EA048942B1 - TISSUE FACTOR ANTIBODY-DRUG CONJUGATES AND THEIR APPLICATION IN CANCER TREATMENT - Google Patents

Description

Cross reference to related application

The present invention claims priority to U.S. Provisional Patent Application No. 62/580,877, filed November 2, 2017, the contents of which are incorporated herein by reference in their entirety.

Field of technology to which the present invention relates

The present invention relates to anti-tissue factor (TF) antibody-drug conjugates and methods of using them to treat cancer, such as advanced cervical cancer.

Prior art of the present invention

Tissue factor (TF), also called thromboplastin, factor III, or CD142, is a protein present in subendothelial tissue, platelets, and leukocytes that is required to initiate thrombin formation from prothrombin as a zymogen. Thrombin formation ultimately leads to blood clotting. TF enables cells to initiate coagulation cascades, and it functions as a high-affinity receptor for coagulation factor VII (FVII), a serine protease. The resulting complex provides the catalytic event that facilitates the initiation of protease-mediated coagulation cascades through specific, limited proteolysis. Unlike other cofactors of these protease-mediated cascades, which circulate as nonfunctional precursors, TF is an active initiator that is fully functional upon expression on cell surfaces.

TF is a cell surface receptor for factor VIIa (FVIIa), a serine protease. Binding of FVIIa to TF initiates signaling processes within the cell, with this signaling function playing a role in angiogenesis. While angiogenesis is a normal process in growth and development and in wound healing, it is also essential in the transition of tumors from a latent state to a malignant state. When cancer cells acquire the ability to produce proteins that participate in angiogenesis (i.e., angiogenic growth factors), these proteins are released by the tumor into nearby tissues, thereby stimulating the growth of new blood vessels from existing healthy blood vessels toward and into the tumor. Once new blood vessels penetrate the tumor, the tumor can rapidly increase in size and invade local tissues and organs. Through new blood vessels, cancer cells can then enter the bloodstream and settle in other organs to form new tumors, which is also known as metastasis.

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

Cervical cancer is a major health problem worldwide, with an estimated incidence of over 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 and 13,000 deaths from cervical cancer annually. See Hillemanns et al., 2016, Oncol. Res. Treat. 39:501–506. The main types of cervical cancer are squamous cell carcinoma and adenocarcinoma. Chronic infections with human papillomavirus (HPV) types 16 and 18 account for the majority of cervical cancer cases. Platinum-taxane-based therapy has been the standard of first-line treatment for cervical cancer. Bevacizumab, an anti-VEGF antibody, has been approved by the US Food and Drug Administration for use in combination with chemotherapy for the treatment of cervical cancer, which has shown an improvement in overall survival in clinical trials. First-line (1L) treatment for advanced cervical cancer includes bevacizumab in combination with paclitaxel and a platinum (eg, cisplatin or carboplatin) or paclitaxel and topotecan. Despite an objective response rate (ORR) of 48% and a median overall survival (OS) of approximately 18 months, unfortunately, almost all patients experience disease recurrence after this 1L treatment. See Tewari et al., 2014, N Engl J Med., 370:734–743. In second-line (2L) treatment, there is no approved therapy and patients are often treated with monotherapy options including but not limited to pemetrexed, topotecan, docetaxel, nab-paclitaxel, vinorelbine, and in some cases bevacizumab. A meta-analysis of monotherapy has demonstrated a modest response rate of only 10.9% (i.e., 60 responders out of 552 patients) and a median overall survival (OS) of approximately 7 months. See, e.g., Burotto et al., 2015, Oncologist 20.125–126; 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 96:103-1 048942

107; and Torfs et al., 2012, Eur. J. Cancer. 48:1332-1340. The 5-year relative survival rate for stage IV cervical cancer is only 15%, indicating a high need for improved treatment options for cervical cancer.

The present invention satisfies this need by providing highly specific and potent anti-TF antibody-drug conjugates, particularly for use in the treatment of cervical cancer.

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

The essence of the invention

Provided herein are methods of treating cervical cancer in a subject comprising administering to the subject an antibody-drug conjugate that binds to tissue factor (TF). In some aspects, provided herein is a method of treating cervical cancer in a subject, the method comprising administering to the subject an antibody-drug conjugate that binds to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog thereof (e.g., a functional peptide analog) or a functional derivative thereof, and wherein the antibody-drug conjugate is administered at a dose in the range of about 1.5 mg/kg to about 2.1 mg/kg. In a further embodiment, the dose is about 2.0 mg/kg. In some of any embodiments provided herein, the antibody drug conjugate is administered once about every 1 week, 2 weeks, 3 weeks, or 4 weeks. In some of any embodiments provided herein, the antibody drug conjugate is administered once about every 3 weeks. In some of any embodiments provided herein, the subject has previously been treated with one or more therapeutic agents and has not responded to the treatment, wherein the one or more therapeutic agents is not an antibody drug conjugate. In some of any embodiments provided herein, the subject has previously been treated with one or more therapeutic agents and has relapsed the disease following treatment, wherein the one or more therapeutic agents is not an antibody drug conjugate. In some of any embodiments provided herein, the subject has previously been treated with one or more therapeutic agents and has exhibited disease progression during treatment, wherein the one or more therapeutic agents is not an antibody drug conjugate. According to some of any embodiments provided herein, the one or more therapeutic agents comprise a platinum-based therapeutic agent. According to some of any embodiments provided herein, the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, and bevacizumab. According to some of any embodiments provided herein, the subject has exhibited disease progression during or following treatment with: a) paclitaxel and cisplatin, b) paclitaxel and carboplatin, or c) paclitaxel and topotecan. In some of any embodiments provided herein, the subject has been treated with bevacizumab. In some of any embodiments provided herein, the subject is not suitable for treatment with bevacizumab. In some of any embodiments provided herein, the subject is not a candidate for definitive therapy. In some of any embodiments provided herein, definitive therapy comprises radiation therapy and/or exenterative surgery. In some of any embodiments provided herein, the subject has failed to respond to treatment with up to two prior systemic treatment regimens. In some of any embodiments provided herein, the subject has relapsed following treatment with up to two prior systemic treatment regimens. In some of any embodiments provided herein, the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma. According to some of any of the embodiments provided herein, the cervical cancer is an advanced stage cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer. According to some of any of the embodiments provided herein, the cervical cancer is a recurrent cervical cancer. According to some of

- 2 048942 of any of the embodiments provided herein, monomethyl auristatin is monomethyl auristatin E (MMAE). According to some of any of the embodiments provided herein, the anti-TF antibody, or antigen-binding fragment thereof, of the antibody drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof. According to some of any of the embodiments provided herein, the anti-TF antibody, or antigen-binding fragment thereof, of the antibody drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:

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

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

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

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

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

a) MS is:

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

According to some of any of the embodiments presented herein, the linker is attached to sulfhydryl groups of the anti-TF antibody obtained by partial reduction or full reduction of the anti-TF antibody or antigen-binding fragment thereof. According to a further embodiment, the linker is attached to MMAE, wherein the antibody-drug conjugate is characterized by the following structure:

- 3 048942

Ab-MC-w-PXB-MMAF wherein p is a number from 1 to 8, S is a sulfhydryl group of an anti-TF antibody, and Ab is an anti-TF antibody or antigen-binding fragment thereof. According to a further embodiment, the average p value in the population of antibody drug conjugates is about 4. According to some of any embodiments provided herein, the antibody drug conjugate is tisotumab vedotin. According to some of any embodiments provided herein, the route of administration for the antibody drug conjugate is intravenous (e.g., intravenous infusion). According to some of any 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 the cervical cancer cells express TF. According to some of any embodiments presented herein, after administration of the antibody-drug conjugate, the subject experiences an improvement in one or more therapeutic effects relative to baseline. According to a further embodiment, the one or more therapeutic effects are selected from the group consisting of tumor size resulting from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. According to some of any of the embodiments provided herein, the size of the tumor resulting 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 resulting from cervical cancer prior to administration of the antibody drug conjugate. According to some of any 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 about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. According to some of any of the embodiments provided herein, the subject exhibits progression-free survival for 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 eighteen 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. According to some of any of the embodiments provided herein, the subject exhibits overall survival for 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 eighteen months, at least

-4 048942 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. According to some of any of the embodiments provided herein, the duration of the response to the antibody drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen 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. According to some of any embodiments provided herein, the subject experiences 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. According to some of any 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 one or more adverse events. According to some of any embodiments provided herein, the one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general deterioration in physical health. According to some of any embodiments provided herein, the one or more adverse events are a grade 3 or higher adverse event. According to some of any embodiments provided herein, the one or more adverse events are a serious adverse event. According to some of any embodiments provided herein, the one or more adverse events are conjunctivitis and/or keratitis, and the additional agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, and/or a steroid-containing eye drop. According to some of any embodiments provided herein, the antibody drug conjugate is administered as a monotherapy. According to some of any embodiments provided herein, the subject is a human. According to some of any embodiments provided herein, the antibody drug conjugate is in a pharmaceutical composition comprising the antibody drug conjugate and a pharmaceutically acceptable carrier. Also provided herein are articles of manufacture comprising an antibody drug conjugate that binds to TF. In some aspects, provided herein is an article of manufacture comprising: a) a medicament comprising an antibody drug conjugate, wherein the antibody drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog thereof (e.g., a functional peptide analog) or a functional derivative thereof; and b) a package insert comprising instructions for using the medicament comprising the antibody drug conjugate in a method of treating cervical cancer in a subject according to any of any of the embodiments provided herein. In a further embodiment, the medicament comprising the antibody drug conjugate is in a container selected from the group consisting of a vial, a syringe, and an infusion bag. In a further embodiment, the container comprises the antibody drug conjugate in a dosage amount of from about 4 mg to about 500 mg. According to a further embodiment, the container comprises the antibody drug conjugate in a dosage amount of from about 20 mg to about 60 mg. According to a further embodiment, the container comprises the antibody drug conjugate in a dosage amount of about 40 mg. According to another further embodiment, the container comprises the antibody drug conjugate in a dosage amount of 40 mg. According to another further embodiment, the container comprises the antibody drug conjugate in a concentration of from about 5 mg/mL to about 15 mg/mL. According to some of any embodiments provided herein, the medicament comprising the antibody drug conjugate is a lyophilized powder. According to a further embodiment, the lyophilized powder is reconstituted with a suitable diluent to result in a final concentration of from about 5 mg/mL to about 15 mg/mL. According to some of any embodiments provided herein, the medicament comprising

- 5 048942 a conjugate of an antibody and a drug, intended for administration by intravenous infusion or injection. According to an additional embodiment, a medicinal product containing a conjugate of an antibody and a drug is intended for administration by intravenous infusion.

Brief description of the drawings

The patent data file or application file shall contain at least one drawing in colour. Copies of the present patent or patent application publication with the drawing(s) in colour will be provided by the Office upon request and payment of the required fee.

Fig. 1 is a schematic diagram showing the mechanism of action (MOA) of the antibody drug conjugate tizotumab vedotin.

Fig. 2 is a flow chart showing the design of a dose-escalation study for the treatment of patients with cancer using tizotumab vedotin. Q3w indicates that the treatment cycle is given every three weeks.

Fig. 3 is a graph showing the most common treatment-related adverse events (AEs) occurring in a total of >4 patients after treatment with tizotumab vedotin across all doses tested. N=27 represents 27 patients.

Fig. 4A and 4B are graphs showing A) mean plasma tizotumab vedotin concentration and B) mean free MMAE concentration over time across Cycle 1 and Cycle 2 for all dose-finding cohorts.

Fig. 5 is a graph showing the best percent change in tumor size from baseline in 27 patients. (i) Represents patient 1 with cervical cancer treated with 2.2 mg/kg tizotumab vedotin. (ii) Represents patient 2 with cervical cancer treated with 1.2 mg/kg tizotumab vedotin. Baseline was defined as the last available measurement performed before the first cycle of tizotumab vedotin.

Fig. 6 is a computed tomography (CT) scan of the lung metastasis of Patient 2. This patient had cervical cancer and was treated with 1.2 mg/kg tizotumab vedotin.

Fig. 7 is a graph showing the most common adverse events (AEs) in 34 treated patients with cervical cancer.

Fig. 8 is a graph showing the best percentage change in target lesion from baseline. ^a Indicates that two patients were excluded from the study before the CT scan and are therefore not plotted. ^b Indicates PD due to the appearance of a new lesion on the same scan. Baseline was defined as the last available measurement performed before the first cycle of tizotumab vedotin treatment.

Fig. 9 is a graph showing the best percentage change in target lesion from baseline. ^a Denotes a patient who had node disease and persistent non-target lesions at PR as the best response. ^b Denotes a patient who had node disease, persistent non-target lesions, and a new lesion at PD as the best response. Baseline was defined as the last available measurement performed before the first cycle of tizotumab vedotin.

Fig. 10 is a graph showing the time to response and the duration of response. ^a Response is defined as unconfirmed + confirmed response.

Fig. 11 is a flow chart showing the design of a phase II study to evaluate treatment with tizotumab vedotin in patients with previously treated, recurrent, or metastatic cancer who have received at least one prior line of systemic therapy. ^a Represents tizotumab vedotin infusion at a concentration of 2.0 mg/kg on day 1 of each cycle until disease progression. Each treatment cycle was 3 weeks (Q3W). ^b Represents CT or MRI scanning every 6 weeks (±7 days) for the first 30 weeks of treatment and every 12 weeks (±7 days) thereafter, regardless of treatment delays. ^c Represents optional.

Detailed disclosure of the present invention

I. Definitions.

In order that the present invention may be more clearly understood, certain terms are first set forth. In the context of the present invention, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

The expression and/or when used herein shall be construed as a specific disclosure of each of the two stated features or components, with or without the other. Thus,

- 6 048942 zom, the expression and/or in the context of a phrase such as A and/or B herein is intended to include A and B, A or B, A (alone) and B (alone). Similarly, the expression and/or in the context of 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 (alone); B (alone); and C (alone).

It should be understood that the aspects and embodiments of the present invention described herein include comprising, consisting of, and consisting essentially of the aspects and embodiments.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and Oxford Dictionary Of Biochemistry And Molecular Biology, latest edition, 2000, Oxford University Press, provide the skilled person with a general dictionary of many terms used in the present invention.

Units, prefixes and symbols are designated in their accepted form according to the International System of Units (SI). Numerical ranges include the numbers defining the range. The headings provided herein are not limitations of the various aspects of the present invention, which may be made with reference to the description as a whole. Accordingly, the terms defined immediately below are more fully defined with reference to the description in its entirety.

The terms tissue factor, TF, CD142, tissue factor antigen, TF antigen, and CD142 antigen are used interchangeably herein and, unless otherwise specified, include any variants, isoforms, and species homologs of human tissue factor that are naturally expressed by cells or expressed on the surface of cells transfected with a tissue factor gene. Tissue factor may be a sequence with 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 low molecular weight light (L) chains, and one pair of heavy (H) chains, all four joined together by disulfide bonds. The structure of the immunoglobulins is well characterized. See, e.g., Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)). Briefly, each heavy chain typically consists of a heavy chain variable region (abbreviated herein as 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. Each light chain typically consists of a light chain variable region (abbreviated herein as VL or VL) and a light chain constant region (CL or CL). The light chain constant region typically consists of a single domain, _CL . The V _H and VL regions can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in sequence and/or shape of structurally defined loops), also called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs). Each VH and VL typically consists of three CDRs and four FRs arranged, from amino terminus to 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)). Typically, the amino acid residues in this region are numbered using the method described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991) (phrases such as variable domain residue numbering as in Kabat or according to Kabat, herein refer to this numbering system for heavy chain variable domains or light chain variable domains). Using this numbering system, the actual linear amino acid sequence of the peptide may contain fewer or additional amino acids due to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion (residue 52a according to Kabat) after residue 52 of the VH CDR2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after residue 82 of the heavy chain FR. The Kabat residue numbering can be determined for a given antibody by aligning the regions of homology of the antibody sequence with a standard Kabat numbered sequence. The immunoglobulin may be any of the well-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 the class or subclass of antibodies (e.g., IgM or IgGl) that are encoded by the heavy chain constant region genes.

The term antibody (Ab) in the context of the present invention refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or any derivative thereof, which has the ability to specifically bind to an antigen under standard physiological conditions over time.

- 7 048942 it has a half-life comprising significant periods of time, such as at least about 30 minutes, at least about 45 minutes, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 or more days, etc., or any other appropriate functionally defined period (such as a period of time sufficient to induce, stimulate, enhance and/or modulate the physiological response associated with binding of the antibody to the antigen, and/or a period of time sufficient for the antibody to cause effector activity). The variable regions of the heavy and light chains of the immunoglobulin molecule comprise a binding domain that interacts with the antigen. The constant regions of antibodies (Ab) 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, which is the first component in the classical complement pathway. As noted above, as used herein, the term antibody, unless otherwise indicated or clearly contradicted by context, includes fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., an antigen-binding fragment). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antigen-binding fragments encompassed by the term antibody include (i) a Fab' or Fab fragment, a monovalent fragment consisting of the V _L , V _H , C _L , and C _H 1 domains, or a monovalent antibody as described in WO 2007059782 (Genmab A/S); (ii) F(ab') ₂ fragments, bivalent fragments containing two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment, consisting essentially of the _VH and _CH1 domains; (iv) an Fv fragment, consisting essentially of the _VL and VH domains of one arm of an antibody; (v) a dAb fragment (Ward et al., Nature 341, 544-546 (1989)), which consists essentially of the VH domain and is also called a domain antibody (Holt et al; Trends Biotechnol, 2003 Nov;21(11):484-90); (vi) camelid antibodies or nanoantibodies (Revets et al; Expert Opin Biol Ther. 2005 Jan;5(1):111-24) and (vii) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, V _L and VH, are encoded by separate genes, they can be joined, using recombinant techniques, by a synthetic linker that allows them to be produced as a single protein chain in which the V _L and VH regions are paired to form monovalent molecules (known as single-chain antibodies or single-chain Fv (scFv), see, for example, Bird et al., Science 242, 423-426 (1988) and Huston et al., PNAS USA 85, 5879-5883 (1988)). Such single chain antibodies are encompassed by the term antibody unless otherwise indicated or clearly indicated by context. Although such antigen-binding fragments are generally included within the meaning of the term antibody, they are individually and collectively unique features of the present invention, having distinct biological properties and functionality. These and other useful antibody fragments in the context of the present invention are further discussed herein. It should also be understood that the term antibody, unless otherwise indicated, also includes polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides such as chimeric antibodies and humanized antibodies, and antibody fragments that retain the ability to specifically bind to an antigen (e.g., antigen-binding fragments) obtained by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques. The resulting antibody may be of any isotype. Unless otherwise specified and unless the context otherwise requires, the term antibody also includes an antigen-binding fragment or antigen-binding portion of any of the above-mentioned immunoglobulins.

