Therapy combinations including anti-FOLR1 immune complexes

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 on September 17, 2015; U.S. Provisional Patent Application No. 62 / 242,669 filed on October 16, 2015; and U.S. Provisional Patent Application No. 62 / 250,756 filed on November 4, 2015, each of which is incorporated herein by reference in its entirety.

[0002] Reference to Sequence Listing Submitted Electronically via EFS-Web The content of the electronically submitted sequence listing (Name: 2921_077PC03_SL.txt, Size: 19,451 bytes, and Creation Date: September 13, 2016) is incorporated herein by reference in its entirety.

[0003] The field of the present invention generally relates 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, for example, ovarian cancer.

Background Art

[0004] Cancer is one of the leading causes of death in developed countries. In the United States alone, more than one million people are diagnosed with cancer and 500,000 people die from cancer each year. Overall, it is estimated that more than one in three people will develop some form of cancer during 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 a 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 the cell. FOLR1 expression in normal tissues is limited to the apical membrane of epithelial cells in the renal proximal tubules, pulmonary alveolar cells, bladder, testes, 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-targeted cancer therapy.

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

[0007] Cisplatin and carboplatin are platinum analogs and alkylated chemotherapeutic agents that have been used alone or in combination with other agents for the treatment of various solid tumors for decades (Lokich et al., Annals. Of Oncology 9:13-21 (1998)). Carboplatin has been reported to have less gastrointestinal effect compared to cisplatin (Lokich et al.). However, carboplatin causes the negative side effect of bone marrow suppression (Lokich et al.). Therefore, improvement in the efficacy and tolerability of treatments using cisplatin and carboplatin is desirable.

[0008] Doxorubicin is an anthracycline antibiotic chemotherapeutic agent used alone or in combination with other chemotherapeutic agents, such as paclitaxel (a mitotic inhibitor chemotherapeutic agent known as 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 cardiotoxicity (see Tacar et al., J. of Pharmacy & Pharmacology, 65:157-170 (2013)). Therefore, improvements in the efficacy and tolerability of doxorubicin-based treatments are desired. Liposome encapsulation of doxorubicin hydrochloride (HCl) salt has also been developed. Liposome delivery of doxorubicin HCl improves drug penetration into tumors, reduces drug clearance, and thereby increases the duration of therapeutic effect. The liposome formulation of doxorubicin also modulates toxicity, specifically the cardiac effects commonly seen with anthracycline antitumor drugs.

[0009] The U.S. Food and Drug Administration (FDA) approved the combination therapy of bevacizumab (an anti-VEGF antibody called AVASTIN® (GENENTECH, INC.)) with carboplatin and paclitaxel as the 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.ofMedicine 355:2542-2550 (2006)). However, while the addition of bevacizumab to CP therapy increased patient survival benefits, this triple combination (BV / CP) therapy increased procedure-related deaths and the incidence of both non-hematological and hematological adverse events (Cohen et al., see Tables 4-5 above). 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 treatments for cancer, such as combination therapies targeting 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) [Non-Patent Literature 5] Hoeben et al. Pharmacol. Rev. 56:549-580 (2004) [Non-Patent Literature 6] Ferrara et al., Nat. Med. 9:669-676 (2003) [Non-Patent Literature 7] Lokich et al., Annals. Of Oncology 9:13-21 (1998) [Non-Patent Literature 8] Gehl et al., Annals of Oncology, 7:687-639 (1996) [Non-Patent Literature 9] Tacar et al., J. of Pharmacy & Pharmacology, 65:157-170 (2013) [Non-Patent Literature 10] Cohen et al., Oncologist 12:713-718 (2007) [Non-Patent Literature 11] Sandler et al., N. Engl. J. of Medicine 355:2542-2550 (2006) [Summary of the Invention] [Means for Solving the Problem]

