examination. In some embodiments, in 0 stage cervical cancer, cancer is confined to the surface layer of the cervix (cells covering the cervix). In some embodiments, in 1 stage cervical cancer, cancer has grown deep into the cervix, but has not yet spread beyond the cervix. In some embodiments, in 1A stage cervical cancer, invasive cancer can only be diagnosed by microscope, and the deepest infiltration is less than 5mm, and the maximum extension is less than 7mm. In some embodiments, in 1B stage cervical cancer, the lesion is clinically visible and is limited to the cervix. In some embodiments, in stage 2 cervical cancer, the cervical cancer has invaded the uterus but has not invaded the pelvic wall or the lower third of the vagina. In some embodiments, in stage 2A cervical cancer, there is no para-uterine invasion. In some embodiments, in stage 2B cervical cancer, there is para-uterine invasion. In some embodiments, in stage 3 cervical cancer, the tumor extends to the pelvic wall and / or involves the lower third of the vagina and / or causes hydronephrosis or renal insufficiency. In some embodiments, in stage 3A cervical cancer, the tumor involves the lower third of the vagina without extending to the pelvic wall. In some embodiments, in stage 3B cervical cancer, it extends to the pelvic wall and / or causes hydronephrosis or renal insufficiency. In some embodiments, in stage 4 cervical cancer, the cancer has extended beyond the true pelvis or involved the mucosa of the bladder or rectum. In some embodiments, in stage 4A cervical cancer, the tumor has spread to adjacent organs. In some embodiments, in stage 4B cervical cancer, the tumor has spread to distant organs. In some embodiments, the cervical cancer is advanced cervical cancer, such as grade 3 or 4 cervical cancer. In some embodiments, the advanced cervical cancer is metastatic cervical cancer. In some embodiments, the cervical cancer is metastatic cervical cancer and recurrent cervical cancer. In some embodiments, the cervical cancer is metastatic cervical cancer. In some embodiments, the cervical cancer is recurrent cervical cancer.

[0216] In some embodiments of the methods or uses provided herein, the subject has previously been treated for cervical cancer. In some embodiments, the subject is unresponsive to treatment (e.g., the subject experiences disease progression during treatment). In some embodiments, the one or more therapeutic agents administered to the subject are not anti-TF antibody-drug conjugates described herein. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some embodiments, the one or more therapeutic agents administered to the subject are platinum-based therapeutic agents. In some embodiments, the one or more therapeutic agents administered to the subject are gemcitabine and fluorouracil. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and cisplatin. In some embodiments, the one or more therapeutic agents given to the object are paclitaxel and carboplatin. In some embodiments, the one or more therapeutic agents given to the object are paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents given to the object are bevacizumab. In some embodiments, the one or more therapeutic agents given to the object are selected from the group consisting of chemotherapeutic agents, pemetrexed, albumin-bound paclitaxel (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 and cisplatin and paclitaxel, a combination of bevacizumab and carboplatin and paclitaxel, and a combination of bevacizumab and paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents given to the object are chemotherapeutic agents. In some embodiments, the one or more therapeutic agents given to the object are cisplatin. In some embodiments, the one or more therapeutic agents given to the object are carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject is paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and topotecan.In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and cisplatin and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and carboplatin and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and paclitaxel and topotecan. In some embodiments, the subject has been treated with radiation therapy for cervical cancer but has not responded to the radiation. In some embodiments, the subject has not responded to treatment with no more than two prior systemic treatment regimens. In some embodiments, the subject has not responded to treatment with one or two prior systemic treatment regimens. In some embodiments, the subject has not responded to treatment with one prior systemic treatment regimen. In some embodiments, the subject has not responded to treatment with two prior systemic treatment regimens.

[0217] In some embodiments of the methods or uses provided herein, the subject has previously been treated for cervical cancer with one or more therapeutic agents. In some embodiments, the subject relapses after treatment. In some embodiments, the one or more therapeutic agents administered to the subject are not anti-TF antibody-drug conjugates described herein. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some embodiments, the one or more therapeutic agents administered to the subject are platinum-based therapeutic agents. In some embodiments, the one or more therapeutic agents administered to the subject are gemcitabine and fluorouracil. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are bevacizumab. In some embodiments, the one or more therapeutic agents administered to the subject are selected from the group consisting of chemotherapeutic agents, pemetrexed, albumin-bound 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 and cisplatin and paclitaxel, a combination of bevacizumab and carboplatin and paclitaxel, and a combination of bevacizumab and paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are chemotherapeutic agents. In some embodiments, the one or more therapeutic agents administered to the subject are cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject are carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject is paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and cisplatin and paclitaxel.In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and carboplatin and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and paclitaxel and topotecan. In some embodiments, the subject has been treated with radiation therapy for cervical cancer but has relapsed after radiation therapy. In some embodiments, the subject has relapsed after no more than two prior systemic treatment regimens. In some embodiments, the subject has relapsed after treatment with one or two prior systemic treatment regimens. In some embodiments, the subject has relapsed after treatment with one prior systemic treatment regimen. In some embodiments, the subject has relapsed after treatment with two prior systemic treatment regimens.

[0218] In some embodiments of the methods or uses provided herein, the subject has previously been treated for cervical cancer with one or more therapeutic agents. In some embodiments, the subject experiences disease progression after treatment. In some embodiments, the one or more therapeutic agents administered to the subject are not anti-TF antibody-drug conjugates described herein. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some embodiments, the one or more therapeutic agents administered to the subject are platinum-based therapeutic agents. In some embodiments, the one or more therapeutic agents administered to the subject are gemcitabine and fluorouracil. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are bevacizumab. In some embodiments, the one or more therapeutic agents administered to the subject are selected from the group consisting of chemotherapeutic agents, pemetrexed, albumin-bound 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 and cisplatin and paclitaxel, a combination of bevacizumab and carboplatin and paclitaxel, and a combination of bevacizumab and paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are chemotherapeutic agents. In some embodiments, the one or more therapeutic agents administered to the subject are cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject are carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject is paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and cisplatin and paclitaxel.In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab and carboplatin and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab and paclitaxel and topotecan. In some embodiments, the subject has previously received radiation therapy for cervical cancer and has experienced disease progression after radiation therapy. In some embodiments, the subject has experienced disease progression after no more than two prior systemic treatment regimens. In some embodiments, the subject has experienced disease progression after treatment with one or two prior systemic treatment regimens. In some embodiments, the subject has experienced disease progression after treatment with one prior systemic treatment regimen. In some embodiments, the subject has experienced disease progression after treatment with two prior systemic treatment regimens.

[0219] B. Route of administration

[0220] The antibody-drug conjugates or antigen-binding fragments thereof described herein can be administered by any suitable route and mode. Suitable routes for administering the antibody-drug conjugates of the present invention are well known in the art and can be selected by a person of ordinary skill in the art. In one embodiment, the antibody-drug conjugate is administered parenterally. Parenteral administration refers to a form of administration other than intestinal and topical administration, usually by injection, including but not limited to epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, intratendonal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion. In some embodiments, the route of administration of the antibody-drug conjugates or antigen-binding fragments thereof described herein is intravenous injection or infusion. In some embodiments, the route of administration of the antibody-drug conjugates or antigen-binding fragments thereof described herein is intravenous infusion.

[0221] C. Dosage and frequency of administration

[0222] In one aspect, the present invention provides a method for treating a subject having cervical cancer as described herein with a specific dose of an antibody-drug conjugate or antigen-binding fragment thereof as described herein, wherein the antibody-drug conjugate or antigen-binding fragment as described herein is administered to the subject at a specific frequency.

[0223] In one embodiment of the methods or uses provided herein, the subject is administered an antibody-drug conjugate or an antigen-binding fragment thereof as described herein at a dose within the range of about 1.5 mg / kg to about 2.1 mg / kg of the subject's 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 some embodiments, the dose is 2.0 mg / kg, and the antibody-drug conjugate is tesotumomab vedotin.

[0224] In one embodiment of the methods or uses or products for use provided herein, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to the subject at a dose ranging from about 0.65 mg / kg to about 2.1 mg / kg of the subject's body weight. In certain embodiments, 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 one embodiment, the dose is about 0.9 mg / kg. In one embodiment, the dose is about 1.3 mg / kg. In one embodiment, the dose is about 2.0 mg / kg. In certain embodiments, 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 one embodiment, the dose is 0.9 mg / kg. In one embodiment, the dose is 1.3 mg / kg. In one 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 tezomib vedotin. In some embodiments, the dose is 0.9 mg / kg and the anti-TF antibody-drug conjugate is tisotumomab vedotin. In some embodiments, the dose is 1.3 mg / kg and the anti-TF antibody-drug conjugate is tisotumomab vedotin. In some embodiments, the dose is 2.0 mg / kg and the anti-TF antibody-drug conjugate is tisotumomab 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.

[0225] In one embodiment of the methods or uses provided herein, the antibody-drug conjugate or its antigen-binding fragment described herein is administered to the subject approximately once every 1 to 4 weeks. In certain embodiments, the antibody-drug conjugate or its antigen-binding fragment described herein is administered approximately once every 1 week, approximately once every 2 weeks, approximately once every 3 weeks, or approximately once every 4 weeks. In one embodiment, the antibody-drug conjugate or its antigen-binding fragment described herein is administered approximately once every 3 weeks. In one embodiment, the antibody-drug conjugate or its antigen-binding fragment described herein is administered once every 3 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is about 0.65 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is about 0.7 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 0.7 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 0.7 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 0.7 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 0.75 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 0.75 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 0.75 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 0.75 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 0.8 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 0.8 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 0.8 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 0.8 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 0.85 mg / kg and is administered about once every week. In some embodiments, the dosage is about 0.85 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 0.85 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 0.85 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 0.9 mg / kg and is administered about once every week. In some embodiments, the dosage is about 0.9 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 0.9 mg / kg and is administered about once every 3 weeks.In some embodiments, the dose is about 0.9 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.0 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 1.0 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 1.0 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.0 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.1 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 1.1 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 1.1 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.1 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.2 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 1.2 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 1.2 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.2 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.3 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 1.3 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 1.3 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.3 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.4 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 1.4 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 1.4 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.4 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.4 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.5 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 1.5 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 1.5 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 1.5 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 1.6 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 1.6 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 1.6 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 1.6 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 1.7 mg / kg and is administered about once every 1 week.In some embodiments, the dosage is about 1.7 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 1.7 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 1.7 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 1.8 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 1.8 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 1.8 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 1.8 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 1.9 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 1.9 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 1.9 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 1.9 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 2.0 mg / kg and is administered about once every week. In some embodiments, the dose is about 2.0 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 2.0 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 2.0 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 2.1 mg / kg and is administered about once every week. In some embodiments, the dose is about 2.1 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 2.1 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 2.1 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is 0.65 mg / kg and is administered about once every week. In some embodiments, the dose is 0.65 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is 0.65 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is 0.65 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 0.7 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 0.7 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 0.7 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 0.7 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 0.75 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 0.75 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 0.75 mg / kg and is administered approximately once every 3 weeks.In some embodiments, the dose is 0.75 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.2 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 1.2 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 1.2 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 1.2 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 1.3 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 1.3 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 1.3 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 1.3 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 1.4 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 1.4 mg / kg and is administered approximately once every 2 weeks.In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.7 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 1.7 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 1.7 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 1.7 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 1.8 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 1.8 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 1.8 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 1.8 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 1.9 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 1.9 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 1.9 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 1.9 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 2.0 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 2.0 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 2.0 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 2.0 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 2.1 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 2.1 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 2.1 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 2.1 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 2.0 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days).In some embodiments, the dose is 2.0 mg / kg and is administered once every 3 weeks. In some embodiments, the dose is 2.0 mg / kg and is administered once every 3 weeks, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 2.0 mg / kg and is administered once every 3 weeks, and the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dose is reduced to 1.3 mg / kg. In some embodiments, the dose is 1.3 mg / kg and is administered once every 3 weeks. In some embodiments, the dose is 1.3 mg / kg and is administered once every 3 weeks, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 1.3 mg / kg and is administered once every 3 weeks, and the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dose is reduced to 0.9 mg / kg. In some embodiments, the dose is about 0.9 mg / kg and is administered about once a week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 0.9 mg / kg and is administered once a week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is about 0.65 mg / kg and is administered about once a week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 0.65 mg / kg and is 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 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.