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

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

Human antibody (HuMAb) refers to an antibody that contains variable regions in which

- 8 048942 in which both the FR and the CDR are derived from human germline immunoglobulin sequences. In addition, if the antibody comprises a constant region, the constant region is also derived from human germline immunoglobulin sequences. The human antibodies of the present invention may comprise amino acid residues not encoded by human germline immunoglobulin sequences (e.g., in the case of mutations introduced using random or site-directed 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 germline 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 synonymously.

A humanized antibody refers to an antibody in which some, most, or all of the amino acids outside the CDRs of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. According to one embodiment of a humanized form of an antibody, some, most, or all of the amino acids outside the CDRs have been replaced with amino acids from human immunoglobulins, while some, most, or all of the amino acids within one or more CDRs remain unchanged.

Minor additions, deletions, insertions, substitutions or modifications of amino acids are permitted, provided that they do not eliminate the ability of the antibody to bind to a particular antigen. The humanized antibody retains an antigen specificity similar to that of the parent antibody. In some embodiments, the CDRs of the humanized antibody comprise a CDR from a non-human mammalian antibody. In other embodiments, the CDRs of the humanized antibody comprise a CDR from an engineered synthetic antibody.

A chimeric antibody refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.

Antibody to an antigen refers to an antibody that specifically binds to an antigen. For example, an anti-TF antibody specifically binds to TF.

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

The term hypervariable region, HVR or HV, as used herein, refers to the regions of the variable domain of an antibody that are hypervariable in sequence and/or shape of structurally defined loops. Antibodies typically contain six HVRs; three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). In native antibodies, H3 and L3 exhibit the greatest diversity of the six HVRs, and H3 in particular is thought to play a special role in conferring high specificity to antibodies. See, e.g., Xu et al. Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003)). Furthermore, naturally occurring heavy chain-only antibodies from camelids are functional and stable in the absence of a light chain. See, for example, Hamers-Casterman et al., Nature 363:446448 (1993) and Sheriff et al., Nature Struct. Bioh 3:733–736 (1996).

A number of variations are used in defining the boundaries of HVRs and are included herein. HVRs, which are Kabat complementarity determining regions (CDRs), are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, ^5th Ed. Public Health Service, National Institute of Health, Bethesda, MD (1991)). Chothia HVRs instead involve the arrangement of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). HVRs in the context of the contact numbering scheme are based on analysis of available complex crystal structures. Residues from each of these HVRs are listed below.

- 9 048942

Loop Kabat Chothia "Contact" L1 L24-L34 L26-L34 L30-L36 L2 L50-L56 L50-L56 L46-L55 L3 L89-L97 L91-L96 L89-L96 N1 N31-N35B N26-N32 N30-N35B (numbering according to Kabat) N1 N31-N35 N26-N32 H30-H35 (Chothia numbering) N2 N50-N65 N53-N56 N47-N58 NZ N95-N102 N95-N102 N93-N101

As used herein, the terms binding or specifically binds in the context of binding of an antibody to a predetermined antigen typically represents binding with an affinity corresponding to a _KD of about 10 ^-7 M or less, such as 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, as determined, for example, by surface plasmon resonance (SPR) technology on a BIAcore 3000 instrument using the antigen as the ligand and the antibody as the analyte, and the antibody binds to the predetermined antigen with an affinity corresponding to a _KD that is at least ten times lower, such as at least 100 times lower, such as at least 1,000 times lower, such as at least 10,000 times lower, such as at least 100,000-fold lower than that for binding to a non-specific antigen (e.g., BSA, casein) other than a predetermined antigen or a closely related antigen. The amount at which the affinity is lower depends on the K _D of the antibody, so that if the K _D of the antibody is very low (i.e., the antibody is highly specific), then the amount at which the affinity for the antigen is lower than the affinity for the non-specific antigen may be at least 10,000-fold.

The term kd (sec ^-1 ) as used herein refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the kof value.

The term _ka (M ^-1 x sec ^-1 ) as used herein refers to the association rate constant of a particular antibody-antigen interaction.

The term K _D (M) as used herein refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

The term K _A (M ^-1 ) as used herein refers to the equilibrium association constant of a particular antibody-antigen interaction and is obtained by dividing ka by 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 another moiety (e.g., MMAE or MMAF) as described herein.

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

The abbreviation PAB stands for self-cleaving spacer: усУ

The abbreviation MC refers to the maleimidocaproyl extender moiety:

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

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. The uncontrolled division and growth of cells results in the formation of malignant tumors, which invade nearby tissues and may also metastasize to distant parts of the body through the lymphatic system or bloodstream. After metastasis, the distant tumors may be referred to as having originated from a pre-metastatic tumor. For example, a tumor that originated from a malignant tumor

- 10 048942 cervical cancer refers to a tumor that is the result of metastasis of cervical cancer.

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

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

An effective amount, or a therapeutically effective amount, or a therapeutically effective dosage refers to an amount effective, at the required dosages and at the required intervals of administration, to achieve the desired therapeutic result. Such desired therapeutic results include preventing the manifestation of a disease in a subject or promoting regression of the disease, as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods of the disease, or preventing deterioration or loss of capacity due to disease damage. The ability of a therapeutic agent to promote regression of a disease can be assessed using a number of methods known to the practitioner, such as in human subjects in clinical trials, in animal model systems with the ability to predict efficacy in humans, or by assaying the activity of the agent in in vitro assays. A therapeutically effective amount of an anti-TF antibody drug conjugate can vary according to factors such as the stage of the disease, the age, sex, and weight of the individual, and the ability of the anti-TF antibody drug conjugate to elicit the desired response in the individual. A therapeutically effective amount is also one in which the therapeutically beneficial effects offset any toxic or adverse effects of the anti-TF antibody-drug conjugate.

A therapeutically effective amount of a drug (e.g., an anti-TF antibody-drug conjugate) includes a prophylactically effective amount, which is any amount of a drug that, when administered alone or in combination with an anti-cancer agent to a subject at risk of developing cancer (e.g., a subject experiencing a precancerous condition) or experiencing a recurrence of cancer, inhibits the development or recurrence of cancer. In some embodiments, the prophylactically effective amount prevents the development or recurrence of cancer entirely. Inhibiting the development or recurrence of cancer means either reducing the likelihood of developing or recurring cancer, or preventing the development or recurrence of cancer entirely.

As used herein, a subtherapeutic dose means a dose of a therapeutic compound (e.g., an antibody-drug conjugate) 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).

As an example, an anticancer agent promotes regression of cancer in a subject. According to some embodiments, a therapeutically effective amount of a drug promotes regression of cancer to the point of eliminating the cancer. Stimulating regression of cancer means that administration of an effective amount of a drug, alone or in combination with an anticancer agent, results in a decrease in the rate of tumor growth or size, the degree of tumor necrosis, a decrease in the severity of at least one symptom of the disease, an increase in the frequency and duration of symptom-free periods of the disease, a prevention of deterioration or loss of capacity due to disease. In addition, the terms effective and efficacy in relation to treatment include both pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote regression of a malignant tumor in a patient. Physiological safety refers to the level of toxicity or other undesirable physiological effects at the cellular, organ and/or organismal level (adverse effects) due to administration of the drug.

As an example of treating tumors, a therapeutically effective amount of an anticancer agent provides inhibition of cell growth or tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, or at least

- 11 048942 at least approximately 100% in the treated subject(s) (e.g., one or more treated subjects) compared to the untreated subject(s) (e.g., one or more untreated subjects).

According to other embodiments of the present invention, tumor regression can 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. Despite these final measures of therapeutic efficacy, the evaluation of immunotherapeutic drugs should also take into account patterns of immune responses.

A durable response refers to a sustained effect in terms of tumor growth suppression after treatment has ceased. For example, the tumor size may remain the same or decrease compared to the size at the beginning of the administration phase. According to some embodiments, a durable response is characterized by a duration at least as long as the duration of treatment, at least 1.5x, 2.0x, 2.5x or 3.0x longer than the duration of treatment.

In the context of this document, a complete response, or CR, refers to the disappearance of all target lesions; a partial response, or PR, refers to at least a 30% reduction in the sum of the longest diameters (SLD) of target lesions, taking the baseline SLD as the reference point; and stable disease, or SD, refers to neither a sufficient reduction in target lesions to qualify for a PR nor a sufficient increase to qualify for a PD, taking the nadir SLD since the start of treatment as the reference point.

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

In the context of this document, overall response rate, or ORR, refers to the sum of the proportion of patients with a complete objective response (CR) and the proportion of patients with a partial objective response (PR).

In the context of this document, 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.

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

The use of the term constant dose in relation to the methods and dosages of the present invention means a dose that is administered to a patient regardless of the patient's weight or body surface area (BSA). A constant dose is therefore not given as a mg/kg dose, but rather as an absolute amount of the agent (e.g., the anti-TF antibody-drug conjugate). For example, a 60 kg individual and a 100 kg individual would receive the same dose of the antibody-drug conjugate (e.g., 240 mg of the anti-TF antibody-drug conjugate).

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

The phrase pharmaceutically acceptable salt as used herein refers to pharmaceutically acceptable organic or inorganic salts of a compound of the present invention. Illustrative salts include, but are not limited to, salts that are sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, phosphoric acid hydrogen salt, isonicotinate, lactate, salicylate, citrate hydrogen, 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'-methylenebis-(2-hydroxy-3-naphthoate)), alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., magnesium), and ammonium salts. A pharmaceutically acceptable salt may include another molecule such as an acetate ion, a succinate ion, or another counterion. The counterion may be any organic or inorganic component that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In cases where multiple charged atoms are part of a pharmaceutically acceptable salt, they may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

Administration refers to the physical introduction of a therapeutic agent into a subject using

- 12 048942 any of a number of delivery methods and systems known to those skilled in the art. Exemplary routes of administration of the anti-TF antibody-drug conjugate include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). The phrase parenteral administration as used herein means routes of administration other than enteral and local administration, typically by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. The therapeutic agent may be administered by a route other than parenteral or orally. Other routes other than parenteral include local, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical. The administration can also be carried out, for example, once, multiple times and/or over one or more extended periods.

The terms baseline or baseline value, as used interchangeably herein, may refer to a measure of severity or characteristic of a symptom prior to administration of a therapy (e.g., an antibody drug conjugate described herein) or at the start of administration of a therapy. The baseline value may be compared to a reference value to determine a decrease in severity or improvement in a symptom of a TF-associated disease described herein (e.g., cervical cancer). The terms reference or reference value, as used interchangeably herein, may refer to a measure of severity or characteristic of a symptom following administration of a therapy (e.g., an antibody drug conjugate described herein). The reference value may be measured one or more times during a dosing regimen or course of treatment or at the completion of a dosing regimen or course of treatment. A reference value may be an absolute value; a relative value; a value that has an upper and/or lower limit; a range of values; an average value; a median value: an average value; or a value compared to a baseline value.

Similarly, a baseline value may be an absolute value; a relative value; a value that has an upper and/or lower limit; a range of values; an average value; a median value; a mean value; or a value compared to a reference value. The reference value and/or baseline value may be obtained for one individual, two different individuals, or a group of individuals (e.g., a group of two, three, four, five, or more individuals).

The term monotherapy as used herein means that the antibody-drug conjugate is the only anti-cancer agent administered to the subject during the course of treatment. However, other therapeutic agents may be administered to the subject. For example, monotherapy may include anti-inflammatory agents or other agents administered to a subject with cancer to treat symptoms associated with the cancer, but not symptoms of the primary cancer itself, including, for example, inflammation, pain, weight loss, and general malaise.

An adverse event (AE) as used herein is any unfavorable and generally unexpected or unacceptable sign (including abnormal laboratory findings), symptom or disease associated with the use of a medical intervention. A medical intervention may be accompanied by one or more associated AEs, and each AE may be of the same or different severity. Reference to ways in which adverse events can be modified means a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with another treatment regimen.

A serious adverse event, or SAE, in the context of this document is an adverse event that meets one of the following criteria:

Is fatal or life-threatening (in the context of 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 could hypothetically have resulted in death if it had been more serious.

Leads to permanent or significant disability.

It is a congenital anomaly/developmental defect.

Is medically significant, i.e. defined as an event that puts the patient at risk or requires medical or surgical intervention to prevent one of the above outcomes. The decision as to whether an AE is medically significant should be based on medical judgment or scientific evidence.

Hospitalization or prolongation of hospitalization is required, except for the following: 1) standard treatment

- 13 048942 or monitoring of a primary disease not associated with any deterioration in the condition, 2) planned or pre-planned treatment of an existing condition that is not related to the indication in the study and that has not worsened since the signing of the informed consent, and social reasons and short-term hospitalization instead of caregiver care in the absence of any deterioration in the general condition of the patient.

It should be understood that the use of an alternative (e.g., "or") means either one, both, or any combination of the alternatives. In the context of this document, the singular forms should be understood as referring to one or more of any specified or listed components.

The terms "about" or "consisting essentially of" refer to a value or composition that is within an acceptable range of error 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., the limitations of the measurement system. For example, "about" or "consisting essentially of" may mean within 1 or more than 1 standard deviation, in accordance with practice in the art. Alternatively, "about" or "consisting essentially of" may mean a range of up to 20%. In addition, particularly with respect to biological systems or processes, the terms may provide for a difference in value of up to an order of magnitude or up to 5 times. Where particular values or compositions are provided in the application and claims, unless otherwise indicated, a value of "about" or "consisting essentially of" shall be construed as being within an acceptable range of error for that particular value or composition.

The expressions once approximately every week, once approximately every two weeks, once approximately every three weeks or any other similar expressions regarding the time intervals between doses as used herein are intended to be approximations. Once approximately every week may include every seven days ± one day, i.e. the time interval from every six days to every eight days. Once approximately every two weeks may include every fourteen days ± two days, i.e. the time interval from every twelve days to every sixteen days. Once approximately every three weeks may include every twenty-one days ± three days, i.e. the time interval from every eighteen days to every twenty-four days. Similar approximations apply, for example, to the time intervals of once approximately every four weeks, once approximately every five weeks, once approximately every six weeks and once approximately every twelve weeks.

As described herein, any concentration range, percentage range, ratio range, or whole number range shall be understood to include the value of any whole number within the stated range and, where applicable, fractional parts thereof (such as tenths and hundredths of a whole number), unless otherwise stated.

The various aspects described in the present invention are described in more detail in the following subsections.

II. Antibody-drug conjugates.

The present invention relates to anti-TF antibody-drug conjugates that are useful for treating cancer in a subject. In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer is advanced cervical cancer (e.g., stage 3 cervical cancer or stage 4 cervical cancer or metastatic cervical cancer). In some embodiments, the advanced cervical cancer is metastatic cancer. In some embodiments, the subject has recurrent, recurrent, and/or metastatic cervical cancer.

A. Antibody to TF.

In general, the antibodies of the present invention immunospecifically bind TF and exhibit cytostatic and cytotoxic effects on malignant cells, such as cervical cancer cells. The antibodies of the present invention are preferably monoclonal, and may be polyspecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments obtained using a Fab expression library, and TF-binding fragments of any of the above. The immunoglobulin molecules of the present invention may belong to any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of an immunoglobulin molecule.

According to certain embodiments of the present invention, the antibodies are human antigen-binding fragments as described herein and include, but are not limited to, Fab, Fab' and F(ab') ₂ , Fd, single-chain Fv (scFv), single-chain antibodies linked to di

- 14 048 942 sulfide-linked Fv (sdFv) and fragments comprising either a V _L or V _H domain. Antigen-binding fragments, including single-chain antibodies, may comprise variable region(s) alone or in combination with all or part of the hinge, CH1, CH2, CH3, and CL domains. Also included in the present invention are antigen-binding fragments comprising any combination of variable region(s) with the hinge, CH1, CH2, CH3, and CL domains. Preferably, the antibodies or antigen-binding fragments thereof are those of human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camelid, horse, or chicken.

The antibodies of the present invention may be monospecific, bispecific, trispecific, or multispecific. Multispecific antibodies may be specific for different epitopes of TF or may be specific for both TF and a heterologous protein. See, e.g., PCT Publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., 1991, J. Immunol. 147:60 69; U.S. Patent Application Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., 1992, J. Immunol. 148:1547 1553.

The antibodies of the present invention may be described or referred to in the context of the particular CDRs they comprise. The precise amino acid sequence boundaries of these CDRs or FRs may be readily determined using any of a number of well-known schemes, 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 scheme); Al-Lazikani et al., (1997) JMB 273,927-948 (Chothia numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), Antibody-antigen interactions: Contact analysis and binding site topography, J. Mol. Biol. 262, 732-745. (Contact numbering scheme); Lefranc MP et al., IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains, Dev Comp Immunol, 2003 Jan;27(l):55-77 (IMGT numbering scheme); 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 scheme); and Martin et al., Modeling antibody hypervariable loops: a combined algorithm, PNAS, 1989, 86(23):9268-9272, AbM numbering scheme). The boundaries of these CDRs may vary depending on the identification scheme used. According to some embodiments, the CDR or complementarity determining region, or individual specified CDRs (e.g., CDR-H1, CDRH2, CDR-H3), of a given antibody or region thereof (e.g., its variable region) should be understood to encompass a CDR (or a particular CDR) as defined by any of the above-mentioned schemes. For example, if a particular CDR (e.g., CDR-H3) is indicated to comprise the amino acid sequence of the corresponding CDR within the amino acid sequence of a given V _H or V _L region, such CDR should be understood to comprise the sequence of the corresponding CDR (e.g., CDR-H3) within the variable region as defined by any of the above-mentioned schemes. A scheme may be indicated to identify a particular CDR or particular CDRs, such as a CDR defined by the Kabat, Chothia, AbM, or IMGT method.

The CDR sequences of the anti-TF antibodies and anti-TF antibody-drug conjugates herein are presented according to the IMGT numbering scheme as described in Lefranc, M. P. et al., Dev. Col. Immunol., 2003, 27, 55-77.

According to certain embodiments, antibodies of the present invention comprise one or more CDRs of antibody 011. See WO 2011/157741 and WO 2010/066803. The present invention encompasses 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 is derived from monoclonal antibody 011, and (b) a set of four framework regions, wherein said set of framework regions differs from the set of framework regions in monoclonal antibody 011, and wherein said antibody or derivative thereof immunospecifically binds TF. According to certain embodiments, the anti-TF antibody is 011. Antibody 011 is also known as tizotumab.

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

In one aspect, the present disclosure provides an anti-TF antibody comprising 1, 2, 3, 4, 5 or 6 of the CDR sequences of tizotumab.

