EA046283B1 - METHODS FOR TREATING CANCER USING A COMBINATION OF A PLATINUM-BASED DRUG AND A CONJUGATE OF ANTIBODY TO TISSUE FACTOR WITH A DRUG - Google Patents

Description

Description

Link to related applications

This application claims priority to US Provisional Application No. 62/646,256, filed March 21, 2018, and US Provisional Application No. 62/753,730, filed October 31, 2018, the contents of each of which are incorporated herein by reference in their entirety. .

Representation of a sequence listing in an ASCII text file

The contents of the following representation in an ASCII text file are incorporated herein by reference in their entirety: Machine Readable Form (CRF) of the Sequence Listing (File Name: 761682000640SEQLIST.TXT, Record Date: March 7, 2019, Size: 6 KB)

Field of technology to which the present invention relates

The present invention relates to methods of treating cancer, such as bladder cancer and cervical cancer, using a combination of a platinum-based agent and an anti-tissue factor (anti-TF) antibody-drug conjugate.

BACKGROUND OF THE INVENTION

Tissue factor (TF), also called thromboplastin, factor III or CD142, is a protein present in subendothelial tissue, platelets and leukocytes, required to initiate the formation of thrombin from zymogenic prothrombin. The formation of thrombin ultimately leads to blood clotting. TF allows cells to initiate the coagulation cascade, and it acts as a high-affinity receptor for coagulation factor VIIa (FVIIa), a serine protease. The resulting complex mediates the catalytic event that is responsible for initiating coagulation protease cascades through specific limited proteolysis. Unlike other cofactors of these protease cascades, which circulate as nonfunctional precursors, TF is a potent initiator that is fully functional when expressed on the cell surface.

TF is the cell surface receptor for the serine protease factor VIIa (FVIIa). The binding of FVIIa to TF triggers intracellular signaling processes, and this signaling function plays a role in angiogenesis. While angiogenesis is a normal process of growth and development, as well as wound healing, it is also a fundamental step in the transition of a tumor from a dormant state to a malignant state. When cancer cells acquire the ability to produce proteins that are involved in angiogenesis (ie, angiogenic growth factors), these proteins are released by the tumor into nearby tissue, thereby stimulating the sprouting of new blood vessels from existing healthy blood vessels to and into the tumor. Once new blood vessels enter the tumor, the tumor can quickly increase in size and invade nearby tissues and organs. Through new blood vessels, cancer cells can enter the bloodstream and settle in other organs, forming new tumors, also known as metastases.

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

Platinum-based agents are alkylating agents that covalently bind to DNA and cross-link DNA strands, resulting in inhibition of DNA synthesis and function, as well as inhibition of transcription. Single agent carboplatin has been used as a first-line option for recurrent or metastatic disease for several decades. In a phase 2 trial of carboplatin monotherapy for the treatment of recurrent or metastatic squamous cell carcinoma of the cervix, the overall response rate was 15% (6/41) with major toxicities including nausea and vomiting (48%), anemia (47%), leukopenia ( 38%) and thrombocytopenia (22%) (Weiss et al., 1990, Gynecol. Oncol. 39, 332-336). The addition of paclitaxel was evaluated in a phase 3 trial of cisplatin with or without paclitaxel, which demonstrated a significant improvement in PFS (progression-free survival) in subjects with stage IVB recurrent or persistent squamous cell carcinoma of the cervix; in addition, the response rate was significantly higher with the combination regimen. Objective responses (OR) were observed in 19% (6% complete responses + 13% partial responses) of subjects receiving cisplatin compared with 36% (15% complete + 21% partial) receiving carboplatin + paclitaxel (P = .002) . Median PFS was 2.8 and 4.8 months, respectively, for cisplatin compared with carboplatin + paclitaxel (P < .001). At the time of data collection there was no difference in median survival (8.8 months versus 9.7 months) (Moore et al, 2004). Despite the increased efficacy observed with cisplatin, the toxicity profile for this agent is worse than for carboplatin. The interchangeability of these two agents has been evaluated in several trials, including the phase 3 trial, JCOG050. This trial demonstrated similar efficacy of cisplatin plus paclitaxel compared with carboplatin plus paclitaxel (median OS, 18.3 months versus 17.5 months, respectively; HR, 0.994 (90% CI, 0.79 to 1.25; P = .032), and

- 1 046283 is considered a standard treatment option for patients with stage IVB, recurrent or persistent cervical carcinoma (Kitagawa et al., 2015, J. Clin. Oncol. 33, 2129-2135).

Bladder cancer is a life-threatening and progressive disease that usually begins in the epithelial lining (ie, urothelium) of the bladder. Invasive bladder cancer can spread to the lymph nodes, other pelvic organs (causing problems with kidney and bowel function), or other organs of the body such as the liver and lungs. Standard treatments for bladder cancer include surgery, radiation therapy, chemotherapy, and biological therapy. Bladder cancer is the fifth most common cancer diagnosis in the United States. Because patients are at high risk of recurrence and progression, bladder cancer is the most expensive of all cancers to treat per patient over a lifetime. Despite its incidence and prevalence, bladder cancer research is severely underfunded, resulting in little progress in improving bladder cancer treatment.

Cervical cancer is a major health problem worldwide, with an estimated incidence of more than 500,000 new cases and 250,000 deaths annually. See Tewari et al., 2014, N Engl J Med., 370:734-743. In the European Union, there are approximately 34,000 new cases of cervical cancer and 13,000 deaths annually. See Hillemans et al., 2016, Oncol. Res. Treat. 39:501-506. The main types of cervical cancer are squamous cell carcinoma and adenocarcinoma. Long-term infections with human papillomavirus (HPV) types 16 and 18 cause most cases of cervical cancer. Standard first-line therapy for cervical cancer has been platinum-based therapy and taxane-based therapy. Bevacizumab, an anti-VEGF antibody, has been approved by the US Food and Drug Administration for use in combination with chemotherapy to treat cervical cancer, improving overall survival in clinical trials. First-line (1L) treatment for advanced cervical cancer consists of bevacizumab in combination with paclitaxel plus a platinum-based agent (eg, 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, almost all patients relapse after this course of 1L treatment. See Tewari et al, 2014, N Engl J Med., 370:734-743. There is no approved therapy for second-line (2L) treatment, and patients are often treated with a single agent, including but not limited to: pemetrexed, topotecan, docetaxel, nab-paclitaxel, vinorelbine, and in some cases bevacizumab. A meta-analysis of single-agent treatment demonstrates a modest response rate of only 10.9% (ie, 60 responders out of 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. Oncol. 26:210-214; Fiorica et al., 2009, Gynecol. Oncol. 115:285-289; Garcia et. al., 2007, Am. J. Clin. Oncol. 30-428-431; Gonçalves et al., 2008, Gynecol. Oncol. 108:42-46; Homesley et al., 2008, Int. J. Clin. Oncol. 13:62-65; McLachlan et al., 2017, Clin. Oncol. (R. 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, 2004, Gynecol. Oncol. 92:639-643; Rose et al, 2006, Gynecol. Oncol. 102:210-213; Santin et al, 2011, Gynecol. Oncol. 122:495-500; Schilder et al, 2005, Gynecol. Oncol. 96:103-107; and Torfs et al, 2012, Em. J. Cancer. 48:1332–1340. The relative five-year survival rate for stage IV cervical cancer is only 15%, indicating a high need for improved cervical cancer treatment.

There remains an unmet need for combination therapies with an acceptable safety profile and high efficacy for the treatment of cancer, in particular for the treatment of bladder and cervical cancer. The present invention addresses this need by providing methods for treating cancer, such as bladder cancer and cervical cancer, using a combination of a platinum-based agent and an anti-tissue factor (anti-TF) antibody-drug conjugate.

All references cited herein, including patent applications, patent publications and scientific literature, are incorporated herein by reference in their entirety, as if each individual reference were specifically and individually incorporated by reference.

Summary of the present invention

Provided herein is a method of treating cancer in a subject, the method comprising administering to the subject a platinum-based agent and an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof, conjugated with monomethyl auristatin or a functional analogue or a functional derivative thereof. In some embodiments, the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg/kg to about 2.1 mg/kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 1.3 mg/kg. In some embodiments, the antibody-drug conjugate is administered at a dose of

- 2 046283 cabbage soup 1.3 mg/kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 2.0 mg/kg. In some embodiments, the antibody-drug conjugate is administered at a dose of 2.0 mg/kg. In some of the embodiments provided herein, the antibody-drug conjugate is administered once approximately every week, once approximately every 2 weeks, once approximately every 3 weeks, or once approximately every 4 weeks. In some of the embodiments provided herein, the antibody-drug conjugate is administered once approximately every 3 weeks. In some of the embodiments provided herein, the antibody-drug conjugate is administered once every 3 weeks. In some of the embodiments provided herein, the platinum-based agent is administered at a dose of about AUC=4 to about AUC=6. In some of the embodiments provided herein, the platinum-based agent is administered at a dose of about AUC=5. In some of the embodiments provided herein, the platinum-based agent is administered at a dose of AUC=5. In some of the embodiments provided herein, the platinum-based agent is administered once approximately every week, once approximately every 2 weeks, once approximately every 3 weeks, or once approximately every 4 weeks. In some of the embodiments provided herein, the platinum-based agent is administered once approximately every 3 weeks. In some of the embodiments provided herein, the platinum-based agent is administered once every 3 weeks. In some of the embodiments provided herein, the cancer is bladder cancer. In some of the embodiments provided herein, the cancer is cervical cancer. In some of the embodiments provided herein, the subject is not a candidate for radical treatment. In some of the embodiments provided herein, definitive treatment includes radiation therapy and/or exenteration. In some of the embodiments provided herein, the subject has not received prior systemic therapy for cervical cancer. In some of the embodiments provided herein, the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma. In some of the embodiments herein, cervical cancer is a common cervical cancer. In some of the embodiments provided herein, advanced cervical cancer is stage 3 or stage 4 cervical cancer. In some of the embodiments provided herein, advanced cervical cancer is metastatic cervical cancer. In some embodiments herein, cervical cancer is recurrent cervical cancer. In some of the embodiments provided herein, the monomethyl auristatin is monomethyl auristatin E (MMAE). In some of the embodiments provided herein, the anti-TF antibody or antibody-drug conjugate antigen binding fragment thereof is a monoclonal antibody or monoclonal antigen binding fragment thereof. In some embodiments herein, an anti-TF antibody or an antibody-drug conjugate antigen binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following:

(i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1;

(ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following:

(i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4;

(ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDRs of the anti-TF antibody or antigen binding fragment thereof are defined according to the IMGT numbering system. In some embodiments provided herein, an anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:7, and a variable region light chain containing an amino acid sequence that is at least 85% identical to the amino acid sequence according to SEQ ID NO:8. In some embodiments herein, an anti-TF antibody or an antibody-drug conjugate antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a variable region

- 3 046283 light chain containing the amino acid sequence according to SEQ ID NO:8. In some of the embodiments provided herein, the anti-TF antibody of the antibody-drug conjugate is tizotumab. In some of the embodiments provided herein, the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and monomethyl auristatin. In some of the embodiments provided herein, the linker is a cleavable peptide linker. In some of the embodiments provided herein, the cleavable peptide linker is characterized by the formula: -MC-vc-PAB-, where:

a) MS is:

O

O

b) vc is a valine-citrulline dipeptide, and c) PAB is:

ABOUT

In some of the embodiments provided herein, the linker is attached to the sulfhydryl residues of an anti-TF antibody produced by partial or complete reduction of an anti-TF antibody or an antigen-binding fragment thereof. In some of the embodiments provided herein, the linker is attached to MMAE, wherein the antibody-drug conjugate has the following structure:

Ab-MC-vc-PAB-MMAE where p is a number from 1 to 8, S is a sulfhydryl residue of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof. In some of the embodiments provided herein, the average p value of the population of antibody-drug conjugates is about 4. In some of the embodiments provided herein, the antibody-drug conjugate is tizotumab-vedotin. In some of the embodiments provided herein, the route of administration for the antibody-drug conjugate is intravenous. In some of the embodiments provided herein, the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin. In some of the embodiments provided herein, the platinum-based agent is carboplatin. In some of the embodiments provided herein, the platinum-based agent is cisplatin. In some of the embodiments provided herein, the route of administration for the platinum-based agent is intravenous. In some of the embodiments provided herein, the platinum-based agent and the antibody-drug conjugate are administered sequentially. In some of the embodiments provided herein, the platinum-based agent and the antibody-drug conjugate are administered simultaneously. In some of the embodiments provided herein, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20 %, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60% At least about 70% or at least about 80% of cervical cancer cells express TF. In some of the embodiments provided herein, one or more therapeutic effects in a subject

- 4 046283 improve after administration of an antibody-drug conjugate and a platinum-based agent relative to the baseline level. In some of the embodiments provided herein, one or more therapeutic effects are selected from the group consisting of the following: tumor size derived from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. In some of the embodiments provided herein, the size of a tumor arising from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25% , at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, according to by at least about 70% or at least about 80% relative to the size of the tumor originating from cervical cancer prior to administration of the platinum-based antibody-drug conjugate. In some of the embodiments provided 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 at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In some of the embodiments provided herein, the 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 two years, at least about three years, at least about four years, or at least about five years after administration of the platinum-based antibody-drug conjugate. In some of the embodiments provided 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, according to 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 after administration of the platinum-based antibody-drug conjugate. In some of the embodiments provided herein, the duration of response to the antibody-drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the platinum-based antibody-drug conjugate. In some of the embodiments provided herein, a subject is characterized by having one or more adverse events and is further administered an additional therapeutic agent to eliminate or reduce the severity of one or more adverse events. In some of the embodiments provided herein, the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events. In some embodiments herein, one or more of the adverse events are the following: hemorrhage, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, mucositis, constipation, decreased appetite, diarrhea, vomiting, neutropenia, febrile neutropenia, decreased platelet count or increased bleeding. In some of the embodiments provided herein, one or more of the adverse events is a grade 3 or higher adverse event. In some of the embodiments provided herein, one or more adverse events constitute a serious adverse event. In some of the embodiments provided herein, one or more of the adverse events is conjunctivitis and/or keratitis, and the additional agent is a

- 5 046283 preservative-free eye drops, ophthalmic vasoconstrictor and/or steroid eye drops. In some of the embodiments provided herein, the subject is a human. In some of the embodiments provided herein, the antibody-drug conjugate is contained in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutical acceptable carrier. In some of the embodiments provided herein, the platinum-based agent is contained in a pharmaceutical composition comprising the platinum-based agent and a pharmaceutically acceptable carrier.

In addition, this document provides a kit containing the following:

(a) a dosage ranging from about AUC=4 to about AUC=6 of a platinum-based agent;

(b) a dosage ranging from about 1.5 mg/kg to about 2.1 mg/kg of an antibody-drug conjugate that binds tissue factor (TF), wherein the antibody-drug conjugate contains an anti-TF antibody or an antigen-binding agent thereof fragment conjugated to monomethyl auristatin or a functional analogue or a functional derivative thereof; and (c) instructions for use of the platinum-based agent and the antibody-drug conjugate according to some of the embodiments provided herein. In some embodiments, the platinum-based agent is carboplatin. In some of the embodiments provided herein, the antibody-drug conjugate is tizotumab-vedotin.

Brief description of graphic materials

Fig. 1A-E are a series of graphs showing the antitumor activity of the combination of tizotumab-vedotin and cisplatin in a xenograft mouse model of cervical cancer. A) Average tumor size in mice after treatment with 4 mg/kg IgG1 control (open black circle), 4 mg/kg IgG1-MMAE control (filled black circle), 4 mg/kg cisplatin (open black square), 2 mg /kg tizotumab-vedotin (filled black square) or 2 mg/kg tizotumab-vedotin in combination with 4 mg/kg cisplatin (open black triangle). The black inverted arrow indicates the day of tizotumab-vedotin dosing. The black filled inverted triangle indicates the day of cisplatin dosing. Tumor burden was assessed using a caliper. Error bars indicate standard error of the mean. * indicates p < 0.05 treatment with tizotumab-vedotin + cisplatin compared with treatment with one agent. B) Average tumor size in mice after treatment with 4 mg/kg IgG1 control (open black circle), 4 mg/kg IgG1-MMAE control (filled black circle), 4 mg/kg cisplatin (open black square), 4 mg /kg tizotumab-vedotin (filled black square) or 4 mg/kg tizotumab-vedotin in combination with 4 mg/kg cisplatin (open black triangle). The black inverted arrow indicates the day of tizotumab-vedotin dosing. The black inverted triangle indicates the day of cisplatin dosing. Tumor burden was assessed using a caliper. Error bars indicate standard error of the mean. * indicates p < 0.05 treatment with tizotumab-vedotin + cisplatin compared with treatment with one agent. C) Average tumor size in mice on day 38 after treatment with 4 mg/kg IgG1 control (group 01), 4 mg/kg IgG1-MMAE control (group 02), 4 mg/kg tizotumab-vedotin (group 03), 2 mg/kg tizotumab-vedotin (group 04), 1 mg/kg tizotumab-vedotin (group 05), 0.5 mg/kg tizotumab-vedotin (group 06), 4 mg/kg cisplatin (group 07), 4 mg /kg tizotumab-vedotin in combination with 4 mg/kg cisplatin (group 08), 2 mg/kg tizotumab-vedotin in combination with 4 mg/kg cisplatin (group 09), 1 mg/kg tizotumab-vedotin in combination with 4 mg /kg cisplatin (group 10) or 0.5 mg/kg tizotumab-vedotin in combination with cisplatin 4 mg/kg (group 11). D) Percent tumor-free survival at a threshold tumor size of 1000 mm ³ in mice treated with 4 mg/kg IgG1-MMAE control (group 02), 4 mg/kg tizotumab-vedotin alone (group 03), 4 mg/kg tizotumab-vedotin in combination with 4 mg/kg cisplatin (group 08) or 4 mg/kg cisplatin alone (group 07). E) Percentage of tumor-free survival with a threshold tumor size of 1000 mm ³ in mice treated with 4 mg/kg IgG1-MMAE control (group 02), 2 mg/kg tizotumabvedotin alone (group 04), 2 mg/kg tizotumab-vedotin combination with 4 mg/kg cisplatin (group 09) or 4 mg/kg cisplatin only (group 07).

Fig. 2A-D is a graph showing the antitumor activity of the combination of tizotumab-vedotin and cisplatin in a mouse model of bladder cancer. A) Average tumor size in mice after treatment with control IgG1-MMAE (filled black circle), cisplatin (open black square), tizotumab-vedotin (filled black square), or tizotumab-vedotin plus cisplatin (open black triangle). The black inverted arrow indicates the day of tizotumab-vedotin dosing. The black filled inverted triangle indicates the day of cisplatin dosing. Tumor burden was assessed using a caliper. Error bars indicate standard error of the mean. B) Average tumor size in mice at day 25 after treatment with IgG1-MMAE control, tizotumab-vedotin, cisplatin, or tizotumab-vedotin plus cisplatin. C) Average tumor size in mice on day 32 after treatment with tizotumab-vedotin or tizotumab-vedotin in combination with cisplatin. D) About

- 6,046,283 cent tumor-free survival at a threshold tumor size of 500 mm ³ in mice treated with IgGl-MMAE control, tizotumab-vedotin alone, cisplatin alone, tizotumab-vedotin in combination with cisplatin.

Fig. 3A-C is a graph showing the antitumor activity of the combination of tizotumab-vedotin and carboplatin in a mouse model of cervical cancer. A) Average tumor size in mice after treatment with 2 mg/kg IgG1 control (open circle), 2 mg/kg IgG1-MMAE control (filled circle), 2 mg/kg tizotumab-vedotin (filled square), 40 mg/kg kg carboplatin (open square), 80 mg/kg carboplatin (open diamond), 2 mg/kg tizotumab-vedotin in combination with 40 mg/kg carboplatin (open triangle), or 2 mg/kg tizotumab-vedotin in combination with 80 mg/kg kg carboplatin (solid triangle). Arrows indicate the day of treatment. Tumor burden was assessed using a caliper. Error bars indicate standard error of the mean. B) Average tumor size in mice at day 20 after treatment with 2 mg/kg IgG1 control (open circle), 2 mg/kg IgG1-MMAE control (filled circle), 2 mg/kg tizotumab-vedotin (filled square) ), 40 mg/kg carboplatin (open square), 80 mg/kg carboplatin (open diamond), 2 mg/kg tizotumab-vedotin in combination with 40 mg/kg carboplatin (open triangle), or 2 mg/kg tizotumab-vedotin in combinations with 80 mg/kg carboplatin (filled triangle). C) Percentage of progression-free survival at a tumor size threshold of 750 ^mm3 in mice treated with 2 mg/kg IgG1 control (open circle), 2 mg/kg IgG1-MMAE control (filled circle), 2 mg/kg tizotumabvedotin (filled circle) square), 40 mg/kg carboplatin (open square), 80 mg/kg carboplatin (open diamond), 2 mg/kg tizotumab-vedotin in combination with 40 mg/kg carboplatin (open triangle) or 2 mg/kg tizotumab-vedotin in combination with 80 mg/kg carboplatin (filled triangle).

Fig. 4A-B is a graph showing the antitumor activity of the combination of tizotumab-vedotin and cisplatin in a mouse cervical cancer xenograft model. A) Mean tumor volume in mice after treatment with 2 mg/kg IgG1 control (light gray circle), 2 mg/kg IgG1-MMAE control (gray square), 2 mg/kg tizotumab-vedotin (light gray triangle) , 40 mg/kg carboplatin (dark gray triangle) or 2 mg/kg tizotumab-vedotin in combination with 40 mg/kg carboplatin (black circle). Arrows indicate the day of treatment. Tumor burden was assessed using a caliper. Error bars indicate standard error of the mean. B) Percentage of progression-free survival at a threshold tumor size of 1000 m ³ in mice treated with 2 mg/kg IgG1 control, 2 mg/kg IgG1-MMAE control, 2 mg/kg tizotumab-vedotin, 40 mg/kg carboplatin, or 2 mg/kg kg tizotumab-vedotin in combination with 40 mg/kg carboplatin.

Detailed Description of the Present Invention I.

Definitions

To make the present disclosure easier to understand, certain terms are first defined. Each of the following terms used in this application, unless otherwise expressly provided herein, has the meaning set forth below. Additional definitions are provided in this application.

As used herein, the term and/or is to be understood as specifically disclosing each of the two specified features or components, with or without the other. Thus, the term and/or, as used herein in a phrase such as A and/or B, is intended to include A and B, A or B, A (alone) and B (alone). Likewise, the term and/or, when used in a phrase such as A, B and/or C, is intended to cover each of the following: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (separately); B (separately); and C (separately).

The aspects and embodiments of the present invention described herein are intended to include comprising, consisting of, and consisting essentially of the aspects and embodiments.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled 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 the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide those skilled in the art with a common vocabulary for many of the terms used in the present disclosure.

Units, prefixes and symbols are indicated in their accepted form according to the Systeme International de Unites (SI). Numeric ranges include numbers that define a range. The headings set forth herein are not intended to limit the various aspects of the present disclosure, which may be obtained by reference to the description as a whole. Accordingly, the terms defined immediately below are more fully defined with reference to the present specification as a whole.

The terms tissue factor, TF, CD142, tissue factor antigen, TF antigen, and CD142 antigen are used interchangeably herein and, unless otherwise noted, include

- 7 046283 itself any variants, isoforms and species homologues of human tissue factor that are naturally expressed by cells or expressed on cells transfected with the tissue factor gene. In some embodiments, the tissue factor comprises an amino acid sequence that can be found under Genbank accession number NP 001984.

The term immunoglobulin refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) chains and one pair of heavy (H) chains, all four linked by disulfide bonds. The structure of immunoglobulins has been well studied. See, for example, Fundamental Immunology, chap. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)). Briefly, each heavy chain typically consists of a heavy chain variable region (abbreviated VH or VH) and a heavy chain constant region (CH or CH). The heavy chain constant region typically consists of three domains: CH1, CH2 and CH3. Heavy chains are usually linked together by disulfide bonds in the so-called hinge region. Each light chain typically consists of a light chain variable region (abbreviated V _L or VL) and a light chain constant region ( _CL or CL). The light chain constant region typically consists of a single domain, C _L . CL can be of the k (kappa) or λ (lambda) isotype. The terms constant domain and constant region are used interchangeably in this document. Unless otherwise noted, the numbering of amino acid residues in the constant region corresponds 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). The immunoglobulin can be derived from any of the generally known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3 and IgG4. An isotype refers to a class or subclass of antibodies (such as IgM or IgG1) that is encoded by heavy chain constant region genes.

The term variable region or variable domain refers to the heavy or light chain domain of an antibody that is involved in the binding of the antibody to an antigen. The heavy chain and light chain variable regions (VH and VL, respectively) of a native antibody can be further subdivided into hypervariable regions (or hypervariable regions that may be hypervariable in sequence and/or in the shape of structurally defined loops), also called complementarity determining regions (CDRs). ), interspersed with regions that are more conserved, called framework regions (FR). The terms complementarity determining regions and CDRs, synonymous with hypervariable regions or HVRs, are known in the art to refer to non-contiguous amino acid sequences in the variable regions of an antibody that confer antigen specificity and/or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-FEZ, CDRH3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). Framework regions and FRs are known in the art to refer to the non-CDR portions of the heavy and light chain variable regions. Typically, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4) and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR -L3 and FR-L4). Within each V _H and V _L , three CDRs and four FRs are typically located from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mot Biol, 195, 901-917 (1987).

The term antibody (Ab) in the context of the present invention refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of any of them, which has the ability to specifically bind to an antigen under typical physiological conditions with a half-life of significant periods of time, such as at least about 30 min, at least about 45 min, at least about one hour (h), at least about 2 hours, at least about 4 hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, approximately 48 hours or more, approximately three, four, five, six, seven or more days, etc. or any other appropriate functionally defined period (eg, time sufficient to induce, stimulate, enhance and/or modulate the physiological response associated with the binding of the antibody to the antigen and/or time sufficient for the antibody to engage effector activity). The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with the antigen. Antibody constant regions (Abs) can mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system, such as C1q, the first component in the classical complement pathway. The antibody may also be a bispecific antibody, diabody, multispecific antibody, or the like.

As used herein, the term monoclonal antibody refers to a preparation of antibody molecules that are recombinantly produced with one primary amino acid sequence.

- 8 046283 activity. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. Accordingly, the term human monoclonal antibody refers to antibodies exhibiting a single binding specificity that contain variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced using a hybridoma that includes a B cell derived from a transgenic or transchromosomal non-human animal, such as a transgenic mouse, with a genome containing a human heavy chain transgene and a human light chain transgene fused to an immortalized cell .

An isolated antibody refers to an antibody that is substantially free of other antibodies having a different antigen specificity (eg, an isolated antibody that specifically binds to TF is substantially free of antibodies that specifically bind to antigens other than TF). However, an isolated antibody that specifically binds to TF may exhibit cross-reactivity with other antigens, such as TF molecules from another species. Moreover, the isolated antibody may be substantially free of other cellular material and/or chemicals. In one embodiment, the isolated antibody includes an antibody conjugate attached to another agent (eg, a small molecule drug). In some embodiments, the isolated anti-TF antibody includes a conjugate of an anti-TF antibody with a small molecule drug (eg, MMAE or MMAF).

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

As used herein, the term humanized antibody refers to a genetically engineered non-human antibody that contains human antibody constant domains and non-human variable domains modified to provide high levels of sequence homology to human variable domains. This can be achieved by grafting the six complementarity determining regions (CDRs) of non-human antibodies, which together form the antigen binding site, onto a homologous human acceptor framework region (FR) (see WO92/22653 and EP0629240). To fully restore the binding affinity and specificity of the parent antibody, it may be necessary to replace the framework residues of the parent antibody (ie, the non-human antibody) in the human framework regions (back mutations). Structural homology modeling can help identify amino acid residues in framework regions that are important for the binding properties of an antibody. Thus, a humanized antibody may contain non-human CDR sequences, primarily human framework regions, optionally containing one or more back mutations of amino acids in the non-human amino acid sequence, and fully human constant regions. Optionally, additional amino acid modifications, which are not necessarily back mutations, can be used to produce a humanized antibody with preferred characteristics, such as affinity and biochemical properties.

