Therapeutic combinations comprising Anti-FOLR1 immunoconjugates

Abstract

To provide methods of administering combinations to treat cancers, e.g., ovarian cancers, with greater clinical efficacy and / or decreased toxicity.SOLUTION: Therapeutic combinations of immunoconjugates that bind to FOLR1 (e.g., IMGN853) with anti-VEGF agents (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin are provided. Combinations of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent and / or doxorubicin can result in synergistic efficacy against tumors.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 220,028, filed September 17, 2015; U.S. Provisional Patent Application No. 62 / 242,669, filed October 16, 2015; and U.S. Provisional Patent Application No. 62 / 250,756, filed November 4, 2015, each of which is incorporated by reference herein in its entirety.

[0002] Reference to sequence listings submitted electronically via EFS-Web The contents of the electronically submitted sequence listing (Name: 2921_077PC03_SL.txt, Size: 19,451 bytes, and Creation Date: September 13, 2016) are incorporated herein by reference in their entirety.

[0003] The field of the invention relates generally to combinations of anti-FOLR1 immunoconjugates with anti-VEGF agents, platinum-based agents, and / or doxorubicin, and the use of such combinations in the treatment of cancer, eg, ovarian cancer. [Background technology]

[0004] Cancer is one of the leading causes of death in developed countries, with over one million people diagnosed with cancer each year in the United States alone, and 500,000 deaths. Overall, it is estimated that more than one in three people will develop some form of cancer in their lifetime.

[0005] Folate receptor 1 (FOLR1), also known as folate receptor-alpha (FRα) or folate-binding protein, is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein with strong binding affinity for folate and reduced folate derivatives. (See Leung et al., Clin. Biochem. 46:1462-1468 (2013)). FOLR1 mediates the delivery of physiological folate, 5-methyltetrahydrofolate, into cells. FOLR1 expression in normal tissues is restricted to the apical membrane of epithelial cells in renal proximal tubules, lung alveolar cells, bladder, testis, choroid plexus, and thyroid gland (Weitman SD, et al., Cancer Res. 52:3396-3401 (1992); Antony AC, Ann. Rev. Nutr. 16:501-521 (1996); Kalli KR, et al., Gynecol. Oncol. 108:619-626 (2008)). FOLR1 is overexpressed in epithelial-derived tumors, such as ovarian, uterine, breast, endometrial, pancreatic, renal, lung, colorectal, and brain tumors. This expression pattern of FOLR1 makes it a desirable target for FOLR1-directed cancer therapy.

[0006] Vascular endothelial growth factor-A (VEGF), also known as vascular permeability factor (VPF), is the prototypic member of the VEGF family of proteins and a key regulator of angiogenesis (Hoeben et al., Pharmacol. Rev. 56:549-580 (2004); Ferrara et al., Nat. Med. 9:669-676 (2003)). Angiogenesis, the process of new blood vessel development from pre-existing vasculature, is important for at least wound healing, organ regeneration, and the female reproductive system (Hoeben et al., supra; Ferrara et al., supra). Angiogenesis is also important in pathological processes, including tumor initiation, growth, and metastasis (Hoeben et al., supra; Ferrara et al., supra). VEGF is a pro-angiogenic factor that is highly expressed in normal lung, kidney, heart, adrenal gland, liver, spleen, and gastric mucosal tissues, and in many human tumors (Hoeben et al., supra). Its elevated or misexpression and pro-angiogenic function in tumors make VEGF a desirable target for targeted cancer therapy.

[0007] Cisplatin and carboplatin are platinum analogue and alkylating chemotherapy agents that have been used alone or in combination with other drugs for the treatment of various solid tumors for several decades (Lokich et al., Annals of Oncology 9:13-21 (1998)). Carboplatin has been reported to have reduced gastrointestinal effects compared to cisplatin (Lokich et al.). However, carboplatin causes negative side effects such as bone marrow suppression (Lokich et al.). Therefore, improving the efficacy and tolerability of treatment with cisplatin and carboplatin is desirable.

[0008] Doxorubicin is an anthracycline antibiotic chemotherapy agent that has also been used to treat various cancers, either alone or in combination with other chemotherapy agents, such as paclitaxel (an antimitotic chemotherapy agent called TAXOL® (Bristol Myers Squibb)), see also Gehl et al., Annals of Oncology, 7:687-639 (1996)). The usefulness of doxorubicin as a cancer treatment is limited by its toxicity, particularly its cardiac toxicity (see Takar et al., J. of Pharmacy & Pharmacology, 65:157-170 (2013)). Therefore, improving the efficacy and tolerability of treatment with doxorubicin is also desirable. A liposome-encapsulated form of the hydrochloride (HCl) salt of doxorubicin has also been developed. Liposomal delivery of doxorubicin HCl improves tumor drug penetration and reduces drug clearance, thereby increasing the duration of therapeutic efficacy. Liposomal formulations of doxorubicin also reduce toxicity, particularly cardiac effects, commonly seen with anthracycline antitumor drugs.

[0009] The U.S. Food and Drug Administration (FDA) has approved the combination of bevacizumab (an anti-VEGF antibody called AVASTIN® (GENENTECH, INC.)) with carboplatin and paclitaxel as a first-line treatment for advanced, recurrent non-squamous non-small cell lung cancer (NSCLC) (see Cohen et al., Oncologist 12:713-718 (2007)). The combination of carboplatin and paclitaxel (CP therapy) was previously the first-line treatment for NSCLC (Sandler et al., N. Engl. J. of Medicine 355:2542-2550 (2006)). However, while the addition of bevacizumab to CP therapy increased patient survival benefit, this triple combination (BV / CP) therapy increased treatment-related deaths and the incidence of both non-hematological and hematological adverse events (Cohen et al., supra, Tables 4-5). More recently, bevacizumab has also been approved in combination with chemotherapy agents for the treatment of cervical cancer, platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

[0010] There remains an unmet medical need for more effective therapies for the treatment of cancer, such as combination therapies that target FOLR1-expressing tumor cells. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Leung et al.,Clin.Biochem.46:1462-1468(2013) [Non-patent document 2] Weitman SD, et al., Cancer Res.52:3396-3401(1992) [Non-patent document 3] Antony AC,Ann.Rev.Nutr.16:501-521(1996) [Non-patent document 4] Kalli K R, et al., Gynecol. Oncol. 108:619 - 626(2008)

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Summary of the Invention

Means for Solving the Problems

[0012] Provided herein are combinations of anti-FOLR1 immunoconjugates (e.g., IMGN853) with anti-VEGF agents, platinum-based agents, and / or doxorubicin. Also provided herein are methods of treating patients with cancer using such combinations. As described in more detail below, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, platinum-based agent, and / or doxorubicin can provide synergistic efficacy against tumors. For example, the anti-VEGF agent, platinum-based agent, and / or doxorubicin can enhance the efficacy of the anti-FOLR1 immunoconjugate (e.g., IMGN853), and / or the anti-FOLR1 immunoconjugate (e.g., IMGN853) can enhance the efficacy of the anti-VEGF agent, platinum-based agent, and / or doxorubicin. By combining an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin, the combined effectiveness of these agents can be achieved even when using smaller and / or less frequent doses of the anti-FOLR1 immunoconjugate (e.g., IMGN853) and / or the anti-VEGF agent, platinum-based agent, and / or doxorubicin. Furthermore, the combination can produce less toxicity than either the anti-VEGF agent, platinum-based agent, and / or doxorubicin alone, the anti-FOLR1 immunoconjugate (e.g., IMGN853) alone, and / or the anti-VEGF agent, platinum-based agent, and / or doxorubicin or the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0013] In one example, a method for treating a patient with cancer includes administering to a patient in need thereof an immunoconjugate that binds to FOLR1, the immunoconjugate comprising a heavy chain variable region (VH) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 9, a VH CDR2 sequence of SEQ ID NO: 10, and a VH CDR3 sequence of SEQ ID NO: 12, and a light chain variable region (VL) CDR1 sequence of SEQ ID NO: 6, a VL CDR2 sequence of SEQ ID NO: 7, and a VL CDR3 sequence of SEQ ID NO: 8. The method includes administering the immune complex comprising an antibody or antigen-binding fragment thereof comprising the CDR2 sequence of SEQ ID NO: 8 and the VL CDR3 sequence of SEQ ID NO: 8, and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

[0014] In one example, a method for treating a patient with cancer includes administering to a patient in need thereof an immunoconjugate that binds to FOLR1, the immunoconjugate comprising an antibody or antigen-binding fragment thereof comprising the VH CDR1 sequence of SEQ ID NO: 19, the VH CDR2 sequence of SEQ ID NO: 11, and the VH CDR3 sequence of SEQ ID NO: 12, and a light chain variable region (VL) CDR1 sequence of SEQ ID NO: 6, the VL CDR2 sequence of SEQ ID NO: 7, and the VL CDR3 sequence of SEQ ID NO: 8; and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

[0015] In one example, the immunoconjugate (e.g., IMGN853) is administered in combination with an anti-VEGF agent (e.g., bevacizumab). In one example, the immunoconjugate (e.g., IMGN853) is administered in combination with a platinum-based agent. In one example, the immunoconjugate is administered in combination with doxorubicin.

[0016] In one example, the immunoconjugate (e.g., IMGN853) is administered in combination with an anti-VEGF agent and a platinum-based agent. In one example, the immunoconjugate (e.g., IMGN853) is administered in combination with an anti-VEGF agent and doxorubicin. In one example, the immunoconjugate (e.g., IMGN853) is administered in combination with a platinum-based agent and doxorubicin.

[0017] In one example, the immune complex that binds to FOLR1 comprises an antibody or antigen-binding fragment thereof comprising a VH comprising the sequence of SEQ ID NO: 3 and a VL comprising the sequence of SEQ ID NO: 5. In one example, the antibody or antigen-binding fragment is huMov19.

[0018] In one example, the immunoconjugate (e.g., IMGN853) includes a cytotoxin, and the cytotoxin is a maytansinoid. In one example, the maytansinoid is DM4.

[0019] In one example, the immunoconjugate (eg, IMGN853) includes a linker, and the linker is sulfo-SPDB.

[0020] In one example, the immune complex is IMGN853.

[0021] In one example, the administration is a first line therapy. In one example, the administration is a second line therapy. In one example, the administration is a third line therapy.

[0022] In one example, the immunoconjugate (eg, IMGN853) is administered intravenously or intraperitoneally.

[0023] In one example, administration of an immunoconjugate (eg, IMGN853) and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof produces a synergistic effect.

[0024] In one example, administration of an immunoconjugate (e.g., IMGN853) and an anti-VEGF agent produces no greater toxicity than administration of the immunoconjugate alone or the anti-VEGF agent alone. In one example, administration of an immunoconjugate (e.g., IMGN853) and a platinum-based agent produces no greater toxicity than administration of the immunoconjugate alone or the platinum-based agent alone. In one example, administration of an immunoconjugate (e.g., IMGN853) and doxorubicin produces no greater toxicity than administration of the immunoconjugate alone or doxorubicin alone. In one example, administration of an immunoconjugate (e.g., IMGN853), an anti-VEGF agent, and a platinum-based agent produces no greater toxicity than administration of taxol, an anti-VEGF agent, or a platinum-based agent, and the platinum-based agent is carboplatin or cisplatin.

[0025] In one example, the immunoconjugate (e.g., IMGN853) is administered once every three weeks or once every four weeks. In one example, the immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg adjusted ideal body weight (AIBW), at a dose of about 5 mg / kg AIBW, or at a dose of about 6 mg / kg AIBW.

[0026] In one example, the immunoconjugate (e.g., IMGN853) is administered once a week. In one example, the immunoconjugate (e.g., IMGN853) is administered at a dose of about 1.1 mg / kg AIBW, about 1.8 mg / kg AIBW, about 2.0 mg / kg AIBW, or about 2.5 mg / kg AIBW.

[0027] In one example, the immunoconjugate (e.g., IMGN853) is administered once every two weeks. In one example, the immunoconjugate (e.g., IMGN853) is administered at a dose of about 2.0 mg / kg AIBW, about 2.5 mg / kg AIBW, about 3.0 mg / kg AIBW, about 3.5 mg / kg AIBW, or about 4.0 mg / kg AIBW.

[0028] In one example, the anti-VEGF agent includes an antibody or antigen-binding fragment thereof that binds to VEGF or a VEGF receptor. In one example, the antibody or antigen-binding fragment thereof that binds to VEGF is bevacizumab. In one example, the antibody or antigen-binding fragment thereof that binds to VEGF is very similar to bevacizumab and does not have clinically meaningful differences in safety and efficacy compared to bevacizumab (e.g., ABP 215 (Amgen), BCD-021 (Biocad)).

[0029] In one example, the anti-VEGF agent comprises a tyrosine kinase inhibitor, hi one example, the tyrosine kinase inhibitor is selected from the group consisting of cediranib, pazopanib, axitinib, vatalanib, semaxanib, sunitinib, sorafenib, ramucirumab, and aflibercept.

[0030] In one example, the anti-VEGF agent comprises a soluble VEGF receptor. In one example, the soluble VEGF receptor is a VEGF-TRAP.

[0031] In one example, the anti-VEGF agent is administered once every three weeks or once every two weeks. In one example, the anti-VEGF agent is administered at a dose of about 15 mg / kg, about 10 mg / kg, or about 7.5 mg / kg.

[0032] In one example, bevacizumab is administered at a dose of 15 mg / kg every three weeks. In one example, bevacizumab is administered at a dose of 10 mg / kg every two weeks.

[0033] In one example, the platinum-based agent is carboplatin. In one example, the carboplatin is administered once every three weeks. In one example, the carboplatin is administered at a dose that achieves an area under the curve (AUC) of 4 mg / ml min, 5 mg / ml min, 6 mg / ml min, or 7 mg / ml min.

[0034] In one example, the platinum-based agent is cisplatin. In one example, cisplatin is administered every three weeks or once every four weeks. In one example, cisplatin is administered at a dose of about 50-70 mg / m, about 75-100 mg / m 2 , or about 100 mg / m 2 is administered at a dose of

[0035] In one example, the doxorubicin is pegylated doxorubicin, liposomal doxorubicin, or pegylated liposomal doxorubicin. In one example, the doxorubicin is administered once every four weeks. In one example, the doxorubicin is administered at a dose of 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m 2 , or 50 mg / m 2 is administered at a dose of

[0036] In one example, the anti-VEGF agent is bevacizumab, which is administered at a dose of 15 mg / kg every three weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 4 mg / kg AIBW every three weeks. In one example, the anti-VEGF agent is bevacizumab, which is administered at a dose of 15 mg / kg every three weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 5 mg / kg AIBW every three weeks. In one example, the anti-VEGF agent is bevacizumab, which is administered at a dose of 15 mg / kg every three weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 6 mg / kg AIBW every three weeks.

[0037] In one example, the anti-VEGF agent is bevacizumab, which is administered at a dose of 10 mg / kg every two weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 4 mg / kg AIBW every four weeks. In one example, the anti-VEGF agent is bevacizumab, which is administered at a dose of 10 mg / kg every two weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 5 mg / kg AIBW every four weeks. In one example, the anti-VEGF agent is bevacizumab, which is administered at a dose of 10 mg / kg every two weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 6 mg / kg AIBW every four weeks.

[0038] In one example, carboplatin is administered with bevacizumab and an immunoconjugate (e.g., IMGN853). In one example, carboplatin is administered once every three weeks. In one example, carboplatin is administered at a dose that achieves an area under the curve (AUC) of 4 mg / ml min, 5 mg / ml min, 6 mg / ml min, or 7 mg / ml min.

[0039] In one example, the platinum-based agent is carboplatin, which is administered once every 3 weeks to achieve an AUC of 4 mg / ml·min, and the immunoconjugate (e.g., IMGN853) is administered once every 3 weeks at a dose of 4 mg / kg AIBW.

[0040] In one example, the platinum-based agent is carboplatin, which is administered once every 3 weeks to achieve an AUC of 4 mg / ml·min, and the immunoconjugate (e.g., IMGN853) is administered once every 3 weeks at a dose of 5 mg / kg AIBW.

[0041] In one example, the platinum-based agent is carboplatin, which is administered once every 3 weeks to achieve an AUC of 5 mg / ml min, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 5 mg / kg AIBW once every 3 weeks.

[0042] In one example, the platinum-based agent is carboplatin, which is administered once every 3 weeks to achieve an AUC of 5 mg / ml·min, and the immunoconjugate (e.g., IMGN853) is administered once every 3 weeks at a dose of 6 mg / kg AIBW.

[0043] In one example, the doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is about 30 mg / m 2 once every four weeks at a dose of 4 mg / kg AIBW and the immunoconjugate (e.g., IMGN853) is administered once every four weeks at a dose of 4 mg / kg AIBW.

[0044] In one example, doxorubicin is PLD, and PLD is about 30 mg / m 2 once every four weeks at a dose of 0.1 mg / kg AIBW and the immunoconjugate (e.g., IMGN853) is administered once every four weeks at a dose of 5 mg / kg AIBW.

[0045] In one example, doxorubicin is PLD, and PLD is about 40 mg / m 2 once every four weeks at a dose of 0.1 mg / kg AIBW and the immunoconjugate (e.g., IMGN853) is administered once every four weeks at a dose of 5 mg / kg AIBW.

[0046] In one example, doxorubicin is PLD, and PLD is about 40 mg / m 2 once every four weeks at a dose of 0.1 mg / kg AIBW and the immunoconjugate (e.g., IMGN853) is administered once every four weeks at a dose of 6 mg / kg AIBW.

[0047] In one example, the cancer is ovarian, peritoneal, fallopian tube, endometrial, or lung cancer.

[0048] In one example, the cancer is ovarian cancer. In one example, the ovarian cancer is epithelial ovarian cancer. In one example, the ovarian cancer is platinum-resistant, recurrent, or refractory.

[0049] In one example, the cancer is platinum-refractory. In one example, the cancer is primary platinum-refractory. In one example, the cancer is platinum-sensitive.

[0050] In one example, the cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0051] In one example, the cancer is ovarian cancer, and the administration results in a reduction of CA125. In one example, the peritoneal cancer is primary peritoneal cancer. In one example, the endometrial cancer is serous endometrial cancer. In one example, the lung cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), adenocarcinoma, and bronchioloalveolar carcinoma.

[0052] In one example, the cancer has been previously treated with bevacuzimab. In one example, the cancer has not been previously treated with bevacuzimab (i.e., the patient is "bevacuzimab naive").

[0053] In one example, the cancer is metastatic or advanced.

[0054] In one example, the cancer expresses FOLR1. In one example, FOLR1 expression is measured by immunohistochemistry (IHC). In one example, the IHC has a staining score of at least 1 heterogeneous, at least 1 homogeneous, at least 2 heterogeneous, at least 2 homogeneous, or at least 3 heterogeneous. In one example, at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of the cells in a sample obtained from a patient have an IHC staining score of at least 2 (moderate). In one example, at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of the cells in a sample obtained from a patient have an IHC staining score of at least 3.

[0055] In one example, the method further includes administering a steroid to the patient. In one example, the steroid is dexamethasone. In one example, the steroid is administered in eye drops. In one example, the eye drops are preservative-free lubricating eye drops.

[0056] In one example, the immunoconjugate (eg, IMGN853) and the anti-VEGF agent, platinum-based agent, doxorubicin, or combination thereof are administered in separate pharmaceutical compositions.

[0057] A kit is also provided herein. In one example, the kit includes an immunoconjugate that binds to FOLR1, the immunoconjugate comprising an antibody or antigen-binding fragment thereof comprising the VH CDR1 sequence of SEQ ID NO: 9, the VH CDR2 sequence of SEQ ID NO: 10, and the VH CDR3 sequence of SEQ ID NO: 12, and the VL CDR1 sequence of SEQ ID NO: 6, the VL CDR2 sequence of SEQ ID NO: 7, and the VL CDR3 sequence of SEQ ID NO: 8; an anti-VEGF agent, a platinum-based agent, or doxorubicin; and instructions for administering the immunoconjugate with the anti-VEGF agent, platinum-based agent, or doxorubicin. In one example, the anti-VEGF agent is an anti-VEGF antibody. In one example, the anti-VEGF antibody is bevacizumab. In one example, the anti-VEGF agent is a tyrosine kinase inhibitor. In one example, the tyrosine kinase inhibitor is selected from the group consisting of cediranib, pazopanib, axitinib, vatalanib, semaxanib, sunitinib, sorafenib, ramucirumab, and aflibercept. In one example, the anti-VEGF agent is a soluble VEGF receptor. In one example, the soluble VEGF receptor is VEGF-TRAP. In one example, the platinum-based agent is carboplatin or cisplatin. In one example, the doxorubicin is pegylated liposomal doxorubicin. In one example, the immunoconjugate is IMGN853.