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

- 15 048942 IMGT numbering.

An anti-TF antibody described herein may comprise any suitable variable domain framework sequence, so long as the antibody retains the ability to bind to TF (e.g., human TF). As used herein, the heavy chain framework regions are designated HC-FR1-FR4 and the light chain framework regions are designated LC-FR1FR4. In some embodiments, an anti-TF antibody comprises the heavy chain variable domain framework sequence of SEQ ID NOs: 9, 10, 11, and 12 (HC-FR1, HC-FR2, HCFR3, and HC-FR4, respectively). In some embodiments, an anti-TF antibody comprises the light chain variable domain framework sequence of SEQ ID NOs: 13, 14, 15, and 16 (LC-FR1, LC-FR2, LC-FR3, and LC-FR4, respectively).

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

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

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

EVQLLESGGGLVQPGGSLRLSCAASGTFFSNYAMSWVRQAPGKGLEWVSSISGS

GDYTYYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSPWGYYLDSWGQG

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

DIQMTQSPPSLSASAGDRVTITCRASQGISSRLAWYQQKPEKAPKSLIYAASSLQSGVPSR

FSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ Ш NO:8).

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

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

b) CDR-H2 (ISGSGDYT (SEQ ID NO: 2)); And

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

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

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

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

c) HC-FR3 (YYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO: 11)); And

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

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

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

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

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

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

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

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

c) LC-FR3 (SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 15)); And

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

According to 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:

(a) a heavy chain variable domain comprising:

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

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

- 16 048942 (3) HC-FR2, comprising the amino acid sequence of SEQ ID NO: 10;

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

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

(6) CDR-H3 comprising the amino acid sequence of 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:

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

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

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

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

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

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

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

In some embodiments, provided herein is an anti-TF antibody comprising a heavy chain variable domain comprising an amino acid sequence having at least 85, 86, 87, 88, 89, 9θ, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In certain embodiments, the heavy chain variable domain comprising an amino acid sequence having at least 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7 comprises substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence and retains the ability to bind to a TF (e.g., human TF). In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 7. In certain embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., in the FRs). In some embodiments, an anti-TF antibody comprises the heavy chain variable domain sequence of SEQ ID NO: 7, including post-translational modifications of such sequence. In a specific embodiment, the heavy chain variable domain comprises one, two, or three CDRs selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3.

In some embodiments, provided herein is an anti-TF antibody comprising a light chain variable domain comprising an amino acid sequence having at least 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the light chain variable domain comprising an amino acid sequence having at least 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8 allows for substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence and retains the ability to bind to a TF (e.g., human TF). In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 8. In certain embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside of the CDRs (i.e., in the FRs). In some embodiments, an anti-TF antibody comprises the light chain variable domain sequence of SEQ ID NO: 8, including post-translational modifications of such sequence. In a specific embodiment, the light chain variable domain comprises one, two, or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

In some embodiments, an anti-TF antibody comprises a heavy chain variable domain as in any of the above embodiments and a light chain variable domain as in any of the above embodiments. In one embodiment, the antibody comprises the heavy chain variable domain sequence of SEQ ID NO: 7 and the light chain variable domain sequence of SEQ ID NO: 8, including the post-translational moieties

- 17 048942 modifications of such sequences.

According to some embodiments, the anti-TF antibody of the anti-TF antibody drug conjugate comprises: i) a heavy chain CDR1 shown in SEQ ID NO: 1, a heavy chain CDR2 shown in SEQ ID NO: 2, a heavy chain CDR3 shown in SEQ ID NO: 3; and ii) a light chain CDR1 shown in SEQ ID NO: 4, a light chain CDR2 shown in SEQ ID NO: 5, and a light chain CDR3 shown in SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody drug conjugate are defined according to the IMGT numbering scheme.

According to some embodiments, the anti-TF antibody of the anti-TF antibody drug conjugate comprises: i) an amino acid sequence that is at least 85% identical to the heavy chain variable region set forth in SEQ ID NO: 7, and ii) an amino acid sequence that is at least 85% identical to the light chain variable region set forth in 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 WO 2011/157741 and WO 2010/066803.

The antibodies of the present invention may also be described or referred to in the context of their binding affinity to TF. Preferred binding affinities include those 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, ^5x10 ' ¹⁰ M, ^10-10 M, ^5x10-11 M, 10' ¹¹ M, 5x10' ¹² M, 10' ¹² M, 5x10' ¹³ M, 10' ^{13 M} , 5x10' ¹⁴ M, 10' ¹⁴ M, 5x10' ¹⁵ M or 10' ¹⁵ M.

There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, containing heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further subdivided into subclasses, for example, the following subclasses are expressed in humans: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in several polymorphic variants, called allotypes (reviewed in Jefferis and Lefranc 2009. mAbs Vol 1 Issue 4 1-7), any of which is suitable for use in some of the embodiments presented herein. Common allotypic variants in human populations are those designated by the letters a, f, n, z, or combinations thereof. According to any of the embodiments provided herein, the antibody may comprise a heavy chain Fc region comprising a human IgG Fc region. According to further embodiments, the human IgG Fc region is human IgG1.

Antibodies also include derivatives that are modified, i.e., by covalently attaching any type of molecule to the antibody such that the covalent attachment does not interfere with the binding of the antibody to TF or the manifestation of a cytostatic or cytotoxic effect on HD cells. For example, but not limited to, antibody derivatives include antibodies that have been modified, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting/blocking groups, proteolysis, coupling to a cellular ligand or other protein, etc. Any of a variety of 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, a derivative may contain one or more non-standard amino acids.

B. Structure of antibody-drug conjugate.

In some aspects, the anti-TF antibody-drug conjugates described herein comprise a linker between the anti-TF antibody or antigen-binding fragment thereof described herein and the 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 dipeptide (vc), and paminobenzyl carbamate (PAB). In some embodiments, the cleavable peptide linker is characterized by the formula MC-vc-PAB-, wherein:

- 18 048942

a) MS is:

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

In some embodiments, the linker is a cleavable peptide linker comprising maleimidocaproyl (MC). In some embodiments, the cleavable peptide linker is characterized by the formula MC-, wherein:

a) MS is:

In some embodiments, the linker is attached to sulfhydryl groups of the 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 groups of the 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 groups of the 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 described herein between the anti-TF antibody or antigen-binding fragment thereof described herein and the cytostatic or cytotoxic drug. Auristatins have been shown to disrupt microtubule dynamics, GTP hydrolysis, and nuclear and cell division (see Woyke et al. (2001) Antimicrob. Agents and Chemother. 45(12): 3580–3584) and have anticancer (see U.S. Patent Application No. 5,663,149) and antifungal activities (see Pettit et al., (1998) Antimicrob. Agents and Chemother. 42: 2961–2965). For example, auristatin E can be reacted with p-acetylbenzoic acid or benzoylvaleric acid to yield AEB and AEVB, respectively. Other typical auristatin derivatives include AFP, MMAF (monomethyl auristatin F), and MMAE (monomethyl auristatin E). Suitable auristatins and analogs, derivatives and auristatin prodrugs, as well as suitable linkers for conjugating auristatins to Ab, are described, for example, in U.S. Patent Application Nos. 5,635,483, 5,780,588, and 6,214,345 and International Patent Application Publications WO 02088172, WO 2004010957, WO 2005081711, WO 2005084390, WO 2006132670, WO 03026577, WO 200700860, WO 207011968, and WO 205082023. In some embodiments of the anti-TF antibody drug conjugates described herein, the cytostatic or cytotoxic drug is auristatin or a functional analog thereof (e.g., a functional peptide based on it) or a functional derivative thereof. According to some embodiments, the auristatin is monomethyl auristatin or a functional analog thereof (e.g., a functional peptide based on it) or a functional derivative thereof.

- 19 048942

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

MMAE where the wavy line represents the linker attachment site.

According to one embodiment, the auristatin is monomethyl auristatin F (MMAF)

MMAF where the wavy line denotes the linker attachment site.

According to one embodiment, the cleavable peptide linker has the formula: MC-vc-PAB-, and is attached to MMAE. The resulting auristatin linker, MC-vcPAB-MMAE, is also referred to as vcMMAE. The vcMMAE drug-linker moiety and methods of conjugation are disclosed in WO2004010957, US7659241, US7829531 and US7851437. When vcMMAE is attached to an anti-TF antibody or antigen-binding fragment thereof described herein, the resulting structure is as follows:

AKMSlch PAB MMAK where p is a number from 1 to 8, e.g., p can be 3-5, S is a sulfhydryl group of an anti-TF antibody, and AB is an anti-TF antibody or antigen-binding fragment thereof described herein. In one embodiment, the average p in the population of antibody-drug conjugates is about 4. In some embodiments, p is determined by hydrophobic interaction chromatography (HIC), e.g., by separating the drug-loaded molecules based on increasing hydrophobicity, with the least hydrophobic unconjugated form eluting first, to the most hydrophobic form with 8 drug units eluting last, with the percent peak area corresponding to the relative distribution of the particular drug-loaded antibody-drug conjugate molecules. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols). In some embodiments, p is determined using reversed-phase high-performance liquid chromatography (RP-HPLC), such as by first performing a reduction reaction to completely dissociate the heavy and light chains of the ADC, then separating the light and heavy chains and their respective drug-loaded forms on an RP column, wherein the percent peak resulting from the integration of the light chain and heavy chain peaks, along with the assigned drug loading for each peak, is used to calculate a 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 has the formula: MC-vc-PAB-, and is attached to MMAF. The resulting auristatin linker, MC-vcPAB-MMAF, is also referred to as vcMMAF. In another embodiment, the non-cleavable linker MC is attached to MMAF. The resulting auristatin linker MC-MMAF is also referred to as mcMMAF. The drug-linker moieties vcMMAF and mcMMAF and methods of conjugation are disclosed in WO 2005081711 and US 7,498,298. When vcMMAF or mcMMAF is attached to an anti-TF antibody or antigen-binding fragment thereof described herein, the resulting structure is as follows:

-20048942

mAb-MC-MMAF, wherein p is a number from 1 to 8, e.g., p can be 3-5, S is a sulfhydryl group of an anti-TF antibody, and Ab or mAb is an anti-TF antibody or antigen-binding fragment thereof, as described herein. In one embodiment, the average p in the population of antibody-drug conjugates is about 4. In some embodiments, p is determined by hydrophobic interaction chromatography (HIC), e.g., by separating the drug-loaded molecules based on increasing hydrophobicity, with the least hydrophobic unconjugated form eluting first, to the most hydrophobic form with 8 drug units eluting last, with the peak area percentage corresponding to the relative distribution of the particular drug-loaded antibody-drug conjugate molecules. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols). In some embodiments, p is determined using reversed-phase high-performance liquid chromatography (RP-HPLC), such as by first performing a reduction reaction to completely dissociate the heavy and light chains of the ADC, then separating the light and heavy chains and their respective drug-loaded forms on an RP column, wherein the percent peak resulting from the integration of the light chain and heavy chain peaks, along with the assigned drug loading for each peak, is used to calculate a weighted average drug to antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

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

C. Nucleic acids, host cells and methods of production.

In some aspects, provided herein are also nucleic acids encoding an anti-TF antibody or antigen-binding fragment thereof as described herein. Further provided herein are vectors comprising nucleic acids encoding an anti-TF antibody or antigen-binding fragment thereof as described herein. Further provided herein are host cells expressing nucleic acids encoding an anti-TF antibody or antigen-binding fragment thereof as described herein. Further provided herein are host cells comprising vectors comprising nucleic acids encoding an anti-TF antibody or antigen-binding fragment thereof as described herein. Methods for producing an anti-TF antibody, a linker, and an antibody-drug conjugate are described in U.S. Patent Application No. 9,168,314.

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, the antibodies are produced in a CHO cell using a GS expression vector system as disclosed in De la Cruz Edmunds et al., 2006, Molecular Biotechnology 34; 179-190, EP216846, US Patent Application No. 5,981,216, WO 87/04462, EP323997, US Patent Application No. 5,591,639, US Patent Application No. 5,658,759, EP338841, US Patent Application No. 5,879,936, and US Patent Application No. 5,891,693.

After the antibodies have been isolated and purified from the cell medium using techniques well known in the art, they are conjugated to auristatin via a linker as described in U.S. Patent Application No. 9,168,314.

The anti-TF monoclonal antibodies 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 methods based on recombinant DNA technology. Monoclonal antibodies can also be isolated from antibody phage 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 an antigen of interest, for example in the form of cells expressing the antigen on the surface or nucleic acid encoding the antigen of interest. Monoclonal antibodies can also be obtained from hybridomas derived from antibody-expressing cells of immunized humans or non-human mammals such as rats, dogs, primates, etc.

In one embodiment, the antibody of the present invention is a human antibody. Human monoclonal antibodies directed against tissue factor can be produced using transgenic or transchromosomal mice that carry elements 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 collectively referred to herein as transgenic mice.

The HuMAb mouse has a human immunoglobulin gene minilocus that encodes unrearranged sequences of the human immunoglobulin heavy (μ- and γ-) and light κ-chains, together with targeted mutations that inactivate the endogenous μ- and κ-chain loci (Lonberg, N. et al., Nature, 368, 856-859 (1994)). Consequently, mice have reduced levels of expression of IgM or anti-mouse IgM, and in response to immunization, the introduced transgenes encoding human heavy and light chains undergo a process of class switching and somatic mutation to produce high-affinity monoclonal human IgGK (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N. Handbook of Experimental Pharmacology 113, 49-101 (1994), Lonberg, N. and Huszar. D., Intern. Rev. Immunol, Vol. 13 6593 (1995) and Harding, F. and Lonberg, N. Ann, NY. 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. 5:647-656 (1993), Tuaillon at al., J. Immunol, 152:2912-2920 (1994), Taylor, L. et al., International Immunology, 6:579-591 (1994), Fishwild, D. et al., Nature Biotechnology, 14:845-851 (1996). See also U.S. Patent Application No. 5,545,806, U.S. Patent Application No. 5,569,825, U.S. Patent Application No. 5,625,126, U.S. Patent Application No. 5,633,425, U.S. Patent Application No. 5,789,650, U.S. Patent Application No. 5,877,397, U.S. Patent Application No. 5,661,016, U.S. Patent Application No. 5,814,318, U.S. Patent Application No. 5,874,299, U.S. Patent Application No. 5,770,429, U.S. Patent Application No. 5,545,807, 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 modification in their endogenous light chain (kappa) genes (as described in Chen et al., EMBO J. 12:821-830 (1993)), a CMD modification in their endogenous heavy chain genes (as described in Example 1 of WO 01/14424), the presence of a human kappa light chain KCo5 transgene (as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)) and the presence of a human heavy chain HCo7 transgene (as described in U.S. Patent Application No. 5,770,429).

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

The transgenic mouse strain HCo17 (see also US 2010/0077497) was generated by co-injection of the 80-kb pHC2 insert (Taylor et al. (1994) Int. Immunol., 6:579–591), the 1-kb pVX6 insert, and the 460-kb yIgH24 chromosome fragment as a yeast artificial chromosome. The strain was named (HCo17) 25950. (HCo17) 25950 mice were then crossed with mice carrying the CMD mutation (described in Example 1 of PCT publication WO 01109187), the JKD mutation (Chen et al., (1993) EMBO J. 12:811-820), and the (KC05) 9272 transgene (Fishwild et al. (1996) Nature Biotechnology, 14:845-851). The resulting mice express human immunoglobulin heavy and light chain transgenes in a homozygous form for a disruption in the structure of the endogenous kappa heavy and light chain gene loci.

The HCo20 transgenic mouse strain is the result of co-injection of the pHC2 heavy chain minilocus 30 transgene, the YAC yIgH10 containing the variable region (Vh) germline sequence, and the pVx6 minilocus construct (described in WO 09097006). The (HCo20) mice were then crossed with mice carrying 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 10 transgenes of human immunoglobulin heavy and light kappa chains in a homozygous form for a disruption in the structure of the endogenous heavy and light kappa chain loci.

In order to produce HuMab mice with the beneficial effects of the Balb/c strain, HuMab mice were crossed

- 22 048942 were crossed with KCO05 [MIK] (Balb) mice, which were obtained by backcrossing mice of the KC05 strain (as described in Fishwild et al. (1996) Nature Biotechnology, 14:845-851) to wild-type Balb/c mice to produce the mice described in WO 09097006. Using this cross, Balb/c hybrids were created for the HCo12, HCo17 and HCo20 strains.

In the KM mouse strain, the endogenous mouse kappa light chain gene has been disrupted in a homozygous form as described in Chen et al., EMBO J. 12:811-820 (1993), and the endogenous mouse heavy chain gene has been disrupted in a homozygous form as described in Example 1 of WO 01/09187. This mouse strain carries a 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 gene transchromosome consisting of the hCF fragment of chromosome 14 (SC20), as described in WO 02/43478.

Splenocytes from such transgenic mice can be used to produce hybridomas that secrete human monoclonal antibodies according to well-known techniques, the monoclonal or polyclonal antibodies of the present invention, or the antibodies of the present invention from other species can also be produced transgenically by obtaining another non-human mammal or plant that is transgenic for the immunoglobulin heavy and light chain sequences of interest and producing the antibody therefrom in a form that can be isolated. In combination with transgenic production in mammals, the antibodies can be produced and isolated from the milk of goats, cows or other mammals. See, for example, U.S. Patent Application No. 5,827,690, U.S. Patent Application No. 5,756,687, U.S. Patent Application No. 5,750,172, and U.S. Patent Application No. 5,741,957.

In addition, the human antibodies of the invention or the antibodies of the invention from other species can be produced using display-type technologies, including, but not limited to, phage display, retroviral display, ribosome display, and other techniques, using techniques well known in the art, and the resulting molecules can be subjected to further maturation, such as affinity maturation, and such techniques are well known in the art (see, e.g., Hoogenboom et al., J. Mol. Biol. 227(2):381-388 (1992) (phage display), Vaughan et al., Nature Biotech, 14:309 (1996) (phage display), Hanes and Plucthau, PNAS USA 94:4937-4942 (1997) (ribosome display), Parmley and Smith, Gene, 73:305-318 (1988) (phage display), Scott, TIBS. 17:241-245 (1992), Cwirla et al., PNAS USA, 87:6378-6382 (1990), Russel et al., Nucl. Acids Research, 21:1081-4085 (1993), Hogenboom et al., Immunol, Reviews, 130:43-68 (1992), Chiswell and McCafferty, TIBTECH, 10:80-84 (1992) and U.S. Patent Application No. 5,733,743). If display technologies are used to produce antibodies that are not human, such antibodies may be humanized.