[0226] In one embodiment of the methods or uses provided herein, the antibody-drug conjugate or its antigen-binding fragment described herein is administered to a subject at a fixed dose between 50 mg and 200 mg, such as a dose of 50 mg or a dose of 60 mg or a dose of 70 mg or a dose of 80 mg or a dose of 90 mg or a dose of 100 mg or a dose of 110 mg or a dose of 120 mg or a dose of 130 mg or a dose of 140 mg or a dose of 150 mg or a dose of 160 mg or a dose of 170 mg or a dose of 180 mg or a dose of 190 mg or a dose of 200 mg. In some embodiments, the fixed dose is administered to the subject approximately once every 1 to 4 weeks. In certain embodiments, the fixed dose is administered to the subject approximately once every 1 week, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks. In some embodiments, the fixed dose is administered to the subject approximately once every 3 weeks (such as ± 3 days). In some embodiments, the fixed dose is administered to the subject once every 3 weeks. In some embodiments, the fixed dose is administered to the subject once every 3 weeks and the antibody-drug conjugate is tesotumomab vedotin.

[0227] In one embodiment of the methods or uses provided herein, the antibody-drug conjugate or its antigen-binding fragment described herein is administered to a subject at a uniform dose between 50 mg and 200 mg, such as a dose of 50 mg or a dose of 60 mg or a dose of 70 mg or a dose of 80 mg or a dose of 90 mg or a dose of 100 mg or a dose of 110 mg or a dose of 120 mg or a dose of 130 mg or a dose of 140 mg or a dose of 150 mg or a dose of 160 mg or a dose of 170 mg or a dose of 180 mg or a dose of 190 mg or a dose of 200 mg. In some embodiments, a fixed dose is administered to a subject approximately every 1 to 4 weeks. In certain embodiments, a fixed dose is administered to a subject approximately every 1 week, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks. In some embodiments, a fixed dose is administered to a subject approximately every 3 weeks (such as ± 3 days). In some embodiments, a fixed dose is administered to a subject once every 3 weeks. In some embodiments, the fixed dose is administered to the subject once every 3 weeks and the antibody-drug conjugate is tesotumomab vedotin.

[0228] In some embodiments, the methods of treatment or uses described herein further include administering one or more other therapeutic agents. In some embodiments, one or more other therapeutic agents are administered simultaneously with the antibody-drug conjugates or antigen-binding fragments thereof described herein (e.g., tesotumomab vedotin). In some embodiments, one or more other therapeutic agents are administered sequentially with the antibody-drug conjugates or antigen-binding fragments thereof described herein.

[0229] D. Treatment results

[0230] In one aspect, the method of treating cervical cancer with an antibody-drug conjugate or antigen-binding fragment thereof as described herein results in one or more therapeutic effects in a subject being improved relative to baseline after administration of the antibody-drug conjugate. In some embodiments, the one or more therapeutic effects are the size of a tumor derived from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, overall survival, or any combination thereof. In one embodiment, the one or more therapeutic effects are the size of a tumor derived from cervical cancer. In one embodiment, the one or more therapeutic effects are a reduction in tumor size. In one embodiment, the one or more therapeutic effects are stable disease. In one embodiment, the one or more therapeutic effects are partial responses. In one embodiment, the one or more therapeutic effects are complete responses. In one embodiment, the one or more therapeutic effects are objective response rates. In one embodiment, the one or more therapeutic effects are duration of response. In one embodiment, the one or more therapeutic effects are time to response. In one embodiment, the one or more therapeutic effects are progression-free survival. In one embodiment, the one or more therapeutic effects are overall survival. In one embodiment, the one or more therapeutic effects are cancer regression.

[0231] In one embodiment of the methods or uses provided herein, the response to treatment with the antibody-drug conjugate or antigen-binding fragment thereof described herein may include the following criteria (RECIST criteria 1.1):

[0232]

[0233] In one embodiment of the methods or uses provided herein, the effectiveness of treatment with an antibody-drug conjugate or its antigen-binding fragment described herein is assessed by determining the objective response rate. In some embodiments, the objective response rate is the proportion of patients whose tumor size has been reduced by a predetermined number in the shortest time. In some embodiments, the objective response rate is based on RECIST version 1.1. In one embodiment, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80%. In some embodiments, the objective response rate is at least about 20%-80%. In some embodiments, the objective response rate is at least about 30%-80%. In some embodiments, the objective response rate is at least about 40%-80%. In some embodiments, the objective response rate is at least about 50%-80%. In some embodiments, the objective response rate is at least about 60%-80%. In some embodiments, the objective response rate is at least about 70%-80%. In some embodiments, the objective response rate is at least about 80%. In some embodiments, the objective response rate is at least about 85%. In some embodiments, the objective response rate is at least about 90%. In some embodiments, the objective response rate is at least about 95%. In some embodiments, the objective response rate is at least about 98%. In some embodiments, the objective response rate is at least about 99%. In some embodiments, the objective response rate is 100%.

[0234] In one embodiment of the methods or uses provided herein, the response to treatment with an antibody-drug conjugate or antigen-binding fragment thereof described herein is assessed by measuring the size of a tumor derived from cervical cancer. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from cervical cancer before administration of the antibody-drug conjugate. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 10%-80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 20%-80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 30%-80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 40%-80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 50%-80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 60%-80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 70%-80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 85%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by at least about 99%. In one embodiment, the size of a tumor derived from cervical cancer is reduced by 100%. In one embodiment, the size of a tumor derived from cervical cancer is determined by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor derived from cervical cancer is determined by computed tomography (CT). In some embodiments, the size of a tumor derived from cervical cancer is determined by pelvic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19 (3): 205.

[0235] In one embodiment of the methods or uses provided herein, the response to treatment with an antibody-drug conjugate as described herein (e.g., tisotumab vedotin) or an antigen-binding fragment thereof promotes regression of tumors derived from cervical cancer. In one embodiment, the tumor derived from cervical cancer is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from cervical cancer before administration of the antibody-drug conjugate. In one embodiment, the tumor derived from cervical cancer regresses by at least about 10%-80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 20%-80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 30%-80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 40%-80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 50%-80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 60%-80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 70%-80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 80%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 85%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 90%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 95%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 98%. In one embodiment, the tumor derived from cervical cancer regresses by at least about 99%. In one embodiment, the tumor derived from cervical cancer regresses by 100%. In one embodiment, the regression of the tumor is determined by measuring the size of the tumor using magnetic resonance imaging (MRI). In one embodiment, the regression of the tumor is determined by measuring the size of the tumor using computed tomography (CT). In one embodiment, the regression of the tumor is determined by measuring the size of the tumor using a pelvic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205.

[0236] In some embodiments of the methods or uses provided herein, the response to treatment with the antibody-drug conjugates or antigen-binding fragments thereof described herein promotes regression of the number of tumors derived from cervical cancer. In some embodiments, the regression of the number of tumors is determined by detecting the number of tumors in the subject using MRI, CT scan or pelvic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205.

[0237] In one embodiment of the methods or uses described herein, the reaction of treating with an antibody-drug conjugate or its antigen-binding fragment as described herein is evaluated by measuring the time of progression-free survival after administering an antibody-drug conjugate. In some embodiments, the subject exhibits 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 of progression-free survival after administering an antibody-drug conjugate. In some embodiments, the subject exhibits at least about 6 months of progression-free survival after administering an antibody-drug conjugate. In some embodiments, the subject exhibits at least about 1 year of progression-free survival after administering an antibody-drug conjugate. In some embodiments, the subject exhibits at least about 2 years of progression-free survival after administering an antibody-drug conjugate. In some embodiments, the subject exhibits a progression-free survival of at least about 3 years after administration of the antibody-drug conjugate. In some embodiments, the subject exhibits a progression-free survival of at least about 4 years after administration of the antibody-drug conjugate. In some embodiments, the subject exhibits a progression-free survival of at least about 5 years after administration of the antibody-drug conjugate.

[0238] In one embodiment of the methods or uses described herein, the reaction of treating with an antibody-drug conjugate or its antigen-binding fragment as described herein is evaluated by measuring the time of the total survival after administering the antibody-drug conjugate. In some embodiments, the subject exhibits 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 of total survival after administering the antibody-drug conjugate. In some embodiments, the subject exhibits at least about 6 months of total survival after administering the antibody-drug conjugate. In some embodiments, the subject exhibits at least about 1 year of total survival after administering the antibody-drug conjugate. In some embodiments, the subject exhibits at least about 2 years of total survival after administering the antibody-drug conjugate. In some embodiments, the subject exhibits at least about 3 years of total survival after administering the antibody-drug conjugate. In some embodiments, the subject exhibits an overall survival of at least about 4 years following administration of the antibody-drug conjugate. In some embodiments, the subject exhibits an overall survival of at least about 5 years following administration of the antibody-drug conjugate.