As used herein, the term chimeric antibody refers to an antibody in which the variable region is derived from a non-human species (eg, rodents) and the constant region is derived from another species, such as a human. Chimeric antibodies can be produced by antibody engineering. Antibody engineering is a term used generally for various types of antibody modifications and is a process well known to those skilled in the art. In particular, a chimeric antibody can be produced using standard DNA techniques as described in Sambrook et al, 1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Ch. 15. Thus, a chimeric antibody may be a genetically or enzymatically engineered recombinant antibody. One skilled in the art will have knowledge of creating a chimeric antibody, and thus the production of a chimeric antibody according to the present invention can be accomplished by methods other than those described herein. Chimeric monoclonal antibodies for therapeutic use are designed to reduce the immunogenicity of antibodies. Typically, they may contain non-human (eg, murine) variable regions that are specific for the antigen of interest,

- 9 046283 and constant domains of the heavy and light chains of human antibodies. The terms variable region or variable domains as used in the context of chimeric antibodies refer to the region that includes the CDRs and framework regions of both the immunoglobulin heavy and light chains.

Anti-antigen antibody refers to an antibody that binds to an antigen. For example, an anti-TF antibody is an antibody that binds to a TF antigen.

An antigen-binding portion or antigen-binding fragment of an antibody refers to one or more antibody fragments that retain the ability to specifically bind to an antigen bound to the whole antibody. Examples of antibody fragments (eg, antigen binding fragment) include, but are not limited to: Fv, Fab, Fab', Fab'-SH, F(ab') ₂ ; diabodies; linear antibodies; single chain antibody molecules (eg scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called Fab' fragments, each with one antigen-binding site, and a residual Pc fragment, the name of which reflects its ability to readily crystallize. Treatment with pepsin produces an F(ab')2 fragment that contains two antigen-binding sites and is still able to cross-link antigen.

Percentage (%) sequence identity with respect to the reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps if necessary to achieve the maximum percentage of sequence identity and excluding any conservative substitutions as part of sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved in a variety of ways known to those skilled in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared. For example, the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which may alternatively be stated as a given amino acid sequence A that has or contains a certain % sequence identity to, with, or against a given amino acid sequence B) calculated as follows:

100 x fraction X/Y, where X is the number of amino acid residues scored as identical sequence matches in this program when aligning A and B, and where Y is the total number of amino acid residues in B. It is clear that if the length of the amino acid sequence is A is not equal to the length of the amino acid sequence B, the % identity of the sequences of A with respect to B will not equal the % identity of the sequences of B with respect to A.

As used herein, the terms binding, binds, or specifically binds in the context of the binding of an antibody to a predetermined antigen is generally binding with an affinity corresponding to a Kd of about 10 ^-6 M or less, for example, 10 ^-7 M or less, for example, about 10 ^-8 M or less, such as about 10 ^-9 M or less, about 10 ^-10 M or less, or about 10 ^-11 M or even less, when determined, for example, using biolayer interferometry (BLI) technology ) in an Octet HTX instrument using an antibody as a ligand and an antigen as an analyte, and wherein the antibody binds to a predetermined antigen with an affinity corresponding to a K _D that is at least ten times lower, e.g., at least 100 times lower , e.g., at least 1000 times lower, e.g., at least 10,000 times lower, e.g., at least 100,000 times lower, than its KD of binding to a nonspecific antigen (e.g., BSA, casein), different from a predetermined antigen or closely related antigen. The amount at which the KD of binding is lower depends on the KD of the antibody, so that when the KD of an antibody is very low, the amount at which the KD of binding to an antigen is lower than the KD of binding to a nonspecific antigen can be at least 10,000-fold (i.e. i.e. the antibody is highly specific).

As used herein, the term KD (M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. As used herein, the term affinity and KD are inversely proportional, i.e. higher affinity is implied to mean lower KD, and lower affinity is meant to be higher Kd.

The term ADC refers to an antibody-drug conjugate, which in the context of the present invention refers to an anti-TF antibody that is linked to a drug moiety (eg, MMAE or MMAF) as described herein.

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The abbreviations vc and val-cit refer to the dipeptide valine-citrulline.

The abbreviation RAB refers to self-cleavage spacer:

The abbreviation MC refers to the stretcher - maleimidocaproyl:

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

A platinum-based agent refers to a molecule or composition including a molecule containing a coordination complex including the chemical element platinum and useful as a chemotherapeutic drug. Platinum-based agents generally act by inhibiting DNA synthesis, and some have alkylating activity. Platinum-based agents include those currently used as part of a chemotherapy regimen, those currently in development, and those that may be developed in the future.

Cancer refers to a broad group of different diseases characterized by the uncontrolled growth of abnormal cells in the body. Cancer or cancerous tissue may include a tumor. Unregulated cell division and growth leads to the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. After metastasis, distal tumors can be said to have originated from the tumor before metastasis. For example, a tumor derived from cervical cancer refers to a tumor that results from metastasized cervical cancer.

Treatment or therapy of a subject refers to any type of intervention or process performed on a subject or the administration of an active agent to a subject for the purpose of reversing, alleviating, reducing the intensity of, inhibiting, delaying or preventing the occurrence, progression, development, severity or recurrence of a symptom, complication, condition or biochemical parameters associated with the disease. In some embodiments, the disease is cancer.

Subject includes any human or non-human animal. The term non-human animal includes, without limitation, vertebrates such as non-human primates, sheep, dogs and rodents such as mice, rats and guinea pigs. In some embodiments, the subject is a human. The terms subject and patient and individual are used interchangeably herein.

An effective amount, or therapeutically effective amount, or therapeutically effective dosage of a drug or therapeutic agent is any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes its regression, as evidenced by a reduction in severity symptoms of a disease, increasing the frequency and duration of asymptomatic periods of the disease, or preventing impairment or disability due to the disease. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to the skilled practitioner, for example, in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by analyzing the activity of the agent in in vitro assays.

As an example of treating tumors, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least 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 about 96%, at least about 97%, at least about 98%, or at least about 99% in the treated subject(s) (e.g., one or more treated subjects) compared to untreated subject(s) (eg, one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by 100% in the treated subject(s) (e.g., one or more treated subjects) compared to untreated subject(s).

- 11 046283 treated subject(s) (eg, one or more untreated subjects).

In other embodiments of the present disclosure, tumor regression may be observed and continue 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. days. Despite these finite measures of therapeutic efficacy, evaluation of immunotherapeutic drugs must also consider immune-mediated response patterns.

A therapeutically effective amount of a drug (eg, an anti-TF antibody-drug conjugate or a platinum-based agent) includes a prophylactically effective amount, which is any amount of a drug that, when administered alone or in combination with an anticancer agent, to a subject at risk of developing cancer (eg, a subject characterized by the presence of a precancerous condition) or suffering from recurrent cancer, inhibits the development or recurrence of cancer. In some embodiments, the prophylactically effective amount completely prevents the development or recurrence of cancer. Inhibiting the development or recurrence of cancer means either reducing the likelihood of developing or recurring cancer or completely preventing the development or recurrence of cancer.

As used herein, the term subtherapeutic dose means a dose of a therapeutic compound (e.g., an anti-TF antibody-drug conjugate or platinum-based agent) 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) .

Immune-mediated response pattern refers to the clinical response pattern often observed in cancer patients treated with immunotherapies that produce antitumor effects by inducing cancer-specific immune responses or by modifying native immune processes. This pattern of response is characterized by a beneficial therapeutic effect that follows an initial increase in tumor burden or the appearance of new lesions, which, when evaluated with traditional chemotherapeutic agents, would be classified as disease progression and would be synonymous with drug failure. Accordingly, proper evaluation of immunotherapies may require long-term monitoring of the effects of these agents on the target disease.

As an example, an anticancer agent stimulates regression of cancer in a subject. In some embodiments, a therapeutically effective amount of a drug stimulates regression of the cancer to the point of elimination. Promoting cancer regression means that administration of an effective amount of a drug, alone or in combination with an anticancer agent, results in a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one symptom of the disease, an increase in the frequency and duration of asymptomatic periods of the disease, or the prevention of a disorder functions or disability due to impairment due to disease. In addition, the terms effective and efficacy as applied to treatment include both pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to stimulate cancer regression in a patient. Physiological safety refers to the level of toxicity or other undesirable physiological effects at the cellular, organ and/or body level (adverse effects) resulting from the administration of a drug.

Sustained response refers to the sustained effect on reducing tumor growth after stopping treatment. For example, the tumor size may remain the same or smaller than the size at the beginning of the administration phase. In some embodiments, the sustained response is characterized by a duration at least as long as the duration of treatment or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

As used herein, the term complete response or CR refers to the disappearance of all target lesions; partial response or PR refers to a reduction in the sum of the longest diameters (SLD) of the target lesions by at least 30%, taking the initial SLD as the reference; and stable disease or SD refers to neither a sufficient reduction in target lesions to qualify as PR nor a sufficient increase to qualify as PD, taking as the reference the smallest SLD since the start of treatment.

As used herein, the term progression-free survival or PFS refers to the length of time during and after treatment during which the disease being treated (eg, cancer) does not worsen. Progression-free survival may include the period of time during which patients experienced a complete or partial response, as well as the period of time during which patients experienced stable disease.

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

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As used herein, the term overall survival or OS refers to the percentage of individuals in a group who are likely to be alive after a specified period of time.

As used herein, the term dose based on body weight means that the dose administered to a subject is calculated based on the body weight of the subject. For example, when a 60 kg subject requires 2.0 mg/kg of a platinum agent or anti-TF antibody-drug conjugate, the appropriate amount of platinum agent or anti-TF antibody-drug conjugate can be calculated and used (i.e. e. 120 mg) for administration to the specified subject.

The use of the term fixed dose in relation to a method according to the present disclosure means that the subject is administered two or more different agents (eg, a platinum-based agent and an anti-TF antibody-drug conjugate) in specified (fixed) ratios to each other. In some embodiments, the fixed dose is based on the amount (eg, mg) of the agent. In certain embodiments, the fixed dose is based on the concentration (eg, mg/ml) of the agents. For example, a 3:1 ratio of platinum agent to anti-TF antibody-drug conjugate administered to a subject may mean that the subject is administered about 240 mg of platinum agent and about 80 mg of anti-TF antibody-drug conjugate, or about 3 mg /ml of platinum-based agent and about 1 mg/ml of anti-TF antibody-drug conjugate.

When used in connection with the methods and dosages of the present disclosure, the term constant dose means a dose that is administered to a subject without regard to the body weight or body surface area (BSA) of the subject. Thus, the constant dose is not provided as a mg/kg dose, but as an absolute amount of the agent (eg, anti-TF antibody-drug conjugate and/or platinum-based agent). For example, a subject weighing 60 kg and a subject weighing 100 kg would receive the same dose of antibody or antibody-drug conjugate (eg, 240 mg of anti-TF antibody-drug conjugate or, eg, 750 mg of a platinum-based agent).

The phrase pharmaceutically acceptable indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients in the composition and/or with the mammal being treated with it.

As used herein, the phrase pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound of the present invention. Examples of salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate , ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e. 4,4'-methylene-bis-( 2-hydroxy-3-naphthoate)), alkali metal salts (eg sodium and potassium), alkaline earth metal salts (eg magnesium) and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or another counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may contain more than one charged atom in its structure. Cases where multiple charged atoms are part of a pharmaceutically acceptable salt may contain multiple counterions. Therefore, a pharmaceutically acceptable salt may contain one or more charged atoms and/or one or more counterions.

Administration or administration refers to the physical administration of a therapeutic agent to a subject using any of the various delivery methods and systems known to those skilled in the art. Exemplary routes of administration of an anti-TF antibody-drug conjugate and/or platinum-based agent include the following: intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, such as by injection or infusion (eg, intravenous infusion). As used herein, the phrase parenteral administration means methods of administration other than enteral and topical, typically by injection, and includes, without limitation, the following: intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal , intraperitoneal, transtracheal, subcuticular, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. The therapeutic agent can be administered non-parenterally or orally. Other non-parenteral routes of administration include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods.

The terms baseline or baseline, used interchangeably herein, may refer to a measurement or characteristic of a symptom before the administration of therapy

- 13 046283 (for example, an anti-TF antibody-drug conjugate as described herein and/or a platinum-based agent as described herein) or at the beginning of the administration of therapy. The baseline value can be compared to a reference value to determine a reduction or improvement in a symptom of a disease contemplated herein, such as a TF-associated disease contemplated herein (eg, bladder cancer or cervical cancer). The terms reference or reference value, used interchangeably herein, may refer to a measurement or characterization of a symptom following administration of a therapy (an anti-TF antibody-drug conjugate as described herein and/or a platinum-based agent as described herein ). The reference value may be measured one or more times during a dosing regimen or treatment cycle or upon completion of a dosing regimen or treatment cycle. The reference value may be an absolute value; relative value; a value characterized by an upper and/or lower limit; range of values; average value; median value; the average or value compared to the original value.

Likewise, the original value may be an absolute value; relative value; a value characterized by an upper and/or lower limit; range of values; average value; median value; average value or value compared to a reference value. The reference value and/or initial value can be obtained from one individual, from two different individuals, or from a group of individuals (eg, a group of two, three, four, five or more individuals).

As used herein, monotherapy means that the anti-TF antibody-drug conjugate or platinum-based agent is the only anticancer agent administered to the subject during the treatment cycle. However, other therapeutic agents may be administered to the subject. For example, during a monotherapy period, anti-inflammatory drugs or other agents may be administered to a subject with cancer to treat symptoms associated with the cancer, but not the underlying cancer itself, including, for example, inflammation, pain, weight loss, and general malaise.

As used herein, the term adverse event (AE) is any adverse and generally unintended or unwanted sign (including abnormal laboratory findings), symptom or disease associated with the use of medical treatment. Medical treatment may be characterized by the presence of one or more associated AEs, and each AE may be characterized by the same or different levels of severity. Reference to methods capable of modifying adverse events means a treatment regimen that reduces the frequency and/or severity of one or more AEs associated with the use of another treatment regimen.

As used herein, the term serious adverse event or SAE is an adverse event that meets one of the following criteria:

Is fatal or life-threatening (in the definition of a serious adverse event, life-threatening refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically could have resulted in death if it had been more severe.

Causes permanent or significant disability/disability.

Is a congenital anomaly/birth defect.

Is significant from a medical point of view, i.e. is defined as an event that poses a risk to the patient or may require medical or surgical intervention to prevent one of the outcomes listed above. Medical and scientific judgment must be used when deciding whether an AE is medically significant.

Requires hospitalization or extension of existing hospitalization, except for the following: 1) planned treatment or observation of the underlying disease, not associated with any deterioration of the condition; 2) planned or pre-planned treatment of a pre-existing condition that is not related to the indication being studied and has not worsened since the signing of the informed consent; and 3) social reasons and temporary assistance in the absence of any deterioration in the general condition of the patient.

The use of an alternative (for example, or) should be understood to mean one, both, or any combination of the alternatives. As used herein, the singular forms are to be understood as referring to one or more of any quoted or enumerated component.

The terms about or containing substantially refer to a value or composition that is within the acceptable error range for a particular value or composition as determined by one skilled in the art, which will depend in part on how the value or composition is measured or determined , i.e. limitations of the measurement system. For example, approximately or substantially may mean within 1 or more than 1 standard deviation according to practice in the art. Alternatively, about (approx.

- 14 046283 positive) or essentially containing can mean a range of up to 20%. Additionally, especially in relation to biological systems or processes, these terms can mean up to an order of magnitude or up to a factor of 5. When specific values or compositions are presented in this application and claims, unless otherwise stated, the value of about (approximately) or essentially being within the acceptable error range for that particular value or composition should be assumed.

The terms once approximately every week, once approximately every two weeks, or any other similar dosing interval terms used herein mean approximate numbers. Once approximately every week may include every seven days ± one day, i.e. every six days - every eight days. Once approximately every two weeks may include every fourteen days ± two days, i.e. every twelve days - every sixteen days. Once approximately every three weeks may include every twenty-one days ± three days, i.e. every eighteen - every twenty-four days. Similar approximations apply, for example, to the following: once approximately every four weeks, approximately once every five weeks, approximately once every six weeks, and once approximately every twelve weeks. In some embodiments, a dosing interval of once approximately every six weeks or once approximately every twelve weeks means that the first dose can be administered on any day of the first week, and then the next dose can be administered on any day in the sixth or twelfth week , respectively. In other embodiments, a dosing interval of once approximately every six weeks or once approximately every twelve weeks means that the first dose is administered on a specific day of the first week (eg, Monday) and then the next dose is administered on the same day of the sixth or twelfth week (i.e. Monday), respectively.

As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the range and, where appropriate, fractions thereof (e.g., one-tenth and one-hundredth of an integer), unless otherwise specified.

Various aspects of the present disclosure are described in more detail in the following subsections.

II. Combination therapy

The present invention relates to anti-TF antibody-drug conjugates that bind to TF for use in the treatment of cancer, wherein the antibody-drug conjugate is intended to be administered or is to be administered in combination with a platinum-based agent, wherein the antibody-drug conjugate contains an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof. In another aspect, the present invention relates to a platinum-based agent for use in the treatment of cancer, wherein the platinum-based agent is intended to be administered or is 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 conjugated to monomethyl auristatin or a functional analog or functional derivative thereof. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer is advanced cervical cancer (eg, stage 3 cervical cancer or stage 4 cervical cancer or metastatic cervical cancer). In some embodiments, advanced cervical cancer is metastatic cancer. In some embodiments, the subject is characterized by having recurrent, recurrent, and/or metastatic cervical cancer.

A. Antibody to TF

Typically, anti-TF antibodies of the present disclosure bind TFs, such as human TF, and have a cytostatic and cytotoxic effect on malignant cells, such as bladder cancer cells or cervical cancer cells. The anti-TF antibodies of the present disclosure are preferably monoclonal and can be multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab' fragments), fragments produced by a Fab expression library, and TF-binding fragments of any of the above. In some embodiments, anti-TF antibodies of the present disclosure specifically bind TF. The immunoglobulin molecules of the present disclosure may be of any type (eg, IgG, IgE, IgM, IgD, IgA, and IgY), class (eg, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecule.

In some embodiments of the present invention, anti-TF antibodies are antigen binding fragments (e.g., human antigen binding fragments), such as

- 15 046283 described herein, and includes, without limitation, Fab, Fab' and F(ab') ₂ , Fd, single chain Fv (scFv), single chain antibody disulfide linked Fv (sdFv) and fragments containing or domain VL, or VH. Antigen binding fragments, including single chain antibodies, may comprise variable region(s) alone or in combination with all or part of the following: hinge region, CH1, CH2, CH3 and CL domains. Also included in the present disclosure are antigen binding fragments comprising any combination of variable region(s) with a hinge region, CH1, CH2, CH3 and CL domains. In some embodiments, the anti-TF antibodies or antigen-binding fragments thereof are anti-TF antibodies or antigen-binding fragments thereof from human, mouse (eg, mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken.

Antibodies to TF according to the present disclosure may be monospecific, bispecific, trispecific, or more multispecific. Multispecific antibodies may be specific for different TF epitopes or be specific for both a TF and a heterologous protein. See, for example, publications according to PCT WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al, 1991, J. Immunol. 147:60 69; US Patent Nos. 4,474,893; 4714681; 4925648; 5573920; 5601819; Kostelny et al, 1992, J. Immunol. 148:1547 1553.

Antibodies to TF according to the present disclosure can be described or characterized in terms of the specific CDRs that they contain. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well known systems, including those described by Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (Kabat numbering system); Al-Lazikani et al., (1997) JMB 273,927-948 (Chothia numbering system); MacCallum et al, J. Mol. Biol. 262:732-745 (1996), Antibody-antigen interactions: Contact analysis and binding site topography, J. Mol. Biol. 262, 732745. (Contact numbering system); 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 system); Honegger A and Pluckthun A, Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool, J Mol Biol, 2001 Jun 8;309(3):657-70, (Aho numbering system); and Martin et al., Modeling antibody hypervariable loops: a combined algorithm, PNAS, 1989, 86(23):9268-9272, (AbM numbering system). The boundaries of a given CDR may vary depending on the system used for identification. In some embodiments, the CDR or complementarity determining region or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3) of a given antibody or region (e.g., a variable region thereof) is understood to encompass (or a specific) CDR , as defined according to any of the above systems. For example, if a particular CDR (e.g., CDR-H3) is stated to contain the amino acid sequence of the corresponding CDR within a given VH or VL region amino acid sequence, it is intended that such CDR is characterized by the sequence of the corresponding CDR (e.g., CDR-H3) within the variable region. as determined according to any of the above systems. A system for identifying a particular CDR or more CDRs may be specified, for example, CDRs as determined according to the Kabat, Chothia, AbM or IMGT method.

The numbering of amino acid residues in the CDR sequences provided herein follows the IMGT numbering system as described in Lefranc, M. P. et al, Dev. Sotr. Immunol., 2003, 27, 55-77. The CDR sequences provided herein for anti-TF antibodies of the anti-TF antibody-drug conjugate follow the IMGT method as described by Lefranc, M. P. et al, Dev. Sotr. Immunol., 2003, 27, 55-77.

In some embodiments, the antibodies of the present disclosure comprise one or more CDRs of antibody 011. See international patent publications WO 2011/157741 and WO 2010/066803. The disclosure covers an antibody or derivative thereof comprising a heavy or light chain variable domain, wherein said variable domain comprises (a) a set of three CDRs, wherein said set of CDRs are derived from monoclonal antibody 011, and (b) a set of four framework regions, wherein said the set of framework regions is different from the set of framework regions in monoclonal antibody 011, and in which the specified 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 tizotumab.

In one aspect, anti-TF antibodies that compete with tizotumab for binding to TF are also provided herein. Antibodies to TF that bind to the same epitope as tizotumab are also provided herein.

In one aspect, provided herein is an anti-TF antibody comprising 1, 2, 3, 4, 5, or 6 tizotumab CDR sequences.

In one aspect, provided herein is an anti-TF antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following: (i) CDR-H1 comprising an amino acid sequence with

- 16 046283 according to SEQ ID NO:1, (ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2, and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and/or wherein the light chain variable region comprises the following: (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and (iii) a CDR -L3, comprising the amino acid sequence of SEQ ID NO:6, wherein the anti-TF CDRs are defined according to the IMGT numbering system.

An anti-TF antibody described herein may contain any suitable variable domain framework sequence as long as the antibody retains the ability to bind a TF (eg, human TF). As used herein, the heavy chain framework regions are designated HC-FR1-FR4, and the light chain framework regions are designated LC-FR1-FR4. In some embodiments, the anti-TF antibody comprises the heavy chain variable domain framework sequence of SEQ ID NO:9, 10, 11, and 12 (HC-FR1, HC-FR2, HC-FR3, and HCFR4, respectively). In some embodiments, the anti-TF antibody comprises a light chain variable domain framework sequence of SEQ ID NOs: 13, 14, 15, and 16 (LCFR1, LC-FR2, LC-FR3, and LC-FR4, respectively).

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

EVQLLESGGGLVQPGGSLRLSC AASGFTF SNYAMSWVRQAPGKGLEWVS SISGS

GDYTYYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSPWGYYLDSWGQG

TLVTVSS (SEQ III NO:7), and the light chain variable domain contains the amino acid sequence

DIQMTQSPPSLSASAGDRVTITCRASQGISSRLAWYQQKPEKAPKSLIYAASSLQSGVPSR

FSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO 8).

In some embodiments of the anti-TF antibodies described herein, the heavy chain CDR sequences comprise the following:

a) CDR-H1 (GTFFSNYA (SEQ Ш NO:1));

b) CDR-H2 (ISGSSGDYT (SEQ Ш NO:2)); And

c) CDR-H3 (ARSPWGYYLDS (SEQ Ш NO:3)).

In some embodiments of the anti-TF antibodies described herein, the heavy chain FR sequences comprise the following:

a) HC-FR1 (EVQLLESGGGLVQPGGSLRLSCAAS (SEQ Ш NO:9));

b) HC-FR2 (MSWVRQAPGKGLEWVSS (SEQ Ш NO: 10));

c) HC-FR3 (YYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC (SEQ

GO NO: I)); And

d) HC-FR4 (WGQGTLVTVSS (SEQ GO NO: 12)).

In some embodiments of the anti-TF antibodies described herein, the light chain CDR sequences comprise the following:

a) CDR-L1 (QGISSR (SEQ GO NO:4));

b) CDR-L2 (AAS (SEQ GO NO:5)); And

c) CDR-L3 (QQYNSYPYT (SEQ GO NO:6)).

In some embodiments of the anti-TF antibodies described herein, the light chain FR sequences comprise the following:

a) LC-FR1 (DIQMTQSPPSLSASAGDRVTITCRAS (SEQ GO NO: 13));

b) LC-FR2 (LAWYQQKPEKAPKSLIY (SEQ GO NO: 14));

c) LC-FR3 (SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ GO

NO: 15)); And

d) LC-FR4 (FGQGTKLEIK (SEQ GO NO: 16)).

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

(a) a heavy chain variable domain comprising the following:

(1) HC-FR1 containing the amino acid sequence according to SEQ ID NO:9;

(2) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1;

- 17 046283 (3) HC-FR2, containing the amino acid sequence according to SEQ ID NO:10;

(4) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2;

(5) HC-FR3 containing the amino acid sequence according to SEQ ID NO:11;

(6) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and (7) HC-FR4 comprising the amino acid sequence of SEQ ID NO:12, and/or (b) a light chain variable domain comprising the following:

(1) LC-FR1 containing the amino acid sequence according to SEQ ID NO:13;

(2) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4;

(3) LC-FR2 containing the amino acid sequence according to SEQ ID NO:14;

(4) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5;

(5) LC-FR3 containing the amino acid sequence according to SEQ ID NO:15;

(6) CDR-L3 containing the amino acid sequence according to SEQ ID NO:6; and (7) LC-FR4 containing the amino acid sequence according to SEQ ID NO:16.

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

In some embodiments, provided herein is an anti-TF antibody comprising a heavy chain variable domain comprising an amino acid sequence characterized by at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:7. In certain embodiments, a heavy chain variable domain comprising an amino acid sequence characterized by 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 with respect to the reference sequence, and retains TF binding ability (e.g. , human TF). In certain embodiments, as many as 1 to 10 amino acids have been replaced, inserted, and/or deleted in SEQ ID NO:7. In certain embodiments, substitutions, insertions, or deletions (eg, 1, 2, 3, 4, or 5 amino acids) occur in regions outside the CDR (ie, in the FR). In some embodiments, the anti-TF antibody comprises a heavy chain variable domain sequence of SEQ ID NO:7, including post-translational modifications to that sequence. In a specific embodiment, the heavy chain variable domain comprises one, two, or three CDRs selected from the following: (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 containing the amino acid sequence of SEQ ID NO:3.

In some embodiments, provided herein is an anti-TF antibody comprising a light chain variable domain comprising an amino acid sequence characterized by at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:8. In certain embodiments, a light chain variable domain comprising an amino acid sequence characterized by 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 TF ( e.g. human TF). In certain embodiments, as many as 1 to 10 amino acids have been replaced, inserted, and/or deleted in SEQ ID NO:8. In certain embodiments, substitutions, insertions, or deletions (eg, 1, 2, 3, 4, or 5 amino acids) occur in regions outside the CDR (ie, in the FR). In some embodiments, the anti-TF antibody comprises a light chain variable domain sequence of SEQ ID NO:8, including post-translational modifications to that sequence. In a specific embodiment, the light chain variable domain comprises one, two, or three CDRs selected from the following: (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 containing the amino acid sequence of SEQ ID NO:6.

In some embodiments, the anti-TF antibody comprises a heavy chain variable domain

- 18 046283 low chain as in any of the embodiments presented above, and a light chain variable domain as in any of the embodiments presented above. In one embodiment, the antibody comprises a heavy chain variable domain sequence of SEQ ID NO:7 and a light chain variable domain sequence of SEQ ID NO:8, including post-translational modifications of these sequences.

In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate comprises the following: i) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 containing the amino acid sequence according to SEQ ID NO: 3; and ii) a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 containing the amino acid sequence of SEQ ID NO: 5, and a light chain CDR3 containing the amino acid sequence of SEQ ID NO: 6, wherein the antibody CDR to TFs are defined according to the IMGT numbering system.

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

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

In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate is tizotumab, which is also known as antibody 011, as described in international patent publications WO 2011/157741 and WO 2010/066803.

The anti-TF antibodies of the present invention can also be described or defined in terms of their binding affinity to a TF (eg, human TF). Preferred binding affinities include binding affinities with a dissociation constant or Kd of less than 5x10 ^-2 M, 10 ^-2 M, 5x10 ^-3 M, 10 ^-3 M, 5x10 ^-4 M, 10 ^-4 M, 5x10 ^-5 M, 10 ^-5 M, 5x10 ^-6 M, 10 ^-6 M, 5x10 ^-7 M, 10 ^-7 M, 5x10 ^-8 M, 10 ^-8 M, 5x10 ^{-9 M, 10 -9 M} , 5x100 ^-10 M, 10 ^-10 M, 5x10 ^-11 M, 10 ^-11 M, 5x10 ^-12 M, 10 ^{-12 M, 5x10 -13 M} , 10 ^-13 M, 5x 10 ^-14 M, 10 ^-14 M, 5x 10 ^-15 M or 10 ^-15 M.

