Eribulin-Based Antibody-Drug Conjugates and Methods of Use

Abstract

There remains a need for more effective methods and dosing regimens for treating subjects with FRA-expressing cancers with anti-FRA ADCs, such as MORAb-202, e.g., that reduce the side effects of treatment. [Solution] Linker toxins and antibody-drug conjugates are disclosed that bind to human oncology antigen targets, such as folate receptor alpha, and / or provide anti-tubulin drug activity. The linker toxins and antibody-drug conjugates contain an eribulin drug moiety and can be internalized into target antigen-expressing cells. The disclosure further relates to methods and compositions for use in treating cancer by administering the antibody-drug conjugates provided herein.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 362,882, filed April 12, 2022, and No. 63 / 366,029, filed June 8, 2022, which are incorporated by reference herein.

[0002] The present disclosure relates to methods of treating folate receptor alpha (FRA)-expressing cancers using antibody drug conjugates (ADCs) that bind to the folate receptor alpha and provide anti-tubulin drug activity. The disclosure further relates to methods of reducing the risk of side effects, such as interstitial lung disease (ILD), in a subject being treated. [Background technology]

[0003] Cancer is one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012. The most common causes of cancer death are lung cancer (1.59 million deaths); liver cancer (745,000 deaths); gastric cancer (723,000 deaths); colorectal cancer (694,000 deaths); breast cancer (521,000 deaths); and esophageal cancer (400,000 deaths). The number of new cancer cases is expected to rise by approximately 70% over the next 20 years, reaching approximately 22 million new cancer cases per year (World Cancer Report 2014).

[0004] Microtubules are dynamic filamentous cytoskeletal proteins that are involved in various cellular functions including intracellular migration and transport, cell signaling, and maintenance of cell shape. Microtubules also play a crucial role in mitosis by forming the spindle required to separate chromosomes into two daughter cells. In all cells, the biological function of microtubules is primarily regulated by their polymerization dynamics, which occurs by the reversible non-covalent addition of α- and β-tubulin dimers to both ends of the microtubule. This dynamic behavior and the resulting control of microtubule length are crucial for proper spindle function. Even minor changes in microtubule dynamics can result in the engagement of the spindle checkpoint, arresting cell cycle progression during mitosis, and subsequently cell death (Mukhtar et al. (2014) Mol. Cancer Ther. 13:275-84). Cancer cells, due to their rapid cell division, are generally more sensitive than normal cells to compounds that bind to tubulin and disrupt its normal function. This makes tubulin inhibitors and other microtubule-targeting agents a promising drug class for the treatment of cancer (Dumontet and Jordan (2010) Nat. Rev. Drug Discov. 9:790-803).

[0005] Folate receptor alpha (FRA) is a glycophosphatidylinositol (GPI)-linked membrane protein that binds folate. Although the role of FRA in normal and cancerous tissue biology is not fully understood, it is highly overexpressed in a high percentage of epithelial-derived ovarian cancers (O'Shannessy et al. (2013) Int. J. Gynecol. Pathol. 32(3):258-68) as well as a proportion of non-small cell lung cancers (Christoph et al. (2014) Clin. Lung Cancer 15(5):320-30). FRA also has limited expression in normal tissues. These properties make FRA an attractive target for cancer immunotherapy. Summary of the Invention [Problem to be solved by the invention]

[0006] The inventors have previously demonstrated effective treatment of folate receptor alpha (FRA)-expressing cancers using compounds, e.g., ADCs, e.g., anti-FRA ADCs, e.g., MORAb-202, that have biological activity against FRA-expressing tumor cells. However, there remains a need for more effective methods and dosing regimens for treating subjects with FRA-expressing cancers with anti-FRA ADCs, e.g., MORAb-202, that, e.g., reduce the side effects of treatment. [Means for solving the problem]

[0007] The present disclosure provides improved methods and dosing regimens for treating folate receptor alpha (FRA)-expressing cancers using anti-FRA ADCs, such as MORAb-202.

[0008] In various embodiments, the present disclosure provides a method of treating folate receptor alpha (FRA)-expressing cancer, comprising administering to a subject in need thereof a compound of formula (I): Ab-(LD)p (I) (In the formula, The Ab is an internalizing anti-folate receptor alpha antibody or an internalizing antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2) and SEQ ID NO:3 (HCDR3) as defined by the Kabat numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2) and SEQ ID NO:6 (LCDR3); or three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2) and SEQ ID NO:9 (HCDR3) as defined by the IMGT numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2) and SEQ ID NO:12 (LCDR3); D is eribulin; L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; and p is an integer from 1 to 8. and administering to the subject an antibody-drug conjugate compound represented by the formula: 2 ) is administered at a dose of 8 mg to 50 mg of antibody-drug conjugate per body surface area (BSA) of the subject.

[0009] In various embodiments, the disclosure provides a method of reducing the risk of interstitial lung disease (ILD) in a subject being treated for an FRA-expressing cancer, comprising administering to the subject a compound of formula (I): Ab-(LD)p (I) (In the formula, The Ab is an internalizing anti-folate receptor alpha antibody or an internalizing antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2) and SEQ ID NO:3 (HCDR3) as defined by the Kabat numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2) and SEQ ID NO:6 (LCDR3); or three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2) and SEQ ID NO:9 (HCDR3) as defined by the IMGT numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2) and SEQ ID NO:12 (LCDR3); D is eribulin; L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; and p is an integer from 1 to 8. of antibody-drug conjugate, the antibody-drug conjugate being administered to the subject at a concentration of about 1000 mg / mL per square meter (m 2 ) is administered at a dose of 8 mg to 50 mg of antibody-drug conjugate per body surface area (BSA) of the subject.

[0010] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the antibody-drug conjugate is MORAb-202.

[0011] In some embodiments, p is an integer from 3 to 4.

[0012] In some embodiments, the dose of the ADC is 1 ml 2 In some embodiments, the dose of the ADC is 1 mg to 44 mg per BSA of the subject. 2 In some embodiments, the dose is 11 mg to 44 mg per milliliter of BSA of the subject. 2 In some embodiments, the dose is 1 ml to 8 mg / ml of BSA. 2 In some embodiments, the dose is 33 mg per 1 ml of BSA of the subject. 2 In some embodiments, the dose is 25 mg per 1 ml of BSA of the subject. 2 In some embodiments, the dose is 17 mg per 1 ml of BSA of the subject. 2 In some embodiments, the dose is 15 mg per 1 ml of BSA of the subject. 2 In some embodiments, the dose is 10 mg per 1 ml of BSA of the subject. 2 of subject's BSA.

[0013] In some embodiments, the ADC is administered to the subject once every three weeks. In some embodiments, the ADC is administered to the subject once every two weeks. In some embodiments, the ADC is administered to the subject once a week.

[0014] In some embodiments, the subject has a body weight value in the upper quartile for body weight.

[0015] In some embodiments, the methods disclosed herein reduce the risk of ILD in a subject by at least 5%, at least 10%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% following administration of the ADC, as compared to a treatment in which the ADC is administered at a body weight-based dose, e.g., a dose of 0.5 to 2 mg per kilogram of body weight (BW) of the subject, e.g., a dose of 0.9 mg to 1.2 mg per kilogram of BW.

[0016] In some embodiments, the methods disclosed herein further comprise administering a corticosteroid. In some embodiments, the corticosteroid is administered prophylactically. In some embodiments, the corticosteroid is administered simultaneously or sequentially with the antibody-drug conjugate. In some embodiments, the corticosteroid is administered before or after the ADC is administered. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the dexamethasone is administered at a dose of 4 mg dexamethasone. In some embodiments, the dexamethasone is administered at least once a day or twice a day. In some embodiments, the dexamethasone is administered at the initiation of treatment with the ADC for at least 3 days. In some embodiments, the dexamethasone is administered orally. In some embodiments, the corticosteroid is prednisone. In some embodiments, the prednisone is administered at a dose of at least 0.5 mg, at least 1 mg, or at least 2 mg prednisone. In some embodiments, the prednisone is administered at a dose of 0.5 mg. In some embodiments, the prednisone is administered at a dose of 1 mg. In some embodiments, the prednisone is administered at a dose of 2 mg. In some embodiments, the prednisone is administered at least once daily. In some embodiments, the prednisone is administered for at least 14 days prior to the initiation of treatment with the ADC. In some embodiments, the prednisone is administered orally. In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the methylprednisolone is administered at a dose of 500-1000 mg methylprednisolone. In some embodiments, the methylprednisolone is administered at least once daily. In some embodiments, the prednisone is administered for at least 3 days prior to the initiation of treatment with the ADC. In some embodiments, the prednisone is administered intravenously.

[0017] In some embodiments, the ADC is administered intravenously.

[0018] In some embodiments, the folate receptor alpha expressing cancer treated by the methods disclosed herein is ovarian cancer, breast cancer, non-small cell lung cancer or endometrial cancer. In some embodiments, the ovarian cancer is platinum resistant ovarian cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the non-small cell lung cancer is metastatic non-small cell lung cancer.

[0019] In some embodiments, the FRA-expressing cancer treated by the methods disclosed herein is a metastatic cancer. In some embodiments, the metastatic cancer does not have a genomic alteration. In some embodiments, the metastatic cancer has at least one genomic alteration. In some embodiments, the at least one genomic alteration is at least one of the following genes: EGFR, ALK, PI3K, AKT, mTOR, RET, MET, BRAF, NTRK, ROS1, and any gene involved in the RAS-MAPK pathway. In some embodiments, the metastatic cancer is a non-small cell lung cancer (NSCLC). In some embodiments, the FRA-expressing cancer is a refractory cancer. In some embodiments, the refractory cancer is refractory to at least one prior treatment, e.g., an approved treatment, e.g., a targeted therapy. As used herein, a "targeted therapy" is a cancer therapy that targets specific genes and / or proteins involved in the growth and / or survival of cancer cells. In some embodiments, the targeted therapy is a targeted therapy against any one of the following genes or variants thereof: EGFR, ALK, BRAF, RET, MET, NTRK, and ROS1. In some embodiments, the refractory cancer is refractory to an approved therapy, such as a platinum-based therapy and / or an immunotherapy-based therapy (e.g., a checkpoint inhibitor therapy). In some embodiments, the refractory cancer is refractory to a platinum-based therapy and an immunotherapy-based therapy (e.g., a checkpoint inhibitor therapy), which are administered simultaneously or sequentially. In some embodiments, the platinum-based therapy is a platinum doublet chemotherapy, and the immunotherapy-based therapy is a PD-1 inhibitor or a PD-L1 inhibitor. In various embodiments, the refractory cancer is refractory to an anti-CTLA4 inhibitor. In various embodiments, the refractory cancer is refractory to radiation therapy. In various embodiments, the refractory cancer is refractory to surgery. In various embodiments, the refractory cancer is refractory to chemotherapy. In various embodiments, the subject with refractory cancer is refractory to three or fewer prior systemic therapies, such as two or fewer prior systemic therapies. In some embodiments, the subject with refractory cancer is refractory to one or fewer prior chemotherapy treatments.

[0020] In some embodiments, the subject being treated by the methods disclosed herein does not have one or more of the following: interstitial lung disease (ILD) and / or pneumonitis, a history of ILD and / or pneumonitis, clinically significant lung-specific disease, pleural effusion, pericardial effusion, prior treatment with pneumonectomy, prior chest radiation therapy within the past two years, an autoimmune disorder with pulmonary involvement, a connective tissue disorder with pulmonary involvement, or an inflammatory disorder with pulmonary involvement. In some embodiments, the subject being treated does not have one or more of the following prior treatments for FRA-expressing cancer: a high neutrophil-to-lymphocyte ratio, or a serum albumin level at the start of treatment less than 3 g / dL. [Brief description of the drawings]

[0021] [Figure 1] Figure 1 shows the results of an exposure-response (ER) analysis of ORR in subjects with platinum-resistant ovarian cancer (PROC). Subjects were stratified into exposure quartiles. Dots represent observed median exposure and ORR per quartile. Vertical bars represent exact 90% confidence intervals. In the upper panel, the solid curve represents the logistic regression fit. In the upper panel, the shaded bands represent the 90% confidence interval of the fitted curve. [Diagram 2] Results of exposure-response (ER) analysis for PROC subjects and ILD in each tumor type are shown. Subjects were stratified into exposure quartiles. Points represent observed median exposure and ORR per quartile. Vertical bars represent exact 90% confidence intervals. In the upper panel, the solid curve represents the logistic regression fit for reference subjects with a median age of 60 years. In the upper panel, the shaded bands represent the 90% confidence interval of the fitted curve. [Figure 3A] Figure 1 shows the results of simulations of different dosing regimens of MORAb-202. AIBW = adjusted ideal body weight; BW = body weight; BSA = body surface area. The orange lines in the top panel are LOESS fit error bars. BW quartiles are indicated by the bracketed values ​​on the x-axis in the bottom panel. [Figure 3B]Figure 1 shows the results of simulations of different dosing regimens of MORAb-202. AIBW = adjusted ideal body weight; BW = body weight; BSA = body surface area. The orange lines in the top panel are LOESS fit error bars. BW quartiles are indicated by the bracketed values ​​on the x-axis in the bottom panel. [Figure 4] Predicted median MORAb-202 concentrations over time with BW-adjusted and BSA-adjusted titration regimens are shown. [Diagram 5] 1 shows a study design using a BSA-based titration regimen for subjects with ovarian cancer (OC) and / or endometrial cancer (EC). [Figure 6] 1 shows a study design using a BSA-adjusted titration regimen for subjects with metastatic non-small cell lung cancer (NSCLC). [Figure 7] 1 shows a study design using a BSA-adjusted dose-finding regimen for subjects with platinum-resistant high-grade serous ovarian, primary peritoneal, or fallopian tube cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The methods of the present disclosure may be more readily understood by reference to the following detailed description taken in conjunction with the accompanying drawings, which form a part of this disclosure: It is to be understood that the present disclosure is not limited to the specific methods described and / or illustrated herein, and that the terminology used herein is for the purpose of describing the detailed embodiments by way of example only, and is not intended to limit the methods claimed.

[0023] Throughout this specification, the description herein refers to methods of using compositions, e.g., anti-FRA ADCs, e.g., MORAb-202. Where this disclosure describes or claims features or embodiments relating to methods of using the compositions, such features or embodiments are equally applicable to the compositions.

[0024] When a range of values ​​is expressed, it includes embodiments using any specific value within that range. Moreover, reference to values ​​stated in a range includes every value within that range. All ranges include their endpoints and can be combined. When values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The use of "or" is intended to mean "and / or," unless the specific context in which it is used dictates otherwise. All references cited herein are incorporated by reference for all purposes. In the event of a conflict between a reference and the present specification, the present specification shall control.

[0025] It will be appreciated that certain features of the methods of the present disclosure, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the methods of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0026] Throughout the specification and claims, various terms relating to the described aspects are used. Unless otherwise indicated, such terms should be given their ordinary meaning in the art. Other specifically defined terms should be interpreted consistent with the definitions provided herein.

[0027] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0028] In connection with numerical values ​​and ranges, the term "about" or "approximately" refers to a value or range that approximates or is close to the stated value or range such that the embodiment can function as intended, such as having a desired amount of nucleic acid or polypeptide in a reaction mixture, as will be apparent to one of skill in the art from the teachings contained herein. This is due, at least in part, to the various characteristics of nucleic acid composition, age, race, sex, anatomical and physiological variations, and imprecision of biological systems. Thus, these terms encompass values ​​that exceed those that result from systematic error. It should be understood that this definition of "about" applies throughout this disclosure, unless otherwise specified in a particular context, for example, in describing the average number of drug moieties per individual antibody moiety or in a mixture of ADCs.

[0029] The term "agent" is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological materials, or combinations thereof. The terms "therapeutic agent," "drug," or "drug moiety" refer to an agent capable of modulating a biological process and / or possessing biological activity.

[0030] The term "antibody" is used in its broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination of the above, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. The heavy chain of an antibody is made up of a heavy chain variable domain (V H ) and heavy chain constant region (C H The light chain comprises a light chain variable domain (V L ) and the light chain constant domain (C L). For purposes of this application, mature heavy and light chain variable domains each contain three complementarity determining regions (CDR1, CDR2 and CDR3) within four framework regions (FR1, FR2, FR3 and FR4), arranged from N-terminus to C-terminus as FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. An "antibody" may be naturally occurring or artificial, such as a monoclonal antibody produced by conventional hybridoma technology. The term "antibody" includes full-length monoclonal and polyclonal antibodies, as well as antibody fragments such as Fab, Fab', F(ab')2, Fv and single chain antibodies. An antibody may be any one of the five major immunoglobulin classes: IgA, IgD, IgE, IgG and IgM or subclasses thereof (e.g., isotypes IgG1, IgG2, IgG3, IgG4). The term further includes human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule that contains an antigen recognition site, so long as it exhibits the desired biological activity.

[0031] The term "chimeric antibody" as used herein refers to an antibody in which the amino acid sequences of the immunoglobulin molecules are derived from two or more species. In some cases, the variable regions of both the heavy and light chains correspond to the variable regions of an antibody derived from one species having the desired specificity, affinity and activity, while the constant regions are homologous to antibodies derived from another species (e.g., human), thereby minimizing the immune response in the latter species.

[0032] The term "human antibody," as used herein, refers to an antibody produced by a human or an antibody having the amino acid sequence of an antibody produced by a human.

[0033] As used herein, the term "humanized antibody" refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulins. Generally, a humanized antibody will contain substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions being of human immunoglobulin sequences. The humanized antibody will also optionally contain at least a portion of an immunoglobulin constant region (Fc), typically the Fc of a human immunoglobulin. Humanized antibodies can be further modified by substitution of residues either within the Fv framework regions and / or replaced non-human residues to refine and optimize antibody specificity, affinity and / or activity.

[0034] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies that populate the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically contain a large number of antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the nature of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring that the antibody be produced by any particular method. For example, monoclonal antibodies to be used in this disclosure may be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be produced by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J. Mol. Biol. 222:581-97, for example.

[0035] The monoclonal antibodies described herein specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of one or more chains is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies so long as they specifically bind to a target antigen and / or exhibit the desired biological activity.

[0036] The terms "antibody-drug conjugate", "antibody conjugate", "conjugate", "immunoconjugate" and "ADC" are used interchangeably and refer to a compound (e.g., eribulin) or a derivative thereof linked to an antibody (e.g., an anti-FRA antibody) and have the general formula: Ab-(LD) p (Formula I), where Ab = antibody moiety (i.e., antibody or antigen-binding fragment), L = linker moiety, D = drug moiety, and p = number of drug moieties per antibody moiety.

[0037] The term "antigen-binding fragment" or "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., FRA). Antigen-binding fragments preferably also retain the ability to internalize into antigen-expressing cells. In some embodiments, antigen-binding fragments also retain immune effector activity. It has been shown that fragments of full-length antibodies can perform the antigen-binding function of the full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" or "antigen-binding portion" of an antibody include: (i) V L , V H , C L and C H1 (ii) a F(ab')2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a V H and C H1 (iv) a Fd fragment consisting of the V domain of a single arm of an antibody;L and V H (v) an Fv fragment consisting of a single variable domain, e.g., a V H and (vi) isolated complementarity determining regions (CDRs). In addition, the two domains of the Fv fragment, the V L and V H are encoded by separate genes, but using recombinant methods they can be joined together with synthetic linkers to form V L and V H The regions can be made into a single protein chain (known as single-chain Fv (scFv)) that pairs to form a monovalent molecule. See, e.g., Bird et al. (1988) Science 242:423-6; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-83. Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" or "antigen-binding portion" of an antibody and are known in the art as an exemplary type of binding fragment that can be internalized into a cell upon binding. See, e.g., Zhu et al. (2010) 9:2131-41; He et al. (2010) J. Nucl. Med. 51:427-32; and Fitting et al. (2015) MAbs 7:390-402. In certain embodiments, scFv molecules can be incorporated into fusion proteins. Other forms of single chain antibodies, such as diabodies, are also included. H and V LBispecific antibodies are bivalent in that the domains are expressed on a single polypeptide chain, but use a linker that is too short to allow pairing between the two domains on the same chain, thus forcing them to pair with complementary domains on another chain to create two antigen-binding sites (see, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-8; and Poljak et al. (1994) Structure 2:1121-3). Antigen-binding fragments are obtained using conventional techniques known to those skilled in the art, and such binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies. Antigen-binding fragments can be prepared by cleaving the intact protein, for example, by protease or chemical cleavage.

[0038] "Body surface area" or "BSA" as used herein refers to the total surface area of ​​a subject being treated by the methods disclosed herein. By calculating the subject's body surface area, the optimal dosage of a compound, such as an antibody-drug conjugate, such as an anti-FRA ADC, to be administered to the subject can be determined. In general, the value of the subject's body surface area can be determined by calculation based on the subject's body weight.

[0039] The term "cancer" refers to a physiological condition in mammals in which a cell population is characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, ovarian cancer (e.g., platinum-resistant ovarian cancer), breast cancer (e.g., triple-negative breast cancer), non-small cell lung cancer, endometrial cancer, peritoneal cancer, and fallopian tube cancer. Triple-negative breast cancer refers to breast cancer that is negative for estrogen receptor (ER), progesterone receptor (PR), and Her2 / neu gene expression. More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, liver cancer, bladder cancer, hepatocellular carcinoma, osteosarcoma, melanoma, colon cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, peritoneal cancer, fallopian tube cancer, and various head and neck cancers.

[0040] The terms "cancer cell" and "tumor cell" refer to individual cells or the entire population of cells derived from a tumor, including both non-tumorigenic cells and cancer stem cells. As used herein, the term "tumor cell" is modified with the term "non-tumorigenic" to refer simply to tumor cells that lack regenerative and differentiation capacity, to distinguish them from cancer stem cells.