[0239] In one embodiment of the methods or uses described herein, the response to treatment with an antibody-drug conjugate or its antigen-binding fragment described herein is assessed by measuring the duration of the response to the antibody-drug conjugate after administration of the antibody-drug conjugate. In some embodiments, after administration of the antibody-drug conjugate, the duration of the 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. In some embodiments, after administration of the antibody-drug conjugate, the duration of the response to the antibody-drug conjugate is at least about 6 months. In some embodiments, after administration of the antibody-drug conjugate, the duration of the response to the antibody-drug conjugate is at least about 1 year. In some embodiments, after administration of the antibody-drug conjugate, the duration of the response to the antibody-drug conjugate is at least about 2 years. In some embodiments, after administration of the antibody-drug conjugate, the duration of response to the antibody-drug conjugate is at least about 3 years. In some embodiments, after administration of the antibody-drug conjugate, the duration of response to the antibody-drug conjugate is at least about 4 years. In some embodiments, after administration of the antibody-drug conjugate, the duration of response to the antibody-drug conjugate is at least about 5 years.

[0240] E. Adverse events

[0241] In one aspect, the method of treating cervical cancer with an antibody-drug conjugate or an antigen-binding fragment thereof as described herein results in one or more adverse events developing in the subject. In some embodiments, other therapeutic agents are administered to the subject to eliminate or reduce the severity of the adverse event. In some embodiments, one or more adverse events developed by the subject are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, general physical health deterioration, or any combination thereof. In some embodiments, one or more adverse events are grade 1 or higher adverse events. In some embodiments, one or more adverse events are grade 2 or higher adverse events. In some embodiments, one or more adverse events are grade 3 or higher adverse events. 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 serious adverse events. In some embodiments, one or more adverse events are conjunctivitis and / or keratitis, and the other 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 other 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 other 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 other therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some of any embodiments herein, the subject is treated with an additional therapeutic agent to eliminate or reduce the severity of adverse events such as conjunctivitis and / or keratitis. In some embodiments, the treatment is an ocular cooling pad (such as THERAPEARL eye mask). In some embodiments, one or more adverse events are reactions associated with repeated infusions, and the other therapeutic agent is an antihistamine, acetaminophen, and / or a corticosteroid. In some embodiments, one or more adverse events are neutropenia, and the other therapeutic agent is a growth factor support (G-CSF).

[0242] In one aspect, the subject treated with the antibody-drug conjugate or its antigen-binding fragment described herein is at risk of developing one or more adverse events. In some embodiments, other therapeutic agents are administered to the subject to prevent the development of adverse events or reduce the severity of adverse events. In some embodiments, one or more adverse events at risk of development of the subject are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, loss of appetite, diarrhea, vomiting, peripheral neuropathy, general physical health deterioration, or any combination thereof. In some embodiments, one or more adverse events are grade 1 or higher adverse events. In some embodiments, one or more adverse events are grade 2 or higher adverse events. In some embodiments, one or more adverse events are grade 3 or higher adverse events. 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 serious adverse events. In some embodiments, one or more adverse events are conjunctivitis and / or keratitis, and the other 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 other 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 other 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 other agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some of any embodiments herein, treatment of the subject is given with other therapeutic agents to prevent the development of adverse events or to reduce the severity of adverse events such as conjunctivitis and / or keratitis. In some embodiments, the treatment is an eye cooling pad (such as THERA PEARL eye mask). In some embodiments, one or more adverse events are reactions associated with repeated infusions, and the other agent is an antihistamine, acetaminophen, and / or a corticosteroid. In some embodiments, one or more adverse events is neutropenia, and the other agent is a growth factor support (G-CSF).

[0243] IV. Composition

[0244] In some aspects, also provided herein are compositions (eg, pharmaceutical compositions) comprising any of the anti-TF antibody-drug conjugates described herein.

[0245] Therapeutic formulations are prepared by mixing the active ingredient having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers for storage (Remington: The Science and Practice of Pharmacy, 20th ed., Lippincott Williams & Wiklins, Gennaro ed., Philadelphia, Pennsylvania, 2000).

[0246] Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations used, and include buffers, antioxidants (including ascorbic acid, methionine, vitamin E, sodium metabisulfite); preservatives, isotonic agents, stabilizers, metal complexes (such as zinc protein complexes); chelating agents such as EDTA and / or nonionic surfactants.

[0247] Buffers can be used to control pH within the range of achieving optimal therapeutic effectiveness, especially when stability depends on pH. Buffers can be present in concentrations ranging from about 50 mM to about 250 mM. Suitable buffers for use in the present invention include organic and inorganic acids and salts thereof. For example, citrates, phosphates, succinates, tartrates, fumarates, gluconates, oxalates, lactates, acetates. In addition, buffers can be composed of histidine and trimethylamine salts such as Tris.

[0248] Preservatives may be added to prevent microbial growth, and are typically present in an amount ranging from about 0.2% to 1.0% (w / v). Suitable preservatives for use in the present invention include octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium halides (such as benzalkonium chloride, benzalkonium bromide, benzalkonium iodide), benzethonium chloride; thimerosal, phenol, butyl alcohol or benzyl alcohol; alkyl parabens, such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol, 3-pentanol and m-cresol.

[0249] Tension agents, sometimes referred to as "stabilizers," may be present to regulate or maintain the tension of a liquid in a composition. When used with charged large biomolecules such as proteins and antibodies, they are often referred to as "stabilizers" because they can interact with the charged groups of amino acid side chains, thereby reducing the possibility of intermolecular and intramolecular interactions. Taking the relative amounts of other ingredients into account, tension agents may be present in any amount from about 0.1% by weight to about 25% by weight or from about 1% by weight to about 5% by weight. In some embodiments, tension agents include polyols, trivalent or higher sugar alcohols, such as glycerol, erythritol, arabitol, xylitol, sorbitol, and mannitol.

[0250] Other excipients include agents that can serve as one or more of the following: (1) fillers, (2) solubility enhancers, (3) stabilizers, and (4) agents that prevent denaturation or adhesion to the walls of containers. Such excipients include: polyols (listed above); amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbitol, xylose, ribose, ribitol, myoinisitose, myo-inositol, galactose, galactitol, glycerol, cyclopentane, d-isothiazolidine ... Sugar alcohols (e.g., inositol), polyethylene glycol; sulfur-containing reducing agents, such as urea, glutathione, lipoic acid, sodium thioglycolate, thioglycerol, α-monothioglycerol, and sodium thiosulfate; low molecular weight proteins, such as human serum albumin, bovine serum albumin, gelatin or other immunoglobulins; hydrophilic polymers, such as polyvinyl pyrrolidone; monosaccharides (e.g., xylose, mannose, fructose, glucose; disaccharides (e.g., lactose, maltose, sucrose); trisaccharides (e.g., raffinose); and polysaccharides (e.g., dextrin or dextran).

[0251] A nonionic surfactant or detergent (also referred to as a "wetting agent") may be present to help dissolve the therapeutic agent and protect the therapeutic protein from aggregation caused by agitation, which also exposes the formulation to shear surface stresses without causing denaturation of the active therapeutic protein or antibody. The nonionic surfactant is present in a range of about 0.05 mg / ml to about 1.0 mg / ml or about 0.07 mg / ml to about 0.2 mg / ml. In some embodiments, the nonionic surfactant is present in a range of about 0.001% to about 0.1% w / v or about 0.01% to about 0.1% w / v or about 0.01% to about 0.025% w / v.

[0252] Suitable nonionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), poloxamers (184, 188, etc.), Polyols, Polyoxyethylene sorbitan monoether ( etc.), lauromacrogol 400, polyethylene glycol stearate 40 (polyoxyl40stearate), polyoxyethylene hydrogenated castor oil 10, 50 and 60, glyceryl monostearate, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. Anionic detergents that can be used include sodium lauryl sulfate, sodium dioctyl sulfosuccinate and sodium dioctyl sulfonate. Cationic detergents include benzalkonium chloride and benzethonium chloride.

[0253] WO2015 / 075201 describes formulations comprising the anti-TF antibody-drug conjugates described herein for use in the methods of treatment provided herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is a formulation comprising an anti-TF antibody-drug conjugate, histidine, sucrose, and D-mannitol, wherein the pH of the formulation is about 6.0. In some embodiments, the anti-TF antibody-drug conjugate described herein is a formulation comprising an 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, wherein the pH of the formulation is about 6.0. In some embodiments, the anti-TF antibody-drug conjugate described herein is 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, wherein the pH of the formulation is about 6.0. In some embodiments, the formulation comprises tesotumomab vedotin 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, wherein the pH of the formulation is 6.0.

[0254] In some embodiments provided herein, the formulations comprising an anti-TF antibody-drug conjugate described herein do not comprise a surfactant (ie, are surfactant-free).

[0255] Preparations for in vivo administration must be sterile. Preparations can be sterilized by filtering through a sterile filter membrane. The therapeutic agent compositions herein will generally be placed in a container with a sterile access port, for example, an intravenous solution bag or bottle with a stopper pierceable by a hypodermic injection needle.

[0256] The route of administration is according to known and recognized methods, for example by single or multiple boluses or infusions over a long period of time in an appropriate manner, such as injection or infusion by subcutaneous, intravenous, intraperitoneal, intramuscular, intraarterial, intralesional or intraarticular routes, topical administration, inhalation or by sustained release or extended release.

[0257] The formulations herein may also contain more than one active compound, preferably compounds with complementary activities that do not adversely affect each other, as required for the particular indication being treated. Alternatively or in addition, the composition may contain a cytotoxic agent, a cytokine, or a growth inhibitory agent. These molecules are suitably present in the combination in an effective amount for the intended effect.

[0258] The present invention provides a composition comprising a population of anti-TF antibody-drug conjugates or antigen-binding fragments thereof as described herein, for use in the methods for treating cervical cancer as described herein. In some aspects, provided herein is a composition comprising a population of antibody-drug conjugates, wherein the antibody-drug conjugate comprises a linker linked to MMAE, wherein the antibody-drug conjugate has the following structure:

[0259]

[0260] wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-TF antibody or antigen-binding fragment thereof, and Ab represents an anti-TF antibody or antigen-binding fragment thereof as described herein, such as tesotumomab. In some embodiments, p represents a number from 3 to 5. In some embodiments, the average value of p in the composition is about 4. In some embodiments, the population is a mixed population of antibody-drug conjugates, wherein for each antibody-drug conjugate, p varies between 1 and 8. In some embodiments, the population is a homogeneous population of antibody-drug conjugates, wherein p of each antibody-drug conjugate has the same value.