III. Treatment methods

A. Cervical cancer.

Despite advances in screening, diagnosis, prevention, and treatment, cervical cancer remains a leading cause of cancer-related death among women, accounting for ~4% of all newly diagnosed cancer cases and 4% of all deaths. See Zhu et al., 2016, Drug Des. Devel. Ther. 10:1885–1895. Cervical cancer is the 7th most common cancer in women worldwide and the 16th most common cancer in the European Union. Depending on the stage at initial presentation, cervical cancer will recur in 25–61% of women. See Tempfer et al., 2016, Oncol. Res. Treat. 39:525–533. In most cases, recurrence is diagnosed within 2 years of initial treatment and may occur in a variety of sites. Chemotherapy is the standard treatment for these patients. See Zhu et al., 2016, Drug Des. Devel. Ther. 10:1885-1895. Median overall survival now exceeds one year, but the five-year relative survival rate for stage IV cervical cancer is only 15%, indicating a high need for improved treatments for cervical cancer.

The present invention relates to methods of treating cervical cancer using an antibody drug conjugate described herein. In a preferred aspect, the antibody drug conjugate is tisotumab vedotin. In one aspect, the antibody drug conjugates described herein are for use in a method of treating cervical cancer in a subject. In some embodiments, the subject has not previously been treated for cervical cancer. In some embodiments, the subject has received at least one prior treatment for cervical cancer. In some embodiments, the subject has previously been treated with bevacizumab. In some embodiments, the subject is not suitable for treatment with bevacizumab.

In some embodiments, the subject is not a candidate for radical therapy. In some embodiments, the radical therapy is radiation therapy and/or exenterative therapy. In some embodiments, the radical therapy is radiation therapy. In some embodiments, the radical therapy is exenterative therapy. In a particular embodiment,

- 23 048942 the subject of implementation is a person.

In some embodiments of the methods or uses provided herein, the cervical cancer is an 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 an adenosquamous carcinoma. In some embodiments, the cervical cancer is a squamous cell carcinoma. In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cervical cancer cells express TF. In some embodiments, the percentage of cells 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 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, the cervical cancer is classified into stages using the International Federation of Gynecology and Obstetrics (FIGO) staging system. In some embodiments, the staging is based on a clinical examination. In some embodiments, in stage 0 cervical cancer, the carcinoma is limited to the superficial layer (cell lining) of the cervix. In some embodiments, in stage 1 cervical cancer, the carcinoma has grown deeper into the cervix, but has not yet spread beyond it. In some embodiments, in stage 1A cervical cancer, invasive carcinoma can be diagnosed by microscopy alone and the deepest invasion is less than 5 mm and the greatest extent is less than 7 mm. In some embodiments, in stage 1B cervical cancer, the lesions are clinically visible and are limited to the cervix. In some embodiments, in stage 2 cervical cancer, cervical carcinoma has invaded beyond the uterus but not into the pelvic wall or the lower third of the vagina. In some embodiments, in stage 2A cervical cancer, parametrial invasion is not observed. In some embodiments, in stage 2B cervical cancer, parametrial invasion is observed. In some embodiments, in stage 3 cervical cancer, the tumor invades the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or loss of renal function. In some embodiments, in stage 3A cervical cancer, the tumor involves the lower third of the vagina, with extension into the pelvic wall. In some embodiments, in stage 3B, cervical cancer has extended into the pelvic wall and/or has caused hydronephrosis or loss of renal function. In some embodiments, in stage 4 cervical cancer, the carcinoma has spread beyond the pelvis or has involved the lining of the bladder or rectum. In some embodiments, in stage 4A cervical cancer, the tumor has spread to adjacent organs. In some embodiments, in stage 4B cervical cancer, the tumor has spread to distant organs. In some embodiments, the cervical cancer is advanced cervical cancer, such as stage 3 or stage 4 cervical cancer. In some embodiments, the advanced cervical cancer is metastatic cervical cancer. In some embodiments, the cervical cancer is metastatic cervical cancer and recurrent cervical cancer. In some embodiments, the cervical cancer is metastatic cervical cancer. In some embodiments, the cervical cancer is recurrent cervical cancer.

In some embodiments of the methods or uses provided herein, the subject has previously been treated for cervical cancer. In some embodiments, the subject has not responded to the treatment (e.g., the subject has developed a pro

- 24 048942 disease progression during treatment). In some embodiments, the one or more therapeutic agents administered to the subject is not an anti-TF antibody drug conjugate as described herein. In some embodiments, the one or more therapeutic agents administered to the subject is paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some embodiments, the one or more therapeutic agents administered to the subject is a platinum-based therapeutic agent. In some embodiments, the one or more therapeutic agents administered to the subject is gemcitabine and fluorouracil. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are bevacizumab. In some embodiments, the one or more therapeutic agents administered to the subject are selected from the group consisting of a chemotherapeutic 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, a combination of paclitaxel and topotecan, a combination of bevacizumab and topotecan, a combination of bevacizumab, cisplatin and paclitaxel, a combination of bevacizumab, carboplatin and paclitaxel, and a combination of bevacizumab, paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a chemotherapeutic agent. In some embodiments, the one or more therapeutic agents administered to the subject was cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject was carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject was paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject was topotecan. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of bevacizumab and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject has undergone treatment for cervical cancer using radiation and has not responded to the radiation. In some embodiments, the subject has not responded to treatment with up to two prior systemic treatment regimens. In some embodiments, the subject has not responded to treatment with one or two prior systemic treatment regimens. In some embodiments, the subject has not responded to treatment with one prior systemic treatment regimen. In some embodiments, the subject has not responded to treatment with two prior systemic treatment regimens.

In some embodiments of the methods or uses provided herein, the subject has previously been treated for cervical cancer with one or more therapeutic agents. In some embodiments, the subject has relapsed following treatment. In some embodiments, the one or more therapeutic agents administered to the subject is not an anti-TF antibody drug conjugate as described herein. In some embodiments, the one or more therapeutic agents administered to the subject is paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some embodiments, the one or more therapeutic agents administered to the subject is a platinum-based therapeutic agent. In some

- 25 048942 In some embodiments, the one or more therapeutic agents administered to the subject are gemcitabine and fluorouracil. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are bevacizumab. In some embodiments, the one or more therapeutic agents administered to the subject are selected from the group consisting of a chemotherapeutic 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, a combination of paclitaxel and topotecan, a combination of bevacizumab and topotecan, a combination of bevacizumab, cisplatin and paclitaxel, a combination of bevacizumab, carboplatin and paclitaxel, and a combination of bevacizumab, paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a chemotherapeutic agent. In some embodiments, the one or more therapeutic agents administered to the subject was cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject was carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject was paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject was topotecan. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of bevacizumab and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject was a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject has been treated for cervical cancer using radiation and has relapsed following treatment with radiation. In some embodiments, the subject has relapsed following treatment with no more than two prior systemic treatment regimens. In some embodiments, the subject has relapsed following treatment with one or two prior systemic treatment regimens. In some embodiments, the subject has relapsed after treatment with one prior systemic treatment regimen. In some embodiments, the subject has relapsed after treatment with two prior systemic treatment regimens.

In some embodiments of the methods or uses provided herein, the subject has previously been treated for cervical cancer with one or more therapeutic agents. In some embodiments, the subject has exhibited disease progression following treatment. In some embodiments, the one or more therapeutic agents administered to the subject is not an anti-TF antibody drug conjugate as described herein. In some embodiments, the one or more therapeutic agents administered to the subject is paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some embodiments, the one or more therapeutic agents administered to the subject is a platinum-based therapeutic agent. In some embodiments, the one or more therapeutic agents administered to the subject are gemcitabine and fluorouracil. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject are paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are

- 26,048,942 agents were bevacizumab. According to some embodiments, the one or more therapeutic agents administered to the subject is selected from the group consisting of a chemotherapeutic 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, a combination of paclitaxel and topotecan, a combination of bevacizumab and topotecan, a combination of bevacizumab, cisplatin and paclitaxel, a combination of bevacizumab, carboplatin and paclitaxel, and a combination of bevacizumab, paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a chemotherapeutic agent. In some embodiments, the one or more therapeutic agents administered to the subject is cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject is carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject is paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is topotecan. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and cisplatin. In some embodiments, the one or more therapeutic agents administered to the subject is a combination of bevacizumab and carboplatin. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of paclitaxel and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab and topotecan. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, the one or more therapeutic agents administered to the subject are a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject has previously been treated for cervical cancer using radiation and has experienced disease progression following treatment with radiation. In some embodiments, the subject has experienced disease progression following treatment with no more than two prior systemic treatment regimens. In some embodiments, the subject has exhibited disease progression following treatment with one or two prior systemic treatment regimens. In some embodiments, the subject has exhibited disease progression following treatment with one prior systemic treatment regimen. In some embodiments, the subject has exhibited disease progression following treatment with two prior systemic treatment regimens.

B. Routes of administration.

The antibody or antigen-binding fragment thereof drug conjugate described herein can be administered by any suitable route and method. Suitable routes for administering the antibody drug conjugate of the present invention are well known in the art and can be selected by those skilled in the art. According to one embodiment, the antibody drug conjugate is administered parenterally. Parenteral administration refers to routes of administration other than enteral and local administration, typically by injection, and includes epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal injection and infusion. In some embodiments, the route of administration of the antibody or antigen-binding fragment drug conjugate described herein is intravenous injection or infusion. In some embodiments, the route of administration of the antibody or antigen-binding fragment drug conjugate described herein is intravenous infusion.

C. Dosage and frequency of administration.

According to one aspect, the present invention relates to methods of treating a subject with cervical cancer as described herein using a specific dose of the antibody or antigen-binding fragment thereof and a drug conjugate described herein, wherein the antibody or antigen-binding fragment thereof and a drug conjugate described herein are administered to the subject at a specific frequency.

According to one embodiment of the methods or

- 27 048 942 uses, the antibody or antigen-binding fragment thereof drug conjugate described herein is administered to a subject at a dose in the range of about 1.5 mg/kg to about 2.1 mg/kg of the subject's body weight. In certain embodiments, the dose is about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, or about 2.1 mg/kg. In one embodiment, the dose is about 2.0 mg/kg. In one embodiment, the dose is 2.0 mg/kg. In some embodiments, the dose is 2.0 mg/kg and the antibody drug conjugate is tisotumab vedotin.

According to one embodiment of the methods or uses or product intended for use provided herein, the anti-TF antibody or antigen-binding fragment thereof drug conjugate described herein is administered to a subject at a dose in the range of about 0.65 mg/kg to about 2.1 mg/kg of the subject's body weight. In certain embodiments, the dose is about 0.65 mg/kg, about 0.7 mg/kg, about 0.75 mg/kg, about 0.8 mg/kg, about 0.85 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, or about 2.1 mg/kg. In one embodiment, the dose is about 0.65 mg/kg. In one embodiment, the dose is about 0.9 mg/kg. In one embodiment, the dose is about 1.3 mg/kg. In one embodiment, the dose is about 2.0 mg/kg. In certain embodiments, the dose is 0.65 mg/kg, 0.7 mg/kg, 0.75 mg/kg, 0.8 mg/kg, 0.85 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, or 2.1 mg/kg. In one embodiment, the dose is 0.65 mg/kg. In one embodiment, the dose is 0.9 mg/kg. In one embodiment, the dose is 1.3 mg/kg. In one embodiment, the dose is 2.0 mg/kg. In some embodiments, the dose is 0.65 mg/kg and the anti-TF antibody drug conjugate is tizotumab-vedotin. In some embodiments, the dose is 0.9 mg/kg and the anti-TF antibody drug conjugate is tizotumab-vedotin. In some embodiments, the dose is 1.3 mg/kg and the anti-TF antibody drug conjugate is tizotumab-vedotin. In some embodiments, the dose is 2.0 mg/kg and the anti-TF antibody drug conjugate is tizotumab-vedotin. In some embodiments, for a subject weighing greater than 100 kg, the dose of anti-TF antibody drug conjugate administered is the amount that would be administered if the subject weighed 100 kg. In some embodiments, for a subject weighing greater than 100 kg, the dose of the administered anti-TF antibody-drug conjugate is 65 mg, 90 mg, 130 mg, or 200 mg.

In one embodiment of the methods or uses provided herein, an antibody or antigen-binding fragment thereof drug conjugate described herein is administered to the subject once about every 1 to 4 weeks. In certain embodiments, an antibody or antigen-binding fragment thereof drug conjugate described herein is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks. In one embodiment, an antibody or antigen-binding fragment thereof drug conjugate described herein is administered once about every 3 weeks. In one embodiment, an antibody or antigen-binding fragment thereof drug conjugate described herein is administered once every 3 weeks. In some embodiments, the dose is about 0.65 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 0.65 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 0.65 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 0.65 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 0.7 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 0.7 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 0.7 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 0.7 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 0.75 mg/kg and is administered once about every 1 week. In some embodiments, the dose is approximately 0.75

- 28,048,942 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 0.75 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 0.75 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 0.8 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 0.8 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 0.8 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 0.8 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 0.85 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 0.85 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 0.85 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 0.85 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 0.9 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 0.9 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 0.9 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 0.9 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.0 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.0 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.0 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.0 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.1 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.1 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.1 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.1 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.2 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.2 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.2 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.2 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.3 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.3 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.3 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.3 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.4 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.4 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.4 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.4 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.5 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.5 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.5 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.5 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.6 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.6 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.6 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.6 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.7 mg/kg and is administered once about every 1 week. In some embodiments, the dose is

- 29 048942 about 1.7 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.7 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.7 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.8 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.8 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.8 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.8 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 1.9 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 1.9 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 1.9 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 1.9 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 2.0 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 2.0 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 2.0 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 2.0 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is about 2.1 mg/kg and is administered once about every 1 week. In some embodiments, the dose is about 2.1 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is about 2.1 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is about 2.1 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 0.65 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 0.65 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 0.65 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 0.65 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 0.7 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 0.7 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 0.7 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 0.7 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 0.75 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 0.75 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 0.75 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 0.75 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 0.8 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 0.8 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 0.8 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 0.8 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 0.85 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 0.85 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 0.85 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 0.85 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 0.9 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.0 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.1 mg/kg and is

- 30 048942 is administered once about every 1 week. In some embodiments, the dose is 1.1 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.2 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.3 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.4 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.5 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.6 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.7 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.8 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.9 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.1 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once about every 4 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 3 weeks (e.g., ±3 days). In some embodiments, the dose is 2.0 mg/kg and is administered once every 3 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once every 3 weeks, and the antibody drug conjugate is tisotumab vedotin. In some embodiments, the dose is 2.0 mg/kg and is administered once every 3 weeks, and the antibody drug conjugate is tizotumab vedotin, and the dose is reduced to 1.3 mg/kg if one or more adverse events occur. In some embodiments

- 31 048942 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 occur. In some embodiments, the dose is about 0.9 mg/kg and is administered once about every week and the antibody drug conjugate is tizotumab vedotin. In some embodiments, the dose is 0.9 mg/kg and is administered once every week, and the antibody drug conjugate is tizotumab vedotin. In some embodiments, the dose is about 0.65 mg/kg and is administered once about every week, and the antibody drug conjugate is tizotumab vedotin. In some embodiments, the dose is 0.65 mg/kg and is administered once every week, and the antibody drug conjugate is tizotumab vedotin. In some embodiments, for a subject weighing greater than 100 kg, the dose of anti-TF antibody drug conjugate administered is the amount that would be administered if the subject weighed 100 kg. In some embodiments, for a subject weighing greater than 100 kg, the dose of the administered anti-TF antibody-drug conjugate is 65 mg, 90 mg, 130 mg, or 200 mg.

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

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

In some embodiments, the method of treatment or use described herein also comprises administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are administered simultaneously with the antibody or antigen-binding fragment thereof drug conjugate described herein, such as tisotumab vedotin. In some embodiments, the one or more additional therapeutic agents and the antibody or antigen-binding fragment thereof drug conjugate described herein are administered sequentially.

- 32 048942

D. Treatment result.

In one aspect, a method of treating cervical cancer using the antibody or antigen-binding fragment thereof-drug conjugates described herein results in an improvement in one or more therapeutic effects in a subject after administration of the antibody-drug conjugate, compared to baseline. In some embodiments, the one or more therapeutic effects are cervical cancer tumor size, objective response rate, duration of response, time to response, progression-free survival, overall survival, or any combination thereof. In one embodiment, the one or more therapeutic effects are cervical cancer tumor size. In one embodiment, the one or more therapeutic effects are reduced tumor size. In one embodiment, the one or more therapeutic effects are disease stabilization. In one embodiment, the one or more therapeutic effects are a partial response. In one embodiment, the one or more therapeutic effects are a complete response. In one embodiment, the one or more therapeutic effects are an objective response rate. In one embodiment, one or more therapeutic effects are duration of response. In one embodiment, one or more therapeutic effects are time to response. In one embodiment, one or more therapeutic effects are progression-free survival. In one embodiment, one or more therapeutic effects are overall survival. In one embodiment, one or more therapeutic effects are cancer regression.

According to one embodiment of the methods or uses provided herein, the response to treatment using the antibody or antigen-binding fragment thereof drug conjugate described herein may include the following criteria (RECIST 1.1 criteria): ____________________________________________________

Category Criteria Based on Full answer Disappearance of all target lesions. target (CR) Any pathological lymph nodes hearths should be characterized by a decrease in size defeats along the short axis up to <10 mm. Partial answer > 30% reduction in the sum of the largest diameters (PR) (LD) of target lesions, taking the initial LD sum as the starting point. Stabilization There is no sufficient reduction to diseases (SD) to qualify for PR, nor sufficient increase to qualify for PD, taking as a starting point the lowest LD amount during the trial. Progressing > 20% (and > 5 mm) increase in the sum of LD targets diseases (PD) lesion lesions, taking as a starting point the lowest sum of target LD recorded during the test, or the appearance of one or more new lesions. Based on CR Disappearance of all non-target lesions and non-targeted normalization of tumor marker levels. All hearths lymph nodes should be defeats non-pathological size (< 10 mm along the short axis). SD Persistent presence of one or more non-target lesions and/or maintenance of tumor marker levels above normal limits. PD The appearance of one or more new lesions and/or apparent progression of existing non-target lesions.

- 33 048942

In one embodiment of the methods or uses provided herein, the efficacy of treatment using an antibody or antigen-binding fragment thereof drug conjugate described herein is assessed by measuring the objective response rate. In some embodiments, the objective response rate is the proportion of patients with a reduction in tumor size by a given amount and within a minimum period of time. In some embodiments, the objective response rate is determined based on RECIST v1.1. In one embodiment, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In one embodiment, the objective response rate is at least about 20%-80%. 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%. In one embodiment, the objective response rate 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 100%.

