Methods of treating cancer using a combination of an anti-PD-1 antibody and an anti-tissue factor antibody-drug conjugate

Abstract

The present invention provides an anti-PD-1 antibody comprising a pembrolizumab complementarity-determining region (CDR) and an antibody-drug conjugate combination that binds to tissue factor (TF), the antibody-drug conjugate (such as tisotumab vedotin) comprising monomethyl auristatin E and the CDR of tisotumab, and provides the use of methods thereof for treating cancers (such as breast cancer and cervical cancer). The present invention also provides a composition and a kit for treating cancers (such as breast cancer and cervical cancer), the composition and the kit comprising an anti-PD-1 antibody and an antibody-drug conjugate that binds to TF, the anti-PD-1 antibody comprising the CDR of pembrolizumab, and the antibody-drug conjugate (such as tisotumab vedotin) comprising monomethyl auristatin E and the CDR of tisotumab.

Description

Technical Field

[0001] The present invention relates to methods for treating cancer (such as breast cancer and cervical cancer) using a combination of an anti-PD-1 antibody comprising the complementarity-determining regions (CDRs) of pembrolizumab and an anti-tissue factor (anti-TF) antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethylauristatin E (MMAE), wherein the anti-TF antibody or antigen-binding fragment thereof comprises the CDRs of tisotumab.

[0002] Cross-citation of related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 668,088, filed on May 7, 2018, and U.S. Provisional Application No. 62 / 753,725, filed on October 31, 2018, each of which is incorporated herein by reference in its entirety.

[0004] Submit sequence listing as ASCII text file

[0005] The contents of the following submitted ASCII text file are incorporated herein by reference in their entirety: Computer Readable Form (CRF) Sequence Listing (File Name: 761682000440SEQLIST.TXT, Record Date: April 30, 2019, Size: 17KB). Existing technology

[0006] Tissue factor (TF), also known as coagulant, factor III, or CD142, is a protein found in subendothelial tissue, platelets, and white blood cells. It is required for the formation of thrombin from the zymogen prothrombin. Thrombin formation ultimately leads to blood coagulation. TF initiates the blood coagulation cascade in cells and acts as a high-affinity receptor for coagulation factor VII (FVII, a serine protease). The resulting complex, through specific restricted proteolysis, provides the enzyme-catalyzed events responsible for initiating the coagulation protease cascade. TF differs from other cofactors of these protease cascades that circulate as non-functional precursors in that, when expressed on the cell surface, TF is a fully functional, efficient initiator.

[0007] TF is a cell surface receptor for the serine protease Factor VIIa (FVIIa). The combination of FVIIa and TF initiates a signal transduction process within the cell, which plays a role in angiogenesis. Although angiogenesis is a normal process for growth and wound healing, it is also a fundamental step in the transformation of tumors from a dormant state to a malignant state. When cancer cells acquire the ability to produce proteins involved in angiogenesis (i.e., angiogenic growth factors), these proteins are released by the tumor to adjacent tissues, thereby stimulating new blood vessels to sprout from existing healthy blood vessels toward the tumor or sprout into the tumor. Once new blood vessels enter the tumor, the size of the tumor can rapidly increase and invade local tissues and organs. Through the new blood vessels, cancer cells can further escape into the circulation and remain in other organs to form new tumors, also known as metastasis.

[0008] TF expression is observed in many types of cancer, including cervical cancer, and is associated with more aggressive disease. Furthermore, human TF also exists as a soluble alternatively spliced ​​form, asHTF. Recently, asHTF was found to promote tumor growth (Hobbs et al., 2007, Thrombosis Res. 120(2): S13-S21).

[0009] Human cancers carry many genetic and epigenetic changes that generate new antigens that can be recognized by the immune system (Sjoblom et al., 2006, Science 314: 268-74). The adaptive immune system, which includes T and B lymphocytes, has a powerful anti-cancer potential and responds to a variety of tumor antigens with broad capabilities and exquisite specificity. In addition, the immune system displays considerable plasticity and memory components. Successfully harnessing all of these properties of the adaptive immune system will produce immunotherapies that are different from all cancer treatment modalities. Until recently, cancer immunotherapy has focused heavily on enhancing anti-tumor immune responses by adoptive transfer of activated effector cells, immunization against relevant antigens, or providing nonspecific immunostimulants such as cytokines. However, over the past decade, active efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic options for treating cancer, including the development of ipilimumab, an antibody that binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma. )(Hodi et al., 2010, N Engl J Med 363:711-23) and the development of pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013), an antibody that specifically binds to the programmed death-1 (PD-1) receptor and blocks the inhibitory PD-1 / PD-1 ligand pathway (Hamid and Carvajal, Expert Opin Biol Ther 13(6):847-61 (2013); and McDermott and Atkins, Cancer Med 2(5):662-73 (2013)).

[0010] Breast cancer is by far the most common cancer in women. Each year, more than 180,000 women in the United States and 1 million worldwide are diagnosed with breast cancer. Breast cancer is the leading cause of death among women aged 50 to 55 and the most common non-preventable malignancy among women in the Western Hemisphere. An estimated 2,167,000 women in the United States currently have the disease (National Cancer Institute, Surveillance Epidemiology and End Results (NCI SEER) program, Cancer Statistics Review (CSR), www-seer.ims.nci.nih.gov / Publications / CSR1973 (1998)). Based on cancer incidence rates from 1995 to 1997, a report from the National Cancer Institute (NCI) estimated that approximately 1 in 8 women in the United States (approximately 12.8%) will develop breast cancer in her lifetime (NCI's Surveillance, Epidemiology, and End Results Program (SEER) publication SEER Cancer Statistic's Review 1973-1997). Breast cancer is the second most common form of cancer in women in the United States, second only to skin cancer. An estimated 250,100 new cases of breast cancer are expected to be diagnosed in the United States in 2001. Of these, 192,200 new cases of more advanced (invasive) breast cancer are expected to occur in women (a 5% increase over the previous year), 46,400 new cases of early-stage (in situ) breast cancer are expected to occur in women (a 9% increase over the previous year), and approximately 1,500 new cases of breast cancer are expected to be diagnosed in men (Cancer Facts & FIGS. 2001 American Cancer Society). An estimated 40,600 deaths (40,300 in women and 400 in men) are expected to occur in 2001 due to breast cancer. Breast cancer ranks second only to lung cancer as the leading cause of cancer death in women. Nearly 86% of women diagnosed with breast cancer are still alive five years later, but 24% will die of the disease after 10 years, and almost half (47%) will die of the disease after 20 years.

[0011] Every woman is at risk for breast cancer. Over 70% of breast cancers occur in women with no identifiable risk factors other than age (US General Accounting Office. Breast Cancer, 1971-1991: Prevention, Treatment and Research. GAO / PEMD-92-12; 1991). Only 5 to 10% of breast cancers are associated with a family history of breast cancer (Henderson IC, Breast Cancer. In: Murphy GP, Lawrence WL, Lenhard RE (eds). Clinical Oncology. Atlanta, Ga.: American Cancer Society; 1995: 198-219).

[0012] Cervical cancer is a serious medical problem worldwide, with an estimated annual incidence of over 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 annually. 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 the majority of cervical cancer cases. The standard first-line treatment for cervical cancer is platinum-based therapy plus a taxane-based therapy. Bevacizumab, an anti-VEGF antibody, is approved by the US Food and Drug Administration for use in combination with chemotherapy to treat cervical cancer, where it has improved overall survival in clinical trials. First-line (1L) treatment for advanced cervical cancer includes bevacizumab in combination with either paclitaxel plus platinum (e.g., cisplatin or carboplatin) or paclitaxel plus topotecan. Despite an objective response rate (ORR) of 48% and a median overall survival (OS) of approximately 18 months, unfortunately, nearly all patients relapse after this 1L treatment. See Tewari et al., 2014, N Engl J Med., 370:734-743. No approved therapies are available for second-line (2L) treatment, and patients are typically treated with single-agent modalities, including but not limited to pemetrexed, topotecan, docetaxel, nab-paclitaxel, vinorelbine, and, in some cases, bevacizumab. Pooled analysis of single-agent treatment showed a moderate response rate of only 10.9% (ie, 60 responders among 552 patients) and a median overall survival (OS) of approximately 7 months.See, for example, Burotto et al., 2015, Oncologist 20: 725-726; Candelaria et al., 2009, Int. J. Gynecol. Cancer. 19: 1632-1637; Coronel et al., 2009, Med. al.,2009,Gynecol.Oncol.115:285-289;Garcia et.al.,2007,Am.J.Clin.Oncol.30-428-431;Goncalves et al.,2008,Gynecol.Oncol.108:42-46;Homesley et.al. al., 2008, Int.J.Clin.Oncol.13: 62-65; McLachlan et al. al., 2017, Clin. Oncol. (R. Coll. Radiol.) 29: 153-160; Miller et al., 2008, Gynecol. Oncol. 110: 65-70; Monk et al., 2009, J. Clin. Oncol. 27: 1069-1074; Muggia et al. al., 2004, Gynecol. Oncol. 92: 639-643; Rose et al., 2006, Gynecol. Oncol. 102: 210-213; Santin et al., 2011, Gynecol. Oncol. 122: 495-500; Schilder et al. al.,2005,Gynecol.Oncol.96:103-107; and Torfs et al. et al., 2012, Eur. J. Cancer. 48: 1332-1340. The five-year relative survival rate for stage IV cervical cancer is only 15%, indicating a high need for improved therapies for cervical cancer.

[0013] Targeting multiple, non-redundant molecular pathways that modulate immune responses can enhance anti-tumor immunotherapy. However, not all combinations have acceptable safety and / or efficacy. There remains a need for combination therapies with an acceptable safety profile and high efficacy in cancer treatment, particularly for the treatment of breast and cervical cancer.

[0014] 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 was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0015] Provided herein are methods for treating cancer in an individual, comprising administering to the individual (1) an antibody or an antigen-binding fragment thereof and (2) an antibody-drug conjugate that binds to tissue factor (TF), wherein the (1) antibody binds to programmed death-1 (PD-1) and inhibits PD-1 activity, wherein the (2) antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin E, wherein the anti-PD-1 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:

[0016] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0017] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0018] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0019] Wherein the light chain variable region comprises:

[0020] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0021] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0022] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the CDRs of the anti-PD-1 antibody or antigen-binding fragment thereof are generally defined by the Kabat numbering scheme,

[0023] The anti-TF 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:

[0024] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0025] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0026] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0027] Wherein the light chain variable region comprises:

[0028] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0029] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0030] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined by the IMGT numbering scheme. In some embodiments, the antibody-drug conjugate is administered at a dose range of about 0.9 mg / kg to about 2.1 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 of any of the embodiments herein, the antibody-drug conjugate is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In some embodiments of any of the embodiments herein, the antibody-drug conjugate is administered about once every 3 weeks. In some embodiments of any of the embodiments herein, the antibody-drug conjugate is administered once every 3 weeks. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a flat dose range of about 50 mg to about 500 mg. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a flat dose range of about 200 mg. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a flat dose range of 200 mg. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a flat dose range of about 400 mg. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a flat dose range of 400 mg. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a flat dose range of about ...50 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered approximately once every 6 weeks. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 6 weeks. In some embodiments of any of the embodiments herein, the cancer is breast cancer. In some embodiments of any of the embodiments herein, the cancer is cervical cancer. In some embodiments of any of the embodiments herein, the individual is not a candidate for curative therapy. In some embodiments of any of the embodiments herein, the curative therapy comprises radiation therapy and / or resection surgery.In some embodiments of any of the embodiments herein, the individual has not received prior systemic therapy for cervical cancer. In some embodiments of any of the embodiments herein, the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma. In some embodiments of any of the embodiments herein, the cervical cancer is advanced cervical cancer. In some embodiments of any of the embodiments herein, the advanced cervical cancer is stage 3 or stage 4 cervical cancer. In some embodiments of any of the embodiments herein, the advanced cervical cancer is metastatic cervical cancer. In some embodiments of any of the embodiments herein, the cervical cancer is recurrent cervical cancer. In some embodiments of any of the embodiments herein, the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or monoclonal antigen-binding fragment thereof. In some embodiments of any of the 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, the heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments of any of the 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, the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments of any of the embodiments herein, the anti-TF antibody of the antibody-drug conjugate is tisotumab. In some embodiments of any of the embodiments herein, the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin E. In some embodiments of any of the embodiments herein, the linker is a cleavable peptide linker. In some embodiments of any of the embodiments herein, the cleavable peptide linker has the formula -MC-vc-PAB-, wherein:

[0031] a)MC is:

[0032]

[0033] b) vc is the dipeptide valine-citrulline, and

[0034] c) PAB is:

[0035]

[0036] In some embodiments of any of the embodiments herein, the linker is attached to a sulfhydryl residue of the anti-TF antibody or antigen-binding fragment thereof, wherein the sulfhydryl residue is obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof. In some embodiments of any of the embodiments herein, the linker is attached to MMAE, wherein the antibody-drug conjugate has the following structure:

[0037]

[0038] wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of the anti-TF antibody, and Ab refers to the anti-TF antibody or an antigen-binding fragment thereof. In some embodiments of any of the embodiments herein, the average value of p in the population of antibody-drug conjugates is about 4. In some embodiments of any of the embodiments herein, the antibody-drug conjugate is tesotumomab vedotin. In some embodiments of any of the embodiments herein, the route of administration of the antibody-drug conjugate is intravenous. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising 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 comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 32. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO: 33, and the light chain comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody is pembrolizumab. In some embodiments of any of the embodiments herein, the route of administration of the anti-PD-1 antibody or antigen-binding fragment thereof is intravenous. In some embodiments of any of the embodiments herein, the route of administration of the anti-PD-1 antibody or antigen-binding fragment thereof is subcutaneous. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered sequentially. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered simultaneously. In some embodiments 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 from the individual express TF.In some embodiments 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 from the individual express PD-L1. In some embodiments of any of the embodiments herein, the individual's tumor expresses PD-L1 with a tumor proportion score (TPS) of ≥1%. In some embodiments of any of the embodiments herein, the individual's tumor has high PD-L1 expression (TPS ≥ 50%). In some embodiments of any of the embodiments herein, the individual's tumor expresses PD-L1 with a combined positive score (CPS) of ≥1%. In some embodiments of any of the embodiments herein, the individual's tumor expresses PD-L1 with a combined positive score (CPS) of ≥10%. In some embodiments of any of the embodiments herein, the tumor derived from the cancer comprises one or more cells expressing PD-L1, PD-L2, or both PD-L1 and PD-L2. In some embodiments 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 T cells from the individual express PD-1. In some embodiments of any of the embodiments herein, one or more therapeutic effects in the subject are improved relative to baseline following administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments of any of the embodiments herein, the one or more therapeutic effects are selected from the group consisting of: tumor size derived from the cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. In some embodiments of any of the embodiments herein, the size of the tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer prior to administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments 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 embodiments of any of the embodiments herein, the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of the antibody-drug conjugate and the anti-PD-1 antibody, or antigen-binding fragment thereof. In some embodiments of any of the embodiments herein, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of the antibody-drug conjugate and the anti-PD-1 antibody, or antigen-binding fragment thereof. In some embodiments of any of the embodiments herein, the duration of response to the antibody-drug conjugate after administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof 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 two years, at least about three years, at least about four years, or at least about five years. In some embodiments of any of the embodiments herein, the subject has one or more adverse events and the severity of the one or more adverse events is eliminated or reduced upon further administration of an additional therapeutic agent. In some embodiments of any of the embodiments herein, the subject is at risk of developing one or more adverse events and the severity of the one or more adverse events is prevented or reduced upon further administration of an additional therapeutic agent. In some embodiments of any of the embodiments herein, the 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 worsening of overall physical health. In some embodiments of any of the embodiments herein, the one or more adverse events are Grade 3 or higher adverse events. In some embodiments of any of the embodiments herein, the one or more adverse events are serious adverse events. In some embodiments of any of the embodiments herein, the one or more adverse events are conjunctivitis, conjunctival ulcer, and / or keratitis and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, an antibiotic, and / or a steroid eye drop. In some embodiments of any of the embodiments herein, the subject is human.In some embodiments of any of the embodiments herein, the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is in a pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.

[0039] Also provided herein are kits comprising:

[0040] (a) an antibody or an antigen-binding fragment thereof at a dose ranging from about 50 mg to about 500 mg, wherein the antibody binds to programmed death-1 (PD-1) and inhibits PD-1 activity, wherein the 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:

[0041] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0042] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0043] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0044] Wherein the light chain variable region comprises:

[0045] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0046] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0047] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the CDRs of the anti-PD-1 antibody or antigen-binding fragment thereof are generally defined by the Kabat numbering scheme;

[0048] (b) an antibody-drug conjugate that binds to tissue factor (TF) at a dose range of about 0.9 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 E, wherein the anti-TF 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:

[0049] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0050] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0051] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0052] Wherein the light chain variable region comprises:

[0053] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0054] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0055] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined by the IMGT numbering scheme; and

[0056] (c) Instructions for using the anti-PD-1 antibody or antigen-binding fragment thereof and the antibody-drug conjugate according to some embodiments of any of the embodiments herein. In some embodiments of any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof is pembrolizumab. In some embodiments of any of the embodiments herein, the pembrolizumab dose is 200 mg. In some embodiments of any of the embodiments herein, the pembrolizumab dose is 400 mg. In some embodiments of any of the embodiments herein, the antibody-drug conjugate is tesotumomab vedotin. In some embodiments of any of the embodiments herein, the tesotumomab vedotin dose is 1.3 mg / kg. In some embodiments of any of the embodiments herein, the tesotumomab vedotin dose is 2.0 mg / kg. Sequence Listing <110> Genmab A / S MSD International GmbH <120> Method for treating cancer using a combination of an anti-PD-1 antibody and an anti-tissue factor antibody-drug conjugate <130> 220847-0001-00-WO <150> PCT / US19 / 31166 <151> 2019-05-07 <150> US 62 / 753,725 <151> 2018-10-31 <150> US 62 / 668,088 <151> 2018-05-07 <160> 34 <170> PatentIn version 3.5 <210> 1 <211> 8 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 1 Gly Phe Thr Phe Ser Asn Tyr Ala 1 5 <210> 2 <211> 8 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 2 Ile Ser Gly Ser Gly Asp Tyr Thr 1 5 <210> 3 <211> 11 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 3 Ala Arg Ser Pro Trp Gly Tyr Tyr Leu Asp Ser 1 5 10 <210> 4 <211> 6 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 4 Gln Gly Ile Ser Ser Arg 1 5 <210> 5 <211> 3 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 5 Ala Ala Ser 1 <210> 6 <211> 9 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 6 Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr 1 5 <210> 7 <211> 118 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 7 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Ser Gly Asp Tyr Thr Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Pro Trp Gly Tyr Tyr Leu Asp Ser Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 8 <211> 107 <212> PRT <213> artificial sequence <220> <223> Synthesis structure <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Arg 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 9 <211> 25 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 9 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 10 <211> 17 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 10 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 1 5 10 15 Ser <210> 11 <211> 38 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 11 Tyr Tyr Thr Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys 35 <210> 12 <211> 11 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 12 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 13 <211> 26 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 13 Asp Ile Gln Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 20 25 <210> 14 <211> 17 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 14 Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 1 5 10 15 Tyr <210> 15 <211> 36 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 15 Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 1 5 10 15 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala 20 25 30 Thr Tyr Tyr Cys 35 <210> 16 <211> 10 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 16 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 1 5 10 <210> 17 <211> 5 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 17 Asn Tyr Tyr Met Tyr 1 5 <210> 18 <211> 17 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 18 Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe Lys 1 5 10 15 Asn <210> 19 <211> 11 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 19 Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr 1 5 10 <210> 20 <211> 15 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 20 Arg Ala Ser Lys Gly Val Ser Thr Ser Gly Tyr Ser Tyr Leu His 1 5 10 15 <210> twenty one <211> 7 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> twenty one Leu Ala Ser Tyr Leu Glu Ser 1 5 <210> twenty two <211> 9 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> twenty two Gln His Ser Arg Asp Leu Pro Leu Thr 1 5 <210> twenty three <211> 30 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> twenty three Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 <210> twenty four <211> 14 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> twenty four Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly 1 5 10 <210> 25 <211> 32 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 25 Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr Met Glu 1 5 10 15 Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 26 <211> 11 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 26 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> 27 <211> twenty three <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 27 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys 20 <210> 28 <211> 15 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 28 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 1 5 10 15 <210> 29 <211> 32 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 29 Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 <210> 30 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic construct <400> 30 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 31 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic construct <400> 31 Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe 50 55 60 Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 32 <211> 111 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 32 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser 20 25 30 Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg 85 90 95 Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 33 <211> 446 <212> PRT <213> Artificial sequence <220> <223> synthetic constructs <400> 33 Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe 50 55 60 Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 34 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 34 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser 20 25 30 Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg 85 90 95 Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 Western blot images showing phosphorylation of IRE1 and JNK in cell lysates from MMAE-treated HeLa cells (right channel) compared to untreated HeLa cells (left channel). MMAE treatment leads to phosphorylation of both IRE1 and JNK. pIRE1 indicates phosphorylated IRE1 protein; IRE1 indicates total IRE1 protein; and pJNK indicates phosphorylated JNK protein.