[0261] In some embodiments, the composition comprising the antibody-drug conjugate described herein is co-administered with one or more other 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 other therapeutic agents. In some embodiments, simultaneously refers to administering the antibody-drug conjugate and one or more therapeutic agents to the subject at intervals of less than 1 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 other therapeutic agents. In some embodiments, sequential administration refers to administering the antibody-drug conjugate and one or more other therapeutic agents at an interval 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 to eliminate or reduce the severity of one or more adverse events. In some embodiments, compositions comprising an antibody-drug conjugate described herein are co-administered with one or more therapeutic agents to prevent the development of an adverse event or to reduce the severity of an adverse event.

[0262] In some embodiments, the composition comprising the antibody-drug conjugate described herein is co-administered with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, the antibody-drug conjugate described herein is administered simultaneously with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, simultaneously refers to administering the antibody-drug conjugate and one or more therapeutic agents to the subject at intervals of less than 1 hour, for example, less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes, to eliminate or reduce the severity of one or more adverse events. In some embodiments, the antibody-drug conjugate described herein is administered sequentially with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, sequential administration refers to administering the antibody-drug conjugate and one or more other therapeutic agents at an interval 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 described herein 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 that are used to eliminate or reduce the severity of one or more adverse events are administered prior to the antibody-drug conjugate.

[0263] V. Products and Kits

[0264] In another aspect, an article of manufacture or kit is provided, comprising an anti-TF antibody-drug conjugate as described herein. The article of manufacture or kit may further comprise instructions for using the antibody in the methods of the invention. Thus, in certain embodiments, the article of manufacture or kit comprises instructions for using the anti-TF antibody-drug conjugate in a method of treating cervical cancer in a subject, comprising administering to the subject an effective amount of the anti-TF antibody-drug conjugate. In some embodiments, the cervical cancer is advanced cervical cancer, such as grade 3 cervical cancer or grade 4 cervical cancer. In some embodiments, the advanced cervical cancer is metastatic cancer. In some embodiments, the cervical cancer is metastatic cancer 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 the treatment, has relapsed after treatment, or has experienced disease progression during treatment. In some embodiments of the prior treatment herein, the one or more therapeutic agents are not the antibody-drug conjugate. In some embodiments, the subject is a human.

[0265] The article or kit may further include a container. Suitable containers include, for example, bottles, vials (such as dual-chamber vials), syringes (such as single-chamber or dual-chamber syringes), and test tubes. In some embodiments, the container is a vial. The container may be formed from a variety of materials, such as glass or plastic. The container contains the preparation.

[0266] The preparation or kit may further include a label or package insert on or connected to the container, which may indicate instructions for preparing and / or using the preparation. The label or package insert may further indicate that the preparation can be used for or is intended to be used for subcutaneous, intravenous (such as intravenous infusion) or other modes of administration to treat cervical cancer in a subject, such as cervical cancer described herein (such as advanced cervical cancer, such as grade 3 or 4 or metastatic cervical cancer). The container containing the preparation may be a disposable vial or a vial for multiple uses, allowing repeated administration of the reconstituted preparation. The product or kit may also include a second container containing a suitable diluent. The product or kit may also include other materials desired from a commercial, therapeutic and user perspective, including other buffers, diluents, filters, needles, syringes and package inserts with instructions for use.

[0267] Optionally, the article of manufacture or kit herein further comprises a container comprising a second drug, wherein the anti-TF antibody-drug conjugate is the first drug, and the article of manufacture or kit further comprises instructions on a label or package insert for using the second drug in an effective amount to treat a subject. In some embodiments, the label or package insert indicates that the first and second drugs are to be administered sequentially or simultaneously, as described herein.

[0268] Optionally, the article of manufacture or kit herein further comprises a container comprising a second drug, wherein the second drug is used to eliminate or reduce the severity of one or more adverse events, wherein the anti-TF antibody-drug conjugate is the first drug, and the article of manufacture or kit further comprises instructions on a label or package insert for using the second drug in an effective amount to treat a subject. In some embodiments, the label or package insert indicates that the first and second drugs are to be administered sequentially or simultaneously, as described herein, for example, wherein the label or package insert indicates that the anti-TF antibody-drug conjugate is to be administered first, followed by the second drug.

[0269] In some embodiments, the anti-TF antibody-drug conjugate is present in a container as a lyophilized powder. In some embodiments, the lyophilized powder is placed in an airtight sealed container, such as a vial, ampoule or small medicine bag, indicating the amount of active agent. When the drug is administered by injection, for example, an ampoule of sterile water for injection or saline can be optionally provided as part of the kit for mixing with the drug ingredients before administration. If desired, such a kit can also include one or more of various conventional pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, other containers, etc., which will be obvious to those skilled in the art. The kit can also include printed instructions, as an insert or label, indicating the amount of the components to be administered, administration instructions, and / or guidelines for mixing the components.

[0270] VI. Exemplary Embodiments

[0271] Embodiments provided herein include:

[0272] 1. A method of treating cervical cancer in a subject, the method comprising administering to the subject an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and wherein the antibody-drug conjugate is administered at a dose in the range of about 1.5 mg / kg to about 2.1 mg / kg.

[0273] 2. The method of embodiment 1, wherein the dose is about 2.0 mg / kg.

[0274] 3. The method of embodiment 1 or embodiment 2, wherein the antibody-drug conjugate is administered approximately once every 1 week, 2 weeks, 3 weeks, or 4 weeks.

[0275] 4. The method of any one of embodiments 1-3, wherein the antibody-drug conjugate is administered approximately once every 3 weeks.

[0276] 5. The method of any one of embodiments 1-4, wherein the subject has been previously treated with and has not responded to the treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0277] 6. The method of any one of embodiments 1-4, wherein the subject has been previously treated with one or more therapeutic agents and relapses following such treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0278] 7. The method of any one of embodiments 1-4, wherein the subject has been previously treated with one or more therapeutic agents and experienced disease progression during that treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0279] 8. The method of any one of embodiments 5-7, wherein the one or more therapeutic agents comprises a platinum-based therapeutic agent.

[0280] 9. The method of any one of embodiments 5-7, wherein the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, and bevacizumab.

[0281] 10. The method of any one of embodiments 1-9, wherein the subject experiences disease progression during or after treatment with:

[0282] a) Paclitaxel and cisplatin,

[0283] b) paclitaxel and carboplatin, or

[0284] c) Paclitaxel and topotecan.

[0285] 11. The method of any one of embodiments 1-10, wherein the subject has been treated with bevacizumab.

[0286] 12. The method of any one of embodiments 1-10, wherein the subject is not eligible for bevacizumab treatment.

[0287] 13. The method of any one of embodiments 1-12, wherein the subject is not a candidate for curative therapy.

[0288] 14. The method of embodiment 13, wherein the curative therapy comprises radiation therapy and / or evisceration surgery.

[0289] 15. The method of any one of embodiments 1-14, wherein the subject has not responded to treatment with no more than two prior systemic treatment regimens.

[0290] 16. The method of any one of embodiments 1-14, wherein the subject relapses after treatment with no more than two prior systemic treatment regimens.

[0291] 17. The method of any one of embodiments 1-16, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

[0292] 18. The method of any one of embodiments 1-17, wherein the cervical cancer is advanced cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer.

[0293] 19. The method of any one of embodiments 1-18, wherein the cervical cancer is recurrent cervical cancer.

[0294] 20. The method of any one of embodiments 1-19, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

[0295] 21. The method of any one of embodiments 1-20, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

[0296] 22. The method of any one of embodiments 1-21, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0297] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0298] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0299] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0300] Wherein the light chain variable region comprises:

[0301] (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0302] (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0303] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 5; wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme.

[0304] 23. The method of any one of embodiments 1-22, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:8.

[0305] 24. The method of any one of embodiments 1-23, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.

[0306] 25. The method of any one of embodiments 1-24, wherein the anti-TF antibody of the antibody-drug conjugate is tesotumomab.

[0307] 26. The method of any one of embodiments 1-25, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin.

[0308] 27. A method as described in embodiment 26, wherein the linker is a cleavable peptide linker.

[0309] 28. The method of embodiment 27, wherein the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein:

[0310] a)MC is:

[0311]

[0312] b) vc is the dipeptide valine-citrulline, and

[0313] c) PAB is:

[0314]

[0315] 29. The method of any one of embodiments 26-28, wherein the linker is attached to a thiol residue of the anti-TF antibody, which is obtained by partial reduction or full reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0316] 30. The method of embodiment 29, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the structure:

[0317]

[0318] wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or an antigen-binding fragment thereof.

[0319] 31. A method as described in embodiment 30, wherein the average value of p in the antibody-drug conjugate population is approximately 4.

[0320] 32. The method of any one of embodiments 1-31, wherein the antibody-drug conjugate is tesotumomab vedotin.

[0321] 33. The method of any one of embodiments 1-32, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0322] 34. The method of any of embodiments 1-33, 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.

[0323] 35. The method of any one of embodiments 1-34, wherein one or more therapeutic effects in the subject are improved relative to baseline following administration of the antibody-drug conjugate.

[0324] 36. The method of embodiment 35, wherein one or more treatment effects are selected from the group consisting of size of tumors originating from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

[0325] 37. A method as described in any of embodiments 1-36, wherein the size of the tumor originating from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor originating from cervical cancer before administration of the antibody-drug conjugate.

[0326] 38. A method as described in any of embodiments 1-37, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

[0327] 39. The method of any one of embodiments 1-38, wherein the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

[0328] 40. The method of any of embodiments 1-39, wherein the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years following administration of the antibody-drug conjugate.

[0329] 41. A method as described in any of embodiments 1-40, wherein after administration of the antibody-drug conjugate, 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.

[0330] 42. The method of any one of embodiments 1-41, wherein the subject has one or more adverse events and further receives additional therapeutic agents to eliminate or reduce the severity of the one or more adverse events.

[0331] 43. A method as described in any of embodiments 1-41, wherein the subject is at risk of developing one or more adverse events and further receives additional therapeutic agents to prevent or reduce the severity of one or more adverse events.

[0332] 44. The method of embodiment 42 or embodiment 43, wherein the one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general deterioration of physical health.

[0333] 45. The method of embodiment 42 or embodiment 43, wherein one or more adverse events are grade 3 or higher adverse events.

[0334] 46. ​​The method of embodiment 42 or embodiment 43, wherein one or more adverse events are serious adverse events.

[0335] 47. The method of embodiment 42 or embodiment 43, wherein the one or more adverse events are conjunctivitis and / or keratitis and the other therapeutic agent is preservative-free lubricating eye drops, ocular vasoconstrictors and / or steroid eye drops.

[0336] 48. The method of any one of embodiments 1-47, wherein the antibody-drug conjugate is administered as a monotherapy.

[0337] 49. The method of any one of embodiments 1-48, wherein the subject is a human.