[0058] Also provided herein are methods of administering instructions to a human subject with cancer. In one example, the method includes providing instructions for administering to a human subject with cancer treatment using an immunoconjugate that binds to FOLR1 (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof. In one example, the anti-VEGF agent is an anti-VEGF antibody. In one example, the anti-VEGF antibody is bevacizumab. In one example, the anti-VEGF agent is a tyrosine kinase inhibitor. In one example, the tyrosine kinase inhibitor is selected from the group consisting of cediranib, pazopanib, axitinib, vatalanib, semaxanib, sunitinib, sorafenib, ramucirumab, and aflibercept. In one example, the anti-VEGF agent is a soluble VEGF receptor. In one example, the soluble VEGF receptor is VEGF-TRAP. In one example, the platinum-based agent is carboplatin or cisplatin. In one example, the doxorubicin is pegylated liposomal doxorubicin. In one example, the immunoconjugate is IMGN853. The present invention provides, for example, the following items. (Item 1) 1. A method for treating a patient having cancer, comprising administering to said patient in need thereof: an immune complex that binds to folate receptor 1 (FOLR1), the immune complex comprising an antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) complementarity-determining region (CDR) 1 sequence of SEQ ID NO: 9, a VH CDR2 sequence of SEQ ID NO: 10, and a VH CDR3 sequence of SEQ ID NO: 12, and a light chain variable region (VL) CDR1 sequence of SEQ ID NO: 6, a VL CDR2 sequence of SEQ ID NO: 7, and a VL CDR3 sequence of SEQ ID NO: 8; The method comprises administering an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof. (Item 2) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the anti-VEGF agent. (Item 3) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the platinum-based drug. (Item 4) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the doxorubicin. (Item 5) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the anti-VEGF agent and the platinum-based agent. (Item 6) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the anti-VEGF agent and the doxorubicin. (Item 7) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the platinum-based drug and the doxorubicin. (Item 8) 8. The method according to any one of items 1 to 7, wherein the immune complex that binds to FOLR1 comprises an antibody or an antigen-binding fragment thereof comprising a VH comprising the sequence of SEQ ID NO: 3 and a VL comprising the sequence of SEQ ID NO: 5. (Item 9) 9. The method of claim 8, wherein the antibody or antigen-binding fragment is huMov19. (Item 10) 10. The method of any one of items 1 to 9, wherein the immunoconjugate comprises a cytotoxin, and the cytotoxin is a maytansinoid. (Item 11) 11. The method of claim 10, wherein the maytansinoid is DM4. (Item 12) 12. The method according to any one of items 1 to 11, wherein the immunoconjugate comprises a linker, and the linker is sulfo-SPDB. (Item 13) 13. The method of any one of items 1 to 12, wherein the immune complex is IMGN853. (Item 14) 14. The method of any one of items 1 to 13, wherein said administration is a first-line therapy. (Item 15) 15. The method of any one of items 1 to 14, wherein the immunoconjugate is administered intravenously or intraperitoneally. (Item 16) 16. The method of any one of items 1 to 15, wherein administration of the immunoconjugate with the anti-VEGF agent, the platinum-based agent, the doxorubicin, or a combination thereof produces a synergistic effect. (Item 17) 17. The method of any one of items 1, 2, 5, 6, and 8 to 16, wherein administration of the immunoconjugate and the anti-VEGF agent does not produce greater toxicity than administration of the immunoconjugate alone or the anti-VEGF agent alone. (Item 18) 17. The method of any one of items 1, 3, 5, and 8-16, wherein administration of the immunoconjugate and the platinum-based drug does not produce greater toxicity than administration of the immunoconjugate alone or the platinum-based drug alone. (Item 19) 17. The method of any one of items 1, 4, and 6-16, wherein administration of the immunoconjugate and the doxorubicin does not produce greater toxicity than administration of the immunoconjugate alone or the doxorubicin alone. (Item 20) 17. The method of any one of Items 5 and 8 to 16, wherein administration of the immunoconjugate, the anti-VEGF agent, and the platinum-based agent does not produce greater toxicity than administration of taxol, the anti-VEGF agent, and / or the platinum-based agent, and the platinum-based agent is carboplatin or cisplatin. (Item 21) 21. The method of any one of items 1 to 20, wherein the immunoconjugate is administered once every three weeks or once every four weeks. (Item 22) 22. The method of any one of items 1 to 21, wherein the immunoconjugate is administered at a dose of about 4 mg / kg adjusted ideal body weight (AIBW), at a dose of about 5 mg / kg AIBW, or at a dose of about 6 mg / kg AIBW. (Item 23) The method according to any one of items 1 to 20, wherein the immunoconjugate is administered once a week. 24. The method of any one of items 1 to 20 and 23, wherein the immunoconjugate is administered at a dose of about 1.1 mg / kg AIBW, about 1.8 mg / kg AIBW, about 2.0 mg / kg AIBW, or about 2.5 mg / kg AIBW. (Item 25) 21. The method of any one of items 1 to 20, wherein the immunoconjugate is administered once every two weeks. (Item 26) 26. The method of any one of items 1 to 20 and 25, wherein the immunoconjugate is administered at a dose of about 2.0 mg / kg AIBW, about 2.5 mg / kg AIBW, about 3.0 mg / kg AIBW, about 3.5 mg / kg AIBW, or about 4.0 mg / kg AIBW. (Item 27) 27. The method of any one of items 1, 2, 5, 6, 8-17, and 20-26, wherein the anti-VEGF agent comprises an antibody or antigen-binding fragment thereof that binds to VEGF or a VEGF receptor. (Item 28) 28. The method of claim 27, wherein the antibody or antigen-binding fragment thereof that binds to VEGF is bevacizumab. (Item 29) 27. The method of any one of items 1, 2, 5, 6, 8-17, and 20-26, wherein the anti-VEGF agent comprises a tyrosine kinase inhibitor. (Item 30) 30. The method of item 29, wherein the tyrosine kinase inhibitor is selected from the group consisting of cediranib, pazopanib, axitinib, vatalanib, semaxanib, sunitinib, sorafenib, ramucirumab, and aflibercept. (Item 31) 27. The method of any one of items 1, 2, 5, 6, 8 to 17, and 20 to 26, wherein the anti-VEGF agent comprises a soluble VEGF receptor. (Item 32) 32. The method of claim 31, wherein the soluble VEGF receptor is VEGF-TRAP. (Item 33) 34. The method of any one of items 1, 2, 5, 6, 8-17, and 20-33, wherein the anti-VEGF agent is administered once every three weeks or once every four weeks. (Item 34) 35. The method of any one of items 1, 2, 5, 6, 8-17, and 20-34, wherein the anti-VEGF agent is administered at a dose of about 15 mg / kg, about 10 mg / kg, or about 7.5 mg / kg. (Item 35) 29. The method of item 28, wherein the bevacizumab is administered at a dose of 15 mg / kg once every three weeks. (Item 36) 29. The method of item 28, wherein the bevacizumab is administered at a dose of 10 mg / kg once every two weeks. (Item 37) 37. The method of any one of items 1, 3, 5, 7-16, 18, and 20-36, wherein the platinum-based drug is carboplatin. (Item 38) 38. The method of item 37, wherein the carboplatin is administered once every three weeks. (Item 39) 39. The method of item 37 or 38, wherein the carboplatin is administered at a dose to obtain an area under the curve (AUC) of 4 mg / ml min, 5 mg / ml min, 6 mg / ml min, or 7 mg / ml min. (Item 40) 37. The method of any one of items 1, 3, 5, 7 to 16, 18, and 20 to 36, wherein the platinum-based drug is cisplatin. (Item 41) 41. The method of item 40, wherein cisplatin is administered every three weeks or once every four weeks. (Item 42) The cisplatin is about 50 to 70 mg / m2, about 75 to 100 mg / m 2 , or about 100 mg / m 2 42. The method of claim 40 or 41, wherein the dose is (Item 43) 43. The method of any one of items 1, 4, 6-16, 19, and 21-42, wherein the doxorubicin is pegylated doxorubicin, liposomal doxorubicin, or pegylated liposomal doxorubicin. (Item 44) 44. The method of any one of items 1, 4, 6-16, 19, and 21-43, wherein the doxorubicin is administered once every four weeks. (Item 45) The doxorubicin is 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m2 , or 50 mg / m 2 45. The method of any one of items 1, 4, 6-16, 19, and 21-44, wherein the dose is (Item 46) 21. The method of any one of items 1, 2, 5, 6, and 8-20, wherein the anti-VEGF agent is bevacizumab, the bevacizumab is administered at a dose of 15 mg / kg once every three weeks, and the immunoconjugate is administered at a dose of 4 mg / kg AIBW once every three weeks. (Item 47) 21. The method of any one of items 1, 2, 5, 6, and 8-20, wherein the anti-VEGF agent is bevacizumab, the bevacizumab is administered at a dose of 15 mg / kg once every three weeks, and the immunoconjugate is administered at a dose of 5 mg / kg AIBW once every three weeks. (Item 48) 21. The method of any one of items 1, 2, 5, 6, and 8-20, wherein the anti-VEGF agent is bevacizumab, the bevacizumab is administered at a dose of 15 mg / kg once every three weeks, and the immunoconjugate is administered at a dose of 6 mg / kg AIBW once every three weeks. (Item 49) 21. The method of any one of items 1, 2, 5, 6, and 8-20, wherein the anti-VEGF agent is bevacizumab, the bevacizumab is administered at a dose of 10 mg / kg once every two weeks, and the immunoconjugate is administered at a dose of 4 mg / kg AIBW once every four weeks. (Item 50) 21. The method of any one of items 1, 2, 5, 6, and 8-20, wherein the anti-VEGF agent is bevacizumab, the bevacizumab is administered at a dose of 10 mg / kg once every two weeks, and the immunoconjugate is administered at a dose of 5 mg / kg AIBW once every four weeks. (Item 51) 21. The method of any one of items 1, 2, 5, 6, and 8-20, wherein the anti-VEGF agent is bevacizumab, the bevacizumab is administered at a dose of 10 mg / kg once every two weeks, and the immunoconjugate is administered at a dose of 6 mg / kg AIBW once every four weeks. (Item 52) 51. The method of any one of items 46 to 50, wherein carboplatin is administered. (Item 53) 53. The method of item 52, wherein the carboplatin is administered once every three weeks. (Item 54) 54. The method of item 52 or 53, wherein the carboplatin is administered at a dose to obtain an area under the curve (AUC) of 4 mg / ml min, 5 mg / ml min, 6 mg / ml min, or 7 mg / ml min. (Item 55) 21. The method of any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based agent is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 4 mg / ml min, and the immunoconjugate is administered at a dose of 4 mg / kg AIBW once every three weeks. (Item 56) 21. The method of any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based agent is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 4 mg / ml min, and the immunoconjugate is administered at a dose of 5 mg / kg AIBW once every three weeks. (Item 57) 21. The method of any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based agent is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 5 mg / ml min, and the immunoconjugate is administered at a dose of 5 mg / kg AIBW once every three weeks. (Item 58) 21. The method of any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based agent is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 5 mg / ml min, and the immunoconjugate is administered at a dose of 6 mg / kg AIBW once every three weeks. (Item 59) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is about 30 mg / m 2 once every four weeks at a dose of 4 mg / kg 20. The method of any one of items 1, 4, 6-16, and 19, wherein the compound is administered once every four weeks at a dose of AIBW. (Item 60) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is about 30 mg / m 2 once every four weeks at a dose of 5 mg / kg 20. The method of any one of items 1, 4, 6-16, and 19, wherein the compound is administered once every four weeks at a dose of AIBW. (Item 61) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is about 40 mg / m 2 20. The method of any one of items 1, 4, 6-16, and 19, wherein the immunoconjugate is administered at a dose of 5 mg / kg AIBW once every 4 weeks. (Item 62) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is about 40 mg / m 2 once every four weeks at a dose of 6 mg / kg 20. The method of any one of items 1, 4, 6-16, and 19, wherein the compound is administered once every four weeks at a dose of AIBW. (Item 63) 63. The method of any one of items 1 to 62, wherein the cancer is ovarian, peritoneal, fallopian tube, endometrial, or lung cancer. (Item 64) Item 64. The method of item 63, wherein the cancer is ovarian cancer. (Item 65) Item 65. The method of item 64, wherein the ovarian cancer is epithelial ovarian cancer. (Item 66) 66. The method of item 64 or 65, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. (Item 67) 67. The method of any one of items 64 to 66, wherein the administration results in a reduction of CA125. (Item 68) Item 64. The method of item 63, wherein the peritoneal cancer is primary peritoneal cancer. (Item 69) Item 64. The method of item 63, wherein the endometrial cancer is serous endometrial cancer. (Item 70) Item 64. The method of item 63, wherein the lung cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), adenocarcinoma, and bronchioloalveolar carcinoma. (Item 71) 71. The method of any one of items 1 to 70, wherein the cancer expresses FOLR1. (Item 72) 72. The method of claim 71, wherein the FOLR1 expression is measured by immunohistochemistry (IHC). (Item 73) Item 74. The method of item 71, wherein the IHC has a staining score of at least 1 heterogeneity, at least 1 homogeneity, at least 2 heterogeneity, at least 2 homogeneity, or at least 3 heterogeneity. 72. The method of item 71, wherein at least 25%, at least 50%, or at least 75% of cells in a sample obtained from the patient have an immunohistochemistry (IHC) score of at least 2. (Item 75) 72. The method of item 71, wherein at least 25%, at least 50%, or at least 75% of cells in a sample obtained from the patient have an immunohistochemistry (IHC) score of at least 3. (Item 76) 76. The method of any one of items 1 to 75, further comprising administering a steroid to the patient. (Item 77) 77. The method of claim 76, wherein the steroid is dexamethasone. (Item 78) 78. The method of any one of items 1 to 77, wherein the immunoconjugate and the anti-VEGF agent, platinum-based agent, doxorubicin, or combination thereof are administered in separate pharmaceutical compositions. (Item 79) 79. The method of any one of items 1 to 13 and 15 to 78, wherein the cancer has been previously treated with bevacuzimab. (Item 80) 79. The method of any one of items 1 to 78, wherein the cancer has not been previously treated with bevacuzimab. (Item 81) 81. The method of any one of items 1 to 80, wherein the cancer is primary platinum-refractory. (Item 82) 81. The method of any one of items 1 to 80, wherein the cancer is platinum-resistant. (Item 83) 81. The method of any one of items 1 to 65 and 67 to 80, wherein the cancer is platinum-sensitive. (Item 84) 84. The method of any one of items 1 to 83, wherein the cancer is metastatic or advanced. (Item 85) 85. The method of any one of items 1 to 13 and 15 to 84, wherein the administration is a second line therapy. (Item 86) 85. The method of any one of items 1 to 13 and 15 to 84, wherein said administering is a third line therapy. (Item 87) 72. The method of item 71, wherein at least 33% or at least 66% of cells in a sample obtained from the patient have an immunohistochemistry (IHC) score of at least 2. (Item 88) 72. The method of item 71, wherein 33% or at least 66% of cells in a sample obtained from the patient have an immunohistochemistry (IHC) score of at least 3. (Item 89) An immune complex that binds to FOLR1, comprising an antibody or antigen-binding fragment thereof comprising the VH CDR1 sequence of SEQ ID NO: 9, the VH CDR2 sequence of SEQ ID NO: 10, and the VH CDR3 sequence of SEQ ID NO: 12, and the VL CDR1 sequence of SEQ ID NO: 6, the VL CDR2 sequence of SEQ ID NO: 7, and the VL CDR3 sequence of SEQ ID NO: 8; and anti-VEGF agents, platinum-based agents, or doxorubicin; and A kit comprising instructions for administering the immunoconjugate with the anti-VEGF agent, the platinum-based agent, or doxorubicin. (Item 90) A method of providing instructions to a human subject having cancer, the method comprising providing instructions to the subject to receive cancer treatment using an immunoconjugate that binds to FOLR1 and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof. (Item 91) 91. The kit or method of item 89 or 90, wherein the anti-VEGF agent is an anti-VEGF antibody. (Item 92) 92. The kit or method of item 91, wherein the anti-VEGF antibody is bevacizumab. (Item 93) 91. The kit or method of item 89 or 90, wherein the anti-VEGF agent is a tyrosine kinase inhibitor. (Item 94) 94. The kit or method of item 93, wherein the tyrosine kinase inhibitor is selected from the group consisting of cediranib, pazopanib, axitinib, vatalanib, semaxanib, sunitinib, sorafenib, ramucirumab, and aflibercept. (Item 95) 91. The kit or method of item 89 or 90, wherein the anti-VEGF agent is a soluble VEGF receptor. (Item 96) Item 96. The kit or method of Item 95, wherein the soluble VEGF receptor is VEGF-TRAP. (Item 97) 97. The kit or method of any one of items 89 to 96, wherein the platinum-based drug is carboplatin or cisplatin. (Item 98) 98. The kit or method of any one of items 89 to 97, wherein the doxorubicin is pegylated liposomal doxorubicin. (Item 99) 99. The kit or method of any one of items 89 to 98, wherein the immune complex is IMGN853. (Item 100) 2. The method of claim 1, wherein the immunoconjugate is IMGN853 and is administered at a dose of 6 mg / kg AIBW once every three weeks, and the anti-VEGF agent is bevacizumab and is administered at a dose of 15 mg / kg once every three weeks. (Item 101) 2. The method of claim 1, wherein the immunoconjugate is IMGN853 and is administered at a dose of 6 mg / kg AIBW once every three weeks, and the anti-VEGF agent is bevacizumab and is administered at a dose of 10 mg / kg twice every four weeks. (Item 102) 2. The method of claim 1, wherein the immunoconjugate is IMGN853 and is administered at a dose of 6 mg / kg AIBW once every 3 weeks, and the platinum-based agent is carboplatin and is administered to obtain an AUC of 5 mg / ml min once every 3 weeks. (Item 103) 2. The method of claim 1, wherein the immunoconjugate is IMGN853 and is administered at a dose of 6 mg / kg AIBW once every 3 weeks, and the platinum-based agent is carboplatin and is administered to obtain an AUC of 6 mg / ml min once every 3 weeks. (Item 104) the immunoconjugate is IMGN853, the immunoconjugate is administered at a dose of 6 mg / kg AIBW once every four weeks, the doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is administered at a dose of 40 mg / m 2 10. The method of claim 1, wherein the compound is administered once every four weeks at a dose of [Brief explanation of the drawings]

[0059] [Figure 1] 1 shows the antitumor activity of IMGN853 (5 mg / kg), pegylated liposomal doxorubicin (PLD) (4 mg / kg), and IMGN853+PLD combination therapy in an epithelial ovarian cancer tumor model. [Figure 2A]1 shows the antitumor activity of IMGN853 (5 mg / kg), bevacizumab (5 mg / kg), and IMGN853 + bevacizumab combination therapy in a serous ovarian cancer tumor model. [Figure 2B] 1 shows the antitumor activity of IMGN853 (2.5 mg / kg), bevacizumab (5 mg / kg), and IMGN853 + bevacizumab combination therapy in a serous ovarian cancer tumor model. [Figure 3] 1 shows the antitumor activity of IMGN853 (1.25 mg / kg), paclitaxel (10 mg / kg), bevacizumab (5 mg / kg), IMGN853 + bevacizumab combination therapy, and paclitaxel + bevacizumab combination therapy in a serous ovarian cancer tumor model. [Figure 4] 1 shows the antitumor activity of IMGN853 (5 mg / kg), bevacizumab (5 mg / kg), and IMGN853 + bevacizumab combination therapy in an epithelial ovarian cancer tumor model. [Figure 5] 1 shows the antitumor activity of IMGN853 (5 mg / kg), paclitaxel (10 mg / kg), bevacizumab (5 mg / kg), paclitaxel + bevacizumab combination therapy, and IMGN853 + bevacizumab combination therapy in an epithelial ovarian cancer tumor model. [Figure 6] 1 shows the antitumor activity of IMGN853 (3 mg / kg), IMGN853 (1.5 mg / kg), bevacizumab (5 mg / kg), IMGN853 (3 mg / kg) + bevacizumab combination therapy, and IMGN853 (1.5 mg / kg) + bevacizumab combination therapy in a non-small cell lung cancer tumor model. [Figure 7] The antitumor activity of IMGN853 (5 mg / kg) + carboplatin (100 mg / kg) combination therapy, IMGN853 (5 mg / kg) + carboplatin (100 mg / kg) + bevacizumab (5 mg / kg) triple combination therapy, paclitaxel (10 mg / kg) + carboplatin (100 mg / kg) combination therapy, and paclitaxel (100 mg / kg) + carboplatin (100 mg / kg) + bevacizumab (5 mg / kg) triple combination therapy is shown in a non-small cell lung cancer tumor model. [Figure 8]1 shows the antitumor activity of IMGN853 (2.5 mg / kg), cediranib (1.5 mg / kg), and IMGN853 + cediranib combination therapy in a serous ovarian cancer tumor model. [Figure 9A] IGROV-1 cells were treated with graded concentrations of IMGN853, carboplatin, or both and their effects on proliferation are shown. Combination index (CI) was calculated using median effect analysis. Data from two independent experiments are shown, determined for a range of drug concentrations, with effect ratios (Fa) ranging from 0.4 to 0.7. Data points below the dotted line represent synergistic effects between drug pairs. [Figure 9B] IGROV-1 cells were treated with carboplatin (20 μM) or IMGN853 (8 nM), both alone and in combination, for 6 hours. Cells were washed and cell cycle distribution was determined after 24 hours of culture in drug-free medium. [Figure 9C] IGROV-1 cells were exposed to carboplatin (40 μM) or IMGN853 (16 nM), alone or in combination, for 6 hours and incubated in drug-free medium for an additional 18 hours. Cell extracts were immunoblotted for γH2AX or actin (loading control) as indicated. [Figure 9D] Figure 1 shows the antitumor activity of IMGN853 (2.5 mg / kg) or carboplatin (80 mg / kg), alone and in combination (n=7 mice / group), in platinum-sensitive ovarian cancer patient-derived xenografts (PDX) established in SCID mice. Data are presented as the mean and standard error of the mean (SEM) for each time point. [Figure 9E] Antitumor activity of two consecutive, weekly doses of vehicle, carboplatin (80 mg / kg, i.p.) plus paclitaxel (10 mg / kg), carboplatin plus PLD (4 mg / kg), or carboplatin plus IMGN853 (5 mg / kg) in mice bearing platinum-sensitive PDX tumors (n=7 mice / group) is shown. [Figure 10A]IGROV-1 cells were treated with increasing concentrations of IMGN853, doxorubicin, or both, and their effect on proliferation is shown. Combination coefficients (CI) were calculated using median effect analysis. Data from three independent experiments are shown, and data points below the dotted line represent synergistic effects between drug pairs. [Figure 10B] IGROV-1 cells were treated with doxorubicin (200 nM) or IMGN853 (8 nM), both alone and in combination, for 6 hours. Cells were washed and cell cycle distribution was determined after 24 hours of culture in drug-free medium. [Figure 10C] Figure 1 shows the antitumor activity of two consecutive weekly doses of IMGN853 (5 mg / kg) and PLD (4 mg / kg) alone or in combination (n=8 mice / group) in established platinum-resistant ovarian cancer PDXs in SCID mice. Data are presented as mean and SEM for each time point. [Figure 10D] Mouse body weights measured twice weekly are shown and mean values ​​are plotted relative to vehicle control. [Figure 11A] Figure 1 shows the antitumor activity of IMGN853 (3 mg / kg) alone or in combination with bevacizumab, administered as a single 5 mg / kg dose or two consecutive weekly doses of 2.5 mg / kg (QW x 2), in mice bearing established OV-90 xenografts (n = 7 mice / group). [Figure 11B] Figure 1 shows tumor volumes measured at the end of the study in mice bearing platinum-resistant ovarian cancer PDXs receiving two consecutive weekly doses of bevacizumab (5 mg / kg), alone or in combination with either paclitaxel (10 mg / kg) or IMGN853 (5 mg / kg), and individual tumor sizes plotted according to treatment group. Tumor growth was monitored for up to 102 days. *P=0.011; **P<0.018; ns, not significant (Wilcoxon test, unadjusted). [Figure 12A]OV-90 tumor-bearing mice were treated with a single dose of vehicle, IMGN853 (2.5 mg / kg), bevacizumab (5 mg / kg), or IMGN853 plus bevacizumab, and tumors were harvested 4 days later. Histological staining (H&E) revealed the presence of a large, central necrotic area in tumors from combination-treated mice. Original magnification, 4x; scale bar, 2 mm (600 μm for combination panels). [Figure 12B] Tumor extracts immunoblotted for γH2AX or actin (loading control) as indicated are shown. [Figure 12C] Immunohistochemical evaluation of CD31 expression (upper panel) and maytansine detection (anti-MAY; lower panel) in tumor tissues on day 4. Representative photomicrographs from one of three tumors are shown for each group. Original magnification, 20x; scale bar, 200 μm. DETAILED DESCRIPTION OF THE INVENTION

[0060] The present invention provides combinations of anti-FOLR1 immunoconjugates with anti-VEGF agents, platinum-based agents, doxorubicin, or combinations thereof, and uses of the combinations in the treatment of cancer.

[0061] I. Definition To facilitate the understanding of the present invention, several terms and phrases are defined below.

[0062] As used herein, the term "FOLR1" refers to any native human FOLR1 polypeptide unless otherwise specified. FOLR1 is also referred to as "human folate receptor 1," "folate receptor alpha (FR-α)," and "FRα." The term "FOLR1" encompasses "full-length," unprocessed FOLR1 polypeptides, as well as any form of FOLR1 polypeptide resulting from intracellular processing. The term also encompasses naturally occurring variants of FOLR1, such as those encoded by splice variants and allelic variants. The FOLR1 polypeptides described herein can be isolated from various sources, such as human tissue types or other sources, or prepared by recombinant or synthetic methods. When specifically indicated, "FOLR1" can be used to refer to a nucleic acid encoding a FOLR1 polypeptide. Human FOLR1 sequences are known and include, for example, the sequence published in UniProtKB Accession No. P15328 (including isoforms). As used herein, the term "human FOLR1" refers to FOLR1 comprising the sequence of SEQ ID NO: 1.

[0063] The term "VEGF," as used herein, unless otherwise specified, refers to any native human VEGF polypeptide. VEGF is also referred to as vascular endothelial growth factor-A, VEGF-A, vascular permeability factor, and VPF. The term "VEGF" encompasses "full-length," unprocessed VEGF polypeptides, as well as any form of VEGF polypeptide resulting from intracellular processing. The term also encompasses naturally occurring variants of VEGF, such as those encoded by splice variants and allelic variants. The VEGF polypeptides described herein can be isolated from a variety of sources, such as human tissue types or other sources, or prepared by recombinant or synthetic methods. When specifically indicated, "VEGF" can be used to refer to a nucleic acid encoding a VEGF polypeptide. Human VEGF sequences are known and include, for example, the sequence published in UniProtKB Accession No. P15692 (including isoforms).