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

Antibodies also include derivatives that are modified, i.e. by covalently attaching any type of molecule to an antibody such that the covalent attachment does not prevent the antibody from binding to the TF or being cytostatic or cytotoxic to HD cells. For example, but not by way of limitation, antibody derivatives include antibodies that have been modified, for example, by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting/blocking groups, proteolytic cleavage, binding to a cellular ligand or other protein, etc. .d. Any of numerous chemical modifications can be accomplished using known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. In addition, the derivative may contain one or more non-classical amino acids.

B. Structure of an antibody-drug conjugate

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 a cytostatic or cytotoxic drug. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a cleavable linker.

In some embodiments, the linker is a cleavable peptide linker comprising maleimidocaproyl (MC), valine-citrulline (vc) dipeptide, and paminobenzylcarbamate (PAB). In some embodiments, the cleavable peptide

- 19 046283 the linker is characterized by the following formula: MC-vc-PAB-, where: a) MC is:

O

b) vc is a valine-citrulline dipeptide, and

c) RAV is:

In some embodiments, the linker is a cleavable peptide linker containing maleimidocaproyl (MC). In some embodiments, the cleavable peptide linker is characterized by the following formula: MS-, where:

a) MS is:

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

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 a cytostatic or cytotoxic drug. Auristatins have been shown to interfere with microtubule dynamics, GTP hydrolysis and nuclear and cellular division (see Woyke et al (2001) Antimicrob. Agents and Chemother. 45(12): 3580-3584) and are characterized as anticancer (see US patent No. 5663149 ) and antifungal activity (see Pettit et al., (1998) Antimicrob. Agents and Chemother. 42: 2961-2965). For example, auristatin E can react with p-acetylbenzoic acid or benzoylvaleric acid to form AEB and AEVB, respectively. Other typical auristatin derivatives include AFP, MMAF (monomethyl auristatin F) and MMAE (monomethyl auristatin E). Suitable auristatins and auristatin analogs, derivatives and prodrugs, as well as suitable linkers for conjugating auristatins to antibodies, are described, for example, in US Patent Nos. 5635483, 5780588 and 6214345 and international patent publications WO02088172, WO2004010957, WO20050817 11, WO2005084390, WO2006132670, WO03026577 , WO200700860, WO207011968 and WO205082023. In some embodiments of the anti-TF antibody-drug conjugates described herein, the cytostatic or cytotoxic drug is auristatin or a functional analog (eg, a functional peptide thereof) or a functional derivative thereof. In some embodiments, auristatin is monomethyl auristatin or a functional analog (eg, a functional peptide thereof) or a functional derivative thereof.

In one embodiment, the auristatin is monomethyl auristatin E (MMAE):

- 20 046283

M MAE where the wavy line indicates the attachment site for the linker. In one embodiment, the auristatin is monomethyl auristatin F (MMAF):

MMAF where the wavy line indicates the attachment site for the linker.

In one embodiment, the cleavable peptide linker is characterized by the following formula: MC-vc-PAB-, and is attached to MMAE. The resulting auristatin linker, MC-vc-PABMMAE, is also designated vcMMAE. The vcMMAE linker-drug 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, as described herein, the resulting structure is:

Ab-MC-vc-PAB-MMAE where p is a number from 1 to 8, for example 1, 2, 3, 4, 5, 6, 7 or 8, for example p can be 35, S is the sulfhydryl residue of an anti-TF antibody and Ab means an anti-TF antibody or an antigen-binding fragment thereof, as described herein. In one embodiment, the average p value in a population of antibody-drug conjugates is about 4. In some embodiments, p is measured using hydrophobic interaction chromatography (HIC), for example, by separating drug-loaded species based on increasing hydrophobicity, with the least the hydrophobic, unconjugated form elutes first, and the most hydrophobic, 8-drug form elutes last, and the peak area percentage represents the relative distribution of specific drug-loaded antibody-drug conjugate species. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols). In some embodiments, p is measured using reverse phase high performance liquid chromatography (RP-HPLC), for example, by first performing a reduction reaction to completely dissociate the ADC heavy and light chains, then separating the light and heavy chains and their respective drug-loaded forms on a column. RP, where the percent peak is the result of the integration of the light chain and heavy chain peaks, combined with the assigned drug load for each peak, which is used to calculate the weighted average drug-to-antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

In one embodiment, the cleavable peptide linker is characterized by the following formula: MC-vc-PAB-, and is attached to MMAF. The resulting auristatin linker, MC-vc-PABMMAF, is also designated vcMMAF. In another embodiment, the non-cleavable MC linker is attached to the MMAF. The resulting auristatin linker MC-MMAF is also designated mcMMAF. Both vcMMAF and mcMMAF linker-drug moieties and conjugation methods are disclosed in WO2005081711 and US7498298. When vcMMAF or mcMMAF is attached to an anti-TF antibody or antigen-binding fragment thereof, as described herein, the resulting structure is:

- 21 046283

AB-MC-ts-RAV-MMAR or

mAb-mc-MMAF where p is a number from 1 to 8, for example 1, 2, 3, 4, 5, 6, 7 or 8, for example p can be 35, S represents the sulfhydryl residue of the antibody to TF and Ab or mAb means an anti-TF antibody or antigen-binding fragment thereof, as described herein. In one embodiment, the average p value in a population of antibody-drug conjugates is about 4. In some embodiments, p is measured using hydrophobic interaction chromatography (HIC), for example, by separating drug-loaded species based on increasing hydrophobicity, with the least the hydrophobic, unconjugated form elutes first, and the most hydrophobic, 8 drug molecule form elutes last, and the peak area percentage represents the relative distribution of certain drug-loaded antibody drug conjugate species, see Ouyang, J., 2013, Antibody -Drug Conjugates, Methods in Molecular Biology (Methods and Protocols). In some embodiments, p is measured using reverse phase high performance liquid chromatography (RP-HPLC), for example, by first performing a reduction reaction to completely dissociate the ADC heavy and light chains, then separating the light and heavy chains and their respective drug-loaded forms on a column. RP, where the percentage peak is the result of the integration of the light chain and heavy chain peaks, combined with the assigned drug load for each peak, which is used to calculate the weighted average drug-to-antibody ratio, see Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

In one embodiment, the antibody-drug conjugate is tizotumab-vedotin.

C. Platinum-based product

Generally, the platinum-based agent according to the present disclosure is a molecule or composition containing a molecule containing a coordination complex containing the chemical element platinum, and useful as a chemotherapeutic drug. In some embodiments, the platinum-based agent covalently binds to DNA and cross-links strands, inhibits DNA synthesis, and/or inhibits a transcript. Platinum-based agents include those currently used as part of a chemotherapy regimen, those currently in development, and those that may be developed in the future. Platinum-based agents include, but are not limited to, carboplatin, cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In some embodiments, the platinum-based agent is carboplatin, cisplatin, oxaliplatin, or nedaplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin. In some embodiments, the platinum-based agent is oxaliplatin. In some embodiments, the platinum-based agent is nedaplatin.

D. Nucleic Acids, Host Cells and Production Methods

In some aspects, also provided herein are nucleic acids encoding an anti-TF antibody or antigen binding fragment thereof, as described herein. In addition, provided herein are vectors containing nucleic acids encoding an anti-TF antibody or an antigen-binding fragment thereof, as described herein. In addition, provided herein are host cells expressing nucleic acids encoding an anti-TF antibody or antigen-binding fragment thereof, as described herein. In addition, provided herein are host cells containing vectors containing nucleic acids encoding an anti-TF antibody or antigen-binding fragment thereof, as described herein. Methods for preparing an anti-TF antibody, a linker, and an anti-TF antibody-drug conjugate are described in US Pat. No. 9,168,314.

- 22 046283

The anti-TF antibodies described herein can be produced by well-known recombinant techniques using well-known expression vector systems and host cells. In one embodiment, antibodies are produced in a CHO cell using the GS expression vector system as described in De la Cruz Edmunds et al., 2006, Molecular Biotechnology 34; 179-190, EP216846, US Patent No. 5981216, WO 87/04462, EP323997, US Patent No. 5591639, US Patent No. 5658759, EP338841, US Patent No. 5879936 and US Patent No. 5891693.

Once anti-TF antibodies are isolated and purified from the cellular environment using techniques well known in the art, they are conjugated to auristatin via a linker as described in US Pat. No. 9,168,314.

Monoclonal antibodies to TF described herein can be produced, for example, by the hybridoma method first described by Kohler et al., Nature, 256, 495 (1975), or they can be produced by recombinant DNA methods. Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, in 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 derived from mouse spleen B cells obtained from mice immunized with the antigen of interest, for example, in the form of cells expressing the antigen on the surface, or a nucleic acid encoding the antigen of interest. Monoclonal antibodies can also be produced from hybridomas derived from antibody-expressing cells of immunized humans or non-human mammals such as rats, dogs, primates, etc.

In one embodiment, the antibody (eg, anti-TF antibody) of the present invention is a human antibody. Human monoclonal antibodies directed against TF can be produced using transgenic or transchromosomal mice carrying parts of the human immune system rather than the mouse system. Such transgenic and transchromosomal mice include mice referred to herein as HuMAb mice and KM mice, respectively, and are collectively referred to herein as transgenic mice.

The HuMAb mouse contains a human immunoglobulin gene minilocus that encodes unrearranged human immunoglobulin heavy (μ and γ) and k light chain sequences, together with targeted mutations that inactivate the endogenous μ and k chain loci (Lonberg, N. et al., Nature, 368 , 856-859 (1994)). Accordingly, mice exhibit reduced expression of murine IgM or K, and in response to immunization, introduced human heavy and light chain transgenes undergo class switching and somatic mutation to produce high-affinity human IgG,K monoclonal antibodies (Lonberg, N. et al. (1994), previously reviewed in Lonberg, N. Handbook of Experimental Pharmacology 113, 49-101 (1994), Lonberg, N. and Huszar. D., Intern. Rev. Immunol, Vol. 13 65-93 (1995) and Harding, F. . and Lonberg, N. Ann, N. Y. Acad. Sci 764:536-546 (1995)). The production 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. 5:647656 (1993), Tuaillon et al., J. Immunol, 152:2912-2920 (1994), Taylor, L. et al., International Immunology, 6:579-591 (1994), Fishwild, D. et al., Nature Biotechnology, 14:845-851 (1996). See also US Patent No. 5545806, US Patent No. 5569825, US Patent No. 5625126, US Patent No. 5633425, US Patent No. 5789650, US Patent No. 5877397, US Patent No. 5661016, US Patent No. 5814318, US Patent No. 5874299, US Patent No. 5770429, US Patent No. 5545807, International Patent Publications WO 98/24884, WO 94/25585, WO 93/1227, WO 92/22645, WO 92/03918 and WO 01/09187.

HCo7 mice are characterized by a JKD disruption in their endogenous light chain (kappa) genes (as described in Chen et al, EMBO J. 12:821-830 (1993)), a CMD disruption in their endogenous heavy chain genes (as described in Example 1 of the international patent publication WO 01/14424), the human kappa light chain KCo5 transgene (as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)) and the human heavy chain HCo7 transgene (as described in US Pat. No. 5,770,429) .

HCo12 mice are characterized by a JKD disruption in their endogenous light chain (kappa) genes (as described in Chen et al., EMBO J. 12:821-830 (1993)), a CMD disruption in their endogenous heavy chain genes (as described in Example 1 international patent publication WO 01/14424), the human kappa light chain KCo5 transgene (as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)) and the human heavy chain HCo12 transgene (as described in example 2 of the international patent publication WO 01/14424).

The transgenic mouse strain HCo17 (see also US 2010/0077497) was obtained by co-injection of the 80 kb pHC2 insert. (Taylor et al. (1994) Int. Immunol., 6:579-591), pVX6 1 kb inserts. and a 460 kb fragment of the yeast artificial chromosome yIgH24. This line was designated (HCo17) 25950. The (HCo17) 25950 line was then crossed with mice containing the CMD mutation (described in example 1 of publication according to PCT WO 01109187), the JKD mutation (Chen et al, (1993) EMBO J. 12:811 -820) and transgene (KC05) 9272 (Fishwild et al. (1996) Nature Biotechnology, 14:845-851). The resulting mice express transgenes of the heavy and light chains of human immunoglobulin in

- 23 046283 genetic environment, homozygous for the destruction of endogenous loci of the mouse heavy and light kappa chains.

The HCo20 transgenic mouse strain is the result of co-injection of the minilocus 30 heavy chain transgene pH2, the yIgH10 YAC germline variable region (Vh)-containing transgene, and the pVx6 minilocus construct (described in international patent publication WO09097006). The line (HCo20) was then crossed with mice containing the CMD mutation (described in Example 1 of PCT publication WO 01/09187), the JKD mutation (Chen et al. (1993) EMBO J. 12:811-820) and the (KCO5) 9272 transgene (Fishwild et al.). (1996) Nature Biotechnology, 14:845-851). The resulting mice express human immunoglobulin 10 heavy and light kappa chain transgenes in a genetic environment homozygous for disruption of the endogenous mouse kappa heavy and light chain loci.

To generate HuMab mice with the beneficial effects of the Balb/c line, HuMab mice were crossed with KCO05 [MIK] (Balb) mice, which were obtained by backcrossing the KC05 line (as described in Fishwild et al. (1996) Nature Biotechnology, 14:845- 851) with wild-type Balb/c mice to produce mice as described in international patent publication WO09097006. Using this cross, Balb/c hybrids were created for the HCo12, HCo17 and HCo20 lines.

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

Splenocytes from these transgenic mice can be used to create hybridomas that secrete human monoclonal antibodies according to well-known techniques. In addition, it is possible to produce human monoclonal or polyclonal antibodies of the present invention, or antibodies of the present invention derived from other species, transgenically by generating another non-human mammal or plant that is transgenic for the immunoglobulin heavy and light chain sequences of interest, and production of antibodies in extractable form therefrom. Due to transgenic production in mammals, antibodies can be produced and extracted from the milk of goats, cows or other mammals. See, for example, US Patent No. 5827690, US Patent No. 5756687, US Patent No. 5750172 and US Patent No. 5741957.

In addition, human antibodies of the present invention or antibodies of the present invention from other species can be produced using display technologies, including, but not limited to, phage display, retroviral display, ribosomal display, and other techniques using techniques well known in the art , and the resulting molecules may undergo additional maturation, such as affinity maturation, as such techniques are well known in the art (see, for example, Hoogenboom et al, J. Mol, Biol. 227(2):381-388 (1992 ) (phage display), Vaughan et al, Nature Biotech, 14:309 (1996) (phage display), Hanes and Pluckthau, PNAS USA 94:4937-4942 (1997) (ribosome display), Parmley and Smith, Gene, 73 :305-318 (1988) (phage display), Scott, TIBS.17:241-245 (1992), Cwirla et al, PNaS USA, 87:6378-6382 (1990), Russell 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 US patent No. 5733743). If display technologies are used to produce non-human antibodies, such antibodies can be humanized.

III. Treatment methods

The present invention relates to methods of treating cancer in a subject using an anti-TF antibody-drug conjugate described herein and a platinum-based agent described herein. In one aspect, the antibody-drug conjugate is tizotumab-vedotin. In one aspect, the platinum-based agent is carboplatin. In one aspect, the platinum-based agent is cisplatin. In a specific embodiment, the subject is a human.

In another aspect, the present invention provides an antibody-drug conjugate that binds to TF for use in the treatment of cancer, wherein the antibody-drug conjugate is intended to be administered or is to be administered in combination with a platinum-based agent, wherein the antibody-drug conjugate The agent contains an antibody to TF or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analogue or a functional derivative thereof.

In another aspect, the present invention relates to a platinum-based agent for use in the treatment of cancer, wherein the platinum-based agent is intended to be administered or is to be administered in combination with an antibody-drug conjugate that binds to TF, wherein the antibody-drug conjugate comprises antibody to TF or its antigen

- 24 046283 calling fragment, conjugated with monomethyl auristatin or its functional analogue or its functional derivative.

A. Bladder cancer

Bladder cancer is the fifth most common cancer diagnosis in the United States. The American Cancer Society (ACS) estimates that there were 70,980 new patients with bladder cancer in 2009, and 14,330 people die from bladder cancer each year. The ACS estimates the incidence of bladder cancer to be 1/27 for men and 1/85 for women, and 90% of bladder cancer patients are over 55 years of age. Invasive bladder cancer can spread to the lymph nodes, other organs in the pelvis (causing problems with kidney and bowel function), or other organs of the body such as the liver and lungs. Standard treatments for bladder cancer include surgery, radiation therapy, chemotherapy, and biological therapy.

In some aspects, the present invention provides methods for treating bladder cancer in a subject using an anti-TF antibody-drug conjugate described herein and a platinum-based agent described herein. In one aspect, the antibody-drug conjugate is tizotumab-vedotin. In one aspect, the platinum-based agent is carboplatin. In one aspect, the platinum-based agent is cisplatin. In a specific embodiment, the subject is a human.

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 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 bladder cancer cells from a subject express TF. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 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 bladder cancer cells from the subject express TF. In some embodiments, the percentage of cells that express TF is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells that express TF is determined using flow cytometry. In some embodiments, the percentage of cells that express TF is determined using an enzyme-linked immunosorbent assay (ELISA).

B. Cervical cancer

Cervical cancer remains one of the leading causes of cancer-related death in women, despite advances in screening, diagnosis, prevention and treatment. It accounts for about 4% of the total number of newly diagnosed cancer cases and 4% of the total number of cancer deaths. See Zhu et al., 2016, Drug Des. Devel. Ther. 10:1885-1895. Cervical cancer is the 7th most common form of cancer in women in the world and 16th most common in the European Union. Depending on the stage at initial treatment, cervical cancer recurs in 25-61% of women. See Tempfer et al., 2016, Oncol. Res. Treat. 39:525-533. In most cases, relapse of the disease is diagnosed within 2 years after initial treatment and can be observed in various locations. Chemotherapy is the standard treatment for these patients. See Zhu et al, 2016, Drug Des. Devel. Ther. 10:1885-1895. The average overall survival rate currently exceeds one year, but the five-year relative survival rate for stage IV cervical cancer is only 15%, indicating a significant need for improved treatments for cervical cancer.

In some aspects, provided herein are methods of treating cervical cancer in a subject with an anti-TF antibody-drug conjugate described herein and a platinum-based agent described herein. In one aspect, the antibody-drug conjugate is tizotumab-vedotin. In one aspect, the platinum-based agent is carboplatin. In one aspect, the platinum-based agent is cisplatin. In some embodiments, the subject has not previously received prior systemic therapy for cervical cancer. In some embodiments, chemotherapy is not considered to be prior systemic therapy for cervical cancer. In some embodiments, radiation therapy is not considered to be prior systemic therapy for cervical cancer. In some embodiments, chemotherapy in combination with radiation therapy is not considered to be prior systemic therapy for cervical cancer. According to some options

- 25 046283 there implementation the subject has previously received treatment with chemotherapy and/or radiation therapy. In some embodiments, the subject is not a candidate for radical treatment. In some embodiments, the definitive treatment is radiation therapy and/or exenteration. In some embodiments, the definitive treatment is radiation therapy. In some embodiments, the radical treatment is exenteration. In a specific embodiment, the subject is a human.

In some embodiments of the methods or uses or product for uses provided herein, the cervical cancer is adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, neuroendocrine tumor, vitreous cell carcinoma, or glandular villous adenocarcinoma. In some embodiments, the cervical cancer is an adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma. In some embodiments, the cervical cancer is an adenocarcinoma. In some embodiments, the cervical cancer is adenosquamous carcinoma. In some embodiments, the cervical cancer is squamous cell carcinoma.

In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least 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 subject express TF. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 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 cervical cancer cells from the subject express TF. In some embodiments, the percentage of cells that express TF is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells that express TF is determined using flow cytometry. In some embodiments, the percentage of cells that express TF is determined using an enzyme-linked immunosorbent assay (ELISA).

In some embodiments of the methods or uses or product for uses provided herein, 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, in stage 0 cervical cancer, the carcinoma is limited to the superficial layer (lining cells) of the cervix. In some embodiments, in stage 1 cervical cancer, the carcinoma has penetrated deeper into the cervix but has not yet spread beyond the cervix. In some embodiments, in stage 1A cervical cancer, invasive carcinoma can be diagnosed only by microscopy, with the deepest invasion being less than 5 mm and the most extensive being less than 7 mm. In some embodiments, in stage 1B cervical cancer, the lesions are clinically visible and limited to the cervix. In some embodiments, in stage 2 cervical cancer, the cervical carcinoma has invaded the uterus but not the pelvic wall or the lower third of the vagina. In some embodiments, stage 2A cervical cancer does not have parametrial invasion. In some embodiments, stage 2B cervical cancer has parametrial invasion. In some embodiments, in stage 3 cervical cancer, the tumor extends to the pelvic wall and/or affects the lower third of the vagina and/or causes hydronephrosis or a non-functioning kidney. In some embodiments, in stage 3A cervical cancer, the tumor affects the lower third of the vagina and does not extend to the pelvic wall. In some embodiments, in Stage 3B, cervical cancer has spread to the pelvic wall and/or caused hydronephrosis or a non-functioning kidney. In some embodiments, in stage 4 cervical cancer, the carcinoma has spread beyond the pelvis or has affected the lining of the bladder or rectum. In some embodiments, in stage 4A cervical cancer, the tumor has spread to adjacent organs. According to some embodiments

- 26 046283 for stage 4B cervical cancer, the tumor has spread to distant organs. In some embodiments, 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, 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 a recurrent cervical cancer.

In some embodiments of the methods or uses or product for uses provided herein, the subject has not received prior systemic therapy for cervical cancer. In some embodiments, chemotherapy is not considered to be prior systemic therapy for cervical cancer. In some embodiments, radiation therapy is not considered to be prior systemic therapy for cervical cancer. In some embodiments, chemotherapy in combination with radiation therapy is not considered to be prior systemic therapy for cervical cancer. In some embodiments, the subject has previously received treatment with chemotherapy and/or radiation therapy. In some embodiments, the subject has not responded to treatment with chemotherapy and radiation therapy. In some embodiments, the subject was treated for cervical cancer with chemotherapy and did not respond to chemotherapy. In some embodiments, the subject was treated for cervical cancer with radiation and did not respond to radiation. In some embodiments, the subject has relapsed after treatment with chemotherapy and radiation therapy. In some embodiments, the subject was treated for cervical cancer with chemotherapy and relapsed after treatment with chemotherapy. In some embodiments, the subject was treated for cervical cancer with radiation and relapsed after treatment with radiation. In some embodiments, the subject has experienced disease progression following treatment with chemotherapy and/or radiation therapy. In some embodiments, the subject was treated for cervical cancer with chemotherapy and experienced disease progression after treatment with chemotherapy. In some embodiments, the subject was treated for cervical cancer with radiation and experienced disease progression after treatment with radiation. In some embodiments, the subject has previously received treatment for cervical cancer with one or more therapeutic agents. In some embodiments, the subject has previously received treatment with one or more therapeutic agents and has not responded to treatment. In some embodiments, the subject has previously been treated with one or more therapeutic agents and relapses following treatment. In some embodiments, the subject has previously been treated with one or more therapeutic agents and has experienced disease progression during treatment. In some embodiments, one or more therapeutic agents is selected from the group consisting of the following: a chemotherapy agent, pemetrexed, nab-paclitaxel, vinorelbine, bevacizumab, cisplatin, carboplatin, paclitaxel, topotecan, a combination of bevacizumab and paclitaxel, a combination of bevacizumab and cisplatin, a combination of bevacizumab and carboplatin, 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 is a chemotherapeutic agent. In some embodiments, the one or more therapeutic agents is bevacizumab. In some embodiments, one or more therapeutic agents is cisplatin. In some embodiments, one or more therapeutic agents is carboplatin. In some embodiments, the one or more therapeutic agents is paclitaxel. In some embodiments, one or more therapeutic agents is 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 is a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents is a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents is a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents is a combination of bevacizumab and topotecan. In some embodiments, the one or more therapeutic agents is a combination of bevacizumab, cisplatin, and

- 27 046283 paclitaxel. In some embodiments, the one or more therapeutic agents is a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents is a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject is not a candidate for radical treatment. In some embodiments, the definitive treatment is radiation therapy and/or exenteration. In some embodiments, the definitive treatment is radiation therapy. In some embodiments, the radical treatment is exenteration. In a specific embodiment, the subject is a human.

C. Routes of administration

The platinum-based agent described herein and/or the anti-TF antibody-drug conjugate or antigen binding fragment thereof described herein can be administered by any suitable route and method. Suitable routes of administration of the platinum-based agent and/or antibody-drug conjugate 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 platinum-based agent and/or the anti-TF antibody-drug conjugate is administered parenterally. Parenteral administration refers to routes of administration other than enteral and topical administration, typically by injection, and includes the following: epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion. In some embodiments, the route of administration of the anti-TF antibody-drug conjugate or antigen-binding fragment described herein is by intravenous injection or infusion. In some embodiments, the route of administration of the anti-TF antibody-drug conjugate or antigen-binding fragment described herein is by intravenous infusion. In some embodiments, the route of administration of the platinum-based agent described herein is by intravenous injection or infusion. In some embodiments, the route of administration of the platinum-based agent described herein is by intravenous infusion.

D. Dosage and frequency of administration

In one aspect, the present invention provides methods of treating a subject with cancer, as described herein, with a specific dose of an anti-TF antibody-drug conjugate or antigen binding fragment thereof, as described herein, and a platinum-based agent, as described in herein, wherein the subject is administered an antibody-drug conjugate or antigen-binding fragment thereof, as described herein, and a platinum-based agent, as described herein, at a specific frequency.

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

In one embodiment of the methods or uses or product for uses provided herein, an anti-TF antibody-drug conjugate or antigen binding fragment thereof as described herein is administered to a subject once approximately every 1 to 4 weeks. In certain embodiments, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof, as described herein

- 28 046283 mente, administered once approximately every week, once approximately every 2 weeks, once approximately every 3 weeks or once approximately every 4 weeks. In one embodiment, an anti-TF antibody-drug conjugate or antigen-binding fragment thereof, as described herein, is administered once approximately 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 once approximately every week. In some embodiments, the dose is about 0.9 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 0.9 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 0.9 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.0 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.0 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.0 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.0 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.1 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.1 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.1 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.1 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.2 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.2 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.2 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.2 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.3 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.3 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.3 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.3 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.4 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.4 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.4 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.4 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.5 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.5 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.5 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.5 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.6 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.6 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.6 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.6 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.7 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.7 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.7 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.7 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.8 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.8 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.8 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 1.8 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 1.9 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 1.9 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 1.9 mg/kg and is administered once

- 29 046283 approximately every 3 weeks. In some embodiments, the dose is about 1.9 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 2.0 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 2.0 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 2.0 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 2.0 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is about 2.1 mg/kg and is administered once approximately every week. In some embodiments, the dose is about 2.1 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is about 2.1 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is about 2.1 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once approximately every week. In some embodiments, the dose is 0.9 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.0 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.1 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.2 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.3 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.4 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.5 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.6 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.7 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.8 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once approximately every 4

- 30 046283 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once approximately every week. In some embodiments, the dose is 1.9 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once approximately every week. In some embodiments, the dose is 2.0 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once approximately every week. In some embodiments, the dose is 2.1 mg/kg and is administered once approximately every 2 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once approximately every 3 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once approximately every 4 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once approximately every 3 weeks (eg, ±3 days). In some embodiments, the dose is 2.0 mg/kg and is administered once every 3 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once every 3 weeks, and the antibody-drug conjugate is tizotumab-vedotin. In some embodiments, the dose is 2.0 mg/kg and is administered once every 3 weeks, and the antibody-drug conjugate is tizotumab-vedotin, and the dose is reduced to 1.3 mg/kg if one or more adverse events. In some embodiments, the dose is 1.3 mg/kg and is administered once every 3 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once every 3 weeks, and the antibody-drug conjugate is tizotumab-vedotin. In some embodiments, the dose is 1.3 mg/kg and is administered once every 3 weeks, and the antibody-drug conjugate is tizotumab-vedotin, and the dose is reduced to 0.9 mg/kg if one or more adverse events.