[0338] 50. The method of any one of embodiments 1-49, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

[0339] 51. Use of an antibody-drug conjugate that binds to tissue factor (TF) in a method of treating cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and wherein the antibody-drug conjugate is administered to the subject at a dose ranging from about 1.5 mg / kg to about 2.1 mg / kg.

[0340] 52. The use of an antibody-drug conjugate as described in embodiment 51, wherein the dose is about 2.0 mg / kg.

[0341] 53. The use of an antibody-drug conjugate as described in embodiment 51 or embodiment 52, wherein the antibody-drug conjugate is administered approximately once every 1 week, 2 weeks, 3 weeks or 4 weeks.

[0342] 54. The use of an antibody-drug conjugate as described in any one of embodiments 51-53, wherein the antibody-drug conjugate is administered approximately once every 3 weeks.

[0343] 55. Use of an antibody-drug conjugate as described in any one of embodiments 51-54, wherein the subject has been previously treated with one or more therapeutic agents and has not responded to the treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0344] 56. Use of an antibody-drug conjugate as described in any one of embodiments 51-54, wherein the subject has been previously treated with one or more therapeutic agents and relapses after such treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0345] 57. The use of an antibody-drug conjugate as described in any one of embodiments 51-54, wherein the subject has been previously treated with one or more therapeutic agents and experienced disease progression during the treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0346] 58. Use of an antibody-drug conjugate as described in any one of embodiments 55-57, wherein the one or more therapeutic agents include a platinum-based therapeutic agent.

[0347] 59. The use of an antibody-drug conjugate as described in any one of embodiments 55-57, wherein one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab and bevacizumab.

[0348] 60. The use of an antibody-drug conjugate according to any one of embodiments 51-59, wherein the subject experiences disease progression during or after treatment with:

[0349] a) Paclitaxel and cisplatin,

[0350] b) paclitaxel and carboplatin, or

[0351] c) Paclitaxel and topotecan.

[0352] 61. The use of an antibody-drug conjugate according to any one of embodiments 51-60, wherein the subject has been treated with bevacizumab.

[0353] 62. The use of an antibody-drug conjugate as described in any one of embodiments 51-60, wherein the subject is not eligible for bevacizumab treatment.

[0354] 63. Use of an antibody-drug conjugate as described in any one of embodiments 51-62, wherein the subject is not a candidate for curative therapy.

[0355] 64. The use of an antibody-drug conjugate as described in embodiment 63, wherein the curative therapy comprises radiotherapy and / or visceral resection surgery.

[0356] 65. The use of an antibody-drug conjugate of any one of embodiments 51-64, wherein the subject has not responded to treatment with no more than two prior systemic treatment regimens.

[0357] 66. The use of an antibody-drug conjugate of any one of embodiments 51-64, wherein the subject has relapsed after treatment with no more than two prior systemic treatment regimens.

[0358] 67. The use of an antibody-drug conjugate as described in any one of embodiments 51-66, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma or squamous cell carcinoma.

[0359] 68. The use of an antibody-drug conjugate as described in any one of embodiments 51-67, wherein the cervical cancer is advanced cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer.

[0360] 69. The use of an antibody-drug conjugate as described in any one of embodiments 51-68, wherein the cervical cancer is recurrent cervical cancer.

[0361] 70. The use of an antibody-drug conjugate according to any one of embodiments 51-69, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

[0362] 71. The use of an antibody-drug conjugate according to any one of embodiments 51 to 70, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

[0363] 72. The use of an antibody-drug conjugate according to any one of embodiments 51 to 71, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0364] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0365] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0366] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0367] Wherein the light chain variable region comprises:

[0368] (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0369] (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0370] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 5; wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme.

[0371] 73. The use of an antibody-drug conjugate as described in any one of embodiments 51-72, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:8.

[0372] 74. Use of an antibody-drug conjugate as described in any one of embodiments 51 to 73, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.

[0373] 75. The use of an antibody-drug conjugate according to any one of embodiments 51 to 74, wherein the anti-TF antibody of the antibody-drug conjugate is tesotumomab.

[0374] 76. The use of an antibody-drug conjugate according to any one of embodiments 51 to 75, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and monomethyl auristatin.

[0375] 77. Use of the antibody-drug conjugate as described in embodiment 76, wherein the linker is a cleavable peptide linker.

[0376] 78. Use of an antibody-drug conjugate as described in embodiment 77, wherein the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein:

[0377] a)MC is:

[0378]

[0379] b) vc is the dipeptide valine-citrulline, and

[0380] c) PAB is:

[0381]

[0382] 79. Use of an antibody-drug conjugate as described in any one of embodiments 76 to 78, wherein the linker is connected to the thiol residue of the anti-TF antibody, which is obtained by partial reduction or full reduction of the anti-TF antibody or the antigen-binding fragment thereof.

[0383] 80. The use of an antibody-drug conjugate according to embodiment 79, wherein the linker is connected to MMAE, and wherein the antibody-drug conjugate has the following structure:

[0384]

[0385] wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or an antigen-binding fragment thereof.

[0386] 81. The use of an antibody-drug conjugate as described in embodiment 80, wherein the average value of p in the antibody-drug conjugate population is approximately 4.

[0387] 82. The use of an antibody-drug conjugate as described in any one of embodiments 51-81, wherein the antibody-drug conjugate is tesotumomab vedotin.

[0388] 83. The use of an antibody-drug conjugate as described in any one of embodiments 51-82, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0389] 84. Use of an antibody-drug conjugate as described in any of embodiments 51-83, 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.

[0390] 85. The use of an antibody-drug conjugate as described in any one of embodiments 51-84, wherein one or more therapeutic effects in the subject are improved relative to baseline after administration of the antibody-drug conjugate.

[0391] 86. The use of an antibody-drug conjugate as described in embodiment 85, wherein one or more therapeutic effects are selected from the group consisting of: size of tumors originating from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

[0392] 87. The use of an antibody-drug conjugate as described in any one of embodiments 51-86, wherein the size of a tumor originating from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80% relative to the size of the tumor originating from cervical cancer before administration of the antibody-drug conjugate.

[0393] 88. The use of an antibody-drug conjugate as described in any of embodiments 51-87, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

[0394] 89. The use of an antibody-drug conjugate of any one of embodiments 51-88, wherein the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

[0395] 90. The use of an antibody-drug conjugate of any one of embodiments 51-89, wherein the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

[0396] 91. The use of an antibody-drug conjugate as described in any of embodiments 51-90, wherein after administration of the antibody-drug conjugate, 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.

[0397] 92. The use of an antibody-drug conjugate as described in any one of embodiments 51-91, wherein the subject has one or more adverse events and further receives other therapeutic agents to eliminate or reduce the severity of one or more adverse events.

[0398] 93. Use of an antibody-drug conjugate as described in any one of embodiments 51-91, wherein the subject is at risk of developing one or more adverse events and further receives other therapeutic agents to prevent or reduce the severity of one or more adverse events.

[0399] 94. The use of an antibody-drug conjugate as described in embodiment 92 or embodiment 93, wherein one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general deterioration of physical health.

[0400] 95. The use of an antibody-drug conjugate as described in embodiment 92 or embodiment 93, wherein one or more adverse events are grade 3 or higher adverse events.

[0401] 96. The use of an antibody-drug conjugate as described in embodiment 92 or embodiment 93, wherein one or more adverse events are serious adverse events.

[0402] 97. The use of an antibody-drug conjugate as described in embodiment 92 or embodiment 93, wherein one or more adverse events are conjunctivitis and / or keratitis, and the other therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor and / or a steroid eye drop.

[0403] 98. The use of an antibody-drug conjugate as described in any one of embodiments 51-97, wherein the antibody-drug conjugate is administered as a monotherapy.

[0404] 99. The use of an antibody-drug conjugate as described in any one of embodiments 51-98, wherein the subject is a human.

[0405] 100. The use of an antibody-drug conjugate as described in any one of embodiments 51-99, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

[0406] 101. Use of an antibody-drug conjugate that binds to tissue factor (TF) in the preparation of a medicament for treating cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and wherein the antibody-drug conjugate is administered to the subject at a dose ranging from about 1.5 mg / kg to about 2.1 mg / kg.

[0407] 102. The use according to embodiment 101, wherein the dose is about 2.0 mg / kg.

[0408] 103. The use of embodiment 101 or embodiment 102, wherein the antibody-drug conjugate is administered approximately once every 1 week, 2 weeks, 3 weeks or 4 weeks.

[0409] 104. The use of any one of embodiments 101-103, wherein the antibody-drug conjugate is administered approximately once every 3 weeks.

[0410] 105. The use of any one of embodiments 101-104, wherein the subject has been previously treated with one or more therapeutic agents and has not responded to the treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0411] 106. The use of any one of embodiments 101-104, wherein the subject has been previously treated with one or more therapeutic agents and relapsed following such treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0412] 107. The use of any one of embodiments 101-104, wherein the subject has been previously treated with one or more therapeutic agents and experienced disease progression during that treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0413] 108. The use of any one of embodiments 105-107, wherein the one or more therapeutic agents comprises a platinum-based therapeutic agent.

[0414] 109. The use of any one of embodiments 105-107, wherein the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab and bevacizumab.

[0415] 110. The use of any one of embodiments 101-109, wherein the subject experiences disease progression during or after treatment with:

[0416] a) Paclitaxel and cisplatin,

[0417] b) paclitaxel and carboplatin, or

[0418] c) Paclitaxel and topotecan.

[0419] 111. The use of any one of embodiments 101-110, wherein the subject has been treated with bevacizumab.

[0420] 112. The use of any one of embodiments 101-110, wherein the subject is not eligible for bevacizumab treatment.

[0421] 113. The use of any one of embodiments 101-112, wherein the subject is not a candidate for curative therapy.

[0422] 114. The use as described in embodiment 113, wherein the curative therapy comprises radiation therapy and / or evisceration surgery.

[0423] 115. The use of any one of embodiments 101-114, wherein the subject has not responded to treatment with no more than two prior systemic treatment regimens.

[0424] 116. The use of any one of embodiments 101-114, wherein the subject relapses after treatment with no more than two prior systemic treatment regimens.

[0425] 117. The use of any one of embodiments 101-116, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

[0426] 118. The use of any one of embodiments 101-117, wherein the cervical cancer is advanced cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer.

[0427] 119. The use of any one of embodiments 101-118, wherein the cervical cancer is recurrent cervical cancer.

[0428] 120. The use of any one of embodiments 101-119, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

[0429] 121. The use according to any one of embodiments 101-120, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

[0430] 122. The use according to any one of embodiments 101 to 121, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0431] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0432] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0433] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0434] Wherein the light chain variable region comprises:

[0435] (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0436] (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0437] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 5; wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme.