[0058] Figure 2A and 2B Immunofluorescence images of HeLa cells treated with 100 nM MMAE and imaged at the indicated time points in the presence of MMAE. A) Upper panel shows ER staining with the ER binding dye ER-ID green, and B) lower panel shows RFP-labeled tubulin expressed by the cells.

[0059] Figure 3A and 3B A series of graphs show A) ATP secretion and B) HMGB1 secretion in HeLa cells treated with 100 nM MMAE compared to untreated HeLa cells. Values ​​are shown as the fold change in signal produced by treated HeLa cells compared to untreated HeLa cells. **p < 0.01 and ****p < 0.0001.

[0060] Figure 4A and 4BA series of graphs showing the anti-tumor activity of the combination of tisotumab vedotin and pembrolizumab in a humanized mouse MDA-MB-231 xenograft model. A) Average tumor size in the NSG mouse MDA-MB-231 xenograft model after treatment with IgG1 control (open circles), IgG1-MMAE control (open diamonds), pembrolizumab (closed circles), tisotumab vedotin at a concentration of 0.5 mg / kg (half-filled triangles) or 1 mg / kg (half-filled squares), or the combination of tisotumab vedotin and pembrolizumab at a concentration of 0.5 mg / kg (closed triangles) or 1 mg / kg (closed squares). Inverted open triangles indicate the day of administration of the pembrolizumab dose. Inverted half-filled triangles indicate the day of administration of the IgG1 control, IgG1-MMAE control, or tisotumab vedotin dose. Tumor burden was assessed by caliper measurement. Error bars indicate the standard error of the mean. B) Tumor burden of individual mice in different treatment groups on day 35. Each dot represents one mouse. Anti-PD-1 Ab indicates pembrolizumab.

[0061] Figures 5A to 5C A series of graphs show that both the tesotumab vedotin antibody-drug conjugate and the free MMAE drug drive robust A) ATP secretion and C) HMGB1 release. Activity is specific to the targeted agent (tesotumab vedotin) and the free drug (MMAE). The non-targeted isotype ADC (IgG1-MMAE) does not induce A) ATP or C) HMGB1 secretion. B) Tesotumab vedotin is active against multiple tissue factor-positive cell lines.

[0062] Figure 6 Western blot images show that treatment of HPAFII (pancreatic cancer) or MDA-MB-231 (breast cancer) cells with either the tesotumomab vedotin ADC or MMAE payload for 16 hours triggers multiple ER stress pathways, including phosphorylation of IRE and its downstream targets JNK and ATF4 cleavage. Treatment with the non-targeting H00-MMAE ADC (IgG1 MMAE) does not trigger activation of these ER stress pathways.

[0063] Figure 7A and 7BThis is a series of graphs showing that tissue factor-positive MDA-MB-231 cells killed with various agents were fed to human peripheral blood mononuclear cells (PBMCs) and immune activation was assessed by increased expression of activation markers on innate CD14+ monocytes / macrophages and induction of chemokine and cytokine production. Treatment with either the tesotumab vedotin ADC or MMAE free drug drove monocyte / macrophage activation, as monitored by: A) flow cytometric determination of CD86 expression and B) induced release of innate chemokines, including MIP1β, compared to a non-targeted IgG1-MMAE ADC or the targeted antibody alone (tesotumab).

[0064] Figures 8A to 8C This is a series of graphs showing tissue factor-positive MDA-MB-231 cells killed with various agents were fed to CSFE-labeled human peripheral blood mononuclear cells (PBMCs) in the presence or absence of the PD-1-targeting antibody pembrolizumab for 48 hours. T cell activation was assessed by: A) reduction in CSFE fluorescence, indicating T cell proliferation, and B) and C) cytokine production. Treatment with either tesotumab vedotin or MMAE free drug drove T cell proliferation, which was enhanced by treatment with 2 mg / ml pembrolizumab. B) IL12p70 and C) IFNγ production also increased after exposure to tesotumab vedotin and MMAE-killed cells, and pembrolizumab treatment also increased cytokine production.

[0065] [Implementation Method]

[0066] I. Definition

[0067] To facilitate a clearer understanding of this disclosure, some terms are first defined. As used in this application, unless otherwise indicated herein, the following terms shall have the meanings set forth below. Additional definitions are provided throughout this application.

[0068] As used herein, the term "and / or" should be taken as specifically disclosing each of the two specified features or components, with or without the other. Thus, when used herein in a phrase such as "A and / or B," the term "and / or" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, when used herein in a phrase such as "A, B, and / or C," the term "and / or" is intended to include 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).

[0069] It is to be understood that aspects and embodiments of the present invention described herein include "comprising," "consisting," and "consisting essentially of" aspects and embodiments.

[0070] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure relates. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide general dictionaries of many of the terms used in this disclosure that would be readily apparent to one of ordinary skill in the art.

[0071] Units, prefixes, and symbols are expressed in their SI accepted form. Numerical ranges are inclusive of the values ​​defining the ranges. The headings provided herein are not limitations of the various aspects of the present disclosure, which are provided with reference to the specification as a whole. Therefore, the terms defined therein are more fully defined with reference to the specification as a whole.

[0072] 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, isomers, 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, tissue factor comprises the amino acid sequence found under Genbank Accession No. NP_001984.

[0073] The term "immunoglobulin" refers to a class of structurally related glycoproteins composed of two pairs of polypeptide chains: a pair of low molecular weight light (L) chains and a pair of heavy (H) chains, all four of which are interconnected by disulfide bonds. The structure of immunoglobulins has been described in detail. See, for example, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)). Briefly, each heavy chain generally comprises a heavy chain variable region (abbreviated herein as VH or VH) and heavy chain constant region (C H The heavy chain constant region generally contains three domains C H 1. C H 2 and C H 3. The heavy chains are usually linked to each other via disulfide bonds at the so-called "hinge region". Each light chain generally comprises a light chain variable region (abbreviated herein as V L or VL) and light chain constant region (C L or CL). The light chain constant region generally comprises a domain C L . CL may be of the kappa (kappa) or lambda (lambda) isotype. The terms "constant domain" and "constant region" are used interchangeably herein. Unless otherwise indicated, the numbering of amino acid residues in the constant region is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Immunoglobulins may be derived from any known isotype, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subtypes are also well known to those of ordinary skill in the art and include but are not limited to human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody type or subtype (e.g., IgM or IgG1) encoded by the heavy chain constant region gene.

[0074] 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 the antigen. H and V L) can be further subdivided into hypervariable regions (or hypervariable regions, which may be hypervariable in terms of structure-defining loop sequence and / or form) interspersed between more conserved regions called framework regions (FRs), also known as complementarity determining regions (CDRs). The terms "complementarity determining region" and "CDR" are synonymous with "hypervariable region" or "HVR" and are known in the art and refer to non-contiguous amino acid sequences within the variable region of an antibody that confer antigen specificity and / or binding affinity. Generally, there are three CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region and three CDRs (CDR-L1, CDR-L2, CDR-L3) in 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. Generally, 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 In a sequence of a polypeptide, the three CDRs and four FRs are typically arranged in the following order from amino-terminus to carboxyl-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mot. Biol., 195, 901-917 (1987)).

[0075] The term "antibody" (Ab) in the present invention refers to an immunoglobulin molecule, an immunoglobulin molecule fragment, or any derivative thereof, which has the ability to specifically bind to an antigen under typical physiological conditions with a half-life of a significant period of time, such as at least about 30 minutes, at least about 45 minutes, at least about one hour (h), at least about two hours, at least about four hours, at least about eight hours, at least about 12 hours (h), about 24 hours or more, about 48 hours or more, about three, four, five, six, seven or more days, or any other relevant functionally defined period (such as a time sufficient to induce, promote, enhance and / or modulate a physiological response associated with antibody binding to an antigen and / or a time sufficient for the antibody to recruit 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 (e.g., effector cells) and complement system components such as C1q (the first component in the classical pathway of complement activation). The antibody may also be a bispecific antibody, a diabody, a multispecific antibody, or similar molecules.

[0076] As used herein, the term "monoclonal antibody" refers to a preparation of antibody molecules recombinantly produced with a single primary amino acid sequence. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. Thus, the term "human monoclonal antibody" refers to an antibody displaying a single binding specificity that has variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by hybridomas comprising B cells obtained from transgenic or transchromosomal non-human animals (such as transgenic mice) having a genome comprising human heavy and light chain transgenes and fused to immortalized cells.

[0077] An "isolated antibody" is one 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 to other antigens (such as TF molecules from different species). Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals. In one embodiment, the isolated antibody comprises an antibody conjugate conjugated to another agent (e.g., a small molecule drug). In some embodiments, the isolated anti-TF antibody comprises a conjugate of an anti-TF antibody and a small molecule drug (e.g., MMAE or MMAF).

[0078] "HuMAb" refers to an antibody having a variable region in which the FRs and CDRs are derived from human germline immunoglobulin sequences. In addition, if the antibody comprises a constant region, the constant region is also derived from human germline immunoglobulin sequences. The human antibodies of the present invention may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations formed by random or site-directed mutagenesis in vitro or introduced by somatic mutagenesis in vivo). However, the term "human antibody" as used herein does not include antibodies in which CDR sequences derived from the germline of another mammalian species (such as a mouse) are transplanted to human framework sequences. The terms "human antibody" and "fully human antibody" are used synonymously.

[0079] As used herein, the term "humanized antibody" refers to a genetically engineered non-human antibody that contains a human antibody constant domain and a non-human variable domain modified to contain a high degree of sequence homology with a human variable domain. This can be achieved by transplanting the six non-human antibody complementary determining regions (CDRs) that together form the antigen-binding site onto a homologous human receptor framework region (FR) (see WO92 / 22653 and EP0629240). In order to fully reconstruct the binding affinity and specificity of the parent antibody, it may be necessary to replace the framework residues from the parent antibody (i.e., the non-human antibody) with the adult framework region (back mutation). Structural homology model construction may help identify amino acid residues in the framework region that are important for the binding properties of the antibody. Therefore, a humanized antibody may comprise non-human CDR sequences, primarily human framework regions (optionally comprising one or more amino acid back mutations to non-human amino acid sequences) and fully human constant regions. Alternatively, additional amino acid modifications (not necessarily back mutations) may be added to obtain humanized antibodies with better characteristics (such as affinity and biochemical properties).

[0080] As used herein, the term "chimeric antibody" 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 a human). Chimeric antibodies can be produced by antibody engineering. "Antibody engineering" is a term commonly used for different types of antibody modifications and is a process well known to those skilled in the art. Specifically, chimeric antibodies can be produced using standard DNA techniques such as those described in Sambrook et al., 1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Ch. 15. Thus, chimeric antibodies can be recombinant antibodies that have been genetically or enzymatically engineered. The production of chimeric antibodies is within the knowledge of those skilled in the art, and thus the production of chimeric antibodies according to the present invention can be performed by methods other than those described herein. Chimeric monoclonal antibodies are developed for therapeutic applications in order 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" as used for chimeric antibodies refers to the region comprising the CDRs and framework regions of both the heavy and light immunoglobulin chains.

[0081] An "anti-antigen antibody" refers to an antibody that binds to an antigen. For example, an anti-TF antibody is an antibody that binds to the antigen TF. In another example, an anti-PD-1 antibody is an antibody that binds to the antigen PD-1.

[0082] An "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the binding ability of the intact antibody to specifically bind to an antigen. Examples of antibody fragments (e.g., antigen-binding fragments) include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments (called "Fab" fragments), each with a single antigen-binding site, and a residual "Fc" fragment (the name reflects its ability to crystallize readily). Pepsin treatment produces an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.

[0083] "Percent (%) sequence identity" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a reference polypeptide sequence, after aligning the sequences and introducing gaps (if necessary) to achieve the maximum percentage of sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining the percentage of amino acid sequence identity can be achieved in various ways in the art, for example, using computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software available to the public. One of ordinary skill in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment over the full length of the compared sequences. For example, the % sequence identity of a given amino acid sequence A to, and or relative to a given amino acid sequence B (alternatively phrased as a given amino acid sequence A having or comprising a specific % sequence identity to, and or relative to a given amino acid sequence B) is calculated as follows:

[0084] Multiply 100 by the fraction X / Y

[0085] where X is the number of amino acid residues scored as an identity match by the sequence in the program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % sequence identity of A to B will not be equal to the % sequence identity of B to A.

[0086] As used herein, the terms "binding," "binds," or "specifically binds" in the context of binding of an antibody to a predetermined antigen generally have a binding affinity corresponding to about 10 Å as determined, for example, by biofilm interferometry (BLI) techniques in an OctetHTX instrument using the antibody as the ligand and the antigen as the analyte. -6 M or smaller, such as 10 -7 M or less, such as about 10 -8 M or less, such as about 10 -9 M or smaller, about 10 -10 M or smaller or about 10 -11 M or even smaller K D wherein the affinity of the antibody for binding to the predetermined antigen corresponds to the K D Compared to its K binding to nonspecific antigens (e.g. BSA, casein) other than the predetermined 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 amount of reduction depends on the K of the antibody. D , so when the antibody K D When the K of antigen binding is very low, D Lower than the K for binding to nonspecific antigens D The amount may be at least 10,000-fold (ie, the antibody is highly specific).

[0087] The term "K D "(M)" refers to the dissociation equilibrium constant for a specific antibody-antigen interaction. Affinity (as used herein) and K D The correlation is inversely proportional, that is, higher affinity means lower K D Lower affinity means higher K D .

[0088] The term "ADC" refers to an antibody-drug conjugate, which in the present invention refers to an anti-TF antibody comprising the CDRs of telostatin conjugated to monomethyl auristatin E (MMAE) as described in this application.

[0089] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0090] The abbreviation "PAB" refers to a self-immolative spacer:

[0091]

[0092] The abbreviation "MC" refers to the stretching group maleimidocaproyl:

[0093]

[0094] The term "Ab-MC-vc-PAB-MMAE" refers to an antibody conjugated to the drug MMAE via the MC-vc-PAB linker.

[0095] "Programmed Death-1" (PD-1) refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is primarily expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), hPD-1 variants, isoforms, and species homologs, and analogs having at least one common hPD-1 epitope. In some embodiments, hPD-1 comprises the amino acid sequence found under GenBank Accession No. U64863.

[0096] "Programmed Death Ligand-1" (PD-L1) is one of the two cell surface glycoprotein ligands of PD-1 (the other is PD-L2), which downregulate T cell activation and cytokine secretion when bound to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), hPD-L1 variants, isoforms and species homologs, and analogs having at least one common epitope of hPD-L1. In some embodiments, hPD-L1 comprises the amino acid sequence found under GenBank deposit number Q9NZQ7.

[0097] The "Combined positive score" or "CPS" is the ratio of the number of PD-L1-positive tumor cells and PD-L1-positive mononuclear inflammatory cells (MIC) within the tumor nests and adjacent supporting stroma (the numerator) to the total number of tumor cells (the denominator, i.e., the number of PD-L1-positive and PD-L1-negative tumor cells).

[0098] "Tumor proportion score" or "TPS" is the percentage of viable tumor cells that show partial or complete PD-L1 membrane staining of any intensity in an immunohistochemical assay.

[0099] "Cancer" refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. "Cancer" or "cancer tissue" can include tumors. Unregulated cell division and growth lead to the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. After metastasis, the distant tumor may be said to have "derived from" the pre-metastatic tumor. For example, a tumor derived from cervical cancer refers to a tumor that arose from metastatic cervical cancer.

[0100] "Treatment" or "therapy" of a subject refers to any type of intervention or procedure performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, delaying, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical signs associated with a disease. In some embodiments, the disease is cancer.

[0101] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject," "patient," and "individual" are used interchangeably herein.

[0102] An "effective amount" or "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent refers to 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 the regression of disease, as indicated by reducing the severity of disease symptoms, increasing the frequency and duration of disease-free periods, or preventing disorders or abnormalities resulting from the development of a disease. The ability of a therapeutic agent to promote the regression of disease can be assessed using a variety of methods known to those of skill in the art, such as in human subjects during clinical trials, in animal model systems predictive of human efficacy, or by measuring the activity of the agent in vitro.

[0103] Taking tumor treatment as an example, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% in a treated individual (e.g., one or more treated individuals) relative to an untreated individual (e.g., one or more untreated individuals). In some embodiments, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by 100% in a treated individual (e.g., one or more treated individuals) relative to an untreated individual (e.g., one or more untreated individuals).

[0104] In other embodiments of the present disclosure, tumor regression can be observed and sustained 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. While these are the ultimate measures of therapeutic effectiveness, the evaluation of immunotherapeutic drugs must also consider "immune-related response patterns."

[0105] A therapeutically effective amount of a drug (e.g., an anti-TF antibody-drug conjugate comprising MMAE and the CDRs of tesoluzumab or an anti-PD-1 antibody comprising the CDRs of pembrolizumab) includes a "prophylactically effective amount," which refers to any amount of a drug that, when administered alone or in combination with an anti-cancer agent to an individual at risk of developing cancer (e.g., an individual with a premalignant condition) or an individual at risk of cancer recurrence, inhibits the development or recurrence of cancer. In some embodiments, a prophylactically effective amount completely prevents the development or recurrence of cancer. "Inhibiting" cancer development or recurrence means reducing the likelihood of cancer development or recurrence or completely preventing the development or recurrence of cancer.

[0106] As used herein, a "subtherapeutic dose" refers to a dose of a therapeutic compound (e.g., an anti-TF antibody-drug conjugate comprising MMAE and the CDRs of tesoluzumab or an anti-PD-1 antibody comprising the CDRs of pembrolizumab) that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease (e.g., cancer).

[0107] An "immune-related response pattern" refers to the clinical response pattern typically observed in cancer patients treated with immunotherapeutic agents that produce anti-tumor effects by inducing a cancer-specific immune response or by modulating innate immune processes. This response pattern is characterized by a beneficial treatment effect after an initial increase in tumor burden or the appearance of new lesions. In the evaluation of traditional chemotherapeutic agents, this response pattern would be classified as disease progression and would be synonymous with drug failure. Therefore, appropriate evaluation of immunotherapeutic agents requires long-term monitoring of the effects of these agents on the target disease.