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

In one embodiment of the methods or uses or product for uses provided herein, an anti-TF antibody-drug conjugate or antigen binding fragment thereof, as described herein, is administered to a subject at a constant dose ranging from 50 mg to 200 mg, e.g. , at a constant dose of 50 mg, or a constant dose of 60 mg, or a constant dose of 70 mg, or a constant dose of 80 mg, or a constant dose of 90 mg, or a constant dose of 100 mg, or constant dose of 110 mg, or constant dose of 120 mg, or constant dose of 130 mg, or constant dose of 140 mg, or constant dose of 150 mg, or constant dose of 160 mg, or constant dose 170 mg, or a constant dose of 180 mg, or a constant dose of 190 mg, or a constant dose of 200 mg. In some embodiments, a continuous dose is administered to a subject once approximately every 1 to 4 weeks. According to certain embodiments

- 31 046283 a constant dose is administered to the subject once approximately every week, once approximately every 2 weeks, once approximately every 3 weeks, or once approximately every 4 weeks. In some embodiments, a continuous dose is administered to a subject once approximately every 3 weeks (eg, ±3 days). In some embodiments, a continuous dose is administered to the subject once every 3 weeks. In some embodiments, a sustained dose is administered to the subject once every 3 weeks, and the antibody-drug conjugate is tizotumab-vedotin.

In one embodiment of the methods or uses or product for uses provided herein, a platinum-based agent described herein, such as carboplatin, is administered to a subject at a dose based on the Calvert formula:

Platinum dose (mg) = (target AUC) x (GFR + 25) where AUC is the area under the concentration-time curve (AUC is expressed in mg/mL-min) and GFR is the glomerular filtration rate (GFR is expressed in ml/min). In some embodiments, GFR is estimated from estimated creatine clearance. In some embodiments, serum creatine is measured using the IDMS method. In some embodiments, a platinum-based agent described herein, such as carboplatin, is administered at a dose of about AUC=4 to about AUC=6. In some embodiments, the dose of a platinum-based agent described herein, such as carboplatin, is any of about AUC=4, AUC=4.5, AUC=5, AUC=5.5, or AUC=6. In some embodiments, the dose of a platinum-based agent described herein, such as carboplatin, is about AUC=5. In some embodiments, the dose of a platinum-based agent described herein, such as carboplatin, is AUC=5. In some embodiments, the dose is about AUC=4 and is administered once approximately every week. In some embodiments, the dose is about AUC=4 and is administered once approximately every 2 weeks. In some embodiments, the dose is about AUC=4 and is administered once approximately every 3 weeks. In some embodiments, the dose is about AUC=4 and is administered once approximately every 4 weeks. In some embodiments, the dose is about AUC=4.5 and is administered once approximately every week. In some embodiments, the dose is about AUC=4.5 and is administered once approximately every 2 weeks. In some embodiments, the dose is about AUC=4.5 and is administered once approximately every 3 weeks. In some embodiments, the dose is about AUC=4.5 and is administered once approximately every 4 weeks. In some embodiments, the dose is about AUC=5 and is administered once approximately every week. In some embodiments, the dose is about AUC=5 and is administered once approximately every 2 weeks. In some embodiments, the dose is about AUC=5 and is administered once approximately every 3 weeks. In some embodiments, the dose is about AUC=5 and is administered once approximately every 4 weeks. In some embodiments, the dose is about AUC=5.5 and is administered once approximately every week. In some embodiments, the dose is about AUC=5.5 and is administered once approximately every 2 weeks. In some embodiments, the dose is about AUC=5.5 and is administered once approximately every 3 weeks. In some embodiments, the dose is about AUC=5.5 and is administered once approximately every 4 weeks. In some embodiments, the dose is about AUC=6 and is administered once approximately every week. In some embodiments, the dose is about AUC=6 and is administered once approximately every 2 weeks. In some embodiments, the dose is about AUC=6 and is administered once approximately every 3 weeks. In some embodiments, the dose is about AUC=6 and is administered once approximately every 4 weeks. In some embodiments, the dose of a platinum-based agent described herein, such as carboplatin, is any of AUC=4, AUC=4.5, AUC=5, AUC=5.5, or AUC=6. In some embodiments, the dose of a platinum-based agent described herein, such as carboplatin, is AUC=5. In some embodiments, the dose of a platinum-based agent described herein, such as carboplatin, is AUC=5. In some embodiments, the dose is AUC=4 and is administered once approximately every week. In some embodiments, the dose is AUC=4 and is administered once approximately every 2 weeks. In some embodiments, the dose is AUC=4 and is administered once approximately every 3 weeks. In some embodiments, the dose is AUC=4 and is administered once approximately every 4 weeks. In some embodiments, the dose is AUC=4.5 and is administered once approximately every week. In some embodiments, the dose is AUC=4.5 and is administered once approximately every 2 weeks. According to

- 32 046283 in which embodiments the dose is AUC=4.5 and is administered once approximately every 3 weeks. In some embodiments, the dose is AUC=4.5 and is administered once approximately every 4 weeks. In some embodiments, the dose is AUC=5 and is administered once approximately every week. In some embodiments, the dose is AUC=5 and is administered once approximately every 2 weeks. In some embodiments, the dose is AUC=5 and is administered once approximately every 3 weeks. In some embodiments, the dose is AUC=5 and is administered once approximately every 4 weeks. In some embodiments, the dose is AUC=5.5 and is administered once approximately every week. In some embodiments, the dose is AUC=5.5 and is administered once approximately every 2 weeks. In some embodiments, the dose is AUC=5.5 and is administered once approximately every 3 weeks. In some embodiments, the dose is AUC=5.5 and is administered once approximately every 4 weeks. In some embodiments, the dose is AUC=6 and is administered once approximately every week. In some embodiments, the dose is AUC=6 and is administered once approximately every 2 weeks. In some embodiments, the dose is AUC=6 and is administered once approximately every 3 weeks. In some embodiments, the dose is AUC=6 and is administered once approximately every 4 weeks. In some embodiments, the dose is

AUC=5 and is administered once approximately every 3 weeks (eg, ±3 days). In some embodiments, the dose is AUC=5 and is administered once every 3 weeks. In some embodiments, the dose is AUC=5 and is administered once every 3 weeks, and the platinum-based agent is carboplatin.

In one embodiment of the methods or uses or product for uses provided herein, a platinum-based agent as described herein is administered to a subject at a constant dose ranging from about 50 mg to about 900 mg, for example, at a constant dose, of about 50 mg, or a constant dose of about 60 mg, or a constant dose of about 70 mg, or a constant dose of about 80 mg, or a constant dose of about 90 mg, or a constant dose of about 100 mg, or a constant dose of about 120 mg, or a constant dose of about 140 mg, or a constant dose of about 160 mg, or a constant dose of about 180 mg, or a constant dose of about 200 mg, or a constant dose of about 220 mg, or a constant dose of about 240 mg, or a constant dose of about 260 mg, or a constant dose of about 280 mg, or a constant dose of about 300 mg, or a constant dose of about 320 mg, or a constant dose of about 340 mg, or a constant dose of about 360 mg, or a constant dose of about 380 mg, or a constant dose of about 400 mg, or a constant dose of about 420 mg, or a constant dose of about 440 mg, or a constant dose of about 460 mg, or a constant dose of about 480 mg, or a constant dose of about 500 mg, or a constant dose of about 520 mg, or a constant dose of about 540 mg, or constant a dose of about 560 mg, or a constant dose of about 580 mg, or a constant dose of about 600 mg, or a constant dose of about 620 mg, or a constant dose of about 640 mg, or a constant dose of about 660 mg, or a constant dose of about 680 mg, or a constant dose of about 700 mg, or a constant dose of about 720 mg, or a constant dose of about 740 mg, or a constant dose of about 750 mg, or a constant dose of about 760 mg, or a constant dose of about 780 mg, or a constant dose of about 800 mg, or a constant dose of about 820 mg, or a constant dose of about 840 mg, or a constant dose of about 860 mg , or a constant dose of about 880 mg, or a constant dose of about 900 mg. In some embodiments of the methods or uses or product for uses provided herein, a platinum-based agent as described herein is administered to a subject at a constant dose ranging from 50 mg to 900 mg, for example, at a constant dose of 50 mg, or a constant dose of 60 mg, or a constant dose of 70 mg, or a constant dose of 80 mg, or a constant dose of 90 mg, or a constant dose of 100 mg, or a constant dose of 120 mg, or a constant dose of 140 mg, or a constant dose of 160 mg, or a constant dose of 180 mg, or a constant dose of 200 mg, or a constant dose of 220 mg, or a constant dose of 240 mg, or constant a dose of 260 mg, or a constant dose of 280 mg, or a constant dose of 300 mg, or a constant dose of 320 mg, or a constant dose of 340 mg, or a constant dose of 360 mg, or a constant dose, 380 mg, or a constant dose of 400 mg, or a constant dose of 420 mg, or a constant dose of 440 mg, or a constant dose of 460 mg, or a constant dose of 480 mg, or constant up to

- 33 046283 ze of 500 mg, or a constant dose of 520 mg, or a constant dose of 540 mg, or a constant dose of 560 mg, or a constant dose of 580 mg, or a constant dose of 600 mg, or constant dose of 620 mg, or constant dose of 640 mg, or constant dose of 660 mg, or constant dose of 680 mg, or constant dose of 700 mg, or constant dose of 720 mg, or constant dose 740 mg, or a constant dose of 750 mg, or a constant dose of 760 mg, or a constant dose of 780 mg, or a constant dose of 800 mg, or a constant dose of 820 mg, or a constant dose of 840 mg, or a constant dose of 860 mg, or a constant dose of 880 mg, or a constant dose of 900 mg. In some embodiments, the constant dose is 750 mg. In some embodiments, the continuous dose is 750 mg and the platinum-based agent is carboplatin. In some embodiments, the continuous dose is about 600 mg and is administered once approximately every week. In some embodiments, the continuous dose is about 600 mg and is administered once approximately every 2 weeks. In some embodiments, the continuous dose is about 600 mg and is administered once approximately every 3 weeks. In some embodiments, the continuous dose is about 600 mg and is administered once approximately every 4 weeks. In some embodiments, the continuous dose is about 750 mg and is administered once approximately every week. In some embodiments, the continuous dose is about 750 mg and is administered once approximately every 2 weeks. In some embodiments, the continuous dose is about 750 mg and is administered once approximately every 3 weeks. In some embodiments, the continuous dose is about 750 mg and is administered once approximately every 4 weeks. In some embodiments, the continuous dose is 600 mg and is administered once approximately every week. In some embodiments, the continuous dose is 600 mg and is administered once approximately every 2 weeks. In some embodiments, the continuous dose is 600 mg and is administered once approximately every 3 weeks. In some embodiments, the continuous dose is 600 mg and is administered once approximately every 4 weeks. In some embodiments, the continuous dose is 750 mg and is administered once approximately every week. In some embodiments, the continuous dose is 750 mg and is administered once approximately every 2 weeks. In some embodiments, the continuous dose is 750 mg and is administered once approximately every 3 weeks. In some embodiments, the continuous dose is 750 mg and is administered once approximately every 4 weeks. In some embodiments, the continuous dose is 750 mg and is administered once approximately every 3 weeks (eg, ±3 days). In some embodiments, the continuous dose is 750 mg and is administered once every 3 weeks. In some embodiments, the continuous dose is 750 mg and is administered once every 3 weeks, and the platinum-based agent is carboplatin.

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

- 34 046283 of this agent or its antigen-binding fragment is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:120, 1:140, 1: 160, 1:180, 1:200, 200:1, 180:1, 160:1, 140:1, 120:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3: 1 or 2:1. In some embodiments, the ratio of the concentration (e.g., mg/mL) of the platinum-based agent to the concentration (e.g., mg/mL) of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1: 60, 1:70, 1:80, 1:90, 1:100, 1:120, 1:140, 1:160, 1:180, 1:200, 200:1, 180:1, 160:1, 140:1, 120:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1,40:1.30:1,20:1, 15:1, 10: 1.9:1.8:1.7:1.6:1.5:1.4:1.3:1 or 2:1.

In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg/kg and is administered once approximately every 3 weeks (e.g., ±3 days), and the dose of the platinum-based agent is AUC=5, and its administered once approximately every 3 weeks (eg, ± 3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg/kg and is administered once every 3 weeks and the dose of the platinum-based agent is AUC=5 and is administered once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg/kg and is administered once every 3 weeks, and the antibody-drug conjugate is tizotumab-vedotin, and the dose of the platinum-based agent is AUC= 5, and is administered once every 3 weeks, and the platinum-based agent is carboplatin.

In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg/kg and is administered once approximately every 3 weeks (e.g., ±3 days), and the dose of the platinum-based agent is AUC=5, and its administered once approximately every 3 weeks (eg, ± 3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg/kg and is administered once every 3 weeks and the dose of the platinum-based agent is AUC=5 and is administered once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg/kg and is administered once every 3 weeks, and the antibody-drug conjugate is tizotumab-vedotin, and the dose of the platinum-based agent is AUC= 5, and is administered once every 3 weeks, and the platinum-based agent is carboplatin.

In some embodiments, an anti-TF antibody-drug conjugate or antigen binding fragment thereof, as described herein, and a platinum-based agent, as described herein, are co-administered. In some embodiments, coadministration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate as described herein is administered concomitantly with a platinum-based agent as described herein. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered to the subject less than one hour apart, for example, less than about 30 minutes apart, less than about 30 minutes apart, 15 minutes, at an interval of less than about 10 minutes, or at an interval of less than about 5 minutes. In some embodiments, an anti-TF antibody-drug conjugate as described herein is administered sequentially with a platinum-based agent as described herein. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart hours, at an interval of at least 4 hours, at an interval of at least 5 hours, at an interval of at least 6 hours, at an interval of at least 7 hours, at an interval of at least 8 hours, at an interval of at least 9 hours, at an interval of at least 10 hours, at an interval of at least 11 hours, at an interval of at least 12 hours, at an interval of at least 13 hours, at an interval of at least 14 hours, at an interval of at least 15 hours, at an interval of at least 16 hours, at an interval of at least 17 hours, at an interval of at least 18 hours, at an interval of at least 19 hours, at an interval of at least 20 hours, at an interval of at least 21 hours, at an interval of at least 22 hours, at an interval of at least 23 hours, at an interval of at least 24 hours, at an interval of at least 2 days, at an interval of at least 3 days, at an interval of at least 4 days, at an interval of at least 5 days, at an interval of at least 6 days, at an interval of at least 7 days, at an interval of at least 2 weeks, at an interval of

- 35 046283 for at least 3 weeks, or at intervals of at least 4 weeks.

In some embodiments, a treatment method or use or product for uses described herein further comprises administering one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are administered concomitantly with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein, such as tizotumab-vedotin, and a platinum-based agent as described herein, such like carboplatin. In some embodiments, one or more additional therapeutic agents and an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein, such as tizotumab-vedotin, and a platinum-based agent as described herein, such as carboplatin , administered sequentially.

E. Treatment result

In one aspect, a method of treating cancer with an anti-TF antibody-drug conjugate or an antigen-binding fragment thereof as described herein, such as, for example, tizotumab-vedotin, and a platinum-based agent as described herein, such as, for example, carboplatin, results in an improvement in one or more therapeutic effects in a subject following administration of an antibody-drug conjugate and/or platinum-based agent relative to baseline. In some embodiments, one or more of the therapeutic effects is the following: tumor size of the cancer (eg, bladder cancer or cervical cancer), objective response rate, duration of response, time to response, progression-free survival, overall survival, or any their combination. In one embodiment, the one or more therapeutic effects are the size of the tumor derived from the cancer. In one embodiment, the one or more therapeutic effects are a reduction in tumor size. In one embodiment, the one or more therapeutic effects represent a stable disease. In one embodiment, one or more therapeutic effects constitute a partial response. In one embodiment, one or more therapeutic effects constitute a complete response. In one embodiment, one or more therapeutic effects is an objective response rate. In one embodiment, one or more therapeutic effects is the duration of the response. In one embodiment, one or more therapeutic effects are time to response. In one embodiment, the one or more therapeutic effects are progression-free survival. In one embodiment, the one or more therapeutic effects are overall survival. In one embodiment, one or more therapeutic effects represent regression of the cancer.

In one embodiment of the methods or uses or product for uses provided herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen binding fragment thereof as described herein, such as, for example, tizotumab-vedotin, and A platinum-based agent as described herein, such as carboplatin, may include the following criteria (RECIST (Response Evaluation Criteria in Solid Tumors) criteria 1.1):

- 36 046283

Category Criteria Based on target lesions Full answer (CR) Disappearance of all target lesions. Any abnormal lymph nodes should show a short-axis decrease of <10 mm. Partial response (PR) >30% reduction in the sum of the largest diameter (LD) of target lesions, taking the original sum of LD as reference Stable disease(SD) Neither a sufficient reduction to qualify for a PR nor a sufficient increase to qualify for a PD, using the smallest amount of LD during the test as the reference. Progressive disease (PD) > 20% (and > 5 mm) increase in the sum of LDs of target lesions, taking the smallest sum of target LDs as reference, recorded during the trial or when one or more new lesions appeared. Based on non-target lesions CR Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes should be of nonpathological size (<10 mm short axis). SD Persistence of one or more non-target lesions and/or maintenance of tumor marker levels above normal ranges. P.D. The appearance of one or more new lesions and/or apparent progression of existing non-target lesions.

In one embodiment of the methods or uses or product for uses provided herein, the effectiveness of treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein, such as, for example, tizotumab-vedotin, and an agent on a platinum-based agent described herein, such as, for example, carboplatin, is assessed by measuring the objective response rate. In some embodiments, the objective response rate is the proportion of patients whose tumor size decreased by a predetermined amount and over 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 2080%. In one embodiment, the objective response rate is at least about 30-80%. In one embodiment, the objective response rate is at least about 40-80%. In one embodiment, the objective response rate is at least about 50-80%. In one embodiment, the objective response rate is at least about 60-80%. According to one embodiment, often

- 37 046283 that objective answer is at least about 70-80%. In one embodiment, the objective response rate is at least about 80%. In one embodiment, the objective response rate is at least about 85%. In one embodiment, the objective response rate is at least about 90%. In one embodiment, the objective response rate is at least about 95%. In one embodiment, the objective response rate is at least about 98%. In one embodiment, the objective response rate is at least about 99%. In one embodiment, the objective response rate is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70% or at least 80%. In one embodiment, the objective response rate is at least 20-80%. In one embodiment, the objective response rate is at least 30-80%. In one embodiment, the objective response rate is at least 40-80%. In one embodiment, the objective response rate is at least 50-80%. In one embodiment, the objective response rate is at least 60-80%. In one embodiment, the objective response rate is at least 70-80%. In one embodiment, the objective response rate is at least 80%. In one embodiment, the objective response rate is at least 85%. In one embodiment, the objective response rate is at least 90%. In one embodiment, the objective response rate is at least 95%. In one embodiment, the objective response rate is at least 98%. In one embodiment, the objective response rate is at least 99%. In one embodiment, the objective response rate is 100%.

In one embodiment of the methods or uses or product for uses provided herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen binding fragment thereof described herein, such as, for example, tizotumab-vedotin, and the agent a platinum-based agent described herein, such as, for example, carboplatin, is assessed by measuring the size of a tumor originating from a cancer (eg, bladder cancer or cervical cancer). In one embodiment, the tumor size of 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 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 tumor size, originating from cancer, prior to administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 10-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 20-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 30-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 40-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 50-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 60-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 70-80%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least about 80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 85%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 90%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least about 95%. In one embodiment, the size of the cancer-derived tumor is reduced by at least about 98%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least about 99%. In one embodiment, the tumor size of the cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least by 35%, by at least 40%, by at least 45%, by at least 50%, by at least 60%, by at least 70%, or by at least 80% relative to the size of the tumor occurring from cancer, prior to administration of anti-TF antibody-drug conjugate and/or platinum-based agent. In one embodiment, the size of the cancer-derived tumor is reduced by at least 10-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 20-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 30-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 40-80%. According to

- 38 046283 in one embodiment, the size of the tumor originating from the cancer is reduced by at least 50-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 60-80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 70-80%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least 80%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least 85%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least 90%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least 95%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least 98%. In one embodiment, the size of the tumor originating from the cancer is reduced by at least 99%. In one embodiment, the size of the tumor originating from the cancer is reduced by 100%. In one embodiment, the size of the tumor originating from the cancer is measured using magnetic resonance imaging (MRI). In one embodiment, the size of the tumor originating from the cancer is measured using computed tomography (CT). In some embodiments, the size of a tumor originating from cervical cancer is measured through a pelvic examination. See Choi et al, 2008, J. Gynecol. Oncol. 19(3):205. In some embodiments, the size of a tumor arising from bladder cancer is measured using cytoscopy or cytology. See US 2017/0181988. In some embodiments, the size of the cancer-derived tumor is reduced relative to the size of the tumor prior to administration of the anti-TF antibody-drug conjugate and platinum-based agent. In some embodiments, the size of the cancer-derived tumor is reduced relative to the size of the tumor prior to administration of the anti-TF antibody-drug conjugate. In some embodiments, the size of the tumor originating from the cancer is reduced relative to the size of the tumor prior to administration of the platinum-based agent.

In one embodiment of the methods or uses or product for uses provided herein, the response to treatment with an antibody-drug conjugate or antigen-binding fragment thereof described herein, such as, for example, tizotumab-vedotin, and agents based on platinum described herein, such as, for example, carboplatin, stimulates the regression of tumors originating from cancer (eg, bladder cancer or cervical cancer). In one embodiment, the cancer-derived tumor regresses by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30 %, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80% relative to the size of the cancer-derived tumor prior to administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In one embodiment, the tumor originating from the cancer undergoes regression of at least about 10% to about 80%. In one embodiment, there is regression of the tumor originating from the cancer by at least about 20% to about 80%. In one embodiment, there is regression of the tumor originating from the cancer by at least about 30% to about 80%. In one embodiment, there is regression of the tumor originating from the cancer by at least about 40% to about 80%. In one embodiment, there is regression of the tumor originating from the cancer by at least about 50% to about 80%. In one embodiment, there is regression of the tumor originating from the cancer by at least about 60% to about 80%. In one embodiment, the tumor originating from the cancer undergoes regression of at least about 70% to about 80%. In one embodiment, there is at least about 80% regression of the cancer-derived tumor. In one embodiment, there is at least about 85% regression of the cancer-derived tumor. In one embodiment, there is at least about 90% regression of the cancer-derived tumor. In one embodiment, there is at least about 95% regression of the cancer-derived tumor. In one embodiment, there is at least about 98% regression of the cancer-derived tumor. In one embodiment, there is at least about 99% regression of the cancer-derived tumor. In one embodiment, the cancer-derived tumor regresses by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least by 35%, by at least 40%, by at least 45%, by at least 50%, by at least 60%, by at least 70%, or by at least 80% relative to the size of the tumor occurring from cancer, prior to administration of anti-TF antibody-drug conjugate and/or platinum-based agent. In one embodiment, there is at least 1080% regression of the cancer-derived tumor. In one embodiment, the cancer-derived tumor undergoes regression of at least 20-80%. In one embodiment, tumor regression occurs,

- 39 046283 originating from cancer, at least 30-80%. In one embodiment, there is at least 40-80% regression of the cancer-derived tumor. In one embodiment, there is at least 50-80% regression of the cancer-derived tumor. In one embodiment, there is at least 60-80% regression of the cancer-derived tumor. In one embodiment, there is at least 70-80% regression of the cancer-derived tumor. In one embodiment, there is at least 80% regression of the cancer-derived tumor. In one embodiment, there is at least 85% regression of the cancer-derived tumor. In one embodiment, there is at least 90% regression of the cancer-derived tumor. In one embodiment, there is at least 95% regression of the cancer-derived tumor. In one embodiment, there is at least 98% regression of the cancer-derived tumor. In one embodiment, there is at least 99% regression of the cancer-derived tumor. In one embodiment, there is 100% regression of the cancer-derived tumor. 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 the size of the tumor using a gynecological examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205. In some embodiments, the size of a tumor arising from bladder cancer is measured using cytoscopy or cytology. See US 2017/0181988. In some embodiments, there is regression of the cancer-derived tumor relative to tumor size prior to administration of the anti-TF antibody-drug conjugate and platinum-based agent. In some embodiments, there is regression of the cancer-derived tumor relative to the size of the tumor prior to administration of the anti-TF antibody-drug conjugate. In some embodiments, there is regression of the cancer-derived tumor relative to the size of the tumor prior to administration of the platinum-based agent.

In one embodiment of the methods or uses or product for uses described herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen binding fragment thereof described herein, such as, for example, tizotumab-vedotin, and the agent platinum-based agents described herein, such as, for example, carboplatin, are assessed by measuring progression-free survival time following administration of an anti-TF antibody-drug conjugate and/or a platinum-based agent. In some embodiments, the 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 two years, at least about three years, at least about four years, or at least about five years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least about 6 months after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least about one year after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least about two years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least about three years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least about four years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least about five years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject demonstrates 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

- 40 046283 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 after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject demonstrates progression-free survival of at least 6 months after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least one year after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least two years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least three years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits progression-free survival of at least four years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject demonstrates progression-free survival of at least five years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, response to treatment is assessed by measuring progression-free survival time following administration of an anti-TF antibody-drug conjugate and a platinum-based agent. In some embodiments, response to treatment is assessed by measuring progression-free survival time following administration of the anti-TF antibody-drug conjugate. In some embodiments, response to treatment is assessed by measuring progression-free survival time following administration of a platinum-based agent.

In one embodiment of the methods or uses or product for uses described herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen binding fragment thereof described herein, such as, for example, tizotumab-vedotin, and the agent platinum-based agents described herein, such as, for example, carboplatin, are assessed by measuring the overall survival time after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months 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 after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits an overall survival of at least about 6 months after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least about one year after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least about two years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least about three years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least about four years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least about five years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits 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 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 after administration of the anti-TF antibody-drug conjugate

- 41 046283 vom and/or platinum-based products. In some embodiments, the subject exhibits overall survival of at least 6 months after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least one year after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least two years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least three years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least four years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the subject exhibits overall survival of at least five years after administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, response to treatment is assessed by measuring the overall survival time after administration of the anti-TF antibody-drug conjugate and platinum-based agent. In some embodiments, response to treatment is assessed by measuring the overall survival time after administration of the anti-TF antibody-drug conjugate. In some embodiments, response to treatment is assessed by measuring the time of overall survival after administration of the platinum-based agent.

In one embodiment of the methods or uses or product for uses described herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen binding fragment thereof described herein, such as, for example, tizotumab-vedotin, and the agent platinum-based drugs described herein, such as, for example, carboplatin, are assessed by measuring the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent following administration of the anti-TF antibody-drug conjugate and/or platinum-based agent . In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least 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 after administration of the anti-TF antibody-drug conjugate and/or platinum-based products. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least about 6 months after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least about one year after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least about two years after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least about three years after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least about four years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least about five years after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent 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 at least two years, at least three years, at least four

- 42 046283 years or at least five years after the administration of the anti-TF antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least 6 months after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least one year after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least two years after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least three years after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least four years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and platinum-based agent is at least five years after administration of the antibody-drug conjugate and/or platinum-based agent. In some embodiments, the duration of response is measured after administration of an anti-TF antibody-drug conjugate and a platinum-based agent. In some embodiments, the duration of response is measured after administration of the anti-TF antibody-drug conjugate. In some embodiments, the duration of response is measured after administration of the platinum-based agent.