[0438] 123. The use as described in any one of embodiments 101-122, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:8.

[0439] 124. The use as described in any one of embodiments 101-123, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.

[0440] 125. The use of any one of embodiments 101-124, wherein the anti-TF antibody of the antibody-drug conjugate is tisotumab.

[0441] 126. The use according to any one of embodiments 101 to 125, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin.

[0442] 127. The use as described in embodiment 126, wherein the linker is a cleavable peptide linker.

[0443] 128. The use of embodiment 127, wherein the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein:

[0444] a)MC is:

[0445]

[0446] b) vc is the dipeptide valine-citrulline, and

[0447] c) PAB is:

[0448]

[0449] 129. The use according to any one of embodiments 126 to 128, wherein the linker is connected to a thiol residue of the anti-TF antibody, which is obtained by partial reduction or full reduction of the anti-TF antibody or the antigen-binding fragment thereof.

[0450] 130. The use of embodiment 129, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the following structure:

[0451]

[0452] wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or an antigen-binding fragment thereof.

[0453] 131. The use of embodiment 130, wherein the average value of p in the antibody-drug conjugate population is approximately 4.

[0454] 132. The use of any one of embodiments 101-131, wherein the antibody-drug conjugate is tesotumomab vedotin.

[0455] 133. The use of any one of embodiments 101-132, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0456] 134. The use of any one of embodiments 101-133, 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.

[0457] 135. The use of any one of embodiments 101-134, wherein one or more therapeutic effects in the subject are improved relative to baseline after administration of the antibody-drug conjugate.

[0458] 136. The use as described in embodiment 135, wherein one or more therapeutic effects are selected from the group consisting of size of tumors originating from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

[0459] 137. The use of any one of embodiments 101-136, wherein the size of a tumor originating from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80% relative to the size of the tumor originating from cervical cancer before administration of the antibody-drug conjugate.

[0460] 138. The use of any one of embodiments 101-137, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

[0461] 139. The use of any one of embodiments 101-138, wherein the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

[0462] 140. The use of any one of embodiments 101-139, wherein the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

[0463] 141. The use of any one of embodiments 101-140, wherein after administration of the antibody-drug conjugate, 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.

[0464] 142. The use of any one of embodiments 101-141, wherein the subject has one or more adverse events and further receives an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events.

[0465] 143. The use of any one of embodiments 101-141, wherein the subject is at risk of developing one or more adverse events and further receives an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

[0466] 144. The use of embodiment 142 or embodiment 143, wherein the one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general deterioration of physical health.

[0467] 145. The use of embodiment 142 or embodiment 143, wherein one or more adverse events are grade 3 or higher adverse events.

[0468] 146. The use of embodiment 142 or embodiment 143, wherein one or more adverse events are serious adverse events.

[0469] 147. The use of embodiment 142 or embodiment 143, wherein the one or more adverse events are conjunctivitis and / or keratitis, and the other therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, and / or a steroid eye drop.

[0470] 148. The use of any one of embodiments 101-147, wherein the antibody-drug conjugate is administered as a monotherapy.

[0471] 149. The use of any one of embodiments 101-148, wherein the subject is a human.

[0472] 150. The use of an antibody-drug conjugate as described in any one of embodiments 101-149, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

[0473] 151. An article comprising:

[0474] a) a medicament comprising an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analogue or a functional derivative thereof; and

[0475] b) a package insert comprising instructions for administering a medicament comprising the antibody-drug conjugate for use in a method of treating cervical cancer in a subject according to any one of embodiments 1-50, or comprising the antibody-drug conjugate for use in a method of treating cervical cancer in a subject according to any one of embodiments 51-100.

[0476] 152. The article of manufacture of embodiment 151, wherein the drug comprising the antibody-drug conjugate is in a container selected from the group consisting of a vial, a syringe, and an infusion bag.

[0477] 153. The article of manufacture of embodiment 152, wherein the container comprises the antibody-drug conjugate at a dose of about 4 mg to about 500 mg.

[0478] 154. The article of manufacture of embodiment 152, wherein the container comprises the antibody-drug conjugate at a dose of about 20 mg to about 60 mg.

[0479] 155. The article of manufacture of embodiment 152, wherein the container comprises the antibody-drug conjugate at a concentration of about 5 mg / mL to about 15 mg / mL.

[0480] 156. The article of any one of embodiments 151-154, wherein the drug comprising the antibody-drug conjugate is a lyophilized powder.

[0481] 157. The preparation of embodiment 156, wherein the lyophilized powder is reconstituted with a suitable diluent to a final concentration of about 5 mg / mL to about 15 mg / mL.

[0482] 158. The article of manufacture of any one of embodiments 151-157, wherein the drug comprising the antibody-drug conjugate is administered by intravenous infusion or injection.

[0483] 159. The article of manufacture of embodiment 158, wherein the drug comprising the antibody-drug conjugate is administered by intravenous infusion.

[0484] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention. It should be understood that the embodiments and embodiments described herein are for illustrative purposes only, and those skilled in the art should understand the various modifications or changes made therefrom, and they are included in the subject matter and rights of the present application and within the scope of the appended claims.

[0485] Example

[0486] Example 1: Tesutumomab Vedotin (tisotumab vedotin) Stage I / II in subjects with cancer Safety studies.

[0487] Tesotumab vedotin is an antibody-drug conjugate that includes an antibody that binds to tissue factor (TF), a protease-cleavable linker, and the microtubule disrupting agent MMAE. TF is a protein that is abnormally expressed in many tumors, including cervical cancer, and is associated with a poor prognosis. Y et al. Clin Chim Acta. 2006; 364(1-2): 12-21 and Cocco E et al. BMC Cancer. 2011; 11: 263. Tesotumomab vedotin selectively targets TF to deliver a clinically validated toxic payload to tumor cells ( Figure 1 ). See Breij EC et al. Cancer Res. 2014; 74(4): 1214-1226 and Chu AJ. Int J Inflam. 2011; 2011. doi: 10.4061 / 2011 / 367284.

[0488] method

[0489] A first-in-human Phase I / II dose-escalation study following a 3+3 dose-escalation design was conducted to test the safety of tesotumab vedotin in 27 subjects with various types of locally advanced and / or metastatic cancer, including cervical cancer ( Figure 2 Tesotuzumab vedotin was administered by intravenous infusion on day 1 of a 21-day cycle at a dose ranging from 0.3 mg / kg to 2.2 mg / kg for a total of four cycles (i.e., each treatment cycle was 3 weeks). Patients with stable disease (SD) or better at the end of four cycles had the option to continue treatment with tesotuzumab vedotin for an additional eight cycles ( Figure 2 ). Tumor assessment was performed by CT scan every 6 weeks. To meet SD criteria, the planned CT scan at week 6 had to be SD or better. Two CT scans were performed outside each protocol-defined window.

[0490] Lyophilized vials containing 40 mg of tisotumab vedotin are stored in a refrigerator at 2°C to 8°C. Tisotumab vedotin is reconstituted in 4 ml of water to obtain a reconstituted solution containing 10 mg / mL tisotumab vedotin, 30 mM histidine, 88 mM sucrose, and 165 mM D-mannitol. The pH of the reconstituted antibody-drug conjugate solution is 6.0. According to the dose calculated for the patient, the reconstituted tisotumab vedotin is diluted into a 0.9% NaCl 100 mL infusion bag. After the tisotumab vedotin vial is reconstituted, the intravenous infusion is completed within 24 hours. Use a 0.2 μm inline filter for intravenous infusion. Give a total volume of 100 mL from the prepared infusion bag. No dead volume is provided.

[0491] The primary objective of the study was to evaluate the safety and tolerability in a mixed population of patients with specific solid tumors. The severity of adverse events (AEs) was rated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Secondary objectives of the study included determining the pharmacokinetic (PK) profile of tisotumab vedotin and conducting a preliminary evaluation of antitumor activity according to the evaluation of solid tumor response evaluation criteria [RECIST] version 1.1. Dose-limiting toxicity (DLT) was determined in the first cycle and defined as a grade ≥3 event that may be associated with tisotumab vedotin. The maximum tolerated dose (MTD) is defined as the highest tisotumab vedotin dose level that does not cause unacceptable side effects. Tumor biopsy for TF expression is required at baseline, which is assessed by immunohistochemistry using tisotumab. TF staining intensity is determined using the H scoring system.

[0492] Inclusion criteria for eligible subjects included patients with recurrent, advanced, and / or metastatic cancer that could not be treated with standard therapy; and measurable disease.

[0493] Exclusion criteria included known past or current coagulation defects; ongoing major bleeding; and the presence of CTCAE grade ≥2 peripheral neuropathy.

[0494] result

[0495] The demographics and baseline characteristics of the patients are shown in Table 1. A total of 25 patients withdrew from treatment due to patient choice (4%), disease progression (67%), dose-limiting toxicity (DLT) (4%), AE (15%), or death (4%). Two patients continued treatment after four cycles.

[0496] Table 1. Demographics and baseline characteristics of the patients

[0497]

[0498] Table 2 provides a safety analysis of all 27 patients. A total of 25 patients (93%) experienced treatment-related AEs, the most common of which were fatigue (48%), seizure (48%), and anemia (41%). Nineteen patients experienced grade ≥ 3 treatment-related AEs, the most common of which were fatigue (n = 4), anemia (n = 4), abdominal pain (n = 3), and hyponatremia (n = 3) (Table 2; Figure 3 ). There were no grade 4 events. Seven patients discontinued due to AEs, including grade 1 pneumonia (n=1), grade 3 events of Guillain-Barré syndrome (n=1), diabetes (n=1), fatigue (n=1), and abdominal pain (n=2), and one patient developed grade 2 peripheral swelling and grade 3 pain in the extremities. Three deaths were reported in this study. One patient in the 0.6 mg / kg group died from tumor-related hemorrhage. Two patients in the 0.3 mg / kg group died from disease progression, both deaths were considered unrelated to the study drug. No significant changes in coagulation parameters were observed. The mean prothrombin time at baseline was 11.5 seconds (n=18) and 11.7 seconds by the end of the study (n=17). The mean activated partial thromboplastin time at baseline was 28.2 seconds (n=25) and 27.1 seconds by the end of the study (n=23). Three DLTs were observed in three patients in the 2.2 mg / kg dose group (i.e., type 2 diabetes mellitus, mucositis, and febrile neutropenia, all grade 3).

[0499] Table 2. Overall safety profile of tesotumomab vedotin by dose group

[0500]

[0501]

[0502] * Occurred up to 30 days after treatment. AE denotes adverse event.