[0012] This specification provides combinations of anti-FOLR1 immune complexes (e.g., IMGN853) with anti-VEGF agents, platinum-based drugs, and / or doxorubicin. Methods for treating patients with cancer using such combinations are also provided herein. As detailed below, the combination of anti-FOLR1 immune complexes (e.g., IMGN853) with anti-VEGF agents, platinum-based drugs, and / or doxorubicin can result in synergistic efficacy against tumors. For example, anti-VEGF agents, platinum-based drugs, and / or doxorubicin can enhance the efficacy of anti-FOLR1 immune complexes (e.g., IMGN853), and / or anti-FOLR1 immune complexes (e.g., IMGN853) can enhance the efficacy of anti-VEGF agents, platinum-based drugs, and / or doxorubicin. By combining an anti-FOLR1 immune complex (e.g., IMGN853) with an anti-VEGF agent, a platinum-based drug, and / or doxorubicin, the combined efficacy of these agents can be achieved even when using smaller and / or less frequent doses of the anti-FOLR1 immune complex (e.g., IMGN853) and / or the anti-VEGF agent, platinum-based drug, and / or doxorubicin. Furthermore, the combination can produce any of the following toxicity levels: anti-VEGF agent, platinum-based drug, and / or doxorubicin alone; anti-FOLR1 immune complex (e.g., IMGN853) alone; and / or anti-VEGF agent, platinum-based drug, and / or doxorubicin or anti-FOLR1 immune complex (e.g., IMGN853).

[0013] For example, a method for treating a patient with cancer involves an immune complex that binds to FOLR1, comprising the heavy chain variable region (VH) complementarity-determining region (CDR) 1 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, as well as the light chain variable region (VL) CDR1 sequence of SEQ ID NO: 6 and the VL CDR1 sequence of SEQ ID NO: 7 The treatment involves administering an immune complex comprising an antibody or its antigen-binding fragment containing a CDR2 sequence and the VL CDR3 sequence of Sequence ID No. 8, along with an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

[0014] For example, a method for treating a patient with cancer includes administering to the patient in need an immune complex that binds to FOLR1, comprising an antibody or antigen-binding fragment thereof, which includes the VH CDR1 sequence of SEQ ID NO: 19, the VH CDR2 sequence of SEQ ID NO: 11, the VH CDR3 sequence of SEQ ID NO: 12, and the 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, along with an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

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

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

[0017] In one example, the immune complex that binds to FOLR1 includes an antibody or its antigen-binding fragment containing VH, which contains the sequence of SEQ ID NO: 3, and VL, which contains the sequence of SEQ ID NO: 5. In one example, the antibody or antigen-binding fragment is huMov19.

[0018] In one example, an immune complex (e.g., IMGN853) contains a cytotoxin, which is a mytansinoid. In another example, the mytansinoid is DM4.

[0019] For example, an immune complex (e.g., IMGN853) contains a linker, which is a sulfo-SPDB.

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

[0021] In one example, administration is first-line therapy. In another example, administration is second-line therapy. In yet another example, administration is third-line therapy.

[0022] In one example, the immune complex (e.g., IMGN853) is administered intravenously or intraperitoneally.

[0023] For example, the administration of immune complexes (e.g., IMGN853) and anti-VEGF agents, platinum-based drugs, doxorubicin, or a combination thereof, produces a synergistic effect.

[0024] In one example, administration of an immune complex (e.g., IMGN853) and an anti-VEGF agent does not produce stronger toxicity than administration of the immune complex alone or the anti-VEGF agent alone. In another example, administration of an immune complex (e.g., IMGN853) and a platinum-based drug does not produce stronger toxicity than administration of the immune complex alone or the platinum-based drug alone. In yet another example, administration of an immune complex (e.g., IMGN853) and doxorubicin does not produce stronger toxicity than administration of the immune complex alone or doxorubicin alone. In yet another example, administration of an immune complex (e.g., IMGN853), an anti-VEGF agent, and a platinum-based drug does not produce stronger toxicity than administration of taxol, an anti-VEGF agent, or a platinum-based drug, where the platinum-based drug is carboplatin or cisplatin.

