Method for treating cancer by combining anti-VEGF antibody and anti-tissue factor antibody-drug conjugate

Abstract

The present invention provides a combination of an anti-VEGF antibody (e.g., bevacizumab) and an antibody-drug conjugate that binds tissue factor (TF) (e.g., tesotumab vedotin) and their use in methods for treating cancer, such as cervical cancer. The present invention also provides compositions and kits comprising an anti-VEGF antibody (e.g., bevacizumab) and an antibody-drug conjugate that binds TF (e.g., tesotumab vedotin) for treating cancer, such as cervical cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 752,904, filed on October 30, 2018, the contents of which are incorporated herein by reference in their entirety.

[0003] Sequence listing submitted as ASCII text file

[0004] The following content submitted in an ASCII text file is incorporated herein by reference in its entirety: Computer Readable Form (CRF) Sequence Listing (File Name: 761682001040SEQLIST.TXT, Record Date: October 14, 2019, Size: 17KB). Technical Field

[0005] The present invention relates to methods of treating cancer, such as cervical cancer, using a combination of an anti-VEGF antibody and an anti-tissue factor (anti-TF) antibody-drug conjugate. Background Art

[0006] 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.

[0007] TF is a cell surface receptor for serine protease factor VIIa (FVIIa). The combination of FVIIa and TF starts a signal transduction process in the cell, and the signal transduction function plays a role in angiogenesis. Angiogenesis is a normal process in growth and development and wound healing, but it is also a basic step for tumors to transform 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.

[0008] 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.

[0009] 120(2):S13-S21).

[0010] Angiogenesis inhibitors have emerged as effective targeted therapies for the treatment of patients with a variety of cancers. Bevacizumab, a neutralizing antibody against vascular endothelial growth factor, has been approved for use alone or in combination in a variety of tumor types at multiple doses and durations. Bevacizumab has shown modest single-agent activity in heavily pretreated recurrent cervical cancer. Efficacy observed in 49 patients treated with bevacizumab 15 mg / kg every 21 days included an ORR of 10.9%, a median duration of response of 6.21 months, and a median PFS of 3.4 months. The addition of bevacizumab 15 mg / kg 1Q3W to cisplatin / paclitaxel or paclitaxel / topotecan significantly improved overall survival, making these regimens standard of care for patients with 1L recurrent or metastatic cervical cancer.

[0011] Cervical cancer constitutes a serious medical problem worldwide, with an estimated annual incidence of more than 500,000 new cases and 250,000 deaths. 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 therapy for cervical cancer is platinum-based therapy plus taxane-based therapy. Bevacizumab is an anti-VEGF antibody approved by the US 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 includes bevacizumab combined with paclitaxel plus platinum (e.g., cisplatin or carboplatin) or paclitaxel plus 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 are no approved treatments, and patients are usually treated with single-agent therapy, including but not limited to: pemetrexed, topotecan, docetaxel, albumin-bound paclitaxel, vinorelbine, and in some cases, bevacizumab. A meta-analysis of single-agent treatment 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. The five-year relative survival rate for stage IV cervical cancer is only 15%, indicating a high need for improved therapies for cervical cancer.

[0012] There remains a need for combination therapies with an acceptable safety profile and high efficacy for cancer treatment, particularly for cervical cancer treatment. The present invention meets such needs by providing a method for treating cancers such as cervical cancer using a combination of an anti-VEGF antibody (such as bevacizumab) and an anti-tissue factor (anti-TF) antibody-drug conjugate (e.g., tesotumab vedotin).

[0013] 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

[0014] Provided herein is a method for treating cervical cancer in a subject, the method comprising administering to the subject an anti-VEGF antibody or an antigen-binding fragment thereof and an antibody-drug conjugate that binds tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof. In some embodiments, the antibody-drug conjugate is administered at a dose ranging from about 0.65 mg / kg to about 2.1 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 0.65 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of 0.65 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 0.9 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of 0.9 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 1.3 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of 1.3 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 2.0 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg. In some of any embodiments herein, the antibody-drug conjugate is administered about once every 3 weeks. In some of any embodiments herein, the antibody-drug conjugate is administered once every 3 weeks. In some of any embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose ranging from about 5 mg / kg to about 20 mg / kg. In some of any embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of about 7.5 mg / kg. In some of any embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 7.5 mg / kg. In some of any embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of about 15 mg / kg. In some of any embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg. In some of any of the embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof is administered about once every 3 weeks. In some of any of the embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some of any of the embodiments described herein, the antibody-drug conjugate is administered at least 30 minutes after administration of the anti-VEGF antibody or antigen-binding fragment thereof. In some of any of the embodiments herein, 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.In some of any embodiments herein, the object 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 object 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 antibody-drug conjugates. In some of any embodiments described herein, one or more therapeutic agents are selected from the group consisting of chemotherapeutics, bevacizumab, cisplatin, carboplatin, paclitaxel, topotecan, the combination of bevacizumab and paclitaxel, the combination of bevacizumab and cisplatin, the combination of bevacizumab and carboplatin, the combination of paclitaxel and topotecan, the combination of bevacizumab and topotecan, the combination of bevacizumab and cisplatin and paclitaxel, the combination of bevacizumab and carboplatin and paclitaxel, and the combination of bevacizumab and paclitaxel and topotecan. In some of any embodiments herein, the object is not a candidate for curative therapy. In some embodiments, curative therapy includes radiotherapy and / or visceral resection therapy. 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. In some embodiments, advanced cervical cancer is stage 3 or stage 4 cervical cancer. In some of any embodiments herein, advanced cervical cancer is metastatic cervical cancer. In some of any embodiments herein, the cervical cancer is recurrent cervical cancer. 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:.

[0015] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0016] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0017] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0018] Wherein the light chain variable region comprises:

[0019] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0020] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0021] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6; wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme. 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 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 85% 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 some embodiments, the linker is a cleavable peptide linker. In some embodiments, the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein:

[0022] a)MC is:

[0023]

[0024] b) vc is the dipeptide valine-citrulline, and

[0025] c) PAB is:

[0026] 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 some embodiments, the linker is linked to monomethyl auristatin E (MMAE), wherein the antibody-drug conjugate has the following structure:

[0027]

[0028] 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 some embodiments, the average value of p in a population of the antibody-drug conjugates is about 4. In some embodiments of any of the present invention, the antibody-drug conjugate is tisotumab vedotin. In some embodiments of any of the present invention, the route of administration of the antibody-drug conjugate is intravenous. In some embodiments of any of the present invention, the anti-VEGF antibody or an antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0029] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0030] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0031] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0032] Wherein the light chain variable region comprises:

[0033] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0034] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0035] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:22, wherein the CDRs of the anti-VEGF antibody or antigen-binding fragment thereof are defined by the Kabat numbering scheme. In some of any of the embodiments herein, the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:31, and the light chain variable region comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:32. In some of any of the embodiments herein, the anti-VEGF antibody 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:31, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:32. In some of any of the embodiments herein, the anti-VEGF antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:33, and the light chain comprises the amino acid sequence of SEQ ID NO:34. In some of any of the embodiments herein, the anti-VEGF antibody is bevacizumab. In some of any embodiments herein, the anti-VEGF antibody is a biosimilar of bevacizumab. In some of any embodiments herein, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel, and SB8. In some of any embodiments herein, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel. In some of any embodiments described herein, the route of administration of the anti-VEGF antibody or antigen-binding fragment thereof is intravenous or subcutaneous. In some of any embodiments described herein, the route of administration of the anti-VEGF antibody or antigen-binding fragment thereof is intravenous. In some of any embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered sequentially. In some of any embodiments described herein, the anti-VEGF antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered simultaneously.In some of any of the 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 the cancer cells express TF. In some of any of the embodiments herein, one or more therapeutic effects in a subject are improved relative to baseline following administration of an antibody-drug conjugate and an anti-VEGF antibody or antigen-binding fragment thereof. In some aspects, the one or more therapeutic effects are selected from the group consisting of size of a tumor derived from a cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. In some of any of the embodiments herein, the size of a tumor originating from a 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 the cancer prior to administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof. In some of any of the 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 of the embodiments herein, following administration of the antibody-drug conjugate and the anti-VEGF antibody, or an antigen-binding fragment thereof, 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. In some of any of the embodiments herein, following administration of the antibody-drug conjugate and the anti-VEGF antibody, or an antigen-binding fragment thereof, 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.In some of any of the embodiments herein, after administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof, the duration of remission for 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 any of the embodiments herein, 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. In some of any of the embodiments herein, 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. In some of any embodiments herein, one or more adverse events are anemia, abdominal pain, bleeding, hyperthyroidism, hypothyroidism, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulcer, 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 conjunctivitis, conjunctival ulcer and / or keratitis, and the other agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, an antibiotic and / or a steroid eye drop. 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. In some of any embodiments herein, an anti-VEGF antibody or an antigen-binding fragment thereof is in a pharmaceutical composition comprising an anti-VEGF antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier.

[0036] Also provided herein are kits comprising:

[0037] (a) an anti-VEGF antibody or antigen-binding fragment thereof at a dose ranging from about 5 mg / kg to about 20 mg / kg

[0038] (b) an antibody-drug conjugate that binds to tissue factor (TF) at a dose range of about 0.65 mg / kg to about 2.1 mg / kg, 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

[0039] (c) Instructions for use of an anti-VEGF antibody or antigen-binding fragment thereof and an antibody drug conjugate according to some of any embodiments described herein. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab. In some of any embodiments herein, the antibody-drug conjugate is tisotumab vedotin. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1A -C is a series of graphs showing the antitumor activity of the combination of tesotumomab vedotin and bevacizumab in a cervical cancer xenograft mouse model. Figure 1A : Mean tumor size in mice after treatment with 4 mg / kg IgG1 control (open circles), 4 mg / kg IgG1-MMAE control (closed circles), 2 mg / kg tesotumab vedotin (open squares), 4 mg / kg tesotumab vedotin (closed squares), 15 mg / kg bevacizumab (open diamonds), 2 mg / kg tesotumab vedotin combined with 15 mg / kg bevacizumab (open triangles), or 4 mg / kg tesotumab vedotin combined with 15 mg / kg bevacizumab (closed triangles). Arrows indicate the date of treatment. Tumor burden was assessed by caliper measurement. Error bars indicate the standard deviation of the mean. Figure 1B : Average tumor size in mice on day 21 after first treatment with 4 mg / kg IgG1-MMAE control (solid circles), 2 mg / kg tesotumab vedotin (open squares), 4 mg / kg tesotumab vedotin (solid squares), 15 mg / kg bevacizumab (open diamonds), 2 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (open triangles), or 4 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (solid triangles). Figure 1C : Percent progression-free survival in mice treated with 4 mg / kg IgG1 control (open circles), 4 mg / kg IgG1-MMAE control (closed circles), 2 mg / kg tesotumab vedotin (open squares), 4 mg / kg tesotumab vedotin (closed squares), 15 mg / kg bevacizumab (open diamonds), 2 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (open triangles), or 4 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (closed triangles), with a tumor size cutoff of 500 mm 3 .

[0041] Figure 2A -C is a series of graphs showing the antitumor activity of the combination of tesotumomab vedotin and bevacizumab in a cervical cancer xenograft mouse model. Figure 2A: Mean tumor size in mice after treatment with 0.5 mg / kg IgG1 control (open circles), 1 mg / kg IgG1-MMAE control (closed circles), 0.5 mg / kg tesotumab vedotin (open squares), 1 mg / kg tesotumab vedotin (closed squares), 15 mg / kg bevacizumab (open diamonds), 2 mg / kg tesotumab vedotin combined with 15 mg / kg bevacizumab (open triangles), or 1 mg / kg tesotumab vedotin combined with 15 mg / kg bevacizumab (closed triangles). Arrows indicate the date of treatment. Tumor burden was assessed by caliper measurement. Error bars indicate the standard deviation of the mean. Figure 2B : Average tumor size in mice 14 days after first treatment with 1 mg / kg IgG1 control (open circles), 1 mg / kg IgG1-MMAE control (closed circles), 0.5 mg / kg tesotumab vedotin (open squares), 1 mg / kg tesotumab vedotin (closed squares), 15 mg / kg bevacizumab (open diamonds), 0.5 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (open triangles), or 1 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (closed triangles). Figure 2C : Percent progression-free survival in mice treated with 1 mg / kg IgG1 control (open circles), 1 mg / kg IgG1-MMAE control (closed circles), 0.5 mg / kg tesotumab vedotin (open squares), 1 mg / kg tesotumab vedotin (closed squares), 15 mg / kg bevacizumab (open diamonds), 0.5 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (open triangles), or 1 mg / kg tesotumab vedotin plus 15 mg / kg bevacizumab (closed triangles), with a tumor size cutoff of 1,000 mm 3 . DETAILED DESCRIPTION

[0042] I. Definitions

[0043] 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.

[0044] 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).

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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 that are naturally expressed by cells or expressed on cells transfected with a tissue factor gene. In some embodiments, the tissue factor comprises the amino acid sequence present in Genbank Accession No. NP_001984.

[0049] 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 chains interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Basic Immunology.

[0050] (Fundamental Immunology) Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, New York (1989)). Briefly, 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 H 2 and C H 3. The heavy chains are usually linked to each other by disulfide bonds in the so-called "hinge region". Each light chain usually 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 . CL can be a kappa or lambda isotype. The terms "constant domain" and "constant region" are used interchangeably herein. 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.

[0051] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. H and V L) can be further subdivided into hypervariable regions (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). The terms "complementarity determining region" and "CDR", which are synonymous with "hypervariable region" or "HVR", are known in the art and refer to non-contiguous sequences of amino acids within an antibody variable region that confer antigen specificity and / or binding affinity. Typically, there are three CDRs (CDR-H1, CDR-H2, CDR-H3) for each heavy chain variable region, and three CDRs (CDR-L1, CDR-L2, CDR-L3) for each light chain variable region. "Framework region" and "FR" are known in the art and refer to the non-CDR portions of the heavy and light chain variable regions. Typically, there are four FRs (FR-H1, FR-H2, FR-H3, and FR-H4) in each full-length heavy chain variable region, and four FRs (FR-L1, FR-L2, FR-L3, and FR-L4) in each full-length light chain variable region. H and V L Within a polypeptide, the three CDRs and four FRs are typically arranged from amino-terminus to 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)).

[0052] In the context of the present invention, the term "antibody" (Ab) refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or any derivative thereof, which has the ability to specifically bind to an antigen under typical physiological conditions, and has a long half-life, such as 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, or any other relevant functionally defined time period (such as a time sufficient to induce, promote, enhance and / or regulate a physiological response associated with the binding of the antibody to the antigen and / or a time 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. The antibody may be a bispecific antibody, a diabody, a multispecific antibody or a similar molecule.