[0108] For example, an "anti-cancer agent" promotes the regression of cancer in an individual. In some embodiments, a therapeutically effective amount of a drug promotes the regression of cancer to the extent that the cancer is eliminated. "Promoting cancer regression" refers to the administration of an effective amount of a drug, alone or in combination with an anti-cancer agent, that results 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 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 the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ, and / or organismal level resulting from the administration of the drug.

[0109] A "sustained response" refers to a persistent effect of 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 administration period. In some embodiments, the sustained response has a duration that is at least the same as the treatment period or is at least 1.5, 2.0, 2.5, or 3 times longer than the treatment period.

[0110] As used herein, "complete response" or "CR" means disappearance of all target lesions; "partial response" or "PR" means a decrease of at least 30% in the sum of the longest diameters (SLD) of the target lesions relative to the baseline SLD; and "stable disease" or "SD" means that the target lesions have not shrunk enough to qualify as a PR and have not increased enough to qualify as a PD, relative to the smallest SLD since the start of treatment.

[0111] As used herein, "progression-free survival" or "PFS" refers to the length of time during and after treatment that the disease being treated (e.g., cancer) does not get worse. Progression-free survival can include the amount of time a patient experiences a complete response or partial response, as well as the amount of time a patient experiences stable disease.

[0112] As used herein, "overall response rate" or "ORR" refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0113] As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group who are likely to be alive after a specific period of time.

[0114] The term "weight-based dose" herein refers to a dose calculated based on the individual's weight. For example, if a 60 kg individual requires 2.0 mg / kg of an anti-PD-1 antibody comprising pembrolizumab CDRs or an anti-TF antibody-drug conjugate comprising MMAE and tesolutumab CDRs, an appropriate amount of the anti-PD-1 antibody comprising pembrolizumab CDRs or the anti-TF antibody-drug conjugate comprising MMAE and tesolutumab CDRs (i.e., 120 mg) for administration to the individual can be calculated and used.

[0115] As used in connection with the disclosed methods, the term "fixed dose" refers to the administration of two or more different antibodies (e.g., an anti-PD-1 antibody comprising pembrolizumab CDRs and an anti-TF antibody-drug conjugate comprising MMAE and tesotumab CDRs) 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 an anti-PD-1 antibody comprising pembrolizumab CDRs to an anti-TF antibody-drug conjugate comprising MMAE and tesotumab CDRs to a subject may refer to administering to the subject approximately 240 mg of the anti-PD-1 antibody comprising pembrolizumab CDRs and approximately 80 mg of the anti-TF antibody-drug conjugate comprising MMAE and tesotumab CDRs, or approximately 3 mg / ml of the anti-PD-1 antibody comprising pembrolizumab CDRs and approximately 1 mg / ml of the anti-TF antibody-drug conjugate comprising MMAE and tesotumab CDRs.

[0116] As used in connection with the methods and dosages of the present disclosure, the term "flat dose" refers to a dose administered to a subject without regard to the subject's weight or body surface area (BSA). Thus, a flat dose is not provided as a mg / kg dose, but rather as an absolute amount of a drug (e.g., an anti-TF antibody-drug conjugate comprising MMAE and tesotumab CDRs and / or an anti-PD-1 antibody comprising pembrolizumab CDRs). For example, a subject weighing 60 kg and a subject weighing 100 kg would receive the same dose of the antibody or antibody-drug conjugate (e.g., 240 mg of an anti-TF antibody-drug conjugate comprising MMAE and tesotumab CDRs or, e.g., 200 mg of an anti-PD-1 antibody comprising pembrolizumab CDRs).

[0117] The term "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the mammal to be treated.

[0118] As used herein, the term "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, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-bis-(2-hydroxy-3-naphthoate)), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may include another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Additionally, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Multiple counterions may be present when multiple charged atoms are part of the pharmaceutically acceptable salt. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counteratoms.

[0119] "Administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of the various methods and delivery systems known to those of ordinary skill in the art. Exemplary routes of administration for anti-TF antibody-drug conjugates comprising MMAE and tesoluzumab CDRs and / or anti-PD-1 antibodies comprising pembrolizumab CDRs 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 term "parenteral administration" refers to modes of administration, other than enteral and topical administration, typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. The therapeutic agent may be administered via 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 can also be performed, for example, once, multiple times and / or over one or more extended periods.

[0120] The terms "baseline" or "baseline value," as used interchangeably herein, may refer to a measurement or representation of a symptom prior to or at the start of administration of a therapy (e.g., an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein). A baseline value may be compared to a reference value to determine a reduction or improvement in symptoms of a TF-related disease and / or a PD-1-related disease (e.g., breast cancer or cervical cancer) contemplated herein. The terms "reference" or "reference value," as used interchangeably herein, may refer to a measurement or representation of a symptom after administration of a therapy (e.g., an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein). A reference value may be measured one or more times during or upon 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.

[0121] 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. The reference value and / or baseline value 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 than five individuals).

[0122] As used herein, the term "monotherapy" means that the anti-TF antibody-drug conjugate comprising MMAE and tesoluzumab CDRs or the anti-PD-1 antibody comprising pembrolizumab CDRs is the only anti-cancer agent administered to a subject during a treatment cycle. However, other therapeutic agents may be administered to the subject. For example, an anti-inflammatory agent or other agent administered to a subject with cancer to treat symptoms associated with the cancer but not the actual cancer itself, including, for example, inflammation, pain, weight loss, and general discomfort, may be administered during monotherapy.

[0123] As used herein, an "adverse event" (AE) is any unfavorable and generally unintended or unwanted sign (including abnormal laboratory results), symptom, or disease associated with the use of a medical treatment. A medical treatment may have one or more associated AEs, and each AE may have the same or varying degrees of severity. A method capable of "altering 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.

[0124] As used herein, a "serious adverse event" or "SAE" is an adverse event that meets one of the following criteria:

[0125] 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 could theoretically cause death if it were more severe.

[0126] · Causes persistent or significant disability / incapacity

[0127] Cause congenital abnormalities / birth defects

[0128] 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 to determine whether an AE is "medically significant"

[0129] The need for hospitalization or prolongation of the current hospitalization, excluding 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 form, and 3) social reasons and suspension of care in the absence of any worsening of the patient's overall condition.

[0130] Use of alternatives (eg, "or") should be understood to mean any one, both, or any combination of the alternatives. As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of any recited or enumerated component.

[0131] The terms "about" or "comprising essentially of" refer to within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "comprising essentially of" may refer to within 1 standard deviation or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "comprising essentially of" may refer to a range of up to 20%. In addition, particularly with respect to biological systems or processes, the terms may refer to values ​​of up to an order of magnitude or up to 5 times. When the present application and claims provide a particular value or composition, unless otherwise stated, the meaning of "about" or "comprising essentially of" should be assumed to be within an acceptable error range for that particular value or composition.

[0132] As used herein, the terms "about once a week," "about once every 2 weeks," or any other similar dosing interval terms refer to approximate quantities. "About once a week" may include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "About once every 2 weeks" may include every 14 days ± 2 days, i.e., every 12 days to every 16 days. "About once every 3 weeks" may include every 21 days ± 3 days, i.e., every 18 days to every 24 days. Similar approximations apply, for example, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In some embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to that the first dose can be administered on any day of the 1st week, followed by the next dose being administered on any day of the 6th or 12th week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to that the first dose is administered on a certain day (e.g., Monday) of the 1st week, followed by the next dose being administered on the same day (i.e., Monday) of the 6th or 12th week, respectively.

[0133] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer and, where appropriate, fractional values ​​thereof (such as tenths and hundredths of an integer) within the recited range unless otherwise indicated.

[0134] Various aspects of the disclosure are described in further detail in the following sections.

[0135] II. Combination Therapy

[0136] One aspect of the present invention provides an anti-TF antibody-drug conjugate that binds to TF for use in treating cancer, wherein the antibody-drug conjugate is for administration or to be administered in combination with an anti-PD-1 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 E, and wherein the anti-PD-1 antibody or antigen-binding fragment thereof inhibits PD-1 activity, wherein the anti-PD-1 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:

[0137] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0138] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0139] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0140] Wherein the light chain variable region comprises:

[0141] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0142] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0143] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the CDRs of the anti-PD-1 antibody or antigen-binding fragment thereof are generally defined by the Kabat numbering scheme,

[0144] The anti-TF 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:

[0145] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0146] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0147] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0148] Wherein the light chain variable region comprises:

[0149] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0150] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0151] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the anti-TF antibody or antigen-binding fragment thereof CDRs are defined by the IMGT numbering scheme. In another aspect, the present invention provides an anti-PD-1 antibody or antigen-binding fragment thereof comprising a pembrolizumab CDR for use in treating cancer, wherein the anti-PD-1 antibody is for administration or to be administered in combination with an antibody-drug conjugate that binds to TF, wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof comprising a pembrolizumab CDR conjugated to monomethyl auristatin E, and wherein the anti-PD-1 antibody or antigen-binding fragment thereof inhibits PD-1 activity. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the cancer is cervical cancer. 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.

[0152] A. Anti-TF antibodies

[0153] Generally, 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 breast cancer cells or cervical cancer cells, wherein the anti-TF antibodies or antigen-binding fragments thereof comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0154] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0155] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0156] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0157] Wherein the light chain variable region comprises:

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

[0159] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0160] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the anti-TF antibody or antigen-binding fragment thereof CDRs are defined by the IMGT numbering scheme. The anti-TF antibodies of the present disclosure comprise the CDRs of tezomib and are preferably monoclonal and can be multispecific, human, humanized or chimeric antibodies, single-chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, and TF-binding fragments of any of the foregoing. In some embodiments, the anti-TF antibodies of the present disclosure comprise the CDRs of tezomib and specifically bind to TF. The immunoglobulin molecules of the present disclosure can be immunoglobulin molecules of any class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), type (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subtype.

[0161] In certain embodiments of the present disclosure, the anti-TF antibodies comprise the tezomib CDRs and are antigen-binding fragments (e.g., human antigen-binding fragments) as described herein and include, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fv (scFv), single-chain antibodies, disulfide-linked Fv (sdFv), and V-binding fragments. L or V H 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 the 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, camel, horse, or chicken and comprises the tesotumomab CDRs.

[0162] The anti-TF antibodies disclosed herein comprise the tezomib CDRs and can be monospecific, bispecific, trispecific, or multispecific with greater than trispecificity. Multispecific antibodies can have specificity for different epitopes of TF or can have specificity for TF as well as 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. Patent Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., 1992, J. Immunol. 148:1547-1553.

[0163] The anti-TF antibodies of the present disclosure may be described or specified in terms of the specific CDRs they comprise. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of several well-known schemes, including those described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262: 732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732-745. " ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains, "Dev Comp Immunol, 2003 Jan; 27(1): 55-77 ("IMGT" numbering scheme); Honegger A and Plückthun A, "Yetanother numbering scheme for immunoglobulin variable domains: an automaticmodeling and analysis tool, "J Mol Biol, 2001 Jun 8; 309(3): 657-70 ("Aho" numbering scheme); and Martin et al., "Modeling antibody hypervariable loops: a combined algorithm, "PNAS, 1989, 86(23): 9268-9272 ("AbM" numbering scheme). The boundaries of a given CDR vary depending on the scheme used for identification.In some embodiments, the term "CDR" or "complementary determining region" or individually designated CDRs (e.g., CDR-H1, CDR-H2, CDR-H3) of a given antibody or region thereof (e.g., variable region thereof) is understood to encompass the (specific) CDRs defined in any of the aforementioned schemes. For example, when a specific CDR (e.g., CDR-H3) is described as containing a given V H or V L When referring to an amino acid sequence corresponding to a 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) within the variable region as defined by any of the aforementioned schemes. A specific CDR or schemes for identifying CDRs can be specified, such as CDRs defined by the Kabat, Chothia, AbM, or IMGT methods.

[0164] The amino acid residue numbering in the anti-TF antibody CDR sequences of the anti-TF antibody-drug conjugates provided herein is performed according to the IMGT numbering scheme as described in Lefranc, MP et al., Dev. Comp. Immunol., 2003, 27, 55-77. The anti-TF antibody CDR sequences used in the anti-TF antibody-drug conjugates provided herein are performed according to the IMGT method as described in Lefranc, MP et al., Dev. Comp. Immunol., 2003, 27, 55-77.

[0165] The anti-TF antibodies disclosed herein comprise the 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 comprising (a) a set of three CDRs, wherein the set of CDRs is derived from monoclonal antibody 011, and (b) a set of four framework regions, wherein the set of framework regions differs from the set of framework regions 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 tesotumomab.

[0166] In one aspect, provided herein are anti-TF antibodies comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and wherein the light chain variable region comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the anti-TF antibody CDRs are defined by the IMGT numbering scheme.

[0167] The anti-TF antibodies described herein can comprise any suitable framework variable domain sequence, provided that the antibody retains the ability to bind to TF (e.g., human TF). As used herein, the heavy chain framework region is designated "HC-FR1-FR4" and the light chain framework region is designated "LC-FR1-FR4." In some embodiments, the anti-TF antibodies comprise 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 antibodies comprise 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).

[0168] In some embodiments of the anti-TF antibodies described herein, the heavy chain variable domain comprises the following amino acid sequence:

[0169] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSSISGSGDYTYYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSPWGYYLDSWGQGTLVTVSS (SEQ ID NO: 7), and the light chain variable domain comprises the following amino acid sequence:

[0170] DIQMTQSPPSLSASAGDRVTITCRASQGISSRLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO: 8).

[0171] In some embodiments of the anti-TF antibodies described herein, the heavy chain CDR sequence comprises the following:

[0172] a) CDR-H1 (GTFFSNYA (SEQ ID NO: 1));

[0173] b) CDR-H2(ISGSGDYT(SEQ ID NO:2)); and

[0174] c) CDR-H3 (ARSPWGYYLDS (SEQ ID NO: 3)).

[0175] In some embodiments of the anti-TF antibodies described herein, the heavy chain FR sequence comprises the following:

[0176] a) HC-FR1(EVQLLESGGGLVQPGGSLRLSCAAS(SEQ ID NO:9));

[0177] b) HC-FR2 (MSWVRQAPGKGLEWVSS (SEQ ID NO: 10));

[0178] c) HC-FR3(YYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC(SEQ ID NO:11)); and

[0179] d) HC-FR4 (WGQGTLVTVSS (SEQ ID NO: 12)).

[0180] In some embodiments of the anti-TF antibodies described herein, the light chain CDR sequence comprises the following:

[0181] a) CDR-L1 (QGISSR (SEQ ID NO: 4));

[0182] b) CDR-L2 (AAS (SEQ ID NO: 5)); and

[0183] c) CDR-L3 (QQYNSYPYT (SEQ ID NO: 6)).

[0184] In some embodiments of the anti-TF antibodies described herein, the light chain FR sequence comprises the following:

[0185] a) LC-FR1(DIQMTQSPPSLSASAGDRVTITCRAS(SEQ ID NO:13));

[0186] b) LC-FR2(LAWYQQKPEKAPKSLIY(SEQ ID NO:14));

[0187] c) LC-FR3(SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:15)); and

[0188] d) LC-FR4 (FGQGTKLEIK (SEQ ID NO: 16)).

[0189] In some embodiments, provided herein are anti-TF antibodies that bind 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:

[0190] (a) a heavy chain variable domain comprising:

[0191] (1) HC-FR1 comprising the amino acid sequence of SEQ ID NO: 9;

[0192] (2) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0193] (3) HC-FR2 comprising the amino acid sequence of SEQ ID NO: 10;

[0194] (4) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2;

[0195] (5) HC-FR3 comprising the amino acid sequence of SEQ ID NO: 11;

[0196] (6) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0197] (7) HC-FR4 comprising the amino acid sequence of SEQ ID NO: 12, and / or

[0198] (b) a light chain variable domain comprising:

[0199] (1) LC-FR1 comprising the amino acid sequence of SEQ ID NO: 13;

[0200] (2) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0201] (3) LC-FR2 comprising the amino acid sequence of SEQ ID NO: 14;

[0202] (4) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5;

[0203] (5) LC-FR3 comprising the amino acid sequence of SEQ ID NO: 15;

[0204] (6) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and

[0205] (7) LC-FR4 comprising the amino acid sequence of SEQ ID NO: 16.

[0206] In one aspect, provided herein are anti-TF antibodies 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 are anti-TF antibodies 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. In one aspect, provided herein are anti-TF antibodies comprising a heavy chain variable domain CDR comprising the amino acid sequence of SEQ ID NO: 7 and comprising a light chain variable domain CDR comprising the amino acid sequence of SEQ ID NO: 8.

[0207] 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 in SEQ ID NO: 7 are substituted, inserted, and / or deleted. In certain embodiments, substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., within the FRs). In some embodiments, the anti-TF antibody comprises the heavy chain variable domain sequence of SEQ ID NO: 7, including post-translational modifications of that sequence. In a specific embodiment, the heavy chain variable domain comprises: (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.

[0208] 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 in SEQ ID NO: 8 are substituted, inserted, and / or deleted. In certain embodiments, substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., within the FRs). In some embodiments, the anti-TF antibody comprises the light chain variable domain sequence of SEQ ID NO: 8, including post-translational modifications of that sequence. In a specific embodiment, the light chain variable domain comprises: (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.

[0209] In some embodiments, the anti-TF antibody comprises a heavy chain variable domain as described in any of the embodiments provided above and a light chain variable domain as described in any of the embodiments provided above. In one embodiment, the antibody comprises 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.

[0210] 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 anti-TF antibody CDRs are defined by the IMGT numbering scheme.

[0211] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate comprises: i) an amino acid sequence that has 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 that has at least 85% sequence identity to a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0212] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate comprises tesotumomab CDRs and is a monoclonal antibody.

[0213] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate is tesotumomab, also known as antibody 011 described in WO 2011 / 157741 and WO 2010 / 066803.

[0214] The anti-TF antibodies comprising the CDRs of telostatumab of the present invention may also be described or specified in terms of their binding affinity to TF (e.g., human TF). Preferred binding affinities include those with dissociation constants or Kd less than 5×10 -2 M, 10 -2 M, 5×10 -3 M, 10 -3 M, 5×10 -4 M, 10 -4 M, 5×10 -5 M, 10 -5 M, 5×10 -6 M, 10 -6 M, 5×10 -7 M, 10 -7 M, 5×10 -8 M, 10 -8 M, 5×10 -9 M, 10 -9 M, 5×10 -10 M, 10 -10 M, 5×10 -11 M, 10 -11 M, 5×10 -12 M, 10 -12 M, 5×10 -13 M, 10 -13 M, 5×10 -14 M, 10 -14 M, 5×10 -15 M or 10 -15 M.

[0215] There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, each with heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subtypes, for example, humans exhibit the following subtypes: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in a variety of polymorphic variants, known as allotypes (reviewed in Jefferis and Lefranc 2009. mAbs Vol 1 Issue 4 1-7), any of which are suitable for use in some embodiments herein. Common allotype variants in the human population are designated by the letters a, f, n, z, or a combination thereof. In any of the embodiments herein, the antibody may comprise a heavy chain Fc region comprising a human IgG Fc region. In further embodiments, the human IgG Fc region comprises a human IgG1.

[0216] Antibodies also include modified derivatives, i.e., by covalently linking any type of molecule to the antibody, where such covalent linkage does not prevent the antibody from binding to TF or exhibiting cytostatic or cytotoxic effects on HD cells. For example, but not limited to, antibody derivatives include antibodies modified by, for example, glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage to cellular ligands or other proteins, and the like. Any of a variety of chemical modifications can be performed using known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, and the like. Furthermore, derivatives may contain one or more atypical amino acids.