[0064] The term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target, e.g., a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of the foregoing, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing an antibody, and any other modified immunoglobulin molecule so long as the antibody exhibits the desired biological activity. Antibodies can be of any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) based on the identity of their heavy chain constant domains, designated alpha, delta, epsilon, gamma, and mu, respectively. Different classes of immunoglobulins have distinct and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.

[0065] The term "antibody fragment" refers to a portion of an intact antibody. An "antigen-binding fragment" refers to a portion of an intact antibody that binds to an antigen. An antigen-binding fragment can contain the antigen-determining variable regions of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single-chain antibodies.

[0066] A "blocking" or "antagonizing" antibody is one that inhibits or reduces the biological activity of the antigen to which it binds, such as FOLR1 or VEGF. In some embodiments, a blocking or antagonistic antibody substantially or completely inhibits the biological activity of the antigen. Biological activity can be reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0067] The terms "anti-FOLR1 antibody" or "antibody that binds to FOLR1" refer to an antibody that can bind to FOLR1 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting FOLR1 (e.g., the huMov19(M9346A) antibody). The extent of binding of an anti-FOLR1 antibody to an unrelated, non-FOLR1 protein may be less than about 10% of the binding of the antibody to FOLR1, as measured, for example, by radioimmunoassay (RIA).

[0068] The term "anti-VEGF agent" refers to an agent capable of inhibiting the VEGF pathway. Anti-VEGF agents include, for example, anti-VEGF antibodies (e.g., bevacizumab, ABP 215 (Amgen), BCD-021 (Biocad), etc.) or anti-VEGFR antibodies (e.g., ramucirumab), tyrosine kinase inhibitors (TKIs) (e.g., cediranib or RECENTIN® (IPR Pharmaceuticals Inc.), see Nikolinakos et al., J. Thoracic Oncology 3(6) Suppl. 2:S131-S134 (2008)), and soluble VEGF receptors (e.g., VEGF-Trap; see, for example, Holash et al., PNAS 99(17)11393-11398 (2002)).

[0069] The term "anti-VEGF antibody" or "antibody that binds to VEGF" refers to an antibody that can bind to VEGF with sufficient affinity so that the antibody is useful as a therapeutic agent in targeting VEGF (e.g., bevacizumab). The extent of binding of an anti-VEGF antibody to an unrelated, non-VEGF protein may be less than about 10% of the binding of the antibody to VEGF, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to VEGF has a dissociation constant (Kd) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. In certain embodiments, the antibody or antigen-binding fragment thereof that binds to VEGF is bevacizumab. In certain embodiments, the antibody or antigen-binding fragment thereof that binds to VEGF is closely similar to bevacizumab and does not have clinically meaningful differences in safety and efficacy compared to bevacizumab (e.g., ABP 215 (Amgen), BCD-021 (Biocad)).

[0070] The term "bevacizumab" refers to a specific anti-VEGF antibody. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that contains antigen-binding complementarity-determining regions derived from the murine anti-VEGF monoclonal antibody A.4.6.1 (see Presta et al., Cancer Res. 57:4593-4599 (1997); U.S. Patent No. 6,054,297; U.S. Patent No. 7,365,166; U.S. Patent No. 7,622,115; U.S. Patent No. 8,778,340). Bevacizumab is the active ingredient in Avastin® (Genentech, Inc.) (ibid.).

[0071] The term "paclitaxel" or "PAC" refers to the compound associated with CAS Registry Number 33069-62-4. Paclitaxel is the active ingredient in TAXOL® (Bristol-Myers Squibb Company), Onxol, and ABRAXANE® (Abraxis Bioscience, LLC). Paclitaxel is believed to be a mitotic inhibitor chemotherapeutic agent that binds to tubulin and inhibits microtubule disassembly, preventing cell division and inducing apoptosis.

[0072] The term "platinum-based agent" refers to a platinum-based chemotherapy agent. Platinum-based agents include cisplatin, carboplatin, and oxaliplatin.

[0073] The term "cisplatin" refers to the compound related to CAS Registry Number 15663-27-1. Cisplatin is the active ingredient in PLATINOL® (Bristol-Myers Company), and cisplatin is also referred to as "cisplatinum." Cisplatin is believed to be a platinum-containing alkylating chemotherapy agent that binds to nucleophilic groups in DNA, causing intrastrand and interstrand DNA crosslinks, as well as DNA-protein crosslinks, which lead to apoptosis and cell growth inhibition.

[0074] The term "carboplatin" or "carbo" refers to a compound related to CAS Registry Number 41575-94-4. Carboplatin is the active ingredient in PARAPLATIN® (Bristol-Myers Squibb Co., Corp.). Carboplatin contains a platinum atom complexed with two ammonium groups and a cyclobutane-dicarboxyl residue. The drug is activated intracellularly to form a reactive platinum complex that binds to nucleophilic groups, such as GC-rich sites in DNA, thereby inducing intra- and interstrand DNA crosslinks and DNA-protein crosslinks. These carboplatin-induced DNA and protein effects result in apoptosis and cell growth inhibition. The drug has tumoricidal activity similar to that of its parent compound, cisplatin, but is more stable and less toxic.

[0075] The term "doxorubicin" refers to the compound associated with CAS Registry Number 23214-92-8. Doxorubicin is also referred to as "hydroxydaunorubicin" or "doxorubicin hydrochloride." Doxorubicin is the active ingredient in Adriamycin and Rubex. Liposomal doxorubicin (i.e., doxorubicin encapsulated in lipid spheres or liposomes) is the active ingredient in MYOCET® (Cephalon UK, Ltd.). Pegylated liposomal doxorubicin (PLD) (liposomal doxorubicin with a polyethylene glycol polymer attached) is the active ingredient in DOXIL® (Liposom Technology, Inc.) and Caelyx® (Janssen). Doxorubicin is believed to be an anthracycline antibiotic chemotherapy agent that intercalates between base pairs in the DNA helix, preventing DNA replication. In addition, doxorubicin inhibits topoisomerase II, which leads to increased and stabilized cleavable enzyme-DNA binding complexes during DNA replication, subsequently preventing ligation of nucleotide strands after double-strand breaks. Doxorubicin also forms oxygen free radicals, which cause cytotoxicity following lipid peroxidation of cell membrane lipids.

[0076] The term "treatment option" or "therapy option" refers to a therapeutic regimen that may include, but is not limited to, surgery, radiation therapy, chemotherapy, differentiation therapy, biological therapy, immunotherapy, or administration of one or more anti-cancer agents (e.g., cytotoxic agents, anti-proliferative compounds, and / or anti-angiogenic agents).

[0077] The terms "first-line treatment," "first-line therapy," and "front-line therapy" refer to the preferred, standard initial treatment for a particular condition, e.g., cancer of a given type and stage. These treatments are distinct from "second-line" therapies, which are tried when first-line therapy does not work sufficiently. "Third-line" therapies are tried when first-line and second-line therapies do not work sufficiently.

[0078] For example, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) provided herein and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as a first-line therapy, a second-line therapy (e.g., in patients with platinum-sensitive or platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer), or a third-line therapy (e.g., in patients with platinum-sensitive or platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer). The combination of a FOLR1 immunoconjugate (e.g., IMGN853) provided herein and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as a treatment option in patients who have received zero, one, two, three, four, five, six, or more treatment options prior to treatment with a combination of a FOLR1 immunoconjugate (e.g., IMGN853) described herein and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. The combination of a FOLR1 immunoconjugate provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as a line of therapy in patients who have received at least one, at least two, or at least three lines of therapy prior to treatment with the combination of a FOLR1 immunoconjugate provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In some embodiments, the combination of a FOLR1 immunoconjugate provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as a line of therapy in patients who have received no more than one, no more than two, no more than three, no more than four, no more than five, or no more than six lines of therapy. In certain embodiments, the combination of a FOLR1 immunoconjugate provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as an adjuvant or neoadjuvant therapy.

[0079] The term "adjuvant therapy" refers to systemic therapy given after surgery. In its broadest sense, adjuvant therapy is treatment given in addition to primary therapy to kill any cancer cells that may have spread, even if the spread cannot be detected by radiological or clinical tests.

[0080] The term "neoadjuvant therapy" refers to systemic therapy given before surgery.

[0081] The term "IMGN853" refers to an immunoconjugate described herein containing the huMov19(M9346A) antibody, a sulfoSPDB linker, and a DM4 maytansinoid. The huMov19(M9346A) antibody is an anti-FOLR1 antibody comprising the variable heavy chain sequence SEQ ID NO:3 and the variable light chain sequence SEQ ID NO:5. DM4 refers to N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl) maytansine. "SulfoSPDB" refers to the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate) linker.

[0082] A "monoclonal" antibody or antigen-binding fragment thereof refers to a homogeneous population of antibodies or antigen-binding fragments that are responsible for highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies, which typically include different antibodies directed against different antigenic determinants. The term "monoclonal" antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) mutants, fusion proteins containing an antibody portion, and any other modified immunoglobulin molecule containing an antigen recognition site. Furthermore, a "monoclonal" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof produced in any number of ways, including, but not limited to, by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0083] The term "humanized" antibody or antigen-binding fragment thereof refers to forms of non-human (e.g., murine) antibodies or antigen-binding fragments thereof that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from a complementarity-determining region (CDR) are replaced with residues from a CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) having the desired specificity, affinity, and capacity ("CDR-grafted") (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). In some instances, Fv framework region (FR) residues of a human immunoglobulin are replaced with corresponding residues in an antibody or fragment from a non-human species having the desired specificity, affinity, and capacity. Humanized antibodies or antigen-binding fragments thereof can be further modified by substitution of additional residues either in the Fv framework regions and / or within the replaced non-human residues to refine and optimize the specificity, affinity, and / or capacity of the antibody or antigen-binding fragment. Generally, a humanized antibody or antigen-binding fragment thereof will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions corresponding to a non-human immunoglobulin, while all or substantially all of the FR regions are of the consensus sequence of a human immunoglobulin. A humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat. No. 5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994); and Roguska et al., Protein Eng. 9(10):895-904 (1996).In some embodiments, a "humanized antibody" is a resurfaced antibody.

[0084] The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The heavy or light chain variable region each consists of four framework regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are held in close proximity by the FRs and, together with the CDRs of the other chain, contribute to the formation of the antibody's antigen-binding site. There are at least two techniques for determining CDRs: (1) a method based on interspecies sequence variability (i.e., Kabat et al., Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda, Md.), "Kabat"); and (2) a method based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., J. Molec. Biol. 273:927-948 (1997)). In addition, a combination of these two techniques may be used in the art to determine CDRs.

[0085] The Kabat numbering system is generally used when referring to residues within the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. (5th Ed., 1991, National Institutes of Health, Bethesda, Md.) (“Kabat”)).

[0086] Kabat numbering of amino acid positions refers to the numbering system used for the heavy or light chain variable domains of antibody compilations in Kabat et al. (Sequences of Immunological Interest. (5th Ed., 1991, National Institutes of Health, Bethesda, Md.), "Kabat"). By using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids corresponding to shortening of, or insertion into, the FRs or CDRs of the variable domain. For example, a heavy chain variable domain can contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat, etc.). The Kabat numbering of residues can be determined for a given antibody by alignment of the antibody sequence with the "standard" Kabat numbering sequence in the homologous regions. Chothia instead refers to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). When numbered using the Kabat numbering convention, the ends of the Chothia CDR-H1 loops vary between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme makes insertions at H35A and H35B; if neither 35A nor 35B are present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent the intermediate regions between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. [Table A]

[0087] The term "human" antibody or antigen-binding fragment thereof means an antibody or antigen-binding fragment thereof produced by a human, or an antibody or antigen-binding fragment thereof having an amino acid sequence corresponding to an antibody or antigen-binding fragment thereof produced by a human, using any method known in the art. This definition of a human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0088] The term "chimeric" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof whose amino acid sequence is derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody or antigen-binding fragment thereof from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and capacity, while the constant regions are homologous to sequences in an antibody or antigen-binding fragment thereof from another (usually human) species to avoid eliciting an immune response in that species.

[0089] The terms "epitope" and "antigenic determinant" are used interchangeably herein to refer to a portion of an antigen that can be recognized and specifically bound by a particular antibody. When the antigen is a polypeptide, an epitope can be formed from both contiguous amino acids and non-contiguous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed from contiguous amino acids are typically retained upon denaturation of the protein, whereas epitopes formed by tertiary folding are typically lost upon denaturation of the protein. An epitope typically comprises at least 3, more usually at least 5 or 8-10, amino acids in a unique spatial conformation.

[0090] "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigens slowly and tend to dissociate easily, while high-affinity antibodies generally bind antigens faster and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which can be used for purposes of the present invention. Specific exemplary embodiments are described below.

[0091] As used herein with respect to binding affinity, "or better" refers to stronger binding between a molecule and its binding partner. As used herein, "or better" refers to stronger binding, represented by a smaller Kd number. For example, an antibody with an affinity for an antigen "of 0.6 nM or better" has an affinity for the antigen of <0.6 nM, i.e., 0.59 nM, 0.58 nM, 0.57 nM, etc., or any number less than 0.6 nM.

[0092] "Specifically binds" generally means that an antibody binds to an epitope via its antigen-binding domain and that the binding results in some degree of complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to "specifically bind" to an epitope if it binds to that epitope via its antigen-binding domain more readily than it would to a random, unrelated epitope. The term "specificity" is used herein to define the relative affinity with which an antibody binds to an epitope. For example, antibody "A" can be considered to have higher specificity for a given epitope than antibody "B," or antibody "A" can be said to bind epitope "C" with higher specificity than it has for the related epitope "D."

[0093] "Preferentially binds" means that an antibody specifically binds to an epitope more readily than it would bind to a related, similar, homologous, or analogous epitope. Thus, an antibody that "preferentially binds" to a given epitope is more likely to bind to that epitope than to a related epitope, even if such an antibody may cross-react with the related epitope.

[0094] An antibody is said to "competitively inhibit" the binding of a reference antibody to a given epitope if it preferentially binds to that epitope or an overlapping epitope to such an extent that it interferes with the binding of the reference antibody to that epitope to some extent. Competitive inhibition can be determined by any method known in the art, for example, by competitive ELISA assay. An antibody can be said to competitively inhibit the binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0095] As used herein, the phrases "substantially similar" or "substantially the same" refer to a sufficiently high degree of similarity between two numerical values ​​(typically one associated with an antibody of the invention and the other associated with a reference / comparator antibody) such that one of skill in the art would consider the difference between the two values ​​to have little or no biological and / or statistical significance within the range of the biological characteristic measured by said values ​​(e.g., Kd values). The difference between the two values ​​can be less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% as a function of the value of the reference / comparator antibody.

[0096] An "isolated" polypeptide, antibody, polynucleotide, vector, cell, or composition is a polypeptide, antibody, polynucleotide, vector, cell, or composition in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in a form found in nature. In some embodiments, an isolated antibody, polynucleotide, vector, cell, or composition is substantially pure.

[0097] As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0098] As used herein, the term "immunoconjugate" or "conjugate" refers to a compound or derivative thereof linked to a cell-binding agent (i.e., an anti-FOLR1 antibody or fragment thereof) and defined by the general formula: CLA, where C = cytotoxin, L = linker, and A = antibody or antigen-binding fragment thereof, e.g., an anti-FOLR1 antibody or antibody fragment. An immunoconjugate can also be defined in reverse order by the general formula: ALC.

[0099] A "linker" is any chemical moiety capable of linking a compound, usually a drug (such as a maytansinoid), to a cell-binding agent (such as an anti-FOLR1 antibody or fragment thereof) in a stable, covalent manner. The linker can be, for example, sensitive to or substantially resistant to disulfide bond cleavage under conditions under which the compound or antibody remains active. Suitable linkers are well known in the art and include, for example, disulfide thioether groups.

[0100] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, blastoma, and sarcoma. More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, e.g., primary peritoneal carcinoma (PPC), hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer (including epithelial ovarian cancer (EOC) and advanced EOC), liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial cancer (or uterine carcinoma), salivary gland carcinoma, non-clear cell renal carcinoma, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, various types of head and neck cancer, bone, pituitary gland, testis, and brain cancer (see, e.g., U.S. Pat. No. 8,709,432; U.S. Pat. No. 8,834,877; Zwicke et al., Nano Reviews 3:18496-18506 (2012)). The cancer can be a cancer that expresses FOLR1 (a "FOLR1-expressing cancer" or "FRα-positive" cancer).

[0101] The terms "cancer cells," "tumor cells," and synonyms refer to the entire population of cells derived from a tumor or precancerous lesion, including both non-tumorigenic cells and tumorigenic stem cells (cancer stem cells), which comprise the majority of the tumor cell population. As used herein, the term "tumor cells," when referring simply to tumor cells that lack the ability to reproduce and differentiate, will be modified by the term "non-tumorigenic" to distinguish such tumor cells from cancer stem cells.

[0102] An "advanced" cancer is one that has spread outside the site or organ of origin, either by local invasion or metastasis. The term "advanced" cancer includes both locally advanced and metastatic disease.

[0103] "Metastatic" cancer refers to cancer that has spread from one part of the body to another.

[0104] A "refractory" cancer is one that progresses even when anti-tumor treatment, such as chemotherapy, is administered to the cancer patient. An example of a refractory cancer is one that is platinum-refractory.

[0105] Patients are "platinum-refractory" if they do not respond to platinum-based therapy and progress during the course of treatment or within 4 weeks after the last dose. "Platinum-resistant" patients progress within 6 months of platinum-based therapy. "Partially platinum-sensitive" patients progress between 6 and 12 months of platinum-based therapy. "Platinum-sensitive" patients progress within more than 12 months.

[0106] A "recurrent" cancer is one that grows again, either at the original site or at a distant site, after responding to initial treatment.

[0107] The term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that will be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein when referring to a human subject.

[0108] A "relapsed" patient is one who has signs or symptoms of cancer after remission. Optionally, the patient has relapsed after adjuvant or neoadjuvant therapy.

[0109] Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.

[0110] Combination therapy can provide a "synergistic effect" and demonstrate a "synergistic" effect, i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects achieved by using the compounds separately. Synergistic effects can be achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form; (2) delivered sequentially, alternately, or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes.

[0111] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and that does not contain additional components that are unacceptably toxic to the subject to which the formulation will be administered. The formulation can be sterile.

[0112] An "effective amount" of an antibody, immunoconjugate, or other agent disclosed herein is an amount sufficient to carry out a specifically stated purpose. An "effective amount" can be determined empirically and routinely for a stated purpose.

[0113] The term "therapeutically effective amount" refers to an amount of an antibody, immunoconjugate, or other drug effective to "treat" a disease or disorder in a subject or mammal. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells, reduce tumor size or mass, inhibit (i.e., slow to some extent, and in certain embodiments, stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent, and in certain embodiments stop) tumor metastasis, inhibit tumor growth to some extent, alleviate to some extent one or more symptoms associated with cancer, and / or produce a favorable response such as an increase in progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), a complete response (CR), a partial response (PR), or in some cases stable disease (SD), a decrease in disease progression (PD), a shortened time to progression (TTP), in the case of ovarian cancer, a decrease in CA125, or any combination thereof. See the definition herein of "treating." To the extent that a drug can prevent growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. A "prophylactically effective amount" refers to an amount that is effective, at the dosage and for the period required, to achieve the desired preventive result. Typically, but not necessarily, because prophylactic administration is used in subjects before or at the early stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0114] The term "favorably respond" generally refers to producing a beneficial state in a subject. In the context of cancer treatment, this term refers to providing a therapeutic effect to a subject. A positive therapeutic effect in cancer can be measured in several ways (see W.A. Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, tumor growth inhibition, molecular marker expression, serum marker expression, and molecular imaging techniques can all be used to evaluate the therapeutic efficacy of anti-cancer therapeutic agents. Log 10 Cell Kill(LCK) can be used to quantify tumor cell killing. 10Cell Kill (LCK) is calculated by the formula LCK = (TC) / T d × 3.32, where (TC) (i.e., tumor growth delay (TGD)) is the median time (in days) for tumors in the treated and control groups to reach a given size (excluding tumor-free survivors). d is the tumor doubling time (estimated from a nonlinear exponential curve fit of the daily median of control tumor growth), and 3.32 is the number of cell doublings per logarithm of cell growth. The ability to reduce tumor volume can be evaluated, for example, by measuring the %T / C value, which is the median tumor volume of treated subjects divided by the median tumor volume of control subjects. Regarding tumor growth inhibition, according to the NCI standard, a T / C of 42% or less is the minimum level of anti-tumor activity. A T / C of less than 10% is considered to be a high level of anti-tumor activity, where T / C (%) = median tumor volume of treated subjects / median tumor volume of control × 100. A favorable response can be assessed, for example, by increased progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), or in some cases, stable disease (SD), reduced disease progression (PD), shortened time to progression (TTP), in the case of ovarian cancer, reduced CA125, or any combination thereof.

[0115] PFS, DFS, and OS can be measured by the criteria established by the National Cancer Institute and the U.S. Food and Drug Administration for new drug approval. See Johnson et al., J. Clin. Oncol. 21(7):1404-1411 (2003).

[0116] "Progression-free survival" (PFS) refers to the time from enrollment to disease progression or death. PFS is generally measured using the Kaplan-Meier method and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Generally, progression-free survival refers to the duration of a patient's life without their cancer getting worse.

[0117] "Time to progression" (TTP) is defined as the time from enrollment to disease progression. TTP is generally measured using RECIST 1.1 criteria.

[0118] "Complete response" or "complete remission" or "CR" indicates the disappearance of all signs of tumor or cancer in response to treatment. It does not necessarily mean that the cancer has been cured.

[0119] A "partial response" or "PR" refers to a reduction in the size or volume of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment.

[0120] "Stable disease" refers to disease without progression or recurrence. In stable disease, the tumor has not shrunk enough to be considered a partial response, nor has it grown enough to be considered progressive disease.

[0121] "Progressive disease" refers to the appearance of one additional new lesion or tumor and / or overt progression of an existing non-target lesion. Disease progression can also refer to tumor growth of more than 20 percent from the start of treatment due to an increase in tumor mass or spread.

[0122] "Disease-free survival" (DFS) refers to the length of time during and after treatment that a patient remains disease-free.

[0123] "Overall survival" (OS) refers to the time from patient enrollment to death or censoring at the date of last known survival. OS includes the prolongation of life expectancy compared to untreated or untreated individuals or patients. Overall survival refers to the situation in which a patient continues to survive for a specified period of time, such as 1 year, 5 years, etc., from the time of diagnosis or treatment.

[0124] "Prolonged survival" or "increased chance of survival" means that PFS and / or OS in a treated subject is increased compared to an untreated subject, or compared to a control treatment protocol, such as one used in standard therapy for a type of cancer.

[0125] "Reduction of CA125 levels" can be assessed according to the Gynecologic Cancer Intergroup (GCIG) guidelines. For example, CA125 levels can be measured before treatment to establish a baseline CA125 level. CA125 levels can be measured one or more times during or after treatment, and a decrease in CA125 levels over time compared to baseline levels is considered a reduction in CA125 levels.

[0126] The term "increased expression" or "overexpression" of FOLR1 in a particular tumor, tissue, or cell sample refers to FOLR1 (FOLR1 polypeptide or nucleic acid encoding such a polypeptide) being present at a level higher than that present in a healthy or non-diseased (native, wild-type) tissue or cell of the same type or origin. Such increased expression or overexpression can be caused, for example, by mutation, gene amplification, increased transcription, increased translation, or increased protein stability.