[0041] The term "chemotherapeutic agent" or "anti-cancer agent" is used herein to refer to any chemical compound that is effective in the treatment of cancer, regardless of mechanism of action. Inhibition of metastasis or angiogenesis is often a property of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as nitrogen mustards, ethylenimine compounds, and alkyl sulfonates; antimetabolites, such as folic acid, purine, or pyrimidine antagonists; antimitotic agents, such as antitubulin agents or derivatives thereof, such as eribulin or eribulin mesylate (Halaven™), vinca alkaloids, and auristatins; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, such as DNA minor groove binders; and growth factor receptor antagonists. In addition, chemotherapeutic agents include antibodies, biomolecules, and small molecules. Chemotherapeutic agents can be cytotoxic or cytostatic. The term "cytostatic agent" refers to an agent that inhibits or suppresses cell growth and / or cell proliferation.

[0042] The terms "co-administration" or administration "in combination with" one or more therapeutic agents includes simultaneous and consecutive administration in any order.

[0043] "Corticosteroids" as used herein are any compounds belonging to a class of steroid hormones typically produced in the adrenal cortex of vertebrates. The term, as used herein, also encompasses synthetic analogs of such hormones, such as pharmaceutical compositions that mimic the action of naturally occurring corticosteroids. Dexamethasone is an exemplary embodiment of a corticosteroid. Prednisone is also an exemplary embodiment of a corticosteroid. Methylprednisolone is another exemplary embodiment of a corticosteroid.

[0044] The term "cytotoxic agent" refers to a substance that causes cell death primarily by interfering with the expression activity and / or function of a cell. Examples of cytotoxic agents include, but are not limited to, antimitotic agents such as eribulin, auristatins (e.g., monomethylauristatin E (MMAE), monomethylauristatin F (MMAF)), maytansinoids (e.g., maytansine), dolastatins, duostatins, cryptophycins, vinca alkaloids (e.g., vincristine, vinblastine), taxanes, taxols, and colchicines; anthracyclines (e.g., Dow Jones Infectious Diseases; norubicin, doxorubicin, dihydroxyanthracenedione; cytotoxic antibiotics (e.g., mitomycins, actinomycins, duocarmycins (e.g., CC-1065), aureomycins, duomycins, calicheamicins, endomycins, phenomycins); alkylating agents (e.g., cisplatin); intercalating agents (e.g., ethidium bromide); topoisomerase inhibitors (e.g., etoposide, teniposide); At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 or 213 , P 32 and radioisotopes of lutetium (e.g., Lu 177 ; and toxins of bacterial, fungal, plant or animal origin (e.g., ricin (e.g., ricin A chain), diphtheria toxin, Pseudomonas exotoxin A (e.g., PE40), endotoxins, mitogenin, combrestatin, restrictocin, gelonin, alpha-sarcin, abrin (e.g., abrin A chain), modeccin (e.g., modeccin A chain), chrysin, crotin, Sapaonaria officinalis inhibitor, glucocorticoids).

[0045] An "effective amount" of an ADC as disclosed herein is an amount sufficient to achieve a specifically described purpose, e.g., an amount sufficient to produce a therapeutic effect after administration, such as a reduction in tumor growth rate or tumor volume, a reduction in a cancer symptom, or some other indicator of therapeutic efficacy. An effective amount may be determined in a conventional manner related to the described purpose. The term "therapeutically effective amount" refers to an amount of an ADC effective to treat a disease or disorder of interest. In the case of cancer, a therapeutically effective amount of an ADC may reduce cancer cell numbers, reduce tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or alleviate one or more symptoms. Treatment and therapeutically effective amount of treatment include, but do not necessarily, complete treatment. For example, the term includes, but does not necessarily, completely stop tumor growth.

[0046] The term "epitope" refers to a portion of an antigen that has the ability to be recognized and specifically bound by an antibody. When an antigen is a polypeptide, an epitope can be formed by contiguous amino acids or non-contiguous amino acids that are arranged side by side by folding the polypeptide into a tertiary structure. The epitope bound by an antibody can be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of the antigen-antibody complex, and monitoring the binding of the antibody to a fragment or mutant variant of the antigen or monitoring the solvent accessibility of various portions of the antibody and antigen. Exemplary strategies used to map antibody epitopes include, but are not limited to, array-based oligopeptide scanning, limited proteolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange and mass spectrometry (see, e.g., Gershoni et al. (2007) 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev. Proteomics 2:745-56).

[0047] The term "eribulin" as used herein refers to a synthetic analog of halichondrin B, a macrocyclic compound originally isolated from the marine sponge Halichondria okadais. The term "eribulin drug moiety" refers to the component of an ADC that has the structure of eribulin and is attached to the linker of the ADC at its C-35 amine. Eribulin is a microtubule dynamics inhibitor that is believed to induce cell cycle arrest at the G2 / M phase by binding to tubulin and inhibiting mitotic spindle assembly. The term "eribulin mesylate" refers to the mesylate salt of eribulin, sold under the trade name Halaven™.

[0048] The term "folate receptor alpha" or "FRA" as used herein refers to any naturally occurring form of human FRA. The term encompasses full-length FRA (e.g., NCBI Reference Sequence: NP_000793; SEQ ID NO: 37), as well as any form of human FRA that arises by cellular processing. The term also encompasses naturally occurring variants of FRA, including, but not limited to, splice variants, allelic variants, and isoforms. FRA can be isolated from humans or produced by recombinant or synthetic methods.

[0049] The term "anti-FRA antibody" or "antibody that specifically binds to FRA" refers to any form of antibody or fragment thereof that specifically binds to FRA, including monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments as long as they specifically bind to FRA. Preferably, the anti-FRA antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antibody fragment. MORAb-003 is an exemplary internalizing anti-human FRA antibody that may be used, for example, as part of an anti-FRA ADC in the present disclosure. As used herein, the terms "specific," "specifically binds," and "binds specifically" refer to an antibody that selectively binds to a target antigen epitope. An antibody can be tested for specificity of binding by comparing binding to the appropriate antigen under a given set of conditions with binding to an unrelated antigen or antigen mixture. An antibody is considered specific if it binds to the appropriate antigen with at least 2, 5, 7, and preferably 10-fold greater affinity than an irrelevant antigen or mixture of antigens. In one embodiment, a specific anti-FRA antibody is one that binds only to the FRA antigen and does not bind (or exhibits minimal binding) to other antigens.

[0050] "Internalizing," as used herein in reference to an antibody or antigen-binding fragment, refers to an antibody or antigen-binding fragment that, upon binding to a cell, has the ability to penetrate the lipid bilayer membrane of the cell and be incorporated into an internal compartment of the cell, preferably a degradative compartment (i.e., be "internalized"). For example, an internalizing anti-FRA antibody is one that has the ability to be incorporated into the cell after binding to FRA on the cell membrane.

[0051] The term "interstitial lung disease" refers to any one of a group of lung diseases characterized by inflammation that may lead to pulmonary fibrosis. Interstitial lung disease (ILD) is known to be a potential adverse effect associated with immunotherapy treatment. An "adverse effect" or "AE" is any untoward medical occurrence in a subject administered a compound, which does not necessarily imply a causal relationship with the administered compound or indicate that the compound cannot be used for treatment, but may impose limitations on the use of the compound. Methods for identifying and diagnosing interstitial lung disease are well known in the art, such as, for example, using pulse oximetry to assess oxygen saturation and using chest computed tomography (CT) scans to determine ILD-related lung injury.

[0052] A "linker" or "linker moiety" is any chemical moiety capable of covalently linking a compound, usually a drug moiety such as a chemotherapeutic agent, to another moiety, such as an antibody moiety. The linker can be susceptible to or substantially resistant to acid-induced, peptidase-induced, light-based, esterase-induced, and / or disulfide bond cleavage, provided that the compound or antibody remains active.

[0053] The term "p" or "antibody:drug ratio" or "drug-to-antibody ratio" or "DAR" refers to the number of drug moieties per each antibody moiety, i.e., drug loading or the number of -LD moieties per each antibody or antigen-binding fragment (Ab) in an ADC of Formula I. In compositions comprising multiple copies of an ADC of Formula I, "p" refers to the average number of -LD moieties per each antibody or antigen-binding fragment, also referred to as the average drug loading.

[0054] "Pharmaceutically acceptable" means approved or to be approved by a federal or state regulatory agency for use in animals, or more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0055] A "pharmaceutical composition" refers to a preparation in a form that allows for administration and subsequently provides the intended biological activity and / or therapeutic effect of one or more active ingredients, and that does not contain additional components that are unacceptably toxic to the subject to whom the formulation will be administered. A pharmaceutical composition may be sterile.

[0056] "Pharmaceutical excipients" include materials such as adjuvants, carriers, pH adjusting and buffering agents, isotonicity agents, wetting agents, preservatives, and the like.

[0057] "Protein" as used herein means at least two covalently linked amino acids. The term encompasses polypeptides, oligopeptides, and peptides. In some embodiments, the two or more covalently linked amino acids are linked by peptide bonds. For example, when a protein is made recombinantly using an expression system and a host cell, the protein may be composed of naturally occurring amino acids and peptide bonds. Alternatively, the protein may include synthetic amino acids (e.g., homophenylalanine, citrulline, ornithine, and norleucine) or peptidomimetic structures, i.e., "peptide or protein analogs," such as peptoids.

[0058] For amino acid sequences, sequence identity and / or similarity may be determined using standard techniques known in the art, including, but not limited to, the local sequence identity algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2:482, the sequence identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, the search for similarity method of Pearson and Lipman (1988) Proc. Nat. Acad. Sci. USA 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.), the Best Fit sequence program described by Devereux et al. (1984) Nucl. Acid Res. 12:387-95, preferably using default settings, or by visual inspection. Preferably, the percent identity is calculated by FastDB based on the following parameters: mismatch penalty of 1; gap penalty of 1; gap size penalty of 0.33; and joining penalty of 30 ("Current Methods in Sequence Comparison and Analysis," Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149 (1988), Alan R. Liss, Inc.).

[0059] An example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive pairwise alignments. It can also plot a tree showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle (1987) J. Mol. Evol. 35:351-60; this method is similar to that described by Higgins and Sharp (1989) CABIOS 5:151-3. Useful PILEUP parameters include a default gap weight of 3.00, a default gap length weight of 0.10, and weighted end gaps.

[0060] Another example of a useful algorithm is the BLAST algorithm described in Altschul et al. (1990) J. Mol. Biol. 215:403-10; Altschul et al. (1997) Nucleic Acids Res. 25:3389-402; and Karin et al. (1993) Proc. Natl. Acad. Sci. USA 90:5873-87. A particularly useful BLAST program is the WU-BLAST-2 program, which was derived from Altschul et al. (1996) Methods in Enzymology 266:460-80. WU-BLAST-2 uses several search parameters, most of which are set to default values. Adjustable parameters are set with the following values: overlap width=l, overlap ratio=0.125, word threshold (T)=II. The HSP S and HSP S2 parameters are dynamic values ​​and are established by the program itself depending on the composition of the particular sequence and the composition of the particular database in which the sequence of interest is being searched, however, these values ​​can be adjusted to increase sensitivity.

[0061] A further useful algorithm is Gapped BLAST as reported by Altschul et al. (1993) Nucl. Acids Res. 25:3389-402. Gapped BLAST uses a BLOSUM-62 substitution score; a threshold T parameter set to 9; starting ungapped extension with the 2-hit method, imposing a cost of 10+k for gap lengths of k; Xu set to 16 and Xg set to 40 for the database search step and 67 for the output step of the algorithm. Gapped alignments are initiated by a score corresponding to approximately 22 bits.

[0062] Generally, the amino acid homology, similarity or identity between the proteins disclosed herein and variants thereof, including variants of the FRA and variants of the antibody variable domains (including individual variant CDRs), is at least 80% with the sequences shown herein, and more typically is preferably at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and near or greater than 100% homology or identity.

[0063] Similarly, "percent (%) nucleic acid sequence identity" with respect to nucleic acid sequences of antibodies and other proteins identified herein is defined as the percentage of nucleotide residues in a candidate sequence that are identical with the nucleotide residues in the coding sequence of the antigen binding protein. An exemplary method utilizes the BLASTN module of WU-BLAST-2 set to default parameters, with overlap width and overlap rate set to 1 and 0.125, respectively.

[0064] The terms "subject," "patient," and "participant" are used interchangeably herein to refer to any animal, such as any mammal, including, but not limited to, humans, non-human primates, rodents, etc. In some embodiments, the mammal is a mouse. In some embodiments, the mammal is a human.

[0065] The terms "tumor" and "neoplasm" refer to any mass of tissue resulting from excessive cell growth or proliferation, either benign or malignant, including precancerous lesions.

[0066] As used herein, "treating" or "therapeutic" and grammatically related terms refer to any improvement in any outcome of a disease, such as increased survival, reduced morbidity, and / or reduced side effects that are a by-product of alternative treatment modalities. As will be readily understood in the art, complete eradication of a disease is preferred, although not required for therapeutic procedures. "Treatment" or "treating" as used herein refers to administration, e.g., of an ADC as described, to a subject, e.g., a patient. Treatment can be, for example, curing, palliating, alleviating, altering, ameliorating, ameliorating, reversing, or affecting a disorder, such as cancer, a symptom of a disorder, or a predisposition to a disorder. The terms "treatment" and "therapy" are used interchangeably herein.

[0067] In various embodiments, methods are provided herein for reducing the risk of interstitial lung disease (ILD) in subjects treated with anti-FRA ADC. "Reducing risk" as used herein refers to the change in incidence of ILD (e.g., the change in the number of subjects with ILD) compared to a comparison treatment. For example, treatment with an anti-FRA ADC disclosed herein using a BSA-based titration regimen can reduce the risk of ILD in certain subjects when compared to similar subjects administered an anti-FRA ADC at an equivalent weight-based dose over a given period of time.

[0068] The term "upper quartile of body weight" as used herein refers to a body weight value that falls within the upper 25% of all body weight values ​​for a given group of subjects, such as a group of adults in the general population or a group of subjects suffering from FRA-expressing cancer. As used herein, the term includes values ​​that represent the upper 25% boundary. For example, the upper quartile of body weight for a given group of subjects can be determined by first sorting the subjects' body weight values ​​in ascending order, then dividing the set of values ​​into quarters (also known as quartiles), and finally determining the values ​​between the third and fourth quartiles. Subjects in the upper quartile of body weight have a body weight value that is at least equal to, if not greater than, the value between the third and fourth quartiles. In some embodiments, the value between the third and fourth quartiles for a given group of subjects is approximately or about 80 kilograms.

[0069] Antibody-drug conjugates The disclosed methods include the use of compounds with anti-cancer activity. In particular, the compounds include an antibody moiety (including an antigen-binding fragment thereof) conjugated (i.e., covalently linked by a linker) to a drug moiety, which has, for example, a cytotoxic or cytostatic effect when not conjugated to the antibody moiety. In various embodiments, the drug moiety exhibits reduced or no cytotoxicity when bound to the conjugate, but regains cytotoxicity after cleavage from the linker and antibody moiety.

[0070] In some embodiments, the ADC comprises a peptide cleavable linker linking eribulin to an anti-FRA ADC. In some embodiments, the linker comprises a val-cit moiety. In some embodiments, the linker comprises a PEG spacer. In some embodiments, the linker comprises a Mal-(PEG)2-Val-Cit-pAB linker that joins eribulin to an anti-FRA antibody (e.g., an anti-FRA antibody such as MORAb-003). In some embodiments, the anti-FRA ADC is MORAb-202. "MORAb-202" refers to an anti-FRA ADC in which the anti-FRA antibody or antigen-binding fragment comprises a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16, the linker moiety comprises Mal-(PEG)2-Val-Cit-pAB, and the linker is linked to eribulin via the C-35 amine. In some embodiments, the structure of MORAb-202 (including the sequence of the anti-FRA antibody portion in the ADC) is disclosed in PCT Application No. PCT / US2017 / 020529 (published as WO 2017 / 151979), which is incorporated by reference in its entirety.

[0071] In some embodiments, an anti-FRA ADC (e.g., MORAb-202) exhibits particularly advantageous properties in various categories, including (i) the ability to retain one or more therapeutic properties exhibited by the antibody and drug moieties alone, (ii) the ability to maintain the specific binding properties of the antibody moiety; (iii) optimal drug loading and drug-to-antibody ratio; (iv) the ability to enable delivery of the drug moiety, e.g., intracellular delivery, via stable association with the antibody moiety; (v) the ability to maintain ADC stability as an intact conjugate until the time of transport or delivery to the target site; (vi) minimal aggregation of the ADC before or after administration; (vii) the ability to achieve a therapeutic effect of the drug moiety, e.g., a cytotoxic effect, following cleavage in the cellular environment; (viii) in vivo anti-cancer therapeutic efficacy that is comparable to or superior to that of the antibody and drug moiety alone; (ix) minimal off-target killing by the drug moiety; and / or (x) desirable pharmacokinetic and pharmacodynamic properties, ease of formulation, and toxicological / immunological profile.

[0072] The disclosed ADC compounds can selectively deliver an effective dose of a cytotoxic or cytostatic agent to FRA-expressing cancer cells or FRA-expressing tumor tissue. The disclosed ADCs have been found to have potent cytotoxic and / or cytostatic activity against cells expressing FRA. Exemplary FRA-expressing cancers include, but are not limited to, ovarian cancer (e.g., serous ovarian cancer, clear cell ovarian cancer, or platinum-resistant ovarian cancer), lung cancer (e.g., non-small cell lung cancer, e.g., metastatic non-small cell lung cancer), breast cancer (e.g., triple-negative breast cancer), and endometrial cancer.

[0073] An exemplary ADC has Formula I: Ab-(LD) p (I) where Ab=an internalizing anti-folate receptor alpha antibody or an internalizing antigen-binding fragment thereof, L=a cleavable linker moiety, D=a drug moiety, and p=the number of drug moieties per each antibody moiety. has.

[0074] antibody The antibody portion (Ab) of Formula I includes within its scope any antibody or antigen-binding fragment that specifically binds to a FRA on a cancer cell. The antibody or antigen-binding fragment may have a dissociation constant (K) of ≦1 mM, ≦100 nM, or ≦10 nM, or any magnitude therebetween, as measured, for example, by BIAcore® analysis. D In certain embodiments, K D In some embodiments, K D is 500 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM.

[0075] In some embodiments, the antibody portion is a four-chain antibody (also called an immunoglobulin) and comprises two heavy chains and two light chains, hi some embodiments, the antibody portion is a two-chain half antibody (one light chain and one heavy chain) or is an antigen-binding fragment of an immunoglobulin.

[0076] In some embodiments, the antibody moiety is an internalizing antibody or an internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody binds to FRA expressed on the surface of a cell and enters the cell upon binding. In some embodiments, the FRA targeting antibody moiety is MORAb-003. In some embodiments, the drug moiety of the ADC is released from the antibody moiety of the ADC after the ADC enters and resides in a cell expressing the target cancer antigen (i.e., after the ADC is internalized).

[0077] The amino acid and nucleic acid sequences of exemplary antibodies that may be used in the ADCs disclosed herein are provided in Tables 1-9.

[0078] [Table 1]

[0079] [Table 2]

[0080] [Table 3]

[0081] [Table 4]

[0082] [Table 5]

[0083] [Table 6]

[0084] [Table 7]

[0085] [Table 8]

[0086] [Table 9]

[0087] [Table 10]

[0088] [Table 11]

[0089] In various embodiments, the ADCs disclosed herein may comprise a set of MORAb-003 heavy and light chain variable domains listed in the table above, or a set of six MORAb-003 CDR sequences (Kabat and / or IMGT) from the heavy and light chains listed in the table above. In some embodiments, the ADCs further comprise human heavy and light chain constant domains or fragments thereof. For example, the ADCs may comprise a human IgG heavy chain constant domain (such as IgG1) and a human kappa or lambda light chain constant domain. In various embodiments, the antibody portion of the described ADCs comprises a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain together with a human Igkappa light chain constant domain. In some embodiments, the anti-FRA antibody portion of the ADCs comprises the complete heavy and light chain sequences listed in the table above.

[0090] In various embodiments, the anti-FRA antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: as defined by the Kabat numbering system (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), a heavy chain CDR1 (HCDR1) comprising SEQ ID NO:1, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO:2, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO:3; a light chain CDR1 (LCDR1) comprising SEQ ID NO:4, a light chain CDR2 (LCDR2) comprising SEQ ID NO:5, and a light chain CDR3 (LCDR3) comprising SEQ ID NO:6.

[0091] In some embodiments, the anti-FRA antibody, or antigen-binding fragment thereof, comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 comprises SEQ ID NO:7, heavy chain CDR2 comprises SEQ ID NO:8, heavy chain CDR3 comprises SEQ ID NO:9; light chain CDR1 comprises SEQ ID NO:10, light chain CDR2 comprises SEQ ID NO:11, and light chain CDR3 comprises SEQ ID NO:12, as defined by the IMGT numbering system (International ImMunoGeneTics Information System (IMGT®)).

[0092] In various embodiments, the anti-FRA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-FRA antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 13 and a light chain variable region amino acid sequence of SEQ ID NO: 14, or a sequence at least 95% identical to the above-mentioned sequences. In some embodiments, the anti-FRA antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 13 and a light chain variable region amino acid sequence at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 14.

[0093] In various embodiments, the anti-FRA antibody comprises a human IgG1 heavy chain constant domain together with a human Igκ light chain constant domain.