[0053] The term "monoclonal antibody" as used herein refers to the preparation of antibody molecules produced recombinantly with a single primary amino acid sequence. Monoclonal antibody compositions display a single binding specificity and affinity for a specific epitope. Therefore, the term "human monoclonal antibody" refers to an antibody that exhibits a single binding specificity, which has a variable region and a constant region derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by hybridomas, which include B cells obtained from transgenic or transchromosomal non-human animals such as transgenic mice having a genome comprising a human heavy chain transgene and a light chain transgene, fused with immortalized cells.

[0054] 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 isolated antibody includes an antibody conjugate linked to another agent (e.g., a small molecule drug). In some embodiments, the isolated anti-TF antibody includes a conjugate of an anti-TF antibody and a small molecule drug (e.g., MMAE or MMAF).

[0055] "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.

[0056] The term "humanized antibody" as used herein refers to a genetically engineered non-human antibody comprising a human antibody constant domain and a non-human variable domain modified to comprise a high level of sequence homology with a human variable domain. This can be achieved by transplanting 6 non-human antibody complementary determining regions (CDRs) (which together form an antigen binding site) onto a homologous human receptor framework region (FR) (see WO92 / 22653 and EP0629240). In order to fully rebuild the binding affinity and specificity of the parent antibody, it may be necessary to replace the framework residues from the parent antibody (i.e., non-human antibody) with human framework regions (reverse mutations). Structural homology modeling can help identify amino acid residues in the framework region that are important for the binding properties of antibodies. Therefore, a humanized antibody can comprise a non-human CDR sequence, mainly a human framework region, optionally comprising one or more amino acid reverse mutations to a non-human amino acid sequence, and a completely human constant region. Optionally, other amino acid modifications (not necessarily reverse mutations) can be applied to obtain a humanized antibody with preferred properties (such as affinity and biochemical properties).

[0057] The term "chimeric antibody" as used herein refers to an antibody in which the variable region is derived from a non-human species (e.g., derived from a rodent) and the constant region is derived from a different species, such as humans. Chimeric antibodies can be produced by antibody engineering. "Antibody engineering" is a general term for antibody modification of different types, and is a method well known to those skilled in the art. Specifically, chimeric antibodies can be generated by using standard DNA techniques as described in Sambrook et al., 1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Chapter 15. Therefore, chimeric antibodies can be genetically or enzyme-engineered recombinant antibodies. Producing chimeric antibodies is within the knowledge of those skilled in the art, and therefore, chimeric antibodies according to the present invention can be produced by other methods except as described herein. Chimeric monoclonal antibodies for therapeutic applications have been developed to reduce antibody immunogenicity. They generally contain non-human (e.g., mouse) variable regions specific for the antigen of interest, and human constant antibody heavy and light chain domains. The term "variable region" or "variable domain" used in the context of chimeric antibodies refers to the region comprising the immunoglobulin heavy and light chain CDRs and framework regions.

[0058] "Anti-antigen antibody" refers to an antibody that can bind to an antigen. For example, an anti-TF antibody is an antibody that can bind to the antigen TF. In another example, an anti-VEGF antibody is an antibody that binds to the antigen VEGF.

[0059] 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 (such as scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, whose name reflects its ability to crystallize readily. Pepsin treatment produces an F(ab') 2 Fragments that have two antigen-binding sites and are still able to cross-link antigen.

[0060] "Percentage (%) of sequence identity relative to a reference peptide sequence" is defined as: the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a reference polypeptide sequence after the sequences are aligned and a gap is introduced (if necessary) to achieve the maximum percentage of sequence identity, and any conservative substitutions are not considered as part of the sequence identity. Alignment for the purpose of determining the percentage of amino acid sequence identity can be achieved in different ways within the technical scope of the art, for example, using computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software available from public channels. Those skilled in the art can determine suitable parameters for aligning sequences, including any algorithm required for achieving full-length maximum alignment of the sequences being compared. For example, the % sequence identity of a given amino acid sequence A with, and or for a given amino acid sequence B (which can also be alternatively expressed as a given amino acid sequence A having or comprising a specific sequence identity % with, and or for a given amino acid sequence B) is calculated as follows:

[0061] 100 times the fraction X / Y

[0062] wherein X is the number of amino acid residues that are scored as being matched by sequence identity in the program's alignment of A and B, and wherein Y is the total number of amino acid residues in B. It will be understood that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity of A to B will not be equal to the % sequence identity of B to A.

[0063] As used herein, the terms "bind", "engage", or "specifically bind" in the context of antibody binding to a predetermined antigen generally refer to binding with an affinity corresponding to about 10 -6 M or less, for example, 10-7 M or smaller, such as about 10 -8 M or smaller, such as about 10 -9 M or smaller, about 10 -10 M or smaller, or about 10 -11 M or smaller K D , and wherein the affinity of the antibody for binding to a predetermined antigen corresponds to such a K D , the K D The K of the antibody binding to nonspecific antigens (e.g., BSA, casein) other than the intended antigen or closely related antigens. D At least ten times lower, such as at least 100 times lower, for example at least 1,000 times lower, such as at least 10,000 times lower, for example at least 100,000 times lower. D The lower amount depends on the K of the antibody. D Therefore, when the antibody K D When the K of antigen binding is very low, D Lower than the K for binding to nonspecific antigen D The amount can be at least 10,000-fold (ie, the antibody is highly specific).

[0064] The term "K D "(M)" refers to the dissociation equilibrium constant for a particular antibody-antigen interaction. As used herein, affinity and K D Inversely proportional, that is, higher affinity is intended to indicate a lower K D , while lower affinity is intended to indicate a higher K D .

[0065] 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 a drug moiety as described in this application (eg, MMAE or MMAF).

[0066] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0067] The abbreviation "PAB" refers to a self-immolative spacer group:

[0068]

[0069] The abbreviation "MC" refers to the extending group maleimidocaproyl:

[0070]

[0071] The term "Ab-MC-vc-PAB-MMAE" refers to an antibody conjugated to the drug MMAE via a MC-vc-PAB linker.

[0072] "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 "derived from" cervical cancer refers to a tumor that is a result of cervical cancer that has metastasized.

[0073] "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.

[0074] "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.

[0075] An "effective amount" or "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of disease or promotes 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.

[0076] For example, for the treatment of tumors, a therapeutically effective amount of an anticancer agent inhibits at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 98%, at least about 99% cell growth or tumor growth in a treated subject (e.g., one or more treated subjects) relative to an untreated subject (e.g., one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anticancer agent inhibits 100% cell growth or tumor growth in a treated subject (e.g., one or more treated subjects).

[0077] In other embodiments of the disclosure, tumor regression may be observed and persist 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.

[0078] A therapeutically effective amount of a drug (e.g., an anti-TF antibody-drug conjugate or an anti-VEGF antibody) 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.

[0079] As used herein, a "subtherapeutic dose" is a dose of a therapeutic compound (e.g., an anti-TF antibody-drug conjugate or an anti-VEGF antibody) that is lower than the conventional or typical dose of the therapeutic compound when administered alone to treat a hyperproliferative disease (e.g., cancer).

[0080] "Immune-related response pattern" refers to a clinical response pattern often observed in cancer patients treated with immunotherapeutics, which produce anti-tumor effects by inducing cancer-specific immune responses or by modifying natural immune processes. This response pattern is characterized by a beneficial therapeutic effect followed by an initial increase in tumor burden or the appearance of new lesions, which would be classified as disease progression and would be synonymous with drug failure when evaluating traditional chemotherapeutics. Therefore, proper evaluation of immunotherapeutics may require long-term monitoring of the effects of these therapeutics on the target disease.

[0081] 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.

[0082] "Sustained remission" 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 the size at the beginning of the dosing period. In some embodiments, the duration of sustained remission is at least the same as the duration of treatment, or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

[0083] As used herein, "complete response" or "CR" means the disappearance of all target lesions; "partial response" or "PR" means that the sum of the longest diameters of the target lesions (SLD) is reduced by at least 30% with the baseline SLD as a reference; "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 with the smallest SLD since the start of treatment as a reference.

[0084] 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 remission or partial remission, as well as the time a patient experiences stable disease.

[0085] As used herein, "overall response rate" or "ORR" refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0086] 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.

[0087] The term "weight-based dose" as used herein refers to a dose administered to a subject that is calculated based on the subject's weight. For example, when a subject weighing 60 kg requires 2.0 mg / kg of an anti-VEGF antibody or anti-TF antibody-drug conjugate, one can calculate and use an appropriate amount of anti-VEGF antibody or anti-TF antibody-drug conjugate (i.e., 120 mg) for administration to the subject.

[0088] The term "fixed dose" as used in connection with the methods of the present disclosure refers to administering two or more different antibodies (e.g., an anti-VEGF antibody and an anti-TF antibody-drug conjugate) to a subject in a specific (fixed) ratio relative to one another. In some embodiments, the fixed dose is based on the amount of antibody (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (e.g., mg / ml). For example, administering a 3:1 ratio of anti-VEGF antibody to anti-TF antibody-drug conjugate to a subject can mean administering about 240 mg of anti-VEGF antibody and about 80 mg of anti-TF antibody-drug conjugate or about 3 mg / ml of anti-VEGF antibody and about 1 mg / ml of anti-TF antibody-drug conjugate to a subject.

[0089] The term "flat dose" as used with respect to the methods and doses of the present disclosure refers to the dose that is administered to a subject regardless of the subject'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 and / or an anti-VEGF antibody). For example, a subject weighing 60 kg and a subject weighing 100 kg would receive the same dose of antibody or antibody-drug conjugate (e.g., 240 mg anti-TF antibody-drug conjugate or, for example, 240 mg anti-VEGF antibody).

[0090] 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.

[0091] 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.

[0092] "Administering" or "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 anti-TF antibody-drug conjugates and / or anti-VEGF antibodies 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 a non-parenteral route 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.

[0093] The terms "baseline" or "baseline value", used interchangeably herein, may refer to a measurement or characterization of a symptom prior to administration of a therapy (e.g., an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody 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 a symptom of a TF-related disease and / or a VEGF-related disease (e.g., cervical cancer) contemplated herein. The terms "reference" or "reference value", used interchangeably herein, may refer to a measurement or characterization of a symptom after administration of a therapy (e.g., an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody 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 having 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 baseline value.

[0094] 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).

[0095] As used herein, the term "monotherapy" means that the anti-TF antibody-drug conjugate or anti-VEGF antibody is the only anti-cancer 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.

[0096] 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.

[0097] As used herein, a “serious adverse event” or “SAE” is an adverse event that meets one of the following criteria:

[0098] 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 serious.

[0099] · Causes persistent or severe disability / incapacity

[0100] Constitutes a congenital anomaly / birth defect

[0101] Is medically significant, 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 significant”

[0102] · The need for hospitalization or prolongation of an existing hospitalization, except for the following: 1) routine treatment or monitoring of the underlying disease, not accompanied by any worsening of the disease; 2) elective or pre-planned treatment of a pre-existing condition that is not related to the indication for the study and has not worsened since the signing of the informed consent, and 3) social reasons and suspension of care in the absence of any worsening of the patient's general condition.

[0103] 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.

[0104] 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.

[0105] As used herein, the terms "about once a week", "about once every two 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. In some embodiments, a dosing interval of about once every six weeks or about once every twelve weeks means that the first dose can be given on any day of the first week, and then the next dose can be given on any day of the sixth week or the twelfth week, respectively. In other embodiments, a dosing interval of about once every six weeks or about once every twelve weeks means that the first dose is given on a specific day (e.g., Monday) of the first week, and then the next dose is given on the same day (i.e., Monday) of the sixth week or the twelfth week, respectively.

[0106] 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.

[0107] Various aspects of the disclosure are described in further detail in the following subsections.

[0108] II. Combination Therapy

[0109] One aspect of the present invention provides an anti-TF antibody-drug conjugate that binds to TF for use in the treatment of cervical cancer, wherein the antibody-drug conjugate is or will be administered in combination with an anti-VEGF antibody or an antigen-binding fragment thereof, 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.

[0110] In some embodiments, the anti-TF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of tisotumab or a biosimilar thereof. In some embodiments, the anti-TF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of tisotumab. In some embodiments, the anti-TF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of tisotumab or a biosimilar thereof.

[0111] In some embodiments, the anti-TF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of tisotumab. In some embodiments, the anti-TF antibody is tisotumab. In some embodiments, the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the complementarity determining region (CDR) of bevacizumab or a biosimilar thereof.

[0112] In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a complementarity determining region (CDR) of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody is bevacizumab. In some embodiments, the cervical cancer is advanced cervical cancer (e.g., 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.

[0113] In another aspect, the present invention provides an anti-VEGF antibody or an antigen-binding fragment thereof for the treatment of cervical cancer, wherein the anti-VEGF antibody or an antigen-binding fragment thereof is administered or will be administered in combination with an antibody-drug conjugate that binds to TF, wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof coupled to monomethyl auristatin or a functional analog or functional derivative thereof. In some embodiments, the anti-TF antibody or an antigen-binding fragment thereof comprises the complementary determining regions (CDRs) of tisotumab or a biosimilar thereof. In some embodiments, the anti-TF antibody or an antigen-binding fragment thereof comprises the complementary determining regions (CDRs) of tisotumab. In some embodiments, the anti-TF antibody or an antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of tisotumab or a biosimilar thereof. In some embodiments, the anti-TF antibody or an antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of tisotumab. In some embodiments, the anti-TF antibody is tisotumab. In some embodiments, the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a complementary determining region (CDR) of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a complementary determining region (CDR) of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody is bevacizumab. In some embodiments, the cervical cancer is advanced cervical cancer (e.g., stage 3 cervical cancer or stage 4 cervical cancer or metastatic cervical cancer). In some embodiments, advanced cervical cancer is metastatic cancer. In some embodiments, the subject has recurrent, recurrent and / or metastatic cervical cancer.

[0114] A. Anti-TF antibodies

[0115] Typically, the anti-TF antibodies of the present disclosure bind to TF (e.g., human TF) and exert cytostatic and cytotoxic effects on malignant cells such as cervical cancer cells. The anti-TF 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. In some embodiments, the anti-TF antibodies of the present disclosure specifically bind to TF. 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.

[0116] In certain embodiments of the present disclosure, the anti-TF antibody is an antigen-binding fragment (e.g., a human antigen-binding fragment) described herein and includes, but is not limited to, Fab, Fab', and F(ab'). 2 , Fd, single-chain Fv (scFv), single-chain antibody, disulfide-linked Fv (sdFv) and V L or V H The antigen-binding fragment, including the single-chain antibody, 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. In some embodiments, the anti-TF antibody or antigen-binding fragment thereof is human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camelid, horse or chicken.