[0127] The terms "treating" or "treatment" or "treat" or "alleviating" or "alleviating" and the like refer to a therapeutic measure that cures, delays, relieves symptoms, and / or halts progression of a diagnosed condition or disorder. Thus, those in need of treatment include those already diagnosed with the disorder or those suspected of having the disorder. In certain embodiments, a subject is successfully "treated" for cancer according to the methods of the present invention if the patient exhibits one or more of the following: a reduction in the number or complete absence of cancer cells; a reduction in tumor burden; an inhibition or absence of cancer cell invasion into peripheral organs, including, for example, the spread of cancer into soft tissue and bone; an inhibition or absence of tumor metastasis; an inhibition or absence of tumor growth; an alleviation of one or more symptoms associated with the particular cancer; a reduction in morbidity and mortality; an improvement in quality of life; a reduction in the tumorigenicity, frequency, or tumorigenic potential of the tumor; a reduction in the number or frequency of cancer stem cells within the tumor; differentiation of tumorigenic cells into a non-tumorigenic state; an increased progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), a complete response (CR), a partial response (PR), stable disease (SD), a reduction in disease progression (PD), a shortened time to progression (TTP), or, in the case of ovarian cancer, a reduction in CA125, or any combination thereof.

[0128] Protective or prophylactic measures refer to measures that prevent and / or delay the onset of the targeted condition or disorder. Thus, those in need of protective or prophylactic measures include those prone to having the disorder and those in whom the disorder is to be prevented.

[0129] The term "instructions for use" means providing written instructions for applicable therapies, medications, procedures, treatment regimens, etc., by any means, such as in the form of a package insert or other written promotional material.

[0130] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers can be linear or branched, can comprise modified amino acids, and can be interrupted by non-amino acids. The term also encompasses amino acid polymers that are modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within this definition are polypeptides containing, for example, one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. Because the polypeptides of the present invention are based on antibodies, it is understood that in certain embodiments, the polypeptides can occur as single chains or associated chains.

[0131] The term "identical" or percent "identity" in the context of two or more nucleic acids or polypeptides refers to two or more sequences or subsequences that, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, are the same or have a specified percentage (%) of the same nucleotide or amino acid residues, not considering any conservative amino acid substitutions as part of the sequence identity. Percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to align amino acid or nucleotide sequences are known in the art. One such non-limiting example of a sequence alignment algorithm is that described in Karlin et al., Proc. Natl. Acad. Sci., 87:2264-2268 (1990), as modified in Karlin et al., Proc. Natl. Acad. Sci., 90:5873-5877 (1993), and the NBLAST and XBLAST programs (Altschul et al., 1994). Alignment of sequences is performed using the algorithm incorporated in Altschul et al., Nucleic Acids Res., 25:3389-3402 (1991). In certain embodiments, Gapped BLAST can be used as described in Altschul et al., Nucleic Acids Res., 25:3389-3402 (1997). BLAST-2, WU-BLAST-2 (Altschul et al., Methods in Enzymology, 266:460-480 (1996)), ALIGN, ALIGN-2 (Genentech, South San Francisco, California), or Megalign (DNASTAR) are further publicly available software programs that can be used to align sequences. In certain embodiments, the percent identity between two nucleotide sequences is determined using the GAP program of the GCG software (e.g., using the NWSgapdna.CMP matrix, and a gap weight of 40, 50, 60, 70, or 90, and a length weight of 1, 2, 3, 4, 5, or 6). In certain alternative embodiments, the percent identity between two amino acid sequences can be determined using the GAP program of the GCG software package, which incorporates the algorithm of Needleman and Wunsch (J. Mol. Biol. (48): 444-453 (1970)) (e.g., using the Blossum 62 matrix or the PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, or 5). Alternatively, in certain embodiments, the percent identity between nucleotide or amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4:11-17 (1989)). For example, percent identity can be determined using the ALIGN program (version 2.0) and using PAM120 with a residue table, a gap length penalty of 12, and a gap penalty of 4. Appropriate parameters for maximal alignment with particular alignment software can be determined by one of skill in the art.In certain embodiments, default parameters of the alignment software are used. In certain embodiments, the percent identity "X" of a first amino acid sequence to a second amino acid sequence is calculated as 100 x (Y / Z), where Y is the number of amino acid residues scored as perfect matches in the alignment of the first and second sequences (as aligned by visual inspection or a specific sequence alignment program), and Z is the total number of residues in the second sequence. If the length of the first sequence is longer than the second sequence, the percent identity of the first sequence to the second sequence will be longer than the percent identity of the second sequence to the first sequence.

[0132] As a non-limiting example, whether any particular polynucleotide has a particular percentage (%) of sequence identity (e.g., at least 80% identical, at least 85% identical, at least 90% identical, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99% identical) to a reference sequence can be determined in certain embodiments using the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics The alignment of sequences can be determined using a program such as the Bestfit program (University Research Computer Group, University Research Park, 575 Science Drive, Madison, WI 53711). Bestfit uses the local homology algorithm of Smith and Waterman (Advances in Applied Mathematics 2:482-489 (1981)) to find the best homologous segment between two sequences. When using Bestfit or any other sequence alignment program to determine whether a particular sequence is, for example, 95% identical to a reference sequence according to the present invention, parameters are set so that the percentage of identity is calculated over the entire length of the reference nucleotide sequence and gaps in homology are allowed up to 5% of the total number of nucleotides in the reference sequence.

[0133] In some embodiments, two nucleic acids or polypeptides of the invention are substantially identical, i.e., they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99% nucleotide or amino acid residue identity when compared and aligned for maximum correspondence, as determined using a sequence comparison algorithm or by visual inspection. Identity can exist over a region of the sequences that is at least about 10, about 20, about 40-60, or any integer value therebetween, residues in length, and can also extend over a region longer than 60-80 residues, e.g., at least about 90-100 residues; in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared, e.g., the coding regions of the nucleotide sequences.

[0134] A "conservative amino acid substitution" is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art, and include basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of phenylalanine for tyrosine is a conservative substitution. In some embodiments, conservative substitutions in the sequences of the polypeptides and antibodies of the present invention do not abolish binding of the polypeptide or antibody containing the amino acid sequence to the antigen(s), i.e., FOLR1 or VEGF, to which the polypeptide or antibody binds. Methods for identifying conservative nucleotide and amino acid substitutions that do not eliminate antigen binding are well known in the art (see, e.g., Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94:412-417 (1997)).

[0135] As used in this disclosure and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0136] Wherever an embodiment is described herein with the word "comprising," it is understood that other similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0137] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both "A and B," "A or B," and "A" and "B." Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0138] II. Anti-FOLR1 immune complex Described herein are methods of administering immune complexes (e.g., IMGN853) that specifically bind to FOLR1. These agents are referred to herein as "FOLR1-immune complexes or anti-FOLR1 immune complexes." The amino acid and nucleotide sequences of human FOLR1 are known in the art and are also provided herein as SEQ ID NO: 1 and SEQ ID NO: 2, respectively. SEQ ID NO:1 - Human folate receptor 1 MAQRMTTQLLLLLVWVAVVGEAQTRIAWARTELLNVCMNAKHHKEKPGPEDKLHEQCRPWRKNACCSTNTSQEAHKDVSYLYRFNWNHCGEMAACKRHFIQDTCLYECSPNLGPWIQQVDQSWRKER VLNVPLCKEDCEQWWEDCRTSYTCKSNWHKGWNWTSGFNKCAVGAACQPFHFYFPTPTVLCNEIWTHSYKVSNYSRGSGRCIQMWFDPAQGNPNEEVARFYAAAMSGAGPWAAWPFLLSLALMLLWLLS SEQ ID NO:2 - Human folate receptor 1 nucleic acid sequence atggctcagcggatgacaacacagctgctgctccttctagtgtgggtggctgtagtaggggaggctcagacaaggattgcatgggccaggactgagcttctcaatgtctgcatgaacgccaagcaccacaaggaaaagccaggccccgaggacaagttgcatgagcagtgtcgaccctggaggaagaatgcctgctgttctaccaacaccagccaggaagcccataaggatgtttcctacctatatagattcaactggaaccactgtggagagatggcacctgcctgcaaacggcatttcatccaggacacctgcctctacgagtgctcccccaacttggggccctggatccagcaggtggatcagagctggcgcaaagagcgggtactgaacgtgcccctgtgcaaagaggactgtgagcaatggtgggaagattgtcgcacctcctacacctgcaagagcaactggcacaagggctggaactggacttcagggtttaacaagtgcgcagtgggagctgcctgccaacctttccatttctacttccccacacccactgttctgtgcaatgaaatctggactcactcctacaaggtcagcaactacagccgagggagtggccgctgcatccagatgtggttcgacccagcccagggcaaccccaatgaggaggtggcgaggttctatgctgcagccatgagtggggctgggccctgggcagcctggcctttcctgcttagcctggccctaatgctgctgtggctgctcagc

[0139] The anti-FOLR1 immunoconjugate contains a cell-binding agent linked to a cytotoxin. The cell-binding agent can be an anti-FOLR1 antibody or an antigen-binding fragment thereof. Examples of therapeutically effective anti-FOLR1 antibodies can be found in U.S. Application Publication No. US2012 / 0009181, which is incorporated herein by reference. An example of a therapeutically effective anti-FOLR1 antibody is huMov19(M9346A) (comprising the sequences of SEQ ID NOs: 3 and 5). The polypeptides of SEQ ID NOs: 3-5 comprise the variable domain of the heavy chain of huMov19(M9346A), the variable domain light chain version 1.00 of huMov19, and the variable domain light chain version 1.60, respectively. In certain embodiments, the huMov19 anti-FOLR1 antibody is composed of the variable domain heavy chain represented by SEQ ID NO: 3 and the variable domain light chain represented by SEQ ID NO: 5 (huMov19 version 1.60). In certain embodiments, the huMov19(M9346A) antibody is encoded by a plasmid deposited with the American Type Culture Collection (ATCC), located at 10801 University Boulevard, Manassas, VA 20110, under the terms of the Budapest Treaty on April 7, 2010, having ATCC accession numbers PTA-10772 and PTA-10773 or 10774.

[0140] The amino acid sequence of huMov19 is provided in Tables 1-4 below: [Table 1] [Table 2] [Table 3] [Table 4]

[0141] In some embodiments, the anti-FOLR1 immune complex comprises a humanized antibody or antigen-binding fragment thereof. In some embodiments, the humanized antibody or fragment is a resurfaced antibody or antigen-binding fragment thereof. In other embodiments, the anti-FOLR1 immune complex comprises a fully human antibody or antigen-binding fragment thereof.

[0142] In certain embodiments, the anti-FOLR1 immunoconjugate has one or more of the following effects: inhibiting tumor cell proliferation, reducing the tumorigenicity of a tumor by reducing the frequency of cancer stem cells in the tumor, inhibiting tumor growth, increasing patient survival, inducing cell death in tumor cells, differentiating tumorigenic cells to a non-tumorigenic state, or preventing or reducing metastasis of tumor cells.

[0143] In certain embodiments, the anti-FOLR1 immune complex comprises an antibody with antibody-dependent cellular cytotoxicity (ADCC) activity.

[0144] In some embodiments, anti-FOLR1 immunoconjugates can reduce tumor volume. The ability of anti-FOLR1 immunoconjugates to reduce tumor volume can be assessed, for example, by measuring the T / C% value, which is the median tumor volume of treated subjects divided by the median tumor volume of control subjects. In certain embodiments, immunoconjugates or other agents that specifically bind to human FOLR1 induce cell death via a cytotoxic agent. For example, in certain embodiments, an antibody against human FOLR1 is conjugated to a maytansinoid that is activated in tumor cells expressing FOLR1 by protein internalization. In certain embodiments, anti-FOLR1 immunoconjugates can inhibit tumor growth. In certain embodiments, anti-FOLR1 immunoconjugates can inhibit tumor growth in vivo (e.g., in xenograft mouse models and / or in humans with cancer). In certain embodiments, anti-FOLR1 immunoconjugates can reduce CA125 in ovarian cancer patients.

[0145] The FOLR1-binding molecule can be an antibody or antigen-binding fragment that specifically binds to FOLR1 containing the CDRs of huMov19(M9346A) with up to four (i.e., 0, 1, 2, 3, or 4) conservative amino acid substitutions per CDR, for example, where the antibody or fragment does not contain the six CDRs of mouse Mov19 (i.e., SEQ ID NOS: 6-9, 16, and 12). The polypeptide can comprise one of the individual variable light chains or variable heavy chains described herein. The antibody and polypeptide can also comprise both a variable light chain and a variable heavy chain.

[0146] In some embodiments, the FOLR1-binding molecule is an antibody or antigen-binding fragment comprising the sequences of SEQ ID NOs: 6-10 and 12. In some embodiments, the FOLR1-binding molecule is an antibody or antigen-binding fragment comprising the sequences of SEQ ID NOs: 6-9 and 11 and 12. In some embodiments, the FOLR1-binding molecule is an antibody or antigen-binding fragment comprising the sequences of SEQ ID NOs: 6-8, 19, 11, and 12.

[0147] Also provided are polypeptides comprising a polypeptide having at least about 90% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. In certain embodiments, the polypeptide comprises a polypeptide having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. Thus, in certain embodiments, the polypeptide comprises (a) a polypeptide having at least about 95% sequence identity to SEQ ID NO:3, and / or (b) a polypeptide having at least about 95% sequence identity to SEQ ID NO:4 or SEQ ID NO:5. In certain embodiments, the polypeptide comprises (a) a polypeptide having the amino acid sequence of SEQ ID NO:3, and / or (b) a polypeptide having the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5. In certain embodiments, the polypeptide is an antibody and / or polypeptide that specifically binds to FOLR1. In certain embodiments, the polypeptide is a murine, chimeric, or humanized antibody that specifically binds to FOLR1. In certain embodiments, a polypeptide having a certain percentage (%) of sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5 differs from SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5 by only conservative amino acid substitutions.

[0148] The polypeptides can include one of the individual light or heavy chains described herein. Antibodies and polypeptides can also include both light and heavy chains.

[0149] Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein (1975) Nature 256:495. Using the hybridoma method, a mouse, hamster, or other suitable host animal is immunized as described above to induce the production by lymphocytes of antibodies that will specifically bind to the immunizing antigen. Lymphocytes can also be immunized in vitro. After immunization, lymphocytes are isolated and fused with a suitable myeloma cell line, for example, using polyethylene glycol, to form hybridoma cells, which can then be selected from unfused lymphocytes and myeloma cells. Hybridomas producing monoclonal antibodies specifically directed against the selected antigen, as determined by immunoprecipitation, immunoblot, or in vitro binding assays (e.g., radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA)), can then be propagated either in vitro culture using standard methods (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, 1986) or in vivo as ascites tumors in animals. Monoclonal antibodies can then be purified from the culture medium or ascites fluid as described above for polyclonal antibodies.

[0150] Alternatively, monoclonal antibodies can also be produced using recombinant DNA methods, as described in U.S. Patent No. 4,816,567. Polynucleotides encoding the monoclonal antibodies are isolated from mature B cells or hybridoma cells, for example, by RT-PCR using oligonucleotide primers that specifically amplify genes encoding the antibody heavy and light chains, and their sequences are determined using conventional procedures. The isolated polynucleotides encoding the heavy and light chains are then cloned into a suitable expression vector, which is transfected into host cells that do not otherwise produce immunoglobulin proteins, such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, and the host cells produce the monoclonal antibodies. Alternatively, recombinant monoclonal antibodies or fragments thereof of the desired species can be isolated from phage display libraries expressing the CDRs of the desired species, as described in (McCafferty et al., 1990, Nature, 348:552-554; Clackson et al., 1991, Nature, 352:624-628; and Marks et al., 1991, J. Mol. Biol., 222:581-597).

[0151] The polynucleotide(s) encoding a monoclonal antibody can be further modified in a number of different ways using recombinant DNA technology to generate alternative antibodies. In some embodiments, for example, the constant domains of the light and heavy chains of a murine monoclonal antibody can be replaced with regions of a human antibody, e.g., to generate 1) chimeric antibodies, or with non-immunoglobulin polypeptides, to generate fusion antibodies. In some embodiments, the constant regions are truncated or removed to generate desired antibody fragments of the monoclonal antibody. Site-directed or high-density mutagenesis of the variable regions can be used to optimize the specificity, affinity, etc. of the monoclonal antibody.

[0152] In some embodiments, the monoclonal antibody against human FOLR1 is a humanized antibody. In some embodiments, the humanized antibody is a resurfaced antibody. In certain embodiments, such antibodies are used therapeutically to reduce antigenicity and HAMA (human anti-mouse antibody) responses when administered to a human subject. Humanized antibodies can be produced using various techniques known in the art. In certain alternative embodiments, the antibody against FOLR1 is a human antibody.

[0153] Human antibodies can be prepared directly using a variety of techniques known in the art: Immortalized human B lymphocytes can be generated by in vitro immunization or isolated from immunized individuals that produce antibodies against a target antigen (see, e.g., Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer et al., 1991, J. Immunol., 147(1):86-95; and U.S. Patent No. 5,750,373). Human antibodies can also be selected from phage libraries, which express human antibodies, as described, for example, in Vaughan et al., 1996, Nat. Biotech., 14:309-314; Sheets et al., 1998, Proc. Nat'l. Acad. Sci., 95:6157-6162; Hoogenboom and Winter, 1991, J. Mol. Biol., 227:381; and Marks et al., 1991, J. Mol. Biol., 222:581). Techniques for generating and using antibody phage libraries are also described in U.S. Patent Nos. 5,969,108, 6,172,197, 5,885,793, 6,521,404; 6,544,731; 6,555,313; 6,582,915; 6,593,081; 6,300,064; 6,653,068; 6,706,484; and 7,264,963, as well as Rothe et al., 2007, J. Mol. Bio., doi:10.1016 / j.jmb.2007.12.018 (each of which is incorporated by reference herein in its entirety). Affinity maturation and chain shuffling strategies (Marks et al., 1992, Bio / Technology 10:779-783, incorporated by reference in its entirety) are known in the art and can be employed to generate high-affinity human antibodies.

[0154] Humanized antibodies can also be made in transgenic mice containing human immunoglobulin loci that are capable, upon immunization, of producing a repertoire of human antibodies in the absence of endogenous immunoglobulin production. This technique is described in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016.

[0155] The polypeptides of the present invention can be recombinant, natural, or synthetic polypeptides, including antibodies against human FOLR1, or fragments thereof.

[0156] Polypeptides and analogs can be further modified to contain additional chemical moieties not normally part of the protein. The derivatized moieties can improve the solubility, biological half-life, or absorption of the protein. The moieties can also reduce or eliminate any desired side effects of the protein. A review of these moieties can be found in REMINGTON'S PHARMACEUTICAL SCIENCES, 20th ed., Mack Publishing Co., Easton, PA (2000).

[0157] Methods known in the art for purifying antibodies and other proteins include those described, for example, in U.S. Patent Publication Nos. 2008 / 0312425, 2008 / 0177048, and 2009 / 0187005, each of which is incorporated herein by reference in its entirety.

[0158] Suitable drugs or prodrugs are known in the art. The drug or prodrug can be a cytotoxic agent. The cytotoxic agent used in the cytotoxin conjugates of the invention can be any compound that causes or induces cell death or reduces cell viability in some way, including, for example, maytansinoids and maytansinoid analogs.

[0159] Such conjugates can be prepared by using linking groups to link the drug or prodrug to the antibody or functional equivalent. Suitable linking groups are well known in the art and include, for example, disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, and esterase labile groups.

[0160] The drug or prodrug can be linked to the anti-FOLR1 antibody or fragment thereof, for example, through a disulfide bond. The linker molecule or cross-linker contains a reactive chemical group that can react with the anti-FOLR1 antibody or fragment thereof. The reactive chemical group for reaction with the cell-binding agent can be N-succinimidyl ester and N-sulfosuccinimidyl ester. In addition, the linker molecule contains a reactive chemical group, which can be a dithiopyridyl group that can react with the drug to form a disulfide bond. Linker molecules include, for example, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) (see, e.g., Carlsson et al., Biochem. J., 173:723-737 (1978)), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) (see, e.g., U.S. Pat. No. 4,563,304), N-succinimidyl 4-(2-pyridyldithio)2-sulfobutanoate (sulfo-SPDB) (see U.S. Publication No. 20090274713), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP) (see, e.g., CAS Registry No. 341498-08-6), 2-iminothiolane, or acetylsuccinic anhydride. For example, an antibody or cell-binding agent can be modified with a cross-linking reagent, and the resulting antibody or cell-binding agent containing a free or protected thiol group can then be reacted with a disulfide- or thiol-containing maytansinoid to produce a conjugate. The conjugate can be purified by chromatography, including but not limited to, HPLC, size exclusion, adsorption, ion exchange, and affinity capture, dialysis, or tangential flow filtration.

[0161] In another embodiment of the invention, an anti-FOLR1 antibody is linked to a cytotoxin drug via a disulfide bond and a polyethylene glycol spacer to enhance the potency, solubility, or efficacy of the immunoconjugate. Such cleavable hydrophilic linkers are described in WO 2009 / 0134976. An additional advantage of this linker design is the desired high monomer ratio and minimal aggregation of the antibody-drug conjugate. In this embodiment, a polyethylene glycol spacer ((CH2CHO)) is used with a narrow range of drug loading from 2 to 8. n=1-14 Conjugates of cell-binding agents and drugs linked via a disulfide group (-SS-) having 2-hydroxybenzoates are specifically contemplated and have been shown to exhibit relatively potent biological activity against cancer cells and to have the desirable biochemical properties of high conjugation yields and high monomer ratios, along with minimal protein aggregation.

[0162] Antibody-maytansinoid conjugates with non-cleavable linkers can also be prepared. Such cross-linkers are described in the art (see U.S. Publication No. 20050169933) and include, but are not limited to, N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC). In some embodiments, antibodies are modified with cross-linking reagents such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC), sulfo-SMCC, maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), sulfo-MBS, or succinimidyl iodoacetic acid to introduce 1 to 10 reactive groups, as described in the literature (Yoshitake et al., Eur. J. Biochem., 101:395-399 (1979); Hashida et al., J. Applied Biochem., 56-63 (1984); and Liu et al., Biochem., 18:690-697 (1979)). The modified antibody is then reacted with a thiol-containing maytansinoid derivative to produce a conjugate. The conjugate can be purified by gel filtration through a Sephadex G25 column, or by dialysis or tangential flow filtration. The modified antibody is treated with a thiol-containing maytansinoid (1–2 molar equivalents per maleimide group), and the antibody-maytansinoid conjugate is purified by gel filtration through a Sephadex G-25 column, chromatography on a ceramic hydroxyapatite column, dialysis, or tangential flow filtration, or a combination of these methods. Typically, an average of 1–10 maytansinoids are linked per antibody. One method is to modify the antibody with succinimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) to introduce maleimide groups, followed by reaction of the modified antibody with a thiol-containing maytansinoid to yield a thioether-linked conjugate. Again, this results in a conjugate with 1–10 drug molecules per antibody molecule. Maytansinoid conjugates of antibodies, antibody fragments, and other proteins are prepared in the same manner.