[0094] In various embodiments, the anti-FRA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 15 or a sequence at least 95% identical to SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16 or a sequence at least 95% identical to SEQ ID NO: 16. In particular embodiments, the antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16 or a sequence at least 95% identical to the above-mentioned sequences. In some embodiments, the anti-FRA antibody has a heavy chain amino acid sequence at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 15 and / or a light chain amino acid sequence at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 16. In some embodiments, the anti-FRA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-FRA antibody comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:35 (including nucleotides encoding a leader sequence) or SEQ ID NO:31 (excluding nucleotides encoding a leader sequence); and a light chain encoded by the nucleotide sequence of SEQ ID NO:36 (including nucleotides encoding a leader sequence) or SEQ ID NO:32 (excluding nucleotides encoding a leader sequence). In some embodiments, the heavy chain amino acid sequence lacks a C-terminal lysine. In various embodiments, the anti-FRA antibody has the amino acid sequence of an antibody produced by the cell line deposited under the provisions of the Budapest Treaty with the American Type Culture Collection (ATCC, 10801 University Blvd., Manassas, Va. 20110-2209) under accession number PTA-7552 on April 24, 2006, or such a sequence lacking a heavy chain C-terminal lysine. In various embodiments, the anti-FRA antibody is MORAb-003 (USAN name: farletuzumab) (Ebel et al. (2007) Cancer Immunity 7:6) or an antigen-binding fragment thereof.

[0095] In various embodiments, the amino acid substitutions are single residues. Insertions are usually in the range of about 1 to about 20 amino acid residues, although much larger insertions are tolerated as long as the biological function of the anti-FRA is retained. Deletions are usually in the range of about 1 to about 20 amino acid residues, although in some cases deletions can be much larger. Substitutions, deletions, insertions or any combination thereof can be used to arrive at the final derivative or variant. Generally, these changes are made to a few amino acids to minimize changes in the molecule, particularly the immunogenicity and specificity of the antigen-binding protein. However, larger changes can be tolerated in certain circumstances. Generally, conservative substitutions are made according to the following diagram shown as Table 10.

[0096] [Table 12]

[0097] In some embodiments, the FRA targeting antibody moiety is MORAb-003. In some embodiments, FRA targeting antibody moieties such as MORAb-003 provide, among other things, improved drug:antibody ratios, tumor targeting, bystander killing, therapeutic efficacy and reduced off-target killing. Improved therapeutic efficacy can be measured in vitro or in vivo and can include reduced tumor growth rate and / or reduced tumor volume.

[0098] Linker In various embodiments, the linker of an anti-FRA ADC is stable outside a cell in a form sufficient to be therapeutically effective. In some embodiments, the linker is stable outside a cell, such that the ADC remains intact when present in extracellular conditions (e.g., before being transported or delivered to an FRA-expressing cell). The term "intact" as used in reference to an ADC means that the antibody moiety remains attached to the drug moiety. As used herein, "stable" in reference to a linker or an ADC that includes a linker means that no more than about 20%, no more than about 15%, no more than about 10%, no more than about 5%, no more than about 3%, or no more than about 1% (or any percentage therebetween) of the linker is cleaved in a sample of the ADC (or is otherwise not intact in the case of the entire ADC) when the ADC is present in extracellular conditions.

[0099] Whether a linker is stable outside a cell can be determined, for example, by placing an anti-FRA ADC in plasma for a predetermined time (e.g., 2, 4, 6, 8, 16, or 24 hours) and then quantifying the amount of free drug moiety present in the plasma. Stability allows time for the ADC to localize to the target tumor cells and prevents premature release of the drug, which could reduce the therapeutic index of the ADC by indiscriminately damaging both normal and tumor tissues. In some embodiments, the linker is stable outside the target cell and releases the drug moiety from the ADC upon entry into the cell, thereby allowing the drug moiety to bind to its target (e.g., to microtubules). Thus, an effective linker will be one that (i) maintains the specific binding properties of the antibody moiety; (ii) allows delivery, e.g., intracellular delivery, of the drug moiety via stable association with the antibody moiety; (iii) remains stable and intact until the ADC is transported or delivered to its target site; and (iv) achieves the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage.

[0100] Linkers can be "cleavable" or "non-cleavable" (Ducry and Stump, Bioconjugate Chem. (2010) 21:5-13). Cleavable linkers are designed to release the drug when subjected to certain environmental factors, such as when internalized into a target cell, while non-cleavable linkers generally rely on degradation of the antibody moiety itself.

[0101] In some embodiments, the linker is a cleavable linker. A cleavable linker refers to any linker that includes a cleavable moiety. As used herein, the term "cleavable moiety" refers to any chemical bond that can be cleaved. Suitable cleavable chemical bonds are well known in the art and include, but are not limited to, acid labile bonds, protease / peptidase labile bonds, photolabile bonds, disulfide bonds, and esterase labile bonds. A linker that includes a cleavable moiety may allow the release of the drug moiety from the ADC by cleavage at a specific site of the linker. In various embodiments, when the anti-FRA antibody is cleaved from the linked toxin, the activity of the toxin is activated or increased.

[0102] In some embodiments, the linker is cleavable by a cleavage agent, e.g., an enzyme, present in the intracellular environment (e.g., in a lysosome or endosome or caveolae). The linker can be, for example, a peptide linker that is cleaved by an intracellular peptidase or a protease enzyme, including but not limited to, a lysosomal or endosomal protease. In some embodiments, the linker is a cleavable peptide linker. As used herein, a cleavable peptide linker refers to any linker that includes a cleavable peptide moiety. The term "cleavable peptide moiety" refers to any chemically bonded amino acid (natural or synthetic amino acid derivative) that can be cleaved by an agent present in the intracellular environment. For example, the linker can include a valine-citrulline (Val-Cit) sequence that is cleavable by a peptidase, such as a cathepsin, e.g., cathepsin B.

[0103] In some embodiments, the linker is an enzyme-cleavable linker, and the cleavable peptide moiety in the linker is cleavable by an enzyme. In some embodiments, the cleavable peptide moiety is cleavable by cathepsin B. An exemplary dipeptide that can be cleaved by cathepsin B is valine-citrulline (Val-Cit) (Dubowchik et al. (2002) Bioconjugate Chem. 13:855-69).

[0104] In some embodiments, the linker or the cleavable peptide moiety in the linker comprises an amino acid unit. In some embodiments, the amino acid unit allows for cleavage of the linker by a protease, thus facilitating release of the drug moiety from the ADC upon exposure to one or more intracellular proteases, such as one or more lysosomal enzymes (Doronina et al. (2003) Nat. Biotechnol. 21:778-84; Dubowchik and Walker (1999) Pharm. Therapeutics 83:67-123). Exemplary amino acid units include, but are not limited to, dipeptides. Exemplary dipeptides include, but are not limited to, valine-citrulline (Val-Cit). In some embodiments, the amino acid unit in the linker comprises Val-Cit. The amino acid unit may include naturally occurring amino acid residues and / or minor amino acids and / or non-naturally occurring amino acid analogs, such as citrulline.

[0105] In some embodiments, a linker in an anti-FRA ADC disclosed herein comprises at least one spacer unit that links the antibody moiety to the drug moiety. In some embodiments, the spacer unit links a cleavage site (e.g., a cleavable peptide moiety) in the linker to the antibody moiety. In some embodiments, the linker comprises one or more polyethylene glycol (PEG) moieties, e.g., 1, 2, 3, 4, 5, or 6 PEG moieties. In some embodiments, the linker comprises two PEG moieties.

[0106] In some embodiments, the spacer unit in the linker comprises one or more PEG moieties. In some embodiments, the spacer unit is -(PEG) m - and m is 2. In some preferred embodiments, the spacer unit comprises (PEG)2.

[0107] In some embodiments, the spacer unit indirectly links the antibody moiety to the drug moiety, hi some embodiments, the spacer unit indirectly links the antibody moiety to the drug moiety through a cleavable peptide moiety and a linking moiety for joining the spacer unit to the antibody moiety, e.g., a maleimide moiety.

[0108] The spacer unit, in various embodiments, is attached to the anti-FRA antibody moiety (ie, an anti-FRA antibody or an antigen-binding fragment thereof) via a maleimide moiety (Mal).

[0109] A spacer unit that is attached to an antibody or antigen-binding fragment via a Mal is referred to herein as a "Mal-spacer unit." The term "maleimide moiety" as used herein means a compound that comprises a maleimide group and is reactive with sulfhydryl groups, such as sulfhydryl groups of cysteine ​​residues in an antibody moiety. In some embodiments, a Mal-spacer unit is reactive with cysteine ​​residues of an antibody or antigen-binding fragment. In some embodiments, a Mal-spacer unit is tethered to an antibody or antigen-binding fragment via a cysteine ​​residue. In some embodiments, a Mal-spacer unit comprises a (PEG)2 moiety.

[0110] In certain embodiments, the linker comprises a Mal-spacer unit and a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Cit. In some embodiments, the linker comprises Mal-(PEG)2 and Val-Cit.

[0111] In some embodiments, the Mal-spacer unit links the anti-FRA antibody moiety (i.e., an anti-FRA antibody or antigen-binding fragment thereof) to a cleavable moiety in the linker. In some embodiments, the Mal-spacer unit links the antibody or antigen-binding fragment to a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises a Mal-spacer unit-amino acid unit. In some embodiments, the Mal-spacer unit comprises a PEG moiety. In some embodiments, the amino acid unit comprises Val-Cit.

[0112] In some embodiments, the linker comprises the structure: Mal-spacer unit-Val-Cit. In some embodiments, the linker comprises the structure: Mal-(PEG)2-Val-Cit. In some embodiments, the linker comprises the structure: Mal-(PEG)2-Val-Cit-pAB.

[0113] In some embodiments, the cleavable moiety in the linker is linked to the drug moiety, such as eribulin, using another spacer unit. In some embodiments, eribulin is linked to the cleavable moiety in the linker by a self-immolative spacer unit. In certain embodiments, eribulin is linked to the cleavable moiety in the linker by a self-immolative spacer unit, the cleavable moiety comprises Val-Cit, and an additional spacer unit comprising (PEG)2 links the cleavable moiety to the anti-FRA antibody moiety. In certain embodiments, eribulin is linked to the anti-FRA antibody via a Mal-spacer unit in the linker linked to a Val-Cit cleavable moiety and a pAB self-immolative spacer unit.

[0114] A spacer unit can be "self-immolative" or "non-self-immolative". A "non-self-immolative" spacer unit is one in which some or all of the spacer unit remains attached to the drug moiety upon cleavage of the linker. Examples of non-self-immolative spacer units include, but are not limited to, glycine spacer units and glycine-glycine spacer units. A non-self-immolative spacer unit may eventually degrade over time, but does not immediately release the entire linked native drug even under cellular conditions. A "self-immolative" spacer unit allows for the release of the native drug moiety under intracellular conditions. An "native drug" is one in which no part of the spacer unit or other chemical modification remains after cleavage / degradation of the spacer unit.

[0115] Self-immolation chemistries are known in the art and can be readily selected for the disclosed ADCs. In various embodiments, the spacer unit that connects the cleavable moiety in the linker to the drug moiety (e.g., eribulin) is self-immolative and undergoes self-immolation simultaneously with or immediately before / after cleavage of the cleavable moiety under intracellular conditions.

[0116] In certain embodiments, the self-immolative spacer unit in the linker comprises a p-aminobenzyl unit. In some embodiments, p-aminobenzyl alcohol (pABOH) is linked to an amino acid unit or other cleavable moiety in the linker via an amide bond, creating a carbamate, methylcarbamate or carbonate between pABOH and the drug moiety (Hamann et al. (2005) Expert Opin. Ther. Patents 15:1087-103). In some embodiments, the self-immolative spacer unit is or comprises p-aminobenzyloxycarbonyl (pAB). Without being bound by theory, it is believed that the self-immolation of pAB involves a spontaneous 1,6-elimination reaction (Jain et al. (2015) Pharm Res 32:3526-40).

[0117] In various embodiments, the structure of p-aminobenzyloxycarbonyl (pAB) used in the disclosed ADCs is shown below: [ka]

[0118] In various embodiments, the self-immolative spacer unit links the cleavable moiety in the linker to the C-35 amine of eribulin. In some embodiments, the self-immolative spacer unit is pAB. In some embodiments, pAB links the cleavable moiety in the linker to the C-35 amine of eribulin. In some embodiments, pAB undergoes self-immolation upon cleavage of the cleavable moiety, and eribulin is released from the ADC in its native active form. In some embodiments, an anti-FRA antibody (e.g., MORAb-003) is tethered to the C-35 amine of eribulin by a linker comprising Mal-(PEG)2-Val-Cit-pAB.

[0119] In some embodiments, pAB undergoes self-immolation upon cleavage of the cleavable peptide moiety in the linker. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises the amino acid unit-pAB. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pAB(VCP). In various aspects, the antibody moiety of the ADC is conjugated to the drug moiety via a linker, the linker comprising a Mal-spacer unit, a cleavable amino acid unit and pAB. In some embodiments, the spacer unit comprises a PEG moiety. In some embodiments, the linker comprises Mal-(PEG)2-Val-Cit-pAB.

[0120] In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimide moiety (Mal), a polyethylene glycol (PEG) moiety, valine citrulline (Val-Cit or "vc"), and pAB. In these embodiments, the maleimide moiety covalently links the linker-drug moiety to the antibody moiety, and pAB serves as a self-immolative spacer unit. Such linkers may be referred to as "m-vc-pAB" linkers, "Mal-VCP" linkers, "Mal-(PEG)2-VCP" linkers, or "Mal-(PEG)2-Val-Cit-pAB" linkers. In some embodiments, the drug moiety is eribulin. The structure of Mal-(PEG)2-Val-Cit-pAB-eribulin is provided below. pAB of the Mal-(PEG)2-Val-Cit-pAB linker is attached to the C-35 amine of eribulin. [ka]

[0121] ADCs comprising Mal-(PEG)2-Val-Cit-pAB-Eribulin have been discovered to demonstrate a particular combination of desirable properties, particularly when paired with an anti-FRA antibody or antigen-binding fragment thereof, such as MORAb-003. These functional properties are also illustrated in the Examples provided in PCT Application No. PCT / US2017 / 020529 (published as WO 2017 / 151979), which is incorporated herein by reference in its entirety.

[0122] In some embodiments, an ADC comprises Mal-(PEG)2-Val-Cit-pAB-eribulin and an antibody moiety comprising an internalizing anti-FRA antibody or antigen-binding fragment thereof that retains the ability to target and internalize tumor cells. In some embodiments, an ADC comprises Mal-(PEG)2-Val-Cit-pAB-eribulin and an internalizing anti-FRA antibody or an internalizing antigen-binding fragment thereof that targets FRA-expressing tumor cells. In some embodiments, an internalizing antibody or internalizing antigen-binding fragment thereof that targets FRA-expressing tumor cells comprises three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO:3 (HCDR3), as defined by the Kabat numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3); or three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2), and SEQ ID NO:9 (HCDR3), as defined by the IMGT numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2), and SEQ ID NO:12 (LCDR3). In some embodiments, an internalizing antibody or internalizing antigen-binding fragment thereof that targets FRA-expressing tumor cells comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, an internalizing antibody or internalizing antigen-binding fragment thereof that targets FRA-expressing tumor cells comprises a human IgG1 heavy chain constant domain and an Igκ light chain constant domain.

[0123] In some embodiments, the ADC has Formula I: Ab-(LD) p (I) (In the formula, (i) the Ab is an internalizing anti-folate receptor alpha (FRA) antibody or an internalizing antigen-binding fragment thereof, comprising three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2) and SEQ ID NO:3 (HCDR3), as defined by the Kabat numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2) and SEQ ID NO:6 (LCDR3); or three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2) and SEQ ID NO:9 (HCDR3), as defined by the IMGT numbering system; and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2) and SEQ ID NO:12 (LCDR3); (ii) D is eribulin; (iii) L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; and (iv) p is an integer from 1 to 20. has.

[0124] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the internalizing antibody is MORAb-003. In some embodiments, p is 1 to 8 or 1 to 6. In some embodiments, p is 2 to 8 or 2 to 5. In some embodiments, p is 3 to 4. In some embodiments, p is 4.

[0125] Drug portion The drug moiety (D) of the ADCs described herein is an anti-tubulin agent, such as eribulin.

[0126] In some embodiments, the drug moiety is eribulin and the linker of the ADC is attached via the C-35 amine of eribulin.

[0127] In various embodiments, the native form of eribulin used to conjugate the linker and antibody moiety is shown below. [ka]

[0128] In certain embodiments, the ADC is prepared by reacting an intermediate, which is a precursor of the linker, with eribulin under appropriate conditions. In certain embodiments, reactive groups on eribulin and / or on the intermediate or linker are used. The product of the reaction between eribulin and the intermediate is then reacted with an anti-FRA antibody or antigen-binding fragment under appropriate conditions. Alternatively, the linker or intermediate may first be reacted with an antibody or derivatized antibody, and then reacted with eribulin.

[0129] A number of different reactions are available for covalently linking eribulin and / or linker to the antibody moiety. This is often accomplished by reaction of one or more amino acid residues, such as sulfhydryl groups of cysteine, of the antibody molecule. For example, non-specific covalent linking can be performed using a carbodiimide reaction to link a carboxy group (or amino group) on a compound to an amino group (or carboxy group) on the antibody moiety. In addition, bifunctional agents such as dialdehydes or imidoesters can also be used to link an amino group on a compound to an amino group on the antibody moiety. Schiff base reactions can also be used to link drugs to binding agents. This method involves periodate oxidation of drugs containing glycol or hydroxy groups, thus forming an aldehyde, which then reacts with the binding agent. Linking occurs through the formation of a Schiff base with the amino group of the binding agent. Isothiocyanates can also be used as coupling agents to covalently link drugs to binding agents. Other techniques are known to those skilled in the art and are within the scope of this disclosure.

[0130] Drug Loading Drug loading is represented by p, also referred to herein as the drug-to-antibody ratio (DAR). Drug loading can range from 1 to 20 drug moieties per antibody moiety. In some embodiments, p is an integer from 1 to 20. In some embodiments, p is an integer from 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p is an integer from 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments, p is an integer from 3 to 4. In other embodiments, p is 1, 2, 3, 4, 5, or 6, preferably 3 or 4.

[0131] Drug loading may be limited by the number of attachment sites on the antibody moiety. In some embodiments, the linker moiety (L) of the ADC is attached to the antibody moiety through a chemically active group on one or more amino acid residues on the antibody moiety. For example, the linker may be attached to the antibody moiety (e.g., at the N-terminus or C-terminus, the ε-amino group of one or more lysine residues, the free carboxylic acid group of one or more glutamic or aspartic acid residues, or the sulfhydryl group of one or more cysteine ​​residues) via a free amino, imino, hydroxyl, thiol, or carboxyl group. The site to which the linker is attached may be a native residue in the amino acid sequence of the antibody moiety, or it may be introduced into the antibody or antigen-binding fragment by, for example, recombinant DNA techniques (e.g., introducing a cysteine ​​residue into the amino acid sequence) or protein biochemistry (e.g., by reduction, pH adjustment, or hydrolysis).

[0132] In some embodiments, the number of drug moieties that can be conjugated to an anti-FRA antibody moiety is limited by the number of free cysteine ​​residues. For example, if the attachment is to a cysteine ​​thiol group, the anti-FRA antibody moiety may have only one or a few cysteine ​​thiol groups, or may have only one or a few sufficiently reactive thiol groups to which a linker may be attached. Generally, antibodies do not contain many free and reactive cysteine ​​thiol groups that can be linked to a drug moiety. In fact, most cysteine ​​thiol residues in antibodies are present as disulfide bridges. Conjugating too many linker-toxins to an antibody can destabilize the antibody by reducing cysteine ​​residues available for disulfide bridge formation. Thus, the optimal drug:antibody ratio should increase the potency of the ADC (by increasing the number of drug moieties attached per antibody) without destabilizing the antibody moiety. In some embodiments, the optimal ratio may be about 3-4.

[0133] In some embodiments, a ratio of about 3-4 is provided when the linker is attached to the antibody moiety through a Mal moiety. In some embodiments, a ratio of about 3-4 is provided when the linker comprises a short spacer unit (e.g., a short PEG spacer unit such as (PEG)2). In some embodiments, a ratio of about 3-4 is provided when the linker comprises a peptide cleavable moiety. In some embodiments, an ADC comprising Mal-(PEG)2-Val-Cit-pAB-Eribulin tethered to an anti-FRA antibody such as MORAb-003 has a ratio of about 3-4.

[0134] In some embodiments, the antibody moiety, e.g., MORAb-003, is exposed to reducing conditions prior to conjugation to generate one or more free cysteine ​​residues. In some embodiments, the antibody may be reduced under partial or complete reducing conditions with a reducing agent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP), which may generate reactive cysteine ​​thiol groups. In certain embodiments, the antibody may be subjected to denaturing conditions to expose reactive nucleophilic groups on amino acid residues, such as lysine or cysteine.