[0217] B. Antibody-Drug Conjugate Structure

[0218] In some aspects, the anti-TF antibody-drug conjugates described herein comprise a linker between an anti-TF antibody or antigen-binding fragment thereof as described herein and monomethyl auristatin E (MMAE). In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a cleavable linker.

[0219] In some embodiments, the linker is a cleavable peptide linker comprising a maleimidocaproyl group (MC), a dipeptide valine-citrulline (vc), and p-aminobenzylcarbamate (PAB). In some embodiments, the cleavable peptide linker has the formula -MC-vc-PAB-, wherein:

[0220] a)MC is:

[0221]

[0222] b) vc is the dipeptide valine-citrulline, and

[0223] c) PAB is:

[0224]

[0225] In some embodiments, the linker comprises a cleavable peptide linker of maleimidocaproyl (MC). In some embodiments, the cleavable peptide linker has the formula MC-, wherein:

[0226] a)MC is:

[0227]

[0228] In some embodiments, the linker is a thiol residue attached to an anti-TF antibody or antigen-binding fragment thereof comprising the CDRs of tesotumomab, wherein the thiol residue is obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof. In some embodiments, the linker is a thiol residue attached to an anti-TF antibody or antigen-binding fragment thereof comprising the CDRs of tesotumomab, wherein the thiol residue is obtained by partial reduction of the anti-TF antibody or antigen-binding fragment thereof. In some embodiments, the linker is a thiol residue attached to an anti-TF antibody or antigen-binding fragment thereof comprising the CDRs of tesotumomab, wherein the thiol residue is obtained by complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0229] In some aspects, the anti-TF antibody-drug conjugates described herein comprise a linker as described herein between an anti-TF antibody or antigen-binding fragment thereof as described herein and monomethyl auristatin E (MMAE). Auristatins such as MMAE 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. Patent No. 5,663,149) and antifungal activity (see Pettit et al., (1998) Antimicrob. Agents and Chemother. 42: 2961-2965). MMAE and suitable linkers for conjugating MMAE to Abs are described, for example, in U.S. Patent Nos. 5,635,483, 5,780,588, and 6,214,345 and International Patent Application Publications WO02088172, WO2004010957, WO2005081711, WO2005084390, WO2006132670, WO03026577, WO200700860, WO207011968, and WO205082023. The anti-TF antibody-drug conjugates described herein comprise MMAE and tesotumomab CDRs.

[0230] Monomethylauristatin E (MMAE) has the following structure:

[0231]

[0232] The wavy lines represent the locations where the connectors are attached.

[0233] In one embodiment, a cleavable peptide linker has the formula -MC-vc-PAB- and is attached to MMAE. The resulting linker, auristatin MC-vc-PAB-MMAE, is also designated vcMMAE. The vcMMAE drug linker moiety and conjugation methods are disclosed in WO2004010957, US7659241, US7829531, and US7851437. When vcMMAE is attached to an anti-TF antibody or antigen-binding fragment thereof comprising the CDRs of telostatin as described herein, the resulting structure is:

[0234]

[0235] Wherein P represents a number from 1 to 8, e.g., 1, 2, 3, 4, 5, 6, 7, or 8, e.g., P can be 3 to 5, S represents a sulfhydryl residue of the anti-TF antibody, and AB designates an anti-TF antibody or antigen-binding fragment thereof as described herein. In one embodiment, the average value of P in a population of antibody-drug conjugates is about 4. In some embodiments, P is measured by hydrophobic interaction chromatography (HIC), e.g., to resolve drug-loaded species based on increasing hydrophobicity, where the least hydrophobic unconjugated form elutes first and the most hydrophobic drug form elutes last, and the peak area percentage represents the relative distribution of antibody-drug conjugate species loaded with a particular drug. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols). In some embodiments, P is measured by reverse-phase high-performance liquid chromatography (RP-HPLC), for example, by first performing a reduction reaction to completely dissociate the heavy and light chains of the ADC, followed by separation of the light and heavy chains and their corresponding drug-loaded forms on an RP column, wherein the percentage peak is derived from the integration of the light and heavy chain peaks, combined with the drug loading 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).

[0236] In one embodiment, the antibody-drug conjugate is tesotumomab vedotin.

[0237] C. Anti-PD-1 Antibodies

[0238] Generally, the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure binds to PD-1 (e.g., human PD-1), wherein the anti-PD-1 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:

[0239] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0240] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0241] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0242] Wherein the light chain variable region comprises:

[0243] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0244] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0245] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the anti-PD-1 antibody or antigen-binding fragment thereof CDRs are generally defined by the Kabat numbering scheme. The anti-PD-1 antibodies of the present disclosure comprise pembrolizumab CDRs and are preferably monoclonal and can be multispecific, human, humanized or chimeric antibodies, single-chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, and PD-1 binding fragments of any of the foregoing. In some embodiments, the anti-PD-1 antibodies described herein comprise pembrolizumab CDRs and specifically bind to PD-1 (e.g., human PD-1). The immunoglobulin molecules of the present disclosure can be immunoglobulin molecules of any class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), type (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subtype.

[0246] In certain embodiments of the present disclosure, the antibodies are antigen-binding fragments (e.g., human antigen-binding fragments) as described herein and include, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fv (scFv), single-chain antibodies, disulfide-linked Fv (sdFv), and V-containing fragments. L or V HFragments of the PD-1 domain. 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 the hinge region, CH1, CH2, CH3, and CL domains. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken and comprises the pembrolizumab CDRs.

[0247] The anti-PD-1 antibodies disclosed herein comprise pembrolizumab CDRs and can be monospecific, bispecific, trispecific, or multispecific with greater than trispecificity. Multispecific antibodies can have specificity for different epitopes of PD-1 or can have specificity for PD-1 as well as 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. Patent Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., 1992, J. Immunol. 148:1547-1553.

[0248] The anti-PD-1 antibodies of the present disclosure may be described or specified with respect to the specific CDRs that they comprise. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of several well-known schemes, including those described in: Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262: 732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732-745. " ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains, "Dev Comp Immunol, 2003 Jan; 27(1): 55-77 ("IMGT" numbering scheme); Honegger A and Plückthun A, "Yetanother numbering scheme for immunoglobulin variable domains: an automaticmodeling and analysis tool, "J Mol Biol, 2001 Jun 8; 309(3): 657-70 ("Aho" numbering scheme); and Martin et al., "Modeling antibody hypervariable loops: a combined algorithm, "PNAS, 1989, 86(23): 9268-9272 ("AbM" numbering scheme). The boundaries of a given CDR vary depending on the scheme used for identification.In some embodiments, the term "CDR" or "complementary determining region" or individually designated CDRs (e.g., CDR-H1, CDR-H2, CDR-H3) of a given antibody or region thereof (e.g., variable region thereof) is understood to encompass the (specific) CDRs defined in any of the aforementioned schemes. For example, when a specific CDR (e.g., CDR-H3) is described as containing a given V H or V L When referring to an amino acid sequence corresponding to a 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 aforementioned schemes. A specific CDR or schemes for identifying CDRs can be specified, such as CDRs defined by the Kabat, Chothia, AbM, or IMGT methods.

[0249] The numbering of amino acid residues in the CDR sequences of the anti-PD-1 antibodies and antigen-binding fragments provided herein is generally according to the Kabat numbering scheme as described in Kabat EA, et al., 1991, Sequences of proteins of Immunological interest, In: NIH Publication No. 91-3242, US Department of Health and Human Services, Bethesda, MD.

[0250] The anti-PD-1 antibodies of the present disclosure comprise the antibody pembrolizumab CDRs. See U.S. Patent Nos. 8,354,509 and 8,900,587. The present disclosure encompasses anti-PD-1 antibodies or derivatives thereof comprising a heavy or light chain variable domain comprising (a) a set of three CDRs, wherein the set of CDRs is from the monoclonal antibody pembrolizumab, and (b) a set of four framework regions, wherein the set of framework regions is different from the set of framework regions in the monoclonal antibody pembrolizumab and wherein the anti-PD-1 antibody or derivative thereof binds to PD-1. In certain embodiments, the anti-PD-1 antibody is pembrolizumab. The antibody pembrolizumab is also known as (Merck & Co., Inc., Kenilworth, NJ, USA).

[0251] In one aspect, provided herein is an anti-PD-1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and wherein the light chain variable region comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the anti-PD-1 antibody CDRs are generally defined by the Kabat numbering scheme.

[0252] In one embodiment, the anti-PD-1 antibody comprises a light chain variable domain comprising a framework sequence and a hypervariable region, wherein the framework sequence comprises the amino acid sequences LC-FR1 to LC-FR4 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.

[0253] In some embodiments of the anti-PD-1 antibodies described herein, the heavy chain variable domain comprises the following amino acid sequence:

[0254] QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS (SEQ ID NO: 31) and the light chain variable domain comprises the following amino acid sequence: EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK (SEQ ID NO: 32).

[0255] In some embodiments of the anti-PD-1 antibodies described herein, the heavy chain CDR sequence comprises the following:

[0256] a) CDR-H1(NYYMY(SEQ ID NO:17));

[0257] b) CDR-H2 (GINPSNGGTNFNEKFKN (SEQ ID NO: 18)); and

[0258] c) CDR-H3 (RDYRFDMGFDY (SEQ ID NO: 19)).

[0259] In some embodiments of the anti-PD-1 antibodies described herein, the heavy chain FR sequence comprises the following:

[0260] a) HC-FR1 (QVQLVQSGVEVKKPGASVKVSCKASGYTFT (SEQ ID NO: 23));

[0261] b) HC-FR2 (WVRQAPGQGLEWMG (SEQ ID NO: 24));

[0262] c) HC-FR3 (RVTTLTTDSSTTTAYMELKSLQFDDTAVYYCAR (SEQ ID NO: 25)); and

[0263] d) HC-FR4 (WGQGTTVTVSS (SEQ ID NO: 26)). In some embodiments of the anti-PD-1 antibodies described herein, the light chain CDR sequence comprises the following:

[0264] a) CDR-L1 (RASKGVSTSGYSYLH (SEQ ID NO: 20));

[0265] b) CDR-L2 (LASYLES (SEQ ID NO: 21)); and

[0266] c) CDR-L3 (QHSRDLPLT (SEQ ID NO: 22)).

[0267] In some embodiments of the anti-PD-1 antibodies described herein, the light chain FR sequence comprises the following:

[0268] a) LC-FR1 (EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 27));

[0269] b) LC-FR2(WYQQKPGQAPRLLIY(SEQ ID NO:28));

[0270] c) LC-FR3 (GVPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 29)); and

[0271] d) LC-FR4 (FGGGTKVEIK (SEQ ID NO: 30)).

[0272] In some embodiments, provided herein are anti-PD-1 antibodies that bind to PD-1 (e.g., human PD-1), wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody comprises:

[0273] (a) a heavy chain variable domain comprising:

[0274] (1) HC-FR1 comprising the amino acid sequence of SEQ ID NO: 23;

[0275] (2) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0276] (3) HC-FR2 comprising the amino acid sequence of SEQ ID NO: 24;

[0277] (4) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18;

[0278] (5) HC-FR3 comprising the amino acid sequence of SEQ ID NO: 25;

[0279] (6) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0280] (7) HC-FR4 comprising the amino acid sequence of SEQ ID NO: 26, and / or

[0281] (b) a light chain variable domain comprising:

[0282] (1) LC-FR1 comprising the amino acid sequence of SEQ ID NO: 27;

[0283] (2) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0284] (3) LC-FR2 comprising the amino acid sequence of SEQ ID NO: 28;

[0285] (4) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21;

[0286] (5) LC-FR3 comprising the amino acid sequence of SEQ ID NO: 29;

[0287] (6) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22; and

[0288] (7) LC-FR4 comprising the amino acid sequence of SEQ ID NO: 30.

[0289] In one aspect, provided herein are anti-PD-1 antibodies comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31 or comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32. In one aspect, provided herein are anti-PD-1 antibodies comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31 and comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32. In one aspect, provided herein are anti-PD-1 antibodies comprising a heavy chain variable domain CDR comprising the amino acid sequence of SEQ ID NO: 31 and comprising a light chain variable domain CDR comprising the amino acid sequence of SEQ ID NO: 32.

[0290] In some embodiments, provided herein are anti-PD-1 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 PD-1 (e.g., human PD-1). In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 31 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., within the FRs). In some embodiments, the anti-PD-1 antibody comprises the heavy chain variable domain sequence of SEQ ID NO: 31, including post-translational modifications of that sequence. In one specific embodiment, the heavy chain variable domain comprises: (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.

[0291] In some embodiments, provided herein are anti-PD-1 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 PD-1 (e.g., human PD-1). In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 32 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., within the FRs). In some embodiments, the anti-PD-1 antibody comprises the light chain variable domain sequence of SEQ ID NO: 32, including post-translational modifications of that sequence. In one specific embodiment, the light chain variable domain comprises: (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.

[0292] In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable domain as described in any of the embodiments provided above and a light chain variable domain as described in any of the embodiments provided above. In one embodiment, the antibody comprises a heavy chain variable domain sequence of SEQ ID NO: 31 and a light chain variable domain sequence of SEQ ID NO: 32, including post-translational modifications of these sequences.

[0293] In some embodiments, the anti-PD-1 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, wherein the anti-PD-1 antibody CDRs are generally defined by the Kabat numbering scheme.

[0294] In some embodiments, the anti-PD-1 antibody comprises: i) an amino acid sequence that has 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 that has at least 85% sequence identity to a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32.

[0295] In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises

[0296] QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 33), and the light chain comprises

[0297] EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:34) amino acid sequence.

[0298] In some embodiments, provided herein are anti-PD-1 antibodies comprising a heavy chain 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: 33. In certain embodiments, the heavy chain 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: 33 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and retains the ability to bind to PD-1 (e.g., human PD-1). In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 33 are substituted, inserted, and / or deleted. In certain embodiments, substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., within the FRs). In some embodiments, the anti-PD-1 antibody comprises the heavy chain sequence of SEQ ID NO: 33, including post-translational modifications thereof. In a specific embodiment, the heavy chain comprises: (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.

[0299] In some embodiments, provided herein are anti-PD-1 antibodies comprising a light chain 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: 34. In certain embodiments, the light chain 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: 34 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and retains the ability to bind to PD-1 (e.g., human PD-1). In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 34 are substituted, inserted, and / or deleted. In certain embodiments, substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., within the FRs). In some embodiments, the anti-PD-1 antibody comprises the light chain sequence of SEQ ID NO: 34, including post-translational modifications of that sequence. In a specific embodiment, the light chain comprises: (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.

[0300] In some embodiments, the anti-PD-1 antibody comprises pembrolizumab CDRs and is a monoclonal antibody.

[0301] In some embodiments, the anti-PD-1 antibody is pembrolizumab, also known as the antibody described in U.S. Pat. Nos. 8,354,509 and 8,900,587.

[0302] The anti-PD-1 antibodies of the present invention comprising the CDRs of pembrolizumab may also be described or specified in terms of their binding affinity to PD-1 (e.g., human PD-1). Preferred binding affinities include a dissociation constant or Kd of less than 5×10 -2 M, 10 -2 M, 5×10 -3 M, 10 -3 M, 5×10 -4 M, 10 -4 M, 5×10 -5 M, 10 -5 M, 5×10 -6 M, 10 -6 M, 5×10 -7 M, 10 -7M, 5×10 -8 M, 10 -8 M, 5×10 -9 M, 10 -9 M, 5×10 -10 M, 10 -10 M, 5×10 -11 M, 10 -11 M, 5×10 -12 M, 10 -12 M, 5×10 -13 M, 10 -13 M, 5×10 -14 M, 10 -14 M, 5×10 -15 M or 10 -15 Those of M.

[0303] There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, each with heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subtypes, for example, humans exhibit the following subtypes: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in a variety of polymorphic variants, known as allotypes (reviewed in Jefferis and Lefranc 2009. mAbs Vol 1 Issue 4 1-7), any of which are suitable for use in some embodiments herein. Common allotype variants in the human population are designated by the letters a, f, n, z, or a combination thereof. In any of the embodiments herein, the antibody may comprise a heavy chain Fc region comprising a human IgG Fc region. In further embodiments, the human IgG Fc region comprises a human IgG1.

[0304] Antibodies also include modified derivatives, i.e., by covalently linking any type of molecule to the antibody, and the covalent link does not prevent the antibody from binding to PD-1. For example, but not limited to, antibody derivatives include antibodies modified by, for example, glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage 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, derivatives may contain one or more atypical amino acids.

[0305] D. Nucleic Acids, Host Cells, and Production Methods

[0306] In some aspects, nucleic acids encoding anti-TF antibodies or antigen-binding fragments thereof as described herein or anti-PD-1 antibodies or antigen-binding fragments thereof as described herein are also provided herein. Further provided herein are nucleic acid vectors comprising nucleic acid encoding anti-TF antibodies or antigen-binding fragments thereof as described herein or anti-PD-1 antibodies or antigen-binding fragments thereof as described herein. Further provided herein are host cells expressing nucleic acids encoding anti-TF antibodies or antigen-binding fragments thereof as described herein or anti-PD-1 antibodies or antigen-binding fragments thereof as described herein. Further provided herein are host cells comprising vectors comprising nucleic acids encoding anti-TF antibodies or antigen-binding fragments thereof as described herein or anti-PD-1 antibodies or antigen-binding fragments thereof as described herein. Methods for producing anti-TF antibodies, linkers, and anti-TF antibody-drug conjugates are described in U.S. Patent No. 9,168,314.

[0307] The anti-TF antibodies or anti-PD-1 antibodies described herein can be produced by well-known recombinant techniques using well-known expression vector systems and host cells. In one embodiment, the antibodies are produced in CHO cells using the GS expression vector system disclosed in De la Cruz Edmunds et al., 2006, Molecular Biotechnology 34:179-190, EP 216846, U.S. Pat. No. 5,981,216, WO 87 / 04462, EP 323997, U.S. Pat. No. 5,591,639, U.S. Pat. No. 5,658,759, EP 338841, U.S. Pat. No. 5,879,936, and U.S. Pat. No. 5,891,693.

[0308] After isolation and purification of the anti-TF antibody from cell culture medium using techniques well known in the art, it was conjugated to monomethyl auristatin E via a linker as described in US Pat. No. 9,168,314.

[0309] The monoclonal anti-TF antibodies described herein or the anti-PD-1 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, for example, the techniques described 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 such as rats, dogs, primates, etc.

[0310] In one embodiment, the antibodies of the present invention (e.g., anti-TF antibodies comprising the CDRs of telostatumab or anti-PD-1 antibodies comprising the CDRs of pembrolizumab) are human antibodies. Human monoclonal antibodies against TF or PD-1 can be produced using transgenic or transgenic mice that carry parts of the human immune system rather than the mouse system. Such transgenic and transgenic mice include mice referred to herein as HuMAb mice and KM mice, respectively, and are collectively referred to herein as "transgenic mice."

[0311] HuMAb mice contain 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 IgGκ 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. 1365-93 (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 at al., J. Immunol, 152: 2912-2920 (1994), Taylor, L. et al., International Immunology, 6: 579-591 (1994), Fishwild, D. et al., Nature Biotechnology, 14: 845-851 (1996). See also U.S. Patent No. 5,545,806, U.S. Patent No. 5,569,825, U.S. Patent No. 5,625,126, U.S. Patent No. 5,633,425, U.S. Patent No. 5,789,650, U.S. Patent No. 5,877,397, U.S. Patent No. 5,661,016, U.S. Patent No. 5,814,318, U.S. Patent No. 5,874,299, U.S. Patent No. 5,770,429, U.S. Patent No. 5,545,807, WO 98 / 24884, WO 94 / 25585, WO 93 / 1227, WO 92 / 22645, WO 92 / 03918, and WO 01 / 09187.