In one embodiment of the methods or uses provided herein, the response to treatment using the antibody or antigen-binding fragment thereof drug conjugate described herein is assessed by measuring the size of the tumor resulting from the cervical cancer. In one embodiment, the size of the tumor resulting from the 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 resulting from the cervical cancer before administration of the antibody drug conjugate. According to one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 10%-80%. According to one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 20%-80%. According to one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 30%-80%. According to one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 40%-80%. According to one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 50%-80%. According to one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 60%-80%. According to one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 70%-80%. In one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 80%. In one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 85%. In one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 90%. In one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 95%. In one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 98%. In one embodiment, the size of the tumor resulting from cervical cancer is reduced by at least about 99%. In one embodiment, the size of the tumor resulting from cervical cancer is reduced by 100%. In one embodiment, the size of the tumor resulting from cervical cancer is measured using magnetic resonance imaging (MRI). In one embodiment, the size of the tumor resulting from

- 34 048942 resulting from cervical cancer is measured using computed tomography (CT). In some embodiments, the tumor size resulting from cervical cancer is measured using a gynecologic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205.

In one embodiment of the methods or uses provided herein, the response to treatment using a conjugate of an antibody or antigen-binding fragment thereof and a drug, such as, for example, tisotumabvedotin, described herein promotes regression of a tumor resulting from cervical cancer. In one embodiment, the tumor resulting from cervical cancer 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 tumor resulting from cervical cancer prior to administration of the antibody-drug conjugate. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 10%-80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 20%-80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 30%-80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 40%-80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 50%-80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 60%-80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 70%-80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 80%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 85%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 90%. According to one embodiment, the tumor resulting from cervical cancer regresses by at least about 95%.

In one embodiment, the tumor resulting from cervical cancer regresses by at least about 98%. In one embodiment, the tumor resulting from cervical cancer regresses by at least about 99%. In one embodiment, the tumor resulting from cervical cancer regresses by 100%. In one embodiment, tumor regression is determined by measuring tumor size using magnetic resonance imaging (MRI). In one embodiment, tumor regression is determined by measuring tumor size using computed tomography (CT). In some embodiments, tumor regression is determined by measuring tumor size using a gynecologic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205.

In some embodiments of the methods or uses provided herein, a response to treatment using an antibody or antigen-binding fragment thereof-drug conjugate described herein promotes regression in the number of tumors resulting from cervical cancer. In some embodiments, regression in the number of tumors is determined by detecting the number of tumors in a subject using an MRI, CT scan, or gynecologic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205.

According to one embodiment of the methods or uses described herein, the response to treatment using an antibody or antigen-binding fragment thereof drug conjugate described herein is assessed by measuring progression-free survival following administration of the antibody drug conjugate. According to some embodiments, the subject has progression-free survival for 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 eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of the antibody drug conjugate. In some embodiments, the subject experiences progression-free survival for at least about 6 months following administration.

- 35 048942 antibody drug conjugate. According to some embodiments, the subject experiences progression-free survival for at least about one year after administration of the antibody drug conjugate. According to some embodiments, the subject experiences progression-free survival for at least about two years after administration of the antibody drug conjugate. According to some embodiments, the subject experiences progression-free survival for at least about three years after administration of the antibody drug conjugate. According to some embodiments, the subject experiences progression-free survival for at least about four years after administration of the antibody drug conjugate. According to some embodiments, the subject experiences progression-free survival for at least about five years after administration of the antibody drug conjugate.

According to one embodiment of the methods or uses described herein, the response to treatment using an antibody or antigen-binding fragment thereof drug conjugate described herein is assessed by measuring overall survival following administration of the antibody drug conjugate. According to some embodiments, the subject has 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 eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of the antibody drug conjugate. In some embodiments, the subject has an overall survival of at least about 6 months after administration of the antibody-drug conjugate. In some embodiments, the subject has an overall survival of at least about one year after administration of the antibody-drug conjugate.

In some embodiments, the subject has an overall survival of at least about two years after administration of the antibody drug conjugate. In some embodiments, the subject has an overall survival of at least about three years after administration of the antibody drug conjugate. In some embodiments, the subject has an overall survival of at least about four years after administration of the antibody drug conjugate. In some embodiments, the subject has an overall survival of at least about five years after administration of the antibody drug conjugate.

According to one embodiment of the methods or uses described herein, the response to treatment using the antibody or antigen-binding fragment thereof-drug conjugate described herein is assessed by measuring the duration of the response to the antibody-drug conjugate after administration of the antibody-drug conjugate. In some embodiments, the duration of the response to the antibody drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen 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. In some embodiments, the duration of the response to the antibody drug conjugate is at least about 6 months after administration of the antibody drug conjugate. In some embodiments, the duration of the response to the antibody drug conjugate is at least about one year after administration of the antibody drug conjugate. In some embodiments, the duration of the response to the antibody drug conjugate is at least about two years after administration of the antibody drug conjugate. In some embodiments, the duration of the response to the antibody drug conjugate is at least about three years after administration of the antibody drug conjugate. In some embodiments, the duration of the response to the antibody drug conjugate is at least about four years after administration of the antibody drug conjugate. In some embodiments,

- 36 048942 the duration of response to the antibody-drug conjugate is at least approximately five years after administration of the antibody-drug conjugate.

E. Adverse events.

In one aspect, a method of treating cervical cancer using the antibody or antigen-binding fragment thereof drug conjugates described herein causes the subject to develop one or more adverse events. In some embodiments, the subject is administered an additional therapeutic agent to eliminate or reduce the severity of the adverse event. In some embodiments, the one or more adverse events developed by the subject are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, general deterioration in physical health, or any combination thereof. In some embodiments, the one or more adverse events are a grade 1 adverse event or higher. In some embodiments, the one or more adverse events are a grade 2 adverse event or higher. In some embodiments, one or more adverse events are a grade 3 or higher adverse event. In some embodiments, one or more adverse events are a grade 1 adverse event. In some embodiments, one or more adverse events are a grade 2 adverse event. In some embodiments, one or more adverse events are a grade 3 adverse event. In some embodiments, one or more adverse events are a grade 4 adverse event. In some embodiments, one or more adverse events are a serious adverse event. In some embodiments, one or more adverse events are conjunctivitis and/or keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. In some embodiments, the one or more adverse events are conjunctivitis and keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. In some embodiments, the one or more adverse events are conjunctivitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. In some embodiments, the one or more adverse events are keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. In some of any of the embodiments provided herein, the subject is administered the treatment agent with or without an additional therapeutic agent to eliminate or reduce the severity of the adverse event (e.g., conjunctivitis and/or keratitis). In some embodiments, the treatment agent is eye cooling pads (e.g., THERA PEARL eye mask or the like). In some embodiments, one or more adverse events are a recurrent infusion reaction, and the additional therapeutic agent is an antihistamine, acetaminophen, and/or a corticosteroid. In some embodiments, one or more adverse events are neutropenia, and the additional therapeutic agent is growth factor as a maintenance therapy (G-CSF).

In one aspect, a subject treated with the antibody or antigen-binding fragment thereof drug conjugates described herein is at risk of developing one or more adverse events. In some embodiments, the subject is administered an additional therapeutic agent to prevent the adverse event from developing or to reduce the severity of the adverse event. In some embodiments, the one or more adverse events that the subject is at risk of developing are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, general deterioration in physical health, or any combination thereof. In some embodiments, the one or more adverse events are a grade 1 adverse event or higher. In some embodiments, the one or more adverse events are a grade 2 adverse event or higher. In some embodiments, the one or more adverse events are a grade 3 or higher adverse event. In some embodiments, the one or more adverse events are a grade 1 adverse event. In some embodiments, the one or more adverse events are a grade 1 adverse event. In some embodiments, the one or more adverse events are a grade 1 adverse event.

- 37 048942 in which embodiments, the one or more adverse events are a grade 2 adverse event. According to some embodiments, the one or more adverse events are a grade 3 adverse event. According to some embodiments, the one or more adverse events are a grade 4 adverse event. According to some embodiments, the one or more adverse events are a serious adverse event. According to some embodiments, the one or more adverse events are conjunctivitis and/or keratitis, and the additional agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. According to some embodiments, the one or more adverse events are conjunctivitis and keratitis, and the additional agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. In some embodiments, the one or more adverse events are conjunctivitis and the additional agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. In some embodiments, the one or more adverse events are keratitis and the additional agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid-containing eye drop, or any combination thereof. In some of any of the embodiments provided herein, the treating agent is administered to the subject with or without an additional therapeutic agent to prevent the development of the adverse event or to reduce the severity of the adverse event (e.g., conjunctivitis and/or keratitis). In some embodiments, the treating agent is eye cooling pads (e.g., THERA PEARL eye mask or the like). In some embodiments, one or more adverse events are a recurrent infusion reaction and the additional agent is an antihistamine, acetaminophen, and/or a corticosteroid. In some embodiments, one or more adverse events are neutropenia and the additional agent is growth factor as maintenance therapy (G-CSF).

IV. Compositions.

In some aspects, the present disclosure also provides compositions (e.g., a pharmaceutical composition) comprising any of the anti-TF antibody-drug conjugates described herein.

Preservable therapeutic formulations are prepared by mixing the active ingredient of 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 nontoxic to recipients at the dosages and concentrations employed, and include buffers, antioxidants including ascorbic acid, methionine, vitamin E, sodium metabisulfite; preservatives, isotonizing agents, stabilizers, metal complexes (e.g., Zn-protein complexes); chelating agents such as EDTA, and/or nonionic surfactants.

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

Preservatives may be added to prevent the growth of microorganisms and are typically present at a concentration in the range of about 0.2% to 1.0% (w/v). Suitable preservatives for use with the present invention include octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium halides (e.g. chloride, bromide, iodide), benzethonium chloride; thimerosal, phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol.

Tonicity adjusting agents, sometimes known as stabilizers, may be present to adjust or maintain the tonicity of the fluid in the composition. When used with large charged biomolecules such as proteins and antibodies, they are often referred to as stabilizers because they can interact with the charged groups of the amino acid side chains to reduce the potential for inter- and intramolecular interactions. Tonicity adjusting agents may be present in any amount in the range of about 0.1% to about 25% by weight, or about 1% to about 5% by weight, with

- 38 048942 taking into account the relative amounts of other ingredients. According to some embodiments, the tonicity adjusting agents include polyhydric sugar alcohols, trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.

Additional excipients include those which may serve as one or more of the following: (1) bulking agents, (2) solubility enhancers, (3) stabilizers, and (4) agents which prevent denaturation or adhesion to the wall of the container. Such excipients include: polyhydric sugar alcohols (listed above); amino acids such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine, etc.; sugars or sugar alcohols such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbose, xylose, ribose, ribitol, myo-inositol, myo-inositol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), polyethyleneglycol; sulfur-containing reducing agents such as urea, glutathione, lipoic acid, sodium thioglycolate, thioglycerol, a-monothioglycerol, and sodium thiosulfate; low molecular weight proteins such as human serum albumin, bovine serum albumin, gelatin, or other immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides (e.g., xylose, mannose, fructose, glucose); disaccharides (e.g., lactose, maltose, sucrose); trisaccharides such as raffinose; and polysaccharides such as dextrin or dextran.

Nonionic surfactants or detergents (also known as wetting agents) may be present to aid in the dissolution of the therapeutic agent, as well as to protect the therapeutic protein from agitation-induced aggregation, which also allows the drug to be subjected to shear stress in the surface layer without causing denaturation of the active therapeutic protein or antibody. Nonionic surfactants are present at a concentration in the range of about 0.05 mg/mL to about 1.0 mg/mL, or about 0.07 mg/mL to about 0.2 mg/mL. In some embodiments, the nonionic surfactants are present at a concentration in the range of about 0.001% to about 0.1% w/v, or about 0.01% to about 0.1% w/v, or about 0.01% to about 0.025% w/v.

Suitable nonionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), poloxamers (184, 188, etc.), PLURONIC® polyols, TRITON®, polyoxyethylene sorbitan monoethers (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 comprising an anti-TF antibody conjugate described herein for use in the treatment methods provided herein are described in WO 2015/075201. In some embodiments, an anti-TF antibody drug conjugate described herein is in a formulation comprising an anti-TF antibody drug conjugate, histidine, sucrose, and D-mannitol, wherein the formulation has a pH of about 6.0. In some embodiments, an 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 at a concentration of about 88 mM, D-mannitol at a concentration of about 165 mM, wherein the formulation has a pH of about 6.0. In some embodiments, the anti-TF antibody drug conjugate described herein is in a formulation comprising the anti-TF antibody drug conjugate at a concentration of 10 mg/mL, histidine at a concentration of 30 mM, sucrose at a concentration of 88 mM, D-mannitol at a concentration of 165 mM, and the formulation has a pH of 6.0. In some embodiments, the formulation comprises tisotumab vedotin at a concentration of 10 mg/mL, histidine at a concentration of 30 mM, sucrose at a concentration of 88 mM, D-mannitol at a concentration of 165 mM, and the formulation has a pH of 6.0.

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

In order for the formulations to be used for in vivo administration, they must be sterile. The sterility of the formulation can be ensured by filtration through sterile filter membranes. The therapeutic compositions herein are typically placed in a container with a sterile access port, such as an intravenous solution bag or a vial with a stopper for piercing with a hypodermic needle.

The route of administration is consistent with known and accepted methods, such as single or multiple bolus administrations or infusion over a long period of time in a suitable manner, for example, injection or infusion via subcutaneous, intravenous, intraperitoneal,

- 39 048942 intramuscular, intraarterial, intralesional or intra-articular routes, local administration, inhalation or administration using slow-release or extended-release devices.

The composition according to the present document may also contain more than one active compound, according to the need for a particular indication to be treated, wherein preferably such compounds are characterized by complementary types of activity that do not negatively affect each other. Alternatively, or in addition, the composition may contain a cytotoxic agent, a cytokine or a growth inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the intended purpose.

The present invention relates to compositions comprising a population of antibody-drug conjugates of an anti-TF antibody or antigen-binding fragment thereof as described herein, for use in a method of treating cervical cancer as described herein. In some aspects, the present invention provides 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:

aL-MCl?AB-MMlE wherein p is a number from 1 to 8, S is a sulfhydryl group of an anti-TF antibody or antigen-binding fragment thereof, and AB is 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 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 for each antibody drug conjugate. In some embodiments, the population is a homogeneous population of antibody drug conjugates, wherein each antibody drug conjugate has the same p value.

In some embodiments, a composition comprising an antibody drug conjugate described herein is co-administered with one or more additional therapeutic agents. In some embodiments, the co-administration is simultaneous or sequential. In some embodiments, an antibody drug conjugate described herein is co-administered with one or more additional therapeutic agents. In some embodiments, simultaneously means that the antibody drug conjugate and the one or more therapeutic agents are administered to the subject less than one hour apart, such as less than about 30 minutes apart, less than about 15 minutes apart, less than about 10 minutes apart, or less than about 5 minutes apart. In some embodiments, an antibody drug conjugate described herein is co-administered with one or more additional therapeutic agents. In some embodiments, sequential administration means that the antibody drug conjugate and the one or more additional therapeutic agents are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 6 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart.

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In some embodiments, a composition comprising an antibody drug conjugate as described herein is co-administered with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, a composition comprising an antibody drug conjugate as described herein is co-administered with one or more therapeutic agents to prevent the development of an adverse event or to reduce the severity of an adverse event.

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

V. Products and sets.

According to another aspect, an article of manufacture or a kit is provided that comprises an anti-TF antibody drug conjugate as described herein. The article of manufacture or kit may further comprise instructions for using the antibody in the methods of the present invention. Thus, according to certain embodiments, the article of manufacture or kit comprises instructions for using an anti-TF antibody drug conjugate in methods of treating cervical cancer in a subject comprising administering to the subject an effective amount of an anti-TF antibody drug conjugate. According to some embodiments, the cervical cancer is advanced cervical cancer, such as stage 3 cervical cancer or stage 4 cervical cancer. According to some embodiments, the advanced cervical cancer is metastatic cancer. According to some embodiments, the cervical cancer is metastatic cancer and recurrent cancer. According to some embodiments, the cervical cancer is recurrent cancer. In some embodiments, the subject has previously been treated with one or more therapeutic agents and has not responded to the treatment, has recurred after treatment, or has shown disease progression during treatment. In some prior treatment embodiments provided herein, the one or more therapeutic agents are not an antibody-drug conjugate. In some embodiments, the subject is a human.

The product or kit may additionally include a container. Suitable containers

- 41 048942 include, for example, bottles, vials (such as dual-chamber vials), syringes (such as single- or dual-chamber syringes) and test tubes. According to some embodiments, the container is a vial. The container may be made of a number of materials, such as glass or plastic. The container contains the composition.

The article or kit may further comprise a label or package insert that is presented on or associated with the container and that may provide directions for reconstitution and/or use of the composition. The label or package insert may further indicate that the composition is suitable or intended for subcutaneous, intravenous (e.g., intravenous infusion) or other routes of administration for the treatment of cervical cancer in a subject, such as cervical cancer as described herein (e.g., advanced cervical cancer, such as stage 3 or stage 4 cervical cancer or metastatic cervical cancer). The container containing the composition may be a single-use vial or a multi-use vial that allows for repeated administrations of the reconstituted composition. The article or kit may further comprise a second container containing a suitable diluent. The article or kit may additionally include other materials desirable from a commercial, therapeutic, or user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

The article of manufacture or kit according to the present document optionally further comprises a container containing a second drug, wherein the conjugate of the antibody to TF and the drug is the first drug, and wherein the article of manufacture or kit further comprises instructions on the label or package insert for treating the subject with the second drug, in an effective amount. According to some embodiments, the label or package insert indicates that the first and second drugs are to be administered sequentially or simultaneously, as described herein.

The article of manufacture or kit according to the present document optionally further comprises a container containing a second drug, wherein the second drug is intended to eliminate or reduce the severity of one or more adverse events, wherein the conjugate of the antibody to TF and the drug is the first drug, and wherein the article of manufacture or kit further comprises instructions on the label or package insert for treating the subject with the second drug, in an effective amount. According to some embodiments, the label or package insert indicates that the first and second drugs are to be administered sequentially or simultaneously, as described herein, for example, the label or package insert indicates that the conjugate of the antibody to TF and the drug is to be administered first, followed by the administration of the second drug.