[0163] In another embodiment of the present invention, the FOLR1 antibody is linked to the drug via a non-cleavable bond mediated by a PEG spacer. Suitable cross-linking reagents containing hydrophilic PEG chains that form a linker between the drug and the anti-FOLR1 antibody or fragment are also well known in the art or commercially available (e.g., from Quanta Biodesign, Powell, Ohio). Suitable PEG-containing cross-linkers can also be synthesized from commercially available PEG itself using standard synthetic chemistry techniques known to those skilled in the art. The drug is reacted with a bifunctional PEG-containing cross-linker to form a compound of the following formula: ZX l -(-CH2-CH2-O-) n -Y p Compounds of formula -D can be obtained by the methods detailed in U.S. Patent Publication No. 20090274713 and WO2009 / 0134976, which can then be reacted with a cell-binding agent to provide a conjugate. Alternatively, the cell-binding agent can be modified with a bifunctional PEG crosslinker to introduce a thiol-reactive group (such as a maleimide or haloacetamide), which can then be treated with a thiol-containing maytansinoid to provide a conjugate. Alternatively, the cell-binding agent can be modified with a bifunctional PEG crosslinker to introduce a thiol moiety, which can then be treated with a thiol-reactive maytansinoid (such as a maytansinoid bearing a maleimide or haloacetamide) to provide a conjugate.

[0164] Examples of suitable PEG-containing linkers include linkers having an N-succinimidyl ester or N-sulfosuccinimidyl ester moiety for reaction with an anti-FOLR1 antibody or fragment thereof, and a maleimide or haloacetyl-based moiety for reaction with a compound. The PEG spacer can be incorporated into any crosslinker known to those of skill in the art by the methods described herein.

[0165] In some embodiments, the linker is a linker containing at least one charged group, as described, for example, in U.S. Patent Publication No. 2012 / 0282282, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the charged or pro-charged crosslinker contains sulfonate, phosphate, carboxyl, or quaternary amine substituents, which significantly increase the solubility of the modified cell-binding agent and cell-binding agent-drug conjugate, particularly for monoclonal antibody-drug conjugates with 2 to 20 drug / antibody linked moieties. Conjugates prepared from linkers containing pro-charged moieties will generate one or more charged moieties after the conjugate is metabolized in cells. In some embodiments, the linker is selected from the group consisting of N-succinimidyl 4-(2-pyridyldithio)-2-sulfopentanoate (sulfo-SPP) and N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB).

[0166] Many of the linkers disclosed herein are described in detail in U.S. Patent Publication Nos. 2005 / 0169933, 2009 / 0274713, and 2012 / 0282282, as well as WO2009 / 0134976; the contents of which are incorporated herein by reference in their entireties.

[0167] The present invention includes embodiments in which about 2 to about 8 drug molecules ("drug load"), e.g., maytansinoids, are linked to an anti-FOLR1 antibody or fragment thereof. "Drug load," as used herein, refers to the number of drug molecules (e.g., maytansinoids) that can be attached to a cell-binding agent (e.g., an anti-FOLR1 antibody or fragment thereof). In one embodiment, the number of drug molecules that can be attached to a cell-binding agent is, on average, about 2 to about 8 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, , 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1). N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1) and N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)maytansine (DM4) can be used.

[0168] Thus, in one embodiment, the immunoconjugate contains one maytansinoid per antibody. In another embodiment, the immunoconjugate contains two maytansinoids per antibody. In another embodiment, the immunoconjugate contains three maytansinoids per antibody. In another embodiment, the immunoconjugate contains four maytansinoids per antibody. In another embodiment, the immunoconjugate contains five maytansinoids per antibody. In another embodiment, the immunoconjugate contains six maytansinoids per antibody. In another embodiment, the immunoconjugate contains seven maytansinoids per antibody. In another embodiment, the immunoconjugate contains eight maytansinoids per antibody.

[0169] In one embodiment, an immunoconjugate (e.g., an immunoconjugate comprising the linker SPDB and the maytansinoid DM4) comprises about 1 to about 8 maytansinoids per antibody. In another embodiment, an immunoconjugate (e.g., an immunoconjugate comprising the linker SPDB and the maytansinoid DM4) comprises about 2 to about 7 maytansinoids per antibody. In another embodiment, an immunoconjugate (e.g., an immunoconjugate comprising the linker SPDB and the maytansinoid DM4) comprises about 2 to about 6 maytansinoids per antibody. In another embodiment, an immunoconjugate (e.g., an immunoconjugate comprising the linker SPDB and the maytansinoid DM4) comprises about 2 to about 5 maytansinoids per antibody. In another embodiment, an immunoconjugate (e.g., an immunoconjugate comprising the linker SPDB and the maytansinoid DM4) comprises about 3 to about 5 maytansinoids per antibody. In another embodiment, the immunoconjugate (eg, an immunoconjugate comprising the linker SPDB and the maytansinoid DM4) contains about 3 to about 4 maytansinoids per antibody.

[0170] In one embodiment, the composition comprising the immunoconjugate contains, on average, about 2 to about 8 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 , 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1) attached drug molecules (e.g., maytansinoids). In one embodiment, a composition comprising an immunoconjugate has, on average, about 1 to about 8 drug molecules (e.g., maytansinoids) per antibody. In one embodiment, a composition comprising an immunoconjugate has, on average, about 2 to about 7 drug molecules (e.g., maytansinoids) per antibody. In one embodiment, a composition comprising an immunoconjugate has, on average, about 2 to about 6 drug molecules (e.g., maytansinoid) per antibody. In one embodiment, a composition comprising an immunoconjugate has, on average, about 2 to about 5 drug molecules (e.g., maytansinoid) per antibody. In one embodiment, a composition comprising an immunoconjugate has, on average, about 3 to about 5 drug molecules (e.g., maytansinoid) per antibody. In one embodiment, a composition comprising an immunoconjugate has, on average, about 3 to about 4 drug molecules (e.g., maytansinoid) per antibody.

[0171] In one embodiment, a composition comprising an immunoconjugate has, on average, about 2±0.5, about 3±0.5, about 4±0.5, about 5±0.5, about 6±0.5, about 7±0.5, or about 8±0.5 attached drug molecules (e.g., maytansinoid) per antibody. In one embodiment, a composition comprising an immunoconjugate has, on average, about 3.5±0.5 drug molecules (e.g., maytansinoid) per antibody.

[0172] An anti-FOLR1 antibody or fragment thereof can be modified by reacting a bifunctional cross-linking reagent with the anti-FOLR1 antibody or fragment thereof, thereby resulting in the covalent attachment of a linker molecule to the anti-FOLR1 antibody or fragment thereof. As used herein, a "bifunctional cross-linking reagent" is any chemical moiety that covalently links a cell-binding agent to a drug, such as a drug described herein. Alternatively, a portion of the linking moiety is provided by the drug. In this embodiment, the drug includes a linking moiety that is part of a larger linker molecule used to connect the cell-binding agent to the drug. For example, to form the maytansinoid DM1, the side chain of the C-3 hydroxyl group of maytansine is modified to have a free sulfhydryl group (SH). This thiolated form of maytansine can react with the modified cell-binding agent to form a conjugate. Thus, the final linker is constructed from two components, one provided by the cross-linking reagent and the other provided by the side chain from DM1.

[0173] Drug molecules can also be linked to antibody molecules through an intermediate carrier molecule, such as serum albumin.

[0174] As used herein, the phrases "linked to a cell-binding agent" or "linked to an anti-FOLR1 antibody or fragment" refer to a conjugate molecule comprising at least one drug derivative attached to a cell-binding agent, anti-FOLR1 antibody or fragment via a suitable linking group or precursor thereof. Exemplary linking groups are SPDB or sulfo-SPDB.

[0175] In certain embodiments, cytotoxic agents useful in the present invention are maytansinoids and maytansinoid analogs. Examples of suitable maytansinoids include maytansinol and esters of maytansinol analogs. Like maytansinol and maytansinol analogs, these include any drug that inhibits microtubule formation and is highly toxic to mammalian cells.

[0176] Examples of suitable maytansinol esters include those with modified aromatic rings and those with modifications at other positions. Such suitable maytansinoids are described in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866; Nos. 4,450,254; 4,322,348; 4,371,533; 5,208,020; 5,416,064; 5,475,092; 5,585,499; 5,846,545; 6,333,410; 7,276,497 and 7,473,796.

[0177] In certain embodiments, the immunoconjugates of the invention comprise a thiol-containing maytansinoid (DM1), formally known as N 2’ -Deacetyl-N 2’ -(3-mercapto-1-oxopropyl)-maytansine is utilized as the cytotoxic agent. DM1 has the following structural formula (I): [ka] It is represented by (I).

[0178] In another embodiment, the conjugate of the invention comprises a thiol-containing maytansinoid N 2’ -Deacetyl-N 2’ (4-methyl-4-mercapto-1-oxopentyl)-maytansine (e.g., DM4) is utilized as a cytotoxic agent. DM4 has the following structural formula (II): [ka] (II).

[0179] Another maytansinoid containing a side chain containing a sterically hindered thiol bond is N 2’ -deacetyl-N- 2’(4-mercapto-1-oxopentyl)-maytansine (referred to as DM3), which has the following structural formula (III): [ka] (III).

[0180] Each of the maytansinoids taught in U.S. Patent Nos. 5,208,020 and 7,276,497 can also be used in the conjugates of the present invention. In this regard, the entire disclosures of U.S. Patent Nos. 5,208,020 and 7,276,697 are incorporated herein by reference.

[0181] Many positions on the maytansinoid can serve as a position for chemically linking to a linking moiety. For example, the C-3 position bearing a hydroxyl group, the C-14 position modified with hydroxymethyl, the C-15 position modified with hydroxy, and the C-20 position bearing a hydroxy group are all expected to be useful. In some embodiments, the C-3 position serves as a position for chemically linking to a linking moiety, and in some specific embodiments, the C-3 position of maytansinol serves as a position for chemically linking to a linking moiety.

[0182] Structural representations of some of the complexes are shown below: [ka] [ka] [ka]

[0183] Any stereoisomers and mixtures thereof for any compound or complex represented by any of the structural formulas above are also included in the present invention.

[0184] Several descriptions for the production of such antibody-maytansinoid conjugates are provided in U.S. Patent Nos. 6,333,410, 6,441,163, 6,716,821, and 7,368,565, each of which is incorporated herein in its entirety.

[0185] Generally, a solution of antibody in aqueous buffer can be incubated with a molar excess of a maytansinoid having a disulfide moiety bearing a reactive group. The reaction mixture can be quenched by the addition of an excess amine (e.g., ethanolamine, taurine, etc.). The maytansinoid-antibody conjugate can then be purified by gel filtration.

[0186] The number of maytansinoid molecules bound per antibody molecule can be determined by spectrophotometrically measuring the absorbance ratio at 252 nm and 280 nm. The average number of maytansinoid molecules / antibody can be, for example, 1 to 10 or 2 to 5. The average number of maytansinoid molecules / antibody can be, for example, about 3 to about 4. The average number of maytansinoid molecules / antibody can be about 3.5.

[0187] Conjugates of antibodies with maytansinoids or other drugs can be evaluated in vitro for their ability to inhibit the proliferation of various unwanted cell lines. For example, cell lines such as the human lymphoma cell line Daudi and the human lymphoma cell line Ramos can be readily used to evaluate the cytotoxic effects of these compounds. The cells to be evaluated can be exposed to the compound for 4-5 days, and cell viability can be measured in a direct assay using known methods. IC 50 A value can then be calculated from the results of the assay.

[0188] The immunoconjugate can be internalized into cells according to some embodiments described herein. The immunoconjugate can therefore exert a therapeutic effect when it is taken up or internalized by a FOLR1-expressing cell. In some specific embodiments, the immunoconjugate comprises an antibody, antibody fragment, or polypeptide linked to a cytotoxic agent by a cleavable linker, and the cytotoxic agent is cleaved from the antibody, antibody fragment, or polypeptide, where it is internalized into the FOLR1-expressing cell.

[0189] In some embodiments, the immunoconjugates can reduce tumor volume. For example, in some embodiments, treatment with the immunoconjugates results in a T / C% value of less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. In some specific embodiments, the immunoconjugates can reduce tumor size in KB, OVCAR-3, IGROV-1, and / or OV-90 xenograft models. In some embodiments, the immunoconjugates can inhibit metastasis.

[0190] III. Anti-VEGF Agents Described herein are methods of administering an anti-FOLR1 immunoconjugate, such as IMGN853, in combination with an agent that specifically binds VEGF (e.g., bevacizumab) or an agent that specifically binds a VEGF receptor. Anti-VEGF agents include, for example, anti-VEGF or anti-VEGFR antibodies (e.g., bevacizumab), tyrosine kinase inhibitors (TKIs) (e.g., cediranib), and soluble VEGF receptors (e.g., VEGF-Trap). Anti-VEGF agents are known in the art, and certain examples are described in Meadows and Hurwitz, Cold Spring Harbor Perspectives in Medicine 2:a006577(2012), which is incorporated herein by reference in its entirety.

[0191] In certain embodiments, the anti-VEGF agent can inhibit tumor growth. In certain embodiments, the anti-VEGF agent can inhibit tumor growth in vivo (e.g., in xenograft mouse models and / or in humans with cancer). In certain embodiments, the anti-VEGF agent can inhibit angiogenesis.

[0192] In certain embodiments, the anti-VEGF agent is an anti-VEGF or anti-VEGFR antibody or antigen-binding fragment thereof.

[0193] The full length amino acid sequence of human VEGF-A is available at UniProtKB accession number P15692 and herein as SEQ ID NO: 17:

[0194] MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVYVGARCCLMPWSLPGPHPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR (SEQ ID NO: 17), and the signal sequence is MNFLLSWVHWSLALLLYLHHAKWSQA (SEQ ID NO: 18).

[0195] Thus, in some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof binds to an epitope of SEQ ID NO: 17 or an epitope of the mature version of SEQ ID NO: 17 (ie, SEQ ID NO: 17 lacking the signal sequence).

[0196] Anti-VEGF antibodies and antigen-binding fragments thereof can include polypeptides comprising the variable light chains or variable heavy chains described herein. Anti-VEGF antibodies and polypeptides can also comprise both variable light chains and variable heavy chains. Anti-VEGF antibodies, and their variable light chains and variable heavy chains, are described in at least U.S. Patent Nos. 6,884,879; 6,054,297; 7,169,901; 7,365,166; 7,060,269; 7,622,115; 8,778,340; and 7,297,334, all of which are incorporated herein by reference in their entireties.

[0197] In some embodiments, the anti-VEGF antibody is bevacizumab, ABP 215 (Amgen), BCD-021 (Biocad), or ranibizumab. In some embodiments, the anti-VEGF antibody is bevacizumab, ABP 215 (Amgen), or BCD-021 (Biocad). In some embodiments, the anti-VEGF antibody is bevacizumab.

[0198] In some embodiments, the anti-VEGF receptor antibody or antigen-binding fragment thereof binds to VEGFR1, VEGFR2, or VEGFR3. In some embodiments, the anti-VEGF receptor antibody or antigen-binding fragment thereof binds to VEGFR2. In some embodiments, the anti-VEGF receptor antibody is ramucirumab.

[0199] In certain embodiments, the anti-VEGF agent is a tyrosine kinase inhibitor. The tyrosine kinase inhibitor can inhibit, for example, VEGFR1, VEGFR2, and / or VEGFR3. In some embodiments, the tyrosine kinase inhibitor is cediranib. In some embodiments, the tyrosine kinase inhibitor is pazopanib. In some embodiments, the tyrosine kinase inhibitor is axitinib. In some embodiments, the tyrosine kinase inhibitor is vatalanib. In some embodiments, the tyrosine kinase inhibitor is semaxanib. In some embodiments, the tyrosine kinase inhibitor is sunitinib. In some embodiments, the tyrosine kinase inhibitor is sorafenib. In some embodiments, the tyrosine kinase inhibitor is ramucirumab. In some embodiments, the tyrosine kinase inhibitor is aflibercept.

[0200] In certain embodiments, the anti-VEGF agent is a soluble VEGF receptor protein. The soluble VEGF receptor protein can include the extracellular ligand-binding domain of VEGFR1. The soluble VEGF receptor protein can include the extracellular ligand-binding domain of VEGFR2. The soluble VEGF receptor protein can include the extracellular ligand-binding domains of VEGFR1 and VEGFR2. In some embodiments, the soluble VEGF receptor is VEGF-Trap (aflibercept), a fusion protein that combines the Fc portion of human IgG1 with the major extracellular ligand-binding domains of human VEGFR1 and VEGFR2.

[0201] IV. Platinum-based drugs Described herein are methods of administering an anti-FOLR1 immunoconjugate, such as IMGN853, in combination with a platinum-based agent, such as cisplatin, carboplatin, or oxaliplatin.

[0202] Cisplatin is a platinum-based, alkylating chemotherapy agent that forms DNA adducts and is therefore cytotoxic to cells with deficient excision repair (see Huang et al., PNAS 91:10394-10398 (1994)). Cisplatin is the parent compound of carboplatin. Like cisplatin, carboplatin forms DNA adducts that are cytotoxic to cells with deficient excision repair. Exemplary cisplatins include Platinol and Platinol-AQ.

[0203] Carboplatin is considered therapeutically equivalent to cisplatin (showing efficacy in the same and additional tissues compared to cisplatin), but has a significantly different (more favorable) toxicity profile (Lokich et al., Annals of Oncology 9:13-21 (1998)). Exemplary carboplatins include paraplatin.

[0204] Oxaliplatin is a third generation platinum drug. Exemplary oxaplatins include Eloxatin®.

[0205] Administration of a platinum-based agent in combination with an anti-FOLR1 immunoconjugate (e.g., IMGN853) can reduce the amount and / or frequency of the platinum-based agent required to achieve the same efficacy, thereby reducing the toxicity of the treatment. Administration of a platinum-based agent in combination with an anti-FOLR1 immunoconjugate (e.g., IMGN853) can also increase the efficacy of the treatment.

[0206] In some embodiments, the platinum-based agent is cisplatin, carboplatin, or oxaliplatin. In some embodiments, the platinum-based agent is cispatin or carboplatin. In some embodiments, the platinum-based agent is cisplatin. In some embodiments, the platinum-based agent is carboplatin.

[0207] V. Doxorubicin Described herein are methods of administering anti-FOLR1 immunoconjugates, such as IMGN853, in combination with doxorubicin.

[0208] Doxorubicin is an anthracycline antibiotic chemotherapy agent that can bind to DNA-associated enzymes such as topoisomerases and intercalate into DNA base pairs, thereby resulting in a range of cytotoxic effects and eventual cell apoptosis (Tacar et al., J. of Pharmacy & Pharmacology, 65:157-170 (2013)).

[0209] In some embodiments, the doxorubicin is pegylated. In some embodiments, the doxorubicin is not pegylated.

[0210] In some embodiments, the doxorubicin is liposomal. In some embodiments, the doxorubicin is not liposomal.

[0211] In some embodiments, the doxorubicin is pegylated, liposomal doxorubicin.

[0212] Exemplary doxorubicins include MYOCET® (Cephalon UK, Ltd.), DOX-NP (Avanti Polar Lipids, Inc.), CAELYX® (Janssen), and DOXIL® (Liposom Technology, Inc.).

[0213] Administration of doxorubicin in combination with an anti-FOLR1 immunoconjugate (e.g., IMGN853) can reduce the amount and / or frequency of doxorubicin required to achieve the same efficacy, thereby reducing the toxicity of the treatment. Administration of doxorubicin in combination with an anti-FOLR1 immunoconjugate (e.g., IMGN853) can also increase the efficacy of the treatment.

[0214] VI. Pharmaceutical Compositions and Kits As provided herein, anti-FOLR1 immunoconjugates (e.g., IMGN853) can be used in combination with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin to treat cancer.

[0215] In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) and the anti-VEGF agent (e.g., bevacizumab) are contained within the same pharmaceutical composition. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) and the anti-VEGF agent (e.g., bevacizumab) are contained within two separate pharmaceutical compositions within a single kit. In other embodiments, the kit comprises instructions for administering the anti-FOLR1 immune conjugate (e.g., IMGN853) and the anti-FOLR1 immune conjugate (e.g., IMGN853) and the anti-VEGF agent (e.g., bevacizumab). In other embodiments, the kit comprises instructions for administering the anti-VEGF agent (e.g., bevacizumab) and the anti-VEGF agent (e.g., bevacizumab) and the anti-FOLR1 immune conjugate (e.g., IMGN853).

[0216] In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) and the platinum-based agent are contained within the same pharmaceutical composition. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) and the platinum-based agent are contained within two separate pharmaceutical compositions within a single kit. In other embodiments, the kit comprises an anti-FOLR1 immune conjugate (e.g., IMGN853) and instructions for administering the anti-FOLR1 immune conjugate (e.g., IMGN853) and the platinum-based agent. In other embodiments, the kit comprises a platinum-based agent and instructions for administering the platinum-based agent and the anti-FOLR1 immune conjugate (e.g., IMGN853).

[0217] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are contained within the same pharmaceutical composition. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are contained within two separate pharmaceutical compositions within a single kit. In other embodiments, the kit includes instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin. In other embodiments, the kit includes instructions for administering doxorubicin and a platinum-based agent and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0218] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853), the anti-VEGF agent (e.g., bevacizumab), and the platinum-based agent are contained within the same pharmaceutical composition. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853), the anti-VEGF agent (e.g., bevacizumab), and the platinum-based agent are contained within two or three separate pharmaceutical compositions within a single kit.

[0219] In other embodiments, the kit comprises an anti-FOLR1 immunoconjugate (e.g., IMGN853) and instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and a platinum-based agent. In other embodiments, the kit comprises an anti-VEGF agent (e.g., bevacizumab) and instructions for administering the anti-VEGF agent (e.g., bevacizumab), an anti-FOLR1 immunoconjugate (e.g., IMGN853), and a platinum-based agent. In other embodiments, the kit comprises a platinum-based agent and instructions for administering the platinum-based agent, an anti-VEGF agent (e.g., bevacizumab), and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0220] In other embodiments, the kit comprises instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), as well as an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and a platinum-based agent. In other embodiments, the kit comprises instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853) and a platinum-based agent, as well as an anti-FOLR1 immunoconjugate (e.g., IMGN853), a platinum-based agent, and an anti-VEGF agent (e.g., bevacizumab). In other embodiments, the kit comprises instructions for administering an anti-VEGF agent (e.g., bevacizumab) and a platinum-based agent, as well as an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0221] In other embodiments, the kit comprises an anti-FOLR1 immunoconjugate (e.g., IMGN853) and instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and doxorubicin. In other embodiments, the kit comprises an anti-VEGF agent (e.g., bevacizumab) and instructions for administering the anti-VEGF agent (e.g., bevacizumab), an anti-FOLR1 immunoconjugate (e.g., IMGN853), and doxorubicin. In other embodiments, the kit comprises doxorubicin and instructions for administering doxorubicin, an anti-VEGF agent (e.g., bevacizumab), and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0222] In other embodiments, the kit comprises instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), as well as an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and doxorubicin. In other embodiments, the kit comprises instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin, as well as an anti-FOLR1 immunoconjugate (e.g., IMGN853), doxorubicin, and an anti-VEGF agent (e.g., bevacizumab). In other embodiments, the kit comprises instructions for administering an anti-VEGF agent (e.g., bevacizumab) and doxorubicin, as well as an anti-VEGF agent (e.g., bevacizumab), doxorubicin, and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0223] In other embodiments, the kit comprises an anti-FOLR1 immunoconjugate (e.g., IMGN853) and instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), a platinum-based agent, and doxorubicin. In other embodiments, the kit comprises a platinum-based agent and instructions for administering the platinum-based agent, the anti-FOLR1 immunoconjugate (e.g., IMGN853), and doxorubicin. In other embodiments, the kit comprises doxorubicin and instructions for administering doxorubicin, a platinum-based agent, and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0224] In other embodiments, the kit comprises instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853) and a platinum-based agent, and an anti-FOLR1 immunoconjugate (e.g., IMGN853), a platinum-based agent, and doxorubicin. In other embodiments, the kit comprises instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin, and an anti-FOLR1 immunoconjugate (e.g., IMGN853), doxorubicin, and a platinum-based agent. In other embodiments, the kit comprises instructions for administering a platinum-based agent and doxorubicin, and a platinum-based agent, doxorubicin, and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0225] In certain embodiments, the pharmaceutical compositions provided herein comprise an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin, and a pharmaceutically acceptable vehicle. In certain embodiments, the pharmaceutical composition further comprises a preservative. These pharmaceutical compositions are used to inhibit tumor growth and treat cancer in human patients.