[0117] The anti-TF 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: 1547 1553.

[0118] The anti-TF antibodies of the present disclosure may be described or designated according to the specific CDRs they contain. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of known schemes, including Kabat et al., (1991), Sequences of Proteins of Immunological Interest, 5th ed., National Institutes of Health, 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); 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.

[0119] 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.

[0120] 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 binds to TF. In some embodiments, the antibody or derivative thereof specifically binds to TF. In certain embodiments, the anti-TF antibody is 011. Antibody 011 is also known as tisotumab.

[0121] In one aspect, anti-TF antibodies that compete with tesotumomab for binding to TF are also provided herein. Anti-TF antibodies that bind to the same epitope as tesotumomab are also provided herein.

[0122] In one aspect, provided herein is an anti-TF antibody comprising 1, 2, 3, 4, 5 or 6 CDR sequences of tesotumomab.

[0123] 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.

[0124] 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 (e.g., 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).

[0125] In some embodiments of the anti-TF antibodies described herein, the heavy chain variable domain comprises the amino acid sequence:

[0126] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSSISGSGDYTYYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSPWGYYLDSWGQGTLVTVSS (SEQ ID NO: 7), and the light chain variable domain comprises the amino acid sequence:

[0127] DIQMTQSPPSLSASAGDRVTITCRASQGISSRLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO: 8).

[0128] In some embodiments of the anti-TF antibodies described herein, the heavy chain CDR sequence comprises the following:

[0129] a) CDR-H1 (GTFFSNYA (SEQ ID NO: 1));

[0130] b) CDR-H2(ISGSGDYT(SEQ ID NO:2)); and

[0131] c) CDR-H3 (ARSPWGYYLDS (SEQ ID NO: 3)).

[0132] In some embodiments of the anti-TF antibodies described herein, the heavy chain FR sequence comprises the following:

[0133] a) HC-FR1(EVQLLESGGGLVQPGGSLRLSCAAS(SEQ ID NO:9));

[0134] b) HC-FR2 (MSWVRQAPGKGLEWVSS (SEQ ID NO: 10));

[0135] c) HC-FR3(YYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC(SEQ ID NO:11)); and

[0136] d) HC-FR4 (WGQGTLVTVSS (SEQ ID NO: 12)).

[0137] In some embodiments of the anti-TF antibodies described herein, the light chain CDR sequence comprises the following:

[0138] a) CDR-L1 (QGISSR (SEQ ID NO: 4));

[0139] b) CDR-L2 (AAS (SEQ ID NO: 5)); and

[0140] c) CDR-L3 (QQYNSYPYT (SEQ ID NO: 6)).

[0141] In some embodiments of the anti-TF antibodies described herein, the light chain FR sequence comprises the following:

[0142] a) LC-FR1(DIQMTQSPPSLSASAGDRVTITCRAS(SEQ ID NO:13));

[0143] b) LC-FR2(LAWYQQKPEKAPKSLIY(SEQ ID NO:14));

[0144] c) LC-FR3(SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:15)); and

[0145] d)LC-FR4(FGQGTKLEIK(SEQ ID NO:16)).

[0146] In some embodiments, provided herein is an anti-TF antibody that binds to TF (e.g., human TF), wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody comprises:

[0147] (a) a heavy chain variable domain comprising:

[0148] (1) HC-FR1 comprising the amino acid sequence of SEQ ID NO: 9;

[0149] (2) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0150] (3) HC-FR2 comprising the amino acid sequence of SEQ ID NO: 10;

[0151] (4) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2;

[0152] (5) HC-FR3 comprising the amino acid sequence of SEQ ID NO: 11;

[0153] (6) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0154] (7) HC-FR4 comprising the amino acid sequence of SEQ ID NO: 12;

[0155] and / or

[0156] (b) a light chain variable domain comprising:

[0157] (1) LC-FR1 comprising the amino acid sequence of SEQ ID NO: 13;

[0158] (2) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0159] (3) LC-FR2 comprising the amino acid sequence of SEQ ID NO: 14;

[0160] (4) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5;

[0161] (5) LC-FR3 comprising the amino acid sequence of SEQ ID NO: 15;

[0162] (6) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and

[0163] (7) LC-FR4 comprising the amino acid sequence of SEQ ID NO: 16;

[0164] 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.

[0165] 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 (e.g., conservative substitutions), insertions or deletions relative to the reference sequence and retains the ability to bind to TF (e.g., human TF). In certain embodiments, a total of 1 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 (i.e., 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.

[0166] 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 (e.g., conservative substitutions), insertions or deletions relative to the reference sequence and retains the ability to bind to TF (e.g., human TF). In certain embodiments, a total of 1 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 (i.e., 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.

[0167] 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.

[0168] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate comprises: i) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and ii) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody are defined by the IMGT numbering scheme.

[0169] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate comprises: i) an amino acid sequence having at least 85% sequence identity to a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and ii) an amino acid sequence having at least 85% sequence identity to a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0170] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate is a monoclonal antibody.

[0171] 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.

[0172] The anti-TF antibodies of the invention may also be described or specified in terms of their binding affinity for TF (e.g., human TF). Preferred binding affinities include dissociation constants or Kd of 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.

[0173] There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subclasses, for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in a variety of polymorphic variants called allotypes (reviewed in Jefferis and Lefranc 2009mAbsVol1Issue 4 1-7), any of which are suitable for use in some embodiments herein. Common allotype variants in the population are variants marked 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.

[0174] 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.

[0175] B. Antibody-drug conjugate structure

[0176] 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.

[0177] 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:

[0178] a)MC is:

[0179]

[0180] b) vc is the dipeptide valine-citrulline, and

[0181] c) PAB is:

[0182]

[0183] 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:

[0184] a)MC is:

[0185]

[0186] 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.

[0187] 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 have been shown to interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cell division (see Woyke et al., (2001) Antimicrob. Agents and Chemother. 45(12):3580-3584) and 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 (e.g., a functional peptide thereof) or a functional derivative thereof. In some embodiments, the auristatin is monomethyl auristatin or a functional analog (eg, a functional peptide) or a functional derivative thereof.

[0188] In some embodiments, the auristatin is monomethyl auristatin E (MMAE):

[0189] The wavy line indicates the linker attachment site.

[0190] In some embodiments, the auristatin is monomethyl auristatin F (MMAF):

[0191]

[0192] The wavy line indicates the linker attachment site.

[0193] In one embodiment, the cleavable peptide linker has the formula: MC-vc-PAB-, and is linked to MMAE. The resulting linker-auritin 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:

[0194]

[0195] Wherein, p represents a number from 1 to 8, for example, 1, 2, 3, 4, 5, 6, 7 or 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 a weighted average of the drug to antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0196] In one embodiment, the cleavable peptide linker has the formula: MC-vc-PAB- and is linked to MMAF. The resulting linker-auritasin 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-auritasin 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:

[0197]

[0198] or

[0199]

[0200] Wherein, p represents a number from 1 to 8, for example, 1, 2, 3, 4, 5, 6, 7 or 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, 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 a weighted average of the drug to antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0201] In one embodiment, the antibody-drug conjugate is tesotumomab vedotin.

[0202] C. Anti-VEGF Antibody

[0203] Typically, the anti-VEGF antibodies or antigen-binding fragments thereof of the present disclosure bind to VEGF, e.g., human VEGF. In some embodiments, the anti-VEGF antibodies or antigen-binding fragments thereof comprise the complementarity determining regions (CDRs) of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibodies or antigen-binding fragments thereof comprise the complementarity determining regions (CDRs) of bevacizumab. In some embodiments, the anti-VEGF antibodies or antigen-binding fragments thereof comprise the heavy chain variable region and the light chain variable region of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibodies or antigen-binding fragments thereof comprise the heavy chain variable region and the light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody is bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0204] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0205] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0206] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0207] Wherein the light chain variable region comprises:

[0208] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0209] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0210] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are depicted using the Kabat numbering scheme (Kabat, EA, et al. (1991) Popular Protein Sequences in Immunology, 5th ed., U.S. Department of Health and Human Services, NTH Publication No. 91-3242).

[0211] The anti-VEGF 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 VEGF binding fragments of any of the above. In some embodiments, the anti-VEGF antibodies described herein specifically bind to VEGF (e.g., human VEGF). The immunoglobulin molecules of the present disclosure may be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass.

[0212] In certain embodiments of the present disclosure, the antibodies are antigen-binding fragments described herein (e.g., human antigen-binding fragments) and include, but are not limited to, Fab, Fab', and F(ab'). 2 , Fd, single-chain Fv (scFv), single-chain antibody, disulfide-linked Fv (sdFv) and V L or V H Fragments of domains. 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. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camelid, horse, or chicken.

[0213] The anti-VEGF antibodies disclosed herein can be monospecific, bispecific, trispecific, or more multispecific. Multispecific antibodies can be specific for different epitopes of VEGF, or specific for both VEGF 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: 1547 1553.

[0214] The anti-VEGF antibodies of the present disclosure may be described or designated according to the specific CDRs they contain. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of known schemes, including Kabat et al., (1991), Sequences of Proteins of Immunological Interest, 5th ed., National Institutes of Health, 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., (1998) JMB 273, 927-948 ("Chothia" 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.

[0215] In some embodiments, the anti-VEGF antibody molecules of the present disclosure comprise the CDRs of the antibody bevacizumab, also referred to as A4.6.1. See U.S. Patent No. 6,884,879. In some embodiments, the CDRs of the antibody bevacizumab are depicted using the Kabat numbering scheme (Kabat, EA, et al. (1991) Popular Protein Sequences in Immunology, 5th Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242). The present disclosure encompasses anti-VEGF antibodies or derivatives thereof comprising a heavy chain or light chain variable domain, the variable domain comprising: (a) a set of three CDRs, wherein the CDR set is from the monoclonal antibody bevacizumab, and (b) a set of four framework regions, wherein the framework region set is different from the framework region set in the monoclonal antibody bevacizumab, and wherein the anti-VEGF antibody or derivative thereof binds to VEGF. In certain embodiments, the anti-VEGF antibody is bevacizumab. The antibody bevacizumab is also referred to as

[0216] In one aspect, provided herein is an anti-VEGF 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: 17, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and wherein the light chain variable region comprises: (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0217] In one embodiment, an anti-VEGF 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: 27 (LC-FR1), SEQ ID NO: 28 (LC-FR2), SEQ ID NO: 29 (LC-FR3), and SEQ ID NO: 30 (LC-FR4), respectively; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 20; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 21; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0218] In some embodiments of the anti-VEGF antibodies described herein, the heavy chain variable domain comprises the amino acid sequence:

[0219] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS (SEQ ID NO: 31), and the light chain variable domain comprises the amino acid sequence:

[0220] DIQMTQSPSSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKR (SEQ ID NO: 32).

[0221] In some embodiments of the anti-VEGF antibodies described herein, the heavy chain CDR sequence comprises the following:

[0222] a) CDR-H1 (GYTFTNYGMN (SEQ ID NO: 17));

[0223] b) CDR-H2 (WINTYTGEPTYAADFKR (SEQ ID NO: 18)); and

[0224] c) CDR-H3 (YPHYYGSSHWYFDV (SEQ ID NO: 19)). In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0225] In some embodiments of the anti-VEGF antibodies described herein, the heavy chain FR sequence comprises the following:

[0226] a) HC-FR1 (EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 23));

[0227] b) HC-FR2 (WVRQAPGKGLEWVG (SEQ ID NO: 24));

[0228] c) HC-FR3 (RFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAK (SEQ ID NO: 25)); and

[0229] d) HC-FR4 (WGQGTLVTVSS (SEQ ID NO: 26)).

[0230] In some embodiments of the anti-VEGF antibodies described herein, the light chain CDR sequence comprises the following:

[0231] a) CDR-L1(SASQDISNYLN(SEQ ID NO:20));

[0232] b) CDR-L2 (FTSSLHS (SEQ ID NO: 21)); and

[0233] c) CDR-L3 (QQYSTVPWT (SEQ ID NO: 22)). In some embodiments, the CDRs of an anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0234] In some embodiments of the anti-VEGF antibodies described herein, the light chain FR sequence comprises the following:

[0235] a) LC-FR1(DIQMTQSPSSLSSASVGDRVTITC(SEQ ID NO:27));

[0236] b) LC-FR2(WYQQKPGKAPKVLIY(SEQ ID NO:28));

[0237] c) LC-FR3 (GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 29)); and

[0238] d) LC-FR4 (FGQGTKVEIKR (SEQ ID NO:30)).

[0239] In some embodiments, provided herein is an anti-VEGF antibody that binds to VEGF (e.g., human VEGF), wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody comprises:

[0240] (a) a heavy chain variable domain comprising:

[0241] (1) HC-FR1 comprising the amino acid sequence of SEQ ID NO: 23;

[0242] (2) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0243] (3) HC-FR2 comprising the amino acid sequence of SEQ ID NO: 24;

[0244] (4) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18;

[0245] (5) HC-FR3 comprising the amino acid sequence of SEQ ID NO: 25;

[0246] (6) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0247] (7) HC-FR4 comprising the amino acid sequence of SEQ ID NO: 26;

[0248] and / or

[0249] (b) a light chain variable domain comprising:

[0250] (1) LC-FR1 comprising the amino acid sequence of SEQ ID NO: 27;

[0251] (2) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0252] (3) LC-FR2 comprising the amino acid sequence of SEQ ID NO: 28;

[0253] (4) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21;

[0254] (5) LC-FR3 comprising the amino acid sequence of SEQ ID NO: 29;

[0255] (6) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22; and

[0256] (7) LC-FR4 comprising the amino acid sequence of SEQ ID NO: 30; In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0257] In one aspect, provided herein is an anti-VEGF antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, or a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32. In one aspect, provided herein is an anti-VEGF antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32.

[0258] In some embodiments, provided herein are anti-VEGF 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: 31. 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: 31 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and retains the ability to bind to VEGF (e.g., human VEGF). In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 31. 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 (i.e., in the FR). In some embodiments, the anti-VEGF antibody comprises a heavy chain variable domain sequence of SEQ ID NO: 31, 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: 17, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0259] In some embodiments, provided herein are anti-VEGF 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: 32. 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: 32 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and retains the ability to bind to VEGF (e.g., human VEGF). In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 32. 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-VEGF antibody comprises a light chain variable domain sequence of SEQ ID NO: 32, 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: 20, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0260] In some embodiments, the anti-VEGF 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: 31 and the light chain variable domain sequence of SEQ ID NO: 32, including post-translational modifications of these sequences.

[0261] In some embodiments, the anti-VEGF antibody comprises: i) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and ii) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme.

[0262] In some embodiments, the anti-VEGF antibody comprises: i) an amino acid sequence having at least 85% sequence identity to a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:31, and ii) an amino acid sequence having at least 85% sequence identity to a light chain variable region comprising the amino acid sequence of SEQ ID NO:32.