F. Adverse events

In one aspect, a method of treating cancer (eg, bladder cancer or cervical cancer) with anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein, such as, for example, tizotumab-vedotin, and platinum-based agents. agent described herein, such as, for example, carboplatin, results in the development of one or more adverse events in the subject. In some embodiments, the subject is administered an additional therapeutic agent to eliminate or reduce the severity of the adverse event. In some embodiments, one or more adverse events that develop in the subject are: increased bleeding, hemorrhage, liver dysfunction (eg, elevated liver enzymes), mucositis, neutropenia, febrile neutropenia, peripheral neuropathy, decreased platelet count, vomiting, neuropathy, conjunctivitis, keratitis, conjunctival ulceration, symblepharon, infusion-related reactions or general deterioration of health, or any combination thereof. In some embodiments, one or more adverse events that develop in the subject are the following: anemia, abdominal pain, hemorrhage, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, constipation, decreased appetite, diarrhea, vomiting, neutropenia, decreased platelet count, peripheral neuropathy or general deterioration in physical health, or any combination thereof. In some embodiments, the one or more adverse events are a grade 1 or higher adverse event. In some embodiments, the one or more adverse events are a grade 2 or higher adverse event. In some embodiments, the one or more adverse events are a grade 3 or higher adverse event. In some embodiments, one or more adverse events constitute a grade 1 adverse event. In some embodiments, the one or more adverse events constitute a grade 2 adverse event. In some embodiments, the one or more adverse events are a grade 3 adverse event. In some embodiments, the one or more adverse events are a grade 4 adverse event. In some embodiments, one or more adverse events constitute a serious adverse event. In some embodiments, one or more of the adverse events is conjunctivitis, conjunctival ulceration, and/or keratitis, and the additional therapeutic agent is a preservative-free lubricant eye drop, an ophthalmic vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments, one or more of the adverse events is conjunctivitis, conjunctival ulceration, and keratitis, and the additional therapeutic agent is a preservative-free lubricant eye drop, an ophthalmic vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments, one or more of the adverse events is conjunctivitis and keratitis, and the additional therapeutic agent is

- 43 046283 preservative-free lubricating eye drops, ophthalmic vasoconstrictor, antibiotic, steroid eye drops or any combination thereof. In some embodiments, one or more of the adverse events is conjunctivitis, and the additional therapeutic agent is a preservative-free lubricant eye drop, an ophthalmic vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments, one or more of the adverse events is keratitis, and the additional therapeutic agent is a preservative-free lubricant eye drop, an ophthalmic vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments provided herein, a subject is treated with an additional therapeutic agent to eliminate or reduce the severity of an adverse event (eg, conjunctivitis, conjunctival ulceration, and/or keratitis). In some embodiments, the treatment is an eye cooling pad (eg, THERA PEARL Eye Mask or the like). In some embodiments, one or more of the adverse events is a recurrent infusion-related reaction, and the additional therapeutic agent is an antihistamine, acetaminophen, and/or a corticosteroid. In some embodiments, one or more of the adverse events is neutropenia, and the additional therapeutic agent is a colony-stimulating factor (G-CSF). In some embodiments, one or more of the adverse events is hyperthyroidism, and the additional agent is a non-selective beta blocker (eg, propranolol) or thionamides. In some embodiments, one or more of the adverse events is hypothyroidism, and the additional agent is a thyroid hormone replacement (eg, levothyroxine or liothyronine).

In one aspect, a subject being treated with anti-TF antibody-drug conjugates or antigen binding fragments thereof described herein, such as, for example, tizotumab-vedotin, and a platinum-based agent described herein, such as, for example , carboplatin, 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 to reduce the severity of the adverse event. In some embodiments, one or more adverse events are at risk for the subject to develop the following: increased bleeding, hemorrhage, liver dysfunction (eg, elevated liver enzymes), mucositis, neutropenia, febrile neutropenia, peripheral neuropathy, decreased platelet count, vomiting, neuropathy, conjunctivitis, keratitis, conjunctival ulceration, symblepharon, infusion-related reactions, or general deterioration of health, or any combination thereof. In some embodiments, one or more of the adverse events to which the subject is at risk is the following: anemia, abdominal pain, hemorrhage, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, constipation, decreased appetite, diarrhea, vomiting, neutropenia, decreased platelet count, peripheral neuropathy, or general deterioration in physical health, or any combination thereof. In some embodiments, the one or more adverse events are a grade 1 or higher adverse event. In some embodiments, the one or more adverse events are a grade 2 or higher adverse event. In some embodiments, the one or more adverse events are a grade 3 or higher adverse event. In some embodiments, one or more adverse events constitute a grade 1 adverse event. In some embodiments, the one or more adverse events constitute a grade 2 adverse event. In some embodiments, one or more of the adverse events is a grade 3 adverse event. In some embodiments, the one or more adverse events are a grade 4 adverse event. In some embodiments, one or more adverse events constitute a serious adverse event. In some embodiments, one or more of the adverse events is conjunctivitis, conjunctival ulceration, and/or keratitis, and the additional agent is a preservative-free lubricant eye drop, an ophthalmic vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments, one or more of the adverse events is conjunctivitis and keratitis, and the additional agent is a preservative-free lubricant eye drop, an ophthalmic vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments, one or more of the adverse events is conjunctivitis, and the additional agent is a preservative-free lubricating eye drop, an ophthalmic vasoconstrictor

- 44 046283 medicine, antibiotic, steroid eye drops or any combination thereof. In some embodiments, one or more of the adverse events is keratitis, and the additional agent is a preservative-free lubricant eye drop, an ophthalmic vasoconstrictor, an antibiotic, a steroid eye drop, or any combination thereof. In some embodiments provided herein, a subject is treated with an additional therapeutic agent to prevent the development of an adverse event or to reduce the severity of an adverse event (eg, conjunctivitis, conjunctival ulceration, and/or keratitis). In some embodiments, the treatment is an eye cooling pad (eg, THERA PEARL Eye Mask or the like). In some embodiments, one or more of the adverse events is a recurrent infusion-related reaction, and the additional agent is an antihistamine, acetaminophen, and/or a corticosteroid. In some embodiments, one or more of the adverse events is neutropenia, and the additional agent is a colony-stimulating factor (G-CSF). In some embodiments, one or more of the adverse events is hyperthyroidism, and the additional agent is a non-selective beta blocker (eg, propranolol) or thionamides. In some embodiments, one or more of the adverse events is hypothyroidism, and the additional agent is a thyroid hormone replacement (eg, levothyroxine or liothyronine).

IV. Compositions

In some aspects, also provided herein are compositions (e.g., pharmaceutical compositions and therapeutic compositions) containing any of the anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein, such as, for example, tizotumab-vedotin, and/ or a platinum-based agent described herein, such as, for example, carboplatin.

Therapeutic compositions are prepared for storage by mixing the ingredient at the required 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).

Acceptable carriers, excipients or stabilizers are non-toxic to recipients at the dosages and concentrations used and include buffers, antioxidants including ascorbic acid, methionine, vitamin E, sodium metabisulfite; preservatives, isotonic additives, stabilizers, metal complexes (for example, Zn-protein complexes); chelating agents such as EDTA and/or nonionic surfactants.

Buffers can be used to adjust the pH within a range that optimizes therapeutic efficacy, especially if stability is pH dependent. Buffers may be present in concentrations ranging from about 50 mM to about 250 mM. Suitable buffering agents for use in the present invention include both organic and inorganic acids and their salts. For example, citrate, phosphate, succinate, tartrate, fumarate, gluconate, oxalate, lactate, acetate. Additionally, buffers may consist of histidine and trimethylamine salts such as Tris.

Preservatives can be added to prevent the growth of microorganisms and are typically present in the range of about 0.2% to 1.0% (w/v). Suitable preservatives for use in the present invention include octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium halides (eg chloride, bromide, iodide), benzethonium chloride; thiomersal, phenol, butyl or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol, 3-pentanol and m-cresol.

Tonicity regulators, sometimes called stabilizers, may be present to control or maintain the tonicity of the liquid in the composition. When used with large charged biomolecules such as proteins and antibodies, they are often called stabilizers because they can interact with charged groups on amino acid side chains, thereby reducing the possibility of intermolecular and intramolecular interactions. Tonicity regulators may be present in any amount from about 0.1% to about 25% by weight, or from about 1% to about 5% by weight, taking into account the relative amounts of other ingredients. In some embodiments, tonicity modifiers include polyhydric sugar alcohols, trihydric or higher sugar alcohols such as glycerol, erythritol, arabitol, xylitol, sorbitol and mannitol.

Additional excipients include agents that may serve 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 wall of the container. Such excipients include the following: polyhydric sugar alcohols (listed above); amino acids such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitol, myoinisitol, galactose, galactitol, glycerol, cyclitols (e.g. inositol), polyethylene glycol ; sulfur-containing reducing agents such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, α-monothioglycerol and sodium thiosulfate; low molecular weight proteins such as human serum albumin, bovine serum albumin, gelatin or other immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides (eg, xylose, mannose, fructose, glucose; disaccharides (eg, lactose, maltose, sucrose); trisaccharides, such as raffinose; and polysaccharides, such as dextrin or dextran.

Non-ionic surfactants or detergents (also known as wetting agents) may be present to aid solubilization of the therapeutic agent as well as to protect the therapeutic protein from aggregation caused by agitation, which also allows the formulation to be exposed to surface shear stress without denaturing the active therapeutic protein or antibodies. Nonionic surfactants are present in the range from about 0.05 mg/ml to about 1.0 mg/ml or from about 0.07 mg/ml to about 0.2 mg/ml. In some embodiments, nonionic surfactants are present in the range of from about 0.001% to about 0.1% w/v, or from about 0.01% to about 0.1% w/v, or from about 0.01% to about 0.025% w/v

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

Formulations containing the anti-TF antibody conjugate described herein for use in the methods of treatment provided herein are described in international patent publication WO2015/075201. In some embodiments, the anti-TF antibody-drug conjugate described herein is in a formulation comprising the anti-TF antibody-drug conjugate, histidine, sucrose, and D-mannitol, the formulation having a pH value of about 6.0. In some embodiments, the anti-TF antibody-drug conjugate described herein is 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 in a concentration of about 88 mM, D-mannitol in a concentration of about 165 mM, the composition having a pH value of about 6.0. In some embodiments, the anti-TF antibody-drug conjugate described herein is in a formulation comprising an anti-TF antibody-drug conjugate at a concentration of 10 mg/mL, a histidine at a concentration of 30 mM, sucrose at a concentration component 88 mm, D-mannitol in a concentration of 165 mm, and the composition is characterized by a pH value of 6.0. In some embodiments, the composition contains tizotumab-vedotin at a concentration of 10 mg/ml, histidine at a concentration of 30 mM, sucrose at a concentration of 88 mM, D-mannitol at a concentration of 165 mM, and the composition is characterized by a pH value, components 6.0.

In some embodiments provided herein, a composition comprising an anti-TF antibody conjugate described herein is surfactant-free (ie, does not include a surfactant).

In order for the formulations to be used for in vivo administration, they must be sterile. The composition can be made sterile by filtration through sterile filter membranes. Therapeutic compositions herein are typically placed in a container having a sterile access port, such as an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic needle.

The route of administration corresponds to known and conventional methods, such as a single or multiple bolus or infusion over a long period of time in a suitable manner, for example, injection or infusion by subcutaneous, intravenous, intraperitoneal, intramuscular, intraarterial, intralesional or intraarticular route, local administration, inhalation or delayed or extended release agents.

The composition described herein may also contain more than one active compound if necessary for the particular indication being treated, preferably compounds with additional activities that do not adversely affect each other. Alternatively or additionally, the composition may contain a cytotoxic agent, qi

- 46 046283 toxin or growth inhibitory agent. Such molecules are suitably present in combination in amounts effective for the intended purpose.

The present invention relates to compositions containing 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 are compositions comprising a population of antibody-drug conjugates, wherein the antibody-drug conjugates comprise a linker attached to MMAE, wherein the antibody-drug conjugate is characterized by the following structure:

Ab-MC-vc-PAB-MMAB where p is a number from 1 to 8, for example 1, 2, 3, 4, 5, 6, 7 or 8, S is a sulfhydryl residue of an anti-TF antibody or an antigen binding fragment thereof, and Ab means an anti-TF antibody or antigen-binding fragment thereof as described herein, such as tizotumab. In some embodiments, p is a number from 3 to 5. In some embodiments, the average p value in the composition is about 4. In some embodiments, the population is a mixed population of antibody-drug conjugates, wherein p ranges from 1 to 8 per conjugate antibodies with drug. In some embodiments, the population is a homogeneous population of antibody-drug conjugates, with each antibody-drug conjugate having the same p-value.

In some embodiments, a composition comprising an anti-TF antibody-drug conjugate or an antigen-binding fragment thereof as described herein, such as, for example, tizotumab-vedotin, is co-administered with a composition containing a platinum-based agent as described herein , such as, for example, carboplatin. In some embodiments, coadministration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate as described herein is administered concomitantly with a platinum-based agent. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered to the subject at an interval of less than about one hour, for example, at an interval of less than about 30 minutes, at an interval of less than about 15 minutes, at an interval of less than about 10 minutes, or at an interval of less than about 5 minutes. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered to the subject less than one hour apart, e.g., less than 30 minutes apart, less than 15 minutes apart , at an interval of less than 10 minutes, or at an interval of less than 5 minutes. In some embodiments, the anti-TF antibody-drug conjugate is administered sequentially with a platinum-based agent. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart hours, at an interval of at least 4 hours, at an interval of at least 5 hours, at an interval of at least 6 hours, at an interval of at least 7 hours, at an interval of at least 8 hours, at an interval of at least 9 hours, at an interval of at least 10 hours, at an interval of at least 11 hours, at an interval of at least 12 hours, at an interval of at least 13 hours, at an interval of at least 14 hours, at an interval of at least 15 hours, at an interval of at least 16 hours, at an interval of at least 17 hours, at an interval of at least 18 hours, at an interval of at least 19 hours, at an interval of at least 20 hours, at an interval of at least 21 hours, at an interval of at least 22 hours, at an interval of at least 23 hours, at an interval of at least 24 hours, at an interval of at least 2 days, at an interval of at least 3 days, at an interval of at least 4 days, at an interval of at least 5 days, from in

- 47 046283 at intervals of at least 6 days, at intervals of at least 7 days, at intervals of at least 2 weeks, at intervals of at least 3 weeks, or at intervals of at least 4 weeks. In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein and/or a platinum-based agent as described herein is coadministered with one or more therapeutic agents to eliminate or reduce the severity of one or more more adverse events. In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein and/or a platinum-based agent as described herein is coadministered with one or more therapeutic agents to prevent the development of an adverse event or reduce severity of the adverse event.

In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein, such as, for example, tizotumabvedotin, and/or a platinum-based agent as described herein, such as, for example, carboplatin, is administered together with one or more additional therapeutic agents. In some embodiments, coadministration is simultaneous or sequential. In some embodiments, an anti-TF antibody-drug conjugate as described herein and/or a platinum-based agent as described herein is administered concomitantly with one or more additional therapeutic agents. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and/or platinum-based agent and one or more therapeutic agents are administered to a subject at an interval of less than about one hour, for example, at an interval of less than about 30 minutes, at an interval of less than about 15 minutes, at an interval of less than about 10 minutes, or at an interval of less than about 5 minutes. In some embodiments, the anti-TF antibody-drug conjugate and/or platinum-based agent is administered sequentially with one or more additional therapeutic agents. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and/or platinum-based agent and one or more therapeutic agents are administered to a subject less than one hour apart, for example, less than 30 minutes apart. at an interval of less than 15 minutes, at an interval of less than 10 minutes, or at an interval of less than 5 minutes. In some embodiments, the anti-TF antibody-drug conjugate and/or platinum-based agent is administered sequentially with one or more additional therapeutic agents. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate and/or platinum-based agent and one or more additional therapeutic agents are administered at least 1 hour apart and at least 2 hours apart. , at an interval of at least 3 hours, at an interval of at least 4 hours, at an interval of at least 5 hours, at an interval of at least 6 hours, at an interval of at least 7 hours , at an interval of at least 8 hours, at an interval of at least 9 hours, at an interval of at least 10 hours, at an interval of at least 11 hours, at an interval of at least 12 hours , at an interval of at least 13 hours, at an interval of at least 14 hours, at an interval of at least 15 hours, at an interval of at least 16 hours, at an interval of at least 17 hours , at an interval of at least 18 hours, at an interval of at least 19 hours, at an interval of at least 20 hours, at an interval of at least 21 hours, at an interval of at least 22 hours , at an interval of at least 23 hours, at an interval of at least 24 hours, at an interval of at least 2 days, at an interval of at least 3 days, at an interval of at least 4 days , at an interval of at least 5 days, at an interval of at least 6 days, at an interval of at least 7 days, at an interval of at least 2 weeks, at an interval of at least 3 weeks , or at intervals of at least 4 weeks.

In some embodiments, a composition comprising an anti-TF antibody-drug conjugate as described herein, such as, for example, tizotumabvedotin, and/or a platinum-based agent as described herein, such as, for example, carboplatin, is administered together with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse effects. In some embodiments, coadministration is simultaneous or sequential. In some embodiments, the anti-TF antibody-drug conjugate and/or drug-based agent

- 48 046283 muds are administered simultaneously with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse effects. In some embodiments, concurrent means that the anti-TF antibody-drug conjugate and/or platinum-based agent and one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events are administered to a subject at an interval of less than about one hour, for example, at an interval of less than about 30 minutes, at an interval of less than about 15 minutes, at an interval of less than about 10 minutes, or at an interval of less than about 5 minutes. In some embodiments, concurrent means that the anti-TF antibody-drug conjugate and/or platinum-based agent and one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events are administered to a subject less than one hour apart, e.g. , at an interval of less than 30 minutes, at an interval of less than 15 minutes, at an interval of less than 10 minutes, or at an interval of less than 5 minutes. In some embodiments, an anti-TF antibody-drug conjugate and/or a platinum-based agent is administered sequentially with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate and/or platinum-based agent and one or more additional therapeutic agents are administered at least 1 hour apart and at least 2 hours apart. , at an interval of at least 3 hours, at an interval of at least 4 hours, at an interval of at least 5 hours, at an interval of at least 6 hours, at an interval of at least 7 hours , at an interval of at least 8 hours, at an interval of at least 9 hours, at an interval of at least 10 hours, at an interval of at least 11 hours, at an interval of at least 12 hours , at an interval of at least 13 hours, at an interval of at least 14 hours, at an interval of at least 15 hours, at an interval of at least 16 hours, at an interval of at least 17 hours , at an interval of at least 18 hours, at an interval of at least 19 hours, at an interval of at least 20 hours, at an interval of at least 21 hours, at an interval of at least 22 hours , at an interval of at least 23 hours, at an interval of at least 24 hours, at an interval of at least 2 days, at an interval of at least 3 days, at an interval of at least 4 days , at an interval of at least 5 days, at an interval of at least 6 days, at an interval of at least 7 days, at an interval of at least 2 weeks, at an interval of at least 3 weeks , or at intervals of at least 4 weeks. In some embodiments, the anti-TF antibody-drug conjugate and/or platinum-based agent is administered prior to administration of one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events are administered prior to administration of the anti-TF antibody-drug conjugate and/or platinum-based agent.

V. Finished products and kits

In another aspect, a product or kit is provided that contains an anti-TF antibody-drug conjugate described herein, such as, for example, tizotumab-vedotin, and/or a platinum-based agent described herein, such as, for example, carboplatin. The finished product or kit may further contain instructions for use of the anti-TF antibody-drug conjugate and/or platinum-based agent in the methods of the present invention. Thus, in certain embodiments, the product or kit contains instructions for use of an anti-TF antibody-drug conjugate and/or a platinum-based agent in methods of treating cancer (e.g., bladder cancer or cervical cancer) in a subject, comprising administering to the subject an effective amount of an anti-TF antibody-drug conjugate and/or a platinum-based agent. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, 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, cervical cancer is a metastatic cancer and a recurrent cancer. In some embodiments, cervical cancer is a recurrent cancer. According to

- 49 046283 In some embodiments, the subject is not a candidate for radical treatment. In some embodiments, the subject has not received prior systemic therapy for cervical cancer. In some embodiments, the subject is a human.

The finished product or kit may further comprise a container. Suitable containers include, for example, bottles, vials (eg, dual chamber vials), syringes (such as single or dual chamber syringes), and tubes. In some embodiments, the container is a vial. The container can be made of various materials such as glass or plastic. The container contains the composition.

The product or kit may further comprise a label or package insert that is located on or attached to the container and may contain directions for reconstitution and/or use of the formulation. The label or package insert may further state that the formulation is applicable or intended for subcutaneous, intravenous (e.g., intravenous infusion), or other routes of administration for the treatment of cancer in a subject, such as bladder cancer or cervical cancer described herein (eg, advanced cervical cancer, such as grade 3 or 4 cervical cancer or metastatic cervical cancer). The container containing the composition may be a single-use vial or a refillable vial, allowing for repeated administration of the formulated composition. The finished product or kit may further comprise a second container containing a suitable diluent. The finished product or kit may further include other materials desirable from a commercial, therapeutic and user perspective, including other buffers, diluents, filters, needles, syringes and package inserts with instructions for use.

The product or kit herein optionally further comprises a container containing a second drug, wherein the anti-TF antibody-drug conjugate is a first drug, and the product or kit further contains label or package insert instructions for treating a subject with using a second drug in an effective amount. In some embodiments, the second drug is a platinum-based agent, as described herein. In some embodiments, the label or package insert indicates that the first and second drugs should be administered sequentially or simultaneously, as described herein.

The finished product or kit herein optionally further comprises a container containing a third drug, wherein the third drug is intended to eliminate or reduce the severity of one or more adverse events, wherein the anti-TF antibody-drug conjugate is the first drug, the drug on the platinum base is a second drug, and the device or kit further includes instructions on the label or package insert for treating the subject with the third drug in an effective amount. In some embodiments, the label or package insert indicates that the first, second, and third drugs should be administered sequentially or simultaneously as described herein, for example, wherein the label or package insert indicates that an anti-TF antibody conjugate The drug should be administered first, then the platinum-based drug should be administered, and then the third drug should be administered.

In some embodiments, the anti-TF antibody-drug conjugate and/or platinum-based agent is present in the container as a lyophilized powder. In some embodiments, the lyophilized powder is contained in a sealed container, such as a vial, ampoule, or sachet, labeled with the amount of active agent. When a pharmaceutical preparation is administered by injection, for example, an ampoule of sterile water for injection or saline may be provided, optionally as part of a kit, so that the ingredients can be mixed before administration. Such kits may further include, as appropriate, one or more different conventional pharmaceutical components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. The kit may also include printed instructions, either in the form of inserts or labels, indicating the quantity of components to be administered, a guide for administration, and/or a guide for mixing the components.

VII. Exemplary Embodiments

Among the embodiments provided herein are:

1. A method of treating cancer in a subject, the method comprising administering to the subject a platinum-based agent and an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or its functional analogue

- 50 046283 or its functional derivatives.

2. The method of Embodiment 1, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg/kg to about 2.1 mg/kg.

3. The method according to embodiment 2, wherein the antibody-drug conjugate is administered at a dose of about 1.3 mg/kg.

4. The method according to embodiment 2, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg/kg.

5. The method according to embodiment 2, wherein the antibody-drug conjugate is administered at a dose of about 2.0 mg/kg.

6. The method according to embodiment 2, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg/kg.

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

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

9. The method according to embodiment 7, wherein the antibody-drug conjugate is administered once every 3 weeks.

10. The method according to one of embodiments 1-9, wherein the platinum-based agent is administered at a dose of about AUC=4 to about AUC=6.

11. The method according to embodiment 10, wherein the platinum-based agent is administered at a dose of about AUC=5.

12. The method according to embodiment 10, wherein the platinum-based agent is administered at a dose of AUC=5.

13. The method of one of embodiments 1-12, wherein the platinum-based agent is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

14. The method of embodiment 13, wherein the platinum-based agent is administered once approximately every 3 weeks.

15. The method according to embodiment 13, wherein the platinum-based agent is administered once every 3 weeks.

16. The method according to one of embodiments 1-15, wherein the cancer is bladder cancer.

17. The method according to one of embodiments 1-15, wherein the cancer is cervical cancer.

18. The method of embodiment 17, wherein the subject is not a candidate for radical treatment.

19. The method according to embodiment 18, wherein the radical treatment includes radiation therapy and/or exenteration.

20. The method of embodiment 17, wherein the subject has not received prior systemic therapy for cervical cancer.

21. The method according to one of embodiments 17-20, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

22. The method according to one of embodiments 17-21, wherein the cervical cancer is advanced cervical cancer.

23. The method of embodiment 22, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

24. The method of embodiment 22 or 23, wherein the advanced cervical cancer is metastatic cervical cancer.

25. The method according to one of embodiments 17-24, wherein the cervical cancer is recurrent cervical cancer.

26. The method according to one of embodiments 1-25, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

27. The method according to one of embodiments 1-26, wherein the anti-TF antibody or an antigen-binding fragment of an antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

28. The method according to one of embodiments 1-27, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following:

(i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1;

(ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; And

- 51 046283 (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following:

(i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4;

(ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen binding fragment thereof is defined according to the IMGT numbering system.

29. The method according to one of embodiments 1-28, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO:8.

30. The method according to one of embodiments 1-29, wherein the anti-TF antibody or an antigen-binding fragment of an antibody-drug conjugate comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7, and a light chain variable region containing the amino acid sequence according to SEQ ID NO:8.

31. The method according to one of embodiments 1-30, wherein the anti-TF antibody of the antibody-drug conjugate is tizotumab.

32. The method according to one of embodiments 1-31, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or an antigen-binding fragment thereof and monomethyl auristatin.

33. The method of embodiment 32, wherein the linker is a cleavable peptide linker.

34. The method according to embodiment 33, wherein the cleavable peptide linker is characterized by the formula: -MC-vc-PAB-, where:

a) MS is:

b) vc is a valine-citrulline dipeptide, and

c) RAV is:

ABOUT

35. The method according to one of embodiments 32-34, wherein the linker is attached to the sulfhydryl residues of an anti-TF antibody obtained by partial reduction or complete reduction of an anti-TF antibody or an antigen-binding fragment thereof.

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

Ab-MC-vc-PAB-MMAE where p is a number from 1 to 8, S is a sulfhydryl residue of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof.

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

38. The method of one of embodiments 1-37, wherein the antibody-drug conjugate is tizotumab-vedotin.

39. The method according to one of embodiments 1-38, wherein the route of administration for the antibody-drug conjugate is intravenous.

40. The method according to one of embodiments 1-39, wherein the agent based on

- 52 046283 platinum is selected from the group consisting of carboplatin, cisplatin, oxaliplatin and nedaplatin.

41. The method according to one of embodiments 1-39, wherein the platinum-based agent is carboplatin.

42. The method according to one of embodiments 1-39, wherein the platinum-based agent is cisplatin.

43. The method according to one of embodiments 1-42, wherein the route of administration for the platinum-based agent is intravenous.

44. The method according to one of embodiments 1-43, wherein the platinum-based agent and the antibody-drug conjugate are administered sequentially.

45. The method according to one of embodiments 1-43, wherein the platinum-based agent and the antibody-drug conjugate are administered simultaneously.

46. The method according to one of embodiments 1-45, 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%, according to at least about 60%, at least about 70%, or at least about 80% of cervical cancer cells express TF.

47. The method according to one of embodiments 1-46, wherein one or more therapeutic effects in the subject are improved following administration of the platinum-based antibody-drug conjugate relative to a baseline level.

48. The method of embodiment 47, wherein the one or more therapeutic effects are selected from the group consisting of the following: tumor size derived from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

49. The method according to one of embodiments 1-48, wherein the size of a tumor originating from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70 % or at least about 80% relative to the size of the tumor originating from cervical cancer prior to administration of the platinum-based antibody-drug conjugate.

50. The method according to one of embodiments 1-49, 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%.

51. The method according to one of embodiments 1-50, wherein the subject demonstrates 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 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 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 after administration of the antibody-drug conjugate and drug-based platinum.

52. The method according to one of embodiments 1-51, 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 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 after administration of the platinum-based antibody-drug conjugate .

53. The method according to one of embodiments 1-52, wherein the duration of response to the antibody-drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months , at least approximately 5 months, at least at

- 53 046283 approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 12 months, according to 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 after administration of the platinum-based antibody-drug conjugate.

54. The method of one of embodiments 1-53, wherein the subject is characterized by the presence of 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.

55. The method of one of embodiments 1-54, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

56. The method of Embodiment 54 or Embodiment 55, wherein one or more of the adverse events are: hemorrhage, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, mucositis, constipation, decreased appetite, diarrhea, vomiting, neutropenia, febrile neutropenia, decreased platelet count, or increased bleeding.

57. The method of embodiment 54 or embodiment 55, wherein the one or more adverse events is a grade 3 or higher adverse event.

58. The method of embodiment 54 or embodiment 55, wherein one or more of the adverse events constitute a serious adverse event.

59. The method of Embodiment 54 or Embodiment 55, wherein one or more of the adverse events is conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricating eye drops, an ophthalmic vasoconstrictor, and/or steroid eye drops.

60. The method according to one of embodiments 1-59, wherein the subject is a human.

61. The method according to one of embodiments 1-60, wherein the antibody-drug conjugate is in a pharmaceutical composition containing the antibody-drug conjugate and a pharmaceutical acceptable carrier.

62. The method according to one of embodiments 1-61, wherein the platinum-based agent is in a pharmaceutical composition containing the platinum-based agent and a pharmaceutical acceptable carrier.