[0135] When two or more nucleophilic groups react with a drug-linker intermediate or linker moiety reagent followed by a drug moiety reagent in a reaction mixture containing multiple copies of an antibody moiety and a linker moiety, the resulting product may be a mixture of ADC compounds having a distribution of one or more drug moieties attached to each copy of the antibody moiety in the mixture. In some embodiments, the drug loading of the mixture of ADCs resulting from the conjugation reaction ranges from 1 to 20 drug moieties attached per each antibody moiety. The average number of drug moieties per each antibody moiety (i.e., average drug loading or average p) may be calculated by any conventional method known in the art, such as mass spectrometry (e.g., reversed-phase LC-MS) and / or high performance liquid chromatography (e.g., HIC-HPLC). In some embodiments, the average number of drug moieties per each antibody moiety is determined by hydrophobic interaction chromatography-high performance liquid chromatography (HIC-HPLC). In some embodiments, the average number of drug moieties per each antibody moiety is determined by reversed-phase liquid chromatography mass spectrometry (LC-MS). In some embodiments, the average number of drug moieties per each antibody moiety is about 3 to about 4; about 3.1 to about 3.9; about 3.2 to about 3.8; about 3.2 to about 3.7; about 3.2 to about 3.6; about 3.3 to about 3.8; or about 3.3 to about 3.7. In some embodiments, the average number of drug moieties per each antibody moiety is about 3.2 to about 3.8. In some embodiments, the average number of drug moieties per each antibody moiety is about 3.8. In some embodiments, the average number of drug moieties per each antibody moiety is 3 to 4; 3.1 to 3.9; 3.2 to 3.8; 3.2 to 3.7; 3.2 to 3.6; 3.3 to 3.8; or 3.3 to 3.7. In some embodiments, the average number of drug moieties per each antibody moiety is 3.2 to 3.8. In some embodiments, the average number of drug moieties per each antibody moiety is 3.8.

[0136] In some embodiments, the average number of drug moieties per each antibody moiety is about 3.5 to about 4.5; about 3.6 to about 4.4; about 3.7 to about 4.3; about 3.7 to about 4.2; or about 3.8 to about 4.2. In some embodiments, the average number of drug moieties per each antibody moiety is about 3.6 to about 4.4. In some embodiments, the average number of drug moieties per each antibody moiety is about 4.0. In some embodiments, the average number of drug moieties per each antibody moiety is 3.5 to 4.5; 3.6 to 4.4; 3.7 to 4.3; 3.7 to 4.2; or 3.8 to 4.2. In some embodiments, the average number of drug moieties per each antibody moiety is 3.6 to 4.4. In some embodiments, the average number of drug moieties per each antibody moiety is 4.0.

[0137] In various embodiments, the term "about" when used in reference to the average number of drug moieties per individual antibody moiety or in a mixture of ADCs means ±10%. It is to be understood that this definition of "about" applies to all statements within the present disclosure about the average number of drug moieties per individual antibody moiety or in a mixture of ADCs.

[0138] Individual ADC compounds or "species" having particular DAR ratios can be identified in the mixture by mass spectrometry and separated by UPLC or HPLC, such as hydrophobic interaction chromatography (HIC-HPLC). In certain embodiments, homogeneous or near homogeneous ADCs of a single loading level can be separated from the conjugation mixture, for example, by electrophoresis or chromatography.

[0139] In some embodiments, the drug loading and / or average drug loading of the ADC (e.g., of MORAb-202) is about 4. In some embodiments, a drug loading and / or average drug loading of about 4 provides beneficial properties. See, e.g., PCT / US2017 / 020529 (published as WO 2017 / 151979), which is incorporated by reference herein in its entirety.

[0140] In some embodiments, the ADC has Formula I: Ab-(LD) p (I) (In the formula, (i) the Ab is an internalizing anti-folate receptor alpha antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14; (ii) D is eribulin; (iii) L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; and (iv) p is an integer from 1 to 8. has.

[0141] In some embodiments, the ADC has Formula I: Ab-(LD) p (I) (In the formula, (i) Ab is an internalizing anti-folate receptor alpha antibody, or an antigen-binding fragment thereof, comprising a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16; (ii) D is eribulin; (iii) L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; and (iv) p is an integer of about 4. has.

[0142] therapeutic use In various embodiments, disclosed herein are methods of using the disclosed anti-FRA ADCs, such as an ADC comprising the six CDR amino acid sequence of MORAb-003 linked to a linker comprising Mal-(PEG)2-Val-Cit-pAB, for example MORAb-202, in treating a subject for a disorder, such as an oncological disorder, for example an FRA-expressing cancer. The ADCs can be administered alone or in combination (e.g., simultaneously or sequentially) with a second therapeutic agent (e.g., a corticosteroid, such as dexamethasone, prednisone or methylprednisolone), and can be administered in any pharma- ceutically acceptable formulation. In particular, the methods disclosed herein provide for the use of the disclosed anti-FRA ADCs for the treatment of a subject with an FRA-expressing cancer, where the dosage of the ADC is based on the subject's body surface area (BSA). In some embodiments, the treatment methods using BSA titration can reduce the risk of interstitial lung disease (ILD) in a subject in need of treatment with an anti-FRA ADC. In some embodiments, the methods disclosed herein provide for the use of the disclosed anti-FRA ADCs for the treatment of a subject who has received at least one systemic anti-cancer therapy (e.g., a cytotoxic or targeted anti-cancer agent). In some embodiments, the methods disclosed herein provide for the use of the disclosed anti-FRA ADCs for the treatment of a subject with metastatic cancer, e.g., metastatic non-small cell lung cancer. In some embodiments, a subject with metastatic non-small cell lung cancer treated by the methods of the present disclosure does not have a genomic alteration. In some embodiments, a subject with metastatic FRA-expressing cancer (e.g., metastatic non-small cell lung cancer) has at least one genomic alteration (e.g., at least one unknown or known genomic alteration). Examples of known genomic alterations include, but are not limited to, genomic alterations in any one of the following genes: EGFR, ALK, PI3K, AKT, mTOR, RET, MET, BRAF, NTRK, ROS1, and any gene involved in the RAS-MAPK pathway. In some embodiments, a subject with metastatic FRA-expressing cancer has at least one known genomic alteration in at least one of any of the aforementioned genes.As used herein, "genomic alteration" refers to any alteration in the genome, including, but not limited to, somatic mutations, copy number alterations, and gene fusions. In some embodiments, the methods disclosed herein provide for the use of the disclosed anti-FRA ADCs for the treatment of a subject with a refractory cancer. As used herein, a "refractory cancer" is a cancer that is refractory to, i.e., has failed to respond to, at least one prior treatment therapy. In some embodiments, a subject with a refractory cancer is refractory to a targeted therapy, such as a therapy specifically targeted against any one of the following genes or variants thereof: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog 1 (BRAF), ret proto-oncogene (RET), MET proto-oncogene, receptor tyrosine kinase (MET), neurotrophic receptor tyrosine kinase (NTRK), and receptor tyrosine kinase (ROS1). As used herein, a "targeted therapy" is a cancer therapy that targets specific genes and / or proteins involved in the growth and / or survival of cancer cells. As used herein, the term "mutant" refers to any naturally occurring variant of a gene, including, but not limited to, splice variants, allelic variants, isoforms, and homologs (e.g., paralogs or orthologs). In contrast to genes that contain genomic alterations, variants of genes are not associated with or related to diseases or disorders, such as cancer. In some embodiments, any one of the aforementioned genes (or variants thereof) that the targeted therapy is specifically targeted to may contain at least one genomic alteration. For example, a targeted therapy may be specific for a mutation in NTRK1, while another targeted therapy may be specific for a mutation in NTRK2.

[0143] In some embodiments, the subject with refractory cancer is refractory to platinum-based therapy (e.g., platinum doublet chemotherapy) and / or immunotherapy-based therapy (e.g., immune checkpoint inhibitors, such as PD-1 inhibitors or PD-L1 inhibitors). In some embodiments, the subject with refractory cancer is refractory to treatment with platinum doublet chemotherapy and immune checkpoint inhibitors (e.g., PD-1 inhibitors or PD-L1 inhibitors), where the platinum doublet chemotherapy and immune checkpoint inhibitors are administered simultaneously or sequentially. In various embodiments, the subject with refractory cancer is refractory to no more than three prior systemic therapies, such as no more than two prior systemic therapies. In some embodiments, the subject with refractory cancer is refractory to no more than one prior chemotherapy.

[0144] In various embodiments, ADC treatment efficacy can be evaluated with respect to toxicity as well as efficacy indicators and adjusted accordingly. Efficacy measures include, but are not limited to, objective response rate (ORR). ORR can be measured after a given time after treatment, for example, 24 weeks after treatment initiation. ORR can be determined based on tumor evaluation according to RECIST, for example, RECIST 1.1. As used herein, "RECIST" refers to Response Evaluation Criteria in Solid Tumors (RECIST), a set of standardized guidelines used to measure how well cancer patients respond to treatment (Therass et al. (2000) J Natl Cancer Inst. 92:205-16). As used herein, "RECIST 1.1" refers to version 1.1 of RECIST, in which the guidelines have been revised and updated compared to previous versions of RECIST (Eisenhauer et al. (2009) Eur J Cancer. 45:228-47).

[0145] In some embodiments, the methods disclosed herein for treating an FRA-expressing cancer comprise administering to a subject in need thereof a therapeutically effective amount of an ADC of formula (I) as disclosed herein, such as MORAb-202, wherein the ADC is administered to the subject in a dose based on the subject's body surface area (BSA).

[0146] In some embodiments, the methods disclosed herein for reducing the risk of ILD in a subject being treated for an FRA-expressing cancer comprise administering to the subject an ADC of Formula (I) as disclosed herein, such as MORAb-202, wherein the ADC is administered to the subject at a dose relative to the subject's BSA.

[0147] In some embodiments, the ADC is 2 In some embodiments, the ADC is administered at a dose of 8 mg to 50 mg per square meter (m 2 In some embodiments, the ADC is administered at a dose of 8 mg to 44 mg per square meter (m 2 In some embodiments, the ADC is administered at a dose of 11 mg to 44 mg per square meter (m 2 In some embodiments, the dose is administered at a dose of 8 mg to 10 mg per square meter (m 2 ) of the subject's BSA. In some embodiments, the ADC is 2 In some embodiments, the ADC is administered at a dose of 33 mg per square meter (m 2 In some embodiments, the ADC is administered at a dose of 25 mg per square meter (m 2 In some embodiments, the ADC is administered at a dose of 17 mg per square meter (m 2 ) of the subject's BSA. In some embodiments, the ADC is administered at a dose of 15 mg per square meter (m 2) of the subject's BSA. In some embodiments, the ADC is administered at a dose of 10 mg per square meter (m 2 ) is administered at a dose of 8 mg per BSA of the subject. Any of these doses can be administered once a week, once every two weeks, or once every three weeks.

[0148] BSA can be calculated using any commonly accepted method known in the art. Formulas for calculating a subject's body surface area (BSA) include, for example, the Dubois-Dubois formula (or any variant thereof) (Dubois D, Dubois EF. (1916) Arch Intern Med. 1916; 17: 863-871), the Mosteller formula (or any variant thereof) (Mosteller RD. (1987) N Engl J Med. 22; 317 (17): 1098) or the Haycock formula (Haycock GB et al. (1978) J Pediatr. Jul; 93 (1): 62-6). An exemplary BSA calculation formula is provided below: (II) BSA(m 2 )=0.20247×height(m) 0.725 ×Weight (kg) 0.425 (Dubois-Dubois); (III) BSA(m 2 ) = 0.007184 × height (cm) 0.725 ×Weight (kg) 0.425 (Dubois-Dubois variant); (IV) BSA(m 2 ) = ([height (cm) x weight (kg)] / 3600) 1 / 2 (Mosteller); or (V)BSA(m 2 ) = 0.024265 × height (cm) 0.3964 ×BW(kg) 0.5378 (Haycock).

[0149] In some embodiments, the actual dose of ADC administered to a subject may be calculated as follows: (VI) Scheduled dose (mg / m 2 )×Body surface area (BSA)(m 2 ) = actual dose (mg) As used herein, a "proposed dose" refers to a dose selected from the dose ranges provided above to be administered to a subject, e.g., 8 mg to 50 mg. For example, when calculated according to Formula III above using hypothetical values ​​of height of 160 cm and BW of 80 kg, the proposed dose is 1.8 square meters (m 2 For a subject with an exemplary BSA of 33 mg / m 2 In this particular example, the amount or actual dose of ADC administered to the subject, according to Formula VI provided above, is 60.5 mg.

[0150] In some embodiments, the treatment dose may be recalculated on day 1 of each treatment cycle using the subject's height measured at the time of intake and the subject's weight measured on or prior to day 1 of each treatment cycle, for example, 2 days prior to day 1 of each treatment cycle.

[0151] In some embodiments, the ADC is administered weekly, every two weeks, every three weeks, monthly, or any time therebetween. In some embodiments, the ADC is administered once every three weeks. In some embodiments, the ADC may be administered in a 21-day cycle. A once every three weeks or a 21-day treatment cycle may also be referred to as "Q3W". In some embodiments, the ADC is administered once every two weeks. In some embodiments, the ADC may be administered in a 14-day cycle. A once every two weeks or a 14-day treatment cycle may also be referred to as "Q2W". In some embodiments, the ADC is administered once a week. In some embodiments, the ADC may be administered in a 7-day cycle. A once a week or a 7-day treatment cycle may also be referred to as "QW".

[0152] In some embodiments, the ADC is at 8 mg / m 2 ~50mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 8 mg / m once every 3 weeks. 2 ~50mg / m 2 In some embodiments, the ADC is administered at a BSA-equivalent dose of 8 mg / m once every two weeks.2 ~50mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 33 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 33 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 33 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 17 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 17 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 17 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 15 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 15 mg / m once every 3 weeks. 2 In some embodiments, the ADC is administered at a BSA-equivalent dose of 15 mg / m once every two weeks. 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 8 mg / m 2 ~10mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 8 mg / m once every 3 weeks. 2 ~10mg / m 2 In some embodiments, the ADC is administered at a BSA-equivalent dose of 8 mg / m once every two weeks. 2 ~10mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 10 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 10 mg / m once every 3 weeks. 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 10 mg / m 2 In some embodiments, the ADC is administered at a BSA equivalent dose of 8 mg / m 2In some embodiments, the ADC is administered at a BSA equivalent dose of 8 mg / m once every 3 weeks. 2 In some embodiments, the ADC is administered at a BSA-equivalent dose of 8 mg / m once every two weeks. 2 The drug is administered once a week at a BSA-equivalent dose.

[0153] Without being bound by theory, BSA-based titration as disclosed herein may, for example, result in lower exposure levels in subjects with higher body weight (BW) when administered the disclosed ADC, which may help reduce ILD risk. Without being bound by theory, BW-based titration may result in higher exposure for subjects in the upper quartile of body weight compared to subjects with lower body weight. Other exemplary titration regimens that may reduce the total dose and exposure burden of treated subjects include titration using BW with a maximum total dose ceiling or adjusted ideal body weight (AIBW). In some embodiments, BSA-based titration may be preferred due to its ease of use, familiarity with practitioners, and reduced potential for dosing errors.

[0154] In some embodiments, subjects treated with an anti-FRA ADC as disclosed herein have a body weight in the upper quartile of body weight. In some embodiments, subjects treated with an anti-FRA ADC as disclosed herein weigh at least 80 kg.

[0155] In some embodiments, the risk of ILD in a subject treated with an anti-FRA ADC as disclosed herein is reduced by at least 5%, at least 10%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% after administration of a BSA-equivalent dose of the ADC, as compared to a treatment in which the ADC is administered in a body weight (BW)-equivalent dose. In some embodiments, the comparative treatment is administered at a dose of 0.5-2 mg per kilogram of subject body weight (BW), such as at a dose of 0.9 mg-1.2 mg per kilogram of BW. For example, in some embodiments, the comparative treatment may be administered at a dose of 0.9 mg per kilogram of subject BW, which is equivalent to a dose of 33 mg per square meter of subject BSA. In some embodiments, an exemplary 80 kg BW subject would receive a 0.9 mg / kg BW-equivalent dose of ADC, resulting in an actual dose of 72 mg. By comparison, the same subject would receive a 33 mg / m 2 When a BSA equivalent dose of ADC is administered, the actual dose will be 59.4 mg.

[0156] In some embodiments, the method as disclosed herein may further comprise administration of one or more additional therapeutic agents, such as one or more additional oncology agents. In some embodiments, the additional agents comprise corticosteroids. Without being bound by theory, it is hypothesized that a potential mechanism of ILD may involve FRA-independent interactions between anti-FRA ADC as disclosed herein and pulmonary macrophages in a proinflammatory lung microenvironment. "FRA-independent interactions" refers to interactions, e.g., binding, between anti-FRA ADC and cells that are not triggered by recognition and binding of FRA antigens on cells. This interaction may lead to induction of cytokines in the lung tissue of a subject. Furthermore, without being bound by theory, when anti-FRA ADC is internalized into macrophages, free eribulin may subsequently be released into the lung tissue of a subject. Without being bound by theory, when free eribulin is released into the lung tissue, tissue damage may occur due to the bystander effect of the ADC disclosed herein. Thus, the development of ILD is driven by an immune-mediated mechanism. Without being bound by theory, administration of corticosteroids may alleviate the symptoms of ILD or prevent its development all together due to their immunomodulatory and anti-inflammatory effects.

[0157] In some embodiments, the corticosteroid may be administered prophylactically. As used herein, "administered prophylactically" refers to administering a treatment, e.g., a corticosteroid, to a subject before the subject exhibits or develops symptoms of an ILD. In some embodiments, the corticosteroid is administered simultaneously or sequentially with an ADC. In some embodiments, the corticosteroid is administered before or after an ADC is administered. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the corticosteroid is prednisone. In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the corticosteroid (e.g., dexamethasone, prednisone, or methylprednisolone) may be administered orally or intravenously. In some embodiments, when the corticosteroid (e.g., dexamethasone or prednisone) is administered orally, it may be administered in an amount of 1 to 10 mg, e.g., 0.5 to 2 mg, e.g., 2 to 5 mg, e.g., 0.5 mg, 1 mg, 2 mg, or 4 mg. In some embodiments, dexamethasone is administered at a dose determined to be therapeutically effective, for example, 4 mg of dexamethasone. In some embodiments, dexamethasone is administered at least once a day, for example, twice a day. In some embodiments, dexamethasone is administered for several days (e.g., 1, 2, 3, 4, 5 or more) prior to or at the start of treatment with the ADC. In some embodiments, dexamethasone is administered for at least 3 days at the start of treatment with the ADC. In some embodiments, dexamethasone is administered orally. In some embodiments, prednisone is administered at a dose determined to be therapeutically effective, for example, 0.5 mg, 1 mg, or 2 mg of prednisone. In some embodiments, prednisone is administered at 0.5 mg of prednisone. In some embodiments, prednisone is administered at 1 mg of prednisone. In some embodiments, prednisone is administered at 2 mg of prednisone. In some embodiments, prednisone is administered at least once a day.In some embodiments, prednisone is administered for several days (e.g., 10, 11, 12, 13, 14 or more) prior to or at the start of treatment with the ADC. In some embodiments, prednisone is administered for at least 14 days prior to the start of treatment with the ADC. In some embodiments, prednisone is administered orally. In some embodiments, when the corticosteroid (e.g., methylprednisolone) is administered intravenously, it may be administered in an amount of 300-1200 mg, such as 400-1100 mg, such as 500-1000 mg, such as 500 mg, 750 mg or 1000 mg. In some embodiments, methylprednisolone is administered in an amount of 30-130 mg, such as 40-125 mg. In some embodiments, methylprednisolone is administered at 1 mg per kg of subject body weight. In some embodiments, methylprednisolone is administered at 2 mg per kg of subject body weight. In some embodiments, methylprednisolone is administered intravenously. In some embodiments, methylprednisolone is administered orally. In some embodiments, when methylprednisolone is administered orally, it may be administered in an amount of 5-100 mg, such as 5-90 mg, such as 5-80 mg, such as 10-80 mg, such as 10-70 mg, such as 10-60 mg. In some embodiments, methylprednisolone is administered orally at 0.5-1.5 mg per kg of subject weight. In some embodiments, methylprednisolone is administered orally at 0.5 mg per kg of subject weight. In some embodiments, methylprednisolone is administered orally at 1 mg per kg of subject weight. In some embodiments, methylprednisolone is administered orally at 1.5 mg per kg of subject weight. In some embodiments, methylprednisolone is administered orally at least once a day. In some embodiments, methylprednisolone is administered for several days (e.g., 1, 2, 3, 4, 5 or more) prior to or at the start of treatment with an ADC, hi some embodiments, methylprednisolone is administered for at least 3 days prior to the start of treatment with an ADC.

[0158] The methods of the present disclosure may be applied to human subjects in need of treatment, such as subjects suffering from cancer, e.g., FRA-expressing cancer. In some embodiments, the methods disclosed herein may be applied to non-human mammals with FRA-expressing cancer for veterinary purposes or as animal models of human disease. In the latter regard, such animal models may be useful for evaluating the therapeutic efficacy (e.g., testing dosages and time courses of administration) of the methods of the present disclosure.

[0159] The ADCs disclosed herein may be administered to a subject by any route of administration suitable for exerting a therapeutic effect. In some embodiments, the ADCs are administered to a subject intravenously.

[0160] In some embodiments, the disclosure features a method of treating a cancer that expresses FRA. The method can be used to treat any human or non-human mammalian subject with an FRA-expressing cancer, such as one in which disruption of tubulin provides a therapeutic benefit. Methods for identifying subjects with FRA-expressing cancers are known in the art and can be used to identify subjects suitable for treatment with the disclosed ADCs. The FRA-expressing cancer can be a primary or metastatic FRA-expressing cancer or an FRA-expressing cancer that is resistant to platinum-based therapy, such as a platinum-resistant cancer. Non-limiting examples of FRA-expressing cancers include gastric cancer, ovarian cancer (e.g., serous ovarian cancer, clear cell ovarian cancer, or platinum-resistant ovarian cancer), lung cancer (e.g., non-small cell lung cancer, e.g., metastatic non-small cell lung cancer), lung carcinoid, colorectal cancer, breast cancer (e.g., triple-negative breast cancer or hormone receptor (HR)-positive and HER2-low expressing breast cancer), endometrial cancer (e.g., serous endometrial cancer), peritoneal cancer (e.g., primary peritoneal cancer), fallopian tube cancer, pancreatic cancer, renal cancer (e.g., renal cell carcinoma), cervical cancer, esophageal cancer, and osteosarcoma. In some embodiments, the FRA-expressing cancer is ovarian cancer, e.g., platinum-resistant ovarian cancer. In some embodiments, the FRA-expressing cancer is breast cancer, e.g., triple-negative breast cancer (TNBC). In some embodiments, the FRA-expressing cancer is non-small cell lung cancer (NSCLC), e.g., metastatic non-small cell lung cancer. In some embodiments, the FRA-expressing cancer is endometrial cancer.