[0312] HCo7 mice have a JKD disruption in their endogenous light chain (κ) gene (as described by Chen et al., EMBO J. 12:821-830 (1993)), a CMD disruption in their endogenous heavy chain gene (as described in Example 1 of WO 01 / 14424), a KCo5 human κ light chain transgene (as described by 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).

[0313] The HCo12 mouse has a JKD disruption in its endogenous light chain (κ) gene (as described by 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 by 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).

[0314] The HCo17 transgenic mouse strain (see also US 2010 / 0077497) was generated by coinjecting an 80 kb insert of pHC2 (Taylor et al. (1994) Int. Immunol., 6:579-591), a 1 kb insert of pVX6, and a -460 kb yeast artificial chromosome fragment of the yIgH24 chromosome. This strain was designated (HCo17)25950. The (HCo17)25950 strain was then bred with mice harboring 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 and kappa light chain transgenes in a homozygous background that interrupts the endogenous mouse heavy and kappa light chain loci.

[0315] The HCo20 transgenic mouse line is the result of coinjection of the following: the minilocus 30 heavy chain transgene pHC2, YACyIgH10 containing the germline variable region (Vh), and the minilocus construct pVx6 (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 homozygous background that disrupts the endogenous mouse heavy chain and kappa light chain loci.

[0316] To generate HuMab mice that possess the advantages of the Balb / c strain, HuMab mice were crossed with KCO05[MIK](Balb) mice, which were generated by backcrossing the KC05 strain (as described in Fishwild et al. (1996) Nature Biotechnology, 14:845-851) with wild-type Balb / c mice, to produce mice as described in WO09097006. Using this backcrossed Balb / c, hybrid mice of the HCo12, HCo17, and HCo20 strains were generated.

[0317] In the KM mouse strain, the endogenous mouse κ light chain gene has been disrupted by homozygosity as described in Chen et al., EMBO J. 12:811-820 (1993), and the endogenous mouse heavy chain gene has been disrupted by homozygosity 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 composed of chromosome 14 segment hCF (SC20), as described in WO 02 / 43478.

[0318] Splenocytes from these transgenic mice can be used to produce hybridomas that secrete human monoclonal antibodies according to well-known techniques. Human monoclonal or polyclonal antibodies of the present invention, or antibodies of the present invention derived from other species, can also be transgenically produced by generating another non-human mammal or plant transgenic for the immunoglobulin heavy and light chain sequences of interest and producing the antibodies in a form that can be recovered therefrom. For transgenic production in mammals, antibodies can be produced and recovered in the milk of goats, cows, 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.

[0319] In addition, human antibodies of the present invention or antibodies of the present invention from other species can be produced by display techniques, including but not limited to phage display, retroviral display, ribosome display and other techniques using techniques well known in the art, and the resulting molecules can be subjected to additional maturation such as affinity maturation, which techniques are well known in the art (see, for example, Hoogenboom et al., J. Mol, Biol. 227(2):381-388 (1992) (phage display), Vaughan et al., Nature Biotech, 14:309 (1996) (phage display), Hanes and Plucthau, PNAS USA 94:4937-4942 (1997) (ribosome display), Parmley and Smith, Gene, 73:305-318 (1988) (phage display), Scott, TIBS. 17:241-245 (1992), Cwirla et al. ... 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 a non-human antibody is produced using display technology, the antibody can be humanized.

[0320] III. Binding and Other Assays

[0321] In one aspect, the antibodies of the invention are assayed by, for example, known methods such as enzyme-linked immunosorbent assay (ELISA), immunoblotting (e.g., Western blotting), flow cytometry (e.g., FACS), TM), immunohistochemistry, immunofluorescence, etc. to test its antigen binding activity.

[0322] In another aspect, competition assays can be used to identify antibodies that compete with any of the antibodies described herein for binding to TF (e.g., telostatumab) or PD-1 (e.g., pembrolizumab). Cross-competing antibodies can be readily identified based on their ability to cross-compete in standard TF or PD-1 binding assays such as Biacore analysis, ELISA assays, or flow cytometry (see, e.g., WO2013 / 173223). In certain embodiments, the competing antibody binds to the same epitope (e.g., a linear or conformational epitope) as bound by any of the antibodies disclosed herein (e.g., telostatumab or pembrolizumab). Detailed exemplary methods for locating epitopes bound by antibodies are provided in Morris "Epitope Mapping Protocols," in Methods in Molecular Biology Vol. 66 (Humana Press, Totowa, NJ, 1996).

[0323] In an exemplary competition assay, immobilized PD-1 is incubated in a solution containing a first labeled antibody (e.g., pembrolizumab) that binds to PD-1 and a second unlabeled antibody to be tested for its ability to compete with the first antibody for binding to PD-1. The second antibody may be present in the hybridoma supernatant. As a control, immobilized PD-1 is incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. Following incubation under conditions permissive for binding of the first antibody to PD-1, excess unbound antibody is removed and the amount of label associated with the immobilized PD-1 is measured. If the amount of label associated with the immobilized PD-1 is substantially reduced in the test sample relative to the control sample, this indicates that the second antibody is competing with the first antibody for binding to PD-1. See, e.g., Harlow et al. Antibodies: A Laboratory Manual. Ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1988). In some embodiments, an anti-PD-1 antibody competes with another antibody for binding to PD-1 if it blocks binding of another PD-1 antibody (e.g., pembrolizumab) to PD-1 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-PD-1 antibody does not compete with another antibody for binding to PD-1 if it blocks binding of another PD-1 antibody (e.g., pembrolizumab) to PD-1 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, the PD-1 is human PD-1.

[0324] 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 antibody for binding to TF if it blocks binding of another TF antibody (e.g., tisotumab) 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 antibody for binding to TF if it blocks binding of another TF antibody (e.g., tisotumab) 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, the TF is human TF.

[0325] IV. Treatment Methods

[0326] The present invention provides methods for treating cancer in a subject using the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein. In one aspect, the antibody-drug conjugate is tesotumomab vedotin. In one aspect, the anti-PD-1 antibody is pembrolizumab. In specific embodiments, the subject is a human.

[0327] In another aspect, the present invention provides an antibody-drug conjugate that binds to TF for use in treating cancer, wherein the antibody-drug conjugate is for administration or to be administered in combination with an anti-PD-1 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 E, wherein the anti-PD-1 antibody or antigen-binding fragment thereof inhibits PD-1 activity, wherein the anti-PD-1 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:

[0328] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0329] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0330] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0331] Wherein the light chain variable region comprises:

[0332] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0333] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0334] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the CDRs of the anti-PD-1 antibody or antigen-binding fragment thereof are generally defined by the Kabat numbering scheme,

[0335] The anti-TF 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:

[0336] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0337] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0338] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0339] Wherein the light chain variable region comprises:

[0340] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0341] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0342] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined by the IMGT numbering scheme.

[0343] In another aspect, the present invention provides an anti-PD-1 antibody or an antigen-binding fragment thereof for treating cancer, wherein the anti-PD-1 antibody is for administration or to 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 conjugated to monomethyl auristatin E, and wherein the anti-PD-1 antibody or antigen-binding fragment thereof inhibits PD-1 activity, wherein the anti-PD-1 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:

[0344] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0345] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0346] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0347] Wherein the light chain variable region comprises:

[0348] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0349] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0350] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the CDRs of the anti-PD-1 antibody or antigen-binding fragment thereof are generally defined by the Kabat numbering scheme,

[0351] The anti-TF 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:

[0352] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0353] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0354] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0355] Wherein the light chain variable region comprises:

[0356] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0357] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0358] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined by the IMGT numbering scheme.

[0359] A. Breast cancer

[0360] The 2014 WHO (World Health Organization) World Cancer Report states that breast cancer is the second most common cancer worldwide, with over 1 million new cases each year. The report states that in 2000, approximately 400,000 women died from breast cancer, accounting for 1.6% of all female deaths. Breast cancer deaths are much higher in wealthy countries (2% of all female deaths) than in economically disadvantaged regions (0.5%). Therefore, breast cancer is closely associated with Western lifestyles. As developing countries successfully achieve lifestyles similar to those in Europe, North America, Australia, New Zealand, and Japan, they will also face much higher rates of cancer, especially breast cancer. Recent data support this prediction and show that breast cancer increased by 20% from 2008 to 2012 (Carter D. "New global survey shows an increasing cancer burden". Am J Nurs. 2014 Mar; 114(3): 17).

[0361] In some aspects, the present invention provides methods of treating breast cancer in a subject using an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer. In one aspect, the antibody-drug conjugate is tesotumomab vedotin. In one aspect, the anti-PD-1 antibody is pembrolizumab. In specific embodiments, the subject is human.

[0362] 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 breast cancer cells from the individual express TF. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% of the breast cancer cells from the individual express TF. In some embodiments, the percentage of cells expressing TF is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing TF is determined using flow cytometry. In some embodiments, the percentage of cells expressing TF is determined using enzyme-linked immunosorbent assay (ELISA).

[0363] 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 breast cancer cells from the individual express PD-L1. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% of breast cancer cells from the individual express PD-L1. In some embodiments of any of the embodiments herein, the individual's tumor expresses PD-L1 with a tumor proportion score (TPS) of ≥1%. In some embodiments herein, the individual's tumor has high PD-L1 expression (TPS ≥ 50%). In some embodiments herein, the individual's tumor expresses PD-L1 with a combined positive score (CPS) of ≥1%. See US 2017 / 0285037. In some embodiments herein, the individual's tumor expresses PD-L1 with a combined positive score (CPS) of ≥10%. In some embodiments, the percentage of cells expressing PD-L1 is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing PD-L1 is determined using flow cytometry. In some embodiments, the percentage of cells expressing PD-L1 is determined using enzyme-linked immunosorbent assay (ELISA).

[0364] In some embodiments, a tumor derived from breast cancer comprises one or more cells expressing PD-L1, PD-L2, or both PD-L1 and PD-L2.

[0365] 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 T cells from the individual express PD-1. 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 T cells from the individual express PD-1. In some embodiments, the percentage of cells expressing PD-1 is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing PD-1 is determined using flow cytometry. In some embodiments, the percentage of cells expressing PD-1 is determined using enzyme-linked immunosorbent assay (ELISA).

[0366] B. Cervical cancer

[0367] Despite advances in screening, diagnosis, prevention, and treatment, cervical cancer remains a leading cause of cancer-related death in women. It accounts for approximately 4% of all newly diagnosed cancer cases and 4% of all cancer deaths. See Zhu et al., 2016, Drug Des. Devel. Ther. 10:1885-1895. Cervical cancer is the seventh most common cancer in women worldwide and the 16th most common cancer in the European Union. Depending on the stage at which cervical cancer initially presents, 25 to 61% of women will experience a recurrence. 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 can be observed in a variety of locations. Chemotherapy is the standard of care for these patients. See Zhu et al., 2016, Drug Des. Devel. Ther. 10:1885-1895. Median overall survival is currently over one year, however the five-year relative survival for stage IV cervical cancer is only 15%, indicating a high need for improved treatments for cervical cancer.

[0368] In some aspects, provided herein are methods of treating cervical cancer in a subject using an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein. In one aspect, the antibody-drug conjugate is telocyclizumab vedotin. In one aspect, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the subject has not previously received prior systemic therapy for cervical cancer. In some embodiments, chemotherapy is not considered prior systemic therapy for cervical cancer. In some embodiments, radiation therapy is not considered prior systemic therapy for cervical cancer. In some embodiments, a combination of chemotherapy and radiation therapy is not considered prior systemic therapy for cervical cancer. In some embodiments, the subject has previously been 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 resection surgery. In some embodiments, the curative therapy is radiation therapy. In some embodiments, the curative therapy is resection surgery. In specific embodiments, the subject is human.

[0369] 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 chorioglandular adenocarcinoma. 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.

[0370] 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 the individual 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 the individual express TF. In some embodiments, the percentage of cells expressing TF is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing TF is determined using flow cytometry. In some embodiments, the percentage of cells expressing TF is determined using enzyme-linked immunosorbent assay (ELISA).

[0371] 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 the individual express PD-L1. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% of cervical cancer cells from the individual express PD-L1. In some embodiments of any of the embodiments herein, the individual's tumor expresses PD-L1 with a tumor proportion score (TPS) of ≥1%. In some embodiments herein, the individual's tumor has high PD-L1 expression (TPS ≥ 50%). In some embodiments herein, the individual's tumor expresses PD-L1 with a combined positive score (CPS) of ≥1%. See US 2017 / 0285037. In some embodiments herein, the individual's tumor expresses PD-L1 with a combined positive score (CPS) of ≥10%. In some embodiments, the percentage of cells expressing PD-L1 is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing PD-L1 is determined using flow cytometry. In some embodiments, the percentage of cells expressing PD-L1 is determined using enzyme-linked immunosorbent assay (ELISA).

[0372] In some embodiments, a tumor derived from cervical cancer comprises one or more cells expressing PD-L1, PD-L2, or both PD-L1 and PD-L2.

[0373] 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 T cells from the individual express PD-1. 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 T cells from the individual express PD-1. In some embodiments, the percentage of cells expressing PD-1 is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing PD-1 is determined using flow cytometry. In some embodiments, the percentage of cells expressing PD-1 is determined using enzyme-linked immunosorbent assay (ELISA).

[0374] In some embodiments of the methods or uses provided herein, or products for use, the cervical cancer is stage 0, 1, 2, 3, or 4 cervical cancer. In some embodiments, the cervical cancer is stage 0, 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B cervical cancer. In some embodiments, cervical cancer is staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. In some embodiments, staging is based on clinical examination. In some embodiments, stage 0 cervical cancer is confined to the surface layers (lining cells) of the cervix. In some embodiments, stage 1 cervical cancer is cancer that has grown into the deep layers of the cervix but has not spread beyond the cervix. In some embodiments, stage 1A cervical cancer is invasive cancer that can only be diagnosed by microscopy and has a deepest invasion of less than 5 mm and a maximum spread of less than 7 mm. In some embodiments, stage 1B cervical cancer is clinically visible and confined to the cervix. In some embodiments, stage 2 cervical cancer is cervical cancer that has invaded beyond the uterus but not to the pelvic wall or the lower third of the vagina. In some embodiments, stage 2A cervical cancer has no para-uterine invasion. In some embodiments, stage 2B cervical cancer has para-uterine invasion. In some embodiments, stage 3 cervical cancer has tumors that have spread to the pelvic wall and / or involve the lower third of the vagina and / or result in enlarged or stunted kidneys. In some embodiments, stage 3A cervical cancer has tumors that involve the lower third of the vagina and have not spread to the pelvic wall. In some embodiments, stage 3B cervical cancer has spread to the pelvic wall and / or result in enlarged or stunted kidneys. In some embodiments, stage 4 cervical cancer has cancer that has spread beyond the true pelvic cavity or involves the bladder or rectal mucosa. In some embodiments, stage 4A cervical cancer has spread to adjacent organs. In some embodiments, stage 4B cervical cancer 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.

[0375] In some embodiments of the methods or uses provided herein, or products for use, the individual has not received prior systemic therapy for cervical cancer. In some embodiments, chemotherapy is not considered prior systemic therapy for cervical cancer. In some embodiments, radiation therapy is not considered prior systemic therapy for cervical cancer. In some embodiments, a combination of chemotherapy and radiation therapy is not considered prior systemic therapy for cervical cancer. In some embodiments, the individual has previously received chemotherapy and / or radiation therapy. In some embodiments, the individual did not respond to chemotherapy and radiation therapy. In some embodiments, the individual received chemotherapy for cervical cancer and did not respond to the chemotherapy. In some embodiments, the individual received radiation therapy for cervical cancer and did not respond to the radiation. In some embodiments, the individual relapsed after chemotherapy and radiation therapy. In some embodiments, the individual received chemotherapy for cervical cancer and relapsed after the chemotherapy. In some embodiments, the individual received radiation therapy for cervical cancer and relapsed after the radiation. In some embodiments, the individual experienced disease progression after chemotherapy and / or radiation therapy. In some embodiments, the individual received chemotherapy for cervical cancer and experienced disease progression after the chemotherapy. In some embodiments, the individual is receiving radiation therapy for cervical cancer and experiences disease progression following treatment with the radiation therapy. In some embodiments, the individual has previously been treated with one or more therapeutic agents for cervical cancer. In some embodiments, the individual has previously been treated with one or more therapeutic agents and has not responded to the treatment. In some embodiments, the individual has previously been treated with one or more therapeutic agents and has relapsed following treatment. In some embodiments, the individual has previously been treated with one or more therapeutic agents and experienced disease progression during treatment. In some embodiments, the one or more therapeutic agents are selected from the group consisting of a chemotherapeutic agent, pemetrexed, nab-paclitaxel, vinorelbine, bevacizumab, cisplatin, carboplatin, paclitaxel, and 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, cisplatin, and paclitaxel, the combination of bevacizumab, carboplatin, and paclitaxel, and the combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the one or more therapeutic agents are chemotherapeutic agents. In some embodiments, the one or more therapeutic agents are bevacizumab. In some embodiments, the one or more therapeutic agents are cisplatin. In some embodiments, the one or more therapeutic agents are carboplatin. In some embodiments, the one or more therapeutic agents are paclitaxel. In some embodiments, the one or more therapeutic agents are topotecan. In some embodiments, the one or more therapeutic agents is a combination of bevacizumab and paclitaxel.In some embodiments, the one or more therapeutic agents are a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents are a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents are a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents are a combination of bevacizumab and topotecan. In some embodiments, the one or more therapeutic agents are a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents are a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents are a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the individual is not a candidate for curative therapy. In some embodiments, the curative therapy is radiation therapy and / or resection. In some embodiments, the curative therapy is radiation therapy. In some embodiments, the curative therapy is resection. In specific embodiments, the individual is human.

[0376] C. Route of Administration

[0377] The anti-PD-1 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 of administration. Suitable routes of administration for the antibodies and / or antibody-drug conjugates of the present invention are well known in the art and can be selected by one of ordinary skill in the art. In one embodiment, the anti-PD-1 antibodies and / or anti-TF antibody-drug conjugates described herein are administered parenterally. Parenteral administration refers to modes of administration other than enteral and topical administration, typically by injection, and includes epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, 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 for the anti-TF antibody-drug conjugates or antigen-binding fragments described herein is intravenous injection or infusion. In some embodiments, the anti-TF antibody-drug conjugates or antigen-binding fragments described herein are administered by intravenous infusion. In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments described herein are administered by intravenous injection or infusion. In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments described herein are administered by intravenous infusion. In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments described herein are administered by subcutaneous administration.

[0378] D. Dosage and frequency of administration

[0379] In one aspect, the present invention provides a method for treating an individual having cancer as described herein using a specific dose of an anti-TF antibody-drug conjugate, or antigen-binding fragment thereof, as described herein and an anti-PD-1 antibody, or antigen-binding fragment thereof, as described herein, wherein the antibody-drug conjugate, or antigen-binding fragment thereof, as described herein and the anti-PD-1 antibody, or antigen-binding fragment thereof, as described herein, are administered to the individual at a specific frequency.