[0226] Pharmaceutical compositions for use as described herein can be administered by any means for either local or systemic treatment. Administration can include topical, e.g., transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders; pulmonary (e.g., by inhalation or insufflation of powders or sprays, including nebulizers; intratracheal, intranasal, epidermal, and transdermal); oral; or parenteral, e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. In some embodiments, the pharmaceutical composition is formulated for intravenous (iv) administration. In some embodiments, the pharmaceutical composition is formulated for intraperitoneal (ip) administration.

[0227] VII.How to use As provided herein, anti-FOLR1 immunoconjugates (e.g., IMGN853) can be used in combination with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin to treat cancer.

[0228] VII.A. Cancer Options Cancers that can be treated by this method include, but are not limited to, neoplasia, tumor, metastasis, or any disease or disorder characterized by unregulated cell growth.Cancer can be primary or metastatic cancer.Specific examples of cancers that can be treated by the methods encompassed by the present invention include, but are not limited to, ovarian cancer, peritoneal cancer, fallopian tube cancer, lung cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, brain cancer, uterine cancer, non-clear cell renal carcinoma, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, endometrial cancer, and head and neck cancer.

[0229] More specific examples of such cancers include ovarian cancer, epithelial ovarian cancer, ovarian primary peritoneal cancer, or ovarian fallopian tube cancer. In some embodiments, the subject has previously untreated ovarian cancer. In some embodiments, the subject has newly diagnosed, previously untreated ovarian cancer (e.g., not previously treated with an anti-VEGF antibody, e.g., bevacizumab ("bevacizumab naive")). In other embodiments, the subject has previously treated ovarian cancer (e.g., previously treated with an anti-VEGF antibody, e.g., bevacizumab). In some embodiments, the subject has newly diagnosed, previously untreated (e.g., not previously treated with an anti-VEGF antibody, e.g., bevacizumab ("bevacizumab naive")), stage III (suboptimally and macroscopically optimally regressed) and IV epithelial ovarian primary peritoneal or fallopian tube cancer. In other embodiments, the subject has stage III (suboptimally and macrooptimally regressed) and IV epithelial ovarian, primary peritoneal, or fallopian tube cancer that has been previously treated (e.g., previously treated with an anti-VEGF antibody, e.g., bevacizumab). In some embodiments, the subject has platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. In other embodiments, the subject has platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.

[0230] In certain embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is administered to patients diagnosed with or with ovarian cancer, epithelial ovarian cancer, primary ovarian peritoneal cancer, or ovarian fallopian tube cancer who have not previously been treated with an anti-VEGF antibody, e.g., bevacizumab ("bevacizumab-naive"). In other embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is administered to patients diagnosed with or with ovarian cancer, epithelial ovarian cancer, primary ovarian peritoneal cancer, or ovarian fallopian tube cancer who have previously been treated with an anti-VEGF antibody, e.g., bevacizumab. In certain aspects of the above embodiments, the cancer is platinum-resistant, platinum-sensitive, platinum-sensitive recurrent, platinum-resistant recurrent, platinum-refractory, primary platinum-refractory, or recurrent.

[0231] The combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered to patients who have been previously treated with bevacizumab. In some embodiments, bevacizumab was administered as a single agent in the previous treatment. In some embodiments, bevacizumab was administered as part of a combination therapy in the previous treatment.

[0232] The combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered to patients who have not been previously treated with bevacizumab (i.e., the patients are "bevacizumab naive").

[0233] In certain embodiments, the cancer is ovarian, peritoneal, fallopian tube, endometrial, or lung cancer. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to ovarian, peritoneal, fallopian tube, endometrial, or lung cancer as a first-line therapy, a second-line therapy, a third-line therapy, or a fourth or later-line therapy. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to ovarian, peritoneal, fallopian tube, endometrial, or lung cancer as an adjuvant therapy or neoadjuvant therapy.

[0234] In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the ovarian cancer is epithelial ovarian cancer (EOC). In certain embodiments, the ovarian cancer (e.g., EOC) is platinum-resistant, recurrent, or refractory. A combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to EOC, e.g., platinum-resistant, recurrent, or refractory EOC, as a first-line therapy, a second-line therapy, a third-line therapy, or a fourth or later-line therapy. A combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to EOC, e.g., platinum-resistant, recurrent, or refractory EOC, as an adjuvant or neoadjuvant therapy.

[0235] In certain embodiments, the cancer is peritoneal cancer. In certain embodiments, the peritoneal cancer is primary peritoneal cancer. A combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to primary peritoneal cancer as a first-line therapy, a second-line therapy, a third-line therapy, or a fourth or later-line therapy. A combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or The doxorubicin combination can be administered as adjuvant or neoadjuvant therapy for primary peritoneal cancer.

[0236] In certain embodiments, the cancer is endometrial cancer. In certain embodiments, the endometrial cancer is serous endometrial cancer. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to serous endometrial cancer as a first-line therapy, a second-line therapy, a third-line therapy, or a fourth or later line therapy. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to serous endometrial cancer as an adjuvant therapy or neoadjuvant therapy.

[0237] In certain embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the lung cancer is adenocarcinoma or bronchioloalveolar carcinoma. A combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to lung cancer, such as NSCLC, adenocarcinoma, or bronchioloalveolar carcinoma, as first-line therapy, second-line therapy, third-line therapy, or fourth or later-line therapy. A combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to lung cancer, such as NSCLC, adenocarcinoma, or bronchioloalveolar carcinoma, as adjuvant therapy or neoadjuvant therapy.

[0238] In certain embodiments, the cancer is platinum-refractory. In certain embodiments, the cancer is primary platinum-refractory. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to platinum-refractory or primary platinum-refractory cancer as a first-line therapy, a second-line therapy, a third-line therapy, or a fourth or later-line therapy. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to platinum-refractory or primary platinum-refractory cancer as an adjuvant or neoadjuvant therapy.

[0239] In certain embodiments, the cancer is platinum-sensitive. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to platinum-sensitive cancers as a first-line therapy, a second-line therapy, a third-line therapy, or a fourth or subsequent line therapy. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to platinum-sensitive cancers as an adjuvant therapy or neoadjuvant therapy.

[0240] In certain embodiments, the cancer is metastatic or advanced cancer. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to metastatic or advanced cancer as a first-line therapy, a second-line therapy, a third-line therapy, or a fourth or later-line therapy. The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin can be administered to metastatic or advanced cancer as an adjuvant therapy or a neoadjuvant therapy.

[0241] Administration of a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as a "second-line" therapy includes administration where the first-line therapy was, for example, administration of a single agent, administration of a combination of agents, surgery, radiation, or a combination thereof.

[0242] Administration of a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as a "third-line" therapy includes administration where the first-line therapy was, for example, administration of a single agent, administration of a combination of agents, surgery, radiation, or a combination thereof, and the second-line therapy was, for example, administration of a single agent, administration of a combination of agents, surgery, radiation, or a combination thereof. Thus, administration of a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as a "third-line" therapy includes administration after, for example, the first-line therapy was administration of a single agent and the second-line therapy was administration of a combination of agents. Administration of a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as a "third-line" therapy includes, for example, administration after a first-line therapy in which the combination of agents was administered and a second-line therapy in which the single agents were administered. Administration of a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as a "third-line" therapy includes, for example, administration after a first-line therapy in which the combination of agents was administered and a second-line therapy in which the combination of agents was administered. Administration of a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as a "third line" therapy also includes, for example, administration after a first line therapy that was administration of the drug combination and surgery, as well as after a second line therapy that was administration of the drug combination.

[0243] In some embodiments, the cancer is a cancer that expresses FOLR1 (polypeptide or nucleic acid). In some embodiments, a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is administered to a patient with increased levels of FOLR1 expression, e.g., as described in U.S. Published Application No. 2012 / 0282175 or International Published Application WO2012 / 135675, both of which are incorporated by reference in their entireties. Exemplary antibodies, assays, and kits for detecting FOLR1 are provided in WO2014 / 036495 and WO2015 / 031815, both of which are incorporated by reference in their entireties. Thus, in some embodiments, FOLR1 protein expression is measured by immunohistochemistry (IHC), and a staining intensity score and / or staining uniformity score is assigned by comparison with a control (e.g., a calibration control) that exhibits a predetermined score (e.g., an intensity score of 3 is assigned to the test sample if the intensity corresponds to the level 3 calibration control, or an intensity score of 2 (moderate) is assigned to the test sample if the intensity corresponds to the level 2 calibration control). "Homogeneous" (i.e., at least 25% and less than 75% of cells stained) staining uniformity instead of "heterogeneous" (i.e., at least 25% and less than 75% of cells stained) or "focal" (i.e., greater than 0% and less than 25% of cells stained) also indicates increased FOLR1 expression. Staining intensity and staining uniformity scores can be used alone or in combination (e.g., 2 homogeneous, 2 heterogeneous, 3 homogeneous, 3 heterogeneous, etc.). In another example, increased FOLR1 expression can be determined by detecting an increase of at least 2-fold, at least 3-fold, or at least 5-fold compared to a control value (e.g., expression level in tissues or cells from a subject without cancer or with cancer in which FOLR1 levels are not elevated). In some embodiments, the staining uniformity score is based on the percentage of stained cells.

[0244] In some embodiments, the cancer is a cancer that expresses FOLR1 at a level of 1 heterogeneity or higher by IHC. In some embodiments, the cancer is a cancer that expresses FOLR1 at a level of 2 heterogeneity or higher by IHC. In some embodiments, the cancer is a cancer that expresses FOLR1 at a level of 3 heterogeneity or higher by IHC. In some embodiments, the cancer is a lung cancer that expresses FOLR1 at a level of 2 heterogeneity or higher by IHC. In some embodiments, the cancer is a lung cancer that expresses FOLR1 at a level of 3 heterogeneity or higher by IHC. In some embodiments, the cancer is an ovarian cancer that expresses FOLR1 at a level of 2 heterogeneity or higher by IHC. In some embodiments, the cancer is an ovarian cancer that expresses FOLR1 at a level of 3 heterogeneity or higher by IHC. In some embodiments, the cancer is an endometrial cancer that expresses FOLR1 at a level of 2 heterogeneity or higher by IHC. In some embodiments, the cancer is an endometrioid carcinoma that expresses FOLR1 at levels heterogeneous or higher by IHC.

[0245] In some embodiments, at least one cell in the sample obtained from the patient has a FOLR1 score of at least 1. In some embodiments, at least one cell in the sample obtained from the patient has a FOLR1 score of at least 2 (moderate). In some embodiments, at least one cell in the sample obtained from the patient has a FOLR1 score of at least 3.

[0246] In some embodiments, at least 25% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 1. In some embodiments, at least 33% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 1. In some embodiments, at least 50% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 1. In some embodiments, at least 66% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 1. In some embodiments, at least 75% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 1.

[0247] In some embodiments, at least 25% of cells in a sample obtained from a patient have a FOLR1 IHC score of at least 2 (moderate). In some embodiments, at least 33% of cells in a sample obtained from a patient have a FOLR1 IHC score of at least 2 (moderate). In some embodiments, 25-75% of cells in a sample obtained from a patient have a FOLR1 IHC score of at least 2 (moderate). In some embodiments, at least 50% of cells in a sample obtained from a patient have a FOLR1 IHC score of at least 2 (moderate). In some embodiments, at least 66% of cells in a sample obtained from a patient have a FOLR1 IHC score of at least 2 (moderate). In some embodiments, at least 75% of cells in a sample obtained from a patient have a FOLR1 IHC score of at least 2 (moderate).

[0248] In some embodiments, at least 25% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 33% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 50% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 66% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 75% of the cells in the sample obtained from the patient have a FOLR1 IHC score of at least 3.

[0249] In one embodiment, immunological detection of FOLR1 (by immunohistochemistry) is scored using an H-score, which combines a staining intensity score (e.g., a score of 0-3, where 0 represents no staining and 3 represents strong staining) with the percentage of cells positive for membrane staining (i.e., homogeneity). The H-score can be calculated as follows: H score = [0 * (Percentage of cells stained with 0 intensity (%))] + [1 * (Percentage of cells stained with intensity 1 (%))] + [2 * (Percentage of cells stained at intensity 2 (%))] + [3 * (percentage of cells stained with intensity 3)]. H-scores can therefore range from 0 (no cell membrane staining) to 300 (all cell membranes stained with intensity 3).

[0250] VII.B. Medication As provided herein, anti-FOLR1 immunoconjugates (e.g., IMGN853) can be administered at specific doses and / or at specific time intervals. Administration of anti-FOLR1 immunoconjugates (e.g., IMGN853) can be, for example, intravenous or intraperitoneal. Dosing regimens for anti-FOLR1 immunoconjugates (e.g., IMGN853) are provided, for example, in WO2014 / 186403, WO2015 / 054400, and WO2015 / 149018, each of which is incorporated herein by reference in its entirety.

[0251] For example, an anti-FOLR1 immunoconjugate (e.g., IMGN853) can be administered at a dose of about 0.15 mg / kg to about 7 mg / kg, where kilograms of body weight are adjusted to ideal body weight (IBW), lean body weight (LBW), body surface area (BSA), or adjusted ideal body weight (AIBW). An anti-FOLR1 immunoconjugate (e.g., IMGN853) can also be administered at a dose of about 1 mg / kg to about 6 mg / kg IBW, LBW, BSA, or AIBW. An anti-FOLR1 immunoconjugate (e.g., IMGN853) can also be administered at a dose of about 3 mg / kg to about 6 mg / kg IBW, LBW, BSA, or AIBW. An anti-FOLR1 immunoconjugate (e.g., IMGN853) can also be administered using split dosing.

[0252] Anti-FOLR1 immune conjugates (e.g., IMGN853) can be administered at a dose of about 0.15 mg / kg to about 7 mg / kg of total body weight (TBW). Anti-FOLR1 immune conjugates (e.g., IMGN853) can also be administered at a dose of about 1 mg / kg to about 6 mg / kg TBW. Anti-FOLR1 immune conjugates (e.g., IMGN853) can also be administered at a dose of about 3 mg / kg to about 6 mg / kg TBW.

[0253] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every three weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every three weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every three weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every three weeks.

[0254] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 4 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 4 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 4 weeks.

[0255] In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered every two weeks. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 2.0 mg / kg AIBW every two weeks. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 2.5 mg / kg AIBW every two weeks. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 3 mg / kg AIBW every two weeks. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 3.5 mg / kg AIBW every two weeks. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every two weeks.

[0256] In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered once a week. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 1.1 mg / kg AIBW weekly. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 1.8 mg / kg AIBW weekly. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 2.0 mg / kg AIBW weekly. In some embodiments, the anti-FOLR1 immune conjugate (e.g., IMGN853) is administered at a dose of about 2.5 mg / kg AIBW weekly.

[0257] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered once a week for three weeks on a four-week schedule (e.g., on days 1, 8, and 15 of a 28-day cycle).

[0258] As provided herein, the anti-VEGF agent can be administered at a specific dose and / or at a specific time interval. The anti-VEGF agent (e.g., bevacizumab) can also be administered using divided doses. The administration of the anti-VEGF agent (e.g., bevacizumab) can be, for example, intravenous.

[0259] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every three weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle).

[0260] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of about 15 mg / kg. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of about 10 mg / kg. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of about 7.5 mg / kg.

[0261] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of about 15 mg / kg. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered twice every four weeks at a dose of about 10 mg / kg each time. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 7.5 mg / kg.

[0262] In some embodiments, the anti-VEGF agent is a soluble VEGF receptor, e.g., VEGF-TRAP. In some embodiments, the anti-VEGF agent, e.g., VEGF-TRAP, is administered every two weeks. In some embodiments, the anti-VEGF agent, e.g., VEGF-TRAP, is administered at a dose of about 4 mg / kg. In some embodiments, the anti-VEGF agent, e.g., VEGF-TRAP, is administered at a dose of about 4 mg / kg every two weeks.

[0263] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of about 15 mg / kg, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every three weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of about 15 mg / kg, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every three weeks at a dose of about 4 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of about 15 mg / kg, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every three weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of about 15 mg / kg, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every three weeks at a dose of about 6 mg / kg AIBW.

[0264] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 4 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every four weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every four weeks.

[0265] As provided herein, the platinum-based drug can be administered at a specific dose and / or at a specific time interval. The administration of the platinum-based drug can be, for example, intravenous. The platinum-based drug can be, for example, carboplatin or cisplatin.

[0266] As provided herein, carboplatin can be administered at a specific dose and / or at a specific time interval. Administration of carboplatin can be, for example, intravenous.

[0267] In some embodiments, the carboplatin is administered every three weeks.

[0268] The formula for calculating the dosage is based on the patient's glomerular filtration rate (GFR in mL / min) and the carboplatin injection target area under the concentration versus time curve (AUC in mg / mL min), and can be used: total dose (mg) = (target AUC) × (GFR + 25).

[0269] In some embodiments, carboplatin is administered at a dose that produces an AUC of 4 mg / mL min. In some embodiments, carboplatin is administered at a dose that produces an AUC of 5 mg / mL min. In some embodiments, carboplatin is administered at a dose that produces an AUC of 6 mg / mL min. In some embodiments, carboplatin is administered at a dose that produces an AUC of 7 mg / mL min.

[0270] In some embodiments, carboplatin is administered at a dose that produces an AUC of 4 mg / mL·min every 3 weeks. In some embodiments, carboplatin is administered at a dose that produces an AUC of 5 mg / mL·min every 3 weeks. In some embodiments, carboplatin is administered at a dose that produces an AUC of 6 mg / mL·min every 3 weeks. In some embodiments, carboplatin is administered at a dose that produces an AUC of 7 mg / mL·min every 3 weeks.

[0271] In some embodiments, the carboplatin is administered every four weeks.

[0272] In some embodiments, carboplatin is administered at 360 mg / m 2 In some embodiments, carboplatin is administered at a dose of about 300 mg / m 2 is administered at a dose of

[0273] In some embodiments, carboplatin is administered at 360 mg / m every 4 weeks. 2In some embodiments, carboplatin is administered at a dose of about 300 mg / m every 4 weeks. 2 is administered at a dose of

[0274] As provided herein, cisplatin can be administered at a specific dose and / or at a specific time interval. The administration of cisplatin can be, for example, intravenous.

[0275] In some embodiments, cisplatin is administered every four weeks. In some embodiments, cisplatin is administered every three weeks.

[0276] In some embodiments, cisplatin is at about 100 mg / m 2 In some embodiments, cisplatin is administered at a dose of about 75-100 mg / m 2 In some embodiments, cisplatin is administered at a dose of about 50-70 mg / m 2 In some embodiments, cisplatin is administered at a dose of about 20 mg / m 2 is administered at a dose of

[0277] In some embodiments, cisplatin is administered at about 100 mg / m every 4 weeks. 2 In some embodiments, cisplatin is administered at a dose of about 75-100 mg / m every 4 weeks. 2 is administered at a dose of

[0278] In some embodiments, cisplatin is administered at about 50-70 mg / m every 3 weeks. 2 is administered at a dose of

[0279] In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 3 weeks.

[0280] In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 3 weeks.

[0281] In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 3 weeks.

[0282] In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 3 weeks.

[0283] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg AIBW, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min , and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg AIBW, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL min , and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0284] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0285] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0286] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, the carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg AIBW, the carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg AIBW, and the carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL min. The anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every 3 weeks.

[0287] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 4 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every three weeks at a dose producing an AUC of 4 mg / mL·min. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 4 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 4 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 6 mg / kg AIBW.

[0288] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 5 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every three weeks at a dose producing an AUC of 5 mg / mL·min. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 5 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 5 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 6 mg / kg AIBW.

[0289] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 6 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every three weeks at a dose producing an AUC of 6 mg / mL·min. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 6 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 6 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 6 mg / kg AIBW.

[0290] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 7 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every three weeks at a dose producing an AUC of 7 mg / mL·min. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 7 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 5 mg / kg AIBW. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered every two weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every four weeks (e.g., on days 1 and 15 of a 28-day cycle) at a dose of about 10 mg / kg each time, carboplatin is administered every three weeks at a dose producing an AUC of 7 mg / mL·min, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every four weeks at a dose of about 6 mg / kg AIBW.

[0291] As provided herein, doxorubicin can be administered at a specific dose and / or at a specific time interval. Administration of doxorubicin (e.g., pegylated liposomal doxorubicin (PLD)) can be, for example, intravenous.

[0292] In some embodiments, doxorubicin (eg, PLD) is administered every four weeks.

[0293] In some embodiments, doxorubicin (e.g., PLD) is administered at about 30 mg / m 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 35 mg / m 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 40 mg / m 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 45 mg / m 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 50 mg / m 2 is administered at a dose of

[0294] In some embodiments, doxorubicin (e.g., PLD) is administered at about 30 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 35 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 40 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 45 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 50 mg / m every 4 weeks. 2 is administered at a dose of

[0295] In some embodiments, doxorubicin (e.g., PLD) is administered at about 30 mg / m every 4 weeks. 2and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 30 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 30 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 30 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 4 weeks.

[0296] In some embodiments, doxorubicin (e.g., PLD) is administered at about 35 mg / m every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 35 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 35 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 35 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 4 weeks.

[0297] In some embodiments, doxorubicin (e.g., PLD) is administered at about 40 mg / m every 4 weeks. 2and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 40 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 40 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 40 mg / m every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 4 weeks.

[0298] In some embodiments, doxorubicin (e.g., PLD) is administered at about 45 mg / m every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 45 mg / m every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 45 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 45 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 4 weeks.

[0299] In some embodiments, doxorubicin (e.g., PLD) is administered at about 50 mg / m every 4 weeks. 2and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 50 mg / m every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 50 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 4 mg / kg AIBW every 4 weeks. 2 In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of about 50 mg / m every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 5 mg / kg AIBW every 4 weeks. 2 and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of about 6 mg / kg AIBW every 4 weeks.

[0300] In one example, an immunoconjugate that binds to FOLR1 (e.g., IMGN853) and an anti-VEGF agent are administered simultaneously. In one example, an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent are administered in separate pharmaceutical compositions. In one example, an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent are administered in the same pharmaceutical composition. In one example, an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent are administered sequentially. In such an example, a platinum-based agent or doxorubicin can optionally be administered simultaneously with the anti-FOLR1 immunoconjugate (e.g., IMGN853) (in the same pharmaceutical composition or separate pharmaceutical compositions). A platinum-based agent or doxorubicin can also optionally be administered simultaneously with the anti-VEGF agent (in the same pharmaceutical composition or separate pharmaceutical compositions). The platinum-based agent or doxorubicin can also be administered in any order with the anti-FOLR1 immunoconjugate (eg, IMGN853) and / or anti-VEGF agent, optionally in any order.

[0301] In one example, the immunoconjugate that binds to FOLR1 (e.g., IMGN853) and the platinum-based agent are administered simultaneously. In one example, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the platinum-based agent are administered in separate pharmaceutical compositions. In one example, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the platinum-based agent are administered in the same pharmaceutical composition. In one example, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the platinum-based agent are administered sequentially. In such an example, the anti-VEGF agent or doxorubicin can optionally be administered simultaneously with the anti-FOLR1 immunoconjugate (e.g., IMGN853) (in the same pharmaceutical composition or separate pharmaceutical compositions). The anti-VEGF agent or doxorubicin can also optionally be administered simultaneously with the platinum-based agent (in the same pharmaceutical composition or separate pharmaceutical compositions). The anti-VEGF agent or doxorubicin can also be administered, optionally sequentially, with the anti-FOLR1 immunoconjugate (e.g., IMGN853) and / or platinum-based agent.