[0263] In some embodiments of the anti-VEGF antibodies described herein, the heavy chain comprises the amino acid sequence:

[0264] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:33), while the light chain contains the amino acid sequence:

[0265] DIQMTQSPSSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:34).

[0266] In some embodiments, the anti-VEGF antibody is a monoclonal antibody.

[0267] In some embodiments, the anti-VEGF antibody is bevacizumab, which is also known as and antibody A.4.6.1 as described in U.S. Pat. No. 6,884,879 and Presta et al., Cancer Res., 1997, 57:4593-4599.

[0268] In some embodiments, the anti-VEGF antibody is a biosimilar of bevacizumab. In some embodiments, the biosimilar of bevacizumab is selected from the following group: bevacizumab-awwb (Amgen, USA), bevacizumab-bvzr (Pfizer, USA), FKB238 (AstraZeneca, USA / Fujifilm Kyowa Kirin Biologics, Japan), BCD-021 (Biocad, Russia), BCD500 (BIOCND, South Korea), Krabeva (Biocon, India), BI 695502 (Boehringer Ingelheim, Germany), CT-P16 (Celltrion, South Korea), CHS-5217 (Coherus, USA), DRZ_BZ (Dr Reddy's Laboratories, India), (India Hetero (Lupin), Bevax (Spain mAbxience), ONS-1045 (US Oncobiologics / Viropro), PF-06439535 (US Pfizer), HD204 (Singapore Prestige Biopharma), Bevacirel (India Information Biosciences (Reliance Life Sciences) / Lupin), and SB8 (Korea Samsung Bioepis (Biogen / Samsung / Merck). In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel and SB8. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax and Bevacirel. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax and Bevacirel. Bevacizumab-awwb is also known as and ABP215. Bevacizumab-BVZR is also known as

[0269] The anti-VEGF antibodies of the invention may also be described or specified in terms of their binding affinity for VEGF (e.g., human VEGF). Preferred binding affinities include dissociation constants or Kd of 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.

[0270] There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subclasses, for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in a variety of polymorphic variants called allotypes (reviewed in Jefferis and Lefranc 2009mAbsVol1Issue 4 1-7), any of which are suitable for use in some embodiments herein. Common allotype variants in the population are variants marked 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.

[0271] The antibodies also include modified derivatives, i.e., by covalently attaching any type of molecule to the antibody, such that the covalent attachment does not prevent the antibody from binding to VEGF. For example, but not limited to, antibody derivatives include antibodies that have been modified, such as by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, attachment to cellular ligands or other proteins, etc. Any of a variety of chemical modifications can be performed by known techniques, including but not limited to: specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. In addition, the derivatives may contain one or more non-classical amino acids.

[0272] D. Nucleic Acids, Host Cells and Production Methods

[0273] In some aspects, nucleic acids encoding the anti-TF antibodies or antigen-binding fragments thereof described herein or the anti-VEGF antibodies or antigen-binding fragments thereof described herein are also provided herein. Vectors comprising nucleic acids encoding the anti-TF antibodies or antigen-binding fragments thereof described herein or the anti-VEGF antibodies or antigen-binding fragments thereof described herein are also provided herein. Host cells expressing nucleic acids encoding the anti-TF antibodies or antigen-binding fragments thereof described herein or the anti-VEGF antibodies or antigen-binding fragments thereof described herein are also provided herein. Host cells comprising vectors comprising nucleic acids encoding the anti-TF antibodies or antigen-binding fragments thereof described herein or the anti-VEGF antibodies or antigen-binding fragments thereof described herein are also provided herein. Methods for producing anti-TF antibodies, linkers, and anti-TF antibody-drug conjugates are described in U.S. Pat. No. 9,168,314.

[0274] The anti-TF antibodies described herein or the anti-VEGF 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 De la Cruz Edmunds et al., 2006, Molecular Biotechnology 34; 179-190, EP216846, U.S. Pat. No. 5,981,216, WO 87 / 04462, EP323997, U.S. Pat. No. 5,591,639, U.S. Pat. No. 5,658,759, EP338841, U.S. Pat. No. 5,879,936, and U.S. Pat. No. 5,891,693.

[0275] After the anti-TF 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.

[0276] The monoclonal anti-TF antibodies described herein or the anti-VEGF antibodies described herein can be produced, for example, by the hybridoma method first described by Kohler et al., Nature, 256, 495 (1975), or can be produced 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 (3): 581-597 (1991). Monoclonal antibodies can be obtained from any suitable source. Thus, for example, monoclonal antibodies can be obtained from hybridomas prepared from murine splenic B cells obtained from mice immunized with an antigen of interest, for example, in the form of cells expressing the antigen on their 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 (e.g., rats, dogs, primates, etc.).

[0277] In one embodiment, the antibodies of the invention (e.g., anti-TF antibodies or anti-VEGF antibodies) are human antibodies. Human monoclonal antibodies against TF or VEGF can be generated using transgenic or transchromosomal mice that carry a portion of the human immune system rather than the mouse system. 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."

[0278] 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.

[0279] The HCo7 mouse has a JKD disruption in its endogenous light chain (κ) 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 κ 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).

[0280] The HCo12 mouse has a JKD disruption in its endogenous light chain (κ) 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 κ light chain transgene (as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)), and an HCo12 human heavy chain transgene (as described in Example 2 of WO 01 / 14424).

[0281] The HCo17 transgenic mouse strain (see also US 2010 / 0077497) was generated by co-injection of an 80 kb insert of pHC2 (Taylor et al., (1994) Int. Immunol., 6:579-591), a Kb insert of pVX6, and a -460 kb yeast artificial chromosome fragment of the yIgH24 chromosome. This strain was designated (HCo17) 25950. The (HCo17) 25950 line was then bred with mice containing the CMD mutation (described in Example 1 of PCT Publication WO 01109187), the JKD mutation (Chen et al., (1993) EMBO J. 12:811-820), and the (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.

[0282] 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) line was then bred with mice containing the CMD mutation (described in Example 1 of PCT Publication WO 01 / 09187), the JKD mutation (Chen et al., (1993) EMBO J. 12:811-820), and the (KCO5)9272 transgene (Fishwild et al., (1996) Nature Biotechnology, 14:845-851). The resulting mice express the 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.

[0283] 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.

[0284] In the KM mouse strain, the endogenous mouse κ 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 κ 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.

[0285] 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.

[0286] In addition, human antibodies of the invention or antibodies of the invention from other species can be produced by display-type techniques using techniques well known in the art, including but not limited to phage display, retroviral display, ribosome display and other techniques, and the resulting molecules can be subjected to additional maturation, such as affinity maturation, as such techniques are well known in the art (see, e.g., Hoogenboom et al., J. Mol, Biol. 227(2):381-388 (1992) (phage display), Vaughan et al., Nature Biotech, 14:309 (1996) (phage display), Hanes and Plucthau, PNAS USA 94:4937-4942 (1997) (ribosome display), Parmley and Smith, Gene, 73:305-318 (1988) (phage display), Scott, TIBS. 17:241-245 (1992), Cwirla et al., PNAS 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.

[0287] III. Combination Tests and Other Tests

[0288] In one aspect, the antigen binding activity of the antibodies of the invention is tested, for example, by known methods such as enzyme-linked immunosorbent assay (ELISA), immunoblotting (e.g., Western blot), flow cytometry (e.g., FACS), TM), immunohistochemistry, immunofluorescence, etc.

[0289] In another aspect, competitive assays can be used to identify antibodies that compete with any of the antibodies described herein for binding to TF (e.g., tisotumab) or VEGF (e.g., bevacizumab). Cross-competing antibodies can be easily identified based on their ability to cross-compete in standard TF or VEGF binding assays such as Biacore analysis, ELISA assays, or flow cytometry (see, e.g., WO 2013 / 173223). In certain embodiments, such competing antibodies bind to the same epitope (e.g., linear or conformational epitope) as any of the antibodies disclosed herein (e.g., tisotumab or bevacizumab). A detailed description of exemplary methods for mapping epitopes bound by antibodies is provided in Morris, Methods in Molecular Biology, Vol. 66, Epitope Mapping Protocols (Humana Press, Totowa, NJ, 1996).

[0290] In an exemplary competitive assay, fixed VEGF is incubated in a solution comprising a first labeled antibody (e.g., bevacizumab) that binds to VEGF and a second unlabeled antibody to be tested for its ability to compete with the first antibody for binding to VEGF. The second antibody may be present in the hybridoma supernatant. As a control, fixed VEGF is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to VEGF, excess unbound antibody is removed and the amount of the marker associated with fixed VEGF is measured. If the amount of the marker associated with fixed VEGF in the test sample is significantly reduced relative to the control sample, this indicates that the second antibody competes with the first antibody for binding to VEGF. See, for example, Harlow et al., Antibodies: A Laboratory Manual. Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1988). In some embodiments, an anti-VEGF antibody competes with another VEGF antibody (e.g., bevacizumab) for binding to VEGF if it blocks binding of the other antibody to VEGF by more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% in a competition assay. In some embodiments, an anti-VEGF antibody does not compete with another VEGF antibody (e.g., bevacizumab) for binding to VEGF if it blocks binding of the other antibody to VEGF by less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% in a competition assay. In some embodiments, the VEGF is human VEGF.

[0291] Similar competition assays can be performed to determine whether an anti-TF antibody competes with tisotumab for binding to TF. In some embodiments, an anti-TF antibody competes with another TF antibody (e.g., tisotumab) for binding to TF if it blocks the binding of the other antibody to TF by more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% in a competition assay. In some embodiments, an anti-TF antibody does not compete with another TF antibody (e.g., tisotumab) for binding to TF if it blocks the binding of the other antibody to TF by less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% in a competition assay. In some embodiments, TF is human TF.

[0292] IV. Treatment Methods

[0293] A. Cervical cancer

[0294] 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 female cancer worldwide and the sixteenth most common cancer in the European Union. Depending on the initial stage of presentation, 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.

[0295] The present invention provides a method for treating cervical cancer in a subject using the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein. In some embodiments, the anti-TF antibody-drug conjugate comprises the complementarity determining regions (CDRs) of tisotumab vedotin or a biosimilar thereof. In some embodiments, the anti-TF antibody-drug conjugate comprises the complementarity determining regions (CDRs) of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin or a biosimilar thereof. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region, wherein the heavy chain variable region comprises:

[0296] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0297] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0298] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0299] Wherein the light chain variable region comprises:

[0300] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0301] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0302] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the CDRs of the anti-TF antibody-drug conjugate are drawn using the IMGT numbering scheme. In some embodiments, the antibody-drug conjugate is tezomib vedotin. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region, wherein the heavy chain variable region comprises:

[0303] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0304] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0305] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0306] Wherein the light chain variable region comprises:

[0307] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0308] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0309] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme. In one aspect, the anti-VEGF antibody is bevacizumab. In another aspect, the anti-VEGF antibody is a biosimilar of bevacizumab. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel, and SB8. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel, and SB8. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel. Bevacizumab-awwb is also known as and ABP215. Bevacizumab-BVZR is also known as In certain embodiments, the subject is a human.

[0310] In another aspect, the present invention provides an antibody-drug conjugate that binds TF as described herein for the treatment of cervical cancer, wherein the anti-VEGF antibody or antigen-binding fragment thereof as described herein is administered or will be administered in combination with the antibody-drug conjugate. In some embodiments, the anti-TF antibody-drug conjugate comprises the complementary determining regions (CDRs) of tisotumab vedotin or a biosimilar thereof. In some embodiments, the anti-TF antibody-drug conjugate comprises the complementary determining regions (CDRs) of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin or a biosimilar thereof. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region, wherein the heavy chain variable region comprises:

[0311] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0312] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0313] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0314] Wherein the light chain variable region comprises:

[0315] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0316] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0317] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the CDRs of the anti-TF antibody-drug conjugate are drawn using the IMGT numbering scheme. In some embodiments, the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof inhibits VEGF activity, and wherein the anti-VEGF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region, wherein the heavy chain variable region comprises:

[0318] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0319] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0320] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0321] Wherein the light chain variable region comprises:

[0322] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0323] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0324] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme. In one aspect, the anti-VEGF antibody is bevacizumab. In another aspect, the anti-VEGF antibody is a biosimilar of bevacizumab. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel, and SB8. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel, and SB8. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel. Bevacizumab-awwb is also known as and ABP 215. Bevacizumab-BVZR is also known as In certain embodiments, the subject is a human.

[0325] In another aspect, the present invention provides an anti-VEGF antibody or antigen-binding fragment thereof as described herein for use in the treatment of cervical cancer, wherein the antibody-drug conjugate that binds TF as described herein is administered or will be administered in combination with an anti-VEGF antibody. In some embodiments, the anti-TF antibody-drug conjugate comprises the complementary determining regions (CDRs) of tisotumab vedotin or a biosimilar thereof. In some embodiments, the anti-TF antibody-drug conjugate comprises the complementary determining regions (CDRs) of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin or a biosimilar thereof. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region of tisotumab vedotin. In some embodiments, the anti-TF antibody-drug conjugate comprises the heavy chain variable region and the light chain variable region, wherein the heavy chain variable region comprises:

[0326] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0327] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0328] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0329] Wherein the light chain variable region comprises:

[0330] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0331] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0332] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the CDRs of the anti-TF antibody-drug conjugate are drawn using the IMGT numbering scheme. In some embodiments, the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof inhibits VEGF activity, and wherein the anti-VEGF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab or a biosimilar thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region of bevacizumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof comprises the heavy chain variable region and the light chain variable region, wherein the heavy chain variable region comprises:

[0333] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0334] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0335] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0336] Wherein the light chain variable region comprises:

[0337] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0338] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0339] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the CDRs of the anti-VEGF antibody are drawn using the Kabat numbering scheme. In one aspect, the anti-VEGF antibody is bevacizumab. In another aspect, the anti-VEGF antibody is a biosimilar of bevacizumab. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel, and SB8. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel, and SB8. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel. In some embodiments, the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel. Bevacizumab-awwb is also known as and ABP215. Bevacizumab-BVZR is also known as In certain embodiments, the subject is a human.

[0340] In some embodiments, the subject has been previously treated with chemotherapy and / or radiation therapy. 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 a human.

[0341] In some embodiments of the methods or uses or products for use provided herein, the cervical cancer is adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, neuroendocrine tumor, glassy cell carcinoma, or vestibular gland carcinoma. In some embodiments, the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma. In some embodiments, the cervical cancer is adenocarcinoma. In some embodiments, the cervical cancer is adenocarcinoma. In some embodiments, the cervical cancer is adenosquamous carcinoma. In some embodiments, the cervical cancer is squamous cell carcinoma.