[0380] In embodiments of one of the methods or uses or articles for use provided herein, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to an individual at a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg of the individual's body weight. In certain embodiments, the dose is about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, or about 2.1 mg / kg. In some embodiments of the methods or uses or articles for use provided herein, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to an individual at a dose ranging from 0.9 mg / kg to 2.1 mg / kg of the individual's body weight. In certain embodiments, the dose is 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, or 2.1 mg / kg. In one embodiment, the dose is about 2.0 mg / kg. In one embodiment, the dose is 2.0 mg / kg. In some embodiments, the dose is 2.0 mg / kg and the anti-TF antibody-drug conjugate is tesotumomab vedotin. In one embodiment, the dose is about 1.3 mg / kg. In one embodiment, the dose is 1.3 mg / kg. In some embodiments, the dose is 1.3 mg / kg and the anti-TF antibody-drug conjugate is tesotumomab vedotin. In some embodiments, for individuals weighing more than 100 kg, the dose of anti-TF antibody-drug conjugate administered is the amount administered to an individual weighing 100 kg. In some embodiments, for individuals weighing more than 100 kg, the dose of anti-TF antibody-drug conjugate administered is 65 mg, 90 mg, 130 mg, or 200 mg.

[0381] In one embodiment of the methods, uses, or products for use provided herein, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject approximately once every 1 to 4 weeks. In certain embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered approximately once every 1 week, approximately once every 2 weeks, approximately once every 3 weeks, or approximately once every 4 weeks. In one embodiment, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered approximately once every 3 weeks. In one embodiment, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered once every 3 weeks. In some embodiments, the dose is about 0.9 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is about 0.9 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is about 0.9 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is about 0.9 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is about 0.9 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is about 1.0 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.0 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.0 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.0 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.1 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.1 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.1 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.1 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.2 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.2 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.2 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.2 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.3 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.3 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.3 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.3 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.4 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.4 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.4 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.4 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.5 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.5 mg / kg and is administered approximately once every 2 weeks.In some embodiments, the dosage is about 1.5 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.5 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.6 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.6 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.6 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.6 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.7 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.7 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.7 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.7 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.8 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.8 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.8 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.8 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 1.9 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 1.9 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 1.9 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 1.9 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 2.0 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 2.0 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 2.0 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 2.0 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is about 2.1 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is about 2.1 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is about 2.1 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is about 2.1 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 0.9 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 0.9 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 0.9 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 0.9 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dosage is 1.0 mg / kg and is administered approximately once every 1 week. In some embodiments, the dosage is 1.0 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dosage 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 dose is 1.2 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 1.2 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.2 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every 1 week. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every 3 weeks. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every 4 weeks. In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every 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 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 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 4 weeks. In some embodiments, the dose is 1.7 mg / kg and is administered approximately once every 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 dosage is 2.0 mg / kg and is administered once every 3 weeks. In some embodiments, the dosage is 2.0 mg / kg and is administered once every 3 weeks and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage of the antibody-drug conjugate is adjusted if one or more adverse events occur. In some embodiments, the dosage 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 dosage is reduced to 1.3 mg / kg. In some embodiments, the dosage is 1.3 mg / kg and is administered once every 3 weeks. In some embodiments, the dosage is 1.3 mg / kg and is administered once every 3 weeks and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dosage 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 dosage is reduced to 0.9 mg / kg.

[0382] 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 as described herein is administered to a subject at a uniform dose ranging from about 50 mg to about 200 mg, such as a uniform dose of about 50 mg, or a uniform dose of about 60 mg, or a uniform dose of about 70 mg, or a uniform dose of about 80 mg, or a uniform dose of about 90 mg, or a uniform dose of about 100 mg, or a uniform dose of about 110 mg, or a uniform dose of about 120 mg, or a uniform dose of about 130 mg, or a uniform dose of about 140 mg, or a uniform dose of about 150 mg, or a uniform dose of about 160 mg, or a uniform dose of about 170 mg, or a uniform dose of about 180 mg, or a uniform dose of about 190 mg, or a uniform dose of about 200 mg. In some embodiments, the uniform dose is administered to a subject about once every 1 to 4 weeks. In certain embodiments, a uniform dose is administered to an individual about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In some embodiments, a uniform dose is administered to an individual about once every 3 weeks (e.g., ±3 days). In some embodiments, a uniform dose is administered to an individual once every 3 weeks. In some embodiments, a uniform dose is administered to an individual once every 3 weeks and the antibody-drug conjugate is telolimumab vedotin.

[0383] In one embodiment of the methods, uses, or products for use provided herein, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is administered to a subject at a uniform dose ranging from 50 mg to 200 mg, such as a uniform dose of 50 mg, or a uniform dose of 60 mg, or a uniform dose of 70 mg, or a uniform dose of 80 mg, or a uniform dose of 90 mg, or a uniform dose of 100 mg, or a uniform dose of 110 mg, or a uniform dose of 120 mg, or a uniform dose of 130 mg, or a uniform dose of 140 mg, or a uniform dose of 150 mg, or a uniform dose of 160 mg, or a uniform dose of 170 mg, or a uniform dose of 180 mg, or a uniform dose of 190 mg, or a uniform dose of 200 mg. In some embodiments, the uniform dose is administered to a subject about once every 1 to 4 weeks. In certain embodiments, the uniform dose is administered to a subject about once every 1 week, about every 2 weeks, about every 3 weeks, or about every 4 weeks. In some embodiments, a uniform dose is administered to a subject approximately once every 3 weeks (e.g., ±3 days). In some embodiments, a uniform dose is administered to a subject once every 3 weeks. In some embodiments, a uniform dose is administered to a subject once every 3 weeks and the antibody-drug conjugate is tesotumomab vedotin.

[0384] In one embodiment of the methods or uses or products for use provided herein, an anti-PD-1 antibody or antigen-binding fragment thereof as described herein is administered to a subject in a uniform dose range of about 50 mg to about 500 mg, such as a uniform dose of about 50 mg, or a uniform dose of about 60 mg, or a uniform dose of about 70 mg, or a uniform dose of about 80 mg, or a uniform dose of about 90 mg, or a uniform dose of about 100 mg, or a uniform dose of about 120 mg, or a uniform dose of about 140 mg, or a uniform dose of about 160 mg, or a uniform dose of about 180 mg, or a uniform dose of about A uniform dose of 200 mg, or a uniform dose of about 220 mg, or a uniform dose of about 240 mg, or a uniform dose of about 260 mg, or a uniform dose of about 280 mg, or a uniform dose of about 300 mg, or a uniform dose of about 320 mg, or a uniform dose of about 340 mg, or a uniform dose of about 360 mg, or a uniform dose of about 380 mg, or a uniform dose of about 400 mg, or a uniform dose of about 420 mg, or a uniform dose of about 440 mg, or a uniform dose of about 460 mg, or a uniform dose of about 480 mg, or a uniform dose of about 500 mg. In some embodiments, the uniform dose is about 200 mg. In some embodiments of the methods or uses or products for use provided herein, the anti-PD-1 antibody or antigen-binding fragment thereof as described herein is administered to the individual in a uniform dose range of 50 mg to 500 mg, such as a uniform dose of 50 mg or a uniform dose of 60 mg or a uniform dose of 70 mg or a uniform dose of 80 mg or a uniform dose of 90 mg or a uniform dose of 100 mg or a uniform dose of 120 mg or a uniform dose of 140 mg or a uniform dose of 160 mg or a uniform dose of 180 mg. Or a uniform dose of 200 mg or a uniform dose of 220 mg or a uniform dose of 240 mg or a uniform dose of 260 mg or a uniform dose of 280 mg or a uniform dose of 300 mg or a uniform dose of 320 mg or a uniform dose of 340 mg or a uniform dose of 360 mg or a uniform dose of 380 mg or a uniform dose of 400 mg or a uniform dose of 420 mg or a uniform dose of 440 mg or a uniform dose of 460 mg or a uniform dose of 480 mg or a uniform dose of 500 mg. In some embodiments, the uniform dose is 200 mg. In some embodiments, the uniform dose is 200 mg and the anti-PD-1 antibody is pembrolizumab. In some embodiments, the uniform dose is 400 mg. In some embodiments, the uniform dose is 400 mg and the anti-PD-1 antibody is pembrolizumab. In some embodiments, the uniform dose is about 140 mg and is administered approximately once every 1 week. In some embodiments, the uniform dose is about 140 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 140 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 140 mg and is administered approximately once every 4 weeks.In some embodiments, the uniform dose is about 160 mg and is administered approximately once every week. In some embodiments, the uniform dose is about 160 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 160 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 160 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is about 180 mg and is administered approximately once every week. In some embodiments, the uniform dose is about 180 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 180 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 180 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is about 200 mg and is administered approximately once every 1 week. In some embodiments, the uniform dose is about 200 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 200 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 200 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is about 220 mg and is administered approximately once every week. In some embodiments, the uniform dose is about 220 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 220 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 220 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is about 240 mg and is administered approximately once every week. In some embodiments, the dose is about 240 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 240 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 240 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is about 260 mg and is administered approximately once every week. In some embodiments, the uniform dose is about 260 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 260 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 260 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is about 360 mg and is administered approximately once every week. In some embodiments, the uniform dose is about 360 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 360 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 360 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is about 360 mg and is administered approximately once every 5 weeks. In some embodiments, the uniform dose is about 360 mg and is administered approximately once every 6 weeks. In some embodiments, the uniform dose is about 400 mg and is administered approximately once every 1 week. In some embodiments, the uniform dose is about 400 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is about 400 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is about 400 mg and is administered approximately once every 4 weeks.In some embodiments, the uniform dose is about 400 mg and is administered approximately every 5 weeks. In some embodiments, the uniform dose is about 400 mg and is administered approximately every 6 weeks. In some embodiments, the uniform dose is about 440 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is about 440 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is about 440 mg and is administered approximately every 3 weeks. In some embodiments, the uniform dose is about 440 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is about 440 mg and is administered approximately every 5 weeks. In some embodiments, the uniform dose is about 440 mg and is administered approximately every 6 weeks. In some embodiments, the uniform dose is 140 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is 140 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is 140 mg and is administered approximately every 3 weeks. In some embodiments, the uniform dose is 140 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is 160 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is 160 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is 160 mg and is administered approximately every 3 weeks. In some embodiments, the uniform dose is 160 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is 180 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is 180 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is 180 mg and is administered approximately every 3 weeks. In some embodiments, the uniform dose is 180 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is 200 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is 200 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is 200 mg and is administered approximately every 3 weeks. In some embodiments, the uniform dose is 200 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is 220 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is 220 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is 220 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is 220 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is 240 mg and is administered approximately once every 1 week. In some embodiments, the uniform dose is 240 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is 240 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is 240 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is 260 mg and is administered approximately once every 1 week. In some embodiments, the uniform dose is 260 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is 260 mg and is administered approximately once every 3 weeks.In some embodiments, the uniform dose is 260 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is 360 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is 360 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is 360 mg and is administered approximately every 3 weeks. In some embodiments, the uniform dose is 360 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is 360 mg and is administered approximately every 5 weeks. In some embodiments, the uniform dose is 360 mg and is administered approximately every 6 weeks. In some embodiments, the uniform dose is 400 mg and is administered approximately every 1 week. In some embodiments, the uniform dose is 400 mg and is administered approximately every 2 weeks. In some embodiments, the uniform dose is 400 mg and is administered approximately every 3 weeks. In some embodiments, the uniform dose is 400 mg and is administered approximately every 4 weeks. In some embodiments, the uniform dose is 400 mg and is administered approximately every 5 weeks. In some embodiments, the uniform dose is 400 mg and is administered approximately every 6 weeks. In some embodiments, the uniform dose is 440 mg and is administered approximately once every 1 week. In some embodiments, the uniform dose is 440 mg and is administered approximately once every 2 weeks. In some embodiments, the uniform dose is 440 mg and is administered approximately once every 3 weeks. In some embodiments, the uniform dose is 440 mg and is administered approximately once every 4 weeks. In some embodiments, the uniform dose is 440 mg and is administered approximately once every 5 weeks. In some embodiments, the uniform dose is 440 mg and is administered approximately once every 6 weeks. In some embodiments, the uniform dose is 200 mg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the uniform dose is 200 mg and is administered once every 3 weeks. In some embodiments, the uniform dose is 200 mg and is administered once every 3 weeks and the antibody is pembrolizumab. In some embodiments, the uniform dose is 400 mg and is administered approximately once every 6 weeks (e.g., ±6 days). In some embodiments, the uniform dose is 400 mg and is administered once every 6 weeks. In some embodiments, the uniform dose is 400 mg and is administered once every 6 weeks and the antibody is pembrolizumab.

[0385] In some embodiments of the methods or uses or products for use provided herein, an anti-PD-1 antibody or antigen-binding fragment thereof as described herein and an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein are administered to an individual 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-PD-1 antibody or antigen-binding fragment thereof as described herein (e.g., mg) to the amount of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof as 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 1:10 :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 an anti-PD-1 antibody or antigen-binding fragment thereof as described herein (e.g., mg) to the amount of an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as 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, 1:90, 1:10 :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.In some embodiments, the ratio of the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof as described herein (e.g., mg / ml) to the concentration of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof as 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 0, 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-PD-1 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, 1:100, 1:115, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:310, 1:320, 1:330, 1:340, 1:350, 1:360, 1:370, 1:380, 1:390, 1:400 0, 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.

[0386] In some embodiments, the dose of an 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 an anti-PD-1 antibody described herein is 200 mg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 2.0 mg / kg and is administered once every 3 weeks and the dose of an anti-PD-1 antibody described herein is 200 mg and is administered once every 3 weeks. In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 2.0 mg / kg and is administered once every 3 weeks, the antibody-drug conjugate is tesotumumab vedotin, and the dose of an anti-PD-1 antibody is 200 mg and is administered once every 3 weeks, the anti-PD-1 antibody is pembrolizumab.

[0387] In some embodiments, the dose of an 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 an anti-PD-1 antibody described herein is 400 mg and is administered approximately once every 6 weeks (e.g., ±6 days). In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 2.0 mg / kg and is administered once every 3 weeks and the dose of an anti-PD-1 antibody described herein is 400 mg and is administered once every 6 weeks. In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 2.0 mg / kg and is administered once every 3 weeks, the antibody-drug conjugate is tesotumumab vedotin, and the dose of an anti-PD-1 antibody is 400 mg and is administered once every 6 weeks, the anti-PD-1 antibody is pembrolizumab.

[0388] In some embodiments, the dose of an 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 an anti-PD-1 antibody described herein is 200 mg and is administered approximately once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered once every 3 weeks and the dose of an anti-PD-1 antibody described herein is 200 mg and is administered once every 3 weeks. In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered once every 3 weeks, the antibody-drug conjugate is tesotumab vedotin, and the dose of an anti-PD-1 antibody is 200 mg and is administered once every 3 weeks, the anti-PD-1 antibody is pembrolizumab.

[0389] In some embodiments, the dose of an 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 an anti-PD-1 antibody described herein is 400 mg and is administered approximately once every 6 weeks (e.g., ±6 days). In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered once every 3 weeks and the dose of an anti-PD-1 antibody described herein is 400 mg and is administered once every 6 weeks. In some embodiments, the dose of an anti-TF antibody-drug conjugate described herein is 1.3 mg / kg and is administered once every 3 weeks, the antibody-drug conjugate is tesotumumab vedotin, and the dose of an anti-PD-1 antibody is 400 mg and is administered once every 6 weeks, the anti-PD-1 antibody is pembrolizumab.

[0390] In some embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is co-administered with an anti-PD-1 antibody or antigen-binding fragment thereof as described herein. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate as described herein is administered simultaneously with an anti-PD-1 antibody as described herein. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein are administered to a subject less than about one hour apart, such as less than about 30 minutes apart, less than about 15 minutes apart, less than about 10 minutes apart, or less than about 5 minutes apart. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein are administered to a subject less than one hour apart, such as less than 30 minutes apart, less than 15 minutes apart, less than 10 minutes apart, or less than 5 minutes apart. In some embodiments, the anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein are administered sequentially. In some embodiments, sequential administration refers to the administration of an anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein 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.

[0391] In some embodiments, the methods of treatment or uses described herein further comprise administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are administered concurrently with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein (such as tesotumab vedotin) and an anti-PD-1 antibody or antigen-binding fragment thereof as described herein (such as pembrolizumab). In some embodiments, the one or more additional therapeutic agents are administered sequentially with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein and an anti-PD-1 antibody or antigen-binding fragment thereof as described herein.

[0392] E. Treatment results

[0393] In one aspect, methods of treating cancer using an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein and an anti-PD-1 antibody or antigen-binding fragment thereof as described herein result 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 tumor size derived from the cancer (e.g., breast cancer or cervical cancer), objective response rate, duration of response, time to response, progression-free survival, overall survival, or any combination thereof. In one embodiment, the one or more therapeutic effects are tumor size derived from the cancer. In some embodiments, the one or more therapeutic effects are a decrease in tumor size. In some embodiments, the one or more therapeutic effects are stable disease. In some embodiments, the one or more therapeutic effects are partial responses. In some embodiments, the one or more therapeutic effects are complete responses. In some embodiments, the one or more therapeutic effects are objective response rates. In some embodiments, the one or more therapeutic effects are duration of response. In some embodiments, the one or more therapeutic effects are time to response. In some embodiments, the one or more therapeutic effects are progression-free survival. In some embodiments, the one or more therapeutic effects are overall survival. In some embodiments, the one or more therapeutic effects are cancer regression.

[0394] In one embodiment of the methods, uses, or products for use provided herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein and an anti-PD-1 antibody or antigen-binding fragment thereof as described herein may include the following criteria (RECIST criteria 1.1):

[0395]

[0396]

[0397] In one embodiment of the methods, uses, or products for use provided herein, the effectiveness of treatment with the anti-TF antibody-drug conjugates or antigen-binding fragments thereof and the anti-PD-1 antibodies or antigen-binding fragments thereof described herein is assessed by measuring the objective response rate. In some embodiments, the objective response rate is the proportion of patients whose tumor size is reduced by a predefined amount and maintained for a minimum period of time. In some embodiments, the objective response rate is based on RECIST v1.1. In one embodiment, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In one embodiment, the objective response rate is at least about 20% to 80%. In one embodiment, the objective response rate is at least about 30% to 80%. In one embodiment, the objective response rate is at least about 40% to 80%. In one embodiment, the objective response rate is at least about 50% to 80%. In one embodiment, the objective response rate is at least about 60% to 80%. In one embodiment, the objective response rate is at least about 70% to 80%. In one embodiment, the objective response rate is at least about 80%. In one embodiment, the objective response rate is at least about 85%. In one embodiment, the objective response rate is at least about 90%. In one embodiment, the objective response rate is at least about 95%. In one embodiment, the objective response rate is at least about 98%. In one embodiment, the objective response rate is at least about 99%. In one embodiment, the objective response rate is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80%. In one embodiment, the objective response rate is at least 20% to 80%. In one embodiment, the objective response rate is at least 30% to 80%. In one embodiment, the objective response rate is at least 40% to 80%. In one embodiment, the objective response rate is at least 50% to 80%. In one embodiment, the objective response rate is at least 60% to 80%. In one embodiment, the objective response rate is at least 70% to 80%. In one embodiment, the objective response rate is at least 80%. In one embodiment, the objective response rate is at least 85%. In one embodiment, the objective response rate is at least 90%. In one embodiment, the objective response rate is at least 95%. In one embodiment, the objective response rate is at least 98%. In one embodiment, the objective response rate is at least 99%. In one embodiment, the objective response rate is 100%.