[0161] In some embodiments, the disclosure features a method of reducing the risk of ILD in a subject with an FRA-expressing cancer, the subject being in need of treatment. The method may be used in any human or non-human mammalian subject with an FRA-expressing cancer for the purpose of reducing the risk of ILD. The FRA-expressing cancer may be a primary or metastatic FRA-expressing cancer or an FRA-expressing cancer that is resistant to platinum-based therapy, such as a platinum-resistant cancer. Non-limiting examples of FRA-expressing cancers include gastric cancer, ovarian cancer (e.g., serous ovarian cancer, clear cell ovarian cancer, or platinum-resistant ovarian cancer), lung cancer (e.g., non-small cell lung cancer, e.g., metastatic non-small cell lung cancer), lung carcinoid, colorectal cancer, breast cancer (e.g., triple-negative breast cancer or hormone receptor (HR)-positive and HER2-low expressing breast cancer), endometrial cancer (e.g., serous endometrial cancer), peritoneal cancer (e.g., primary peritoneal cancer), fallopian tube cancer, pancreatic cancer, kidney cancer (e.g., renal cell carcinoma), cervical cancer, esophageal cancer, and osteosarcoma. In some embodiments, the FRA-expressing cancer is ovarian cancer, such as platinum-resistant ovarian cancer. In some embodiments, the FRA-expressing cancer is breast cancer, such as triple-negative breast cancer (TNBC). In some embodiments, the FRA-expressing cancer is non-small cell lung cancer (NSCLC), such as metastatic non-small cell lung cancer. In some embodiments, the FRA-expressing cancer is endometrial cancer.

[0162] In various embodiments, the methods disclosed herein include administering an anti-FRA ADC, such as MORAb-202, at a dose of, for example, 8 to 50 mg / m 2 The BSA equivalent dose used in the treatment of ovarian cancer, platinum resistant ovarian cancer, breast cancer, triple negative breast cancer, non-small cell lung cancer, or endometrial cancer. In some embodiments, the methods disclosed herein are used to treat primary peritoneal or fallopian tube cancer. In some embodiments, the BSA equivalent dose used in the treatment of ovarian cancer, platinum resistant ovarian cancer, breast cancer, triple negative breast cancer, non-small cell lung cancer, or endometrial cancer is 33 mg / m administered once every three weeks (Q3W). 2 A BSA equivalent dose of 25 mg / m administered Q3W is used to treat platinum-resistant ovarian cancer (PROC). 2 A BSA equivalent dose of 17 mg / m administered Q3W is used to treat PROC. 2A BSA equivalent dose of 15 mg / m administered once every two weeks (Q2W) is used to treat PROC. 2 A BSA equivalent dose of 8 mg / m administered once weekly (QW) is used to treat PROC. 2 ~10mg / m 2 A BSA equivalent dose of 33 mg / m is used to treat PROC. In some embodiments, the PROC is serous ovarian cancer. In some embodiments, the PROC is high-grade serous ovarian cancer. In some embodiments, a BSA equivalent dose of 33 mg / m 2 A Q3W BSA equivalent dose is used to treat primary peritoneal cancer. In some embodiments, 25 mg / m 2 A Q3W BSA equivalent dose is used to treat primary peritoneal cancer. In some embodiments, 17 mg / m 2 A Q3W BSA equivalent dose is used to treat primary peritoneal cancer. In some embodiments, 15 mg / m 2 A Q2W BSA equivalent dose is used to treat primary peritoneal cancer. In some embodiments, 8 mg / m 2 ~10mg / m 2 A QW BSA equivalent dose is used to treat primary peritoneal cancer. In some embodiments, 33 mg / m 2 A Q3W BSA equivalent dose is used to treat fallopian tube cancer. In some embodiments, 25 mg / m 2 A Q3W BSA equivalent dose is used to treat fallopian tube cancer. In some embodiments, 17 mg / m 2 A Q3W BSA equivalent dose is used to treat fallopian tube cancer. In some embodiments, 15 mg / m 2 A Q2W BSA equivalent dose is used to treat fallopian tube cancer. In some embodiments, 8 mg / m 2 ~10mg / m 2 QW BSA equivalent dose is used to treat fallopian tube cancer. In some embodiments, the subject treated by the methods disclosed herein has cancer that has recurred within 6 months of receiving platinum-based therapy.

[0163] In some embodiments, subjects who experience a treatment-related adverse event (TRAE) may subsequently receive a reduced dose level of MORAb-202. 2 Subjects receiving a BSA equivalent dose of 25 mg / m 2 In some embodiments, a reduced dose of 25 mg / m 2 Subjects receiving a BSA equivalent dose of 17 mg / m 2 In some embodiments, a reduced dose of 25 mg / m 2 Subjects receiving a BSA equivalent dose of 15 mg / m 2 In some embodiments, a reduced dose of 25 mg / m 2 Subjects receiving a BSA equivalent dose of 8 mg / m2 and experiencing TRAEs should be subsequently 2 ~10mg / m 2 In some embodiments, a reduced dose of 15 mg / m 2 Subjects receiving a BSA equivalent dose of 8 mg / m2 and experiencing TRAEs should be subsequently 2 ~10mg / m 2In some embodiments, the TRAEs are determined according to NCI CTCAE v5 and assigned to a particular grade level. As used herein, NCI CTCAE v5 refers to the National Cancer Institute Common Terminology Criteria for Adverse Events, 5th Edition, which is a descriptive terminology used to report adverse events and provides a grading (severity) scale for each adverse event term. In some embodiments, the TRAEs are Grade 1 or higher (e.g., Grade 2, 3, or 4) infusion reactions. In some embodiments, the TRAEs are Grade 1 or higher (e.g., Grade 2, 3, 4) interstitial lung disease (ILD) or pneumonitis. In some embodiments, the TRAEs are Grade 3 or 4 or a decrease in neutrophil count below 1000 cells / μl in a blood sample of the subject. In some embodiments, the TRAEs are Grade 3 or higher febrile neutropenia. In some embodiments, a TRAE is a grade 2 or greater or a decrease in platelet count below 75,000 cells / μl of a subject's blood sample. In some embodiments, a TRAE is any symptomatic or asymptomatic laboratory test result of grade 3 or greater. In some embodiments, a TRAE is any non-hematological toxicity of grade 3 or greater.

[0164] In some embodiments, the methods disclosed herein include administering an anti-FRA ADC, such as MORAb-202, at a dose of, for example, 8-50 mg / m 2 The BSA-equivalent dose used reduces the risk of ILD.

[0165] Before starting treatment, the subject can be evaluated by certain clinical criteria to identify subjects who are potentially at increased risk of severe respiratory complications. If the subject is determined to be potentially at increased risk of severe respiratory complications, the subject can be excluded from treatment by the methods disclosed herein. In some embodiments, the subject treated by the above-mentioned method is evaluated by pulmonary function test (PFT) before treatment. In some embodiments, the subject who is evaluated by PFT and subsequently treated does not have one or more of the following results: FEV1 / FVC ratio less than 0.7, FEV1 (forced expiratory volume in one second) less than 80%, FVC (forced vital capacity) less than 80% or DLCO (diffusing capacity of lung carbon monoxide) less than 80%. In some embodiments, the subject treated by the aforementioned method does not have one or more of the following at the start of treatment: interstitial lung disease (ILD) and / or pneumonitis, a history of ILD and / or pneumonitis, a pulmonary specific clinically significant disease, a pleural effusion, a pericardial effusion, prior treatment with a pneumonectomy, a history of chest radiotherapy within the past two years, an autoimmune disorder with pulmonary involvement, a connective tissue disorder with pulmonary involvement, or an inflammatory disorder with pulmonary involvement. Exemplary pulmonary specific clinically significant diseases include, but are not limited to, any underlying pulmonary disorder (e.g., pulmonary embolism), asthma, chronic obstructive pulmonary disease (COPD), restrictive lung disease, or any other pulmonary specific inflammatory disease or condition.

[0166] In some embodiments, the subject treated by the above method does not have one or more of the following: prior treatment with four or more therapies for FRA-expressing cancer, high neutrophil-to-lymphocyte ratio, or serum albumin level at the start of treatment less than 3 g / dL. As used herein, "high neutrophil-to-lymphocyte ratio" refers to a higher ratio of neutrophil cells to lymphocyte cells or "neutrophil-to-lymphocyte ratio" (NLR) in a blood sample of the subject compared to the average NLR of a comparison population, such as a group of adults in the general population or a group of subjects suffering from FRA-expressing cancer. In some embodiments, the high NLR can be at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9. The NLR can be calculated using any method known in the art. For example, the NLR can be calculated by dividing the neutrophil count by the lymphocyte count. The neutrophil count and lymphocyte count are measured from a peripheral blood sample of the subject. The NLR may be calculated using absolute cell counts of neutrophils and / or lymphocytes or the relative percentages of neutrophils and / or lymphocytes.

[0167] Pharmaceutical Compositions and Formulations The ADC used in carrying out the aforementioned methods can be formulated into a pharmaceutical composition suitable for administration to a subject, e.g., a human subject. In some embodiments, the pharmaceutical composition comprises the ADC and a pharma- ceutically acceptable carrier suitable for the desired delivery method. Suitable carriers include any material that, when combined with the ADC disclosed herein, allows the ADC to retain its anti-tumor function and is generally non-reactive with the subject's immune system. Pharmaceutically acceptable carriers can include any physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharma- ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, mesylate, and the like, and combinations thereof. In some embodiments, the formulation comprises one or more isotonic agents, e.g., sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Pharmaceutically acceptable carriers may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the ADC.

[0168] The pharmaceutical compositions described herein can be in a variety of forms, including, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application.

[0169] The pharmaceutical composition may be solubilized and administered by any route capable of delivering the composition to the tumor site. Potentially effective routes of administration include, but are not limited to, intravenous, parenteral, intraperitoneal, intramuscular, intratumoral, intradermal, intraorgan, orthotopic, etc. The pharmaceutical composition may be lyophilized and stored as a sterile powder, preferably under vacuum, and then reconstituted in bacteriostatic water (e.g., containing a benzyl alcohol preservative) or sterile water prior to injection. Administration may be either systemic or local. The pharmaceutical composition may include an ADC or a pharma- ceutically acceptable salt thereof, such as a mesylate salt. The pharmaceutical composition may further include a corticosteroid, such as dexamethasone, prednisone, or methylprednisolone. Alternatively, in some embodiments, the corticosteroid may be provided in a separate package.

[0170] In various embodiments, kits for use in the therapeutic applications described herein are within the scope of the present disclosure. Such kits may include the ADCs disclosed herein and a carrier, packaging, or container. The carrier, packaging, or container may be compartmented to receive one or more containers, such as vials, tubes, each of which contains one of the separate elements to be used in the methods disclosed herein and / or one or more containers containing a label or package insert containing instructions for use, such as the uses described herein. The carrier, packaging, or container may also include a compartment for a corticosteroid.

[0171] The kit may further comprise one or more other containers associated therewith containing materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes; labeling and / or instructions for use on carriers, packaging, containers, vials and / or tubes listing the contents, and package inserts containing the instructions for use.

[0172] Labeling may be present on or with the container to indicate that the composition is used for a particular therapeutic or non-therapeutic application, such as a prognostic, preventative, diagnostic or clinical testing application. Labeling may also indicate directions for either in vivo or in vitro use, such as those described herein. The instructions and / or other information may be included in one or more package inserts or one or more labels included with or on the kit. Labeling may be on or associated with the container. Labeling may be on the container when letters, numbers or other characters forming the labeling are molded or etched into the container itself. Labeling may be associated with the container when it is present, for example as a package insert, within a receptacle or carrier that also holds the container. Labeling may indicate that the composition is used for the diagnosis or treatment of a condition, such as cancer, as described herein.

[0173] It will be readily apparent that other suitable variations and applications of the methods of the present invention described herein will be obvious to those skilled in the art and may be made using suitable equivalents without departing from the scope of the invention or the embodiments disclosed herein. Having now described the invention in detail, it will be more clearly understood with reference to the following examples, which are included for illustrative purposes only and are not intended to be limiting. EXAMPLES

[0174] Example 1 1.1 Dose-response relationship for ORR in subjects with PROC MORAb-202 was administered to subjects (N=58) with platinum-resistant ovarian cancer (PROC) at doses ranging from 0.3 to 1.2 mg / kg body weight (BW). All doses were administered Q3W. Dose-response determinations were performed to calculate the relationship between dose and objective response rate (ORR) within this dose range.

[0175] 1.2 Dose-response relationships for ILD in each tumor type MORAb-202 was administered at doses ranging from 0.3 to 1.2 mg / kg body weight (BW) to subjects (N=82) with PROC, endometrial cancer (EC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). All doses were administered Q3W. Dose-response determinations were performed to calculate the relationship between dose and ILD rate across this dose range.

[0176] 1.2.1 Results Clinical pharmacology evaluations were performed to assess the dose relationship between MORAb-202 and objective response rate (ORR) or ILD. Dose-response relationships were calculated using logistic regression analysis. The results of these analyses are presented in Tables 11 and 12 below.

[0177] [Table 13]

[0178] [Table 14]

[0179] A dose-response relationship was found between MORAb-202 and ORR in subjects in PROC at doses ranging from 0.68 to 1.2 mg / kg. Similarly, a dose-response relationship was found between MORAb-202 and ILD in subjects of each tumor type (PROC, EC, TNBC, NSCLC) at doses ranging from 0.68 to 1.2 mg / kg. The highest dose of 1.2 mg / kg resulted in the highest ORR in subjects in PROC and the highest ILD rate in subjects of each tumor type. The next lowest dose of 0.9 mg / kg corresponded to lower ORR and ILD rates in both subject groups. Given that the 0.9 mg / kg dose resulted in a lower ILD rate but still provided a therapeutically meaningful benefit (i.e., ORR > 30%), this dose was selected as the starting dose for subsequent simulation experiments.

[0180] 1.2.2 Exposure-Response (ER) Analysis of ORR in PROC Subjects An ORR analysis was performed in PROC subjects (N=58) across the dose range of 0.3-1.2 mg / kg Q3W. Twenty-one subjects in PROC had a PR (partial response) and two subjects had a CR (complete response), for an ORR of 39.7% (23 / 58) across the entire dose range. Exposure (AUC) was the only significant predictor of the probability of objective response in multivariate analysis (as shown in Figure 1). Age, weight, non-high-grade serous OC (vs. high-grade serous OC), ECOG-PS (1 vs. 0), and expansion (vs. dose escalation) were not significant predictors of objective response (OR). Given the linear PK and the lack of saturation of OR at the current dose range, higher doses above 1.2 mg / kg Q3W would be expected to increase the probability of OR. Based on the results of this ER analysis, clinically meaningful efficacy is predicted in the dose range of 0.68-1.2 mg / kg. However, overlapping AUC dependences on ILD are observed, as described in Section 1.2.3.

[0181] 1.2.3 Exposure-Response (ER) Analysis for ILD in PROC and Subjects with Each Tumor Type ER analysis for ILD was performed on data from subjects in PROC at dose ranges of 0.3–1.2 mg / kg Q3W and from subjects in each tumor type (PROC, EC, TNBC, and NSCLC) at dose ranges of 0.9–1.2 mg / kg Q3W (total N=96). ILD was identified in 48 subjects by expert review, with an ILD rate of 50% (48 / 96) across both subject groups and dose ranges. In multivariate analysis, AUC and age were significant predictors, with both higher AUC and higher age predicting higher odds of ILD. Weight, albumin, ECOG-PS (1 vs. 0), study, and tumor type (OC vs. other) were not significant predictors. The odds of ILD by AUC were predicted by median age (60 years) and plotted with observed ILD rates for each exposure quartile group (as shown in Figure 2).

[0182] 1.3 Simulation of dose-finding regimens A variety of different dosing regimens were simulated to select the dose of MORAb-202 that would minimize ILD rates while maintaining a high ORR. A stochastic simulation was performed using the MORAb-202 population pharmacokinetic (PPK) model shown in Table 13 to determine the AUC and C of the various different dosing regimens. max MORAb-202 exposure was found to be dose proportional, and PK was described by a two-compartment model with zero-order intravenous infusion and first-order elimination. BW for CL (total clearance) and BW for serum albumin and volume of distribution were significant covariates. Five dose-finding regimens were simulated: 1) a 63 mg flat dose; 2) a 0.9 mg / kg BW-equivalent dose; 3) a 0.9 mg / kg BW-equivalent dose with a maximum total dose cap of 70 mg; 4) a 1.0 mg / kg adjusted ideal body weight (AIBW)-equivalent dose; and 5) a 33 mg / m 2 (corresponding to a BW equivalent dose of 0.9 mg / kg). All titration regimens were simulated with a Q3W treatment cycle.

[0183] [Table 15]

[0184] 1.3.1 Results The results of the simulation are shown in Figure 3. Fixed dose-based dosing was predicted to result in a 27% lower median AUC for subjects in the highest BW quartile compared to those in the lowest BW quartile. BW-based dosing was predicted to result in a 28% higher median AUC for subjects in the highest BW quartile compared to those in the lowest BW quartile. Dosing regimens such as capping the BW equivalent dose at 70 mg, using AIBW equivalent doses, or using BSA equivalent doses were predicted to result in an AUC that is independent of body weight and therefore may reduce MORAb-202 exposure levels in heavier subjects. The AUC, C for the clinically evaluated range of BW equivalent doses (described in Sections 1.1 and 1.2) and the equivalent BSA equivalent doses were predicted to result in a 27% lower median AUC for subjects in the highest BW quartile compared to those in the lowest BW quartile. max, ORR and ILD predictions are provided in Table 6. 2 A BSA-equivalent dose of 25 mg / m was predicted to provide a median exposure level similar to that of a BW-equivalent dose of 0.9 mg / kg. 2 was predicted to provide a median exposure level similar to the 0.68 mg / kg BW-equivalent dose, while still providing a potential therapeutic benefit of a predicted ORR of approximately 24%.

[0185] [Table 16]

[0186] 1.4 Comparison of BSA-based and BW-based dose setting Based on the clinical pharmacology assessment of the BW equivalent doses evaluated (described in Sections 1.1 and 1.2) and the simulation results of a variety of different dosing regimens (described in Section 1.3), a dose of 33 mg / m Q3W was selected. 2 A BSA-equivalent dose of 33 mg / m was selected based on the results of a simulation analysis showing that this dose would reduce ILD rates while maintaining a therapeutically meaningful benefit (i.e., ORR > 30%). Further simulations were performed to determine the dose of 33 mg / m 2 Methods: The predicted clinical outcomes of a BSA-equivalent dose of 0.01 mg / kg were compared with a BW-equivalent dose of 0.9 mg / kg. All simulated comparisons were based on a Q3W treatment cycle.

[0187] 1.41. Results 33 mg / m 2 The predicted median concentrations of MORAb-202 over time at the 0.5 mg / kg BSA-equivalent dose were found to be similar to the median concentrations of MORAb-202 over the same time period at the 0.9 mg / kg BW-equivalent dose (Figure 4). max The ORR and ILD estimates were also similar for both titrated regimens (Table 15). 2The BSA equivalent of 33 mg / m was predicted to more evenly scale MORAb-202 exposure levels in subjects in each BW quartile compared to the 0.9 mg / kg BW equivalent dose. The BSA equivalent dose-finding approach maintained similar exposures to the BW equivalent dose-finding approach in subjects in the lower BW quartile, while decreasing exposures in subjects in the highest BW quartile. As a result, 2 A BSA-equivalent dose of 0.02 mg / kg was predicted to result in an 18.4% reduction in ILD rate compared with an equivalent 0.9 mg / kg BW-equivalent dose for subjects in the highest BW quartile.

[0188] [Table 17]

[0189] Example 2 2.1 Research details A multicenter, open-label Phase 1 / 2 trial evaluating the safety, tolerability, and efficacy of MORAb-202, a folate receptor alpha (FRA)-targeting antibody-drug conjugate, will be conducted in subjects with select tumor types. The estimated duration of this Phase 1 / 2 study is approximately 2 years, with an enrollment period of approximately 15 months.

[0190] 2.1.1 Purpose The study will have two parts: a dose escalation part and a dose confirmation part.

[0191] 2.1.1.1 Primary purpose The primary objective of the dose escalation part will be to evaluate the safety and tolerability of MORAb-202 in subjects with select tumor types (ovarian cancer (OC), endometrial cancer (EC), non-small cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC)) and to determine the recommended Phase 2 dose (RP2D).

[0192] The primary objectives of the dose confirmation part will be to further evaluate the safety and tolerability of MORAb-202 in subjects with OC and EC at selected doses and to evaluate the preliminary efficacy, as measured by objective response rate (ORR), of MORAb-202.

[0193] 2.1.1.2 Secondary Objectives The secondary objectives of this study are: (i) to evaluate the duration of response (DOR), disease control rate (DCR) and clinical benefit rate (CBR); (ii) to evaluate progression-free survival (PFS) and overall survival (OS); (iii) to determine the pharmacokinetic (PK) profiles of MORAb-202, total antibody and released eribulin in serum or plasma; and (iv) to evaluate the relationship between folate receptor alpha (FRA) expression levels and clinical outcome measures to support the identification of appropriate FRA cut-off time points.