63. Set containing the following:

(a) a dosage ranging from about AUC=4 to about AUC=6 of a platinum-based agent;

(b) a dosage ranging from about 0.9 mg/kg to about 2.1 mg/kg of an antibody-drug conjugate that binds tissue factor (TF), wherein the antibody-drug conjugate contains an anti-TF antibody or an antigen-binding agent thereof fragment conjugated to monomethyl auristatin or a functional analogue or a functional derivative thereof; and (c) instructions for use of the platinum-based agent and the antibody-drug conjugate in accordance with the method of one of embodiments 1-62.

64. The kit according to embodiment 63, wherein the platinum-based agent is carboplatin.

65. The kit according to embodiment 63 or embodiment 64, wherein the antibody-drug conjugate is tizotumab-vedotin.

66. An antibody-drug conjugate that binds to a TF, for use in treating cancer in a subject, wherein the antibody-drug conjugate is intended to be administered or is to be administered in combination with a platinum-based agent, wherein the antibody-drug conjugate comprises an antibody to TF or an antigen-binding fragment thereof, conjugated to monomethyl auristatin or a functional analog or a functional derivative thereof.

67. An antibody-drug conjugate for use according to embodiment 66, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg/kg to about 2.1 mg/kg.

68. An antibody-drug conjugate for use according to embodiment 67, wherein the antibody-drug conjugate is administered at a dose of about 1.3 mg/kg.

69. An antibody-drug conjugate for use according to embodiment 67, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg/kg.

70. An antibody-drug conjugate for use according to embodiment 67, wherein the antibody-drug conjugate is administered at a dose of about 2.0

- 54 046283 mg/kg.

71. An antibody-drug conjugate for use according to embodiment 67, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg/kg.

72. An antibody-drug conjugate for use according to one of embodiments 66-71, wherein the antibody-drug conjugate is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

73. An antibody-drug conjugate for use according to embodiment 72, wherein the antibody-drug conjugate is administered once approximately every 3 weeks.

74. An antibody-drug conjugate for use according to embodiment 72, wherein the antibody-drug conjugate is administered once every 3 weeks.

75. An antibody-drug conjugate for use according to one of embodiments 66-74, wherein the platinum-based agent is administered at a dose of about AUC=4 to about AUC=6.

76. An antibody-drug conjugate for use according to embodiment 75, wherein the platinum-based agent is administered at a dose of about AUC=5.

77. An antibody-drug conjugate for use according to embodiment 75, wherein the platinum-based agent is administered at a dose of AUC=5.

78. An antibody-drug conjugate for use according to one of embodiments 66-77, wherein the platinum-based agent is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks .

79. An antibody-drug conjugate for use according to embodiment 78, wherein the platinum-based agent is administered once approximately every 3 weeks.

80. An antibody-drug conjugate for use in embodiment 78, wherein the platinum-based agent is administered once every 3 weeks.

81. An antibody-drug conjugate for use according to one of embodiments 66-80, wherein the cancer is bladder cancer.

82. An antibody-drug conjugate for use according to one of embodiments 66-80, wherein the cancer is cervical cancer.

83. An antibody-drug conjugate for use according to embodiment 82, wherein the subject is not a candidate for curative treatment.

84. An antibody-drug conjugate for use according to embodiment 83, wherein definitive treatment includes radiation therapy and/or exenteration.

85. An antibody-drug conjugate for use according to embodiment 82, wherein the subject has not received prior systemic therapy for cervical cancer.

86. An antibody-drug conjugate for use according to one of embodiments 82-85, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

87. An antibody-drug conjugate for use according to one of embodiments 82-86, wherein cervical cancer is a common cancer of the cervix.

88. An antibody-drug conjugate for use according to embodiment 87, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

89. An antibody-drug conjugate for use according to embodiment 87 or 88, wherein the advanced cervical cancer is metastatic cervical cancer.

90. An antibody-drug conjugate for use according to one of embodiments 82-89, wherein the cervical cancer is recurrent cervical cancer.

91. An antibody-drug conjugate for use according to one of embodiments 66-90, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

92. An antibody-drug conjugate for use according to one of embodiments 66-91, wherein the anti-TF antibody or antigen-binding fragment of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

93. An antibody-drug conjugate for use according to one of embodiments 66-92, wherein the anti-TF antibody or an antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains the following :

- 55 046283 (i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1;

(ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following:

(i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4;

(ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen binding fragment thereof is defined according to the IMGT numbering system.

94. An antibody-drug conjugate for use according to one of embodiments 66-93, wherein the anti-TF antibody or an antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 85% identical to that of sequence according to SEQ ID NO:7, and a light chain variable region containing an amino acid sequence at least 85% identical to the amino acid sequence according to SEQ ID NO:8.

95. An antibody-drug conjugate for use according to one of embodiments 66-94, wherein the anti-TF antibody or an antigen binding fragment of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a variable a light chain region containing the amino acid sequence of SEQ ID NO:8.

96. An antibody-drug conjugate for use according to one of embodiments 66-95, wherein the antibody to the TF of the antibody-drug conjugate is tizotumab.

97. An antibody-drug conjugate for use according to one of embodiments 66-96, wherein the antibody-drug conjugate further comprises a linker between an anti-TF antibody or an antigen-binding fragment thereof and monomethyl auristatin.

98. An antibody-drug conjugate for use according to embodiment 97, wherein the linker is a cleavable peptide linker.

99. An antibody-drug conjugate for use according to embodiment 98, wherein the cleavable peptide linker is characterized by the formula: -MC-VC-PAB-, wherein:

a) MS is:

b) vc is a valine-citrulline dipeptide, and c) PAB is:

100. An antibody-drug conjugate for use according to one of embodiments 97-99, wherein the linker is attached to sulfhydryl residues of an anti-TF antibody produced by partial reduction or complete reduction of an anti-TF antibody or an antigen-binding fragment thereof.

101. An antibody-drug conjugate for use according to embodiment 100, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the following structure:

where p is a number from 1 to 8, S is a sulfhydryl residue of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof.

102. An antibody-drug conjugate for use according to an embodiment

- 56 046283 leniya 101, with the average p value in the population of antibody-drug conjugates being about 4.

103. An antibody-drug conjugate for use according to one of embodiments 66-102, wherein the antibody-drug conjugate is tizotumab-vedotin.

104. An antibody-drug conjugate for use according to one of embodiments 66-103, wherein the route of administration for the antibody-drug conjugate is intravenous.

105. An antibody-drug conjugate for use according to one of embodiments 66-104, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

106. An antibody-drug conjugate for use in one of embodiments 66-104, wherein the platinum-based agent is carboplatin.

107. An antibody-drug conjugate for use in one of embodiments 66-104, wherein the platinum-based agent is cisplatin.

108. An antibody-drug conjugate for use according to one of embodiments 66-107, wherein the route of administration for the platinum-based agent is intravenous.

109. An antibody-drug conjugate for use according to one of embodiments 66-108, wherein the platinum-based agent and the antibody-drug conjugate are administered sequentially.

110. An antibody-drug conjugate for use according to one of embodiments 66-108, wherein the platinum-based agent and the antibody-drug conjugate are administered simultaneously.

111. An antibody-drug conjugate for use according to one of embodiments 66-110, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, according to 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 at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of cervical cancer cells express TF.

112. An antibody-drug conjugate for use according to one of embodiments 66-111, wherein one or more therapeutic effects in the subject are improved following administration of the platinum-based antibody-drug conjugate relative to a baseline level.

113. An antibody-drug conjugate for use according to embodiment 112, wherein one or more therapeutic effects are selected from the group consisting of the following: tumor size of cervical cancer, objective response rate, duration of response, time to response, survival without progression and overall survival.

114. An antibody-drug conjugate for use according to one of embodiments 66-113, wherein the size of a cervical cancer-derived tumor is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% , at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from cervical cancer, prior to administration of the platinum-based antibody-drug conjugate.

115. An antibody-drug conjugate for use according to one of embodiments 66-114, 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%.

116. An antibody-drug conjugate for use according to one of embodiments 66-115, wherein the subject demonstrates 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 after administration of the antibody-drug conjugate

- 57 046283 means and means based on platinum.

117. An antibody-drug conjugate for use according to one of embodiments 66-116, 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 after administration of the antibody-drug conjugate and platinum-based products.

118. An antibody-drug conjugate for use according to one of embodiments 66-117, wherein the duration of response to the antibody-drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, according to 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 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 after administration of the antibody conjugate with drugs and platinum-based products.

119. An antibody-drug conjugate for use according to one of embodiments 66-118, wherein the subject is characterized by the presence of 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.

120. An antibody-drug conjugate for use in one of embodiments 66-119, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

121. An antibody-drug conjugate for use in Embodiment 119 or Embodiment 120, wherein one or more of the following adverse events are: hemorrhage, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, mucositis, constipation, decreased appetite, diarrhea, vomiting, neutropenia, febrile neutropenia, decreased platelet count or increased bleeding.

122. An antibody-drug conjugate for use in embodiment 119 or embodiment 120, wherein one or more of the adverse events is a grade 3 or higher adverse event.

123. An antibody-drug conjugate for use in embodiment 119 or embodiment 120, wherein one or more of the adverse events constitute a serious adverse event.

124. An antibody-drug conjugate for use in Embodiment 119 or Embodiment 120, wherein one or more of the adverse events is conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricant eye drops, an ophthalmic vasoconstrictor, and/or a steroid. eye drops.

125. An antibody-drug conjugate for use in one of embodiments 66-124, wherein the subject is a human.

126. An antibody-drug conjugate for use according to one of embodiments 66-125, wherein the antibody-drug conjugate is contained in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutical acceptable carrier.

127. An antibody-drug conjugate for use according to one of embodiments 66-126, wherein the platinum-based agent is in a pharmaceutical composition containing the platinum-based agent and a pharmaceutical acceptable carrier.

128. Use of an antibody-drug conjugate that binds to a TF for the production of a drug for the treatment of cancer in a subject, wherein the drug is for use in combination with a platinum-based agent, wherein the antibody-drug conjugate comprises an antibody to the TF or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analogue or functional derivative thereof.

- 58 046283

129. Use according to embodiment 128, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg/kg to about 2.1 mg/kg.

130. Use according to embodiment 129, wherein the antibody-drug conjugate is administered at a dose of about 1.3 mg/kg.

131. Use according to embodiment 129, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg/kg.

132. Use according to embodiment 129, wherein the antibody-drug conjugate is administered at a dose of about 2.0 mg/kg.

133. Use according to embodiment 129, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg/kg.

134. Use according to one of embodiments 128-133, wherein the antibody-drug conjugate is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

135. Use according to embodiment 134, wherein the antibody-drug conjugate is administered once approximately every 3 weeks.

136. Use according to embodiment 134, wherein the antibody-drug conjugate is administered once every 3 weeks.

137. Use according to one of embodiments 128-136, wherein the platinum-based agent is administered at a dose of about AUC=4 to about AUC=6.

138. Use according to embodiment 137, wherein the platinum-based agent is administered at a dose of about AUC=5.

139. Use according to embodiment 137, wherein the platinum-based agent is administered at a dose of AUC=5.

140. Use according to one of embodiments 128-139, wherein the platinum-based agent is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

141. Use according to embodiment 140, wherein the platinum-based agent is administered once approximately every 3 weeks.

142. Use according to embodiment 140, wherein the platinum-based agent is administered once every 3 weeks.

143. Use according to one of embodiments 128-142, wherein the cancer is bladder cancer.

144. Use according to one of embodiments 128-142, wherein the cancer is cervical cancer.

145. Use according to embodiment 144, wherein the subject is not a candidate for radical treatment.

146. Use according to embodiment 145, wherein the definitive treatment includes radiation therapy and/or exenteration.

147. Use according to embodiment 144, wherein the subject has not received prior systemic therapy for cervical cancer.

148. Use according to one of embodiments 144-147, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

149. Use according to one of embodiments 144-148, wherein the cervical cancer is advanced cervical cancer.

150. Use according to embodiment 149, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

151. Use according to embodiment 149 or 150, wherein the advanced cervical cancer is metastatic cervical cancer.

152. Use according to one of embodiments 144-151, wherein the cervical cancer is recurrent cervical cancer.

153. Use according to one of embodiments 128-152, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

154. Use according to one of embodiments 128-153, wherein the anti-TF antibody or antibody-drug conjugate antigen binding fragment thereof is a monoclonal antibody or monoclonal antigen binding fragment thereof.

155. Use according to one of embodiments 128-154, wherein the anti-TF antibody or an antibody-drug conjugate antigen binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following:

(i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1;

- 59 046283 (ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following:

(i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4;

(ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen binding fragment thereof is defined according to the IMGT numbering system.

156. Use according to one of embodiments 128-155, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO:8.

157. Use according to one of embodiments 128-156, wherein the anti-TF antibody or an antibody-drug conjugate antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence according to SEQ ID NO:8.

158. Use according to one of embodiments 128-157, wherein the anti-TF antibody of the antibody-drug conjugate is tizotumab.

159. Use according to one of embodiments 128-158, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen binding fragment thereof and monomethyl auristatin.

160. Use according to embodiment 159, wherein the linker is a cleavable peptide linker.

161. Use according to embodiment 160, wherein the cleavable peptide linker is characterized by the formula: -MC-vc-PAB-, where:

a) MS is:

b) vc is a valine-citrulline dipeptide, and c) PAB is:

162. Use according to one of embodiments 159-161, wherein the linker is attached to the sulfhydryl residues of an anti-TF antibody obtained by partial reduction or complete reduction of an anti-TF antibody or an antigen-binding fragment thereof.

163. Use according to embodiment 162, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the following structure:

where p is a number from 1 to 8, S is a sulfhydryl residue of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof.

164. Use according to embodiment 163, wherein the average p value in the population of antibody-drug conjugates is about 4.

165. Use according to one of embodiments 128-164, wherein the antibody-drug conjugate is tizotumab-vedotin.

166. Use according to one of embodiments 128-165, wherein the route of administration for the antibody-drug conjugate is intravenous.

- 60 046283

167. Use according to one of embodiments 128-166, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin and nedaplatin.

168. Use according to one of embodiments 128-166, wherein the platinum-based agent is carboplatin.

169. Use according to one of embodiments 128-166, wherein the platinum-based agent is cisplatin.

170 Use according to one embodiment 128-169, wherein the route of administration for the platinum-based agent is intravenous.

171. Use according to one of embodiments 128-170, wherein the platinum-based agent and the antibody-drug conjugate are administered sequentially.

172. Use according to one of embodiments 128-170, wherein the platinum-based agent and the antibody-drug conjugate are administered simultaneously.

173. Use according to one of embodiments 128-172, 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%, according to at least about 60%, at least about 70%, or at least about 80% of cervical cancer cells express TF.

174. Use according to one of embodiments 128-173, wherein one or more therapeutic effects in the subject are improved following administration of the platinum-based antibody-drug conjugate relative to baseline.

175. Use according to embodiment 174, wherein the one or more therapeutic effects are selected from the group consisting of the following: tumor size derived from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

176. Use according to one of embodiments 128-175, wherein the size of a tumor originating from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least 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 about 60%, at least about 70%, or at least about 80% relative to the size of the tumor originating from cervical cancer, prior to administration of the platinum-based antibody-drug conjugate.

177. Use according to one of embodiments 128-176, 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%.

178. Use according to one of embodiments 128-177, wherein the subject demonstrates 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 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 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 after administration of the antibody-drug conjugate and drug-based platinum.

179. Use according to one of embodiments 128-178, wherein the subject demonstrates 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 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 after administration of the platinum-based antibody-drug conjugate .

180. Use according to one of embodiments 128-179, wherein the duration of response to the antibody-drug conjugate is at least approximately

- 61 046283 significant 1 month, at least approximately 2 months, at least approximately 3 months, at least approximately 4 months, at least approximately 5 months, at least approximately 6 months, at least approximately 7 months, according to 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 at least about three years, at least about four years, or at least about five years after administration of the platinum-based antibody-drug conjugate.

181. Use according to one of embodiments 128-180, wherein the subject is characterized by the presence of one or more adverse events, and is further administered an additional therapeutic agent to eliminate or reduce the severity of one or more adverse events.

182. Use according to one of embodiments 128-181, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

183. Use according to embodiment 181 or embodiment 182, wherein one or more of the adverse events is the following: hemorrhage, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, mucositis, constipation, decreased appetite, diarrhea, vomiting, neutropenia, febrile neutropenia, decreased platelet count, or increased bleeding.

184. Use according to embodiment 181 or embodiment 182, wherein one or more of the adverse events is a grade 3 or higher adverse event.

185. Use according to embodiment 181 or embodiment 182, wherein one or more of the adverse events constitute a serious adverse event.

186. Use according to embodiment 181 or embodiment 182, wherein one or more of the adverse events is conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricant eye drops, an ophthalmic vasoconstrictor, and/or steroid eye drops.

187. Use according to one of embodiments 128-186, wherein the subject is a human.

188. Use according to one of embodiments 128-187, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutical acceptable carrier.

189. Use according to one of embodiments 128-188, wherein the platinum-based agent is in a pharmaceutical composition containing the platinum-based agent and a pharmaceutically acceptable carrier.

190. A platinum-based agent for use in treating cancer in a subject, wherein the platinum-based agent is intended to be administered or is to be administered in combination with an antibody-drug conjugate that binds to TF, wherein the antibody-drug conjugate comprises an antibody to TF or an antigen-binding fragment thereof, conjugated to monomethyl auristatin or a functional analog or functional derivative thereof.

191. A platinum-based agent for use in embodiment 190, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg/kg to about 2.1 mg/kg.

192. A platinum-based agent for use in embodiment 191, wherein the antibody-drug conjugate is administered at a dose of about 1.3 mg/kg.

193. A platinum-based agent for use in embodiment 191, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg/kg.

194. A platinum-based agent for use in embodiment 191, wherein the antibody-drug conjugate is administered at a dose of about 2.0 mg/kg.

195. A platinum-based agent for use according to embodiment 191, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg/kg.

196. A platinum-based agent for use according to one of embodiments 190-195, wherein the antibody-drug conjugate is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks .

197. A platinum-based agent for use in embodiment 196, wherein the antibody-drug conjugate is administered once approximately every 3 weeks.

198. A platinum-based agent for use according to embodiment 196, wherein

- 62 046283 antibody-drug conjugate is administered once every 3 weeks.

199. A platinum-based agent for use according to one of embodiments 190-198, wherein the platinum-based agent is administered at a dose of about AUC=4 to about AUC=6.

200. A platinum-based agent for use according to embodiment 199, wherein the platinum-based agent is administered at a dose of about AUC=5.

201. A platinum-based agent for use according to embodiment 199, wherein the platinum-based agent is administered at a dose of AUC=5.

202. A platinum-based agent for use according to one of embodiments 190-201, wherein the platinum-based agent is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

203. A platinum-based agent for use according to embodiment 202, wherein the platinum-based agent is administered once approximately every 3 weeks.

204. A platinum-based agent for use according to embodiment 202, wherein the platinum-based agent is administered once every 3 weeks.

205. A platinum-based agent for use according to one of embodiments 190-204, wherein the cancer is bladder cancer.

206. A platinum-based agent for use according to one of embodiments 190-204, wherein the cancer is cervical cancer.

207. A platinum-based agent for use according to embodiment 206, wherein the subject is not a candidate for radical treatment.

208. A platinum-based agent for use according to embodiment 207, wherein definitive treatment includes radiation therapy and/or exenteration.

209. The platinum-based agent for use according to embodiment 206, wherein the subject has not received prior systemic therapy for cervical cancer.

210. A platinum-based agent for use according to one of embodiments 206-209, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

211. A platinum-based agent for use according to one of embodiments 206-210, wherein cervical cancer is a common cancer of the cervix.

212. The platinum-based agent for use according to embodiment 211, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

213. A platinum-based agent for use according to embodiment 211 or 212, wherein the advanced cervical cancer is metastatic cervical cancer.

214. A platinum-based agent for use according to one of embodiments 206-213, wherein the cervical cancer is recurrent cervical cancer.

215. A platinum-based agent for use according to one of embodiments 190-214, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

216. The platinum-based agent for use according to one of embodiments 190-215, wherein the anti-TF antibody or an antigen-binding fragment of an antibody-drug conjugate thereof is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

217. A platinum-based agent for use according to one of embodiments 190-216, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following:

(i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1;

(ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following:

(i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4;

(ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen binding fragment thereof is defined according to the IMGT numbering system.

218. A platinum-based agent for use according to one of embodiments 190-217, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence according to SEQ ID NO:7, and a light chain variable region containing an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:8.

219. Platinum-based agent for use according to one embodiment

- 63 046283

190-218, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:8.

220. A platinum-based agent for use in one of embodiments 190-219, wherein the anti-TF antibody of the antibody-drug conjugate is tizotumab.

221. A platinum-based agent for use according to one of embodiments 190-220, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and monomethyl auristatin.

222. A platinum-based agent for use according to embodiment 221, wherein the linker is a cleavable peptide linker.

223. A platinum-based agent for use according to embodiment 222, wherein the cleavable peptide linker is characterized by the formula: -MC-vc-PAB-, where:

a) MS is:

b) vc is a valine-citrulline dipeptide, and c) PAB is:

224. A platinum-based agent for use according to one of embodiments 221-223, wherein the linker is attached to sulfhydryl residues of an anti-TF antibody obtained by partial reduction or complete reduction of an anti-TF antibody or an antigen-binding fragment thereof.

225. A platinum-based agent for use according to embodiment 224, wherein the linker is attached to MMAE), wherein the antibody-drug conjugate has the following structure:

Ab-MC-vc-AB-MMAE where p is a number from 1 to 8, S is a sulfhydryl residue of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof.

226. A platinum-based agent for use in embodiment 225, wherein the average p-value in the population of antibody-drug conjugates is about 4.

227. A platinum-based agent for use according to one of embodiments 190-226, wherein the antibody-drug conjugate is tizotumab-vedotin.

228. A platinum-based agent for use according to one of embodiments 190-227, wherein the route of administration for the antibody-drug conjugate is intravenous.

229. A platinum-based agent for use according to one of embodiments 190-228, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

230. A platinum-based agent for use according to one of embodiments 190-228, wherein the platinum-based agent is carboplatin.

231. A platinum-based agent for use according to one of embodiments 190-228, wherein the platinum-based agent is cisplatin.

232. A platinum-based agent for use according to one of embodiments 190-231, wherein the route of administration for the platinum-based agent is intravenous.

233. A platinum-based agent for use according to one of embodiments 190-232, wherein the platinum-based agent and the antibody-drug conjugate are administered

- 64 046283 sequentially.

234. A platinum-based agent for use according to one of embodiments 190-232, wherein the platinum-based agent and the antibody-drug conjugate are administered simultaneously.

235. A platinum-based agent for use according to one of embodiments 190-234, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of cervical cancer cells express TF.

236. A platinum-based agent for use according to one of embodiments 190-235, wherein one or more therapeutic effects in the subject are improved following administration of the antibody-drug conjugate and the platinum-based agent relative to a baseline level.

237. A platinum-based agent for use according to embodiment 236, wherein the one or more therapeutic effects are selected from the group consisting of the following: size of tumor originating from cervical cancer, objective response rate, duration of response, time to response, progression-free survival and overall survival.

238. A platinum-based agent for use according to one of embodiments 190-237, wherein the size of a tumor derived from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20 %, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, by at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from cervical cancer, prior to administration of the platinum-based antibody-drug conjugate.

239. A platinum-based agent for use according to one of embodiments 190-238, 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%.

240. A platinum-based agent for use according to one of embodiments 190-239, wherein the subject demonstrates 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 after administration of the antibody-drug conjugate and platinum-based products.

241. A platinum-based agent for use in one of embodiments 190-240, 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 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 after administration of the antibody-drug conjugate and platinum-based products.

242. A platinum-based agent for use according to one of embodiments 190-241, wherein the duration of response to the antibody-drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least 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 approximately 11 months, at least approx.

- 65 046283 specifically 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 after administration of the antibody-drug conjugate and drug platinum based.

243. A platinum-based agent for use according to one of embodiments 190-242, wherein the subject is characterized by the presence of 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.

244. A platinum-based agent for use in one of embodiments 190-243, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

245. A platinum-based agent for use according to embodiment 243 or embodiment 244, wherein one or more of the adverse events is the following: hemorrhage, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, mucositis, constipation, decreased appetite, diarrhea, vomiting , neutropenia, febrile neutropenia, decreased platelet count or increased bleeding.

246. A platinum-based agent for use in embodiment 243 or embodiment 244, wherein one or more of the adverse events is a grade 3 or higher adverse event.

247. A platinum-based agent for use according to embodiment 243 or embodiment 244, wherein one or more of the adverse events constitute a serious adverse event.

248. A platinum-based agent for use in embodiment 243 or embodiment 244, wherein one or more of the adverse events is conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricant eye drops, an ophthalmic vasoconstrictor, and/or steroid ophthalmic agents. drops.

249. A platinum-based agent for use according to one of embodiments 190-248, wherein the subject is a human.

250. A platinum-based agent for use according to one of embodiments 190-249, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutical acceptable carrier.

251. A platinum-based agent for use according to one of embodiments 190-250, wherein the platinum-based agent is in a pharmaceutical composition containing the platinum-based agent and a pharmaceutically acceptable carrier.

252. Use of a platinum-based agent for the production of a medicament for the treatment of cancer in a subject, wherein the medicament is for use in combination with an antibody-drug conjugate that binds to a TF, wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding agent thereof fragment conjugated to monomethyl auristatin or a functional analogue or a functional derivative thereof.

253. Use according to embodiment 252, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg/kg to about 2.1 mg/kg.

254. Use according to embodiment 253, wherein the antibody-drug conjugate is administered at a dose of about 1.3 mg/kg.

255. Use according to embodiment 253, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg/kg.

256. Use according to embodiment 253, wherein the antibody-drug conjugate is administered at a dose of about 2.0 mg/kg.

257. Use according to embodiment 253, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg/kg.

258. Use according to one of embodiments 252-257, wherein the antibody-drug conjugate is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

259. Use according to embodiment 258, wherein the antibody-drug conjugate is administered once approximately every 3 weeks.

260. Use according to embodiment 258, wherein the antibody-drug conjugate is administered once every 3 weeks.

261. Use according to one of embodiments 252-260, wherein the platinum-based agent is administered at a dose of about AUC=4 to about AUC=6.

- 66 046283

262. Use according to embodiment 261, wherein the platinum-based agent is administered at a dose of about AUC=5.

263. Use according to embodiment 261, wherein the platinum-based agent is administered at a dose of AUC=5.

264. Use according to one of embodiments 252-263, wherein the platinum-based agent is administered once about every week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

265. Use according to embodiment 264, wherein the platinum-based agent is administered once approximately every 3 weeks.

266. Use according to embodiment 264, wherein the platinum-based agent is administered once every 3 weeks.

267. Use according to one of embodiments 252-266, wherein the cancer is bladder cancer.

268. Use according to one of embodiments 252-266, wherein the cancer is cervical cancer.

269. Use according to embodiment 268, wherein the subject is not a candidate for radical treatment.

270. Use according to embodiment 269, wherein the definitive treatment includes radiation therapy and/or exenteration.

271. Use according to embodiment 268, wherein the subject has not received prior systemic therapy for cervical cancer.

272. Use according to one of embodiments 268-271, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

273. Use according to one of embodiments 268-272, wherein cervical cancer is advanced cervical cancer.

274. Use according to embodiment 273, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer.

275. Use according to embodiment 273 or 274, wherein the advanced cervical cancer is metastatic cervical cancer.

276. Use according to one of embodiments 268-275, wherein the cervical cancer is recurrent cervical cancer.

277. Use according to one of embodiments 252-276, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

278. Use according to one of embodiments 252-277, wherein the anti-TF antibody or antibody-drug conjugate antigen binding fragment thereof is a monoclonal antibody or monoclonal antigen binding fragment thereof.

279. Use according to one of embodiments 252-278, wherein the anti-TF antibody or an antibody-drug conjugate antigen binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following:

(i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1;

(ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following:

(i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4;

(ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen binding fragment thereof is defined according to the IMGT numbering system.

280. Use according to one of embodiments 252-279, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO:8.

281. Use according to one of embodiments 252-280, wherein the anti-TF antibody or an antibody-drug conjugate antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence according to SEQ ID NO:8.

282. Use according to one of embodiments 252-281, wherein the anti-TF antibody

- 67 046283 antibody drug conjugate is tizotumab.

283. Use according to one of embodiments 252-282, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and monomethyl auristatin.