[0398] In one embodiment of the methods, uses, or products for use provided herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof described herein is assessed by measuring the size of a tumor derived from a cancer (e.g., breast cancer or cervical cancer). In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer before administration of the anti-TF antibody-drug conjugate and / or anti-PD-1 antibody described herein. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 10% to 80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 20% to 80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 30% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 40% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 50% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 60% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 70% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 85%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 99%. In one embodiment, the size of a tumor derived from a 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 the cancer prior to administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 10% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 20% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 30% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 40% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 50% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 60% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 70% to 80%. In one embodiment, the size of a cancer-derived tumor is reduced by at least 80%.In one embodiment, the size of a tumor derived from a cancer is reduced by at least 85%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 90%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 95%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 98%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 99%. In one embodiment, the size of a tumor derived from a cancer is reduced by 100%. In one embodiment, the size of a tumor derived from a cancer is measured by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor derived from a cancer is measured by computed tomography (CT). In some embodiments, the size of a tumor derived from cervical cancer is measured by pelvic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205. In some embodiments, the size of a tumor derived from breast cancer is measured by mammography, ultrasound, or magnetic resonance imaging (MRI). See Gruber et al., 2013, BMC Cancer. 13:328. In some embodiments, the size of a tumor derived from a 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-PD-1 antibody described herein. In some embodiments, the size of a tumor derived from a 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 derived from a cancer is reduced relative to the size of the tumor prior to administration of an anti-PD-1 antibody described herein.

[0399] 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 (such as, for example, tesotumab vedotin) and an anti-PD-1 antibody or antigen-binding fragment thereof described herein (such as, for example, pembrolizumab) promotes regression of a tumor derived from cancer (e.g., breast cancer or cervical cancer). In one embodiment, the tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer before administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In one embodiment, the tumor derived from the cancer is reduced by at least about 10% to about 80%. In one embodiment, the tumor derived from the cancer is reduced by at least about 20% to about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 30% to about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 40% to about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 50% to about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 60% to about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 70% to about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 85%. In one embodiment, the tumor derived from the cancer regresses by at least about 90%. In one embodiment, the tumor derived from the cancer regresses by at least about 95%. In one embodiment, the tumor derived from the cancer regresses by at least about 98%. In one embodiment, the tumor derived from the cancer regresses by at least about 99%. In one embodiment, the size of a cancer-derived tumor 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 cancer-derived tumor prior to administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In one embodiment, the size of a cancer-derived tumor is reduced by at least 10% to 80%. In one embodiment, the size of a cancer-derived tumor is reduced by at least 20% to 80%. In one embodiment, the size of a cancer-derived tumor is reduced by at least 30% to 80%. In one embodiment, the size of a cancer-derived tumor is reduced by at least 40% to 80%. In one embodiment, the size of a cancer-derived tumor is reduced by at least 50% to 80%. In one embodiment, the size of a cancer-derived tumor is reduced by at least 60% to 80%. In one embodiment, the size of a cancer-derived tumor is reduced by at least 70% to 80%. In one embodiment, the tumor derived from the cancer regresses by at least 80%. In one embodiment, the tumor derived from the cancer regresses by at least 85%.In one embodiment, the tumor derived from the cancer regresses by at least 90%. In one embodiment, the tumor derived from the cancer regresses by at least 95%. In one embodiment, the tumor derived from the cancer regresses by at least 98%. In one embodiment, the tumor derived from the cancer regresses by at least 99%. In one embodiment, the tumor derived from the cancer regresses by 100%. In one embodiment, tumor regression is determined by measuring tumor size using magnetic resonance imaging (MRI). In one embodiment, tumor regression is determined by measuring tumor size using computed tomography (CT). In some embodiments, tumor regression is determined by measuring tumor size using a pelvic exam. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205. In some embodiments, tumor regression is determined by mammography, ultrasound, or magnetic resonance imaging (MRI). See Gruber et al., 2013, BMC Cancer. 13:328. In some embodiments, a tumor derived from cancer regresses relative to the size of the tumor prior to administration of an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein. In some embodiments, a tumor derived from cancer regresses relative to the size of the tumor prior to administration of an anti-TF antibody-drug conjugate described herein. In some embodiments, a tumor derived from cancer regresses relative to the size of the tumor prior to administration of an anti-PD-1 antibody described herein.

[0400] In one embodiment of the methods, uses, or products for use described herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-PD-1 antibody or antigen-binding fragment thereof described herein is assessed by measuring progression-free survival time following administration of an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years following administration of an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least about 6 months following administration of an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least about one year following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least about two years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least about three years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least about four years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least about five years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits 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 two years, at least three years, at least four years, or at least five years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least 6 months following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least one year following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein.In some embodiments, a subject exhibits progression-free survival of at least two years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least three years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least four years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits progression-free survival of at least five years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, response to treatment is assessed by measuring the duration of progression-free survival following administration of an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein. In some embodiments, response to treatment is assessed by measuring the duration of progression-free survival following administration of an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein. In some embodiments, response to treatment is assessed by measuring the duration of progression-free survival following administration of an anti-TF antibody-drug conjugate described herein. In some embodiments, response to treatment is assessed by measuring the duration of progression-free survival following administration of an anti-PD-1 antibody described herein.

[0401] In one embodiment of the methods, uses, or products for use described herein, response to treatment with an anti-TF antibody-drug conjugate, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof, described herein is assessed by measuring overall survival time following administration of an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years following administration of an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least about 6 months following administration of an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least about one year following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least about two years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least about three years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least about four years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least about five years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, subjects undergoing administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein exhibit 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 two years, at least three years, at least four years, or at least five years. In some embodiments, subjects undergoing administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein exhibit an overall survival of at least 6 months. In some embodiments, subjects undergoing administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein exhibit an overall survival of at least one year. In some embodiments, subjects undergoing administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein exhibit an overall survival of at least two years.In some embodiments, a subject exhibits an overall survival of at least three years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least four years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, a subject exhibits an overall survival of at least five years following administration of an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 antibody described herein. In some embodiments, response to treatment is assessed by measuring overall survival time following administration of an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein. In some embodiments, response to treatment is assessed by measuring overall survival time following administration of an anti-TF antibody-drug conjugate described herein. In some embodiments, response to treatment is assessed by measuring overall survival time following administration of an anti-PD-1 antibody described herein.

[0402] In one embodiment of the methods, uses, or products for use described herein, the response to treatment with an anti-TF antibody-drug conjugate, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof, described herein is assessed by measuring the duration of response to the anti-TF antibody-drug conjugate, or anti-PD-1 antibody, described herein after administration of the anti-TF antibody-drug conjugate and / or anti-PD-1 antibody described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate, or anti-PD-1 antibody, described herein after administration of the anti-TF antibody-drug conjugate and / or anti-PD-1 antibody 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 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 response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least about 6 months after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least about one year after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least about two years after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least about three years after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least about four years after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein is at least about five years after administration of the antibody-drug conjugate described herein and / or the anti-PD-1 antibody described herein.In some embodiments, the duration of response to the anti-TF antibody-drug conjugates and anti-PD-1 antibodies described herein after administration of an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody 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 response to the anti-TF antibody-drug conjugates and anti-PD-1 antibodies described herein is at least 6 months after administration of the antibody-drug conjugates and / or anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates and anti-PD-1 antibodies described herein is at least 1 year after administration of the antibody-drug conjugates and / or anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least two years after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least three years after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least four years after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response to the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein is at least five years after administration of the antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein. In some embodiments, the duration of response is measured after administration of the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein. In some embodiments, the duration of response is measured after administration of the anti-TF antibody-drug conjugates described herein and the anti-PD-1 antibodies described herein. In some embodiments, the duration of response is measured following administration of an anti-PD-1 antibody described herein.

[0403] F. Adverse Events

[0404] In one aspect, a method of treating cancer (e.g., breast cancer or cervical cancer) using an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-PD-1 antibody or antigen-binding fragment thereof described herein results in a subject experiencing 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 experienced by the subject are anemia, abdominal pain, bleeding, hyperthyroidism, hypothyroidism, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or worsening of overall physical health, or any combination thereof. In some embodiments, the one or more adverse events are Grade 1 or higher. In some embodiments, the one or more adverse events are Grade 2 or higher. In some embodiments, the one or more adverse events are Grade 3 or higher. 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, one or more adverse events are Grade 3 adverse events. In some embodiments, one or more adverse events are Grade 4 adverse events. In some embodiments, one or more adverse events are serious adverse events. In some embodiments, one or more adverse events are conjunctivitis, conjunctival ulceration, and / or keratitis and the additional 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 ulceration, and keratitis and the additional 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 additional 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 additional 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, the one or more adverse events are keratitis and the additional 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 of any of the embodiments herein, the subject is treated with an additional therapeutic agent to eliminate or reduce the severity of the adverse event (e.g., conjunctivitis, conjunctival ulcer, and / or keratitis). In some embodiments, the treatment is an eye ice pad (e.g., THERA PEARL EyeMask or the like). In some embodiments, the one or more adverse events are recurrent infusion-related reactions and the additional therapeutic agent is an antihistamine, acetaminophen, and / or a corticosteroid. In some embodiments, the one or more adverse events are neutropenia and the additional therapeutic agent is a growth factor support (G-CSF).In some embodiments, one or more adverse events is hyperthyroidism and the additional therapeutic agent is a non-selective beta-blocker (e.g., propranolol) or a thioamide. In some embodiments, one or more adverse events is hypothyroidism and the additional therapeutic agent is a thyroid replacement hormone (e.g., levothyroxine or liothyroinine).

[0405] In one aspect, a subject treated with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and an anti-PD-1 antibody or antigen-binding fragment thereof described herein for the treatment of cancer (e.g., breast cancer or cervical cancer) is at risk of developing one or more adverse events. In some embodiments, the subject is administered an additional therapeutic agent to prevent the development of an adverse event or reduce the severity of the adverse event. In some embodiments, the subject is at risk of developing one or more adverse events, which are anemia, abdominal pain, bleeding, hyperthyroidism, hypothyroidism, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or worsening of overall physical health, or any combination thereof. In some embodiments, the one or more adverse events are Grade 1 or higher. In some embodiments, the one or more adverse events are Grade 2 or higher. In some embodiments, the one or more adverse events are Grade 3 or higher. In some embodiments, the one or more adverse events are Grade 1 adverse events. In some embodiments, one or more adverse events are Grade 2 adverse events. In some embodiments, one or more adverse events are Grade 3 adverse events. In some embodiments, one or more adverse events are Grade 4 adverse events. In some embodiments, one or more adverse events are serious adverse events. In some embodiments, one or more adverse events are conjunctivitis, conjunctival ulceration, and / or keratitis and the additional 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 additional 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 additional 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, the one or more adverse events are keratitis and the additional 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 of any of the embodiments herein, the subject is treated with an additional therapeutic agent to prevent the development of the adverse event or reduce the severity of the adverse event (e.g., conjunctivitis, conjunctival ulceration, and / or keratitis). In some embodiments, the treatment is an eye ice pad (e.g., THERA PEARL Eye Mask or the like). In some embodiments, the one or more adverse events are recurrent infusion-related reactions and the additional therapeutic agent is an antihistamine, acetaminophen, and / or a corticosteroid. In some embodiments, the one or more adverse events are neutropenia and the additional therapeutic agent is a growth factor support (G-CSF).In some embodiments, one or more adverse events is hyperthyroidism and the additional therapeutic agent is a non-selective beta-blocker (e.g., propranolol) or a thioamide. In some embodiments, one or more adverse events is hypothyroidism and the additional therapeutic agent is a thyroid replacement hormone (e.g., levothyroxine or liothyroinine).

[0406] V. Composition

[0407] 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-PD-1 antibodies or antigen-binding fragments thereof described herein.

[0408] Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington: The Science and Practice of Pharmacy, 20th Ed., Lippincott Williams & Wiklins, Pub., Gennaro Ed., Philadelphia, Pa. 2000).

[0409] 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., Zn-protein complexes); chelating agents such as EDTA and / or nonionic surfactants.

[0410] Buffers can be used to control the pH within a range that optimizes the effectiveness of the therapeutic agent, particularly if stability is pH-dependent. The buffer can be present in a concentration range of about 50 mM to about 250 mM. Suitable buffers for use in the present invention include organic acids, inorganic acids, and their salts. For example, citrates, phosphates, succinates, tartrates, fumarates, gluconates, oxalates, lactates, and acetates. Additionally, the buffer can include histidine and trimethylamine salts such as Tris.

[0411] Preservatives may be added to prevent microbial growth and are generally present in the range of 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., chloride, bromide, iodide), benzethonium chloride; thimerosal, phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol, 3-pentanol and m-cresol.

[0412] Tonicity agents, sometimes called "stabilizers," may be present to adjust or maintain liquid tonicity in a composition. When used with large, charged 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 likelihood of intermolecular and intramolecular interactions. Tonicity agents may be present in any amount between about 0.1% and about 25% by weight, or between about 1% and about 5% by weight, taking into account the relative amounts of other ingredients. In some embodiments, tonicity agents include polyols, triols, or higher sugar alcohols, such as glycerol, erythritol, arabitol, xylitol, sorbitol, and mannitol.

[0413] Additional excipients include agents that can act as one or more of the following: (1) bulking agents, (2) solubility enhancers, (3) stabilizers, and (4) agents that prevent denaturation or adhesion to the container walls. Such excipients include: polyols (as listed above); amino acids such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamine, threonine, etc.; organic sugars or sugar alcohols such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactitol, glycerol , cyclitols (e.g., inositol), polyethylene glycol; sulfur-containing reducing agents such as urea, glutathione, lipoic acid, sodium hydrothioacetate, 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 polyvinylpyrrolidone; monosaccharides (e.g., xylose, mannose, fructose, glucose); disaccharides (e.g., lactose, maltose, sucrose); trisaccharides such as raffinose; and polysaccharides such as dextrin or dextran.

[0414] A nonionic surfactant or detergent (also known as a "wetting agent") may be present to help solubilize the therapeutic agent and protect the therapeutic protein from agitation-induced aggregation. It also allows the formulation to be exposed to shear surface stress 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.

[0415] Suitable nonionic surfactants include polysorbate (20, 40, 60, 65, 80, etc.), poloxamer (184, 188, etc.), polyols, Polyoxyethylene sorbitan monoether ( Examples of suitable detergents include lauromacrogol 400, polyethylene glycol 40 stearate, polyoxyethylene hydrogenated castor oils 10, 50, and 60, glyceryl monostearate, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. Suitable anionic detergents include sodium lauryl sulfate, sodium dioctylsulfosuccinate, and sodium dioctylsulfonate. Cationic detergents include benzalkonium chloride or benzethonium chloride.

[0416] Formulations comprising the anti-TF antibody-drug conjugates described herein for use in the methods of treatment provided herein are described in WO2015 / 075201. In some embodiments, the anti-TF antibody-drug conjugates described herein are in a formulation comprising an anti-TF antibody-drug conjugate, histidine, sucrose, and D-mannitol, wherein the formulation has a pH of about 6.0. In some embodiments, the anti-TF antibody-drug conjugates described herein are in 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 formulation has a pH of about 6.0. In some embodiments, the anti-TF antibody-drug conjugates described herein are in a formulation comprising an anti-TF antibody-drug conjugate at a concentration of 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 formulation has a pH of about 6.0. In some embodiments, the formulation comprises tesotumomab vedotin at a concentration of 10 mg / ml, histidine at a concentration of 30 mM, sucrose at a concentration of 88 mM, and D-mannitol at a concentration of 165 mM, wherein the pH of the formulation is 6.0.

[0417] In some embodiments provided herein, the formulations comprising the anti-TF antibody-conjugates described herein do not comprise a surfactant (ie, are surfactant-free).

[0418] The formulations for in vivo administration must be sterile. The formulations can be sterilized by filtration through a sterile filtration membrane. The therapeutic compositions herein are typically placed in containers with sterile access ports, such as intravenous solution bags or vials with a stopper pierceable by a hypodermic injection needle.

[0419] The route of administration is according to known and accepted methods, such as single or multiple boluses or infusions over a prolonged period by appropriate means, for example, by subcutaneous, intravenous, intraperitoneal, intramuscular, intraarterial, intralesional or intraarticular routes, topical application, inhalation, or injection or infusion by sustained-release or slow-release means.

[0420] The formulations herein may also contain more than one active compound, depending on the specific indication being treated. Preferably, these active compounds have complementary activities and do not adversely affect each other. Alternatively or additionally, the composition may include a cytotoxic agent, cytokine, or growth inhibitory agent. These molecules are appropriately combined in amounts effective to achieve the intended purpose.

[0421] 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 a method of 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 attached to MMAE, wherein the antibody-drug conjugate has the following structure:

[0422]

[0423] 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 the anti-TF antibody or antigen-binding fragment thereof, and Ab designates an anti-TF antibody or antigen-binding fragment thereof as described herein, such as tesotumomab. In some embodiments, p represents a number from 3 to 5. In some embodiments, the average p value of the composition is about 4. In some embodiments, the population is a mixed population of antibody-drug conjugates, wherein the p value of each antibody-drug conjugate varies from 1 to 8. In some embodiments, the population is a homogeneous population of antibody-drug conjugates, wherein each antibody-drug conjugate has the same p value.

[0424] In some embodiments, a composition comprising an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein is co-administered with a composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof as described herein. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein are administered simultaneously. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein are administered to a subject less than about one hour apart, such as less than about 30 minutes apart, less than about 15 minutes apart, less than about 10 minutes apart, or less than about 5 minutes apart. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein are administered to a subject less than one hour apart, such as less than 30 minutes apart, less than 15 minutes apart, less than 10 minutes apart, or less than 5 minutes apart. In some embodiments, the anti-TF antibody-drug conjugate as described herein and an anti-PD-1 antibody as described herein are administered sequentially. In some embodiments, sequential administration refers to the administration of an anti-TF antibody-drug conjugate described herein and an anti-PD-1 antibody described herein at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein is co-administered with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein is co-administered with one or more therapeutic agents to prevent the development of an adverse event or to reduce the severity of an adverse event.

[0425] In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein is co-administered with one or more additional therapeutic agents. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein and one or more additional therapeutic agents are administered simultaneously. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein and one or more therapeutic agents are administered to a subject less than about one hour apart, such as less than about 30 minutes apart, less than about 15 minutes apart, less than about 10 minutes apart, or less than about 5 minutes apart. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein and one or more therapeutic agents are administered to a subject less than one hour apart, such as less than 30 minutes apart, less than 15 minutes apart, less than 10 minutes apart, or less than 5 minutes apart. In some embodiments, the anti-TF antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein and one or more additional therapeutic agents are administered sequentially. In some embodiments, sequential administration refers to administering the anti-TF antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein and one or more additional therapeutic agents at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 25 hours apart, at least 26 hours apart, at least 27 hours apart, at least 28 hours apart, at least 29 hours apart, at least 30 hours apart, at least 31 hours apart, at least 32 hours apart, at least 33 hours apart, at least 34 hours apart, at least 35 hours apart, at least 36 hours apart, at least 37 hours apart, at least 38 hours apart, at least 39 hours apart, at least 40 hours apart, at least 41 hours apart, at least 42 hours apart, at least 43 hours apart, at least 44 hours apart, at least 45 hours apart, at least 46 hours apart, at least 47 hours apart, at least 48 hours apart, at least 49 hours apart, at least 50 hours apart, at least 51 hours apart, at least 52 hours apart, The administrations are 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.