[0342] 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 from a subject express TF. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% of cervical cancer cells from a subject express TF. In some embodiments, the percentage of cells expressing TF is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing TF is determined using flow cytometry. In some embodiments, the percentage of cells expressing TF is determined using an enzyme-linked immunosorbent assay (ELISA).

[0343] In some embodiments of the methods or uses provided herein or products for uses, 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. In some embodiments, the advanced cervical cancer is grade 3 or grade 4 cervical cancer. In some embodiments, the advanced cervical cancer is metastatic cervical cancer. In some embodiments, the cervical cancer is metastatic and recurrent cervical cancer. In some embodiments, the cervical cancer is metastatic cervical cancer. In some embodiments, the cervical cancer is recurrent cervical cancer.

[0344] In some embodiments, the subject has previously received treatment for cervical cancer. In some embodiments, the subject has previously been treated with one or more therapeutic agents and has no response to treatment. In some embodiments, the subject has previously been treated with one or more therapeutic agents and relapsed after treatment. In some embodiments, the subject has previously been treated with one or more therapeutic agents and experienced disease progression during treatment. In some embodiments, one or more therapeutic agents are selected from the group consisting of chemotherapeutics, 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, one or more therapeutic agents are chemotherapeutics. In some embodiments, one or more therapeutic agents are bevacizumab. In some embodiments, one or more therapeutic agents are cisplatin. In some embodiments, one or more therapeutic agents are carboplatin. In some embodiments, one or more therapeutic agents are paclitaxel. In some embodiments, one or more therapeutic agents are topotecan. In some embodiments, one or more therapeutic agents are a combination of bevacizumab and paclitaxel. In some embodiments, one or more therapeutic agents are a combination of bevacizumab and cisplatin. In some embodiments, one or more therapeutic agents are a combination of bevacizumab and carboplatin. In some embodiments, one or more therapeutic agents are a combination of paclitaxel and topotecan. In some embodiments, one or more therapeutic agents are a combination of bevacizumab and topotecan. In some embodiments, one or more therapeutic agents are a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, one or more therapeutic agents are a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, one or more therapeutic agents are a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject has previously been treated with chemotherapy and / or radiation therapy. In some embodiments, the subject does not respond to treatment with chemotherapy and radiation therapy. In some embodiments, the subject has been treated with chemotherapy for cervical cancer and has not responded to the chemotherapy. In some embodiments, the subject has been treated with radiation therapy for cervical cancer and has not responded to the radiation. In some embodiments, the subject has relapsed after being treated with both chemotherapy and radiation therapy. In some embodiments, the subject has been treated with chemotherapy for cervical cancer and has relapsed after being treated with chemotherapy. In some embodiments, the subject has been treated with radiation therapy for cervical cancer and has relapsed after being treated with radiation therapy. In some embodiments, the subject has experienced disease progression after being treated with chemotherapy and / or radiation therapy. In some embodiments, the subject has been treated with chemotherapy for cervical cancer and has experienced disease progression after being treated with chemotherapy. In some embodiments, the subject has been treated with radiation therapy for cervical cancer and has experienced disease progression after being treated with radiation therapy.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 certain embodiments, the subject is a human.

[0345] B. Route of administration

[0346] The anti-VEGF antibodies or antigen-binding fragments thereof described herein or the anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein can be administered by any suitable route and mode. Suitable routes of administration of the antibodies and / or 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 anti-VEGF antibodies and / or anti-TF antibody-drug conjugates described herein are administered parenterally. Parenteral administration refers to forms of administration other than enteral 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 anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein is intravenous injection or infusion. In some embodiments, the route of administration of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is intravenous infusion. In some embodiments, the route of administration of the anti-VEGF antibody or antigen-binding fragment described herein is intravenous injection or infusion. In some embodiments, the route of administration of the anti-VEGF antibody or antigen-binding fragment described herein is intravenous infusion.

[0347] C. Dosage and frequency of administration

[0348] In one aspect, the present invention provides a method for treating a subject having a cancer described herein with a specific dose of an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-VEGF antibody or antigen-binding fragment thereof described herein, wherein the antibody-drug conjugate or antigen-binding fragment thereof described herein and the anti-VEGF antibody or antigen-binding fragment thereof described herein are administered to the subject at a specific frequency.

[0349] 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.

[0350] In one embodiment of the methods or uses or products for use provided herein, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to a subject about once every 1 to 4 weeks. In certain embodiments, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In one embodiment, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered about once every 3 weeks. In one embodiment, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered once every 3 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 0.65 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 0.65 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 0.7 mg / kg and is administered about 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 dosage is about 0.9 mg / kg, and is administered approximately once a week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 0.9 mg / kg, and is administered approximately once a week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is about 0.9 mg / kg, and is administered approximately on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is about 0.9 mg / kg, and is administered approximately on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 0.9 mg / kg, and is administered approximately on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 0.9 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 0.9 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dosage is reduced to 0.65 mg / kg. In some embodiments, the dosage is 0.9 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dosage is reduced to 0.65 mg / kg. In some embodiments, the dosage 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 dosage is 0.65 mg / kg and is administered once a week, and the antibody-drug conjugate is tisotumab vedotin.In some embodiments, the dosage is 0.65 mg / kg, and is administered on about the 1st, 8th and 15th day of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 0.65 mg / kg, and is administered on about the 1st, 8th and 15th day of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is about 1.2 mg / kg, and is administered on about the 1st, 8th and 15th day of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is about 1.2 mg / kg, and is administered on about the 1st, 8th and 15th day of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 1.2 mg / kg, and is administered on about the 1st, 8th and 15th day of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 1.2 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tesotumab 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.

[0351] In one embodiment of the methods or uses or use products provided herein, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject approximately once per week for 3 consecutive weeks, followed by a rest period of about 1 week, wherein no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle time is approximately 28 days, including the rest period. In one embodiment of the methods or uses or use products provided herein, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject once per week for 3 consecutive weeks, followed by a rest period of 1 week, wherein no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle time is 28 days, including the rest period. Thus, a dosing regimen is provided in which a single weekly dose is administered to a subject to be treated for three consecutive weeks, followed by a rest week. This treatment regimen may also be referred to herein as a "dose-dense regimen" and is the same as a "4-week (28-day) cycle" and "3Q4W". In one embodiment, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject on about days 1, 8, and 15 of a 4-week cycle. In one embodiment, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject on days 1, 8, and 15 of a 4-week cycle. The present invention encompasses embodiments wherein the subject is maintained on a 3Q4W treatment cycle for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more cycles. In another embodiment, the subject is maintained on a 3Q4W treatment cycle for 2 to 48 cycles, such as 2 to 36 cycles, such as 2 to 24 cycles, such as 2 to 15 cycles, such as 2 to 12 cycles, such as 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, or 12 cycles, wherein each cycle is 28 days, as described above. In some embodiments, the subject is maintained on a 3Q4W treatment cycle for 12 cycles or more, such as 16 cycles or more, such as 24 cycles or more, such as 36 cycles or more. In some embodiments, the 3Q4W treatment cycle is administered for no more than 3, no more than 4, no more than 5, or no more than 6 four-week treatment cycles. The number of treatment cycles suitable for any particular subject or group of subjects can be determined by a person skilled in the art (typically a physician). In some embodiments, a dose of about 1.2 mg / kg of an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to the subject approximately once a week for 3 consecutive weeks, followed by a rest period of about 1 week in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is about 28 days in duration, including the rest period.In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 1.2 mg / kg about once a week for 3 consecutive weeks, followed by a 1-week rest period in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is 28 days in length, including the rest period. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 1.2 mg / kg on about days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 1.2 mg / kg on days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 1.2 mg / kg approximately once a week for 3 consecutive weeks, followed by a 1-week rest period in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is about 28 days in length, including the rest period. In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 1.2 mg / kg approximately once a week for 3 consecutive weeks, followed by a 1-week rest period in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is 28 days in length, including the rest period. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 1.2 mg / kg on approximately days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 1.2 mg / kg on approximately days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.9 mg / kg approximately once a week for 3 consecutive weeks, followed by a rest period of about 1 week in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is about 28 days in length, including the rest period. In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.9 mg / kg approximately once a week for 3 consecutive weeks, followed by a rest period of 1 week in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is 28 days in length, including the rest period. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.9 mg / kg on about days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.9 mg / kg on days 1, 8, and 15 of a cycle of about 4 weeks.In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.9 mg / kg approximately once a week for 3 consecutive weeks, followed by a 1-week rest period in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is about 28 days in length, including the rest period. In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 0.9 mg / kg approximately once a week for 3 consecutive weeks, followed by a 1-week rest period in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is 28 days in length, including the rest period. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 0.9 mg / kg on approximately days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 0.9 mg / kg on approximately days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.65 mg / kg about once a week for 3 consecutive weeks, followed by a rest period of about 1 week in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is about 28 days in length, including the rest period. In some embodiments, an anti-TF antibody drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.65 mg / kg about once a week for 3 consecutive weeks, followed by a rest period of 1 week in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle is 28 days in length, including the rest period. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.65 mg / kg on about days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.65 mg / kg on days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of about 0.65 mg / kg approximately once a week for 3 consecutive weeks, followed by a 1-week rest period in which the anti-TF antibody-drug conjugate or antigen-binding fragment thereof is not administered, such that each cycle is about 28 days in length, including the rest period. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 0.65 mg / kg approximately once a week for 3 consecutive weeks, followed by a 1-week rest period in which the anti-TF antibody-drug conjugate or antigen-binding fragment thereof is not administered, such that each cycle is 28 days in length, including the rest period.In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 0.65 mg / kg on about days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a dose of 0.65 mg / kg on about days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, the dose is 0.9 mg / kg and is administered on about days 1, 8, and 15 of an approximately 4-week cycle, and the antibody-drug conjugate is tesotumab vedotin. In some embodiments, the dose is 0.9 mg / kg and is administered on days 1, 8, and 15 of an approximately 4-week cycle, and the antibody-drug conjugate is tesotumab vedotin. In some embodiments, the dose is 0.9 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tesotumab vedotin, and the dose is reduced to 0.65 mg / kg if one or more adverse events occur. In some embodiments, the dosage is 0.9 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dosage is reduced to 0.65 mg / kg. In some embodiments, the dosage is 1.2 mg / kg and is administered on days 1, 8, and 15 of about a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 1.2 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 0.65 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage is 0.65 mg / kg and is administered on days 1, 8, and 15 of a 4-week cycle, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, for a subject 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 a subject weighing more than 100 kg, the dose of anti-TF antibody-drug conjugate administered is 65 mg, 90 mg, 130 mg, or 200 mg.

[0352] In one embodiment of the methods or uses or products for use provided herein, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to a subject in a flat dose ranging from about 50 mg to 200 mg, such as a flat dose of about 50 mg, or a flat dose of about 60 mg, or a flat dose of about 70 mg, or a flat dose of about 80 mg, or a flat dose of about 90 mg, or a flat dose of about 100 mg, or a flat dose of about 110 mg, or a flat dose of about 120 mg, or a flat dose of about 130 mg, or a flat dose of about 140 mg, or a flat dose of about 150 mg, or a flat dose of about 160 mg, or a flat dose of about 170 mg, or a flat dose of about 180 mg, or a flat dose of about 190 mg, or a flat dose of about 200 mg. In some embodiments, the flat dose is administered to a subject about once every 1 to 4 weeks. In certain embodiments, the flat dose is administered to a subject about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In some embodiments, the flat dose is administered to the subject about once every 3 weeks (e.g., ±3 days). In some embodiments, the flat dose is administered to the subject once every 3 weeks. In some embodiments, the flat dose is administered to the subject once every 3 weeks, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the flat dose is administered to the subject about once a week (e.g., ±1 day). In some embodiments, the flat dose is administered to the subject once a week. In some embodiments, the flat dose is administered to the subject about once a week for 3 consecutive weeks, followed by a rest period of about 1 week, in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle time is about 28 days, including a rest period. In some embodiments, the flat dose is administered to the subject once a week for 3 consecutive weeks, followed by a rest period of 1 week, in which no anti-TF antibody drug conjugate or antigen-binding fragment thereof is administered, such that each cycle time is 28 days, including a rest period. In some embodiments, the flat dose is administered to the subject about days 1, 8, and 15 of an approximately 4-week cycle. In some embodiments, a flat dose is administered to the subject on days 1, 8, and 15 of a 4-week cycle. In some embodiments, a flat dose is administered on days 1, 8, and 15 of a 4-week cycle and the antibody-drug conjugate is tesotumab vedotin.

[0353] In one embodiment of the methods or uses or products for use provided herein, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to a subject in a flat dose ranging from 50 mg to 200 mg, such as a flat dose of 50 mg or a flat dose of 60 mg or a flat dose of 70 mg or a flat dose of 80 mg or a flat dose of 90 mg or a flat dose of 100 mg or a flat dose of 110 mg or a flat dose of 120 mg or a flat dose of 130 mg or a flat dose of 140 mg or a flat dose of 150 mg or a flat dose of 160 mg or a flat dose of 170 mg or a flat dose of 180 mg or a flat dose of 190 mg or a flat dose of 200 mg. In some embodiments, the flat dose is administered to a subject about once every 1 to 4 weeks. In certain embodiments, the flat dose is administered to a subject about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In some embodiments, the flat dose is administered to a subject about once every 3 weeks (such as ± 3 days). In some embodiments, the flat dose is administered to the subject once every 3 weeks. In some embodiments, the flat dose is administered to the subject once every 3 weeks, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the flat dose is administered to the subject about once a week (e.g., ±1 day). In some embodiments, the flat dose is administered to the subject once a week. In some embodiments, the flat dose is administered to the subject about once a week for 3 consecutive weeks, followed by a rest period of about 1 week, in which no anti-TF antibody drug conjugate or its antigen-binding fragment is administered, so that each cycle time is about 28 days, including the rest period. In some embodiments, the flat dose is administered to the subject once a week for 3 consecutive weeks, followed by a rest period of 1 week, in which no anti-TF antibody drug conjugate or its antigen-binding fragment is administered, so that each cycle time is 28 days, including the rest period. In some embodiments, the flat dose is administered to the subject on about the 1st, 8th, and 15th days of a 4-week cycle. In some embodiments, the flat dose is administered to the subject on the 1st, 8th, and 15th days of a 4-week cycle. In some embodiments, a flat dose is administered on days 1, 8, and 15 of a 4-week cycle and the antibody-drug conjugate is tesotumomab vedotin.