284. Use according to embodiment 283, wherein the linker is a cleavable peptide linker.

285. Use according to embodiment 284, wherein the cleavable peptide linker is characterized by the formula: -MC-vc-PAB-, where:

a) MS is:

b) vc is a valine-citrulline dipeptide, and c) PAB is:

ABOUT

286. Use according to one of embodiments 283-285, wherein the linker is attached to the sulfhydryl residues of an anti-TF antibody obtained by partial reduction or complete reduction of an anti-TF antibody or an antigen-binding fragment thereof.

287. Use according to embodiment 286, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the following structure:

Ab-MC-vc-AB-MMAE where p is a number from 1 to 8, S is a sulfhydryl residue of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof.

288. Use according to embodiment 287, wherein the average p value in the population of antibody-drug conjugates is about 4.

289. Use according to one of embodiments 252-288, wherein the antibody-drug conjugate is tizotumab-vedotin.

290. Use according to one of embodiments 252-289, wherein the route of administration for the antibody-drug conjugate is intravenous.

291. Use according to one of embodiments 252-290, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin and nedaplatin.

292. Use according to one of embodiments 252-290, wherein the platinum-based agent is carboplatin.

293. Use according to one of embodiments 252-290, wherein the platinum-based agent is cisplatin.

294. Use according to one of embodiments 252-293, wherein the route of administration for the platinum-based agent is intravenous.

295. Use according to one of embodiments 252-294, wherein the platinum-based agent and the antibody-drug conjugate are administered sequentially.

296. Use according to one of embodiments 252-294, wherein the platinum-based agent and the antibody-drug conjugate are administered simultaneously.

297. Use according to one of embodiments 252-296, 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%, according to at least about 60%, at least about 70%, or at least about

- 68 046283

80% of cervical cancer cells express TF.

298. Use according to one of embodiments 252-297, wherein one or more therapeutic effects in the subject are improved following administration of the platinum-based antibody-drug conjugate relative to baseline.

299. Use according to embodiment 298, wherein the one or more therapeutic effects are selected from the group consisting of the following: tumor size derived from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

300. Use according to one of embodiments 252-299, wherein the size of a tumor originating from cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least 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 about 60%, at least about 70%, or at least about 80% relative to the size of the tumor originating from cervical cancer, prior to administration of the platinum-based antibody-drug conjugate.

301. Use according to one of embodiments 252-300, 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%.

302. Use according to one of embodiments 252-301, wherein the subject demonstrates 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 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 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 after administration of the antibody-drug conjugate and drug-based platinum.

303. Use according to one of embodiments 252-302, wherein the subject demonstrates 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 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 after administration of the platinum-based antibody-drug conjugate .

304. Use according to one of embodiments 252-303, wherein the duration of response to the antibody-drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months , at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the antibody-drug conjugate and drug platinum based.

305. Use according to one of embodiments 252-304, wherein the subject is characterized by the presence of one or more adverse events, and is further administered an additional therapeutic agent to eliminate or reduce the severity of one or more adverse events.

306. Use according to one of embodiments 252-305, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

307. Use according to embodiment 305 or embodiment 306, wherein one or more of the adverse events is the following: hemorrhage, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, mucositis, constipation, decreased appetite, dia

- 69 046283 rhea, vomiting, neutropenia, febrile neutropenia, decreased platelet count or increased bleeding.

308. Use according to embodiment 305 or embodiment 306, wherein one or more of the adverse events is a grade 3 or higher adverse event.

309. Use according to embodiment 305 or embodiment 306, wherein one or more of the adverse events constitute a serious adverse event.

310. Use according to embodiment 305 or embodiment 306, wherein one or more of the adverse events is conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricant eye drops, an ophthalmic vasoconstrictor, and/or steroid eye drops.

311. Use according to one of embodiments 252-310, wherein the subject is a human.

312. Use according to one of embodiments 252-311, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutical acceptable carrier.

313. Use according to one of embodiments 252-311, wherein the platinum-based agent is in a pharmaceutical composition containing the platinum-based agent and a pharmaceutical acceptable carrier.

The present invention will be understood more fully with reference to the following examples. However, they should not be construed as limiting the scope of the present invention. It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and should be included within the spirit and scope of this application and the scope of the appended claims. inventions.

Examples

Example 1: Antitumor activity of tizotumab-vedotin in combination with a platinum-based agent in a mouse model of cervical cancer

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

Cisplatin, a platinum-based agent, is used in combination with paclitaxel, a microtubule inhibitor, as a standard treatment option for the treatment of stage IVB, recurrent or persistent cervical carcinoma. See Kitagawa R et al., J Clin Oncol., 33:2129-2135, 2015. The combination of tizotumab-vedotin with a platinum-based agent such as cisplatin was evaluated herein for the treatment of cervical cancer.

Materials and methods

The in vivo antitumor efficacy of tizotumab-vedotin in combination with cisplatin was assessed in a patient-derived xenograft (PDX) mouse model of BALB/c nude mice (Crown Bioscience Inc.).

Xenografts were obtained from tumor samples from patients with cancer. Establishment and characterization of the PDX model was performed after primary implantation in nude mice. Tumor xenografts were passaged approximately three to five times until a stable growth pattern was established. Tumor fragments were obtained from xenografts through serial passage in nude mice. Tumors were cut into 2–3 mm diameter fragments and placed in phosphate buffered saline (PBS) prior to subcutaneous implantation. A PDX model of cervical cancer (HuPrime® CV1248 [R4P5] cervical xenograft model; Crown Bioscience Inc.) was used in this experiment. Tumor size was determined with calipers at least twice a week, and tumor volume was calculated as 0.5 x length x width ² . When tumors reached a volume of 200 mm ³ , mice were randomly divided into 11 groups (7-8 mice per treatment group). Mice were given the following intravenous injections: 1) tizotumab-vedotin alone at dose levels of 0.5 mg/kg, 1 mg/kg, 2 mg/kg, or 4 mg/kg administered on day 0 and day 7 of treatment; 2) cisplatin alone at a dose of 4 mg/kg administered on day 0, day 7 and day 14 of treatment; 3) tizotumab-vedotin at dose levels of 0.5 mg/kg, 1 mg/kg, 2 mg/kg or 4 mg/kg, administered on day 0 and day 7 of treatment in combination with cisplatin at a dose of 4 mg /kg administered on day 0, day 7 and day 14 of treatment; 4) isotype control IgG1 at a dose of 4 mg/kg administered on day 0 and day 7 of treatment; or 5) con

- 70 046283 troll IgG1-MMAE at a dose of 4 mg/kg, administered on day 0 and day 7 of treatment. The mice were monitored for clinical signs of disease. Mice were housed in individually ventilated cages (IVC), with four or five mice per cage, and identified using ear tags.

To determine whether statistically significant differences were observed between tumor volumes in the control and treatment groups, tumor volumes in the treatment groups were compared with those in the control group (eg, treatment groups versus IgG1-MMAE control) using Mann-Whitney analysis in the latter the day when all groups were intact, i.e. on the 38th day. For survival analysis (threshold tumor volume was 1000 mm ³ ). Cox-Mantel analysis was performed on Kaplan-Meier plots with a threshold set at tumor volume >1000 mm ³ .

results

Treatment with tizotumab-vedotin alone effectively inhibited tumor growth (Figures 1A-C) and prolonged survival (Figures 1D and 1E) in a mouse model of cervical cancer at both 2 mg/kg and 4 mg doses. /kg. kg. Treatment with cisplatin alone also inhibited tumor growth (Figures 1A-C) and prolonged survival (Figures 1D and 1E). Treatment with 2 mg/kg or 4 mg/kg tizotumab-vedotin in combination with cisplatin enhanced antitumor activity compared with tizotumab-vedotin alone or cisplatin alone (Fig. 1A-E).

Table A Statistical analysis

Mann-Whitney test Day 38 p-value Criterion Cox- Mantel p-value Tizotumab-vedotin, 4 mg/kg versus IgGl-MMAE, 4 mg/kg <0.001 0.000 Tizotumab-vedotin, 2 mg/kg versus IgGl-MMAE, 4 mg/kg <0.001 0.000 Cisplatin, 4 mg/kg versus IgGl-MMAE, 4 mg/kg <0.05 0.008 Tizotumab-vedotin 4 mg/kg + cisplatin 4 mg/kg versus tizotumab-vedotin 4 mg/kg <0.01 0.001 Tizotumab-vedotin, 4 mg/kg + cisplatin, 4 mg/kg versus cisplatin, 4 mg/kg <0.001 0.000 Tizotumab-vedotin 2 mg/kg + cisplatin 4 mg/kg versus tizotumab-vedotin 2 mg/kg <0.01 0.007 Tizotumab-vedotin, 2 mg/kg + cisplatin, 4 mg/kg versus cisplatin, 4 mg/kg <0.001 0.000

Example 2: Antitumor activity of tizotumab-vedotin in combination with a platinum-based agent in a mouse model of bladder cancer

The combination of tizotumab-vedotin with a platinum-based agent such as cisplatin was evaluated herein for the treatment of bladder cancer.

Materials and methods

The in vivo antitumor efficacy of tizotumab-vedotin in combination with cisplatin was assessed in a PDX mouse model in female nude Crl:NMRI-Foxnl ^nu mice (Envigo RMS SARL, France) (Charles River Discovery Research Services). Xenografts were obtained from tumor samples from patients with cancer. Establishment and characterization of the PDX model was performed after primary implantation in nude mice. Tumor xenografts were passaged approximately three to five times until a stable growth pattern was established. Tumor fragments were obtained from xenografts through serial passage in nude mice. Tumors were cut into 2–3 mm diameter fragments and placed in phosphate buffered saline (PBS) prior to subcutaneous implantation. A PDX model of bladder cancer (bladder xenograft model BXF1036; Charles River Discovery Research Services) was used in this experiment. Tumor size was determined with calipers at least twice a week, and tumor volume was calculated as 0.52 x length x width ² . When the tumors reached a volume of 50-250 mm ³ , the mice were randomly divided into 5 groups. Mice were treated as follows: 1) tizotumab-vedotin alone at a dose level of 0.5 mg/kg administered on day 1 of treatment; 2) cisplatin separately at a dose of 2 mg/kg, administered

- 71 046283 washed on day 1 and day 8 of treatment; 3) tizotumab-vedotin at a dose level of 0.5 mg/kg administered on day 1 of treatment in combination with cisplatin at a dose of 2 mg/kg administered on day 1 and day 8 of treatment; 4) isotype control IgG1 at a dose of 0.5 mg/kg administered on day 1 of treatment; or 5) IgG1-MMAE control at a dose of 0.5 mg/kg administered on day 1 of treatment. Each of the following: IgG1 isotype control, IgG1-MMAE control, and tizotumab-vedotin were in PBS and administered intravenously. Cisplatin was in 0.9% NaCl and was administered subcutaneously. The mice were monitored for clinical signs of disease. Mice were housed in individually ventilated cages (IVC) with a maximum of five mice per cage and identified using ear tags.

To determine whether statistically significant differences were observed between tumor volumes in the control and treatment groups, tumor volumes in the treatment groups were compared with those in the control groups (eg, IG-MMAE control, tizotumab-vedotin alone, or cisplatin alone) using Mann analysis. -Whitney on the last day when all groups were intact, i.e. day 25. Statistical analysis of the difference between the groups receiving tizotumab-vedotin in combination with cisplatin and the groups receiving either tizotumab-vedotin alone or cisplatin alone was performed on day 32.

Tumor progression was plotted on a Kaplan-Meier plot, with a threshold set at tumor volume >500 mm ³ . Kaplan-Meier curves for mice that were treated with tizotumab-vedotin in combination with cisplatin were compared with mice that were treated with IG-MMAE control, tizotumab-vedotin alone, or cisplatin alone using Cox-Mantel analysis on Kaplan plots -Meyer.

results

Treatment with tizotumab-vedotin alone effectively inhibited tumor growth (Fig. 2A-C) and prolonged survival (Fig. 2D) in a PDX model of bladder cancer. Treatment with cisplatin alone (Fig. 2A-C) also inhibited tumor growth and prolonged survival (Fig. 2D). Treatment with tizotumab-vedotin in combination with cisplatin enhanced antitumor activity in a PDX model of bladder cancer compared with tizotumab-vedotin alone or cisplatin alone (Fig. 2A-D). The results of statistical analyzes are shown in table. IN.

Table B

Statistical analysis

Criterion Manna-Whitney p-value Criterion Cox-Mantel p-value Mann-Whitney test, day 25 Tizotumab-vedotin (0.5 mg/kg) versus IgGl- MMAE (0.5 mg/kg) <0.001 <0.0001 Cisplatin (2 mg/kg) versus IgGl-MMAE (0.5 mg/kg) <0.0001 <0.01 Tizotumab-vedotin + cisplatin versus IgGl- MMAE <0.0001 <0.0001 Mann-Whitney test, day 32 Tizotumab-vedotin + cisplatin versus tizotumab-vedotin 0.0089 0.011 Tizotumab-vedotin + cisplatin versus cisplatin <0.001 <0.0001

Example 3: Antitumor activity of tizotumab-vedotin in combination with a platinum-based agent in a mouse model of cervical cancer

The combination of tizotumab-vedotin with a platinum-based agent such as carboplatin was evaluated herein for the treatment of cervical cancer.

Materials and methods

The in vivo antitumor efficacy of tizotumab-vedotin in combination with carboplatin was assessed in a patient-derived xenograft (PDX) mouse model of BALB/c nude mice (Crown Bioscience [Taicang] Inc.). Xenografts were obtained from tumor samples from patients with cancer. Establishment and characterization of the PDX model was performed after primary implantation in nude mice. Tumor fragments were obtained from xenografts through serial passage in nude mice. Tumors were cut into fragments with a diameter of 2-4 mm and placed in a fi

- 72 046283 physiological solution with phosphate buffer (PBS) before subcutaneous implantation. A PDX model of cervical cancer (HuPrime® CV1248 cervical xenograft model [P3]; Crown Bioscience Inc.) was used in this experiment. Tumor size was determined with calipers at least twice a week, and tumor volume was calculated as 0.5 x length x width ² . When tumors reached a volume of 150 mm ³ , mice were randomly divided into 7 groups (10 mice per treatment group). The day of randomization was designated day 0. Mice were given the following intravenous injections: 1) tizotumabvedotin alone at a dose level of 2 mg/kg administered on day 0, day 7, and day 14; 2) carboplatin (Selleck Chemicals, cat. no. S121511) alone at a dose of 40 mg/kg or 80 mg/kg administered on day 0, day 7 and day 14; 3) tizotumab-vedotin at a dose level of 2 mg/kg administered on day 0, day 7 and day 14 in combination with carboplatin at a dose of 40 mg/kg or 80 mg/kg administered on day 0, day 7 and day 14; 4) isotype control IgG1 at a dose of 2 mg/kg administered on day 0, day 7 and day 14; or 5) IgG1-MMAE control at a dose of 2 mg/kg administered on day 0, day 7, and day 14. Mice were monitored for clinical signs of disease. Mice were housed in individually ventilated cages (IVC) with a maximum of five mice per cage and identified using ear tags. To determine whether statistically significant differences were observed between tumor volumes in the control and treatment groups, tumor volumes in the treatment groups were compared with those in the control groups (eg, treatment groups versus IgG1-MMAE control) and combination treatment groups were compared with those in the control groups. treated with either compound alone using Mann-Whitney analysis on the last day when all groups were intact, i.e. day 20. Cox-Mantel analysis was performed on Kaplan-Meier plots to analyze progression-free survival time (tumor size cutoff 750 mm ³ ).

Treatment with 2 mg/kg tizotumab-vedotin alone effectively inhibited tumor growth (Figures 3A and 3B) in a PDX mouse model of cervical cancer. Treatment with carboplatin alone at a dose of 40 or 80 mg/kg did not inhibit tumor growth (Figures 3A and 3B). Treatment with 2 mg/kg tizotumab-vedotin in combination with 40 mg/kg carboplatin effectively enhanced antitumor activity compared with carboplatin alone (Figures 3A and 3B). The combination of 2 mg/kg tizotumab-vedotin and 80 mg/kg carboplatin effectively enhanced antitumor activity compared with carboplatin alone or tizotumab-vedotin alone. All combinations increased progression-free survival time (tumor size cutoff 750 mm ³ ) compared with the agents alone (Figure 3C). The results of statistical analyzes are shown in table. WITH.

Table C

Statistical analysis

Average tumor volume Percentage of mice with tumor volume <750 ^mm3 Mann criterion Whitney day 20 P-value Criterion Cox- Mantela P-value Tizotumab-vedotin versus IgGl-MMAE 0.0068 0.171 Carboplatin, 40 mg/kg versus IgGl-MMAE 0.5787 0.340 Carboplatin, 80 mg/kg versus IgGl-MMAE 0.1716 0.900 Tizotumab-vedotin + carboplatin, 40 mg/kg versus IgGl-MMAE <0.0001 0.019

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Tizotumab-vedotin + carboplatin, 80 mg/kg versus IgGl-MMAE <0.0001 0.003 Tizotumab-vedotin + carboplatin, 40 mg/kg versus tizotumab-vedotin 0.0524 0.029 Tizotumab-vedotin + carboplatin, 40 mg/kg versus carboplatin, 40 mg/kg <0.0001 0.000 Tizotumab-vedotin + carboplatin, 80 mg/kg versus tizotumab-vedotin 0.0011 0.000 Tizotumab-vedotin + carboplatin, 80 mg/kg versus carboplatin, 80 mg/kg <0.0001 0.000

Example 4: Antitumor activity of tizotumab-vedotin in combination with carboplatin in a xenograft mouse model of cervical cancer

The combination of tizotumab-vedotin with the platinum-based agent carboplatin was evaluated herein for the treatment of cervical cancer.

Materials and methods

The in vivo antitumor efficacy of tizotumab-vedotin in combination with carboplatin was assessed in a patient-derived xenograft (PDX) mouse model of NMRI nu/nu nude mice (model CEXF633). Xenografts were obtained from tumor samples from patients with cancer. Establishment and characterization of the PDX model was performed after primary implantation in nude mice. Tumor xenografts were passaged approximately three to five times until a stable growth pattern was established. Tumor fragments were obtained from xenografts through serial passage in nude mice. Tumors were cut into 3–4 mm diameter fragments and placed in phosphate buffered saline (PBS) prior to subcutaneous implantation. Tumor size was determined with calipers at least twice a week, and tumor volume was calculated as 0.5 x length x width ² . When tumors reached a volume of 50-250 mm ³ , mice were randomly divided into 7 groups of 10 mice per treatment group. Mice were treated with the following, all doses administered once a week for 4 weeks (QWx4): 1) tizotumab-vedotin alone at a dose of 2 mg/kg (intravenous); 2) carboplatin alone at a dose of 40 mg/kg (intraperitoneal); 3) tizotumab-vedotin at a dose of 2 mg/kg (intravenous) in combination with carboplatin at a dose of 40 mg/kg (intraperitoneal); 4) isotype control IgG1 at a dose of 2 mg/kg (intravenous); or 5) IgG1-MMAE control at a dose of 2 mg/kg (intravenous). The mean tumor volume was plotted against treatment group (Fig. 4A). To determine whether statistically significant differences were observed between tumor volumes in the control and treatment groups, tumor volumes in the treatment groups were compared using Mann-Whitney analysis on the final day when all groups were intact (Table D). Combination treatment with tizotumab-vedotin and carboplatin was significantly more effective than the single agent treatment groups in both models, as evidenced by a significant reduction in tumor size in mice that received the combination treatment. Analysis of progression-free survival (using a tumor size cutoff of 750 mm ³ ) demonstrated prolonged progression-free survival of the combination group compared with treatment with the agent alone (Cox-Mantel analysis; Fig. 4B; Table D).

Table D

Statistical analysis

Treatment groups compared Analysis day Volume tumors Kaplan-Meier analysis respect

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survival without progression Criterion Manna- Whitney P-value Cox criterion Mantela P-value Tizotumabvedotin, 2 mg/kg + carboplatin, 40 mg/kg By compared to IgGl-bl2- MMAE, 2 mg/kg Day 41 <0.0001 0.000 Tizotumabvedotin, 2 mg/kg + carboplatin, 40 mg/kg By compared to Tizotumabvedotin, 2 mg/kg Day 69 <0.0001 0.000 Tizotumabvedotin, 2 mg/kg + carboplatin, 40 mg/kg By compared to Carboplatin, 40 mg/kg Day 69 <0.0001 0.004

Example 5: Phase II Trial of Tizotumab-Vedotin Alone or in Combination with a Platinum-Based Agent in Newly Recurrent or Stage IVB Cervical Cancer

A phase I/II trial demonstrated sustained efficacy and a manageable safety profile for 2.0 mg/kg tizotumab-vedotin administered to subjects with recurrent, recurrent, and/or metastatic cervical cancer (NCT02001623). These preliminary data suggest a positive risk profile for a population with significant unmet need. Further studies are needed on the use of tizotumab-vedotin as monotherapy and in combination with therapeutic agents (eg, platinum-based agents) in a larger cohort of patients with cervical cancer.

Efficacy, safety and tolerability of 1.3 mg/kg or 2.0 mg/kg tizotumab-vedotin alone or in combination with carboplatin, a platinum-based agent, as first-line therapy in subjects with recurrent or stage cervical cancer IVB was evaluated herein.

Methods

This open-label, multicenter, phase II trial is evaluating the efficacy, safety, and tolerability of tizotumab-vedotin alone or in combination with carboplatin in subjects with first-time relapsed or stage IVB squamous cell, adenosquamous, or adenocarcinoma of the cervix that is not curatively curative with surgery and/or or radiation therapy and have not previously received systemic therapy for recurrent or stage IVB disease. Subjects with recurrent disease who are candidates for radical treatment via pelvic exenteration are not eligible to participate in the trial.

Subjects are symmetrically assigned to one of four treatment groups. Allocation is done to minimize imbalances in disease status (metastatic/recurrent) and histology (squamous/non-squamous). Eligible subjects received tizotumab-vedotin 1.3 mg/kg Q3W, tizotumab-vedotin 2.0 mg/kg Q3W, tizotumab-vedotin 1.3 mg/kg Q3W + carboplatin AUC 5 Q3W, or tizotumab-vedotin 2. 0 mg/kg Q3W + carboplatin AUC 5 Q3W. Treatment cycles are carried out every 21 days (± 3 days). All treatment components are administered intravenously (IV). The trial included approximately 60 people aged >18 years. The duration of the test is approximately 7 years. Inclusion criteria and exclusion criteria for subjects included in the trial are shown in Table. 1.

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Table 1

List of inclusion and exclusion criteria

Inclusion criteria • Must be characterized by the presence of recurrent or stage IVB squamous, adenosquamous, or adenocarcinoma histology of the cervix that is not curatively curable with surgery and/or radiation therapy. • Should not have received prior systemic therapy for recurrent or stage IVB disease. Note: Subjects are excluded if they are candidates for radical treatment via pelvic exenteration. Note: Chemotherapy given in the adjuvant or neoadjuvant setting or in combination with radiation therapy is not considered to be prior systemic therapy.

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• Must be characterized by the presence of an underlying measurable disease according to RECIST vl.l. Note: Lesions located in a previously irradiated area are considered measurable if they have demonstrated progression. • Age >18 years on the date of signing the informed consent. • Acceptable renal function: estimated (Cockcroft-Gault) glomerular filtration rate (GFR) > 50 ml/min. • Acceptable liver function: o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) (if liver tumor/metastasis is present, < 5 ULN is acceptable); o Bilirubin < 1.5 x ULN if direct bilirubin is not < institution ULN, except in subjects diagnosed with Gilbert's syndrome, direct bilirubin < 2 x ULN. • Acceptable hematological status: o Hemoglobin > 5.6 mmol/L (9.0 g/dL). * o Absolute neutrophil count (ANC) > 1500/μl (1.5x10 ⁹ /l). o Platelet count > 100x10 ⁹ /l. *Acceptable hematologic status must be maintained without erythropoietin dependence and without red blood cell (pRBC) transfusion for the last 2 weeks. • Acceptable coagulation status: o For subjects not receiving anticoagulation therapy: -Activated partial thromboplastin time (aPTT) < 1.25 x ULN. - International normalized ratio (INR) <1.2. o For subjects receiving anticoagulant therapy: - aPTT < 1.25 x ULN - INR: (1) Subjects receiving anticoagulant therapy requiring laboratory evaluations for dose titration (warfarin or other vitamin K-dependent anticoagulants) should receive a constant dose ( without active titration)

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for at least 4 weeks before the first scheduled dose of tizotumab-vedotin, and to be eligible, the INR must be <2.5. (2) Subjects taking anticoagulants that do not require laboratory testing for dose titration must have an INR < 1.2 and must not have been on a stable dose for > 4 weeks prior to the first scheduled dose of the study drug. - Concomitant prophylactic use of acetylsalicylic acid (ASA, e.g. aspirin) is prohibited in patients receiving any type of anticoagulant therapy. • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. • Life expectancy > 3 months. • A female subject is eligible to participate if she is not pregnant, breastfeeding, planning to conceive a child, or planning to donate eggs for assisted fertilization purposes during the planned duration of the trial and for at least 6 months after the last entry into the trial, and applies at least one of the following conditions: o Not a woman of childbearing age (WOSVR) • The WOCBP must agree to use adequate contraception during and for 6 months after the last dose of treatment in the trial. Adequate contraception for women is defined as highly effective contraceptive methods. In countries where two highly effective methods of contraception are required, this will be an inclusion criterion. • A fresh specimen from a previously unirradiated lesion must be provided. Subjects for whom fresh samples cannot be obtained (eg, due to inaccessible tumor or safety concerns) may provide archived sample instead of fresh fabric. Note: Aspirates are not accepted.

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• Must have recovered from all AEs associated with previous treatment to < grade 1. Patients with < grade 2 neuropathy or alopecia are eligible for the trial. • Must be willing and able to comply with the prohibitions and restrictions specified in this protocol. • After receiving oral and written information about the trial, subjects must provide signed informed consent before performing any trial-related activities. Exclusion criteria • Clinically significant bilateral hydronephrosis that cannot be relieved with a ureteral stent or percutaneous drainage. • Clinical signs or symptoms of gastrointestinal obstruction are present and parenteral hydration and/or nutrition is required. • Hematologic criteria: known past or current coagulation defects leading to an increased risk of bleeding; diffuse alveolar hemorrhage due to vasculitis; known bleeding diathesis; continued heavy bleeding; trauma with an increased risk of life-threatening bleeding or a history of severe head trauma or intracranial surgery within 8 weeks of the start of the trial. • Ophthalmic criteria: active ocular surface disease at baseline. Subjects with a history of cicatricial conjunctivitis or Steven Johnson syndrome are not eligible to participate. • Cardiovascular criteria: clinically significant heart disease, including unstable angina, acute myocardial infarction within 6 months before the examination; any history of congestive heart failure (New York Heart Association grade III or IV), any history of cardiac ejection fraction <45%; marked baseline prolongation of the QT/QTc interval (eg, repeated demonstration of the QTc interval > 450 ms), complete left bundle branch block

- 79 046283 (defined as a QRS interval > 120 ms in the form of left bundle branch block) or incomplete left bundle branch block.

• Other cancers: known past or current malignancies other than the trial entry diagnosis, excluding the following: non-invasive basal cell or squamous cell carcinoma of the skin; non-invasive superficial bladder cancer; any cancer with a complete response (CR) duration > 5 years.

• Known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (i.e. no evidence of progression) for at least 28 days through repeat imaging (note that repeat imaging must be performed at the time of screening for the trial) Subjects must be clinically stable and not require steroid treatment for at least 14 days prior to the first dose of treatment in the trial.

• Previous therapy:

o Any previous treatment with MMAE-based drugs.

o Previously received para-aortic irradiation.

o Prior radiation therapy (excluding para-aortic irradiation) within 2 weeks (14 days) of initiation of trial treatment. Subjects must have recovered from all radiation-related toxicities, did not require corticosteroids, and did not have radiation pneumonitis. For palliative radiation (<2 weeks of radiation therapy) for non-CNS diseases, a washout period of 1 week is allowed.

o Received prior systemic anticancer therapy, including study agents, within 4 weeks (28 days) prior to the first dose of trial treatment.