[0503] Determination of reaching C max ( Tmax The geometric mean (%CV) of the time (hr), the maximum concentration (C max )(ng / mL) and area under the concentration-time curve (AUC) 0-t (hr*ng / mL) was used to conduct the pharmacokinetic (PK) part of the study (Table 3). Low levels of unconjugated MMAE were measured in the systemic circulation (Figure 4).

[0504] Table 3. Summary of plasma PK parameters of tesotumomab vedotin by dose group in cycle 1

[0505] Dosage (mg / kg) n <![CDATA[T max (hr)]]> <![CDATA[C max (ng / ml)]]> <![CDATA[AUC 0-t (hr*ng / ml)]]> 0.3 3 1.5(73％) 4782.7(12％) 59216.8(3％) 0.6 3 1.2(13％) 12195.3(10％) 368432.7(8％) 0.9 3 1.3(12％) 19811.6(17％) 601926.2(17％) 1.2 3 1.3(12％) 34673.1(19％) 1084672.7(9％) 1.5 3 1.1(9.6％) 23115.6(21％) 794988.4(19％) 1.8 3 1.2(14％) 35416.3(39％) 1504823.8(50％) 2.0 3 1.2(8％) 32296.1(22％) 1256379.7(33％) 2.2 6 1.1(13％) 55530.3(10％) 2037070.5(34％)

[0506] Efficacy was evaluated in 26 patients (Table 4). The best responses observed were partial response (PR) in 1 patient (4%) and stable disease (SD) in 11 patients (41%). The disease control rate (DCR; PR+SD) was 46%, corresponding to 12 of 26 patients. The change in tumor size, expressed as a percentage of baseline, was determined in 27 patients ( Figure 5 ). Tumor size was reduced in 2 patients with cervical cancer relative to baseline, with patient 1 experiencing a reduction in tumor size of approximately 20% when given 2.2 mg / kg of tesotumomab vedotin ( Figure 5 ; (i) ), when given 1.2 mg / kg of tesotumomab vedotin, the tumor size of patient 2 was reduced by approximately 51% ( Figure 5 ; (ii)). Patient 2 is a 43-year-old cervical cancer patient diagnosed with stage 4 disease who had received 3 prior therapies. TF expression was determined in Patient 2, with an H score of 140 (archive). Patient 2 achieved a confirmed PR with a reduction in target lesions of approximately 51%, and sustained benefit for a total of 15 months ( Figure 6 ). Tesutumumab vedotin was well tolerated, and no serious AEs were reported. Patient 2 ultimately experienced disease progression and discontinued treatment.

[0507] Table 4. Confirmed objective responses

[0508]

[0509] a Percentages may not add to 100% due to rounding. b The patient died before the first scan.

[0510] in conclusion

[0511] The MTD was determined to be 2.0 mg / kg and was used in a Phase II study of the efficacy and safety of tesotumomab vedotin in patients with cervical cancer.

[0512] Example 2: Phase IIa study of tesotumomab vedotin in patients with recurrent, recurrent and / or metastatic uterine cancer Role of patients with cervical cancer.

[0513] To evaluate the efficacy, safety, and tolerability of 2.0 mg / kg tesotumab vedotin in patients with recurrent, recurrent, and / or metastatic cervical cancer.

[0514] method

[0515] The Phase IIa single-arm multicenter trial studied the efficacy, safety and tolerability of 2.0 mg / kg tesotumab vedotin in patients with recurrent, recurrent and / or metastatic cervical cancer. A total of 34 patients (n=34) were recruited and received at least 1 dose of tesotumab vedotin. On the first day of a 21-day cycle, each eligible patient received an intravenous (IV) infusion of tesotumab vedotin at a concentration of 2.0 mg / kg (i.e., each treatment cycle was 3 weeks (q3w)).

[0516] Lyophilized vials containing 40 mg of tisotumab vedotin are stored in a refrigerator at 2°C to 8°C. Tisotumab vedotin is reconstituted in 4 ml of water to obtain a reconstituted solution containing 10 mg / mL tisotumab vedotin, 30 mM histidine, 88 mM sucrose, and 165 mM D-mannitol. The pH of the reconstituted antibody-drug conjugate solution is 6.0. According to the dose calculated for the patient to receive 2.0 mg / kg tisotumab vedotin, the reconstituted tisotumab vedotin is diluted into a 0.9% NaCl 100 mL infusion bag. After the tisotumab vedotin vial is reconstituted, the intravenous infusion is completed within 24 hours. Use a 0.2 μm inline filter for intravenous infusion. Give a total volume of 100 mL from the prepared infusion bag. No dead volume is provided.

[0517] The primary objective of the study was to evaluate the safety and tolerability of tesotumomab vedotin. The severity of adverse events (AEs) was rated according to CTCAE version 4.03. The secondary objective was to conduct a preliminary evaluation of the durability of antitumor activity according to RECIST version 1.1. Tumor assessments were performed by CT scan every 6 weeks.

[0518] result

[0519] The demographic and baseline characteristics of the patients are shown in Table 5. A total of 7 patients continued on treatment (22%), and 27 patients withdrew from treatment due to AEs (n=5), disease progression (n=16), or other reasons (n=6).

[0520] Table 5. Demographics and baseline characteristics of the patients

[0521]

[0522] a Patients who have progressed on therapy given for locally advanced disease. b Data from one patient were missing. c These include bevacizumab given as combination therapy in the form of platinum / bevacizumab / paclitaxel or topotecan / bevacizumab / paclitaxel. d Combination therapy with cisplatin, paclitaxel, and bevacizumab. e External beam radiation therapy is given to the cervix or surrounding tissues.

[0523] Common (≥15%) AEs following monotherapy with tetuzumab vedotin were evaluated. Figure 7 ). Grade 3 AEs were reported in 16 patients (47%). There were no grade 4 or 5 events. Compound-specific conjunctival toxicity was observed, but relief measures greatly reduced conjunctival toxicity in patients. Before relief (n=15), 73% of patients experienced conjunctivitis of any grade. After relief (n=19), 32% of patients experienced conjunctivitis of any grade, 5% of which were ≥ grade 3. Risk reduction measures included prophylactic steroids during treatment via IV infusion, lubricating eye drops and wearing a cooling eye mask, and stricter dosage adjustment instructions.

[0524] Efficacy was evaluated in 34 patients (Table 6 and Figure 8 ). Seven patients continued to receive treatment.

[0525] Table 6. Efficacy evaluation

[0526]

[0527] a PFS stands for progression-free survival. b DoR stands for duration of response. c Including 8 confirmed PRs and 3 unconfirmed PRs (1 of which is still ongoing). d Clinical benefit after week 12. DCR denotes disease control rate, CR denotes complete response, and SD denotes stable disease. e The median DoR for confirmed and unconfirmed responses was 5.4 months.

[0528] The trial was subsequently expanded to include additional patients. A total of 55 patients were evaluated for efficacy (Table 7, Fig. 9 and Fig.10 ). Four patients continued to receive treatment.

[0529] Table 7. Efficacy evaluation

[0530] N <![CDATA[ORR a ,N(%) b ]]> ORR 95% CI, % <![CDATA[ All patients evaluable for efficacy ]]> 51 16(31) 19-46 <![CDATA[ Histology ]]> Scaly 27 9(33) 17-54 Adenocarcinoma 18 4(22) 6-48 Glandular scales 4 2(50) 7-93 other 2 1(50) 1-99 Number of prior systemic therapies 1 23 8(35) 16-57 2 17 6(35) 14-62 3-4 11 2(18) 2-52 <![CDATA[ Prior taxane ]]> yes 48 15(31) 19-46 none 3 1(33) 1-91 <![CDATA[ Prior bevacizumab ]]> yes 40 12(30) 17-47 none 11 4(36) 11-69 <![CDATA[ Prior GOG 240 plan c ]]> yes 37 12(32) 18-50 none 14 4(29) 8-58

[0531] a represents the objective response rate. b Combination of unconfirmed + confirmed ORR. c The GOG 240 regimen is defined as bevacizumab + doublet chemotherapy (cisplatin + paclitaxel or topotecan + paclitaxel).

[0532] in conclusion

[0533] Tesotumab vedotin showed strong efficacy and manageable safety in the cervical cancer group. The safety profile of tesotumab vedotin in recurrent cervical cancer was generally consistent with other MMAE-based ADCs. Compound-specific conjunctival events were observed, but mitigation measures greatly reduced toxicity.

[0534] Example 3: Effect of tesotumomab vedotin on patients with previously treated recurrent or metastatic cervical cancer Phase II trial in patients with

[0535] Evaluate the efficacy, safety and tolerability of 2.0 mg / kg tesotumomab vedotin in patients with previously treated recurrent or metastatic cervical cancer (e.g., recurrent and / or metastatic cervical cancer). Preliminary data observed in a group of previously treated cervical cancer patients suggest that the benefit-risk profile for this high unmet need population is positive. See Examples 1 and 2 above.

[0536] method

[0537] This Phase IIa, single-arm, multicenter, international trial evaluated the efficacy, safety, and tolerability of 2.0 mg / kg tesotumab vedotin in patients with recurrent or metastatic cervical cancer. Eligible patients had experienced disease progression during or after treatment with doublet chemotherapy in combination with bevacizumab if they were eligible to receive bevacizumab. Patients had received no more than 2 prior systemic therapies for their metastatic or recurrent disease. Eligible patients were treated with 2.0 mg / kg tesotumab vedotin intravenously (IV) every 3 weeks (1Q3W) until predetermined discontinuation criteria were met ( Fig.11 ). Imaging was obtained every 6 weeks for the first 30 weeks and every 12 weeks thereafter. Responses were confirmed 4 weeks (28 days) after the first response assessment. Approximately 100 patients aged ≥18 years were enrolled in the trial.

[0538] The inclusion and exclusion criteria for patients enrolled in the trial are shown in Table 8.

[0539] Table 8. List of inclusion and exclusion criteria

[0540]

[0541]

[0542]

[0543]

[0544] Lyophilized vials containing 40 mg of tisotumab vedotin are stored in a refrigerator at 2°C to 8°C. Tisotumab vedotin is reconstituted in 4 ml of water to obtain a reconstituted solution containing 10 mg / mL tisotumab vedotin, 30 mM histidine, 88 mM sucrose, and 165 mM D-mannitol. The pH of the reconstituted antibody-drug conjugate solution is 6.0. According to the dose calculated for the patient to receive 2.0 mg / kg tisotumab vedotin, the reconstituted tisotumab vedotin is diluted into a 0.9% NaCl 100 mL infusion bag. After the tisotumab vedotin vial is reconstituted, the intravenous infusion is completed within 24 hours. Use a 0.2 μm inline filter for intravenous infusion. Give a total volume of 100 mL from the prepared infusion bag. No dead volume is provided. For patients who were intolerant to the protocol-specified dosing regimen, dose reductions were permitted to enable the patient to continue treatment with tesotumomab vedotin (Table 9).