[0302] In one example, the immunoconjugate that binds to FOLR1 (e.g., IMGN853) and doxorubicin are administered simultaneously. In one example, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are administered in separate pharmaceutical compositions. In one example, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are administered in the same pharmaceutical composition. In one example, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are administered sequentially. In such examples, the anti-VEGF agent or platinum-based agent can optionally be administered simultaneously with the anti-FOLR1 immunoconjugate (e.g., IMGN853) (in the same pharmaceutical composition or separate pharmaceutical compositions). The anti-VEGF agent or platinum-based agent can also optionally be administered simultaneously with doxorubicin (in the same pharmaceutical composition or separate pharmaceutical compositions). The anti-VEGF agent or platinum-based agent can also be administered, optionally sequentially, with the anti-FOLR1 immunoconjugate (e.g., IMGN853) and / or doxorubicin.

[0303] VII.C. Evaluation and Monitoring In certain embodiments, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is useful for inhibiting tumor growth. In certain embodiments, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is useful for inducing tumor cell differentiation. In certain embodiments, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is useful for reducing tumor volume.

[0304] For example, in some embodiments, treatment with a combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin results in a %T / C value that is less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%.

[0305] In certain embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can reduce tumor size in ovarian cancer (e.g., epithelial ovarian cancer) and / or lung cancer xenograft models. In certain embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can reduce tumor size in ST088, OV90, and / or IGROV-1 xenograft models. In certain embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can reduce tumor size in an H2110 xenograft model.

[0306] In some embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based drug, and / or doxorubicin can inhibit metastasis. In certain embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based drug, and / or doxorubicin can reduce the tumorigenicity of a tumor. The method of use can be an in vivo method.

[0307] In certain embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin produces a synergistic effect. For example, the combination of an anti-VEGF agent (e.g., bevacuzimab) and a FOLR1 immunoconjugate (e.g., IMGN853) can be synergistic as a result of the fact that the anti-VEGF agent (e.g., bevacuzimab) increases or enhances IMGN853 tumor localization or activation. Thus, in some embodiments, the anti-VEGF agent (e.g., bevacuzimab) is administered prior to administration of the FOLR1 immunoconjugate (e.g., IMGN853).

[0308] In certain embodiments, administration of a FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin produces less toxicity than administration of an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In some embodiments, administration of a FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin produces less toxicity than administration of an anti-FOLR1 immunoconjugate. In some embodiments, administration of a FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin produces less toxicity than administration of either an anti-FOLR1 immunoconjugate or an anti-VEGF agent, a platinum-based agent, and / or doxorubicin.

[0309] Each of the above aspects further includes monitoring the subject for cancer recurrence. Monitoring can be accomplished, for example, by assessing progression-free survival (PFS), overall survival (OS), objective response (ORR), complete response (CR), and partial response (PR). In one embodiment, PFS is assessed after initiation of treatment. In some embodiments, PFS is extended by about 1 month, 1.2 months, 2 months, 2.9 months, 3 months, 3.8 months, 4 months, 6 months, 7 months, 8 months, 9 months, 1 year, about 2 years, about 3 years, etc., compared to a control. In one embodiment, PFS is extended by about 2.9 to 3.8 months with a treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin, compared to a control. In one embodiment, PFS is extended by at least about 3.8 months with a treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin compared to a control. In another embodiment, PFS is extended by about 2.3 months with a treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin compared to a control. In one embodiment, PFS is extended by about 6 months with a treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin compared to a control.

[0310] VII.D. Additional Treatment A steroid can be administered in addition to a combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In some embodiments, administration of a steroid in addition to a combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin results in a reduction in headache compared to administration of the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin alone.

[0311] The steroid can be administered at the same time as the immunoconjugate, before administration of the immunoconjugate, and / or after administration of the immunoconjugate. In some embodiments, the steroid is administered about 1 week, about 5 days, about 3 days, about 2 days, or about 1 day or 24 hours before administration of the immunoconjugate. In some embodiments, the steroid is administered within 1 day of administration of the immunoconjugate. In some embodiments, the steroid is administered multiple times. In some embodiments, In some embodiments, the steroid is administered about one day prior to and on the same day as administration of the immunoconjugate. The steroid can be administered via any number of methods, including, for example, topical, pulmonary, oral, parenteral, or intracranial administration. In some embodiments, administration is oral. In some embodiments, administration is intravenous. In some embodiments, administration is both oral and intravenous.

[0312] In some embodiments, the steroid is administered in eye drops, hi some embodiments, the eye drops are preservative-free, lubricating eye drops.

[0313] Another analgesic or other medication for preventing or treating headaches can also be administered in addition to the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. For example, acetaminophine and / or dephenhydramine can be administered in addition to the combination of a FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. The analgesic can be administered before, simultaneously with, or after administration of the immunoconjugate and can be via any suitable route of administration. In some embodiments, the analgesic is administered orally.

[0314] Embodiments of the present disclosure can be further defined by reference to the following non-limiting examples, which detail the preparation of certain antibodies of the present disclosure and methods for using the antibodies of the present disclosure. It will be apparent to those skilled in the art that numerous modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure. [Example]

[0315] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes therein will be suggested to those skilled in the art and will be included within the spirit and scope of the present application.

[0316] Example 1 IMGN853+PLD combination therapy is more active than IMGN853 and PLD monotherapy in the ST088 epithelial ovarian cancer tumor model. The antitumor activity of IMGN853 was evaluated as monotherapy and in combination with pegylated liposomal doxorubicin (PLD) in female SCID mice bearing ST088 human epithelial ovarian cancer patient-derived tumor xenografts. CB17 SCID mice were randomized by tumor volume into groups (n=8 per group) and dosed sequentially. The groups included a control group dosed with IMGN853 formulation buffer (vehicle) ("Control" in Figure 1), an IMGN853 monotherapy group dosed at 5 mg / kg once every 7 days (weekly) for 2 weeks (QW x 2) ("IMGN853" in Figure 1), a PLD monotherapy group dosed at 4 mg / kg QW x 2 ("PLD" in Figure 1), and an IMGN853 + PLD combination group dosed with a 5 mg / kg QW x 2 dose of IMGN853 in combination with a 4 mg / kg QW x 2 dose of PLD ("IMGN853 + PLD" in Figure 1).

[0317] Tumor volume was measured twice weekly in three dimensions using calipers. Body weight was measured twice weekly as an indicator of test drug toxicity. Activity was assessed as described in Bissery et al., Cancer Res. 51:4845-4852 (1991). Figure 1 shows the results.

[0318] IMGN853 dosed at 5 mg / kg QW x 2 was active as monotherapy (T / C 31%, 0 / 8 partial responses (PR), and 0 / 8 complete responses (CR)). Furthermore, IMGN853 monotherapy was well tolerated, and no significant weight loss was observed. PLD dosed at 4 mg / kg QW x 2 was also active as monotherapy (T / C 21%, 0 / 8 PR, and 0 / 8 CR). PLD monotherapy resulted in a median body weight loss (BWL) of 19% at nadir (day 15 post-dose). The IMGN853 + PLD combination was highly active and more active than IMGN853 and PLD monotherapy (T / C 10%, 0 / 8 PR, and 0 / 8 CR). Combination therapy with IMGN853 and PLD resulted in weight loss comparable to PLD monotherapy (16% at nadir). See Figure 1. Thus, combination therapy with IMGN853 and PLD increased efficacy without increasing toxicity.

[0319] Example 2 IMGN853 (5 mg / kg) + bevacizumab combination therapy is more active than IMGN853 monotherapy and anti-bevacizumab monotherapy in the OV90 ovarian cancer tumor model. The antitumor activity of IMGN853 was evaluated in female SCID mice bearing OV90 serous ovarian tumor xenografts as monotherapy and in combination with the anti-VEGF antibody bevacizumab. Mice were randomized by tumor volume into groups (n=6 per group) and then dosed 14 days post-inoculation. Groups included a control group that received a single dose (1×) of IMGN853 formulation buffer (“Vehicle” in FIG. 2A), an IMGN853 single agent group dosed at 5 mg / kg 1× (“IMGN853” in FIG. 2A), a bevacizumab single agent group dosed at 5 mg / kg 1× (“Bevacizumab” in FIG. 2A), and an IMGN853 + bevacizumab combination group dosed at a 5 mg / kg 1× dose of IMGN853 in combination with 5 mg / kg 1× bevacizumab (“IMGN853 + Bevacizumab” in FIG. 2A).

[0320] Tumor volumes were measured once to twice weekly in three dimensions using calipers. Tumor volume was calculated in mm using the formula V = length × width × height × ½. 3 The results are expressed in units (Tomayko and Reynolds, Cancer Chemother. Pharmacol. 24:148-54 (1989)). Body weight was measured twice weekly as an index of toxicity. Activity was assessed as described by Bissery et al. (1991). Figure 2A shows the results.

[0321] At 5 mg / kg, single-dose IMGN853 was active as monotherapy (T / C 36%, 1 / 5 CR, and 0 / 5 tumor-free survival (TFS)). Single-dose bevacizumab at 5 mg / kg was also active as monotherapy (T / C 37%, 0 / 6 CR, and 0 / 6 TFS). The IMGN853 + bevacizumab combination (each 5 mg / kg) was highly active, more active than both IMGN853 and bevacizumab monotherapy (T / C 9%, 6 / 6 CR, 1 / 6 TFS). See Figure 2A. All treatments were well tolerated, and no significant weight loss was observed in any treatment group. Thus, combination therapy with IMGN853 and bevacizumab increased efficacy without increasing toxicity.

[0322] Example 3 IMGN853 (2.5 mg / kg) + bevacizumab combination therapy is more active than IMGN853 and bevacizumab monotherapy in the OV90 ovarian cancer tumor model. The antitumor activity of IMGN853 was evaluated in female SCID mice bearing OV90 serous ovarian tumor xenografts as monotherapy and in combination with the anti-VEGF antibody bevacizumab. Mice were randomized by tumor volume into groups (n=6 per group) and then dosed 14 days post-inoculation. Groups included a control group that received a single dose (1×) of IMGN853 formulation buffer (“Vehicle” in FIG. 2B), an IMGN853 single agent group dosed at 2.5 mg / kg 1× (“IMGN853” in FIG. 2B), a bevacizumab single agent group dosed at 5 mg / kg 1× (“Bevacizumab” in FIG. 2B), and an IMGN853 + bevacizumab combination group that received a 2.5 mg / kg 1× dose of IMGN853 in combination with 5 mg / kg 1× bevacizumab (“IMGN853 + Bevacizumab” in FIG. 2B).

[0323] Tumor volumes were measured once to twice weekly in three dimensions using calipers. Tumor volume was calculated in mm using the formula V = length × width × height × ½. 3 The activity was expressed in units (Tomayko 1989). Body weight was measured twice a week as an index of toxicity. (1991). Figure 2B shows the results.

[0324] At 2.5 mg / kg, single-dose IMGN853 was active as monotherapy (T / C 36%, 0 / 6 CR, and 0 / 6 TFS). At 5.0 mg / kg, single-dose bevacizumab was active (T / C 31%, 0 / 6 CR, and 0 / 6 TFS). As monotherapy, bevacizumab exhibited comparable antitumor activity at these dose levels compared to IMGN853; however, neither agent induced sustained tumor growth inhibition or tumor regression. In stark contrast, the combination of IMGN853 plus bevacizumab resulted in robust tumor regression in all animals (Figure 2B). The IMGN853 + bevacizumab combination (2.5 mg / kg IMGN853 + 5 mg / kg bevacizumab) was more active than both IMGN853 and bevacizumab monotherapy (T / C 17%, 6 / 6 CR, and 0 / 6 TFS). See Figure 2B. Note that a similar combination benefit was achieved when the IMGN853 dose was further reduced to 1.25 mg / kg (Figure 3). All treatments were well tolerated, and no significant weight loss was observed in any treatment group. Thus, combination therapy with IMGN853 and bevacizumab increased efficacy without increased toxicity.

[0325] Next, we examined the effect of fractionated bevacizumab dosing, for which animals received bevacizumab as either a single 5 mg / kg dose or two 2.5 mg / kg doses (QW × 2), both as monotherapy and in combination with 3 mg / kg IMGN853 (Figure 11A). Fractionated dosing did not affect bevacizumab efficacy, and similar (moderate) growth inhibitory effects were seen after treatment with single-agent IMGN853. Exposure to both combination regimens resulted in rapid tumor stabilization and dramatic regression (up to 38% within 10 days of treatment), particularly in the IMGN853 plus 5 mg / kg bevacizumab cohort, where dual therapy was therapeutic for all 7 animals (Figure 11A). Again, IMGN853 and bevacizumab combination treatment was well tolerated.

[0326] Finally, the efficacy of IMGN853 was evaluated in combination with bevacizumab in the same platinum-resistant PDX model, as shown in Figure 11B. Unlike the modest activity seen with IMGN853 monotherapy, single-agent bevacizumab exposure (5 mg / kg, QW × 2) prolonged growth control of these aggressive tumors (data not shown), although no CRs were observed over the 102-day study course. Consistent with the OV-90 results, the combination of IMGN853 and bevacizumab (both 5 mg / kg, QW × 2) induced tumor regression in all mice, superior to either monotherapy. CRs were observed in 7 / 8 animals. Indeed, analysis of tumor volume at the end of the study revealed a significant reduction in tumor burden in the combination treatment group compared with bevacizumab-treated animals alone (Figure 11B). Furthermore, this effect was not reproduced in animals treated with a combination of bevacizumab and paclitaxel (10 mg / kg), indicating that the therapeutic benefit conferred by the addition of IMGN853 to antiangiogenic drugs is functionally specific to the ADC molecule.

[0327] Example 4 IMGN853 (1.25 mg / kg) plus bevacizumab combination therapy is more active than IMGN853 monotherapy, bevacizumab monotherapy, and bevacizumab plus paclitaxel combination therapy in the OV90 ovarian cancer tumor model. The antitumor activity of IMGN853 was evaluated in combination with bevacizumab in female SCID mice bearing OV90 serous ovarian tumor xenografts. Mice were randomized by tumor volume into groups (n=8 per group) and then dosed 14 days post-inoculation. All treatments consisted of a single dose (1X). Groups included a control group dosed with IMGN853 formulation buffer ("Vehicle" in Figure 3), an IMGN853 single agent group dosed at 1.25 mg / kg 1X ("IMGN853-1.25" in Figure 3), a paclitaxel single agent group dosed at 10 mg / kg 1X ("Paclitaxel-10" in Figure 3), a bevacizumab single agent group dosed at 5 mg / kg 1X ("Bevacizumab-5" in Figure 3), an IMGN853 + bevacizumab combination group dosed at 1.25 mg / kg 1X and 5 mg / kg 1X, respectively ("IMGN853+BEV" in Figure 3), and a paclitaxel + bevacizumab combination group dosed at 10 mg / kg 1X and 5 mg / kg 1X, respectively ("PAC+BEV" in Figure 3).

[0328] Tumor volumes were measured in three dimensions using calipers once to twice weekly. Tumor volume was expressed in mm3 using the formula V = length x width x height x 1 / 2 (Tomayko 1989). Body weight was measured twice weekly as an indicator of toxicity. Activity was assessed by Bissery et al. The results were evaluated as described by [Eds.] et al. (1991). Figure 3 shows the results.

[0329] At 1.25 mg / kg, single-dose IMGN853 was active as monotherapy (T / C 37%, 0 / 7 CR, and 0 / 7 TFS). Single-agent paclitaxel was inactive (T / C 94%, 0 / 6 CR, and 0 / 6 TFS). Single-dose bevacizumab was active (T / C 22%, 0 / 8 CR, and 0 / 8 TFS). The paclitaxel + bevacizumab combination was active (T / C 12%, 0 / 8 CR, and 0 / 8 TFS). The IMGN853 + bevacizumab combination was highly active, outperforming all single-agent treatments and paclitaxel + bevacizumab combination treatments (T / C 5%, 5 / 8 CR, and 0 / 8 TFS). See Figure 3. All treatments were well tolerated. Therefore, the combination of bevacizumab and IMGN853 was more effective than the combination of bevacizumab and another treatment.

[0330] Example 5 IMGN853 + bevacizumab combination therapy is more active than IMGN853 and bevacizumab monotherapy in the IGROV-1 epithelial ovarian tumor model. The antitumor activity of IMGN853 was evaluated in female SCID mice bearing IGROV-1 ovarian tumor xenografts as monotherapy and in combination with bevacizumab. Mice were randomized by tumor volume into groups (n=6 per group) and then dosed 14 days post-inoculation. All treatments consisted of a single dose (1X). Groups included a control group dosed with IMGN853 formulation buffer ("Vehicle" in Figure 4), an IMGN853 single agent group dosed at 5 mg / kg 1X ("IMGN853-5" in Figure 4), a bevacizumab single agent group dosed at 5 mg / kg 1X ("Bevacizumab-5" in Figure 4), and an IMGN853 + bevacizumab combination group dosed at 5 mg / kg IMGN853 and 5 mg / kg bevacizumab ("IMGN853+BEV" in Figure 4).

[0331] Tumor volumes were measured once to twice weekly in three dimensions using calipers. Tumor volume was calculated in mm using the formula V = length × width × height × ½. 3The results are expressed in units (Tomayko 1989). Body weight was measured twice a week as an index of toxicity. Activity was assessed as described by Bissery et al. (1991). Figure 4 shows the results.

[0332] IMGN853 was active as monotherapy (T / C 20%, 0 / 4 CR, and 0 / 4 TFS). Bevacizumab was inactive as monotherapy (T / C 51%, 0 / 4 CR, and 0 / 4 TFS). IMGN853 + bevacizumab combination therapy was highly active, more active than IMGN853 and bevacizumab monotherapy (T / C 5%, 3 / 6 CR, and 0 / 6 TFS). See Figure 4. All treatments were well tolerated, and no significant weight loss was observed in any treatment group. Thus, combination therapy with IMGN853 and bevacizumab increased efficacy without increasing toxicity.

[0333] Example 6 The IMGN853 plus bevacizumab combination is more active than IMGN853 monotherapy, bevacizumab monotherapy, and paclitaxel plus bevacizumab combination therapy in the ST088 epithelial ovarian cancer tumor model. The antitumor activity of IMGN853 was evaluated as monotherapy and in combination with bevacizumab in female SCID mice bearing ST088 human epithelial ovarian cancer (EOC) patient-derived tumor xenografts. CB17 SCID mice were randomized by tumor volume into groups (n=8 per group) and then dosed. Groups included a control group (vehicle) dosed with IMGN853 formulation buffer ("Control" in Figure 5), an IMGN853 monotherapy group dosed at 5 mg / kg QW x 2 ("IMGN853" in Figure 5), a bevacizumab monotherapy group dosed at 5 mg / kg QW x 2 ("Bev" in Figure 5), and an IMGN853 + bevacizumab combination group dosed with IMGN853 at 5 mg / kg QW x 2 and bevacizumab at 5 mg / kg QW x 2 ("IMGN853+Bev" in Figure 5).

[0334] For comparison, another group of mice was dosed with paclitaxel at 10 mg / kg QW×2, and an additional group of mice was dosed with a combination of paclitaxel at 10 mg / kg QW×2 and bevacizumab at 5 mg / kg QW×2.

[0335] Tumor volume was measured twice weekly in three dimensions using calipers. Body weight was measured twice weekly as an indicator of toxicity. Activity was assessed as described by Bissery et al. (1991). Figure 5 shows the results.

[0336] IMGN853 dosed at 5 mg / kg QW x 2 was active as monotherapy (T / C 31%) with no regressions (0 / 8 PR and 0 / 8 CR). Bevacizumab dosed at 5 mg / kg QW x 2 was highly active as monotherapy (T / C 6%); however, no regressions (0 / 8 PR and 0 / 8 CR). Paclitaxel dosed at 10 mg / kg QW x 2 was inactive (T / C 71%, 0 / 8 PR, and 0 / 8 CR). The paclitaxel + bevacizumab combination was highly active (T / C 6%, 6 / 8 PR, and 0 / 8 CR). The IMGN853 + bevacizumab combination was also highly active (T / C 3%, 7 / 8 PR, and 0 / 8 CR). The median tumor volume in the group treated with the IMGN853 + bevacizumab combination was smaller than that in the group treated with the paclitaxel + bevacizumab combination at the end of the study (37 vs. 463 mm, respectively, at 109 days post-dose). 3 ) See Figure 5. All treatments were well tolerated and no significant weight loss was observed in any treatment group.

[0337] Example 7 IMGN853 + bevacizumab combination therapy is more active than IMGN853 and bevacizumab monotherapy in the H2110 non-small cell lung cancer tumor model. The antitumor activity of IMGN853 was evaluated as monotherapy and in combination with bevacizumab in female SCID mice bearing H2110 non-small cell lung cancer (NSCLC) tumor xenografts. Mice were randomized by tumor volume into groups (n = 6-10 per group) and then dosed on day 7 post-inoculation. All treatments consisted of a single dose (1X). The groups included a control group dosed with IMGN853 formulation buffer ("Vehicle" in Figure 6), an IMGN853 monotherapy group dosed at 3 mg / kg ("IMGN853 3 mg / kg" in Figure 6), an IMGN853 monotherapy group dosed at 1.5 mg / kg ("IMGN853 1.5 mg / kg" in Figure 6), a bevacizumab monotherapy group dosed at 5 mg / kg ("Bevacizumab 5 mg / kg" in Figure 6), and an IMGN853 + bevacizumab combination group dosed with 5 mg / kg bevacizumab and 3 mg / kg IMGN853 ("IMGN853 3 mg / kg + Bevacizumab" in Figure 6). 5mg / kg"), and an IMGN853 + bevacizumab combination group dosed with 5mg / kg bevacizumab and 1.5mg / kg IMGN853 ("IMGN853 1.5mg / kg+Bev 5mg / kg" in Figure 6).

[0338] Tumor volumes were measured once to twice weekly in three dimensions using calipers. Tumor volume was calculated in mm using the formula V = length × width × height × ½. 3 The data were expressed in units (Tomayko 1989). Body weight was measured twice a week as an index of test drug toxicity. Activity was assessed as described by Bissery et al. (1991). Figure 6 shows the results.

[0339] IMGN853 was active as monotherapy at 3 mg / kg 1X (T / C 25%, 2 / 6PR, 0 / 6CR, and 0 / 6TFS) but was inactive at 1.5 mg / kg 1X (T / C 64%, 1 / 6PR, 0 / 6CR, and 0 / 6TFS). Single-dose bevacizumab at 1X was also active as monotherapy (T / C 22%, 0 / 6PR, 0 / 6CR, and 0 / 6TFS). The combination of IMGN853 at 3 mg / kg 1X + bevacizumab at 5 mg / kg 1X was highly active (T / C 0%, 10 / 10PR, 6 / 10CR, and 4 / 10TFS). The combination of IMGN853 at 1.5 mg / kg 1X + bevacizumab at 5 mg / kg 1X was also highly active (T / C 9%, 3 / 10PR, 1 / 10CR, and 0 / 10TFS). Significant weight loss was observed. Weight loss is believed to be disease-related, as the vehicle-treated group experienced an 11% loss from baseline weight by day 25 post-inoculation. The IMGN853 3 mg / kg monotherapy group experienced a 9% weight loss on day 42 after inoculation, and the IMGN853 1.5 mg / kg monotherapy group experienced an 8% weight loss on day 25 after inoculation. The bevacizumab monotherapy group had a 9% weight loss on day 49 after inoculation. See Figure 6. The IMGN853 + bevacizumab combination therapy was well tolerated, and no significant weight loss was observed. Therefore, combination therapy with IMGN853 and bevacizumab increased efficacy while reducing toxicity.