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

[0026] In one example, the immune complex (e.g., IMGN853) is administered once a week. In another example, the immune complex (e.g., IMGN853) is administered at doses of approximately 1.1 mg / kg AIBW, approximately 1.8 mg / kg AIBW, approximately 2.0 mg / kg AIBW, or approximately 2.5 mg / kg AIBW.

[0027] In one example, the immune complex (e.g., IMGN853) is administered once every two weeks. In another example, the immune complex (e.g., IMGN853) is administered at doses of approximately 2.0 mg / kg AIBW, approximately 2.5 mg / kg AIBW, approximately 3.0 mg / kg AIBW, approximately 3.5 mg / kg AIBW, or approximately 4.0 mg / kg AIBW.

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

[0029] In one example, anti-VEGF agents include tyrosine kinase inhibitors. In one example, tyrosine kinase inhibitors are selected from the group consisting of cedilanib, pazopanib, axitinib, batalanib, semacsanib, sunitinib, sorafenib, ramucirumab, and aflibercept.

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

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

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

[0033] In one example, the platinum-based drug is carboplatin. In one example, carboplatin is administered once every three weeks. In another example, carboplatin is administered at doses that yield the 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 drug is cisplatin. In one example, cisplatin is administered every 3 weeks or every 4 weeks. In one example, cisplatin is administered at approximately 50-70 mg / m2 or approximately 75-100 mg / m2. 2 , or approximately 100 mg / m² 2 It is administered in the following dosage.

[0035] In one example, doxorubicin may be pegylated doxorubicin, liposomal doxorubicin, or pegylated liposomal doxorubicin. In one example, doxorubicin may be administered once every four weeks. In one example, the dose of doxorubicin may be 30 mg / m². 2 , 35 mg / m² 2 , 40 mg / m² 2 , 45 mg / m² 2 , or 50 mg / m² 2 It is administered in the following dosage.

[0036] In one example, the anti-VEGF agent is bevacizumab, administered at a dose of 15 mg / kg every three weeks, and the immune complex (e.g., IMGN853) is administered at a dose of 4 mg / kg AIBW every three weeks. In another example, the anti-VEGF agent is bevacizumab, administered at a dose of 15 mg / kg every three weeks, and the immune complex (e.g., IMGN853) is administered at a dose of 5 mg / kg AIBW every three weeks. In yet another example, the anti-VEGF agent is bevacizumab, administered at a dose of 15 mg / kg every three weeks, and the immune complex (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, administered at a dose of 10 mg / kg every two weeks, and the immune complex (e.g., IMGN853) is administered at a dose of 4 mg / kg AIBW every four weeks. In another example, the anti-VEGF agent is bevacizumab, administered at a dose of 10 mg / kg every two weeks, and the immune complex (e.g., IMGN853) is administered at a dose of 5 mg / kg AIBW every four weeks. In yet another example, the anti-VEGF agent is bevacizumab, administered at a dose of 10 mg / kg every two weeks, and the immune complex (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 immune complex (e.g., IMGN853). In another example, carboplatin is administered once every three weeks. In yet another example, carboplatin is administered at doses that yield the 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 drug is carboplatin, which is administered once every three weeks to obtain an AUC of 4 mg / ml·min, and the immune complex (e.g., IMGN853) is administered once every three weeks at a dose of 4 mg / kg AIBW.

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

[0041] In one example, the platinum-based drug is carboplatin, which is administered once every three weeks to obtain an AUC of 5 mg / ml·min, and the immune complex (e.g., IMGN853) is administered once every three weeks at a dose of 5 mg / kg AIBW.

[0042] In one example, the platinum-based agent is carboplatin, carboplatin 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, doxorubicin is pegylated liposomal doxorubicin (PLD), and PLD is administered at a dose of about 30 mg / m 2 once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 weeks at a dose of 4 mg / kg AIBW.

[0044] In one example, doxorubicin is PLD, and PLD is administered at a dose of about 30 mg / m 2 once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 weeks at a dose of 5 mg / kg AIBW.