[0194] 2.1.1.3 Exploratory purpose The exploratory objectives of this study are: (i) to assess oxygen saturation using pulse oximetry for the detection and monitoring of interstitial lung disease (ILD); (ii) to explore potential blood and tumor pharmacodynamic (PD) biomarkers (e.g., soluble FRA) and correlate with clinical outcome measures including PK, pharmacogenomics (PG), safety and efficacy; (iii) to examine the effect of MORAb-202 on ventricular repolarization (dose escalation part only); (iv) to evaluate the relationship between the number of prior lines of therapy and clinical outcome measures (OC only); and (v) to evaluate the utility of a computer-based algorithm to objectively detect lung parenchymal patterns consistent with ILD (e.g., honeycombing, ground-glass opacity) on high-resolution lung CT images for the detection of possible predisposing lesions, changes indicative of early ILD, and changes associated with resolution of ILD.

[0195] 2.2 Study design MORAb-202 will be administered as an intravenous (IV) infusion once every three weeks (21-day cycle). Treatment will be discontinued upon intolerable toxicity, disease progression, or subject withdrawal for any reason.

[0196] 2.2.1 Folate receptor alpha (FRA) expression analysis All tumor types of choice will be enrolled regardless of tumor FRA expression levels. However, FRA expression levels will be predetermined for analyses correlating FRA levels with efficacy outcomes. Study enrollment requires tumor samples to assess FRA expression levels (as described in the inclusion criteria in Section 2.2.5). After completion of the dose confirmation part, analyses will be performed to identify clinically meaningful FRA cutoff time points.

[0197] 2.2.2 Dose escalation For the dose escalation part, three doses are planned: 0.9, 1.2 and 1.6 mg / kg. A rolling 6 design will be used to recruit up to six subjects per dose level. Subjects will have one of four tumor types: OC, EC, NSCLC and TNBC.

[0198] Additional subjects with OC will be accrued to achieve approximately 10 such subjects per dose level. These additional subjects will not be used for dose escalation decisions, but their safety and efficacy data will contribute to the determination of the RP2D.

[0199] If necessary, other additional subjects may be recruited at the dose level of choice for determination of the RP2D.

[0200] 2.2.2.1 Rolling 6 Design Dose level allocation will be based on the number of subjects currently enrolled in the cohort, the observed number of dose-limiting toxicities (DLTs), and the number of subjects at risk for developing DLTs (i.e., subjects who are enrolled but not yet adjudicable for toxicity). Dose allocation rules are shown in the Rolling 6 Design Dose Determination table.

[0201] Subjects who are not evaluable for DLT will be replaced by the next available subject if the escalation or taper rules have not been met at the time of enrollment of the next available subject into the study.

[0202] 2.2.2.2 Selection of RP2D The RP2D will be determined based on a comprehensive assessment of safety, efficacy, PK and PD data. The DLT and RP2D will be determined by consensus between the sponsor and the investigator.

[0203] Toxicity will be continuously monitored with the Independent Data Monitoring Committee (IDMC) during the dose confirmation part of the study (described in Section 2.2.3). If at any time there are concerns regarding toxicity, the IDMC, investigator, and sponsor will re-evaluate the MORAb-202 dose and consider appropriate actions.

[0204] 2.2.3 Dose Confirmation The dose confirmation part will evaluate the safety and preliminary efficacy of selected dose levels of MORAb-202 in OC and EC subjects. The study design is outlined in Figure 5.

[0205] The dose confirmation portion will have four study treatment cohorts and will enroll approximately 30 patients. If two or more grade 3 or higher ILD / pneumonitis (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE v5.0]) events are observed at any time, the sponsor will suspend enrollment pending the outcome of the IDMC review. The initial cohort will enroll six subjects at 25 mg / m2 MORAb-202.

[0206] If all six subjects in the 25 mg / m2 cohort have been evaluated (clinical and radiological) for ILD for a minimum of 6 weeks after C1D1 (Cycle 1 Day 1) and no grade ≥ 3 ILD events are observed, then six subjects will be enrolled into a second cohort of 33 mg / m2. If all six subjects in the 33 mg / m2 cohort have been evaluated (clinical and radiological) for ILD for a minimum of 6 weeks after C1D1 and have observed less than two grade ≥ 3 ILD events, then the study will proceed with two cohorts, 25 mg / m2 and 33 mg / m2, with nine subjects randomized to each cohort.

[0207] If there is one grade ≥ 3 ILD event after dosing all 6 subjects in the 25 mg / m2 cohort, the cohort will expand to enroll 9 more subjects (for a total of 15). If there are fewer than 2 grade ≥ 3 ILD events after all 15 subjects have completed 6 weeks of observation for ILD assessment, enrollment will begin at the 33 mg / m2 dose level for 6 subjects. If those 6 subjects have fewer than 2 grade ≥ 3 ILD events, the cohort will expand to enroll a total of 15 subjects.

[0208] Data will be analyzed to determine which one or more regimens warrant further investigation. These cohorts will be observed for ILD incidence and severity over the duration of the study. Efficacy will be assessed by ORR at 24 weeks.

[0209] The titration regimen for this study was body surface area (BSA) equivalent titration. The dose levels to be used in this portion of the study were 0.9 mg / kg and 0.68 mg / kg body weight doses, corresponding to BSA doses of 33 mg / m2 and 25 mg / m2, respectively. BSA dose equivalence was confirmed using predictions from the MORAb-202 population PK model (described in Example 1). This revised titration regimen was implemented in the dose confirmation part of the study due to the potential for a reduced ILD risk in heavier subjects while using a dose within the therapeutic index of MORAb-202.

[0210] 2.2.3.1 Research period There will be three periods for each subject: a pre-treatment period, a treatment period and a follow-up period.

[0211] Pretreatment Period: Day -28 to Day -1, CT / Magnetic Resonance Imaging (MRI) scan must be performed within 28 days prior to study drug administration. All clinical and laboratory test results to determine eligibility must be performed within 7 days prior to study drug administration unless otherwise indicated.

[0212] Duration of Treatment: MORAb-202 will be administered as an intravenous infusion once every three weeks (21-day cycle), otherwise known as Q3W. Subjects may continue treatment until intolerable toxicity, disease progression, or subject withdrawal for any reason.

[0213] Follow-up period: After discontinuation of study drug (see Treatment Duration section for discontinuation criteria), a treatment-free visit will be performed, after which all subjects will be followed for survival every 12 weeks for up to 3 years. For subjects who discontinue study treatment for reasons other than progressive disease (PD), tumor assessments must be performed according to the assessment schedule from the date of the last assessment until disease progression is documented or the subject begins another anticancer therapy, whichever occurs first, unless the study is terminated or the subject withdraws consent for follow-up. Data on subsequent anticancer therapy will be collected. If a subject discontinues study treatment due to ILD or has ongoing ILD at the time of treatment discontinuation (e.g., PD or adverse event [AE]), chest CT scans must be continued (per protocol ILD assessment time point) until ILD has resolved or stabilized (no worsening on 3 consecutive chest CT scans).

[0214] All subjects will be followed for survival for three years unless the subject withdraws consent or the sponsor chooses to stop survival follow-up after completion of the primary study analysis.

[0215] Study End: The end of the study will be defined as the last subject / last visit or when the sponsor terminates the study. An earlier data cut-off may be done to allow for the generation of the primary study report.

[0216] 2.2.4 Number of subjects Approximately 36 subjects will be enrolled in the dose escalation portion of the study. Approximately 30 subjects will be enrolled in the dose confirmation portion of the study.

[0217] 2.2.5 Inclusion Criteria Subjects to be included in this study must meet all of the following criteria: 1. Age 18 or above; 2. Dose Escalation: Female (TNBC, EC and OC) or Male / Female (NSCLC adenocarcinoma). Subjects with the following disease characteristics: TNBC: Histologically confirmed metastatic TNBC (defined as estrogen receptor [ER]-negative / progesterone receptor-negative / human epidermal growth factor receptor 2 [HER2]-negative (IHC < 2+ or fluorescence in situ hybridization [FISH]-negative) breast cancer) with prior treatment with at least one line of systemic anticancer therapy (cytotoxic or targeted anticancer agent) in the metastatic setting. - NSCLC adenocarcinoma: Histologically or cytologically confirmed metastatic NSCLC adenocarcinoma: Subjects who have failed previous treatment for metastatic disease, who have not been eligible for or have failed epidermal growth factor receptor (EGFR)-targeted, ALK-targeted, BRAF-targeted or ROS1-targeted therapy, and for whom no alternative standard therapy exists. EC: Histologically confirmed progressive, recurrent or metastatic EC that has relapsed or failed at least one platinum-based regimen or one immunotherapy-based regimen. Ovarian or primary peritoneal or fallopian tube cancer: Histologically confirmed high-grade serous epithelial OC or primary peritoneal or fallopian tube cancer. Subjects must have: Platinum-resistant disease (defined as progression within 6 months after the last dose of the last platinum-containing chemotherapy regimen for at least four cycles) ■Received up to four lines of systemic therapy after the development of platinum resistance. Dosage confirmation: Ovarian or primary peritoneal or fallopian tube cancer: Platinum-resistant disease defined as: For participants with one prior line of platinum-containing therapy: RECIST v1.1 progression >1 month and <6 months after the last dose of the first platinum-containing chemotherapy regimen (at least 4 cycles) ■For participants with 2-3 lines of platinum-containing therapy: RECIST v1.1 progression during or within 6 months of the last dose of the second or third platinum-containing chemotherapy regimen. Patients have been previously treated with up to 3 lines of systemic therapy with monotherapy being appropriate as the next line of therapy. Subjects may have been treated with up to 1 line of therapy after determination of platinum resistance. ■Neoadjuvant ± adjuvant will be considered first line therapy. ■Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (will not be counted as a separate line of therapy). ■Hormone therapy will be counted as a separate line of therapy unless it is given as maintenance. ■Changes in therapy due to toxicity without progression will be considered part of the same line. o Subjects must have a histologically confirmed diagnosis of progressive, recurrent or metastatic EC. All histologies (including carcinosarcoma [only one subject per dose level]) and molecular subtypes will be included. Subjects may have been treated with an immune checkpoint inhibitor (ICI)-containing regimen (or may be ineligible for ICI treatment) and may not have received more than two prior treatment regimens (not including adjuvant therapy if progressive or recurrent / metastatic disease occurred more than 6 months after completion of the last adjuvant therapy cycle). *Note: There are no restrictions regarding prior hormone therapy. 3. Tumor tissue available for % FRA expression by IHC analysis as determined by the vendor. There is no minimum requirement for % FRA expression. However, tumor samples must be evaluable (i.e., sufficient quality and quantity) for IHC analysis. For otherwise eligible subjects with a histology result of "not evaluable," resubmission of the sample will be permitted. Tumor sample submissions must be archival formalin-fixed paraffin-embedded (FFPE) tissue blocks or unstained slides sectioned from the most recent FFPE block or from a fresh biopsy sample obtained at the time of screening but prior to the start of study treatment. 4.Radiographic disease progression during or after most recent therapy as determined by the investigator. 5. Measurable disease meeting the following criteria (dose confirmation part only, confirmed by central review of radiographs): At least one lesion measurable over time using either CT or MRI per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 with a long axis diameter greater than 1.0 cm for non-lymph nodes or a short axis diameter greater than 1.5 cm for lymph nodes. Lesions that have previously received locoregional therapy such as external beam radiation therapy (EBRT) or radiofrequency (RF) ablation must demonstrate evidence of post-radiotherapy progression per RECIST 1.1 to be considered target lesions. Eastern Cooperative Oncology Group performance status (ECOG PS) of 6.0 or 1. 7.Subject is expected to survive at least 3 months after first dose of study drug. 8. Adequate renal function as evidenced by serum creatinine ≤ 1.5 mg / dL or calculated creatinine clearance ≥ 50 mL / min by 12- or 24-hour urine collection. 9. Adequate bone marrow function as evidenced by: Absolute neutrophil count (ANC) ≥ 1.0 x 10 9 / L Hemoglobin (Hgb) ≥ 9.0g / dL Platelet count ≥ 75 × 10 9 / L Growth factors or blood transfusions according to institutional practice to achieve the above values ​​will be permitted as needed. Growth factor and platelet transfusions should not be used within 7 days of initiating study treatment. 10. Adequate liver function as evidenced by: Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except in cases of unconjugated hyperbilirubinemia (e.g., Gilbert syndrome) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN in the case of liver metastases), except in the case of bone metastases. Alkaline phosphatase (ALP) ≤ 3 x ULN, unless the subject is known to have bone metastases, in which case higher ALP values ​​would be acceptable. Albumin > 3.0g / dL. 11. Subjects must undergo a required washout period from the end of prior treatment until the first dose of study medication, which will be as follows: Prior anticancer therapy: Prior chemotherapy, surgery, or radiation therapy: >3 weeks. Prior treatment with thoracic radiation therapy or pneumonectomy is an exclusion (see Exclusion Criteria in Section 2.2.6). Antibodies and other biological therapeutics: ≥ 4 weeks. Endocrine therapy or small molecule targeted therapy: >2 weeks. Immunotherapy: ≥ 4 weeks. 12. Patients with a history of deep vein thrombosis (DVT) within the past 3 months must have completed anticoagulation for at least 1 month prior to initiation of study treatment. Anticoagulation must be continued while on study treatment. 13. Patients at risk for DVT secondary to a central venous catheter or with a past history of DVT or clinical symptoms suggestive of DVT must undergo venous Doppler ultrasound to rule out DVT during screening and prior to the start of study treatment. 14. If the subject has undergone major surgery, the subject must have sufficiently recovered from any toxicities and / or complications from the intervention prior to the start of study treatment. 15. Resolution of anticancer therapy-related or radiation-related toxicity to grade 1 or less severity, except for stable sensory neuropathy (grade ≤ 2), anemia (Hgb ≥ 9.0 g / dL) and alopecia (any grade). 16. Subjects must be willing and able to comply fully with the protocol. 17. Subject must provide written informed consent prior to any study-specific screening procedures.

[0218] 2.2.6 Exclusion criteria Subjects meeting any of the following criteria will be excluded from the study: 1. Subject with endometrial leiomyosarcoma, endometrial stromal sarcoma, or high-grade sarcoma. 2.Subject has previously been treated with any folate receptor targeting agent. 3. Subjects with platinum-refractory OC (defined as disease progression during or within 4 weeks of the last dose of initial platinum-based chemotherapy treatment). 4. Currently enrolled in another clinical trial, or has used any investigational drug or investigational device within the past 28 days or within 5 half-lives of any investigational drug prior to informed consent (if prior treatment with pharmacotherapy meets the parameters of item 11 of the inclusion criteria, those inclusion criteria should be followed). 5. Subjects with brain or subdural metastases are not eligible unless they have completed local therapy and have discontinued corticosteroids for this indication for at least 2 weeks prior to initiating study treatment. Any signs (e.g., radiological) or symptoms of brain metastases must be stable for at least 4 weeks prior to initiating study treatment. 6. Has been diagnosed with meningeal carcinomatosis. 7. Any other invasive malignancy (except histologically confirmed complete excision of non-melanoma skin cancer or carcinoma in situ) that has required treatment (other than curative surgery) or has shown evidence of recurrence / progression within 2 years prior to initiation of study treatment. 8. Significant cardiovascular impairment. History of congestive heart failure greater than New York Heart Association (NYHA) class II within 6 months prior to the first dose of study drug; unstable angina; myocardial infarction; stroke; or cardiac arrhythmia associated with hemodynamic instability. 9. Clinically significant ECG abnormalities, including significant baseline QT prolongation (QTcF) when corrected using the Fridericia formula (repeated QTcF interval >500 ms), history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or use of concomitant medications that prolong QTcF. 10. Known positive for human immunodeficiency virus (HIV). Testing at the time of enrollment is not required. 11. Active viral hepatitis (type B or C as documented by positive serology). Testing at enrollment is not required in the absence of symptoms or medical history, unless per local site requirements. 12. Females who are lactating or pregnant at screening or baseline (as documented by positive beta-human chorionic gonadotropin (β-hCG) or human chorionic gonadotropin (hCG) or equivalent units of β-hCG (or hCG) with a sensitivity of at least 25 IU / L. If a negative screening pregnancy test is achieved more than 72 hours prior to the first dose of study drug, another baseline determination is required. 13. Women of childbearing potential, - Have not used a highly effective method of contraception within 28 days prior to study enrollment, including any of the following: ■ Total abstinence (if that is the preferred and usual way of life) * ■ Intrauterine device or intrauterine hormone-releasing system (IUS) Contraceptive implant ■ Oral contraceptives (subjects must continue taking a stable dose of the same oral contraceptive product for at least 28 days prior to dosing, throughout the study, and for 90 days after discontinuation of study drug) ■ Having a partner who has had a vasectomy and is confirmed to be azoospermic *Do not agree to use highly effective contraception (as described above) throughout the study period and for 90 days after discontinuing study drug. For facilities outside Europe, it is permitted that if highly effective methods are not suitable or acceptable to the subject, the subject must agree to use a medically acceptable method of contraception, i.e. a double barrier method such as a latex or synthetic condom plus diaphragm or cervical / vaginal vault cap and spermicide. Note: All women will be considered of childbearing potential unless they are postmenopausal (amenorrhea for at least 12 consecutive months, of the appropriate age group, and with no other known or suspected causes) or have been surgically sterilized (i.e. bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, in each case at least 1 month prior to treatment). * Abstinence will be considered highly effective only if it is defined as abstinence from heterosexual intercourse for the entire period of risk associated with the study intervention. The reliability of abstinence needs to be evaluated in relation to the duration of the study and the subject's preferred usual lifestyle. 14. For dose escalation only: Men who have had an unsuccessful vasectomy (no documented azoospermia) or men and their female partners who do not meet the above criteria (i.e., not of childbearing potential or practicing highly effective contraception throughout the entire study and for 90 days after discontinuation of study drug). Men who do not agree to use latex or synthetic condoms throughout the entire study and for 90 days after discontinuation of study drug if their female partner is pregnant. Sperm donation will not be permitted during the study and for 90 days after discontinuation of study drug. 15. Abnormal pulmonary function tests (PFT): FEV1 / FVC<0.7, FEV1 or FVC<80%, DLCO<80%. 16. History of interstitial lung disease (ILD) / pneumonitis of any severity, including current ILD / pneumonitis or suspected ILD / pneumonitis at screening or ILD / pneumonitis from prior treatment with anti-cancer therapy. 17. Current infectious pneumonia or history of viral pneumonia. 18. Clinically significant illness specific to the lung, including but not limited to any underlying pulmonary disorder (e.g., pulmonary embolism), asthma, chronic obstructive pulmonary disease (COPD) and restrictive pulmonary disease. 19. Clinically significant pleural or pericardial effusion. 20. History of prior pneumonectomy. 21. History of thoracic radiation therapy. Subjects with a history of thoracic radiation therapy are acceptable if there is documentation that the thoracic radiation therapy was administered more than 2 years prior to the start of study treatment. 22. Any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement. 23. Known history of active TB (Mycobacterium tuberculosis). 24. Non-minor surgery was scheduled during the study that would not delay study treatment. 25. Active (in the investigator's opinion) clinically significant infection requiring systemic therapy within 2 weeks prior to the first dose of study drug. 26. Administration of live, attenuated vaccines within 4 weeks prior to the first dose of study drug, or the expectation that such live attenuated vaccines will be required during the study. Inactivated vaccines (such as Hepatitis A or polio vaccines) are permitted during the study. Seasonal influenza and COVID-19 vaccines that do not contain live virus are permitted. 27. History of hypersensitivity to the monoclonal antibody or contraindication to administration of any of the corticosteroids or excipients (investigators must consult prescribing information for the corticosteroid of choice). 28. Known intolerance to any of the components of the study drug. 29. Has a medical or other condition that, in the opinion of the Investigator, would preclude the subject's participation in the clinical trial. 30. Receiving any prohibited medication in combination with one or more study treatments as described in the eribulin product labeling, unless medication is discontinued within 7 days prior to enrollment. 31. Known psychiatric or substance abuse disorder that would prevent cooperation with the requirements of the study.

[0219] 2.2.7 Research treatment Dosing Schedule: MORAb-202 will be administered as an intravenous infusion once every 3 weeks. One dosing cycle is defined as 21 days (also known as Q3W). The concentration of study drug in the vial is 10 mg / mL. The first infusion of MORAb-202 will be administered over 60 minutes. If no infusion reactions are observed, subsequent infusions may be administered as tolerated, but over 30 minutes.

[0220] 2.2.8 Concomitant medications / combination therapies Prophylactic treatment for hospital-acquired infections, acceptable treatment for DLT events, or continued treatment for complications of AEs are permitted, provided that concomitant treatment should be minimized during the study. At the investigator's discretion, G-CSF or equivalent may be used in accordance with local or national guidelines.

[0221] After consultation with the sponsor, radiation therapy (up to two sessions) for symptomatic isolated non-target lesions while on study treatment may be permitted. Brain lesions requiring radiation may be indicative of disease progression.

[0222] Acceptable treatment for adverse events, e.g., ILD, or continued treatment for adverse events, e.g., complications of ILD, is acceptable. Acceptable treatments include administration of corticosteroids, e.g., dexamethasone. Dexamethasone will be administered orally at 4 mg twice daily on days 1 through 3 of each cycle of MORAb-202.

[0223] 2.2.9 Verdict Efficacy, safety, PK and PD will be assessed.