[0340] Example 8 The IMGN853 + carboplatin combination is more active than the paclitaxel + carboplatin combination in the OV90 ovarian cancer tumor model. The antitumor activity of IMGN853 was evaluated in female SCID mice bearing OV90 ovarian tumor xenografts in combination with carboplatin and in triple combination with both carboplatin and bevacizumab. Mice were randomized by tumor volume into groups (n=6 per group) and then dosed 14 days post-inoculation. All treatments consisted of a single dose (1X). The groups included a control group dosed with IMGN853 formulation buffer ("Vehicle" in Figure 7), an IMGN853 + carboplatin combination group dosed at 5 mg / kg 1X and 100 mg / kg 1X respectively ("CARBO+IMGN853" in Figure 7), an IMGN853 + carboplatin + bevacizumab triple combination group dosed at 5 mg / kg 1X, 100 mg / kg 1X, and 5 mg / kg 1X respectively ("CARBO+IMGN853+Bev" in Figure 7), a paclitaxel + carboplatin combination group dosed at 10 mg / kg 1X and 100 mg / kg 1X respectively ("CARBO+PAC" in Figure 7), and a paclitaxel + carboplatin combination group dosed at 10 mg / kg 1X, 100 mg / kg 1X, and 5 mg / kg 1X respectively. A paclitaxel + carboplatin + bevacizumab triple combination group dosed 1X ("CARBO+PAC+Bev" in Figure 7) was included.

[0341] Tumor volumes were measured once to twice weekly in three dimensions using calipers. Tumor volume was calculated in mm using the formula V = length × width × height × ½. 3 The activity was expressed in units (Tomayko 1989). Body weight was measured twice a week as an index of toxicity. (1991). Figure 7 shows the results.

[0342] The combination of IMGN853 + carboplatin was highly active (T / C 10%, 3 / 6 CR, and 0 / 6 TFS). The combination of paclitaxel + carboplatin was inactive (45% T / C, 0 / 6 CR, and 0 / 6 TFS). The triple combination of IMGN853 + carboplatin + bevacizumab was highly active (5% T / C, 6 / 6 CR, and 0 / 6 TFS). The triple combination of paclitaxel + carboplatin + bevacizumab was active (16% T / C, 1 / 6 CR, and 0 / 6 TFS). The combination therapy of IMGN853 + carboplatin and the triple combination of IMGN853 + carboplatin + bevacizumab were more active than the equivalent paclitaxel-containing combination regimens (i.e., more active than paclitaxel + carboplatin and paclitaxel + carboplatin + bevacizumab). See Figure 7.

[0343] The triple combination of paclitaxel, carboplatin, and bevacizumab resulted in significantly more body weight loss (BWL) at nadir (6.9%) compared with the triple combination of IMGN853, carboplatin, and bevacizumab (2.9% BWL). The BWL at nadir for the IMGN853 and carboplatin combination (12.9%) was comparable to the BWL at nadir for paclitaxel and carboplatin treatment (11.1%). Thus, triple combination therapy with IMGN853, carboplatin, and bevacizumab increased efficacy and reduced toxicity compared with triple combination therapy with paclitaxel, carboplatin, and bevacizumab.

[0344] Example 9 IMGN853 + cediranib combination therapy is more active than IMGN853 and cediranib monotherapy in the OV90 ovarian tumor model. The antitumor activity of IMGN853 was evaluated in combination with the anti-VEGF agent cediranib in female SCID mice bearing OV90 serous ovarian tumor xenografts. Mice were randomized by tumor volume into groups (n=6 per group) and then dosed 14 days post-inoculation. Groups included a control group dosed with IMGN853 formulation buffer ("Vehicle" in Figure 8), an IMGN853 single-agent group dosed at 2.5 mg / kg 1x ("IMGN853 2.5 mg / kg" in Figure 8), a cediranib single-agent group dosed at 1.5 mg / kg once daily for 5 days (qd x 5) ("Cediranib 1.5 mg / kg qd x 5" in Figure 8), and a 2.5 mg / kg Included was an IMGN853 + cediranib combination therapy group ("IMGN853 + cediranib" in Figure 8) dosed with 1x IMGN853 and 1.5mg / kg qd x 5 cediranib.

[0345] Tumor volumes were measured once to twice weekly in three dimensions using calipers. Tumor volume was calculated in mm using the formula V = length × width × height × ½. 3 The data were expressed in units (Tomayko 1989). Body weight was measured twice weekly as an index of test drug toxicity. Activity was assessed as described by Bissery et al. (1991). Figure 8 shows the results.

[0346] IMGN853 monotherapy was active (T / C 31%, T-C 13 days, LCK 0.5, and 0 / 6PR). Cediranib monotherapy was inactive (T / C 80%, T-C 4 days, LCK 0.1, and 0 / 6PR). The IMGN853 + cediranib combination was active (T / C 13% with 1 / 6PR), but TC (47) and LCK (1.7) were higher than either IMGN853 or cediranib monotherapy. See Figure 8. All treatments were well tolerated, and minimal weight loss was observed.

[0347] Example 10 A clinical trial evaluating the combination of IMGN853 with bevacizumab, carboplatin, and / or doxorubicin. Results from preclinical studies evaluating the activity of IMGN853 as a single agent and in combination with bevacizumab, carboplatin, or PLD in the above ovarian cancer xenograft models indicated that IMGN853 in combination with bevacizumab, carboplatin, and / or PLD is a promising regimen for evaluation in clinical trials of epithelial ovarian cancer (EOC) in both the recurrent and upfront settings. A Phase 1b clinical trial will be conducted to evaluate the dual combination of IMGN853 with bevacizumab, carboplatin, and / or PLD in patients with FRα-positive ovarian cancer. The study will include two components: a dose-finding component to determine the maximum tolerated dose (MTD) and recommended dose for the combinations of IMGN853 plus bevacizumab, IMGN853 plus carboplatin, and IMGN853 plus PLD; and a dose-expansion component. The dose-expansion component will evaluate two expansion cohorts: (1) the combination of IMGN853 plus bevacizumab in patients who have not previously received treatment with bevacizumab ("bevacizumab-naive") and (2) the combination of IMGN853 plus bevacizumab in patients who have previously received treatment with bevacizumab. Additional potential cohorts include: (1) the combination of IMGN853 plus carboplatin in patients who have not previously been treated with bevacizumab ("bevacizumab naive"); (2) the combination of IMGN853 plus PLD in patients who have not previously been treated with bevacizumab ("bevacizumab naive"); (3) the triple combination of IMGN853 plus bevacizumab plus PLD in patients who have not previously been treated with bevacizumab ("bevacizumab naive"); or (4) the triple combination of IMGN853 plus bevacizumab plus carboplatin in patients who have not previously been treated with bevacizumab ("bevacizumab naive"); (5 (6) the combination of IMGN853 plus carboplatin in patients previously treated with bevacizumab, (7) the triple combination of IMGN853 plus bevacizumab plus PLD in patients previously treated with bevacizumab, or (8) the triple combination of IMGN853 plus bevacizumab plus carboplatin in patients previously treated with bevacizumab; (9) the triple combination of IMGN853 plus bevacizumab plus carboplatin; and / or (10) the triple combination of IMGN853 plus bevacizumab plus PLD.Response to combination therapy will be assessed using RECIST (when appropriate) and Gynecologic Cancer InterGroup (GCIG) criteria.

[0348] Example 11 The combination of IMGN853 and carboplatin promotes synergistic growth inhibitory effects and cell cycle disruption in vitro, and IMGN853 enhances the antitumor activity of carboplatin in vivo. Carboplatin in combination with paclitaxel represents the standard chemotherapy treatment for EOC patients in the first-line adjuvant setting. To examine whether IMGN853 cotreatment can improve the activity of carboplatin in EOC, we evaluated the combinatorial effect of IMGN853 and carboplatin exposure in inhibiting the growth of the platinum-sensitive ovarian carcinoma cell line, IGROV-1. IGROV-1 cells were treated in vitro with increasing concentrations of IMGN853, carboplatin, or both, and combination activity was assessed using median effect analysis (Figure 9A). The combination was synergistic, indicating that IMGN853 enhanced the efficacy of the platinum compound in these ovarian tumor cells.

[0349] Cell cycle analysis revealed that carboplatin exposure resulted in the accumulation of IGROV-1 cells in both S and G2 / M phases (Figure 9B), an effect previously reported to precede cell death induced by this drug in ovarian cells. Treatment with IMGN853 alone resulted in an enrichment of cells in G2 / M, in accordance with the well-established antimitotic activity of maytansinoids. Consistent with these results, cotreatment with both drugs resulted in an accumulation of nearly half of the viable cells in G2 / M. In response to alkylating agents, We also examined changes in the expression of the phosphorylated form of histone H2AX (γH2AX), a sensitive indicator of DNA damage occurring as a result of mitotic cell death or mitotic cell death. Single-agent IMGN853 treatment induced γH2AX expression in IGROV-1 cells at levels higher than those seen after carboplatin exposure alone. Combination treatment increased the degree of γH2AX upregulation, indicating enhanced DNA damage and consistent with a destructive phenotype (Figure 9C).

[0350] To test whether these in vitro cellular effects translate into improved efficacy in vivo, mice bearing patient-derived xenografts (PDXs) obtained from individuals with EOC were treated with IMGN853 and carboplatin, both as single agents and in combination (Figure 9D). It was previously determined that IMGN853 exhibited strong single-agent activity in this platinum-sensitive PDX model (data not shown); therefore, a suboptimal dose of IMGN853 was selected to allow for evaluation of potential combination improvements in efficacy. Animals received a single dose of IMGN853 (2.5 mg / kg) or carboplatin (80 mg / kg), and each regimen inhibited tumor growth as monotherapy (T / C values ​​of 43% and 20%, respectively, at day 39). Consistent with the in vitro findings above, cotreatment with both agents resulted in a substantial improvement in antitumor activity, inhibiting tumor growth by 97% at the same time point (i.e., T / C value of 3%). Importantly, the combination of IMGN853 and platinum-based therapy was well tolerated, with no toxicity or weight loss observed over the course of the study.

[0351] The combinatorial benefit conferred by IMGN853 / carboplatin treatment was compared with clinically significant chemotherapy combinations in the same PDX model. Tumor-bearing animals received two consecutive weekly doses (QW × 2) of carboplatin (80 mg / kg, intraperitoneally) in combination with intravenous paclitaxel (10 mg / kg), PLD (4 mg / kg), or IMGN853 (5 mg / kg). As expected, carboplatin-paclitaxel dual treatment was effective in this platinum-sensitive model (Figure 9E). Carboplatin and PLD combination treatment, commonly shown in the platinum-sensitive recurrent setting, was also active in suppressing tumor growth. Notably, IMGN853 plus carboplatin combination therapy induced the greatest degree of tumor growth inhibition, including complete regression (CR) in six of seven tumor-bearing mice. In contrast, only two CRs were seen with the carboplatin / PLD combination and none in the carboplatin / paclitaxel-treated group. The carboplatin-paclitaxel doublet was well tolerated in this model, although some delayed toxicity was observed in animals from the PLD / carboplatin and IMGN853 / carboplatin-treated groups (data not shown). The high incidence of CRs strongly suggests superior durability of response for the combination, and overall, the data further support the combination of IMGN853 and carboplatin for improving response to platinum therapy in EOC.

[0352] Example 12 IMGN853 and PLD combination treatment results in superior therapeutic activity in platinum-resistant PDX tumors. In clinical practice, PLD is a widely used second-line treatment for recurrent and / or platinum-resistant EOC, and this treatment is better tolerated than doxorubicin. Similar to what was observed with carboplatin, the combination of IMGN853 and doxorubicin was synergistic in terms of in vitro antiproliferative activity in the IGROV-1 cell line (Figure 10A), resulting in a more pronounced S plus G2 / M cell cycle delay (Figure 10B).

[0353] To extend the in vitro observations, the combination of IMGN853 and PLD was tested in a platinum-resistant EOC PDX model (Figure 10C). Vehicle-treated animals progressed rapidly, with tumors growing to 1500-2000 mm. 3 When tumor volume reached a volume between 100 and 1500 mg / kg, tumors were removed from the study. QW × 2 dosing of IMGN853 (5 mg / kg) inhibited tumor growth by 81% at day 49, and a similar degree of inhibition (83%) was seen when PLD (4 mg / kg) was administered on the same schedule. Even at these effective dose levels, combination treatment resulted in improved and sustained antitumor responses, including complete abrogation of tumor growth in this aggressive model of EOC. Importantly, all regimens were well tolerated, and the addition of IMGN853 to PLD did not result in additional toxicity or changes in body weight compared to PLD treatment alone (Figure 10D). Thus, with regard to platinum-resistant disease, the combination of IMGN853 and PLD provided superior and sustained efficacy compared to the monotherapy activity of either compound alone.

[0354] This study further supports the finding that the synergistic improvement in antitumor activity seen with the IMGN853 / PLD combination in vitro translates into improved and durable efficacy relative to each single-agent treatment in platinum-resistant PDX models, and importantly, is well-tolerated. Combination benefit has previously been reported for another FRα-targeting compound, vintafolide, with PLD in preclinical EOC models, prompting subsequent late-stage clinical evaluation of the combination in Phase II and III human trials. Without being bound by theory, IMGN853 possesses a broader spectrum of activity compared with vintafolide, including a more potent payload, longer circulation time, and "bystander cytotoxicity," i.e., the ability to eradicate adjacent FRα-negative or low-expressing tumor cells. Therefore, the findings provide a rationale for the combination of IMGN853 and PLD in EOC patients with recurrent disease.

[0355] Example 13 IMGN853-bevacizumab combination induces rapid microvascular destruction and extensive necrotic injury in OV-90 xenografts To further our understanding of the mechanism behind the superior efficacy observed with IMGN853 in the presence of bevacizumab in vivo, OV-90 tumors from animals were treated with either IMGN853 (2.5 mg / kg), bevacizumab (5 mg / kg), or the combination and harvested and examined 4 days after dosing (Figures 12A–12C). It is noteworthy that the combination therapy completely halted tumor growth at this early time point, as measured by changes in tumor volume, in contrast to only a delay observed with the corresponding single-agent treatments (see, e.g., Figure 2B). Histological (H&E) staining revealed that tumors from combination-treated mice architecturally contained a large necrotic core surrounded by a smaller rim of viable cells at the periphery (Figure 12A). This degree of cell destruction was not observed in any of the other treatment groups, consistent with the rapid tumor stabilization afforded by the dosing regimen. Next, tumor γH2AX levels were measured by immunoblotting as a pharmacodynamic readout (Figure 12B). As expected, γH2AX expression was negligible in tumors from vehicle-treated mice but was strongly induced after single-agent IMGN853 treatment. Consistent with the observed improvement in antitumor activity, the addition of bevacizumab to IMGN853 resulted in a further increase in γH2AX levels compared to those seen with IMGN853 monotherapy.

[0356] Interestingly, γH2AX upregulation was also observed in tumors after bevacizumab exposure alone, albeit to a lesser extent than IMGN853 (Figure 12B). Although genotoxic insults are the primary inducer of γH2AX, accumulation of this protein can also occur in response to hypoxia. This result therefore indicated that increased hypoxia resulting from bevacizumab-induced vascular destruction contributed to the amplified DNA damage profile. To examine treatment-related effects on microvasculature, immunohistochemical staining was performed using the endothelial cell marker CD31 (Figure 12C, upper panel). Tumors from control and IMGN853-treated mice contained numerous large blood vessels, which were reduced in size and showed a loss of luminal integrity after bevacizumab treatment. Notably, dual administration of IMGN853 and bevacizumab resulted in significant changes in the tumor microvasculature. These included a clear reduction in the number of large branching vasculature structures, and smaller CD31-stained areas lacking distinct lumens and localized primarily to the peripheral rim region. Further staining of corresponding tissue samples with anti-maytansine antibodies confirmed tumor-specific delivery of IMGN853 in mice treated with the ADC-containing regimen (Figure 12C, lower panel).

[0357] Without being bound by theory, the presence of bevacizumab may promote better tumor penetration and exposure to ADC, resulting in more effective eradication of tumor cells.In this regard, it has been well established that bevacizumab treatment can induce the normalization of tumor vasculature, which has been shown to reduce interstitial pressure and improve drug delivery.However, there have been preclinical and clinical observations that tumor uptake of both chemotherapeutic agents and antibodies is reduced after antiangiogenic therapy. ***

[0358] It is understood that the Detailed Description section, and not the Summary and Abstract, is intended to be used to interpret the claims. The Summary and Abstract sections set forth one or more, but not all, exemplary embodiments of the invention contemplated by the inventor(s), and therefore are not intended to limit the scope of the invention and the appended claims in any way.

[0359] The present invention has been described above using functional components that illustrate the implementation of specific functions and relationships thereof. The boundaries of these functional components have been arbitrarily defined herein for the convenience of description. Alternative boundaries may be defined as long as the specific functions and relationships thereof are appropriately implemented.

[0360] The foregoing description of specific embodiments fully reveals the general nature of the present invention, such that those skilled in the art, by applying knowledge within their skill in the art, may readily modify and / or adapt such specific embodiments for various applications without undue experimentation and without departing from the general concept of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description, not limitation, and therefore, the terms or phrases herein will be interpreted by those skilled in the art in light of the teaching and guidance.

[0361] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. 1. A composition comprising an immunoconjugate that binds to folate receptor 1 (FOLR1) for use in treating cancer in a patient in need thereof, comprising: (a) the immune complex is 【Chemical 1】 wherein Ab is an IgG antibody that binds to FOLR1; ＋ Is H ＋ or Na ＋ or other pharmaceutically acceptable cation, and the antibody that binds to FOLR1 comprises a heavy chain variable region (VH) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 9 or 19, a VH CDR2 sequence of SEQ ID NO: 10 or 11, and a VH CDR3 sequence of SEQ ID NO: 12, and a light chain variable region (VL) CDR1 sequence of SEQ ID NO: 6, a VL CDR2 sequence of SEQ ID NO: 7, and a VL CDR3 sequence of SEQ ID NO: 8; and (b) the composition comprises: (i) an anti-VEGF antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 26 and a light chain variable region (VL) of SEQ ID NO: 27, wherein the anti-VEGF antibody is a monoclonal IgG1 antibody; (ii) a platinum-based agent selected from the group consisting of cisplatin, carboplatin, and oxaliplatin; or (iii) An anti-VEGF antibody and a platinum-based drug, wherein the anti-VEGF antibody is a monoclonal IgG1 antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 26 and a light chain variable region (VL) of SEQ ID NO: 27, and the platinum-based drug is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin. The composition is administered in combination with

2. The composition of claim 1 , administered in combination with the anti-VEGF antibody.

3. The composition of claim 1 , administered in combination with the platinum-based drug.

4. The composition of claim 1 , administered in combination with the anti-VEGF antibody and the platinum-based drug.

5. The composition of any one of claims 1 to 4, wherein the antibody that binds to FOLR1 comprises a VH comprising the sequence of SEQ ID NO: 3 and a VL comprising the sequence of SEQ ID NO:

5.

6. The composition of any one of claims 1 to 4, wherein the antibody that binds to FOLR1 comprises (i) a heavy chain comprising an amino acid sequence identical to the amino acid sequence of the heavy chain encoded by the plasmid deposited with the American Type Culture Collection (ATCC) as PTA-10772, and (ii) a light chain comprising an amino acid sequence identical to the amino acid sequence of the light chain encoded by the plasmid deposited with the ATCC as PTA-10774.

7. The composition of any one of claims 1 to 4, wherein the antibody that binds to FOLR1 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO:

15.

8. The composition of any one of claims 1 to 7, wherein the immunoconjugate is administered once every three weeks.

9. The composition of any one of claims 1 to 8, wherein the immunoconjugate is administered at a dose of 6 mg / kg adjusted ideal body weight (AIBW).

10. The composition of any one of claims 1 to 8, wherein the immunoconjugate is administered at a dose of 5 mg / kg AIBW.

11. 11. The composition of any one of claims 1, 2, or 4-10, wherein the anti-VEGF antibody is administered at a dose of 15 mg / kg once every three weeks.

12. The composition of any one of claims 1 or 3 to 11, wherein the platinum-based drug is carboplatin.

13. 13. The composition of claim 12, wherein the carboplatin is administered at a dose to obtain an area under the curve (AUC) of 4 mg / ml.

14. 13. The composition of claim 12, wherein the carboplatin is administered at a dose to obtain an AUC of 5 mg / ml.

15. The composition of any one of claims 12 to 14, wherein the carboplatin is administered once every three weeks.

16. - the antibody that binds to FOLR1 comprises a VH comprising the sequence of SEQ ID NO: 3 and a VL comprising the sequence of SEQ ID NO: 5; - the immunoconjugate is administered intravenously once every three weeks; - the anti-VEGF antibody is administered at a dose of 15 mg / kg once every three weeks; The composition of claim 2.

17. - the antibody that binds to FOLR1 comprises a VH comprising the sequence of SEQ ID NO: 3 and a VL comprising the sequence of SEQ ID NO: 5; - the immunoconjugate is administered intravenously once every three weeks; - the platinum-based drug is carboplatin; - the carboplatin is administered once every three weeks; The composition of claim 3.

18. - the antibody that binds to FOLR1 comprises a VH comprising the sequence of SEQ ID NO: 3 and a VL comprising the sequence of SEQ ID NO: 5; - the immunoconjugate is administered intravenously once every three weeks; - the anti-VEGF antibody is administered at a dose of 15 mg / kg once every three weeks; - the platinum-based drug is carboplatin; - the carboplatin is administered once every three weeks; The composition of claim 4.

19. The composition of any one of claims 16 to 18, wherein the immunoconjugate is administered at a dose of 6 mg / kg AIBW.

20. The immunoconjugate is administered at a dose of 5 mg / kg AIBW. The composition according to any one of claims 16 to 18.

21. The composition of any one of claims 17 to 20, wherein the carboplatin is administered at a dose to obtain an AUC of 5 mg / ml.

22. The composition of any one of claims 17 to 20, wherein the carboplatin is administered at a dose to obtain an AUC of 4 mg / ml.

23. The composition of any one of claims 1 to 2, 4 to 16, and 18 to 22, wherein the anti-VEGF antibody is bevacizumab.

24. 23. The composition of any one of claims 1 to 22, further administered with a steroid, optionally wherein the steroid is dexamethasone.

25. The composition of any one of claims 1 to 24, wherein the cancer is ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer.

26. The composition of any one of claims 1 to 24, wherein the cancer is platinum-resistant epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer.

27. The composition of any one of claims 1 to 26, wherein the cancer expresses FOLR1 and the FOLR1 expression is measured by immunohistochemistry (IHC).

28. 28. The composition of claim 27, wherein at least 25% of cells in a sample obtained from the cancer have an IHC score of at least 2.

29. 28. The composition of claim 27, wherein at least 50% of cells in a sample obtained from the cancer have an IHC score of at least 2.

30. 28. The composition of claim 27, wherein at least 75% of cells in a sample obtained from the cancer have an IHC score of at least 2.

31. The composition of any one of claims 1 to 30, wherein the cancer has been previously treated with bevacizumab.

32. The composition of any one of claims 1 to 30, wherein the cancer has not been previously treated with bevacizumab.

33. The composition of any one of claims 1 to 30 or 32, administered as first line therapy.

34. The composition of any one of claims 1 to 32, administered as a second line therapy.

35. The composition of any one of claims 1 to 32, administered as a third line therapy.

36. The composition of any one of claims 1 to 32, administered as fourth line therapy.

37. The composition of any one of claims 1 to 32, administered as a fifth line therapy.

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