[0426] In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein is co-administered with one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein is administered simultaneously with one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events. In some embodiments, simultaneous means that an anti-TF antibody-drug conjugate as described herein and / or an anti-PD-1 antibody as described herein and one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events are administered to a subject less than about one hour apart, such as less than about 30 minutes apart, less than about 15 minutes apart, less than about 10 minutes apart, or less than about 5 minutes apart. In some embodiments, concurrently refers to administering to a subject an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody as described herein and one or more therapeutic agents for the purpose of eliminating or reducing the severity of one or more adverse events less than one hour apart, such as less than 30 minutes apart, less than 15 minutes apart, less than 10 minutes apart, or less than 5 minutes apart. In some embodiments, sequentially administering refers to administering to a subject an anti-TF antibody-drug conjugate and / or an anti-PD-1 antibody as described herein and one or more additional therapeutic agents less than 1 ... at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 25 hours apart, at least 26 hours apart, at least 27 hours apart, at least 28 hours apart, at least 29 hours apart, at least 30 hours apart, at least 31 hours apart, at least 32 hours apart, at least 33 hours apart, at least 34 hours apart, at least 35 hours apart, at least 36 hours 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 conjugates described herein and / or the anti-PD-1 antibodies described herein are administered prior to one or more therapeutic agents for the purpose of eliminating or reducing the severity of one or more adverse events. In some embodiments, the one or more therapeutic agents for the purpose of eliminating or reducing the severity of one or more adverse events are administered prior to the anti-TF antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein.

[0427] VI. Articles of Manufacture and Kits

[0428] In another aspect, an article of manufacture or kit is provided that comprises an anti-TF antibody-drug conjugate described herein and / or an anti-PD-1 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-PD-1 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-PD-1 antibody described herein in a method for treating cancer (e.g., breast cancer or cervical cancer) in a subject, the method comprising administering to the subject an effective amount of the anti-TF antibody-drug conjugate described herein and / or the anti-PD-1 antibody described herein. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer. 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 metastatic and recurrent. In some embodiments, the cervical cancer is a recurrent cancer. In some embodiments, the individual is not a candidate for curative therapy. In some embodiments, the individual has not received prior systemic therapy for cervical cancer. In some embodiments, the individual is human.

[0429] The article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g., dual-chamber vials), syringes (such as single-chamber or dual-chamber syringes), and test tubes. In some embodiments, the container is a vial. The container can be formed from a variety of materials such as glass or plastic. The container holds the formulation.

[0430] The article of manufacture or kit may further include a label or package insert on or associated with the container, which may indicate instructions for reconstructing and / or using the formulation. The label or package insert may further indicate that the formulation is used for or intended for subcutaneous, intravenous (e.g., intravenous infusion) or other modes of administration for treating individual cancers such as breast cancer or cervical cancer (e.g., advanced cervical cancer such as grade 3 or grade 4 or metastatic cervical cancer) as described herein. The container holding the formulation may be a single-use vial or a multiple-use vial allowing repeated administration of the reconstructed formulation. The article of manufacture or kit may further include a second container comprising a suitable diluent. The article of manufacture or kit may further include other materials required from a commercial, therapeutic and user perspective, including other buffers, diluents, filters, needles, syringes and a package insert containing instructions for use.

[0431] The articles of manufacture or kits herein optionally further comprise a container comprising a second agent, wherein the anti-TF antibody-drug conjugate described herein is the first agent, and the article or kit further comprises instructions on a label or package insert for treating a subject with an effective amount of the second agent. In some embodiments, the second agent is an anti-PD-1 antibody as described herein. In some embodiments, the label or package insert indicates that the first and second agents should be administered sequentially or simultaneously as described herein.

[0432] The articles of manufacture or kits herein optionally further comprise a container comprising a third agent, wherein the third agent 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 agent and the anti-PD-1 antibody described herein is the second agent, and the article or kit further comprises instructions on the label or package insert for treating the subject with an effective amount of the third agent. In some embodiments, the label or package insert indicates that the first, second, and third agents 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 to be administered first, followed by the anti-PD-1 antibody described herein, and then the third agent.

[0433] In some embodiments, the anti-TF antibody-drug conjugates described herein and / or the anti-PD-1 antibodies described herein are present in a container as a lyophilized powder. In some embodiments, the lyophilized powder is in a sealed container such as a vial, ampoule, or pouch, indicating the amount of active agent. When the drug product is administered by injection, an ampoule of, for example, sterile water for injection or saline can be provided (optionally as part of the kit) so that the ingredients can be mixed prior to administration. The kit may further include, if necessary, one or more different conventional pharmaceutical components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as would be apparent to one of ordinary skill in the art. Instructions printed in the form of an insert or label may also be included in the kit, indicating the amounts of the components to be administered, guidelines for administration, and / or guidelines for mixing the components.

[0434] VII. Exemplary Embodiments

[0435] The examples provided herein are:

[0436] 1. A method for treating cancer in an individual, the method comprising administering to the individual (1) an antibody or an antigen-binding fragment thereof and (2) an antibody-drug conjugate that binds to tissue factor (TF), wherein the (1) antibody binds to programmed death-1 (PD-1) and inhibits PD-1 activity, wherein the (2) antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin E, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

[0437] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17;

[0438] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18; and

[0439] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; and

[0440] Wherein the light chain variable region comprises:

[0441] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20;

[0442] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21; and

[0443] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22;

[0444] The anti-TF 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:

[0445] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0446] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0447] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0448] Wherein the light chain variable region comprises:

[0449] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0450] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0451] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined by the IMGT numbering scheme.

[0452] 2. The method of embodiment 1, wherein the antibody-drug conjugate is administered in a dose range of about 0.9 mg / kg to about 2.1 mg / kg, such as 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.

[0453] 3. The method of any one of embodiments 1 to 2, wherein the antibody-drug conjugate is administered at a dose of about 1.3 mg / kg.

[0454] 4. The method of any one of embodiments 1 to 2, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg / kg.

[0455] 5. The method of any one of embodiments 1 to 2, wherein the antibody-drug conjugate is administered at a dose of about 2.0 mg / kg.

[0456] 6. The method of any one of embodiments 1 to 2, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg / kg.

[0457] 7. The method of any one of embodiments 1 to 6, wherein the antibody-drug conjugate is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks.

[0458] 8. The method of embodiment 7, wherein the antibody-drug conjugate is administered approximately once every 3 weeks.

[0459] 9. The method of embodiment 7, wherein the antibody-drug conjugate is administered once every 3 weeks.

[0460] 10. The method of any one of embodiments 1 to 9, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a uniform dose range of about 50 mg to about 500 mg.

[0461] 11. The method of any one of embodiments 1 to 10, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a uniform dose of about 200 mg.

[0462] 12. The method of any one of embodiments 1 to 10, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a uniform dose of 200 mg.

[0463] 13. The method of any one of embodiments 1 to 12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks.

[0464] 14. The method of embodiment 13, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered approximately once every 3 weeks.

[0465] 15. The method of embodiment 13, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks.

[0466] 16. The method of any one of embodiments 1 to 15, wherein the cancer is breast cancer.

[0467] 17. The method of embodiment 16, wherein the breast cancer is ER+ / HER2- breast cancer or triple-negative breast cancer.

[0468] 18. The method of any one of embodiments 1 to 15, wherein the cancer is cervical cancer.

[0469] 19. The method of embodiment 18, wherein the individual is not a candidate for curative therapy.

[0470] 20. The method of embodiment 19, wherein the curative therapy comprises radiation therapy and / or resection surgery.

[0471] 21. The method of embodiment 18, wherein the subject has not received prior systemic therapy for cervical cancer.

[0472] 22. The method of any one of embodiments 18 to 21, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

[0473] 23. The method of any one of embodiments 18 to 22, wherein the cervical cancer is advanced cervical cancer.

[0474] 24. The method of embodiment 23, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

[0475] 25. The method of embodiment 23 or 24, wherein the advanced cervical cancer is metastatic cervical cancer.

[0476] 26. The method of any one of embodiments 18 to 25, wherein the cervical cancer is recurrent cervical cancer.

[0477] 27. The method of any one of embodiments 1 to 26, 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.

[0478] 28. The method of any one of embodiments 1 to 27, 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, the heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 8.

[0479] 29. The method of any one of embodiments 1 to 28, 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, the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0480] 30. The method of any one of embodiments 1 to 29, wherein the anti-TF antibody of the antibody-drug conjugate is tesotumab.

[0481] 31. The method of any one of embodiments 1 to 30, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin E.

[0482] 32. The method of embodiment 31, wherein the linker is a cleavable peptide linker.

[0483] 33. The method of embodiment 32, wherein the cleavable peptide linker has the formula -MC-vc-PAB-, wherein:

[0484] a)MC is:

[0485]

[0486] b) vc is the dipeptide valine-citrulline, and

[0487] c) PAB is:

[0488]

[0489] 34. The method of any one of embodiments 31 to 33, wherein the linker is attached to a thiol residue of the anti-TF antibody or antigen-binding fragment thereof, the thiol residue being obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0490] 35. The method of embodiment 34, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the following structure:

[0491]

[0492] wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of the anti-TF antibody and Ab designates the anti-TF antibody or an antigen-binding fragment thereof.

[0493] 36. The method of embodiment 35, wherein the average value of p in the population of antibody-drug conjugates is about 4.

[0494] 37. The method of any one of embodiments 1 to 36, wherein the antibody-drug conjugate is tesotumomab vedotin.

[0495] 38. The method of any one of embodiments 1 to 37, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0496] 39. The method of any one of embodiments 1 to 38, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising 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 comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 32.

[0497] 40. The method of any one of embodiments 1 to 39, wherein the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region, 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.

[0498] 41. The method of any one of embodiments 1 to 40, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, 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.

[0499] 42. The method of any one of embodiments 1 to 41, wherein the anti-PD-1 antibody is pembrolizumab.

[0500] 43. The method of any one of embodiments 1 to 42, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously.

[0501] 44. The method of any one of embodiments 1 to 42, wherein the route of administration of the anti-PD-1 antibody or antigen-binding fragment thereof is intravenous.

[0502] 45. The method of any one of embodiments 1 to 44, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered sequentially.

[0503] 46. ​​The method of any one of embodiments 1 to 44, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the antibody-drug conjugate are administered simultaneously.

[0504] 47. The method of any one of embodiments 1 to 46, 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 from the individual express TF.

[0505] 48. The method of any one of embodiments 1 to 47, 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 from the individual express PD-L1.

[0506] 49. The method of any one of embodiments 1 to 48, wherein the individual has a tumor that expresses PD-L1 (TPS ≥ 1).

[0507] 50. The method of any one of embodiments 1 to 48, wherein the individual has a tumor with high PD-L1 expression (TPS ≥ 50).

[0508] 51. The method of any one of embodiments 1 to 48, wherein the individual has a tumor that expresses PD-L1 (CPS ≥ 1).

[0509] 52. The method of any one of embodiments 1 to 51, wherein the tumor derived from the cancer comprises one or more cells expressing PD-L1, PD-L2, or both PD-L1 and PD-L2.

[0510] 53. The method of any one of embodiments 1 to 52, 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 T cells from the individual express PD-1.

[0511] 54. The method of any one of embodiments 1 to 53, wherein one or more therapeutic effects of the subject are improved relative to baseline following administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0512] 55. The method of embodiment 54, wherein the one or more therapeutic effects are selected from the group consisting of: tumor size derived from the cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

[0513] 56. The method of any one of embodiments 1 to 55, wherein the size of the tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer prior to administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0514] 57. The method of any one of embodiments 1 to 56, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

[0515] 58. The method of any one of embodiments 1 to 57, wherein the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0516] 59. The method of any one of embodiments 1 to 58, wherein the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0517] 60. The method of any one of embodiments 1 to 59, wherein the duration of response to the antibody-drug conjugate following administration of the antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof 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 two years, at least about three years, at least about four years, or at least about five years.

[0518] 61. The method of any one of embodiments 1 to 60, wherein the subject has one or more adverse events and is further administered an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events.

[0519] 62. The method of any one of embodiments 1 to 61, wherein the subject is at risk of developing ...

Claims

1. Use of an anti-programmed death-1 (PD-1) antibody or an antigen-binding fragment thereof in combination with tisotumab vedotin for preparing a kit for treating breast cancer or cervical cancer in an individual, wherein the anti-programmed death-1 (PD-1) antibody or an antigen-binding fragment thereof inhibits PD-1 activity and comprises a heavy-chain variable region and a light-chain variable region, wherein the heavy-chain variable region consists of the amino acid sequence of SEQ ID NO: 33 and the light-chain variable region consists of the amino acid sequence of SEQ ID NO:

34.

2. Use of an anti-programmed death-1 (PD-1) antibody or an antigen-binding fragment thereof in combination with tisotumab vedotin for preparing a medicament for treating breast cancer or cervical cancer in an individual, wherein the anti-programmed death-1 (PD-1) antibody or an antigen-binding fragment thereof inhibits PD-1 activity and the binding fragment comprises a heavy-chain variable region and a light-chain variable region, wherein the heavy-chain variable region consists of the amino acid sequence of SEQ ID NO: 33 and the light-chain variable region consists of the amino acid sequence of SEQ ID NO:

34.

3. The use according to claim 1 or 2, wherein the tisotumab vedotin is administered in a dose range of 0.9 mg / kg to 2.1 mg / kg.

4. The use according to claim 3, wherein the tisotumab vedotin is administered at a dose of 1.3 mg / kg.

5. The use according to claim 3, wherein the tisotumab vedotin is administered at a dose of 2.0 mg / kg.

6. The use according to any one of claims 1 to 2, wherein the tisotumab vedotin is administered once every 1 week, once every 2 weeks, once every 3 weeks or once every 4 weeks.

7. The use according to claim 6, wherein the tisotumab vedotin is administered once every 3 weeks.

8. The use according to claim 4, wherein the tisotumab vedotin is administered once every 3 weeks.

9. The use according to claim 5, wherein the tisotumab vedotin is administered once every 3 weeks.

10. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered in a flat dose range of 50 mg to 500 mg.

11. The use according to claim 10, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered at a flat dose of 200 mg.

12. The use according to claim 10, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered at a flat dose of 400 mg.

13. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks.

14. The use according to claim 13, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered once every 3 weeks.

15. The use according to claim 11, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered once every 3 weeks.

16. The use according to claim 12, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered once every 3 weeks.

17. The use according to claim 13, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 6 weeks.

18. The use according to claim 11, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 6 weeks.

19. The use according to claim 12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 6 weeks.

20. The use according to claim 1, wherein the kit is for treating breast cancer.

21. The use according to claim 2, wherein the medicament is for treating breast cancer.

22. The use according to claim 20 or 21, wherein the breast cancer is ER+ / HER2− breast cancer or triple-negative breast cancer.

23. The use according to claim 1, wherein the kit is for treating cervical cancer.

24. The use according to claim 2, wherein the medicament is for treating cervical cancer.

25. The use according to claim 23 or 24, wherein the individual is not a candidate for curative therapy.

26. The use according to claim 25, wherein the curative therapy comprises radiotherapy and / or resection surgery.

27. The use according to claim 23 or 24, wherein the individual has not received prior systemic therapy for cervical cancer.

28. The use according to claim 23 or 24, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

29. The use according to claim 23 or 24, wherein the cervical cancer is advanced cervical cancer.

30. The use according to claim 29, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

31. The use according to claim 29, wherein the advanced cervical cancer is metastatic cervical cancer.

32. The use according to claim 23 or 24, wherein the cervical cancer is recurrent cervical cancer.

33. The use according to claim 1 or 2, wherein the administration route of tisotumab vedotin is intravenous.

34. The use according to claim 1 or 2, wherein the anti-PD-1 antibody is pembrolizumab.

35. The use according to claim 1 or 2, wherein the administration route of the anti-PD-1 antibody or antigen-binding fragment thereof is intravenous or subcutaneous.

36. The use according to claim 35, wherein the administration route of the anti-PD-1 antibody or antigen-binding fragment thereof is intravenous.

37. The use according to claim 35, wherein the administration route of the anti-PD-1 antibody or antigen-binding fragment thereof is subcutaneous.

38. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and tisotumab vedotin are administered sequentially.

39. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and tisotumab vedotin are administered simultaneously.

40. The use according to claim 1 or 2, wherein at least 0.1% of the cancer cells from the individual express TF.

41. The use according to claim 1 or 2, wherein at least 0.1% of the cancer cells from the individual express PD-L1.

42. The use according to claim 1 or 2, wherein the individual has a tumor expressing PD-L1 (TPS > 1).

43. The use according to claim 1 or 2, wherein the individual has a tumor with high PD-L1 expression (TPS > 50).

44. The use according to claim 1 or 2, wherein the individual has a tumor expressing PD-L1 (CPS > 1).

45. The use according to claim 1 or 2, wherein the tumor derived from the cancer comprises one or more cells expressing PD-L1, PD-L2, or both PD-L1 and PD-L2.

46. The use according to claim 1 or 2, wherein at least 0.1% of the T cells from the individual express PD-1.

47. The use according to claim 1 or 2, wherein one or more treatment effects of the individual are improved relative to the baseline after administration of tisotumab vedotin and the anti-PD-1 antibody or antigen-binding fragment thereof.

48. The use according to claim 47, wherein the one or more treatment effects are selected from the group consisting of: the size of the tumor derived from the cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

49. The use according to claim 1 or 2, wherein the size of the tumor derived from the cancer is reduced by at least 10% relative to the size of the tumor derived from the cancer before administration of tisotumab vedotin and the anti-PD-1 antibody or antigen-binding fragment thereof.

50. The use according to claim 1 or 2, wherein the objective response rate is at least 20%.

51. The use according to claim 1 or 2, wherein the individual exhibits a progression-free survival of at least 1 month after administration of tisotumab vedotin and the anti-PD-1 antibody or antigen-binding fragment thereof.

52. The use according to claim 1 or 2, wherein the individual exhibits an overall survival of at least 1 month after administration of tisotumab vedotin and the anti-PD-1 antibody or antigen-binding fragment thereof.

53. The use according to claim 1 or 2, wherein the duration of response to tisotumab vedotin after administration of tisotumab vedotin and the anti-PD-1 antibody or antigen-binding fragment thereof is at least 1 month.

54. The use according to claim 1 or 2, wherein the individual has one or more adverse events and is further administered an additional therapeutic agent to clear or reduce the severity of the one or more adverse events.

55. The use according to claim 1 or 2, wherein the individual is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

56. The use according to claim 1 or 2, wherein the individual has one or more adverse events, or is at risk of developing one or more adverse events, and is further administered an additional therapeutic agent to clear, prevent, or reduce the severity of the one or more adverse events, and the 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 deterioration of overall physical health.

57. The use according to claim 1 or 2, wherein the individual has one or more adverse events, or has a risk of developing one or more adverse events, and an additional therapeutic agent is further administered to clear, prevent or reduce the severity of the one or more adverse events, and the one or more adverse events are grade 3 or higher grade adverse events.

58. The use according to claim 1 or 2, wherein the individual has one or more adverse events, or has a risk of developing one or more adverse events, and an additional therapeutic agent is further administered to clear, prevent or reduce the severity of the one or more adverse events, and the one or more adverse events are serious adverse events.

59. The use according to claim 1 or 2, wherein the individual has one or more adverse events, or has a risk of developing one or more adverse events, and an additional therapeutic agent is further administered to clear, prevent or reduce the severity of the one or more adverse events, and the one or more adverse events are conjunctivitis, corneal ulcer and / or keratitis and the additional therapeutic agent is a preservative-free lubricating eye drop, an eye vasoconstrictor, an antibiotic and / or a steroid eye drop.

60. The use according to claim 1 or 2, wherein the individual is a human.

61. The use according to claim 1 or 2, wherein tisotumab vedotin is in a pharmaceutical composition, the pharmaceutical composition comprising the tisotumab vedotin and a pharmaceutically acceptable carrier.

62. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or its antigen-binding fragment is in a pharmaceutical composition, the pharmaceutical composition comprising the anti-PD-1 antibody or its antigen-binding fragment and a pharmaceutically acceptable carrier.

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