[0224] 2.2.10 Biological analysis methods Serum MORAb-202 concentrations will be measured using a drug-antibody ratio (DAR)-tolerant ligand binding assay format designed to specifically quantify toxin-conjugated antibodies (DAR≧1), with any intact molecule of at least 1 DAR being detected. Serum total antibody concentrations will be measured using a validated ligand binding assay format designed to detect farletuzumab, regardless of the level of linker-toxin conjugation present (DAR≧0). Total eribulin concentrations will be measured using a validated liquid chromatography tandem mass spectrometry (LC-MS / MS) method. Anti-drug antibodies (ADA) will be measured using a validated ligand binding assay.

[0225] 2.2.11 Independent Data Monitoring Committee (IDMC) Safety monitoring will be conducted by the IDMC. The functions and members of the IDMC will be described in the Articles of Incorporation of the IDMC.

[0226] The first IDMC will occur after the first 6 subjects have completed treatment (first cohort) and have been observed for 6 weeks (first on-study tumor adjudication timepoint and first scheduled ILD assessment adjudication timepoint), and then after each cohort. If a subject discontinues study treatment for any reason other than drug-related toxicity before completion of the first 6 weeks of study treatment, the subject will be replaced. If 2 or more grade 3 or higher ILD / pneumonitis events are observed in the study, the sponsor will suspend enrollment pending the outcome of the IDMC review. The time of IDMC reviews may also be adjusted or held more frequently if deemed warranted by the sponsor's ongoing safety monitoring.

[0227] 2.2.12 Sample size rationale The primary objective of the dose escalation part is to evaluate the safety and tolerability of MORAb-202 in subjects with selected tumor types (OC, EC, NSCLC, TNBC) and to determine the RP2D. The sample size in this part will be approximately 36 subjects depending on the number of DLTs observed. Additional subjects with OC will be recruited as backfill to achieve approximately 10 subjects with OC per dose level.

[0228] The primary objective of the dose confirmation part of the study is to evaluate the safety and preliminary efficacy of MORAb-202 in subjects with OC and EC. The planned number of subjects will be approximately 30. This part will consist of cohorts of 6 or 9 subjects, approximately 15 subjects for each dose level of MORAb-202 at 25 mg / m2 and 33 mg / m2. The order in which the cohorts are run will depend on the number of grade 3 or higher ILD events observed. Early cohorts will enroll both OC and EC subjects, and one or more final cohorts will enroll only EC subjects (see study overview).

[0229] Data from these cohorts will be analyzed to determine one or more regimens that are acceptable for further investigation. Acceptable regimens will be determined based on how well ILD is controlled in these cohorts treated by the methods described herein.

[0230] Example 3 3.1 Study design This is a Phase 2, open-label, randomized, multicenter study to determine the safety, efficacy, and tolerability of MORAb-202 in participants with metastatic NSCLC AC (adenocarcinoma). Participants will be randomized 1:1 into two arms, with Arm A receiving 33 mg / m 2 and Arm B, 25 mg / m 2 The patients will receive one dose of MORAb-202 every three weeks.

[0231] The study will enroll the following participants:

[0232] Prior treatment with platinum doublet chemotherapy and anti-PD-1 / PD-L1, either administered concomitantly or sequentially No more than two lines of systemic therapy (no more than one line of prior chemotherapy) Participants with no or unknown genomic alterations in the metastatic setting after receiving genomic alterations.

[0233] At least one approved targeted therapy No more than 3 lines of systemic therapy (no more than 1 line of chemotherapy) Participants with known genomic alterations in the metastatic setting after receiving

[0234] Approximately 60 participants will be randomized in a 1:1 ratio, stratified by ECOG PS 0 / 1, to one of the following treatment arms: Arm A (N=30): MORAb-202 33mg / m 2 Q3W Arm B (N=30): MORAb-202 25mg / m 2 Q3W

[0235] All participants will be treated until disease progression according to RECIST v1.1 criteria as determined by the investigator, unacceptable toxicity, withdrawal of consent by the participant to receive study treatment, death, or study termination, whichever occurs first. The maximum treatment duration will be up to 2 years. However, if a participant has established clinical benefit, a decision will be made to treat the participant with additional study therapy cycles beyond 2 years, guided by ongoing safety and tumor assessments.

[0236] To further characterize safety and efficacy at the selected doses, at least 30 FRA-evaluable participants are enrolled in each cohort, and up to 30 additional participants may be enrolled in Arm A or Arm B to ensure approximately 25% FRA elevated expressers are enrolled. All relevant data (safety, efficacy, PK, and PD) will inform sponsor decision-making regarding subsequent clinical development, including determining the relationship to FRA expression through a protocol amendment by enrolling additional participants in expansion cohorts or continued development in a separate study.

[0237] The primary analysis will be performed when all participants in each arm have completed treatment and have a minimum of 6 months of follow-up or when treatment is discontinued early. In the primary analysis, one dose level of MORAb-202 will be selected to continue further evaluation. This dose selection will be based on the overall efficacy and safety data. A safety follow-up visit will occur 30 days after the last study drug dose. All ongoing treatment-related SAEs and ILD / pneumonitis events will be followed until resolution or stabilization. All participants who discontinue treatment for reasons other than disease progression will be followed for continued tumor imaging assessments until disease progression per RECIST v1.1, death, or withdrawal of consent for tumor assessment, whichever occurs first, as determined by the investigator. All participants will be followed every 3 months for survival until all randomized participants have completed 2 years of survival follow-up.

[0238] An overview of the study design is presented in Figure 6.

[0239] 3.1.1 Purpose 3.1.1.1 Primary Objectives and Evaluation Items The primary objectives of this study are (i) to determine the safety and tolerability of MORAb-202 in participants with previously treated non-small cell lung cancer (NSCLC) adenocarcinoma (AC) and (ii) to determine the tumor response to MORAb-202 in participants with previously treated NSCLC AC.

[0240] The primary endpoints of the study are (i) to assess the incidence and severity of adverse events (AEs) / serious AEs (SAEs), treatment-related AEs / SAEs, AEs leading to discontinuation, AEs of special interest (AESIs), deaths and laboratory abnormalities, and (ii) to assess the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by the investigator.

[0241] 3.1.1.2 Secondary Objectives and Endpoints The secondary objectives of the study are: (i) to evaluate the progression-free survival (PFS) of MORAb-202 in participants with previously treated NSCLC AC; (ii) to evaluate the DCR of MORAb-202 in participants with previously treated NSCLC AC; and (iii) to evaluate the duration of response (DoR) of MORAb-202 in participants with previously treated NSCLC AC who achieved CR or PR.

[0242] The secondary endpoints of this study are: (i) to assess PFS by RECIST v1.1 per investigator assessment; (ii) to assess DCR by RECIST v1.1 per investigator assessment; and (iii) to assess DoR by RECIST v1.1 per investigator assessment.

[0243] 3.2 Number of subjects Approximately 60 participants will be randomized in a 1:1 ratio to one of two treatment arms with approximately 30 participants in each arm. Assuming a screening failure rate of approximately 40%, it is estimated that approximately 100 participants will be enrolled, resulting in approximately 60 randomized participants. Randomized participants who discontinue before receiving their first dose of MORAb-202 will be replaced.

[0244] 3.3 Inclusion Criteria Participants were eligible for inclusion in the study only if all of the following criteria were met: 1) Signed written informed consent a) Participant or legally acceptable representative (LAR; if acceptable per local guidelines) must sign and date a written Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approved ICF in accordance with regulatory, local and institutional guidelines, which must be obtained prior to performing any protocol-related procedures that are not part of routine patient care. b) Participants must be willing and able to comply with scheduled clinic visits, treatment schedules, laboratory tests, and other requirements of the study. 2) Participant types and target disease characteristics a) Metastatic NSCLC AC (as defined by the 8th International Society for the Study of Lung Cancer classification) with histological or cytological documentation. b) Participants with no or unknown genomic alterations in the metastatic setting after receiving: i) Prior treatment with platinum doublet chemotherapy and anti-PD-1 / PD-L1, either administered concomitantly or sequentially ii) ≤2 lines of systemic therapy (≤1 line of prior chemotherapy) c) Participants with known genomic alterations in the metastatic setting: i) At least one approved targeted therapy ii) ≤3 lines of systemic therapy (≤1 line of chemotherapy) d) Radiographically documented disease progression during or after last treatment as assessed by the investigator e) Measurable target disease as determined by the investigator per RECIST v1.1. f) Lesions that have previously received locoregional therapy such as external beam radiation therapy (EBRT) or radiofrequency (RF) ablation must demonstrate evidence of disease progression per RECIST v1.1 to be considered target lesions. g) ECOG PS 0 or 1 h) Resolution of toxicity from prior anticancer therapy to a severity of Grade 1 or less (NCI CTCAE v5.0) prior to administration of study drug, except for stable sensory neuropathy (Grade ≤ 2), anemia (hemoglobin [Hgb] ≥ 9.0 g / dL), and long-lasting sequelae (e.g., alopecia, fatigue) that are not expected to interfere with study treatment. i) Either FFPE tissue or freshly obtained biopsies must be available for IHC review at a central laboratory prior to randomization. Tumor samples (tissue block [preferred] or 15 unstained slides) must be evaluable (i.e., of sufficient quality and quantity) for IHC analysis to meet the randomization eligibility criteria. Sample resubmission will be permitted for participants with insufficient tissue quality and quantity but who are otherwise eligible. 3) Age of participants Participants (male or female) must be 18 years of age or older at the time of signing the informed consent. 4) Reproductive status Investigators should advise women of childbearing potential (WOCBP) and male participants who are sexually active with WOCBP regarding the importance of pregnancy prevention, the consequences of unintended pregnancy, and the potential for fetal toxicity due to transmission of the study intervention present in semen to the developing fetus, even if the participant has had a successful vasectomy or the partner is pregnant. The investigator will evaluate the effectiveness of the contraceptive method in relation to the first dose of the study intervention. · Local laws and regulations may require the use of alternative and / or additional methods of contraception. a) Female participants: i) Female participants must have documented evidence in their medical documentation that they are not pregnant. ii) Women who are not of childbearing potential are exempt from the contraception requirement. iii) WOCBP must have a negative high-sensitivity serum or urine pregnancy test within 24 hours prior to the start of the study intervention (minimum sensitivity 25 IU / L or equivalent units of HCG). (1) A serum pregnancy test will be required if the urine test is not confirmatory (e.g., equivocal result). In such cases, if the serum pregnancy test result is positive, the participant must be excluded from participation. (2) The investigator will be responsible for reviewing medical history, menstrual history, and recent sexual activity to reduce the risk of enrolling women with missed early pregnancy. iv) WOCBP must agree to follow the instructions regarding one or more contraceptive methods described below and contained in the ICF. - WOCBP are permitted to use hormonal contraception. v) Female participants are eligible to participate if they are not pregnant or breastfeeding and at least one of the following conditions applies: (1) Not a WOCBP; or (2) Women who are women with fertility problems and who have agreed to use highly effective (annual failure rate less than 1%) contraception with low user dependency during the intervention period and for at least 28 days prior to administration and throughout the study and for 90 days after discontinuing MORAb-202, and to not donate eggs (eggs, oocytes) for reproductive purposes during the same period. b) Male participants: Men who are sexually active with WOCBP must agree to follow the instructions for one or more contraceptive methods as described below. i) Azoospermic men will not be exempt from the contraceptive requirement and will be required to use latex or other synthetic condoms during any sexual activity (e.g., vaginal, anal, or oral) with WOCBP, even if the participant has had a successful vasectomy or his or her partner is pregnant. ii) Male participants will be required to use latex or other synthetic condoms at all times during any sexual activity (e.g., vaginal, anal, oral) with WOCBPs, even if the participant has had a successful vasectomy or his partner is already pregnant or breastfeeding. Men must continue to use condoms during the intervention period and for at least 28 days prior to dosing, throughout the study, and for 90 days after MORAb-202 is discontinued. iii) Female partners of men participating in this study must accept the advice to use highly effective contraception during the intervention period and for at least 90 days after the last dose of the study intervention in the male participant. iv) Male participants with pregnant or lactating partners must agree to remain abstinent from sexual activity or use male condoms during any sexual activity (e.g., vaginal, anal, oral) during the intervention period and for at least 90 days after the last dose of the study intervention, even if the participant has had a successful vasectomy. v) Male participants must refrain from sperm donation during the intervention period and for at least 90 days after administration of the final dose of the study intervention. vi) Breastfeeding partners must accept advice encouraging them to consult with their health care provider regarding the use of appropriate highly effective contraception during the period in which participants are required to use condoms.

[0245] 3.4 Exclusion criteria Participants will be excluded from the study if any of the following criteria apply to them: 1) Medical Condition a) NSCLC histology other than AC (i.e. squamous cell carcinoma; large cell carcinoma). b) Abnormal pulmonary function tests (PFTs): forced expiratory volume in one second (FEV1) < 70% or forced vital capacity (FVC) < 60%, diffusing capacity for carbon monoxide (DLCO) < 80%. c) Pulmonary-specific clinically significant illness not controlled by medical therapy, including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary embolism), asthma, chronic obstructive pulmonary disease (COPD), and restrictive pulmonary disease. d) Clinically significant pleural or pericardial effusion requiring drainage or ascites requiring peritoneal shunt or CART (concentrated ascites filtration and reinfusion) e) History of pneumonectomy. History of lobectomy and segmentectomy >12 months prior to treatment is permitted. f) Recent thoracic radiation therapy. Participants with thoracic or chest wall irradiation are acceptable if documentation of thoracic irradiation occurred more than 12 months prior to the start of study treatment. g) Current infectious pneumonia or history of viral pneumonia with evidence of persistent radiological abnormalities (including COVID-19 related infection). i) History of either suspected or confirmed SARS-CoV-2 infection within 4 weeks prior to randomization, in addition, acute symptoms must have resolved completely and there must be no sequelae that may pose a high risk to participants receiving study treatment, as determined by the Investigator in consultation with the BMS Medical Monitor (or designee). ii) Participants currently in COVID-19 interventional trials may not enter BMS clinical trials until a specified washout period has been achieved. If a study participant has received an investigational COVID-19 vaccine or other IP designed to treat or prevent COVID-19 prior to screening, enrollment must be delayed until the biological effects of the vaccine or IP have stabilized, as determined by documented discussions between the investigator and medical monitor (or designee). NOTE: Based on specific country / region guidelines, COVID-19 polymerase chain reaction (PCR) viral testing may be required prior to randomization and the results of this test may impact study participation. Eligibility must be confirmed by discussing test results with the BMS Medical Monitor (or designee). h) Current ILD / pneumonitis as determined by the investigator or suspected ILD / pneumonitis at screening, or history of ILD / pneumonitis of any severity, including ILD / pneumonitis from prior anti-cancer therapy. i) Spinal cord compression or untreated symptomatic central nervous system (CNS) metastases (brain or leptomeningeal). Participants are eligible if CNS metastases are asymptomatic and not requiring immediate treatment or have been treated, have no MRI or CT evidence of progression for at least 4 weeks after completion of treatment and within 28 days prior to administration of the first dose of study treatment, and have returned to neurological baseline (excluding residual signs or symptoms related to CNS treatment). In addition, participants must have discontinued anticonvulsant therapy and have discontinued corticosteroids or be on a stable or reduced dose of prednisone (or equivalent) ≤ 10 mg daily for at least 2 weeks prior to treatment. Imaging performed within 28 days prior to treatment must have been performed after completion of any CNS-specific therapy with documented stability of CNS disease on radiographs. j) Participants with a medical condition requiring systemic treatment with either corticosteroids or other immunosuppressant therapy at doses greater than 10 mg prednisone equivalent per day within 14 days of study treatment administration, except for adrenal steroid replacement therapy, which is permitted in doses greater than 10 mg prednisone equivalent per day in the absence of active autoimmune disease. i) Treatment with a short-term (<5 days) course of steroids up to 7 days before initiating study treatment is permitted. k) Evidence of active infection, including tuberculosis, within 14 days prior to treatment and uncontrolled infection requiring systemic antibacterial, antiviral or antifungal therapy. i) Uncontrolled or significant cardiovascular condition within 6 months prior to enrollment, including but not limited to any of the following: angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure (as defined by the New York Heart Association), pericarditis, or myocarditis. ii) Ongoing symptomatic arrhythmia, history of clinically significant arrhythmia (e.g. ventricular tachycardia, ventricular fibrillation or torsades de pointes). l) Clinically significant ECG abnormalities, including significant baseline QTcF prolongation (repeated QTcF interval >500 msec), history of risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or use of concomitant medications that prolong QTcF. m) Evidence of active bleeding or medically significant bleeding within 3 months prior to enrollment. n) History of deep vein thrombosis (DVT) within 6 weeks prior to enrollment. Participants who completed anticoagulation for at least 1 month prior to initiating study treatment and continued anticoagulation during study participation were eligible. i) Participants at risk for DVT secondary to a central venous catheter or with a past history of DVT or clinical symptoms suggestive of DVT must undergo venous Doppler ultrasound during screening and prior to the start of study treatment to rule out DVT. o) Any autoimmune, connective tissue or inflammatory disorder with documented or suspected pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.). p) Concurrent malignancy requiring treatment (present at screening) or history of active previous malignancy within 2 years prior to randomization, excluding NSCLC under study (i.e., participants with a history of previous malignancy are eligible if treatment was completed at least 2 years prior to randomization and the participant has no evidence of disease). Participants with a history of previous early stage basal / squamous cell skin cancer or non-invasive or in situ carcinoma (i.e., superficial bladder, prostate, cervical, or breast in situ carcinoma) that had definitive treatment at any time are also eligible. q) Any condition, including medical, emotional, psychiatric or logistical conditions, that, in the opinion of the investigator, may prevent the participant from complying with the protocol or that may increase the risks associated with study participation or study drug administration, or that may interfere with the interpretation of safety results. 2) Prior / concomitant therapy a) Participants who have received prior investigational treatment with an FRA-targeting agent or an FRA-targeting ADC, including MORAb-202. b) Any condition requiring folic acid supplementation (e.g., folic acid deficiency). c) Participants with known intolerance to any component of the study drug. d) Currently enrolled in another clinical trial or, within the past 28 days or within 5 half-lives of the investigational drug (whichever is longer) prior to starting study treatment, has used any investigational drug or investigational device that, in the opinion of the sponsor, may interfere with the study treatment. e) Any major surgery within 4 weeks of the first dose of study treatment. Participants must have recovered from the effects of major surgery or significant trauma at least 14 days prior to receiving the first dose of study treatment. f) Treatment with any live / attenuated vaccine within 30 days of the first study treatment. 3) Physical examination and clinical test findings a) Evidence of organ dysfunction or any clinically significant deviations from normal on physical examination, vital signs, ECG, or clinical laboratory determinations beyond those consistent with the target population. i) Renal insufficiency as evidenced by serum creatinine >1.5 mg / dL or calculated creatinine clearance (CrCL) <50 mL / min by 12- or 24-hour urine collection. ii) Bone marrow insufficiency as evidenced by: (1) Absolute neutrophil count (ANC) < 1.0 × 108T 9 8T / L (2) Hgb<9.0 g / dL (3) Platelet count < 75 × 10 9 / L NOTE: Supportive care such as blood / platelet transfusions necessary to achieve the above values, and hematopoietic stimulants including granulocyte-colony stimulating factor (G-CSF) preparations, are acceptable per institutional practice if administered ≥1 week prior to study treatment. iii) Hepatic insufficiency as evidenced by: (1) Total bilirubin >1.5 × upper limit of normal (ULN), except in patients with unconjugated hyperbilirubinemia (e.g., Gilbert syndrome, which must have total bilirubin <3 × ULN). (2) ALT and aspartate aminotransferase (AST) >3×ULN (>5×ULN for liver metastases), except for bone metastases, and alkaline phosphatase (ALP) >3×ULN, unless the subject is known to have bone metastases, in which case even higher ALP values ​​are permitted. iv) Serum albumin < 3.0 g / dL. b) Known human immunodeficiency virus (HIV) positive and have had an AIDS-defining opportunistic infection within the past year or a current CD4 count <350 cells / μL. Participants with HIV are eligible if: i) Participants must have received antiretroviral therapy (ART) for at least 4 weeks prior to randomization as clinically indicated during study enrollment. ii) Participants will continue ART as clinically indicated during study enrollment. iii) CD4 count and viral load will be monitored according to standard of care by local healthcare providers. Note: HIV testing must be performed in a facility where locally mandated. HIV-positive participants must be excluded if locally mandated. c) Active viral hepatitis B or C as evidenced by: i) Any positive test result for Hepatitis B Virus (HBV) indicating the presence of the virus, for example Hepatitis B surface antigen (HBsAg, Australia Antigen) positivity. ii) Any positive test result for Hepatitis C Virus (HCV) indicating the presence of active viral replication (detectable HCV-ribonucleic acid [RNA]). Note: Participants who are HCV antibody positive and HCV RNA undetectable are eligible for enrollment. iii) Additional or alternative testing to rule out infection is permitted in accordance with institutional guidelines. 4) Allergies and adverse drug reactions a) Any history of severe hypersensitivity (grade 3 or higher) to monoclonal antibodies or eribulin, or contraindication to administration of any of the corticosteroids or excipients. 5) Other exclusion criteria a) Prisoners or involuntarily incarcerated participants. (Note: Only under certain circumstances and in countries where local law permits, prison inmates may be included or permitted to remain as participants; strict conditions apply and are subject to BMS approval). b) Participants who are involuntarily detained for the treatment of either a psychiatric or physical illness (e.g., infectious disease).

[0246] 3.5 Research intervention MORAb-202 will be administered to subjects according to Table 16 below.