In some embodiments, the anti-TF antibody-drug conjugate is present in the container as a lyophilized powder. In some embodiments, the lyophilized powder is in a hermetically sealed container, such as a vial, ampoule, or sachet, on which the amount of the active agent is indicated. If the pharmaceutical is administered by injection, for example, an ampoule of sterile water for injection or saline solution may be provided, optionally as part of a kit, so that the ingredients can be mixed prior to administration. Such kits may further include, if desired, one or more of a number of standard 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. Printed instructions, either in the form of package inserts or labels, indicate the amounts of the components to be administered, and administration recommendations and/or mixing recommendations for the components may also be included in the kit.

VI. Illustrative embodiments.

Among the embodiments presented in this document are:

1. A method for treating cervical cancer in a subject, wherein the method comprises administering to the subject an antibody-drug conjugate that binds to tissue factor (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 thereof or a functional derivative thereof, and wherein the antibody-drug conjugate is administered at a dose in the range of about 1.5 mg/kg to about 2.1 mg/kg.

2. The method according to embodiment 1, wherein the dose is about 2.0 mg/kg.

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

4. The method according to any one of embodiments 1-3, wherein the antibody-drug conjugate is administered once about every 3 weeks.

5. The method according to any one of embodiments 1-4, wherein the subject has previously been subjected to

- 42 048942 has been treated with one or more therapeutic agents and has not responded to the treatment, where one or more therapeutic agents is not an antibody-drug conjugate.

6. The method according to any one of embodiments 1-4, wherein the subject has previously been treated with one or more therapeutic agents and has relapsed the disease following treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate.

7. The method according to any one of embodiments 1-4, wherein the subject has previously been treated with one or more therapeutic agents and has exhibited disease progression during the treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate.

8. The method according to any one of embodiments 5-7, wherein one or more therapeutic agents comprises a platinum-based therapeutic agent.

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

10. The method according to any one of embodiments 1-9, wherein the subject exhibits disease progression during or after treatment:

a) paclitaxel and cisplatin,

b) paclitaxel and carboplatin or

c) paclitaxel and topotecan.

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

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

13. The method according to any one of embodiments 1-12, wherein the subject is not a candidate for radical therapy.

14. The method according to embodiment 13, wherein the radical therapy comprises radiation therapy and/or exenterative surgery.

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

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

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

18. The method according to any one of embodiments 1-17, wherein the cervical cancer is late stage cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer.

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

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

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

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

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

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

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

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

23. The method according to any one of embodiments 1-22, wherein the anti-TF antibody, or antigen-binding fragment thereof, of the antibody-drug conjugate comprises a variable

- 43 048942 a heavy chain region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 8.

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

25. The method according to any one of embodiments 1-24, wherein the anti-TF antibody of the antibody-drug conjugate is tizotumab.

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

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

28. The method according to embodiment 27, wherein the cleavable peptide linker is characterized by the formula -MC-vc-ΡΑΒ-, wherein:

a) MS is:

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

29. The method according to any one of embodiments 26-28, wherein the linker is attached to sulfhydryl groups of the anti-TF antibody obtained by partial reduction or complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

30. The method of embodiment 29, wherein the linker is attached to MMAE, and the antibody-drug conjugate is characterized by the following structure:

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

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

32. The method according to any one of embodiments 1-31, wherein the antibody-drug conjugate is tisotumab vedotin.

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

34. The method of any one of embodiments 1-33, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cervical cancer cells express TF.

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35. The method according to any one of embodiments 1-34, wherein after administration of the antibody-drug conjugate, the subject experiences an improvement in one or more therapeutic effects relative to baseline.

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

37. The method of any one of embodiments 1-36, wherein the cervical cancer tumor size 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 cervical cancer tumor size prior to administration of the antibody drug conjugate.

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

39. The method of any one of embodiments 1-38, wherein the subject exhibits progression-free survival for 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 eighteen 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.

40. The method of any one of embodiments 1-39, wherein the subject has 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 eighteen 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.

41. The method of any one of embodiments 1-40, wherein the duration of the response to the antibody drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen 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.

42. The method according to any one of embodiments 1-41, wherein the subject experiences 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.

43. The method according to any one of embodiments 1-41, 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.

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

45. The method of embodiment 42 or embodiment 43, wherein one or more adverse events is a grade 3 or higher adverse event.

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46. The method of embodiment 42 or embodiment 43, wherein one or more adverse events is a serious adverse event.

47. The method of embodiment 42 or embodiment 43, wherein the one or more adverse events are conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricating eye drops, an ocular vasoconstrictor, and/or steroid-containing eye drops.

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

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

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

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

52. An antibody-drug conjugate for use according to embodiment 51, wherein the dose is about 2.0 mg/kg.

53. An antibody drug conjugate for use according to embodiment 51 or embodiment 52, wherein the antibody drug conjugate is administered once about every 1 week, 2 weeks, 3 weeks, or 4 weeks.

54. An antibody-drug conjugate for use according to any one of embodiments 51-53, wherein the antibody-drug conjugate is administered once about every 3 weeks.

55. An antibody-drug conjugate for use according to any one of embodiments 51-54, wherein the subject has previously been treated with one or more therapeutic agents and has not responded to the treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate.

56. An antibody-drug conjugate for use according to any one of embodiments 51-54, wherein the subject has previously been treated with one or more therapeutic agents and has relapsed following treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate.

57. An antibody-drug conjugate for use according to any one of embodiments 51-54, wherein the subject has previously been treated with one or more therapeutic agents and has exhibited disease progression during treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate.

58. An antibody-drug conjugate for use according to any one of embodiments 55-57, wherein the one or more therapeutic agents comprises a platinum-based therapeutic agent.

59. An antibody-drug conjugate for use according to any one of embodiments 55-57, wherein the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, and bevacizumab.

60. An antibody-drug conjugate for use according to any one of embodiments 51-59, wherein the subject has exhibited disease progression during or following treatment with:

a) paclitaxel and cisplatin,

b) paclitaxel and carboplatin or

c) paclitaxel and topotecan.

61. An antibody-drug conjugate for use according to any one of embodiments 51-60, wherein the subject has been treated with bevacizumab.

62. An antibody-drug conjugate for use according to any one of embodiments 51-60, wherein the subject is not eligible for treatment with bevacizumab.

63. An antibody-drug conjugate for use according to any one of embodiments 51-62, wherein the subject is not a candidate for definitive therapy.

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64. An antibody-drug conjugate for use according to embodiment 63, wherein the definitive therapy comprises radiation therapy and/or exenterative surgery.

65. An antibody-drug conjugate for use according to any one of embodiments 51-64, wherein the subject has not responded to treatment with no more than two prior systemic treatment regimens.

66. An antibody-drug conjugate for use according to any one of embodiments 51-64, wherein the subject has relapsed following treatment with no more than two prior systemic treatment regimens.

67. An antibody-drug conjugate for use according to any one of embodiments 51-66, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma.

68. An antibody-drug conjugate for use according to any one of embodiments 51-67, wherein the cervical cancer is late stage cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer.

69. An antibody-drug conjugate for use according to any one of embodiments 51-68, wherein the cervical cancer is recurrent cervical cancer.

70. An antibody-drug conjugate for use according to any one of embodiments 51-69, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

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

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

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

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

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

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

73. An antibody-drug conjugate for use according to any of embodiments 51-72, wherein the anti-TF antibody, or antigen-binding fragment thereof, of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 8.

74. An antibody-drug conjugate for use according to any one of embodiments 51-73, wherein the anti-TF antibody, or antigen-binding fragment thereof, of the antibody-drug conjugate 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 of SEQ ID NO: 8.

75. An antibody-drug conjugate for use according to any one of embodiments 51-74, wherein the anti-TF antibody of the antibody-drug conjugate is tizotumab.

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

77. An antibody-drug conjugate for use according to embodiment 76, wherein the linker is a cleavable peptide linker.

78. An antibody-drug conjugate for use according to embodiment 77, wherein the cleavable peptide linker is characterized by the formula -MC-VC-PAB-, wherein:

a) MS is:

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

79. An antibody-drug conjugate for use according to any one of embodiments 76-78, wherein the linker is attached to sulfhydryl groups of the anti-TF antibody obtained by partial reduction or full reduction of the anti-TF antibody or antigen-binding fragment thereof.

80. An antibody-drug conjugate for use according to embodiment 79, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate is characterized by the following structure:

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

8E An antibody-drug conjugate for use according to embodiment 80, wherein the average p value in the population of antibody-drug conjugates is about 4.

82. An antibody-drug conjugate for use according to any one of embodiments 51-81, wherein the antibody-drug conjugate is tisotumabvedotin.

83. An antibody-drug conjugate for use according to any one of embodiments 51-82, wherein the route of administration for the antibody-drug conjugate is intravenous.

84. An antibody drug conjugate for use according to any one of embodiments 51-83, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cervical cancer cells express TF.

85. An antibody-drug conjugate for use according to any one of embodiments 51-84, wherein after administration of the antibody-drug conjugate, the subject experiences an improvement in one or more therapeutic effects relative to baseline.

86. An antibody-drug conjugate for use according to embodiment 85, wherein the one or more therapeutic effects are selected from the group consisting of tumor size resulting from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

87. An antibody drug conjugate for use according to any one of embodiments 51-86, wherein the size of the cervical cancer 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 cervical cancer tumor prior to administration of the antibody drug conjugate.

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88. An antibody drug conjugate for use according to any one of embodiments 51-87, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

89. An antibody drug conjugate for use according to any of embodiments 51-88, wherein the subject exhibits progression-free survival for 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 eighteen 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.

90. An antibody drug conjugate for use according to any of embodiments 51-89, wherein the subject exhibits overall survival for 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 eighteen 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.

91. An antibody drug conjugate for use according to any of embodiments 51-90, wherein the duration of the response to the antibody drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen 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.

92. An antibody-drug conjugate for use according to any one of embodiments 51-91, wherein the subject experiences 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.

93. An antibody-drug conjugate for use according to any one of embodiments 51-91, 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.

94. An antibody-drug conjugate for use according to embodiment 92 or embodiment 93, wherein the one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general deterioration in physical health.

- 49 048942

95. An antibody-drug conjugate for use according to embodiment 92 or embodiment 93, wherein the one or more adverse events is a grade 3 or higher adverse event.

96. An antibody-drug conjugate for use according to embodiment 92 or embodiment 93, wherein one or more adverse events is a serious adverse event.

97. An antibody-drug conjugate for use according to embodiment 92 or embodiment 93, wherein the one or more adverse events are conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricating eye drops, an ocular vasoconstrictor, and/or steroid-containing eye drops.

98. An antibody-drug conjugate for use according to any one of embodiments 51-97, wherein the antibody-drug conjugate is administered as monotherapy.

99. An antibody-drug conjugate for use according to any one of embodiments 51-98, wherein the subject is a human.

100. An antibody-drug conjugate for use according to any one of embodiments 51-99, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

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

102. Use according to embodiment 101, wherein the dose is approximately 2.0 mg/kg.

103. The use according to embodiment 101 or embodiment 102, wherein the antibody-drug conjugate is administered once about every 1 week, 2 weeks, 3 weeks, or 4 weeks.

104. The use according to any one of embodiments 101-103, wherein the antibody-drug conjugate is administered once about every 3 weeks.

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

106. The use according to any one of embodiments 101-104, wherein the subject has previously been treated with one or more therapeutic agents and has relapsed the disease following treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate.

107. The use according to any one of embodiments 101-104, wherein the subject has previously been treated with one or more therapeutic agents and has exhibited disease progression during treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate.

108. The use according to any one of embodiments 105-107, wherein one or more therapeutic agents comprises a platinum-based therapeutic agent.

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

110. The use according to any one of embodiments 101-109, wherein the subject exhibits disease progression during or after treatment:

a) paclitaxel and cisplatin,

b) paclitaxel and carboplatin or

c) paclitaxel and topotecan.

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

112. The use according to any one of embodiments 101-110, wherein the subject is not suitable for treatment with bevacizumab.

113. The use according to any one of embodiments 101-112, wherein the subject is not a candidate for radical therapy.

114. The use according to embodiment 113, wherein the radical therapy is provided

- 50 048942 looks at radiation therapy and/or exenterative surgery.

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

116. The use according to any one of embodiments 101-114, wherein the subject has relapsed after treatment with no more than two prior systemic treatment regimens.

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

118. The use according to any one of embodiments 101-117, wherein the cervical cancer is late stage cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer.

119. The use according to any one of embodiments 101-118, wherein the cervical cancer is recurrent cervical cancer.

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

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

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

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

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

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

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

123. The use according to any of embodiments 101-122, wherein the anti-TF antibody, or antigen-binding fragment thereof, of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 8.

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

125. The use according to any one of embodiments 101-124, wherein the anti-TF antibody drug conjugate is tizotumab.

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

127. The use according to embodiment 126, wherein the linker is a cleavable peptide linker.

128. The use according to embodiment 127, wherein the cleavable peptide linker is characterized by the formula -MC-vc-PAB-, wherein:

a) MS is:

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

- 51 048942

129. The use according to any of embodiments 126-128, wherein the linker is attached to sulfhydryl groups of the anti-TF antibody obtained by partial reduction or full reduction of the anti-TF antibody or antigen-binding fragment thereof.

130. The use according to embodiment 129, wherein the linker is attached to MMAE, wherein the antibody-drug conjugate is characterized by the following structure:

AB-MSlch:-PA^MMAE where p is a number from 1 to 8, S is the sulfhydryl group of an antibody to TF, and AB is an antibody to TF or an antigen-binding fragment thereof.

131. The use according to embodiment 130, wherein the average p value in the population of antibody-drug conjugates is approximately 4.

132. The use according to any one of embodiments 101-131, wherein the antibody-drug conjugate is tisotumab vedotin.

133. The use according to any one of embodiments 101-132, wherein the route of administration for the antibody-drug conjugate is intravenous.

134. The use of any one of embodiments 101-133, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cervical cancer cells express TF.

135. The use according to any one of embodiments 101-134, wherein after administration of the antibody-drug conjugate, the subject experiences an improvement in one or more therapeutic effects relative to baseline.

136. The use according to embodiment 135, wherein one or more therapeutic effects are selected from the group consisting of tumor size resulting from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

137. The use according to any one of embodiments 101-136, wherein the size of the tumor resulting 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 resulting from cervical cancer before administration of the antibody drug conjugate.

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

139. The use according to any one of embodiments 101-138, wherein the subject has progression-free survival for 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

-52048942 at least 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 eighteen 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.

140. The use of any one of embodiments 101-139, wherein the subject has 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 eighteen 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.

141. The use according to any of embodiments 101-140, wherein the duration of the response to the antibody drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen 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.

142. The use according to any one of embodiments 101-141, wherein the subject experiences 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.

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

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

145. The use according to embodiment 142 or embodiment 143, wherein one or more adverse events is a grade 3 or higher adverse event.

146. The use according to embodiment 142 or embodiment 143, wherein one or more adverse events is a serious adverse event.

147. The use according to embodiment 142 or embodiment 143, wherein the one or more adverse events are conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricating eye drops, an ocular vasoconstrictor, and/or steroid-containing eye drops.

148. The use according to any one of embodiments 101-147, wherein the antibody-drug conjugate is administered as monotherapy.

149. The use according to any one of embodiments 101-148, wherein the subject is a human.

150. An antibody-drug conjugate for use according to any one of embodiments 101-149, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

151. An article containing:

(a) a medicinal product comprising an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an antibody to TF or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analogue thereof or a functional derivative thereof; and

b) a package insert containing instructions for the use of a medicinal product comprising an antibody-drug conjugate in a method of treating cervical cancer in a subject in

- 53 048942 according to any one of embodiments 1-50, or an antibody-drug conjugate for use according to any one of embodiments 51-100, in a method of treating cervical cancer in a subject.

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

153. The article of embodiment 152, wherein the container comprises an antibody-drug conjugate in a dosage amount of from about 4 mg to about 500 mg.

154. The article of embodiment 152, wherein the container comprises an antibody-drug conjugate in a dosage amount of from about 20 mg to about 60 mg.

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

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

157. The article of embodiment 156, wherein the lyophilized powder is reconstituted with a suitable diluent to result in a final concentration of from about 5 mg/mL to about 15 mg/mL.

158. The article of any one of embodiments 151-157, wherein the medicinal product comprising the antibody-drug conjugate is intended for administration by intravenous infusion or injection.

159. The article of embodiment 158, wherein the medicinal product comprising the antibody-medicinal conjugate is intended for administration by intravenous infusion.

The present invention will be better understood in connection with the following examples. However, they should not be construed in any way as limiting the scope of the present invention. It should be understood that the examples and embodiments described herein are provided for illustrative purposes only, and that various modifications or changes in light of them will be suggested to those skilled in the art and should be included in the spirit and scope of the present invention and the scope of the appended claims.

Examples

Example 1: Phase I/II safety study of tizotumab vedotin in subjects with cancer.

Tizotumab vedotin is an antibody-drug conjugate comprising 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 various tumor types, including cervical cancer, and is associated with poor prognosis. See Forster Y et al. Clin Chim Acta. 20o6;364(1-2):12-21 and Cocco E et al. BMC Cancer. 2011;11:263. Tizotumab vedotin selectively targets TF to deliver clinically validated toxic payload to tumor cells (Fig. 1). See Breij EC et al. Cancer Res. 2014;74(4):1214-1226 and Chu AJ. Int J Inflam. 2011;2011. doi: 10.4061/2011/367284.

Methods

A phase I/II dose-escalation study was conducted using a 3+3 dose-escalation design, first-in-human, to test the safety of tizotumab vedotin in 27 subjects with locally advanced and/or metastatic cancer types, including cervical cancer (Fig. 2). Tizotumab vedotin was administered by intravenous infusion at doses ranging from 0.3 mg/kg to 2.2 mg/kg on day 1 of a 21-day cycle for four cycles (i.e., each treatment cycle was 3 weeks). Patients with stable disease (SD) or better performance at the end of four cycles had the option to continue treatment with tizotumab vedotin for eight additional cycles (Fig. 2). Tumor assessments were performed using CT scans every six weeks. To qualify for SD, the CT scan scheduled by week 6 must be SD or better. Two CT scans were performed outside the window defined by the patient population without protocol deviations.

Lyophilized vials containing 40 mg tizotumab vedotin were stored in a refrigerator at 2°C to 8°C. Tizotumab vedotin was reconstituted in 4 mL of water to yield a reconstituted solution containing 10 mg/mL tizotumab vedotin, 30 mM histidine, 88 mM sucrose, and 165 mM D-mannitol. The reconstituted antibody drug conjugate solution had a pH of 6.0. Reconstituted tizotumab vedotin was diluted in a 100 mL infusion bag with 0.9% NaCl according to the calculated patient dose. Intravenous infusion was completed within 24 hours of reconstitution of the tizotumab vedotin vial. A 0.2 μm in-line filter was used for intravenous infusion. The entire 100 ml volume was administered from the prepared infusion bag. No dead volume was provided.