[0545] Table 9. Dosage adjustment schedule

[0546] Original dose of tetuzumab vedotin Reduced dose of tesotumomab vedotin 2.0 mg / kg 1.3 mg / kg 1.3 mg / kg 0.9 mg / kg 0.9 mg / kg 0.9 mg / kg*

[0547] *If the patient has been treated with 0.9 mg / kg tesotumomab vedotin 1Q3W, do not further reduce the tesotumomab vedotin dose.

[0548] The objectives and endpoints are described in Table 10. Confirmed objective response rate (ORR) and two-sided 95% exact confidence interval were calculated 27 weeks after the last patient received the first dose of tesotumab vedotin. Assuming the true confirmed ORR of tesotumab vedotin was 25%, 100 patients provided 96% power to exclude an ORR of 11% or less (one-sided P value of 2.5%).

[0549] Table 10. Objectives and endpoints

[0550]

[0551] If a patient's trial treatment is discontinued before the end of the treatment regimen, it will not result in the patient's automatic withdrawal from the trial. A patient's trial treatment is discontinued if: radiographic disease progression is confirmed by independent committee review; safety stopping rules are met; unacceptable toxicity requires discontinuation of treatment; the investigator believes that discontinuation of treatment is in the best interest of the patient for safety reasons (such as adverse events); pregnancy; patient choice; and / or initiation of new anticancer treatment. After discontinuation of treatment, the investigator will conduct safety follow-up. Safety follow-up is conducted 15 days ± 5 days after the last dose of tesotumomab vedotin and before the start of new anticancer treatment, including most assessments performed at screening and response assessments. After discontinuation of treatment, patients continue to be followed for post-treatment assessments until death or withdrawal from the trial. Safety stopping rules for discontinuation of treatment included the following ocular toxicity scenarios: first recurrence of conjunctivitis of CTCAE grade ≥3 (despite dose reduction); third recurrence of keratitis of CTCAE grade ≤2 (despite dose reduction); first occurrence of keratitis of CTCAE grade ≥3; ophthalmologic evaluation showing conjunctival / corneal scarring; symblepharon of any grade; fluorescein or conjunctival ulcer of any grade that failed to stabilize or improve after dose reduction; or any dose delay of more than 12 weeks related to ocular toxicity. Safety stopping rules for discontinuation of treatment included the following scenarios for adverse events other than ocular toxicity: second occurrence of grade 3 infusion-related reaction (despite pre-dose administration); first occurrence of grade ≥4 infusion-related reaction; first occurrence of grade ≥4 mucositis; first occurrence of grade ≥4 peripheral neuropathy; any pulmonary or CNS hemorrhagic event of grade ≥2; any hemorrhagic event of grade ≥3 in patients receiving anticoagulation.

[0552] Three adverse events of particular concern are ocular adverse events, adverse events of peripheral neuropathy, and adverse events of hemorrhage. In terms of ocular AEs: AEs of grade 1-2 conjunctivitis were frequently reported in association with tisotumab vedotin treatment. Severe cases of conjunctivitis and keratitis (CTCAE ≥ grade 3) were observed, however, implementation of a comprehensive mitigation plan and preventive measures can significantly reduce the frequency and severity of ocular adverse reactions. To prevent ocular AEs, follow the following ocular premedication guidelines: use preservative-free lubricating eye drops from the start of treatment with tisotumab vedotin until the end of treatment; avoid contact lens use during treatment with tisotumab vedotin; use refrigerator-based ocular cooling pads (such as THERAPEARL eye mask) during infusion, and use them immediately prior to infusion according to the instructions provided with the ocular cooling pad; administer topical ocular vasoconstrictors prior to infusion (such as brimonidine tartrate 0.2% eye drops, 3 drops in each eye before starting infusion; otherwise use according to the product prescribing information). If the patient cannot tolerate ocular vasoconstrictors due to adverse reactions, continued treatment can be discontinued; steroid eye drops (dexamethasone 0.1% eye drops or equivalent, 1 drop in each eye, 3 times a day for 3 days [give eye drops before starting tedotin], otherwise use according to the product prescribing information) are used for 3 days from the date of infusion. Guidelines for ocular treatment are shown in Table 11.

[0553] Table 11. Guidelines for ocular treatment

[0554]

[0555] With respect to AEs of peripheral neuropathy (including peripheral neuropathy; peripheral sensory neuropathy; peripheral motor neuropathy; polyneuropathy): Peripheral neuropathy is a well-known adverse reaction to treatment with chemotherapeutic drugs (including cisplatin and taxanes) and MMAE-based ADCs, and is frequently reported to be associated with treatment with tisotumab vedotin. Most of the reported cases were grade 1-2; however, peripheral neuropathy was the primary reason for permanent discontinuation of tisotumab vedotin treatment. A relief plan was developed, including dose reduction (see Table 9) and dose delay (ie, maintaining the dose until the event improves to ≤ grade 1) to prevent the onset of peripheral neuropathy and the exacerbation of the original condition. With respect to AEs of bleeding: Due to the mode of action of tisotumab vedotin, bleeding events are considered to be of particular concern. Consistent with preclinical findings, no major effects have been found in patients treated with tisotumab vedotin to date in terms of activated partial thromboplastin time (aPTT) or prothrombin time (PT). Epistaxis was the most frequently reported AE, however, almost all cases were grade 1. With the exception of epistaxis, a causal relationship between the majority of reported bleeding events and tesotumomab vedotin treatment was not established.

Claims

1. A method of treating cervical cancer in a subject, the method comprising administering to the subject an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and wherein the antibody-drug conjugate is administered at a dose in the range of about 1.5 mg / kg to about 2.1 mg / kg.

2. The method of claim 1, wherein the dose is about 2.0 mg / kg.

3. The method of claim 1 or 2, wherein the antibody-drug conjugate is administered approximately once every 1 week, 2 weeks, 3 weeks, or 4 weeks.

4. The method of any one of claims 1-3, wherein the antibody-drug conjugate is administered approximately once every 3 weeks.

5. The method of any one of claims 1-4, wherein the subject has been previously treated with and has not responded to one or more therapeutic agents, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

6. The method of any one of claims 1-4, wherein the subject has been previously treated with one or more therapeutic agents and relapses following such treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

7. The method of any one of claims 1-4, wherein the subject has been previously treated with one or more therapeutic agents and experienced disease progression during that treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

8. The method of any one of claims 5-7, wherein the one or more therapeutic agents is a platinum-based therapeutic agent.

9. The method of any one of claims 5-7, wherein the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, liposomal doxorubicin, cetuximab, pembrolizumab, nivolumab, and bevacizumab.

10. The method of any one of claims 1-9, wherein the subject experiences disease progression during or after treatment with: a) Paclitaxel and cisplatin, b) paclitaxel and carboplatin, or c) Paclitaxel and topotecan.

11. The method of any one of claims 1-10, wherein the subject has been treated with bevacizumab.

12. The method of any one of claims 1-10, wherein the subject is not eligible for bevacizumab treatment.

13. The method of any one of claims 1-12, wherein the subject is not a candidate for curative therapy.

14. The method of claim 13, wherein curative therapy comprises radiation therapy and / or evisceration surgery.

15. The method of any one of claims 1-14, wherein the subject has not responded to treatment with no more than two prior systemic therapeutic regimens.

16. The method of any one of claims 1-14, wherein the subject has relapsed after treatment with no more than two prior systemic treatment regimens.

17. The method of any one of claims 1-16, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

18. The method of any one of claims 1-17, wherein the cervical cancer is advanced cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer.

19. The method of any one of claims 1-18, wherein the cervical cancer is recurrent cervical cancer.

20. The method of any one of claims 1-19, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

21. The method of any one of claims 1-20, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

22. The method of any one of claims 1 to 21, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; as well as (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and Wherein the light chain variable region comprises: (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 5; wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme.

23. The method of any one of claims 1 to 22, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence of SEQ ID NO:

8.

24. The method of any one of claims 1 to 23, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

8.

25. The method of any one of claims 1-24, wherein the anti-TF antibody of the antibody-drug conjugate is tesotumomab.

26. The method of any one of claims 1-25, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin.

27. The method of claim 26, wherein the linker is a cleavable peptide linker.

28. The method of claim 27, wherein the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein: a)MC is: b) vc is the dipeptide valine-citrulline, and c) PAB is:

29. The method of any one of claims 26 to 28, wherein the linker is attached to a thiol residue of the anti-TF antibody by partial reduction or full reduction of the anti-TF antibody or antigen-binding fragment thereof.

30. The method of claim 29, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the structure: in, p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or an antigen-binding fragment thereof.

31. The method of claim 30, wherein the average value of p in the population of antibody-drug conjugates is about 4.

32. The method of any one of claims 1-31, wherein the antibody-drug conjugate is tesotumomab vedotin.

33. The method of any one of claims 1-32, wherein the route of administration of the antibody-drug conjugate is intravenous.

34. The method of any of claims 1-33, 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.

35. The method of any one of claims 1-34, wherein one or more therapeutic effects in the subject are improved relative to baseline following administration of the antibody-drug conjugate.

36. The method of claim 35, wherein one or more therapeutic effects are selected from the group consisting of size of tumors originating from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

37. The method of any one of claims 1-36, wherein the size of a tumor derived from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from cervical cancer prior to administration of the antibody-drug conjugate.

38. The method of any one of claims 1-37, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

39. The method of any one of claims 1-38, wherein the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years following administration of the antibody-drug conjugate.

40. The method of any one of claims 1-39, wherein the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years following administration of the antibody-drug conjugate.

41. The method of any one of claims 1-40, wherein after administration of the antibody-drug conjugate, 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.

42. The method of any one of claims 1-41, wherein the subject has one or more adverse events and further receives an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events.

43. The method of any one of claims 1-41, wherein the subject is at risk of developing one or more adverse events and further receives an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

44. The method of claim 42 or 43, wherein one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general deterioration of physical health.

45. The method of claim 42 or 43, wherein one or more adverse events are grade 3 or higher adverse events.

46. ​​The method of claim 42 or 43, wherein one or more adverse events are serious adverse events.

47. The method of claim 42 or 43, wherein the one or more adverse events are conjunctivitis and / or keratitis and the other therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, and / or a steroid eye drop.

48. The method of any one of claims 1-47, wherein the antibody-drug conjugate is administered as a monotherapy.

49. The method of any one of claims 1-48, wherein the subject is a human.

50. The method of any one of claims 1-49, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

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