[0354] In one embodiment of the methods or uses or products for use provided herein, an anti-VEGF antibody or antigen-binding fragment thereof described herein is administered to the subject at a dose ranging from about 5 mg / kg to about 20 mg / kg of the subject's body weight. In certain embodiments, the dose is about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg. In one embodiment, the dose is about 7.5 mg / kg. In one embodiment, the dose is about 7.5 mg / kg, and the anti-VEGF antibody is bevacizumab. In one embodiment, the dose is about 15 mg / kg, and the anti-VEGF antibody is bevacizumab. In one embodiment, the dose is about 15 mg / kg. In certain embodiments, the dose is 5 mg / kg, 6 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg. In one embodiment, the dose is 7.5 mg / kg. In one embodiment, the dose is 15 mg / kg. In one embodiment, the dose is 7.5 mg / kg and the anti-VEGF antibody is bevacizumab. In one embodiment, the dose is 15 mg / kg and the anti-VEGF antibody is bevacizumab.

[0355] In one embodiment of the methods or uses or products for use provided herein, the anti-VEGF antibody or antigen-binding fragment thereof described herein is administered to a subject about once every 1 to 4 weeks. In certain embodiments, the anti-VEGF antibody or antigen-binding fragment thereof described herein is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In one embodiment, the anti-VEGF antibody or antigen-binding fragment thereof described herein is administered about once every 3 weeks. In one embodiment, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered once every 3 weeks. In some embodiments, the dose is about 5 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 5 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 5 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 5 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 6 mg / kg and is administered about once every 1 week. In some embodiments, the dose is about 6 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 6 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 6 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 7 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 7 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 7 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 7 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 7.5 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 7.5 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 7.5 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 7.5 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 7.5 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 8 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 8 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 8 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 8 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 9 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 9 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 9 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 9 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 10 mg / kg and is administered about once every 1 week.In some embodiments, the dosage is about 10 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 10 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 10 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 11 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 11 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 11 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 11 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 12 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 12 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 12 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 12 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 13 mg / kg and is administered about once every week. In some embodiments, the dosage is about 13 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 13 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 13 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 14 mg / kg and is administered about once every week. In some embodiments, the dosage is about 14 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 14 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 14 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 15 mg / kg and is administered about once every week. In some embodiments, the dosage is about 15 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 15 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 15 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 16 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 16 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 16 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 16 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 17 mg / kg and is administered about once every 1 week. In some embodiments, the dosage is about 17 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 17 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 17 mg / kg and is administered about once every 4 weeks.In some embodiments, the dosage is about 18 mg / kg and is administered about once every week. In some embodiments, the dosage is about 18 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 18 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 18 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 19 mg / kg and is administered about once every week. In some embodiments, the dosage is about 19 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 19 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is about 19 mg / kg and is administered about once every 4 weeks. In some embodiments, the dosage is about 20 mg / kg and is administered about once every week. In some embodiments, the dosage is about 20 mg / kg and is administered about once every 2 weeks. In some embodiments, the dosage is about 20 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 20 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is 5 mg / kg and is administered about once every 1 week. In some embodiments, the dose is 5 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is 5 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is 5 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is 6 mg / kg and is administered about once every 1 week. In some embodiments, the dose is 6 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is 6 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is 6 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is 7 mg / kg and is administered about once every 1 week. In some embodiments, the dose is 7 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is 7 mg / kg and is administered about once every 3 weeks. In some embodiments, the dosage is 7 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 7.5 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 7.5 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 7.5 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 7.5 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 8 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 8 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 8 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 8 mg / kg and is administered approximately once every 4 weeks.In some embodiments, the dose is 9 mg / kg and is administered approximately once every week. In some embodiments, the dose is 9 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 9 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 9 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 10 mg / kg and is administered approximately once every week. In some embodiments, the dose is 10 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 10 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 10 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 11 mg / kg and is administered approximately once every week. In some embodiments, the dose is 11 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 11 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 11 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 12 mg / kg and is administered approximately once every week. In some embodiments, the dose is 12 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 12 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 12 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 13 mg / kg and is administered approximately once every week. In some embodiments, the dose is 13 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 13 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 13 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 14 mg / kg and is administered approximately once every week. In some embodiments, the dose is 14 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 14 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 14 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 15 mg / kg and is administered approximately once every week. In some embodiments, the dosage is 15 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 15 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 15 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 16 mg / kg and is administered approximately once every week. In some embodiments, the dosage is 16 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 16 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 16 mg / kg and is administered approximately once every 4 weeks.In some embodiments, the dose is 17 mg / kg and is administered approximately once every week. In some embodiments, the dose is 17 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 17 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 17 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 18 mg / kg and is administered approximately once every week. In some embodiments, the dose is 18 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 18 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 18 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 19 mg / kg and is administered approximately once every week. In some embodiments, the dose is 19 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 19 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 19 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 20 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 20 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 20 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 20 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 7.5 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the dose is 7.5 mg / kg and is administered once every 3 weeks. In some embodiments, the dose is 7.5 mg / kg and is administered once every 3 weeks, and the anti-VEGF antibody is bevacizumab. In some embodiments, the dose is 15 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the dose is 15 mg / kg and is administered once every 3 weeks. In some embodiments, the dose is 15 mg / kg and is administered once every 3 weeks, and the anti-VEGF antibody is bevacizumab.

[0356] In some embodiments of the methods or uses or products for use provided herein, the anti-VEGF antibody or antigen-binding fragment thereof described herein and the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein are administered to a subject at a fixed dose. In some embodiments, the fixed dose is based on the amount of the antibody (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (e.g., mg / ml). In some embodiments, the ratio of the amount of the anti-VEGF antibody or antigen-binding fragment thereof described herein (e.g., mg) to the amount of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (e.g., mg) is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:11 :100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1. In some embodiments, the ratio of the amount of the anti-VEGF antibody or antigen-binding fragment thereof described herein (e.g., mg) to the amount of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (e.g., mg) is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:91 1:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, or 2:1.In some embodiments, the ratio of the concentration of the anti-VEGF antibody or antigen-binding fragment thereof described herein (e.g., mg / ml) to the concentration of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (e.g., mg / ml) is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:9 1, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1. In some embodiments, the ratio of the concentration of the anti-VEGF antibody or antigen-binding fragment thereof described herein (e.g., mg / ml) to the concentration of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (e.g., mg / ml) is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:81, 1:90, 1:10 1:1, 0:1, 1:90, 1:100, 1:120, 1:140, 1:160, 1:180, 1:200, 200:1, 180:1, 160:1, 140:1, 120:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1.

[0357] In some embodiments, the dose of the anti-TF antibody-drug conjugate described herein is 2.0 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days), and the dose of the anti-VEGF antibody described herein is 15 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate described herein is 2.0 mg / kg and is administered once every 3 weeks, and the dose of the anti-VEGF antibody described herein is 15 mg / kg and is administered once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg / kg and is administered once every 3 weeks, and the antibody-drug conjugate is tesotumab vedotin, and the dose of the anti-VEGF antibody is 15 mg / kg and is administered once every 3 weeks, and the anti-VEGF antibody is bevacizumab.

[0358] In some embodiments, the dose of the anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days), and the dose of the anti-VEGF antibody described herein is 7.5 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered once every 3 weeks, and the dose of the anti-VEGF antibody described herein is 7.5 mg / kg and is administered once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg / kg and is administered once every 3 weeks, and the antibody-drug conjugate is tesotumab vedotin, and the dose of the anti-VEGF antibody is 7.5 mg and is administered once every 3 weeks, and the anti-VEGF antibody is bevacizumab.

[0359] In some embodiments, the dose of the anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days), and the dose of the anti-VEGF antibody described herein is 15 mg / kg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered once every 3 weeks, and the dose of the anti-VEGF antibody described herein is 15 mg / kg and is administered once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg / kg and is administered once every 3 weeks, and the antibody-drug conjugate is tesotumab vedotin, and the dose of the anti-VEGF antibody is 15 mg and is administered once every 3 weeks, and the anti-VEGF antibody is bevacizumab.

[0360] In some embodiments, the anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein and the anti-VEGF antibodies or antigen-binding fragments thereof described herein are co-administered. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein are administered simultaneously. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein are administered to a subject at an interval of less than about 1 hour, such as an interval of less than about 30 minutes, an interval of less than about 15 minutes, an interval of less than about 10 minutes, or an interval of less than about 5 minutes. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein are administered to a subject at an interval of less than 1 hour, such as an interval of less than 30 minutes, an interval of less than 15 minutes, an interval of less than 10 minutes, or an interval of less than 5 minutes. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein are administered to a subject at an interval of less than 1 hour, such as an interval of less than 30 minutes, an interval of less than 15 minutes, an interval of less than 10 minutes, or an interval of less than 5 minutes. In some embodiments, the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein are administered sequentially. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate described herein and the anti-VEGF antibody described herein are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart.

[0361] In some embodiments, the methods of treatment or use described herein further comprise administering one or more other therapeutic agents. In some embodiments, the one or more other therapeutic agents are administered simultaneously with the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein, such as tesotumomab vedotin, and the anti-VEGF antibody or antigen-binding fragment thereof described herein, such as bevacizumab. In some embodiments, the one or more other therapeutic agents and the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and the anti-VEGF antibody or antigen-binding fragment thereof described herein are administered sequentially.

[0362] D. Treatment results

[0363] In one aspect, the method of treating cancer with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-VEGF antibody or antigen-binding fragment thereof described herein results in an improvement in one or more therapeutic effects in a subject relative to baseline following administration of the antibody-drug conjugate. In some embodiments, the one or more therapeutic effects are the size of a tumor derived from cancer (e.g., cervical cancer), objective response rate, duration of response, time to reach 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 cancer. In one embodiment, the one or more therapeutic effects are 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 response. In one embodiment, the one or more therapeutic effects are complete response. In one embodiment, the one or more therapeutic effects are objective response rate. 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.

[0364] In one embodiment of the methods or uses or products for use provided herein, the response to treatment with the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and the anti-VEGF antibody or antigen-binding fragment thereof described herein may include the following criteria (RECIST criteria 1.1):

[0365]

[0366]

[0367] In one embodiment of the methods or uses or products for use provided herein, the effectiveness of treatment with the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and the anti-VEGF antibody or antigen-binding fragment thereof 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 is reduced by a predetermined amount 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 one embodiment, the objective response rate is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70% or at least 80%. In some embodiments, the objective response rate is at least 20%-80%. In some embodiments, the objective response rate is at least 30%-80%. In some embodiments, the objective response rate is at least 40%-80%. In some embodiments, the objective response rate is at least 50%-80%. In some embodiments, the objective response rate is at least 60%-80%. In some embodiments, the objective response rate is at least 70%-80%. In some embodiments, the objective response rate is at least 80%. In some embodiments, the objective response rate is at least 85%. In some embodiments, the objective response rate is at least 90%. In some embodiments, the objective response rate is at least 95%. In some embodiments, the objective response rate is at least 98%. In some embodiments, the objective response rate is at least 99%. In some embodiments, the objective response rate is 100%.

[0368] In one embodiment of the methods or uses or products for use provided herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-VEGF antibody or antigen-binding fragment thereof described herein is assessed by measuring the size of a tumor derived from cancer (e.g., cervical cancer). In one embodiment, the size of the tumor derived from 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 cancer prior to administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein. In one embodiment, the size of the tumor derived from cancer is reduced by at least about 10%-80%. In one embodiment, the size of the tumor derived from cancer is reduced by at least about 20%-80%. In one embodiment, the size of the tumor derived from cancer is reduced by at least about 30%-80%. In one embodiment, the size of the tumor derived from cancer is reduced by at least about 40%-80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 50%-80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 60%-80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 70%-80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 85%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 90%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 95%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 98%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 99%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the size of the tumor originating from cancer prior to administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein. In one embodiment, the size of a tumor derived from cancer is reduced by at least 10%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 20%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 30%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 40%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 50%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 60%-80%.In one embodiment, the size of a tumor originating from cancer is reduced by at least 70%-80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 85%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 90%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 95%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 98%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 99%. In one embodiment, the size of a tumor originating from cancer is reduced by 100%. In one embodiment, the size of a tumor originating from cancer is determined by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor originating from cancer is determined by computed tomography (CT). In some embodiments, the size of a tumor originating from cervical cancer is determined by pelvic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205. In some embodiments, the size of a tumor originating from cancer is reduced relative to the size of the tumor prior to administration of an anti-TF antibody drug conjugate described herein and an anti-VEGF antibody described herein. In some embodiments, the size of a tumor arising from cancer is reduced relative to the size of the tumor prior to administration of an anti-TF antibody drug conjugate described herein. In some embodiments, the size of a tumor arising from cancer is reduced relative to the size of the tumor prior to administration of an anti-VEGF antibody described herein.

[0369] In one embodiment of the methods or uses or products for use provided herein, the response to treatment with an antibody-drug conjugate or antigen-binding fragment thereof described herein (e.g., tesotumab vedotin) and an anti-VEGF antibody or antigen-binding fragment thereof described herein (e.g., bevacizumab) promotes regression of a tumor derived from cancer (e.g., cervical cancer). In one embodiment, the tumor derived from cancer is regressed by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from cancer before administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein. In one embodiment, the tumor derived from cancer is regressed by at least about 10% to about 80%. In one embodiment, the tumor derived from cancer is regressed by at least about 20% to about 80%. In one embodiment, the tumor derived from cancer is regressed by at least about 30% to about 80%. In one embodiment, the tumor from cancer regresses at least about 40% to about 80%. In one embodiment, the tumor from cancer regresses at least about 50% to about 80%. In one embodiment, the tumor from cancer regresses at least about 60% to about 80%. In one embodiment, the tumor from cancer regresses at least about 70% to about 80%. In one embodiment, the tumor from cancer regresses at least about 80%. In one embodiment, the tumor from cancer regresses at least about 85%. In one embodiment, the tumor from cancer regresses at least about 90%. In one embodiment, the tumor from cancer regresses at least about 95%. In one embodiment, the tumor from cancer regresses at least about 98%. In one embodiment, the tumor from cancer regresses at least about 99%. In one embodiment, the tumor derived from cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the size of the tumor derived from cancer prior to administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein. In one embodiment, the tumor derived from cancer is reduced by at least 10%-80%. In one embodiment, the tumor derived from cancer is reduced by at least 20%-80%. In one embodiment, the tumor derived from cancer is reduced by at least 30%-80%. In one embodiment, the tumor derived from cancer is reduced by at least 40%-80%. In one embodiment, the tumor derived from cancer is reduced by at least 50%-80%. In one embodiment, the tumor derived from cancer is reduced by at least 60%-80%. In one embodiment, the tumor derived from cancer is reduced by at least 70%-80%. In one embodiment, the tumor derived from cancer is reduced by at least 80%.In one embodiment, the tumor derived from cancer regresses by at least 85%. In one embodiment, the tumor derived from cancer regresses by at least 90%. In one embodiment, the tumor derived from cancer regresses by at least 95%. In one embodiment, the tumor derived from cancer regresses by at least 98%. In one embodiment, the tumor derived from cancer regresses by at least 99%. In one embodiment, the tumor derived from 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 pelvic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205. In some embodiments, the tumor derived from cancer regresses relative to the size of the tumor before administration of the anti-TF antibody drug conjugate described herein and the anti-VEGF antibody described herein. In some embodiments, the tumor derived from cancer regresses relative to the size of the tumor before administration of the anti-TF antibody drug conjugate described herein. In some embodiments, a tumor originating from a cancer regresses relative to the size of the tumor prior to administration of an anti-VEGF antibody described herein.