• Surgery/procedures: major surgery within 4 weeks (28 days) or minor surgery within 7 days before the first dose of treatment in the trial. Subjects must have adequately recovered from toxicity and/or complications caused by the procedure before

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initiation of treatment in the trial. Subjects who have major surgery planned during the treatment period should also be excluded from the trial. • Other: ongoing serious uncontrolled condition; clinically significant active viral, bacterial or fungal infection requiring intravenous or oral (PO) treatment with antimicrobial therapy ending less than 7 days before the first treatment in the trial. • Has intolerance to tizotumab-vedotin or its excipients and severe hypersensitivity to carboplatin. • Has a history or current history of any condition, therapy, or laboratory abnormality that could confound the results of the trial, prevent the subject from participating throughout the trial period, or in the opinion of the treating investigator, participation in the trial is not in the best interests of the subject. • Has a known mental or substance abuse disorder that would interfere with compliance with the requirements of the trial. • WOCBP who has a positive pregnancy test (eg, within 72 hours) before treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Subjects who are postmenopausal or permanently sterilized may be considered to have no reproductive potential.

Carboplatin is provided as a solution for intravenous infusion. It is delivered as a 1-hour infusion with an AUC of 5 mg/mL per minute. The calculated carboplatin dosage will be based on the subject's glomerular filtration rate (GFR in mL/min) and the target area under the concentration-time curve (AUC in mg/mL min) according to Calvert. GFR can be estimated from estimated creatinine clearance or based on the local standards of a given institution. Subjects whose weight change is >10% from baseline or who experience CTCAE renal toxicity >grade 2 (serum creatinine >1.5 x ULN) require carboplatin dosage recalculation for subsequent cycles. Subjects should receive premedication for carboplatin in accordance with the institution's standards of care. Tizotumabvedotin administration by intravenous infusion is started at least 30 minutes after carboplatin administration. Lyophilized vials containing 40 mg tizotumab-vedotin are stored in the refrigerator at 2°C to 8°C. Tizotumab-vedotin is diluted in 4 ml of water, resulting in a prepared solution containing 10 mg/ml tizotumab-vedotin, 30 mM histidine, 88 mM sucrose and 165 mM D-mannitol. The prepared antibody-drug conjugate solution has a pH value of 6.0. The prepared tizotumab-vedotin is diluted in a 100 mL infusion bag with 0.9% NaCl according to the dose calculated for the subject. Intravenous infusion is performed within 24 hours after reconstitution of the tizotumab-vedotin vial. For intravenous infusion, a built-in 0.2 µm filter is used. The entire volume of 100 ml is administered from the prepared infusion bag. No dead volume.

Goals and endpoints are described in Table. 2. Subjects are treated until disease progression, toxicity, or withdrawal of consent. Imaging is obtained every 6 weeks for 32 weeks and then every 12 weeks from the date of the first dose. Acquiring images during

- 81 046283 trials continue until the subject experiences radiographic disease progression, initiates new anticancer therapy, withdraws consent, or the subject dies. Tumor response is analyzed at three time points: failure assessment, early effectiveness assessment, and primary effectiveness assessment, respectively.

Table 2 Goals and endpoints

GOALS ENDPOINTS Basic • Assess antitumor effectiveness of tizotumab-vedotin alone or in combination with carboplatin. • Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) vl.l. Secondary • Assess safety and tolerability of tizotumab-vedotin alone or in combination with carboplatin. • Frequency, duration and severity of adverse events (AEs) and assessment of laboratory safety parameters. • To evaluate the durability of the clinical effect of tizotumab-vedotin alone or in combination with carboplatin. • Assess clinical response with tizotumab alone or in combination with carboplatin. • Assess the pharmacokinetics (PK) and immunogenicity of tizotumab-vedotin alone and in combination with carboplatin. Search engines • Explore the relationship between biomarkers and clinical response. • Assess potential pharmacodynamic biomarkers. • Duration of response (DOR) according to RECIST vl.l. • Time to response (TTR) according to RECIST vl.l. • Progression-free survival (PFS) according to RECIST vl.l. • Overall survival (OS). • TRK and anti-drug antibodies (ADA) associated with tizotumab-vedotin alone and in combination with carboplatin. • TF in tumor biopsies, circulating TF, proteomic analyzes and genomic signatures. • Circulating tissue factor (TF) and proteomic analysis.

For subjects who do not tolerate the dosing schedule specified in the protocol, a dose reduction of tizotumab-vedotin is permitted to allow the subject to continue treatment with tizotumabvedotin alone or in combination with carboplatin (Table 3). The dose of carboplatin may also be reduced (Table 4).

Table 3

Tizotumab-vedotin dose reduction regimen

Current dose of tizotumab-vedotin Reduced dose of tizotumab-vedotin 2.0 mg/kg 1.3 mg/kg 1.3 mg/kg 0.9 mg/kg*

* No more than 2 dose reductions of tizotumab-vedotin are allowed. If AE recurs after a second dose reduction of tizotumab-vedotin, the patient should be permanently withdrawn from trial treatment.

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Table 4

Carboplatin dose reduction regimen

Current dose of carboplatin Reduced dose of carboplatin AUC 5 AUC 4*

*Subject should discontinue carboplatin if carboplatin-related (S)AE recurs and does not resolve to grade < 1 after treatment continues for more than 12 weeks. Dose reduction below AUC 4 is not allowed.

Three adverse events of particular interest were identified during treatment with tizotumab-vedotin alone in a previous trial: 1) ocular adverse events; 2) adverse events of peripheral neuropathy; and 3) adverse bleeding events.

For ocular AEs: Grade 1-2 conjunctivitis AEs have been frequently reported in association with treatment with tizotumab-vedotin. Implementation of a comprehensive risk reduction plan and preventive measures significantly reduced both the incidence and severity of adverse ocular events. In the present trial, to prevent ocular adverse events, all subjects in both treatment groups (i.e., tizotumab-vedotin alone or in combination with carboplatin) were required to adhere to the following ocular pretreatment recommendations: 1) use lubricating, preservative-free eye drops throughout the treatment phase of the trial (i.e., from the first dose of tizotumabvedotin to the safety follow-up visit). Lubricating eye drops should be administered according to the product directions for use; 2) it is recommended not to wear contact lenses during treatment with tizotumab-vedotin from the first dose until the follow-up visit to monitor safety; 3) use cooling eye pads during the infusion, such as THERA PEARL eye mask or similar, which should be applied immediately before the infusion according to the instructions included with the eye cooling pads; 4) administration of a topical ophthalmic vasoconstrictor before infusion (brimonidine tartrate eye drops 0.2% or equivalent, 3 drops in each eye immediately before infusion; otherwise use according to product instructions). If the subject does not tolerate ophthalmic vasoconstrictors due to adverse reactions, further treatment with them may be discontinued; and 5) use of steroid eye drops (0.1% dexamethasone eye drops or equivalent) for the first 3 days of each treatment cycle (i.e., the first drop should be given before starting the tizotumab-vedotin infusion; thereafter, continue treatment for 72 hours). Steroid eye drops should be administered 1 drop into each eye 3 times daily for 3 days or used according to product directions. Recommendations for eye AE are given in Table. 5.

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Table 5

Recommendations for dose modification and toxicity management for ocular adverse events____________________________________________________________________________________

Adverse event and degree of toxicity (CTCAE v4.0) Actions taken with tizotumab-vedotin Actions taken with carboplatin Recommendations for treatment prescribed by an ophthalmologist Conjunctivitis Conjunctivitis 1 degrees Suspend reception dosage until the phenomenon is effective docked. Continue tizotumab vedotin at the same dose level. Continue. Your local ophthalmologist should prescribe frequent use steroid drops for topical use without preservatives. Conjunctivitis 2nd degree 1st ^appearance Suspend reception dosage until the phenomenon improves to <grade 1. Continue tizotumab vedotin at the same dose level. Continue. Your local ophthalmologist should prescribe frequent administration (every 2 hours) of topical steroid drops use without preservatives in combined with prophylaxis with antibiotics without preservatives such as chloramphenicol for as long as your local ophthalmologist deems necessary. Conjunctivitis 2nd degree 2nd ^appearance Stop dosing of tizotumab-vedotin: - If the event has improved to baseline within 6 weeks (calculated from the onset date of grade 2 event), reduce the next dose of tizotumab-vedotin to according to table 3. - If the event has not improved to <grade 1 of baseline within 6 weeks (calculated from the onset date of grade 2 event), stop completely taking tizotumab-vedotin. Withhold until the phenomenon improves to <grade 1. Continue carboplatin at the same dose level.

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Conjunctivitis 2nd degree 3rd ^appearance Stop permanently taking tizotumab-vedotin. Withhold until the phenomenon improves to <grade 1. Continue carboplatin at the same dose level. Conjunctivitis > grade 3 Stop permanently taking tizotumab-vedotin. Withhold until the phenomenon improves to <grade 1. Continue carboplatin at the same dose level. Keratitis Keratitis stage 1 or 2 I ^appearance Suspend reception tizotumab-vedotina, for now the phenomenon does not improve to <1 degree. Reduce the dose of tizotumabvedotin according to Table 3. Withhold until the phenomenon improves to <grade 1. Continue carboplatin at the same dose level. Your local ophthalmologist should prescribe frequent administration (every 2 hours) of topical steroid drops use without preservatives in combined with prophylaxis with antibiotics without preservatives such as chloramphenicol for as long as your local ophthalmologist deems necessary. Keratitis < 2nd degree 2nd ^appearance Suspend reception tizotumab-vedotina, for now the phenomenon does not improve to <1 degree. Reduce the dose of tizotumabvedotin again according to Table 3. Withhold until the phenomenon improves to <grade 1. Continue carboplatin at the same dose level. Keratitis < 2nd degree 3rd ^appearance Stop permanently taking tizotumab-vedotin. Contact the sponsor to discuss continuation Withhold until the phenomenon improves to <grade 1. Continue

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taking carboplatin separately. carboplatin at the same dose level. Keratitis > grade 3 Stop permanently taking tizotumab-vedotin. Contact the sponsor to discuss continuing carboplatin separately. Withhold until the phenomenon improves to <grade 1. Conjunctival ulceration and ophthalmic phenomena of fluorescent spots should be treated as below Any stage I ^appearance Suspend reception tizotumab-vedotina, for now the phenomenon will not be effectively stopped. Reduce the dose of tizotumabvedotin according to Table 3. Withhold until the phenomenon improves to <grade 1. Your local ophthalmologist should prescribe frequent administration (every 2 hours) of topical steroid drops use without preservatives in combined with prophylaxis with antibiotics without preservatives such as chloramphenicol for as long as your local ophthalmologist deems necessary. Any stage > 2nd ^appearance If symptoms are not stabilize/improve after dose reduction, the subject should finally Stop taking tizotumabvedotin. Withhold until the phenomenon improves to <grade 1. Symblepharon should be handled as shown below Any stage Stop permanently taking tizotumab-vedotin. Contact the sponsor to discuss continuing carboplatin separately. Withhold until the phenomenon improves to <grade 1. Contact your local ophthalmologist immediately. All other ophthalmic toxic effects All others ophthalmological Suspend reception dosage until the phenomenon Continue. Local ophthalmologist must appoint

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toxic 1st degree effects will be effective docked. Continue tizotumabvedotin at the same dose level. frequent administration (every 2 hours) of topical steroid drops use without preservatives in combined with prophylaxis with antibiotics without preservatives such as chloramphenicol for as long as your local ophthalmologist deems necessary. All other ophthalmic toxic effects, grade 2, first ^occurrence Suspend reception tizotumab-vedotina, for now the phenomenon will not be effectively stopped. Reduce the dose of tizotumabvedotin according to Table 3. Continue. All other ophthalmic toxic effects grade 2 2nd ^occurrence Stop your dose of tizotumab-vedotin: - If the event improves to baseline within 6 weeks, reduce the next dose of tizotumab-vedotin according to table 3. - If the event does not improve to baseline within 6 weeks, permanently discontinue tizotumabvedotin. Withhold until the phenomenon improves to <grade 1. Continue carboplatin at the same dose level. All other ophthalmic toxic effects grade 2 ^3rd occurrence Stop permanently taking tizotumab-vedotin. Withhold until the phenomenon improves to <grade 1. Continue carboplatin at the same dose level. Contact your local ophthalmologist immediately. All others ophthalmic toxic effects > grade 3 Stop permanently taking tizotumab-vedotin. Withhold until the phenomenon improves to <grade 1. Continue carboplatin on the same dose level.

For AEs related to peripheral neuropathy (including peripheral neuropathy; peripheral sensory neuropathy; peripheral motor neuropathy; polyneuropathy): peripheral neuropathy is a well-known adverse reaction to treatment with platinum- and taxane-based chemotherapeutic agents, as well as MMAE-based ADCs, and is reported to occur in approximately 35% of subjects treated with tizotumab-vedotin. Most reported cases are grade 1-2; however, peripheral neuropathy is a common

- 87 046283 the current reason for complete cessation of treatment with tizotumab-vedotin. Recommendations for AE or peripheral neuropathy are given in Table. 6.

For bleeding-related AEs: Bleeding events are considered to be of particular interest due to the mechanism of action of tizotumab-vedotin. Epistaxis is the most common AE reported, but almost all cases are grade 1. In addition, no clinically significant abnormalities in activated partial thromboplastin time (aPTT) or prothrombin time (PT) were observed. Instructions for dose modification and toxicity management are available (Table 6).

Adverse events (AEs), such as increased bleeding, hemorrhage, elevated liver enzymes, mucositis, neutropenia and peripheral neuropathy, may be associated with the administration of tizotumab-vedotin. Decreased platelet counts, neutropenia, vomiting and neuropathy may be associated with carboplatin administration. Instructions are provided for dose modification and toxicity management for AEs associated with combination treatment with tizotumab-vedotin and carboplatin, such as bleeding, liver dysfunction, mucositis, and neuropathy (Table 6) and for thrombocytopenia, neutropenia, vomiting (Table 7). ).

Table 6

Instructions for dose modification and toxicity management for AEs (bleeding, liver dysfunction, mucositis and neuropathy) associated with the carboplatin plus tizotumab-vedotin treatment group

AE (CTCAE v4.0) Actions taken with tizotumab-vedotin Actions taken with carboplatin Bleeding phenomena

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• Monitor vital signs and ensure site stabilization in accordance with local standards. • Prompt evaluation to identify the underlying etiology of bleeding. Ultimately, treatment should be determined by the underlying diagnosis. • Monitor coagulation and hematologic laboratory parameters including PT, aPTT, fibrinogen, platelets, INR, and hemoglobin as soon as possible. All subjects Pulmonary bleeding of any degree or hemorrhage in CNS > grade 2 Permanently discontinue treatment with tizotumab-vedotin. Withhold until the event resolves to <grade 1 and platelets are within the normal range. Subjects not receiving anticoagulant therapy First ^appearance Hemorrhage (other) ¹ > 3 degrees Withhold dosage until the following has been achieved: a) Bleeding has stopped. b) The level of hemoglobin in the blood is stable. c) There is no bleeding diathesis, which may increase the risk of continuing therapy. d) There are no anatomical or pathological conditions that may increase the risk of rebleeding. When the above criteria are met, the subject may resume treatment with tizotumab-vedotin at the same dose as before the event. Withhold until the event resolves to <grade 1 and platelets are within the normal range.

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> ^2nd appearance Hemorrhage (other) ¹ > 3rd degree Contact the sponsor to discuss whether the subject can continue or should Permanently discontinue treatment with tizotumab-vedotin. Contact the sponsor to determine whether treatment with carboplatin alone can be continued. Subjects on anticoagulant therapy INR>3.0 Subjects receiving therapeutic anticoagulant therapy for those with an INR > 3.0 before tizotumab-vedotin infusion should Withhold tizotumabvedotin until INR is >3.0. Subjects may resume tizotumabvedotin once the INR is >3.0. It is highly recommended to carry out anticoagulant therapy until the above parameters are satisfied. Nothing. Hemorrhage (other) ¹ > 3 degrees Suspend anticoagulant therapy. Contact the sponsor to discuss whether the patient can continue or should Permanently discontinue treatment with tizotumab-vedotin. Contact the sponsor to determine whether treatment with carboplatin alone can be continued. Elevated liver parameters (AST, ALT, or bilirubin) > 3 degrees Contact the sponsor before the next dose to discuss whether to reduce, delay, or Permanently stop taking tizotumab-vedotin. Refrain until the phenomenon resolves to grade 0 or 1. Mucositis

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3rd degree Withhold tizotumabvedotin until the event improves to <grade 2. Treat according to local practice. Nothing. > 4 degrees Permanently stop taking tizotumab-vedotin. Refrain until the phenomenon resolves to grade 0 or 1. Contact the sponsor to discuss continuing carboplatin alone. Peripheral neuropathy (including preferred terms such as: peripheral neuropathy; peripheral sensory neuropathy; peripheral motor neuropathy; polyneuropathy) 2nd and 3rd degree Initial or worsening of a pre-existing condition Withhold tizotumabvedotin until the event improves to <grade 1. Reduce next dose according to table 3. Withhold dosage until the event improves to <grade 1. Reduce the next dose according to Table 4. > 4 degrees Permanently stop taking tizotumab-vedotin. Permanently stop taking carboplatin.

INR = International Normalized Ratio ¹ Any other hemorrhage except luminal or CNS hemorrhage.

Table 7

Dose modification and toxicity management instructions for AEs (thrombocytopenia, neutropenia, vomiting) associated with the carboplatin plus tizotumabvedotin treatment arm

AE (CTSAE v4.0) Toxicity degree (CTCAE v4.0) Actions taken with tizotumabvedotin Actions taken with carboplatin Maintenance therapy Hematological Decreased platelet count 3-4 degree 1st ^appearance Withhold dosage until the event occurs. Withhold dosage until the effect improves to <1 Transfusion platelets can be use in According to

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improve to <grade 1. Resume the same DL. degrees. Reduce the next dose by 1 DL according to Table 4. institutional standards. 3-4 degree 2nd ^appearance Withhold dosage until the event improves to <grade 1. Resume the same DL. Stop. Neutropenia 3-4 degree 1st ^appearance Withhold dosage until the event improves to <grade 1. Resume the same DL. Withhold dosage until the event improves to <grade 1. Reduce the next dose by 1 DL according to Table 4. Apply colony-stimulating factors in accordance with institutional standards. 3-4 degree 2nd ^appearance Withhold dosage until the event improves to <grade 1. Contact sponsor to discuss dose reduction or discontinuation Stop.

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tizotumab vedotin. Febrile neutropenia 3 degree ¹ Withhold dosage until fever resolves and neutrophil count rises to >500/mm ³ Resume same DL. Withhold dosage until fever resolves and neutrophil count rises to >500/ ^mm3 . Reduce the next dose by 1 DL according to Table 4. Enter corticosteroids (initial dose 0.5-1 mg/kg prednisone or equivalent) followed by gradual dose reduction. 4th degree Withhold dosage until the event improves to <grade 1. Contact the sponsor to discuss dose reduction or discontinuation of tizotumab vedotin. Stop. Enter corticosteroids (initial dose 1-2 mg/kg prednisone or equivalent) with followed by gradual dose reduction Not hematological Vomit 4th degree Suspend reception Suspend taking dosage, Special attention should be given dosage until the phenomenon improve to <grade 1. Reduce by 1 DL according to table 3 until the phenomenon is resolved. Reduce next dose per 1 DL according to Table 4. prescribing prophylactic antiemetic therapy in accordance with institutional standards.

DL = dose level; gr = grade stop carboplatin if event recurs > grade 3. Contact the sponsor to discuss dose reduction or discontinuation of tizotumab-vedotin.

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Claims (63)

CLAIM 1. Use of an antibody-drug conjugate that binds to tissue factor (TF) for the manufacture of a medicament for treating cancer in a subject, wherein the medicament is for use in combination with a platinum-based agent, wherein the antibody-drug conjugate comprises an antibody to TF or its antigen-binding fragment conjugated to auristatin; wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1; (ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following: (i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4; (ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen-binding fragment thereof is defined according to the IMGT numbering system; and wherein the platinum-based agent is administered intravenously once every week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. 2. Use according to claim 1, wherein the antibody-drug conjugate is administered at a dose ranging from 0.9 mg/kg to 2.1 mg/kg. 3. Use according to claim 2, wherein the antibody-drug conjugate is administered at a dose of 1.3 mg/kg. 4. Use according to claim 2, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg/kg. 5. Use according to claim 2, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg/kg. 6. Use according to any one of claims 1 to 5, wherein the antibody-drug conjugate is administered once every week, once every 2 weeks, once every 3 weeks or once every 4 weeks. 7. Use according to claim 6, wherein the antibody-drug conjugate is administered once every 3 weeks. 8. Use according to any one of claims 1 to 7, wherein the platinum-based agent is administered at a dose of AUC=4 to AUC=6. 9. Use according to claim 8, wherein the platinum-based agent is administered at a dose of AUC=5. 10. Use according to claim 8, wherein the platinum-based agent is administered at a dose of AUC=5. 11. Use according to any one of claims 1 to 10, wherein the platinum-based agent is administered once every 3 weeks. 12. Use according to any one of claims 1 to 11, wherein the cancer is bladder cancer. 13. Use according to any one of claims 1 to 11, wherein the cancer is cervical cancer. 14. Use according to claim 13, wherein the subject is not a candidate for radical treatment. 15. Use according to claim 14, wherein the radical treatment includes radiation therapy and/or exenteration. 16. The use of claim 13, wherein the subject has not received prior systemic therapy for cervical cancer. 17. Use according to any one of claims 13 to 16, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma or squamous cell carcinoma. 18. Use according to any one of claims 13 to 17, wherein the cervical cancer is advanced cervical cancer. 19. Use according to claim 18, wherein the advanced cervical cancer is stage 3 or stage 4 cervical cancer. 20. Use according to claim 18 or 19, wherein the advanced cervical cancer is metastatic cervical cancer. 21. Use according to any one of claims 13 to 20, wherein the cervical cancer is recurrent cervical cancer. 22. Use according to any one of claims 1 to 21, wherein the auristatin is monomethyl auristatin. 23. Use according to claim 22, wherein the monomethyl auristatin is monomethyl auristatin E - 94 046283 (MMAE). 24. Use according to any one of claims 1 to 23, wherein the anti-TF antibody or an antibody-drug conjugate antigen binding fragment thereof is a monoclonal antibody or a monoclonal antigen binding fragment thereof. 25. Use according to any one of claims 1 to 24, wherein the anti-TF antibody or an antigen-binding fragment of an antibody-drug conjugate thereof contains a heavy chain variable region containing an amino acid sequence at least 85% identical to the amino acid sequence according to SEQ ID NO: 7, and a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO:8. 26. Use according to any one of claims 1 to 25, wherein the anti-TF antibody or an antigen-binding fragment of an antibody-drug conjugate contains a heavy chain variable region containing the amino acid sequence according to SEQ ID NO:7, and a light chain variable region containing the amino acid sequence according to SEQ ID NO:8. 27. Use according to any one of claims 1 to 26, wherein the anti-TF antibody of the antibody-drug conjugate is tizotumab. 28. Use according to any one of claims 1 to 27, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or an antigen-binding fragment thereof and auristatin. 29. Use according to claim 28, wherein the linker is a cleavable peptide linker. 30. Use according to claim 29, wherein the cleavable peptide linker is characterized by the formula: -MC-vc-PAB-, where: a) MS is: b) vc is a valine-citrulline dipeptide, and c) PAB is: 31. Use according to any one of claims 28 to 30, wherein the linker is attached to the sulfhydryl residues of an anti-TF antibody obtained by partial reduction or complete reduction of an anti-TF antibody or an antigen-binding fragment thereof. 32. Use according to claim 31, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate is characterized by the following structure: where p is a number from 1 to 8, S is a sulfhydryl residue of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof. 33. The use of claim 32, wherein the average p value in the population of antibody-drug conjugates is 4. 34. Use according to any one of claims 1 to 33, wherein the antibody-drug conjugate is tizotumab-vedotin. 35. Use according to any one of claims 1 to 34, wherein the route of administration for the antibody-drug conjugate is intravenous. 36. Use according to any one of claims 1 to 35, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin and nedaplatin. 37. Use according to any one of claims 1 to 35, wherein the platinum-based agent is carboplatin. 38. Use according to any one of claims 1 to 35, wherein the platinum-based agent is a - 95 046283 fight cisplatin. 39. Use according to any one of claims 1 to 38, wherein the platinum-based agent and the antibody-drug conjugate are administered sequentially. 40. Use according to any one of claims 1 to 38, wherein the platinum-based agent and the antibody-drug conjugate are administered simultaneously. 41. Use according to any one of claims 1 to 40, wherein 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% cervical cancer cells uteri express TF. 42. The use of any one of claims 1 to 41, wherein one or more therapeutic effects in the subject are improved following administration of the platinum-based antibody-drug conjugate relative to baseline. 43. The use of claim 42, wherein the one or more therapeutic effects are selected from the group consisting of the following: tumor size derived from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. 44. Use according to any one of claims 1 to 43, wherein the size of the tumor originating from cervical cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25 %, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70% or at least 80% relative to the size of the tumor originating from cervical cancer prior to administration of the platinum-based antibody-drug conjugate. 45. Use according to any one of claims 1 to 44, wherein the objective response rate is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least at least 45%, at least 50%, at least 60%, at least 70% or at least 80%. 46. Use according to any one of claims 1 to 45, wherein the subject demonstrates 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, according to at least two years, at least three years, at least four years, or at least five years after administration of the platinum-based antibody-drug conjugate. 47. Use according to any one of claims 1 to 46, wherein the subject demonstrates an overall survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least at least two years, at least three years, at least four years, or at least five years after administration of the platinum-based antibody-drug conjugate. 48. Use according to any one of claims 1 to 47, wherein the duration of response to the antibody-drug conjugate 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 two years, at least three years, at least four years, or at least five years after administration of the platinum-based antibody-drug conjugate. 49. Use according to any one of claims 1 to 48, wherein the subject is characterized by the presence of one or more adverse events, and is further administered an additional therapeutic agent to eliminate or reduce the severity of one or more adverse events. 50. Use according to any one of claims 1 to 49, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events. 51. Use according to claim 49 or 50, wherein one or more of the adverse events are the following: hemorrhage, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulceration, mucositis, constipation, loss of appetite, diarrhea, vomiting, neutropenia, febrile neutropenia, decreased platelet count or increased bleeding. 52. The use of claim 49 or 50, wherein the one or more adverse events is a grade 3 or higher adverse event. - 96 046283 53. The use of claim 49 or 50, wherein one or more of the adverse events constitute a serious adverse event. 54. The use of claim 49 or 50, wherein one or more of the adverse events is conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricating eye drops, an ophthalmic vasoconstrictor, and/or steroid eye drops. 55. Use according to any one of claims 1 to 54, wherein the subject is a human. 56. Use according to any one of claims 1 to 55, wherein the antibody-drug conjugate is in a pharmaceutical composition containing the antibody-drug conjugate and a pharmaceutically acceptable carrier. 57. Use according to any one of claims 1 to 56, wherein the platinum-based agent is in a pharmaceutical composition containing the platinum-based agent and a pharmaceutically acceptable carrier. 58. A cancer treatment kit containing: (a) a dosage ranging from AUC=4 to AUC=6 of a platinum-based agent; (b) a dosage in the range of 1.5 mg/kg to 2.1 mg/kg of an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate contains an anti-TF antibody or an antigen-binding fragment thereof, conjugated with auristatin; wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1; (ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (ii i) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following: (i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4; (ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen-binding fragment thereof is defined according to the IMGT numbering system; and (c) instructions for use of the platinum-based agent and the antibody-drug conjugate in accordance with the use of any one of claims 1 to 57. 59. The kit of claim 58, wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:7, and a variable a light chain region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO:8. 60. The kit according to any one of claims 58, 59, in which the anti-TF antibody or an antigen-binding fragment of an antibody-drug conjugate contains a heavy chain variable region containing the amino acid sequence according to SEQ ID NO:7, and a light chain variable region containing the amino acid sequence according to SEQ ID NO:8. 61. The kit according to any one of claims 58 to 60, wherein the platinum-based agent is carboplatin. 62. The kit according to any one of claims 58-61, wherein the antibody-drug conjugate is tizotumab-vedotin. 63. The use of a platinum-based agent for the production of a drug, wherein the drug is for use in combination with an antibody-drug conjugate that binds to a TF, wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to auristatin; wherein the anti-TF antibody or an antigen-binding antibody-drug conjugate fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 containing the amino acid sequence according to SEQ ID NO:1; (ii) CDR-H2 containing the amino acid sequence according to SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence according to SEQ ID NO:3; and wherein the light chain variable region comprises the following: (i) CDR-L1 containing the amino acid sequence according to SEQ ID NO:4; (ii) CDR-L2 containing the amino acid sequence according to SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDR of the anti-TF antibody or antigen-binding fragment thereof is defined according to the IMGT numbering system; -