The primary objective of the study was to evaluate the safety and tolerability in a mixed

- 54,048,942 patients with certain solid tumors. Adverse event (AE) severity was defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Secondary study objectives included determining the pharmacokinetic (PK) profile of tizotumab vedotin and preliminary assessment of antitumor activity according to Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. Dose-limiting toxicities (DLTs) were assessed during cycle 1 and were defined as grade ≥3 events possibly related to tizotumab vedotin. The maximum tolerated dose (MTD) was defined as the highest tizotumab vedotin dose level that did not cause unacceptable adverse events. Tumor biopsies were required at baseline to determine TF expression, which was assessed by tizotumab-based immunohistochemistry. The intensity of TF staining was determined using a histoscoring system.

Inclusion criteria for eligible subjects included: patients with recurrent, advanced, and/or metastatic cancer who have failed available standard therapy; and measurable disease manifestations.

Exclusion criteria included known past or current bleeding disorders; significant prolonged bleeding; and presence of peripheral neuropathy grade >2 according to CTCAE.

Results

Individual patient data and baseline characteristics are shown in Table 1. A total of 25 patients discontinued treatment due to patient choice (4%), disease progression (67%), dose-limiting toxicity (DLT) events (4%), AEs (15%), or death (4%). Two patients continued therapy beyond four cycles.

Table 1

Individual patient data and baseline characteristics Patient characteristics All patients (n=27) Age in years, median (range) 62 (43-73) Gender, number (% of total number of patients) Men 9 (33%) Women 18 (67%) Performance status (PS) according to the Eastern Joint Oncology Society scale 0 13 (48%) 1 13 (48%) NA 1 (4%) groups, number (% of total number of patients) Type of primary tumor, number (% of total number of patients) Cervix 2 (7%) Other types of tumors 25 (93%) Median number of prior therapies (range) 3(1-14)

The safety results for all 27 patients are presented in Table 2. A total of 25 patients (93%) experienced treatment-related AEs, the most common of which were fatigue (48%), epistaxis (48%), and anemia (41%). Nineteen patients experienced treatment-related grade ≥3 AEs, the most common of which were fatigue (n=4), anemia (n=4), abdominal pain (n=3), and hyponatremia (n=3) (Table 2; Fig. 3). There were no Grade 4 events. Seven patients discontinued treatment due to AEs, which included grade 1 pneumonitis (n=1), grade 3 events of Guillain-Barré syndrome (n=1), diabetes mellitus (n=1), fatigue (n=1), and abdominal pain (n=2), and one patient experienced grade 2 peripheral edema and grade 3 extremity pain. There were three deaths in this study. One patient in the 0.6 mg/kg cohort died of tumor-related bleeding. Two patients in the 0.3 mg/kg cohort died due to disease progression, both deaths were not considered related to study drug. No significant changes in coagulation parameters were observed. The mean prothrombin time at baseline was 11.5 seconds (n=18) and 11.7 seconds at the end of the study (n=17). The median activated partial thromboplastin time at baseline was 28.2 seconds (n=25) and 27.1 seconds (n=23) at study end. Three DLTs (ie, type 2 diabetes mellitus, mucositis, and neutropenic fever, all grade 3) were observed in three patients in the 2.2 mg/kg cohort.

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Table 2

Overall safety profile of tizotumab vedotin by dose-finding cohort

Category AE, η (% of total number of patients)* All doses (n=27) 0.3 mg/kg (p-3) 0.6 mg/kg (p-3) 0.9 mg/kg (p-3) 1.2 mg/kg (p-3) 1.5 mg/kg (p-3) 1.8 mg/kg (p-3) 2.0 mg/kg (p-3) 2.2 mg/kg (p-6) AE 27(100) 3 (100) 3 (100) 3 (100) 3 (100) 3 (100) 3 (100) 3 (100) 6 (100) Serious AE 15 (56) 2(67) 1 (33) 0 2(67) 2(67) 2(67) 2(67) 4(67) AE Degrees >3 19 (70) 2(67) 3(1OO) 2(67) 1 (33) 2(67) 3(100) 2(67) 4(67) Associated with treatment of AE AE, 25 (93) 3 (100) 3(100) 1 (33) 3 (100) 3 (100) 3(100) 3 (100) 6 (100) leading to discontinuation of treatment 7(26) 0 0 0 0 0 2(67) 0 5 (83) AE with fatal outcome 3 (11) 2(67) 1 (33) 0 0 0 0 0 0

* Occurring within a period of up to 30 days after treatment. AE denotes an adverse event.

For the pharmacokinetic (PK) portion of the study, the geometric mean (%CV) of time to C _max (T _max )(hour), maximum concentration (C _max )(ng/mL), and area under the concentration-time curve (AUC) _0-t (hour*ng/mL) were measured (Table 3). Low levels of unconjugated MMAE were measured in the systemic circulation (Fig. 4).

Table 3

Summary of tizotumab vedotin plasma PK parameters by cohort for dose determination for Cycle 1 __________________________________________________________________________

Dose (mg/kg) N Tshah (hour) Stakh (NG/ML) AUCo-t (hour*ng/ml) 0,3 3 1.5 (73%) 4782.7 (12%) 59216.8 (3%) 0,6 z 1.2 (13%) 12195.3 (10%) 368432.7 (8%) 0.9 z 1.3 (12%) 19811.6(17%) 601926.2(17%) 1,2 z 1.3 (12%) 34673.1 (19%) 1084672.7 (9%) 1,5 z 1.1 (9.6%) 23115.6(21%) 794988.4 (19%) 1,8 3 1.2 (14%) 35416.3 (39%) 1504823.8 (50%) 2.0 z 1.2 (8%) 32296.1 (22%) 1256379.7 (33%) 2,2 6 1.1 (13%) 55530.3 (10%) 2037070.5 (34%)

Efficacy was assessed in twenty-six patients (Table 4). The best observed response was partial response (PR) in 1 patient (4%) and stable disease (SD) in 11 patients (41%). The disease control rate (DCR; PR+SD) was 46%, corresponding to 12 of 26 patients. Changes in tumor size, expressed as a percentage of baseline, were determined in 27 patients (Fig. 5). In two patients with cervical cancer, tumor size decreased from baseline, with patient 1 showing approximately 20% tumor size reduction with 2.2 mg/kg tizotumab vedotin (Fig. 5; (i)) and patient 2 showing approximately 51% tumor size reduction with 1.2 mg/kg tizotumab vedotin (Fig. 5; (ii)). Patient 2 was a 43-year-old male patient with cervical cancer diagnosed with stage 4 disease and who had received 3 prior lines of therapy. Patient 2's TF expression level was measured as a histoscore of 140 (archived data). Patient 2 achieved a confirmed PR, with approximately 51% reduction in target lesion, and the benefit lasted for a total of 15 months (Fig. 6). Tizotumab vedotin was well tolerated, and no severe AEs were reported. Patient 2 eventually experienced disease progression and discontinued therapy.

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Table 4 Confirmed objective responses

Confirmed answer according to All doses (n=27) 0.3 mg/kg 0.6 mg/kg 0.9 mg/kg 1.2 mg/kg 1.5 mg/kg 1.8 mg/kg 2.0 mg/kg 2.2 mg/kg RECIST vl.l, (n=3) (n=3) (n=3) (n=3) (n=3) (n=3) (n=3) (11=6) and (% of the total number of shares)' ¹ Complete answer (CR) ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT Partial response (PR) 1 (4) ABOUT O O 1 (33) O ABOUT ABOUT ABOUT Disease stabilization (SD) II (4 1) O 1 (33) 1 (33) 1 (33) O 3 (1OO) 1 (33) 4 (67) Progression of disease (PD) 14 (52) 3(1OO) 1 (33) 2 (67) 1 (33) 3(1OO) O 2 (67) 2 (33) ^No rating 1 (4) O 1 (33) ABOUT O O O ABOUT ABOUT

a Percentages may not add up to 100% due to rounding. ^b The patient died before the first scan was performed.

Conclusion

The identified MTD was 2.0 mg/kg and was used in a phase II study of the efficacy and safety of tizotumab vedotin in patients with cervical cancer.

Example 2. Effect of tizotumab vedotin in a phase IIa study in subjects with recurrent, recurrent and/or metastatic cervical cancer.

The efficacy, safety, and tolerability of 2.0 mg/kg tizotumab vedotin were assessed in patients with recurrent, recurrent, and/or metastatic cervical cancer.

Methods

A single-arm, multicenter, phase IIa study investigated the efficacy, safety, and tolerability of 2.0 mg/kg tizotumab vedotin in patients with recurrent, recurrent, and/or metastatic cervical cancer. A total of 34 patients (n=34) were enrolled and received at least 1 dose of tizotumab vedotin. Each eligible patient was assigned to receive a dose of 2.0 mg/kg tizotumab vedotin by intravenous (IV) infusion on day 1 of a 21-day cycle (i.e., each treatment cycle was 3 weeks (q3w)).

Lyophilized vials containing 40 mg tizotumab vedotin were stored in a refrigerator at 2°C to 8°C. Tizotumab vedotin was reconstituted in 4 mL of water to yield a reconstituted solution containing 10 mg/mL tizotumab vedotin, 30 mM histidine, 88 mM sucrose, and 165 mM D-mannitol. The reconstituted antibody drug conjugate solution had a pH of 6.0. Reconstituted tizotumab vedotin was diluted in a 100 mL infusion bag with 0.9% NaCl to the dose calculated for a patient receiving 2.0 mg/kg tizotumab vedotin. The intravenous infusion was completed within 24 hours of reconstitution of the tizotumab vedotin vial. A 0.2 μm inline filter was used for intravenous infusion. The entire 100 ml volume was administered from a prepared infusion bag. No dead volume was provided.

The primary objective of the study was to evaluate the safety and tolerability of tizotumabavedotin. Adverse event (AE) severity was defined according to CTCAE version 4.03. The secondary objective was to preliminarily assess the duration of antitumor activity according to RECIST version 1.1. Tumor assessments were performed using CT scans every six weeks.

Results

Individual patient data and baseline characteristics are shown in Table 5. A total of 7 patients continued therapy (22%) and 27 patients discontinued treatment due to AEs (n=5), disease progression (n=16), or other reasons (n=6).

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Table 5

Individual patient data and baseline characteristics

Patient characteristics All patients (n=34) Age in years, median (range) 43 (21-73) ECOG score, number (% of total patients) 0 7 (21%) 1 26 (76%) No data available 1 (3%) Cancer type, number (% of total patients) Adenocarcinoma 15 (44%) Adenosquamous 3 (9%) Squamous 15 (44%) No data available 1 (3%) Previous lines of systemic treatment, number (% of total patients) Oh ^a 3 (9%) 1 13 (38%) 2 11 (32%) 3 4 (12%) 4 3 (9%) Previous treatment, ^% Platinum 91% Taxan 91% Bevacizumab® 71% GOG 240 ^d diagram 68% > 1 dual therapy with platinum-based drugs 17% Pre-radiation therapy® 74%

^a Patients progressed on therapy used to treat locally advanced disease. ^b Data were not available for one patient. ^c Including bevacizumab used as part of combination therapy, either as platinum/bevacizumab/paclitaxel or as topotecan/bevacizumab/paclitaxel. ^d Combination therapy with cisplatin, paclitaxel and bevacizumab. ^e External beam radiotherapy applied to the cervix or surrounding tissue.

Following tizotumab vedotin monotherapy, overall (>15%) AEs were assessed (Fig. 7). Grade 3 AEs occurred in 16 patients (47%). There were no grade 4 or grade 5 events. Compound-specific conjunctival toxicity was observed, but risk mitigation measures significantly reduced conjunctival toxicity in patients. Before risk mitigation measures (n=15), 73% of patients experienced any grade conjunctivitis. After risk mitigation measures (n=19), 32% of patients experienced any grade conjunctivitis, and 5% had grade >3. Risk mitigation measures included prophylactic steroid-containing lubricating eye drops and cooling eye masks worn during treatment with IV infusion, as well as stricter dose adjustment guidelines.

Thirty-four patients were evaluable for efficacy (Table 6 and Fig. 8). Seven patients continued to receive treatment.

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Table 6

Definition of efficiency

Tumor response, PFS ^a , and DoR ^b η (% of total patients) N=34 Proportion of patients with objective response (ORR), η (% of total patients) (95% confidence interval) And (32%) (17%-50%) Partial response (PR), η (% of total patients) ⁰ And (32%) DCR (CR + PR + SD) ^d , η (% of total patients) (95% confidence interval) 17 (50%) (35%-65%) Median DoR, months ⁶ 8.3 Median PFS, months 6.4

^a PFS stands for progression-free survival. ^b DoR stands for duration of response. ^{c Including} 8 confirmed PRs and 3 unconfirmed PRs (1 of which is still ongoing). ^d Clinical benefit at 12 weeks. DCR stands for disease control rate, CR stands for complete response, SD stands for stable disease. ^e Median DoR 5.4 months for confirmed and unconfirmed responses.

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

Table 7 Definition of efficiency

N ORR ^a , N (%) ^ь ORR 95% CI, % All patients in whom efficacy could be assessed 51 16(31) 19-46 Histological examination — Squamous 27 9(33) 17-54 Adenocarcinoma 18 4(22) 6-48 Adenosquamous 4 2(50) 7-93 Another 2 1 (50) 1-99 Previous lines of systemic therapy — 1 23 8(35) 16-57 2 17 6(35) 14-62 3-4 11 2(18) 2-52 Previous taxane — Yes 48 15 (31) 19-46 No 3 1 (33) 1-91 Previous bevacizumab — Yes 40 12 (30) 17-47 No 11 4(36) 11-69 Previous GOG scheme 240 ^e Yes 37 12 (32) 18-50 No 14 4(29) 8-58

- 59 048942 ^a Refers to the proportion of patients with an objective response. ^b Combines unconfirmed + confirmed ORR. ^c GOG 240 is defined as bevacizumab + doublet chemotherapy (cisplatin + paclitaxel or topotecan + paclitaxel).

Conclusion

Tizotumab vedotin demonstrated robust efficacy and a manageable safety profile in a cohort of patients with cervical cancer. The safety profile of tizotumab vedotin in recurrent cervical cancer was generally consistent with other MMAE-based ADCs. Compound-specific conjunctival adverse events were observed, but risk mitigation measures substantially reduced toxicity.

Example 3: A phase II study of tizotumab vedotin in subjects with previously treated, recurrent, or metastatic cervical cancer.

Evaluate the efficacy, safety, and tolerability of 2.0 mg/kg tizotumab vedotin in patients with previously treated, advanced cervical cancer (e.g., recurrent and/or metastatic cancer). Preliminary data from a cohort of patients with previously treated cervical cancer suggest a favorable benefit/risk profile for this population with a high unmet need. See Examples 1 and 2 above.

Methods

A single-arm, multicenter, international, phase II study is evaluating the efficacy, safety, and tolerability of 2.0 mg/kg tizotumab vedotin in patients with recurrent or metastatic cervical cancer. Eligible patients have experienced disease progression during or following treatment with doublet chemotherapy in combination with bevacizumab, provided that patients are eligible for bevacizumab. Patients have received no more than 2 prior systemic therapies for metastatic or recurrent disease. Eligible patients are treated with intravenous (IV) tizotumab vedotin 2.0 mg/kg every 3 weeks (1Q3W) until they meet prespecified discontinuation criteria (Fig 11). Images are obtained every 6 weeks for the first 30 weeks and every 12 weeks thereafter. Responses are confirmed no sooner than 4 weeks (28 days) after the first response assessment. The study included approximately 100 patients aged >18 years.

The inclusion criteria and exclusion criteria for patients included in the study are shown in Table 8.

Table 8 List of inclusion and exclusion criteria Inclusion Criteria • Patients with metastatic or recurrent cervical cancer that has spread beyond the pelvis, including histologic features of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, who: o have experienced disease progression during or after treatment with: - doublet chemotherapy containing paclitaxel and cisplatin or carboplatin, OR - paclitaxel and topotecan, and who have received bevacizumab or are eligible for bevacizumab according to local guidelines. o have received no more than 2 prior systemic treatments for recurrent or metastatic cervical cancer. o are not candidates for definitive therapy, including but not limited to radiation therapy or exenterative surgery. • have measurable disease according to RECIST vl. 1, according to independent central assessment based on diagnostic imaging. • Age >18 years. • Acceptable renal function: estimated (Cockcroft-Gault) glomerular filtration rate (GFR) >45 ml/min.

- 60 048942 • Acceptable liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 times the upper limit of normal (ULN) (if liver cancer/liver metastases are present, then < 5 x ULN is allowed); bilirubin < 1.5 x ULN, except for patients diagnosed with Gilbert's syndrome, direct bilirubin < 2 x ULN.

• Acceptable hematological picture: Hemoglobin > 5.6 mmol/L (9.0 g/dL), absolute neutrophil count (ANC) > 1500/µL (1.5x10 ⁹ /L); platelet count > 100x10 ⁹ /L, determined at least 2 weeks after transfusion of blood components and/or growth factors as maintenance therapy.

• Acceptable coagulation profile: International Normalized Ratio (INR) < 1.2 (patients not on anticoagulant therapy) and activated partial thromboplastin time (aPTT) < 1.25 ULN; patients on anticoagulant therapy (eg, warfarin) must be on a constant dose (without active titration) for at least 4 weeks prior to screening and must have an 1NR < 2.5 to be eligible for the study.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, assessed within 7 days of cycle day 1.

• Life expectancy of at least three months.

• Negative serological pregnancy test (in patients aged 18-55 years; in patients aged >55 years, postmenopause must be confirmed in the eCRF). Pregnant or breastfeeding women are not eligible for participation in the study.

• Patients of reproductive potential must consent to the use of appropriate means

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contraception during and 6 months after the last tizotumab vedotin administration. Eligible contraception for women is defined as highly effective contraception. In countries where two highly effective contraceptive methods are required, this will be an inclusion criterion. • All patients must provide a biopsy specimen at screening. Archived or recent core needle biopsy specimens are required (fine needle biopsy specimens are not acceptable). FFPE blocks OR at least 10 slides with 5 micron sections are acceptable for study eligibility. • After receiving verbal and written information about the study, patients must provide a signed informed consent form before engaging in any study-related activities. Exclusion criteria • Hematology: Known past or current bleeding disorders with increased risk of bleeding; diffuse alveolar hemorrhage due to vasculitis; known bleeding diathesis; prolonged significant bleeding; trauma with increased risk of life-threatening bleeding or history of severe head injury or intracranial surgery within two months prior to study entry. • Cardiovascular system: Clinically significant cardiovascular disease, including unstable angina, acute myocardial infarction within 6 months prior to screening; known chronic heart failure (stage III or IV according to the New York Heart Association classification) and/or known reduced cardiac ejection fraction < 45%; marked prolongation of the QT/QTc interval from baseline

- 62 048942 (eg, recurrence of QTc interval >450 ms), complete left bundle branch block (defined as QRS interval >120 ms in left bundle branch block) or incomplete left bundle branch block.