[0370] In one embodiment of the methods or uses or products for use described herein, the response to treatment with the anti-TF antibody-drug conjugates or antigen-binding fragments thereof and the anti-VEGF antibodies or antigen-binding fragments thereof described herein is assessed by measuring the time of progression-free survival after administration of the anti-TF antibody-drug conjugates and / or the anti-VEGF antibodies described herein. In some embodiments, after administration of the anti-TF antibody-drug conjugates and / or the anti-VEGF antibodies described 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. In some embodiments, after administration of the anti-TF antibody-drug conjugates and / or the anti-VEGF antibodies described herein, the subject exhibits a progression-free survival of at least about 6 months. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least about 1 year. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least about 2 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least about 3 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least about 4 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least about 5 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least 6 months. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits a progression-free survival of at least 1 year.In some embodiments, after administration of the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein, the subject exhibits a progression-free survival of at least 2 years. In some embodiments, after administration of the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein, the subject exhibits a progression-free survival of at least 3 years. In some embodiments, after administration of the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein, the subject exhibits a progression-free survival of at least 4 years. In some embodiments, after administration of the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein, the subject exhibits a progression-free survival of at least 5 years. In some embodiments, the response to treatment is assessed by measuring the time of progression-free survival after administration of the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein. In some embodiments, the response to treatment is assessed by measuring the time of progression-free survival after administration of the anti-TF antibody-drug conjugates described herein. In some embodiments, the response to treatment is assessed by measuring the time of progression-free survival after administration of the anti-TF antibody-drug conjugates described herein. In some embodiments, the response to treatment is assessed by measuring the time of progression-free survival after administration of the anti-VEGF antibodies described herein.

[0371] In one embodiment of the methods or uses or products for use described herein, the response to treatment with the anti-TF antibody-drug conjugates or antigen-binding fragments thereof and the anti-VEGF antibodies or antigen-binding fragments thereof described herein is assessed by measuring the time of overall survival after administration of the anti-TF antibody-drug conjugates and / or the anti-VEGF antibodies described herein. In some embodiments, after administration of the anti-TF antibody-drug conjugates and / or the anti-VEGF antibodies described 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. In some embodiments, after administration of the anti-TF antibody-drug conjugates and / or the anti-VEGF antibodies described herein, the subject exhibits an overall survival of at least about 6 months. In some embodiments, following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least about 1 year. In some embodiments, following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least about 2 years. In some embodiments, following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least about 3 years. In some embodiments, following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least about 4 years. In some embodiments, following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least about 5 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least about 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least 6 months. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least 1 year. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least 2 years.In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least 3 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least 4 years. In some embodiments, after administration of an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein, the subject exhibits an overall survival of at least 5 years. In some embodiments, the response to treatment is assessed by measuring the time of overall survival after administration of an anti-TF antibody-drug conjugate described herein and an anti-VEGF antibody described herein. In some embodiments, the response to treatment is assessed by measuring the time of overall survival after administration of an anti-TF antibody-drug conjugate described herein. In some embodiments, the response to treatment is assessed by measuring the time of overall survival after administration of an anti-TF antibody-drug conjugate described herein. In some embodiments, the response to treatment is assessed by measuring the time of overall survival after administration of an anti-VEGF antibody described herein.

[0372] In one embodiment of the methods or uses or products for use described herein, the response to treatment with the anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein and the anti-VEGF antibodies or antigen-binding fragments thereof described herein is assessed by determining the duration of the total response to the anti-TF antibody-drug conjugates or antigen-binding fragments thereof after administration of the anti-TF antibody-drug conjugates or anti-VEGF antibodies described herein. In some embodiments, the duration of remission to the anti-TF antibody-drug conjugates or anti-VEGF antibodies described herein after administration of the anti-TF antibody-drug conjugates or anti-VEGF antibodies described herein is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least about 6 months after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least about 1 year after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least about 2 years after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least about 3 years after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least about 4 years following administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least about 5 years following administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein.In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein after administration of the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein is at least 6 months. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least 1 year after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least 2 years after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least 3 years after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least 4 years after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission for the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein is at least 5 years after administration of the antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein. In some embodiments, the duration of remission is measured after administration of the anti-TF antibody-drug conjugates described herein and the anti-VEGF antibodies described herein. In some embodiments, the duration of remission is measured following administration of an anti-TF antibody drug conjugate described herein. In some embodiments, the duration of remission is measured following administration of an anti-VEGF antibody described herein.

[0373] E. Adverse events

[0374] In one aspect, the method of treating cancer (e.g., cervical cancer) with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-VEGF antibody or antigen-binding fragment thereof described herein results in the subject developing one or more adverse events. In some embodiments, the subject is administered an additional therapeutic agent to eliminate or reduce the severity of the adverse event. In some embodiments, the one or more adverse events developed by the subject are anemia, abdominal pain, bleeding, hyperthyroidism, hypothyroidism, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulcer, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general physical health deterioration or any combination thereof. In some embodiments, the one or more adverse events are grade 1 or higher adverse events. In some embodiments, the one or more adverse events are grade 2 or higher adverse events. In some embodiments, the one or more adverse events are grade 3 or higher adverse events. In some embodiments, the one or more adverse events are grade 1 adverse events. In some embodiments, the one or more adverse events are grade 2 adverse events. In some embodiments, the one or more adverse events are grade 3 adverse events. In some embodiments, the one or more adverse events are grade 1 adverse events. In some embodiments, the one or more adverse events are grade 2 adverse events. In some embodiments, the 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 severe adverse events. In some embodiments, one or more adverse events are conjunctivitis, conjunctival ulcers, and / or keratitis, and the other therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments, one or more adverse events are conjunctivitis, conjunctival ulcers, and keratitis, and the other therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, an antibiotic, 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, an antibiotic, 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, an antibiotic, 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, an antibiotic, 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, an antibiotic, a steroid eye drop, or any combination thereof. In some of any embodiments herein, the subject is given treatment with an additional therapeutic agent to eliminate or reduce the severity of the adverse event (e.g., conjunctivitis, conjunctival ulceration, and / or keratitis). In some embodiments, the treatment is an eye cooling pad (e.g., THERA PEARL eye mask or the like). 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). In some embodiments, one or more adverse events are hyperthyroidism, and the other agent is a non-selective beta-blocker (e.g., propranolol) or thionamide (thionamides). In some embodiments, one or more adverse events are hypothyroidism, and the other agent is a thyroid replacement hormone (e.g., levothyroxine or iodothyroxine).

[0375] In one aspect, a subject treated with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-VEGF antibody or antigen-binding fragment thereof 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, the subject is at risk of developing one or more of the following adverse events: anemia, abdominal pain, bleeding, hyperthyroidism, hypothyroidism, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulcer, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or 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 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 severe adverse events. In some embodiments, one or more adverse events are conjunctivitis, conjunctival ulcers and / or keratitis, and the other agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, an antibiotic, 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, an antibiotic, 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, an antibiotic, 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, an antibiotic, 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, an antibiotic, a steroid eye drop, or any combination thereof. In some of any embodiments herein, treatment is given to a subject with other therapeutic agents to prevent the development of adverse events or to reduce the severity of adverse events (e.g., conjunctivitis, conjunctival ulcers, and / or keratitis). In some embodiments, treatment is an eye cooling pad (e.g., THERA PEARL eye mask or the like). 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 are neutropenia, and the other agent is a growth factor support (G-CSF).In some embodiments, one or more adverse events are hyperthyroidism, and the other agent is a non-selective beta-blocker (e.g., propranolol) or thionamides. In some embodiments, one or more adverse events are hypothyroidism, and the other agent is a thyroid replacement hormone (e.g., levothyroxine or liothyroinine).

[0376] V. Composition

[0377] In some aspects, provided herein are compositions (e.g., pharmaceutical compositions and therapeutic formulations) comprising any of the anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein and / or the anti-VEGF antibodies or antigen-binding fragments thereof described herein.

[0378] 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).

[0379] Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers, antioxidants (including ascorbic acid, methionine, vitamin E, sodium metabisulfite); preservatives, isotonic agents, stabilizers, metal complexes (e.g., zinc protein complexes); chelating agents such as EDTA and / or nonionic surfactants.

[0380] 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.

[0381] 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 (e.g., 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.

[0382] 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.

[0383] 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 a container. Such excipients include: polyols (listed above); amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine, and the like; organic sugars or sugar alcohols, such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbitol, xylose, ribose, ribitol, myo-inositol, galactose, dulcitol, glycerol, cyclotols (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 (such as xylose, mannose, fructose, glucose); disaccharides (such as lactose, maltose, sucrose); trisaccharides (such as raffinose); and polysaccharides (such as dextrin or dextran).

[0384] 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.

[0385] Suitable nonionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), poloxamers (184, 188, etc.), Polyols, Polyoxyethylene sorbitan monoether ( The present invention relates to a kind of detergent comprising the following: 1) a kind of detergent comprising the following: 2) a kind of detergent comprising the following: 3) a kind of detergent comprising the following: 4) a kind of detergent comprising the following: 5) a kind of detergent comprising the following: 6) a kind of detergent comprising the following: 7) a kind of detergent comprising the following: 8) a kind of detergent comprising the following: 9) a kind of detergent comprising the following: 10) a kind of detergent comprising the following: 11) a kind of detergent comprising the following: 12) a kind of detergent comprising the following: 13) a kind of detergent comprising the following: 14) a kind of detergent comprising the following: 15) a kind of detergent comprising the following: 16) a kind of detergent comprising the following: 17) a kind of detergent comprising the following: 18) a kind of detergent comprising the following: 19) a kind of detergent comprising the following: 20) a kind of detergent comprising the following: 21) a kind of detergent comprising the following

[0386] 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.

[0387] 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).

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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:

[0392]

[0393] wherein p represents a number from 1 to 8, e.g., 1, 2, 3, 4, 5, 6, 7, or 8, S represents a sulfhydryl residue of an anti-TF antibody or antigen-binding fragment thereof, and Ab represents an anti-TF antibody or antigen-binding fragment thereof described herein, e.g., 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.

[0394] In some embodiments, a composition comprising an anti-TF antibody-drug conjugate or an antigen-binding fragment thereof described herein is co-administered with a composition comprising an anti-VEGF antibody or an antigen-binding fragment thereof described herein. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate described herein is administered simultaneously with an anti-VEGF antibody described herein. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate described herein and an anti-VEGF antibody described herein are administered to a subject at an interval of less than about 1 hour, such as an interval of less than about 30 minutes, an interval of less than about 15 minutes, an interval of less than about 10 minutes, or an interval of less than about 5 minutes. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate described herein and an anti-VEGF antibody described herein are administered to a subject at an interval of less than 1 hour, such as an interval of less than 30 minutes, an interval of less than 15 minutes, an interval of less than 10 minutes, or an interval of less than 5 minutes. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate described herein and an anti-VEGF antibody described herein are administered to a subject at an interval of less than 1 hour, such as an interval of less than 30 minutes, an interval of less than 15 minutes, an interval of less than 10 minutes, or an interval of less than 5 minutes. In some embodiments, an anti-TF antibody-drug conjugate described herein and an anti-VEGF antibody described herein are administered sequentially. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate described herein and the anti-VEGF antibody described herein are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered after the administration of the anti-VEGF antibody described herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered at least 30 minutes after administration of an anti-VEGF antibody described herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered 30 minutes after administration of an anti-VEGF antibody described herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered about 30 minutes to about 3 hours after administration of an anti-VEGF antibody described herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered about 30 minutes to about 2 hours after administration of an anti-VEGF antibody described herein.In some embodiments, the anti-TF antibody-drug conjugate described herein is administered about 30 minutes to about 60 minutes after the administration of the anti-VEGF antibody described herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered 30 minutes to 3 hours after the administration of the anti-VEGF antibody described herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered 30 minutes to 2 hours after the administration of the anti-VEGF antibody described herein. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered 30 minutes to 60 minutes after the administration of the anti-VEGF antibody described herein. In some embodiments, the composition comprising the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein is co-administered with one or more therapeutic agents to eliminate one or more adverse events or reduce their severity. In some embodiments, the composition comprising the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein is co-administered with one or more therapeutic agents to prevent the development of adverse events or reduce the severity of adverse events.

[0395] In some embodiments, the composition comprising the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody 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 anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein and the one or more other therapeutic agents are administered simultaneously. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein and the one or more therapeutic agents are administered to the subject at an interval of less than about 1 hour, such as an interval of less than about 30 minutes, an interval of less than about 15 minutes, an interval of less than about 10 minutes, or an interval of less than about 5 minutes. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein and the one or more therapeutic agents are administered to the subject at an interval of less than 1 hour, such as an interval of less than 30 minutes, an interval of less than 15 minutes, an interval of less than 10 minutes, or an interval of less than 5 minutes. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein and the one or more therapeutic agents are administered to the subject at an interval of less than 1 hour, such as an interval of less than 30 minutes, an interval of less than 15 minutes, an interval of less than 10 minutes, or an interval of less than 5 minutes. In some embodiments, the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein and the one or more other therapeutic agents are administered sequentially. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein and the one or more other therapeutic agents are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart.

[0396] In some embodiments, the composition comprising the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein is co-administered with one or more therapeutic agents to eliminate one or more adverse events or reduce their severity. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein is administered simultaneously with one or more therapeutic agents to eliminate one or more adverse events or reduce their severity. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein and the one or more therapeutic agents are administered to a subject at intervals of less than about 1 hour, such as intervals of less than about 30 minutes, intervals of less than about 15 minutes, intervals of less than about 10 minutes, or intervals of less than about 5 minutes, to eliminate one or more adverse events or reduce their severity. In some embodiments, concurrently means that the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein and one or more therapeutic agents are administered to a subject at intervals of less than 1 hour, such as intervals of less than 30 minutes, intervals of less than 15 minutes, intervals of less than 10 minutes, or intervals of less than 5 minutes, to eliminate or reduce the severity of one or more adverse events. In some embodiments, the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein and one or more therapeutic agents are administered sequentially to eliminate or reduce the severity of one or more adverse events. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein and the one or more other therapeutic agents are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein is administered prior to 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 are administered prior to an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein to eliminate or reduce the severity of one or more adverse events.