[0247] [Table 18]

[0248] 3.6 Dosage Modifications For participants who experience toxicity but meet the criteria for dose modification, the next dose of MORAb-202 should be reduced to the next lower dose level, as detailed in Table 17. Consultation with the Study Medical Monitor is required prior to any dose reduction. After a dose has been reduced, it cannot be increased again.

[0249] [Table 19]

[0250] Example 4 4.1 Research details A Phase 2, open-label, randomized, multicenter study will be conducted to evaluate the safety, efficacy, and tolerability of MORAb-202 in female participants with platinum-resistant high-grade serous (HGS) ovarian, primary peritoneal, or fallopian tube cancer. The research hypothesis of this study is that MORAb-202 will 2 or 25 mg / m2 Both will have a favorable benefit-risk profile compared with IC chemotherapy as measured by overall response rate (ORR) and safety profile in participants with platinum-resistant high-grade serous ovarian, primary peritoneal or fallopian tube cancer. The study duration will be approximately 4 years.

[0251] 4.1.1 Purpose 4.1.1.1 Primary purpose The primary objectives of the study are (i) to compare the objective response rate of MORAb-202 with investigator's choice (IC) chemotherapy (among all randomized participants); and (ii) to assess the proportion of participants in each arm who experienced treatment-emergent adverse events (TRAEs) leading to discontinuation within 6 months of receiving the first dose of study drug among all treated participants.

[0252] The primary objective endpoints described above are: (i) objective response rate (ORR) by RECIST v1.1 as assessed by the investigator; and (ii) TRAEs leading to discontinuation.

[0253] 4.1.1.2 Secondary Objectives The secondary objectives of this study are (i) to evaluate the disease control rate (DCR) of MORAb-202 and IC chemotherapy in all randomized participants; (ii) to evaluate the duration of response (DoR) of MORAb-202 and IC chemotherapy in all randomized participants; and (iii) to evaluate the progression-free survival (PFS) of MORAb-202 and IC chemotherapy in all randomized participants. The secondary objective endpoints described above are (i) DCR by RECIST v1.1 as per investigator assessment; (ii) DoR by RECIST v1.1 as per investigator assessment; and (iii) PFS by RECIST v1.1 as per investigator assessment.

[0254] 4.2 Study design Participants will be randomized in a 2:2:1 ratio to the following treatment arms: Arm A (N=60): MORAb-202 33 mg / m 2 (25 mg / m 2 Administered once every 3 weeks (21-day cycle) with the option of dose reduction to 50 mg / kg / day. Arm B (N=60): MORAb-202 at 25 mg / m 2 (17 mg / m 2 Administered once every 3 weeks (21-day cycle) with the option of dose reduction to 50 mg / kg / day. Arm C (N=30): IC single agent chemotherapy selected from the following: Paclitaxel at 80 mg / m 2 IV on days 1, 8, 15, and 22 of a 28-day cycle; or Pegylated liposomal doxorubicin (PLD) at 40 mg / m 2 IV on day 1 of a 28-day cycle; or Topotecan at 4 mg / m 2 IV on days 1, 8, and 15 of a 28-day cycle or 1.25 mg / m 2 Administered daily for 5 days on days 1 to 5 of a 21-day cycle.

[0255] MORAb-202 will be administered as an intravenous infusion.

[0256] Participants will be randomized by FRA expression (≧75% tumor staining vs. <75% tumor staining) and number of prior lines of therapy (1 vs. 2-3).

[0257] All participants will be treated until disease progression as determined by the investigator per RECIST v1.1, unacceptable toxicity, withdrawal of consent by the participant to receive study treatment, death, or study termination, whichever occurs first. The maximum treatment duration will be up to 2 years. However, if a participant demonstrates definitive clinical benefit, a decision will be made to treat the participant with additional study therapy cycles beyond 2 years, guided by ongoing safety and tumor assessments.

[0258] An overview of the study design is shown in Figure 7.

[0259] 4.3 Number of participants Approximately 150 participants will be randomized in a 2:2:1 ratio to one of three treatment arms, with approximately 60 participants in the MORAb-202 arms (arms A and B) and 30 participants in the chemotherapy arm (arm C). Assuming a screening failure rate of approximately 25%, it is estimated that approximately 200 participants will be enrolled, resulting in approximately 150 randomized participants.

[0260] 4.4 Inclusion Criteria The main inclusion criteria for participants in this study are as follows: For a participant to be eligible for inclusion in the study, all of the following must be true: HGS Female participants with a histologically confirmed diagnosis of ovarian, primary peritoneal or fallopian tube cancer. Platinum-resistant disease, defined as: For participants who received only one line of platinum-based therapy: progression more than 1 month but up to 6 months after the last dose of at least 4 cycles of platinum-based therapy. For participants who have received two or three lines of platinum-based therapy: progression within six months of receiving the last dose of platinum-based therapy. Participants must have received ≥1 and ≤3 lines of prior systemic therapy with monotherapy appropriate as the next line of therapy. Participants may have been treated with up to 1 line of therapy after determination of platinum resistance. Participants must have had prior treatment with bevacizumab or be deemed medically unsuitable or ineligible / intolerant to receive bevacizumab or could not receive bevacizumab because it was refused or unavailable. Note: (i) Neoadjuvant ± adjuvant chemotherapy will be considered as one line of therapy. (ii) Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered as part of the prior line of therapy. (iii) Therapy changed in the absence of progression will be considered as part of the same line. ·Disease progression per RECIST v1.1 for at least one measurable lesion on or after most recent therapy (as assessed by the investigator). Either formalin-fixed paraffin-embedded (FFPE) tissue (up to 5 years old) or newly obtained biopsy must be available for FRA assessment prior to randomization. Tumor samples (preferably tissue blocks or a minimum of 15 unstained slides) must be evaluable for FRA IHC analysis to meet eligibility criteria. Sample resubmission will be permitted for otherwise eligible participants with non-evaluable FRA IHC. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Participants must be 18 years of age (or the legal age of consent in the jurisdiction in which the study will be conducted) or older at the time of signing the Informed Consent Form (ICF).

[0261] 4.5 Exclusion criteria Participants will be excluded from the study if any of the following apply to them: Clear cell, mucinous, endometrioid or sarcomatous histology, or mixed tumors containing any component of these histologies, or low-grade or borderline ovarian carcinoma. Primary platinum-refractory ovarian cancer, defined as disease progression within one month of the last dose of a first-line platinum-containing regimen. Abnormal pulmonary function tests (PFTs): FEV1<70% or FVC<60% and DLCO<80%. - History of ILD / pneumonitis of any severity, including current ILD / pneumonitis as assessed by the investigator or suspected ILD / pneumonitis at screening or ILD / pneumonitis from prior anti-cancer therapy. Current infectious pneumonia or history of viral pneumonia with evidence of persistent radiological abnormalities (including COVID-19 related infection). Significant third-space fluid collections (e.g., ascites or pleural effusion) requiring repeated drainage. Clinically significant pericardial effusion requiring drainage. Prior treatment with pneumonectomy. Prior treatment with lobectomy or segmentectomy >12 months prior to treatment is permitted. Recent chest radiation therapy. Participants with previous chest or chest wall radiation (e.g., history of breast cancer) may be accepted if the radiation is on record more than 6 months prior to the start of study treatment. Any autoimmune, connective tissue or inflammatory disorder with documented or suspected pulmonary involvement (e.g. rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.). Spinal cord compression or untreated symptomatic central nervous system (CNS) metastases. Participants are eligible if CNS metastases are asymptomatic and not requiring immediate treatment or have been treated and the participant has returned to neurological baseline (excluding residual signs or symptoms related to CNS treatment). In addition, participants must have discontinued anticonvulsant therapy and either been off corticosteroids or been on a stable or reduced dose of prednisone (or equivalent) ≤ 10 mg daily for at least 2 weeks prior to treatment. Imaging performed within 28 days prior to treatment must have been performed after completion of any CNS-specific therapy with documented stability of CNS disease on radiographs · Concurrent malignancy requiring treatment (present at screening) or a history of active previous malignancy within 2 years prior to randomization (i.e. participants with a history of previous malignancy are eligible if treatment was completed at least 2 years prior to randomization and the patient has no evidence of disease). Participants with a history of previous early stage basal / squamous cell skin cancer or carcinoma in situ or carcinoma in situ that had undergone definitive treatment at any time are also eligible. Participants with a medical condition requiring systemic treatment with either corticosteroids or other immunosuppressant therapy at doses greater than 10 mg prednisone equivalent per day within 14 days of study treatment administration, except for adrenal steroid replacement therapy, which is permitted in doses greater than 10 mg prednisone equivalent per day in the absence of active autoimmune disease. - Short-course (<5 days) steroid treatment up to 7 days prior to initiation of study treatment is permitted.

[0262] 4.6 Research interventions Compounds will be administered to participants according to Table 18 below.

[0263] [Table 20]

[0264] Example 5 5.1 Preliminary Results of Phase 1 / 2 Study (Example 2) The dose evaluation part of this study was 25 mg / m 2 and 33 mg / m 2 The study was designed with two sequential cohorts: one for 100 mg / m2 and one for 100 mg / m2. Enrollment for these two sequential cohorts has been completed. A total of 14 subjects were enrolled and treated with MORAb-202, with 7 subjects in each cohort. 2 Further investigation will continue Q3W. This regimen has demonstrated acceptable safety and initial antitumor activity. 25 mg / m for MORAb-202, total antibody and released eribulin 2 The mean PK profile of was comparable to the 0.68 mg / kg dose. BSA-equivalent titration reduced the total amount of drug (mg) in most subjects compared to the BW-based estimated total dose. Additional studies are planned for the biweekly and weekly titration regimens.

[0265] Array of choices: SEQ ID NO:1 (MORAb-003 HC CDR1; Kabat): GYGLS SEQ ID NO:2 (MORAb-003 HC CDR2; Kabat): MISSGGSYTYYADSVKG SEQ ID NO:3 (MORAb-003 HC CDR3; Kabat): HGGDDPAWFAY SEQ ID NO:4 (MORAb-003 LC CDR1; Kabat): SVSSSISSNNLH SEQ ID NO:5 (MORAb-003 LC CDR2: Kabat): GTSNLAS SEQ ID NO:6 (MORAb-003 LC CDR3; Kabat): QQWSSYPYMYT SEQ ID NO:7 (MORAb-003 HC CDR1; IMGT): GFTFSGYG SEQ ID NO:8 (MORAb-003 HC CDR2; IMGT): ISSGGSYT SEQ ID NO:9 (MORAb-003 HC CDR3; IMGT):ARHGDDPAWFAY SEQ ID NO: 10 (MORAb-003 LC CDR1; IMGT): SSISSNN SEQ ID NO: 11 (MORAb-003 LC CDR2; IMGT): GTS SEQ ID NO: 12 (MORAb-003 LC CDR3; IMGT): QQWSSYPYMYT

[0266] SEQ ID NO: 15 (MORAb-003 heavy chain (HC)) [ka]

[0267] SEQ ID NO: 16 (MORAb-003 light chain (LC)) [ka]

[0268] SEQ ID NO:33 (MORAb-003 heavy chain full length preprotein amino acid sequence; leader sequence is underlined) [ka]

[0269] SEQ ID NO:34 (MORAb-003 light chain full length preprotein amino acid sequence (leader sequence underlined)) [ka]

[0270] SEQ ID NO: 35 (MORAb-003 HC nt) [ka]

[0271] SEQ ID NO: 36 (MORAb-003 LC nt) [ka]

[0272] SEQ ID NO: 37 (human FRA) [ka]

[0273] SEQ ID NO:38 (human FRA nucleotides) [ka]

Claims

1. Formula (I): Ab-(LD)p(I) (In the formula, Ab is an internalizing anti-folate receptor alpha (FRA) antibody or its internalizing antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3) as defined by the Kabat numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3); or three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3) as defined by the IMGT numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3); D is Eribrin; L is Mal-(PEG) ２ -A severable linker containing Val-Cit-pAB; and p is an integer between 1 and 8. A pharmaceutical composition for treating FRA-expressing cancer in a subject, comprising an antibody-drug conjugate, wherein the antibody-drug conjugate is distributed in the subject at a rate of 1 square meter (m²). ２ A pharmaceutical composition used to be administered in a dose of 8 mg to 50 mg of the antibody-drug conjugate per body surface area (BSA) of the subject.

2. Formula (I): Ab-(LD)p(I) (In the formula, Ab is an internalizing anti-folate receptor alpha (FRA) antibody or its internalizing antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3) as defined by the Kabat numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3); or three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3) as defined by the IMGT numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3); D is Eribrin; L is Mal-(PEG) ２ -A severable linker containing Val-Cit-pAB; and p is an integer between 1 and 8. A pharmaceutical composition for reducing the risk of interstitial lung disease (ILD) in a subject being treated for FRA-expressing cancer, comprising an antibody-drug conjugate, wherein the antibody-drug conjugate is distributed to the subject in a manner that reduces the risk of interstitial lung disease (ILD) per square meter (m²). ２ A pharmaceutical composition used to be administered in a dose of 8 mg to 50 mg of the antibody-drug conjugate per body surface area (BSA) of the subject.

3. The antibody or antigen-binding fragment is (a) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 14; or (b) Heavy chain containing the amino acid sequence of SEQ ID NO: 15 and light chain containing the amino acid sequence of SEQ ID NO: 16 A pharmaceutical composition according to claim 1 or 2, comprising:

4. The pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate is MORAb-202.

5. The pharmaceutical composition according to claim 1 or 2, wherein p is 3 to 5.

6. The aforementioned dosage is 1 m ２ The pharmaceutical composition according to claim 1 or 2, wherein the amount is 8 mg to 44 mg per BSA of the subject.

7. The aforementioned dosage is 1 m ２ The pharmaceutical composition according to claim 1 or 2, wherein the amount is 25 mg per BSA of the subject.

8. The pharmaceutical composition according to claim 1 or 2, wherein the dose is 12 mg per 1 m² of the target BSA.

9. The pharmaceutical composition according to claim 1 or 2, wherein the dose is 8 mg per 1 m² of the target BSA.

10. The pharmaceutical composition according to claim 6, wherein the antibody-drug conjugate is used to reduce toxicity in the subject by being administered in a dose lower than that per 1 m² of BSA of the subject, and optionally the lower dose is 17 mg, 15 mg, or 8 mg to 10 mg per 1 m² of BSA of the subject.

11. The pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate is used to be administered once every three weeks, once every two weeks, or once a week.

12. The pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate is used to be administered once a week at a dose of 8 mg per 1 m².

13. The pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate is used to be administered once every three weeks at a dose of 25 mg per 1 m².

14. The pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate is used to be administered in a dose of 12 mg per 1 m² in a 21-day cycle.

15. The subject has a weight value that is in the upper quartile group with respect to body weight, as described in claim 1 or 2.

16. The pharmaceutical composition according to claim 1 or 2, wherein, after administration of the antibody-drug conjugate, the risk of interstitial lung disease (ILD) in the subject is reduced by at least 5%, at least 10%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to treatment in which the antibody-drug conjugate is administered at a body weight-based dose, and the body weight-based dose is 0.5 mg to 2 mg per kilogram of body weight of the subject.

17. The pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate is used to be administered together with a corticosteroid.

18. The pharmaceutical composition according to claim 17, wherein the corticosteroid is used to be administered prophylactically to the subject.

19. The pharmaceutical composition according to claim 17, wherein the corticosteroid is used to be administered to the subject simultaneously with or sequentially with the antibody-drug conjugate.

20. The pharmaceutical composition according to claim 17, wherein the corticosteroid is used to be administered to the subject before or after the administration of the antibody-drug conjugate, and optionally the corticosteroid is administered for at least three days.

21. The aforementioned corticosteroids (a) Dexamethasone administered to the subject in a dose of 1 mg to 10 mg; (b) Prednisone administered to the subject in a dose of 0.5 mg to 2 mg; or (c) Methylprednisolone administered to the subject in a dose of 500 mg to 1000 mg. The pharmaceutical composition according to claim 17.

22. The pharmaceutical composition according to claim 17, wherein the corticosteroid is used to be administered to the subject at least once a day.

23. The pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate is used to be administered intravenously to the subject.

24. (a) the subject, 33 mg / m² ２ The antibody-drug conjugate is administered in a dose of 25 mg / m², followed by administration of 25 mg / m². ２ The reduced dose of the antibody-drug conjugate is used to be administered; (b) The subject is administered the antibody-drug conjugate at a dose of 25 mg / m², followed by a reduced dose of the antibody-drug conjugate at 17 mg / m²; (c) The subject is administered the antibody-drug conjugate at a dose of 25 mg / m², followed by a reduced dose of the antibody-drug conjugate at 15 mg / m²; (d) The subject is administered the antibody-drug conjugate at a dose of 15 mg / m², followed by a reduced dose of the antibody-drug conjugate of 8 mg / m² to 10 mg / m²; (e) The subject is administered the antibody-drug conjugate at a dose of 14 mg / m², followed by a reduced dose of the antibody-drug conjugate at 11 mg / m²; or (f) The subject is administered the antibody-drug conjugate at a dose of 11 mg / m², followed by a reduced dose of the antibody-drug conjugate at 8 mg / m². The pharmaceutical composition according to claim 1 or 2.

25. The pharmaceutical composition according to claim 1 or 2, wherein the FRA-expressing cancer is selected from gastric cancer, ovarian cancer, serous ovarian cancer, serous high-grade ovarian cancer, clear cell ovarian cancer, platinum-resistant ovarian cancer, lung cancer, non-small cell lung cancer, metastatic non-small cell lung cancer, pulmonary carcinoid, colorectal cancer, breast cancer, triple-negative breast cancer, hormone receptor (HR)-positive and HER2-low-expressing breast cancer, endometrial cancer, serous endometrial cancer, peritoneal cancer, primary peritoneal cancer, fallopian tube cancer, pancreatic cancer, kidney cancer, renal cell carcinoma, cervical cancer, esophageal cancer, and osteosarcoma.

26. The aforementioned FRA-expressing cancer is (a) Ovarian cancer; (b) Triple-negative breast cancer (TNBC); (c) Non-small cell lung cancer (NSCLC); or (d) Endometrial cancer (EC); The pharmaceutical composition according to claim 25.

27. The pharmaceutical composition according to claim 25, wherein the FRA-expressing cancer is a metastatic cancer, and the metastatic cancer has no genomic changes, or has at least one known genomic change in at least one of the following genes: EGFR, ALK, PI3K, AKT, mTOR, RET, MET, BRAF, NTRK, ROS1, and any gene involved in the RAS-MAPK pathway.

28. The aforementioned FRA-expressing cancer is a refractory cancer. (a) The refractory cancer is refractory to targeted therapy against any one of the following genes or their variants: EGFR, ALK, BRAF, RET, MET, NTRK, and ROS1; or (b) The refractory cancer is refractory to platinum-based and immunotherapy-based therapies, and the therapies are administered concurrently or sequentially. The pharmaceutical composition according to claim 25.

29. (a) At the start of treatment, the subject does not have one or more of the following conditions: interstitial lung disease (ILD) and / or pneumonitis, a history of ILD and / or pneumonitis, a clinically significant disease specific to the lung, pleural effusion, pericardial effusion, a history of prior treatment by pneumonectomy, a history of thoracic radiotherapy within the past two years, an autoimmune disorder with lung lesions, a connective tissue disorder with lung lesions, or an inflammatory disorder with lung lesions; or (b) The pharmaceutical composition according to claim 1 or 2, wherein the subject does not have a history of prior treatment with four or more therapies for the FRA-expressing cancer, a high neutrophil-to-lymphocyte ratio, or a serum albumin level of less than 3 g / dL at the start of treatment.

30. A pharmaceutical product for the treatment of FRA-expressing cancer in a subject, comprising formula (I): Ab-(LD)p(I) (In the formula, Ab is an internalizing anti-folate receptor alpha (FRA) antibody or its internalizing antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3) as defined by the Kabat numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3); or three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3) as defined by the IMGT numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3); D is Eribrin; L is a cleavable linker containing Mal-(PEG)2-Val-Cit-pAB; and p is an integer between 1 and 8. Use of a composition comprising an antibody-drug conjugate, wherein the pharmacopoesis is formulated to be administered to the subject at a dose of 8 mg to 50 mg of the antibody-drug conjugate per square meter (m²) of the subject's body surface area (BSA).

31. A pharmaceutical product for reducing the risk of interstitial lung disease (ILD) in a subject being treated for FRA-expressing cancer, comprising formula (I): Ab-(LD)p(I) (In the formula, Ab is an internalizing anti-folate receptor alpha (FRA) antibody or its internalizing antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3) as defined by the Kabat numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3); or three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3) as defined by the IMGT numbering scheme; and three light chain complementarity-determining regions (LCDRs) containing the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3); D is Eribrin; L is a cleavable linker containing Mal-(PEG)2-Val-Cit-pAB; and p is an integer between 1 and 8. Use of a composition comprising an antibody-drug conjugate, wherein the pharmacopoesis is formulated to be administered to the subject at a dose of 8 mg to 50 mg of the antibody-drug conjugate per square meter (m²) of the subject's body surface area (BSA).

32. The antibody or antigen-binding fragment is (a) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 14; or (b) Heavy chain containing the amino acid sequence of SEQ ID NO: 15 and light chain containing the amino acid sequence of SEQ ID NO: 16 The use according to claim 30 or 31, including the use described in claim 30 or 31.

33. The use according to claim 30 or 31, wherein the dose is 25 mg, 12 mg, or 8 mg per 1 m² of the BSA of the subject.

34. The use according to claim 30 or 31, wherein the antibody-drug conjugate is administered together with a corticosteroid.

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