• Central nervous system: History of any cerebral arteriovenous malformations, cerebral aneurysm, or stroke (transient cerebral ischemic attack > 1 month prior to screening is acceptable).

• Ophthalmology: Active ocular disease at baseline (as assessed by an ophthalmologist if the investigator suspects active ocular disease). Patients with any previous episode of cicatricial conjunctivitis or Stevens-Johnson syndrome (as assessed by the investigator) are not eligible for participation in the study.

• Other cancers/metastases: Known past or current malignancy other than the diagnosis for inclusion in the study, with the exception of: non-invasive basal cell or squamous cell carcinoma of the skin; non-invasive superficial bladder cancer; any treatable cancer with a complete response (CR) duration of > 5 years.

o Brain metastases are acceptable if the following criteria are met: Radical therapy (eg, surgery or stereotactic brain radiation therapy) was completed > 28 days before the first dose of tizotumab vedotin; the patient has no evidence of clinical or radiographic tumor progression; patients have completed perioperative corticosteroid therapy or have had their steroid dose tapered. Continuous steroid therapy is acceptable provided the dose has been stable for 1 month prior to screening.

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• Prohibited medications or regimens: Anticoagulant therapy or antiplatelet therapy, EXCEPT when the patient is no longer actively titrating their anticoagulant therapy (e.g., warfarin) and has been on stable doses for at least 4 weeks prior to screening; cumulative corticosteroid dose > 150 mg (prednisone or equivalent corticosteroid doses) within 2 weeks prior to first tizotumab vedotin administration. • Surgery/procedures: Radical surgery within 4 weeks or open biopsy within 7 days prior to first tizotumab vedotin administration. Patients scheduled for radical surgery during the treatment period should be excluded from the study. • Peripheral neuropathy > stage 2 • Prior therapy: o Any prior treatment with MMAE-based medicinal products. o Any anti-cancer therapy including small molecules, immunotherapy, chemotherapy, monoclonal antibodies or any other experimental medicinal product within 28 days prior to the first administration of tizotumab vedotin. Patients who have not recovered from adverse effects of radiation therapy or symptoms of autoimmune toxicity associated with prior immunotherapy at the time of initiation of the screening procedure are not eligible for participation in the study. • Other: ongoing significant uncontrolled medical condition; clinically significant active viral, bacterial, or fungal infection requiring IV or oral (PO) antimicrobial therapy ending less than 7 days prior to first tizotumab vedotin administration; known positive serologic reaction to human immunodeficiency virus; known history of hepatitis B or C. • The patient has any condition that, in the opinion of the investigator, would make participation in the study less in the best interests of the patient (e.g., worsens well-being) or that may interfere with, limit, or confound the results of protocol-defined assessments. • The patient has a known history of allergy, hypersensitivity, or intolerance to tizotumabavedotin or its excipients.

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Store lyophilized vials containing 40 mg tizotumab vedotin in a refrigerator at 2°C to 8°C. Tizotumab vedotin is reconstituted in 4 mL of water to yield a reconstituted solution containing 10 mg/mL tizotumab vedotin, 30 mM histidine, 88 mM sucrose, and 165 mM D-mannitol. The reconstituted antibody drug conjugate solution has a pH of 6.0. Reconstituted tizotumab vedotin is diluted in a 100 mL infusion bag with 0.9% NaCl to the dose calculated for a patient receiving 2.0 mg/kg tizotumab vedotin. The intravenous infusion is completed within 24 hours of reconstitution of the tizotumab vedotin vial. For intravenous infusion, a 0.2 μm inline filter is used. The entire 100 ml volume is administered from a prepared infusion bag. No dead volume is provided. For patients who are intolerant to the protocol-defined dosing schedule, dose reductions are allowed so that the patient can continue treatment with tizotumab vedotin (Table 9).

Table 9

Dose modification scheme

Previous dose of tizotumabvedotin Reduced dose of tizotumab vedotin • 2.0 mg/kg • 1.3 mg/kg • 1.3 mg/kg • 0.9 mg/kg • 0.9 mg/kg • 0.9 mg/kg*

*If the patient is already being treated with tizotumab vedotin at a dose of 0.9 mg/kg 1Q3W, the dose of tizotumab vedotin is not further reduced.

The objectives and endpoints are described in Table 10. The confirmed proportion of patients with an objective response (ORR) and the 2-sided 95% exact confidence interval are calculated 27 weeks after the last patient received the first dose of tizotumab vedotin. Given that the true confirmed ORR is 25% for tizotumab vedotin, this provides 96% power for 100 patients to exclude the null hypothesis of an ORR of 11% or less (one-sided P-value 2.5%).

Table 10 Goals and Endpoints

GOALS END POINTS Primary • To determine antitumor efficacy in patients with cervical cancer. • Confirmed proportion of patients with objective response (ORR) based on RECIST vl.l, as assessed by an independent review committee. Secondary • Assess duration and time to response. • Assess other clinical outcomes. • Assess safety and tolerability. • Duration of response (DOR). • Time to response (TTR). • Confirmed ORR according to RECIST vl.l, investigator assessment. • Progression-free survival (PFS) according to RECIST vl.l, IRC assessment. • Overall survival (OS). • Laboratory parameters for adverse events and safety. • Pharmacokinetics (PK). • Immunogenicity (anti-drug antibodies [ADA]) of tizotumab vedotin. Search • Evaluate biomarkers associated with clinical response. • TF expression in tumor biopsies before treatment and after progression,

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• To evaluate potential pharmacodynamic biomarkers of tizotumab vedotin. • To evaluate health-related quality of life (HRQL) in patients with cervical cancer treated with tizotumab vedotin. circulating TF, proteomic analyses and genetic variations. • Circulating TF and proteomic analyses. • Relevant questionnaires for HRQL assessment

If a patient's trial treatment is discontinued before completion of the treatment regimen, this does not automatically terminate the patient's participation in the study. A patient's trial treatment is terminated if: radiographic disease progression is confirmed by an independent review committee; the rules for interruption of treatment for safety reasons are followed; unacceptable toxicity requires discontinuation of treatment; the investigator judges that it is in the best interests of the patients to discontinue treatment for safety reasons (eg, an adverse event); pregnancy; the patient's desire; and/or new anticancer therapy is initiated. If treatment is discontinued, the investigators will conduct a follow-up safety visit. The follow-up safety visit occurs 15 days ± 5 days after the last dose of tizotumab vedotin and before initiation of new anticancer therapy, and includes most assessments performed at screening and response assessments. After treatment is discontinued, patients continue to be followed for post-treatment assessments until death or discontinuation from the study. The safety interruption rules for discontinuing treatment include the following, for ophthalmologic toxicity: first recurrence of CTCAE grade > 3 conjunctivitis (despite dose reduction); third recurrence of CTCAE grade < 2 keratitis (despite dose reduction); first occurrence of CTCAE grade > 3 keratitis; ophthalmologic assessment revealing conjunctival/corneal scarring; any grade of symblepharon; any grade of fluorescent conjunctival spots or ulcers that do not stabilize or improve with dose reduction; or any dose delay due to ophthalmologic toxicity exceeding 12 weeks. The safety interruption rules for discontinuing treatment for adverse events other than ophthalmologic toxicity include the following: second occurrence of grade 3 infusion reaction (despite drug preparation); first infusion reaction > grade 4; first mucositis > grade 4; first peripheral neuropathy > grade 4; any pulmonary or CNS hemorrhage event > grade 2; or any hemorrhage event > grade 3 for patients receiving anticoagulant therapy.

Three adverse events of particular interest are ocular adverse events, peripheral neuropathy adverse events, and bleeding adverse events. For ocular AEs, grade 1–2 conjunctivitis AEs have been reported frequently in association with tizotumab vedotin treatment. Severe cases (CTCAE > grade 3) of conjunctivitis and keratitis have been reported, but implementation of a comprehensive mitigation plan and preventive measures significantly reduces both the incidence and severity of ocular adverse reactions. To prevent ocular AEs, the following prescribing recommendations are recommended for ocular safety: use preservative-free lubricating eye drops from the start of tizotumab vedotin treatment until the end of treatment; avoid the use of contact lenses during tizotumab vedotin treatment; use eye cooling pads, refrigerated prior to use, during the infusion, such as THERA PEARL eye mask or similar, applied immediately prior to the infusion according to the instructions supplied with the eye cooling pads; administer a topical ocular vasoconstrictor prior to the infusion (brimonidine tartrate eye drops 0.2% or similar, 3 drops in each eye immediately prior to the start of the infusion; otherwise use according to the product instructions). If the patient is intolerant of ocular vasoconstrictors due to adverse reactions, further treatment with them may be interrupted; and steroid-containing eye drops are prescribed for 3 days beginning on the day of infusion (dexamethasone eye drops 0.1% or equivalent, 1 drop in each eye 3 times daily for 3 days [first drop should be given before starting tizotumab vedotin], otherwise use according to the product instructions). Ocular treatment recommendations are shown in Table 11.

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Claims (49)

Table 11 Recommendations for eye treatment Ophthalmological symptom (definition of severity according to CTCAE) Treatment recommendation (Duration of treatment is determined by the local ophthalmologist) Conjunctivitis grade 1 The local ophthalmologist prescribes frequent administration of topical steroid-containing drops without preservatives. Grade 2 conjunctivitis The local ophthalmologist prescribes frequent dosing (every two hours) of topical preservative-free steroid drops in combination with a preservative-free prophylactic antibiotic such as chloramphenicol. Grade 3 conjunctivitis The local ophthalmologist prescribes frequent dosing (every two hours) of topical preservative-free steroid drops in combination with a preservative-free prophylactic antibiotic such as chloramphenicol. Keratitis grade 1 The local ophthalmologist prescribes frequent administration of a dose of topical steroid-containing drops without preservatives. Grade 2 Keratitis The local ophthalmologist prescribes frequent dosing (every two hours) of topical preservative-free steroid drops in combination with a preservative-free prophylactic antibiotic such as chloramphenicol. Conjunctival ulcers: any grade The local ophthalmologist prescribes frequent dosing (every two hours) of topical preservative-free steroid drops in combination with a preservative-free prophylactic antibiotic such as chloramphenicol. Regarding peripheral neuropathy AEs (including peripheral neuropathy; peripheral sensory neuropathy; peripheral motor neuropathy; polyneuropathy): peripheral neuropathy is a well-known adverse reaction to treatment with chemotherapeutic agents (including cisplatin and taxanes) as well as MMAE-based ADCs, and is frequently reported in association with tizotumab vedotin. Most reported cases are grade 1–2; however, peripheral neuropathy is the leading reason for permanent discontinuation of tizotumab vedotin. To prevent the occurrence of peripheral neuropathy as well as worsening of preexisting conditions, a mitigation plan is implemented, including dose reduction (see Table 9) and dose deferral (i.e., holding the dose until the event improves to < Grade 1). Regarding bleeding AEs: Bleeding events are of particular interest given the mechanism of action of tizotumab vedotin. According to preclinical results, no significant effects on activated partial thromboplastin time (aPTT) or prothrombin time (PT) have been observed in patients treated with tizotumab vedotin to date. Epistaxis is the most frequently reported AE, however, almost all cases are grade 1. With the exception of epistaxis, a causal relationship between the majority of reported bleeding events and tizotumab vedotin treatment has not been established. CLAUSE OF INVENTION 1. Use of an antibody-drug conjugate that binds to tissue factor (TF) for the manufacture of a medicament for the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an antibody to TF or an antigen-binding fragment thereof conjugated to monomethyl auristatin, and wherein the medicament is administered to the subject once every 2 weeks at a dose in the range of 1.5 mg/kg to 2.1 mg/kg. 2. Use of an antibody-drug conjugate that binds to tissue factor (TF) for treating cervical cancer in a subject, wherein the antibody-drug conjugate comprises an antibody to TF or an antigen-binding fragment thereof conjugated to monomethyl auristatin, and wherein the antibody-drug conjugate is administered to the subject once every 2 weeks at a dose in the range of 1.5 mg/kg to 2.1 mg/kg. - 67 048942 3. Use according to paragraph 1 or 2, wherein the dose is 2.0 mg/kg. 4. Use according to claim 1 or 2, wherein the dose is 1.7 mg/kg. 5. The use according to any one of claims 1 to 4, wherein the subject has previously been treated with one or more therapeutic agents and has not responded to the treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate. 6. The use according to any one of claims 1 to 4, wherein the subject has previously been treated with one or more therapeutic agents and has relapsed the disease following treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate. 7. The use according to any one of claims 1 to 4, wherein the subject has previously been treated with one or more therapeutic agents and has experienced disease progression during treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate. 8. The use according to any one of claims 5 to 7, wherein one or more therapeutic agents is a platinum-based therapeutic agent. 9. The use according to any one of claims 5 to 7, wherein one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab and bevacizumab. 10. The use according to any one of claims 1 to 9, wherein the subject has shown progression of the disease during or after treatment: a) paclitaxel and cisplatin, b) paclitaxel and carboplatin or c) paclitaxel and topotecan. 11. The use according to any one of claims 1 to 10, wherein the subject has received treatment with bevacizumab. 12. The use according to any one of claims 1 to 10, wherein the subject is not suitable for treatment with bevacizumab. 13. The use according to any one of claims 1 to 12, wherein the subject is not a candidate for radical therapy. 14. The use according to claim 13, wherein the radical therapy comprises radiation therapy and/or exenterative surgery. 15. Use according to any one of claims 1 to 14, wherein the subject has not responded to treatment with no more than two previous systemic treatment regimens. 16. The use according to any one of claims 1 to 14, wherein the subject has relapsed after treatment with no more than two prior systemic treatment regimens. 17. The use according to any one of claims 1 to 16, wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma or squamous cell carcinoma. 18. The use according to any one of claims 1 to 17, wherein the cervical cancer is late stage cervical cancer, such as stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer. 19. The use according to any one of claims 1 to 18, wherein the cervical cancer is recurrent cervical cancer. 20. The use according to any one of claims 1 to 19, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE). 21. The use according to any one of claims 1 to 20, wherein the antibody to TF, or its antigen-binding fragment, of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof. 22. The use according to any one of claims 1 to 21, wherein the antibody to TF, or antigen-binding fragment thereof, of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and wherein the light chain variable region comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6, wherein the CDRs of the anti-TF antibody, or antigen-binding fragment thereof, antibody-drug conjugate are defined according to the IMGT numbering scheme. 23. The use according to any one of claims 1 to 22, wherein the antibody to TF, or antigen-binding fragment thereof, of the antibody-drug conjugate 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 light chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of - 68 048942 SEQ ID NO: 8. 24. The use according to any one of claims 1 to 23, wherein the antibody to TF, or antigen-binding fragment thereof, the antibody-drug conjugate 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 of SEQ ID NO: 8. 25. The use according to any one of claims 1 to 24, wherein the antibody to TF of the antibody-drug conjugate is tizotumab. 26. The use according to any one of claims 1 to 25, wherein the antibody-drug conjugate further comprises a linker between the TF antibody or antigen-binding fragment thereof and monomethyl auristatin. 27. The use according to claim 26, wherein the linker is a cleavable peptide linker. 28. The use according to claim 27, wherein the cleavable peptide linker is characterized by the formula MC-vc-PAB-, where: a) MS is: b) vc is the dipeptide valine-citrulline and c) PAB is: 29. The use according to any one of claims 26 to 28, wherein the linker is attached to sulfhydryl groups of the anti-TF antibody obtained by partial reduction or complete reduction of the anti-TF antibody or antigen-binding fragment thereof. 30. The use according to claim 29, wherein the linker is attached to MMAE, and the antibody-drug conjugate is characterized by the following structure: AKMC-VC-PAB-MMAE where p is a number from 1 to 8, S is a sulfhydryl group of an anti-TF antibody, and Ab is an anti-TF antibody or an antigen-binding fragment thereof. 31. The use according to claim 30, wherein the average p value in the population of antibody-drug conjugates is 4. 32. The use according to any one of claims 1 to 31, wherein the antibody-drug conjugate is tisotumab-vedotin. 33. The use according to any one of claims 1 to 32, wherein the route of administration for the antibody-drug conjugate is intravenous. 34. The use according to any one of claims 1 to 33, 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% of the cervical cancer cells express TF. 35. The use according to any one of claims 1 to 34, wherein after administration of the antibody-drug conjugate, the subject experiences an improvement in one or more therapeutic effects relative to the baseline. 36. The use according to claim 35, wherein one or more therapeutic effects are selected from the group consisting of tumor size resulting from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. - 69 048942 bridges. 37. The use according to any one of claims 1 to 36, wherein the size of the tumor resulting 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 resulting from cervical cancer before administration of the antibody-drug conjugate. 38. The use according to any one of claims 1 to 37, wherein 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%. 39. The use according to any one of claims 1 to 38, wherein the subject has a progression-free survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least eighteen months, at least two years, at least three years, at least four years, or at least five years after administration of the antibody-drug conjugate. 40. The use according to any one of claims 1 to 39, wherein the subject has 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 eighteen months, at least two years, at least three years, at least four years, or at least five years after administration of the antibody-drug conjugate. 41. The use according to any one of claims 1 to 40, wherein the duration of the 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 eighteen months, at least two years, at least three years, at least four years, or at least five years after administration of the antibody-drug conjugate. 42. The use according to any one of claims 1 to 41, wherein the subject experiences one or more adverse events and is also administered an additional therapeutic agent to eliminate or reduce the severity of one or more adverse events. 43. The use according to any one of claims 1 to 41, wherein the subject is at risk of developing one or more adverse events and is additionally administered an additional therapeutic agent to prevent or reduce the severity of one or more adverse events. 44. Use according to claim 42 or 43, wherein one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy or general deterioration in physical health. 45. Use according to claim 42 or 43, wherein one or more adverse events is a grade 3 or higher adverse event. 46. The use according to claim 42 or 43, wherein one or more adverse events are conjunctivitis and/or keratitis, and the additional agent is preservative-free lubricating eye drops, an ocular vasoconstrictor and/or steroid-containing eye drops. 47. The use according to any one of claims 1 to 46, wherein the antibody-drug conjugate is administered as monotherapy. 48. The use according to any one of paragraphs 1-47, wherein the subject is a human. 49. The use according to any one of claims 1 to 48, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier. -