[0397] VI. Products and Kits

[0398] In another aspect, an article of manufacture or kit is provided, comprising an anti-TF antibody-drug conjugate described herein and / or an anti-VEGF antibody described herein. The article of manufacture or kit may further comprise instructions for using the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein in the methods of the present invention. Thus, in certain embodiments, the article of manufacture or kit comprises instructions for using the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein in a method of treating cancer (e.g., cervical cancer) in a subject, comprising administering to the subject an effective amount of the anti-TF antibody-drug conjugate described herein and / or the anti-VEGF antibody described herein. In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer is advanced cervical cancer. In some embodiments, the advanced cervical cancer is metastatic cervical cancer. In some embodiments, the advanced cervical cancer is stage 3 or stage 4 cervical cancer. In some embodiments, the cervical cancer is a metastatic cancer and a recurrent cancer. In some embodiments, the cervical cancer is a recurrent cancer. In some embodiments, the subject is not a candidate for curative therapy. In some embodiments, the subject is a human.

[0399] The article or kit may further include a container. Suitable containers include, for example, bottles, vials (e.g., dual-chamber vials), syringes (e.g., single-chamber or dual-chamber syringes), and test tubes. In some embodiments, the container is a vial. The container may be formed from a variety of materials, such as glass or plastic. The container contains the preparation.

[0400] 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.

[0401] 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 second drug is an anti-VEGF antibody, as described herein. 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.

[0402] Optionally, the article of manufacture or kit herein further comprises a container comprising a third drug, wherein the third drug is used to eliminate or reduce the severity of one or more adverse events, wherein the anti-TF antibody-drug conjugate described herein is the first drug, the anti-VEGF antibody described herein is the second drug, and the article of manufacture or kit further comprises instructions on the label or package insert for using the third drug in an effective amount to treat the subject. In some embodiments, the label or package insert indicates that the first, second, and third 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 described herein is administered first, followed by the anti-VEGF antibody described herein, followed by the third drug.

[0403] In some embodiments, the anti-TF antibody-drug conjugates described herein and / or the anti-VEGF antibodies described herein are present in a container in the form of a lyophilized powder. In some embodiments, the lyophilized powder is placed in an airtight sealed container, such as a vial, ampoule or pouch, 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 prior to administration. If desired, such a kit can also include one or more of the various conventional pharmaceutical kit components, such as a container with one or more pharmaceutically acceptable carriers, other containers, etc., which will be apparent 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, dosing instructions, and / or guidelines for mixing the components.

[0404] VII. Exemplary Embodiments

[0405] Embodiments provided herein include:

[0406] 1. A method for treating cervical cancer in a subject, the method comprising administering to the subject an anti-VEGF antibody or an antigen-binding fragment thereof and an antibody-drug conjugate that binds tissue factor (TF), wherein the antibody-drug conjugate comprises the anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof.

[0407] 2. The method of embodiment 1, wherein the antibody-drug conjugate is administered at a dose in the range of about 0.65 mg / kg to about 2.1 mg / kg.

[0408] 3. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of about 0.65 mg / kg.

[0409] 4. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of 0.65 mg / kg.

[0410] 5. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of about 0.9 mg / kg.

[0411] 6. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of 0.9 mg / kg.

[0412] 7. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of about 1.3 mg / kg.

[0413] 8. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg / kg.

[0414] 9. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of about 2.0 mg / kg.

[0415] 10. The method of embodiment 2, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg / kg.

[0416] 11. The method of any one of embodiments 1-10, wherein the antibody-drug conjugate is administered approximately once every 3 weeks.

[0417] 12. The method of any one of embodiments 1-10, wherein the antibody-drug conjugate is administered once every 3 weeks.

[0418] 13. The method of any one of embodiments 1-12, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose in the range of about 5 mg / kg to about 20 mg / kg.

[0419] 14. The method of any one of embodiments 1-13, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of about 7.5 mg / kg.

[0420] 15. The method of any one of embodiments 1-13, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 7.5 mg / kg.

[0421] 16. The method of any one of embodiments 1-13, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of about 15 mg / kg.

[0422] 17. The method of any one of embodiments 1-13, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg.

[0423] 18. The method of any one of embodiments 1-17, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered approximately once every 3 weeks.

[0424] 19. The method of any one of embodiments 1-17, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered once every 3 weeks.

[0425] 20. The method of any one of embodiments 1-19, wherein the antibody-drug conjugate is administered at least 30 minutes after administration of the anti-VEGF antibody or antigen-binding fragment thereof.

[0426] 21. The method of any one of embodiments 1-20, 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.

[0427] 22. The method of any one of embodiments 1-20, 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.

[0428] 23. The method of any one of embodiments 1-20, wherein the subject has been previously treated with one or more therapeutic agents and experienced disease progression during treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

[0429] 24. The method of any one of embodiments 21-23, wherein the one or more therapeutic agents are selected from the group consisting of a chemotherapeutic agent, 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.

[0430] 25. The method of any one of embodiments 1-24, wherein the subject is not a candidate for curative therapy.

[0431] 26. The method of embodiment 25, wherein the curative therapy comprises radiation therapy and / or evisceration surgery.

[0432] 27. The method of any one of embodiments 1-26, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

[0433] 28. The method of any one of embodiments 1-27, wherein the cervical cancer is advanced cervical cancer.

[0434] 29. The method of embodiment 28, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

[0435] 30. The method of embodiment 28 or 29, wherein the advanced cervical cancer is metastatic cervical cancer.

[0436] 31. The method of any one of embodiments 1-30, wherein the cervical cancer is recurrent cervical cancer.

[0437] 32. The method of any one of embodiments 1-31, 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.

[0438] 33. The method of any one of embodiments 1-32, 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:

[0439] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0440] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0441] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0442] Wherein the light chain variable region comprises:

[0443] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0444] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0445] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme.

[0446] 34. The method of any one of embodiments 1-33, 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.

[0447] 35. The method of any one of embodiments 1-34, 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.

[0448] 36. The method of any one of embodiments 1-35, wherein the anti-TF antibody of the antibody-drug conjugate is tesotumomab.

[0449] 37. The method of any one of embodiments 1-36, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin.

[0450] 38. A method as described in embodiment 37, wherein the linker is a cleavable peptide linker.

[0451] 39. The method of embodiment 38, wherein the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein:

[0452] a)MC is:

[0453]

[0454] b) vc is the dipeptide valine-citrulline, and

[0455] c) PAB is:

[0456]

[0457] 40. The method of any one of embodiments 37-39, 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.

[0458] 41. The method of embodiment 40, wherein the linker is attached to monomethyl auristatin E (MMAE), wherein the antibody-drug conjugate has the following structure:

[0459]

[0460] 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.

[0461] 42. A method as described in embodiment 41, wherein the average value of p in the antibody-drug conjugate population is approximately 4.

[0462] 43. The method of any one of embodiments 1-42, wherein the antibody-drug conjugate is tesotumomab vedotin.

[0463] 44. The method of any one of embodiments 1-43, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0464] 45. The method of any one of embodiments 1-44, wherein the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0465] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0466] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0467] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0468] Wherein the light chain variable region comprises:

[0469] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0470] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0471] (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the CDRs of the anti-VEGF antibody or antigen-binding fragment thereof are defined by the Kabat numbering scheme.

[0472] 46. ​​A method as described in any of embodiments 1-45, wherein the anti-VEGF antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO:31, and the light chain variable region comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO:32.

[0473] 47. The method of any one of embodiments 1-46, wherein the anti-VEGF antibody 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:31, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:32.

[0474] 48. The method of any one of embodiments 1-47, wherein the anti-VEGF antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:33, and the light chain comprises the amino acid sequence of SEQ ID NO:34.

[0475] 49. The method of any one of embodiments 1-48, wherein the anti-VEGF antibody is bevacizumab.

[0476] 50. The method of any one of embodiments 1-48, wherein the anti-VEGF antibody is a biosimilar of bevacizumab.

[0477] 51. A method as described in embodiment 50, wherein the biosimilar of bevacizumab is selected from the following group: bevacizumab-awwb, bevacizumab-bvzr, FKB238, BCD-021, BCD500, Krabeva, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Bevax, ONS-1045, PF-06439535, HD204, Bevacirel and SB8.

[0478] 52. The method of embodiment 50, wherein the biosimilar of bevacizumab is selected from the group consisting of bevacizumab-awwb, bevacizumab-bvzr, Krabeva, Cizumab, Bevax, and Bevacirel.

[0479] 53. The method of any one of embodiments 1-52, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously.

[0480] 54. The method of embodiment 53, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered intravenously.

[0481] 55. The method of any one of embodiments 1-54, wherein the anti-VEGF antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered sequentially.

[0482] 56. The method of any one of embodiments 1-54, wherein the anti-VEGF antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered simultaneously.

[0483] 57. The method of any of embodiments 1-56, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cancer cells express TF.

[0484] 58. The method of any one of embodiments 1-57, wherein one or more therapeutic effects in the subject are improved relative to baseline following administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof.

[0485] 59. The method of embodiment 58, wherein one or more therapeutic effects are selected from the group consisting of size of cancer-derived tumors, objective...

Claims

1. A combined use of an antibody-drug conjugate that binds tissue factor (TF) and an anti-VEGF antibody or an antigen-binding fragment thereof for the preparation of a kit for the combined treatment of cervical cancer in a subject, wherein the antibody-drug conjugate that binds tissue factor (TF) is tisotumab vedotin; and Wherein the anti-VEGF antibody is bevacizumab.

2. The combined use of an antibody-drug conjugate that binds tissue factor (TF) and an anti-VEGF antibody or an antigen-binding fragment thereof for the preparation of a medicament for the combined treatment of cervical cancer in a subject, wherein the tissue factor (TF) binding antibody-drug conjugate is tisotumomab vedotin; and Wherein the anti-VEGF antibody is bevacizumab.

3. The use according to claim 1 or 2, wherein the antibody-drug conjugate is administered at a dose in the range of 0.65 mg / kg - 2.1 mg / kg.

4. The use according to claim 3, wherein the antibody-drug conjugate is administered at a dose of 0.65 mg / kg.

5. The use according to claim 3, wherein the antibody-drug conjugate is administered at a dose of 0.9 mg / kg.

6. The use according to claim 3, wherein the antibody-drug conjugate is administered at a dose of 1.2 mg / kg.

7. The use according to claim 3, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg / kg.

8. The use according to claim 3, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg / kg.

9. The use according to claim 1 or 2, wherein the antibody-drug conjugate is administered once every 3 weeks.

10. The use of claim 1 or 2, wherein the antibody-drug conjugate is administered once a week for 3 consecutive weeks, followed by a 1-week rest period without any administration of antibody-drug conjugate, so that each cycle time is 28 days, including the rest period.

11. The method of claim 1 or 2, wherein the antibody-drug conjugate is administered on days 1, 8, and 15 of a 4-week cycle.

12. The use according to claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose ranging from 5 mg / kg to 20 mg / kg.

13. The use according to claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 7.5 mg / kg.

14. The use according to claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg.

15. The use according to claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered once every 3 weeks.

16. The use of claim 1 or 2, wherein the antibody-drug conjugate is administered at least 30 minutes after the anti-VEGF antibody or antigen-binding fragment thereof.

17. The use of claim 1 or 2, 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.

18. The use of claim 1 or 2, 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.

19. The use of claim 1 or 2, wherein the subject has been previously treated with one or more therapeutic agents and experienced disease progression during treatment, wherein the one or more therapeutic agents are not the antibody-drug conjugate.

20. The use of claim 19, wherein the one or more therapeutic agents are selected from the group consisting of 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.

21. The use of claim 1 or 2, wherein the subject is not a candidate for curative therapy.

22. The use according to claim 21, wherein the curative therapy comprises radiotherapy and / or evisceration surgery.

23. The use according to claim 1 or 2, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma or squamous cell carcinoma.

24. The use according to claim 1 or 2, wherein the cervical cancer is advanced cervical cancer.

25. The use according to claim 24, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

26. The use according to claim 24, wherein the advanced cervical cancer is metastatic cervical cancer.

27. The use according to claim 1 or 2, wherein the cervical cancer is recurrent cervical cancer.

28. The use of claim 1 or 2, wherein the antibody-drug conjugate is administered intravenously.

29. The use according to claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously.

30. The use according to claim 29, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered intravenously.

31. The use of claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered sequentially.

32. The use of claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered simultaneously.

33. The use of claim 1 or 2, wherein at least 0.1% of cancer cells express TF.

34. The use of claim 1 or 2, wherein one or more therapeutic effects in the subject are improved relative to baseline following administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof.

35. The use of claim 34, wherein the one or more therapeutic effects are selected from the group consisting of size of cancer-derived tumors, duration of remission, time to remission, progression-free survival, and overall survival.

36. The use of claim 1 or 2, wherein the size of the tumor originating from the cancer is reduced by at least 10% relative to the size of the tumor originating from the cancer before administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof.

37. The use of claim 1 or 2, wherein the subject exhibits a progression-free survival of at least 1 month following administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof.

38. The use of claim 1 or 2, wherein the subject exhibits an overall survival of at least 1 month following administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof.

39. The use of claim 1 or 2, wherein the duration of remission for the antibody-drug conjugate is at least 1 month after administration of the antibody-drug conjugate and the anti-VEGF antibody or antigen-binding fragment thereof.

40. The use of claim 1 or 2, 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.

41. The use of claim 1 or 2, 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.

42. The use of claim 40, wherein the one or more adverse events are anemia, abdominal pain, bleeding, hyperthyroidism, hypothyroidism, hypokalemia, hyponatremia, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulcer, constipation, decreased appetite, diarrhea, vomiting, or peripheral neuropathy.

43. The use of claim 40, wherein the one or more adverse events are grade 3 or higher adverse events.

44. The use of claim 40, wherein the one or more adverse events are conjunctivitis, conjunctival ulceration and / or keratitis, and the other therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, an antibiotic and / or a steroid eye drop.

45. The use of claim 1 or 2, wherein the subject is a human.

46. ​​The use of claim 1 or 2, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

47. The use of claim 1 or 2, wherein the anti-VEGF antibody or antigen-binding fragment thereof is in a pharmaceutical composition comprising the anti-VEGF antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.

48. A kit for treating cervical cancer, comprising: (a) an anti-VEGF antibody or antigen-binding fragment thereof in a dose range of 5 mg / kg to 20 mg / kg; (b) an antibody-drug conjugate that binds to tissue factor (TF) at a dose range of 0.65 mg / kg to 2.1 mg / kg, wherein the antibody-drug conjugate is tesotumab vedotin and the anti-VEGF antibody is bevacizumab.

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