[0045] In one example, doxorubicin is PLD, and PLD is administered at a dose of about 40 mg / m 2 once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 weeks at a dose of 5 mg / kg AIBW.

[0046] In one example, doxorubicin is PLD, and PLD is administered at a dose of about 40 mg / m 2 once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 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 may be 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 another example, the peritoneal cancer is primary peritoneal cancer. In another example, the endometrial cancer is serous endometrial cancer. In one example, the lung cancer is selected from a group consisting of non-small cell lung cancer (NSCLC), adenocarcinoma, and bronchioloalveolar carcinoma.

[0052] In one case, the cancer had been previously treated with bevacuzimab. In another case, the cancer had never been previously treated with bevacuzimab (i.e., the patient was "bevacuzimab-naive").

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

[0054] In one case, cancer expresses FOLR1. In one case, FOLR1 expression is measured by immunohistochemistry (IHC). In one case, the IHC has staining scores of at least 1 heterogeneous, at least 1 homogeneous, at least 2 heterogeneous, at least 2 homogeneous, or at least 3 heterogeneous. In one case, at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of cells in a sample obtained from a patient have an IHC staining score of at least 2 (moderate). In one case, at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of 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 another example, the steroid is administered as eye drops. In another example, the eye drops are preservative-free, lubricating eye drops.

[0056] In one example, an immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based drug, doxorubicin, or a combination thereof are administered in separate pharmaceutical compositions.

[0057] Kits are also provided herein. For example, the kit comprises an immune complex that binds to FOLR1 and comprises 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, as well as 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 use of the immune complex with the anti-VEGF agent, a platinum-based agent, or doxorubicin. For example, the anti-VEGF agent is an anti-VEGF antibody. For example, the anti-VEGF antibody is bevacizumab. For 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, batalanib, semacsanib, sunitinib, sorafenib, ramucirumab, and aflibercept. In another example, the anti-VEGF agent is a soluble VEGF receptor. In yet another example, the soluble VEGF receptor is VEGF-TRAP. In yet another example, the platinum-based agent is carboplatin or cisplatin. In yet another example, doxorubicin is pegylated liposomal doxorubicin. In yet another example, the immune complex is IMGN853.

[0058] Methods for explaining the use of the present invention to humans with cancer are also provided herein. For example, the method includes providing instructions for use for cancer treatment using an immune complex that binds to FOLR1 (e.g., IMGN853) and an anti-VEGF agent, a platinum-based drug, doxorubicin, or a combination thereof. For example, the anti-VEGF agent is an anti-VEGF antibody. For example, the anti-VEGF antibody is bevacizumab. For example, the anti-VEGF agent is a tyrosine kinase inhibitor. For example, the tyrosine kinase inhibitor is selected from the group consisting of cediranib, pazopanib, axitinib, batalanib, semacsanib, sunitinib, sorafenib, ramucirumab, and aflibercept. For example, the anti-VEGF agent is a soluble VEGF receptor. For example, the soluble VEGF receptor is VEGF-TRAP. For example, the platinum-based drug is carboplatin or cisplatin. In one example, doxorubicin is pegylated liposomal doxorubicin. In another example, the immune complex is IMGN853. The present invention provides, for example, the following items: (Item 1) A method for treating a patient with cancer, wherein the patient in need of the method An immune complex that binds to folate receptor 1 (FOLR1), comprising an antibody or antigen-binding fragment containing the heavy chain variable region (VH) complementarity-determining region (CDR) 1 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, as well as the 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, The method comprising administering an anti-VEGF agent, a platinum-based drug, doxorubicin, or a combination thereof. (Item 2) The method according to item 1, wherein the immune complex is administered in combination with the anti-VEGF agent. (Item 3) The method according to item 1, wherein the immune complex is administered in combination with the platinum-based drug. (Item 4) The method according to item 1, wherein the immune complex is administered in combination with doxorubicin. (Item 5) The method according to item 1, wherein the immune complex is administered in combination with the anti-VEGF agent and the platinum-based agent. (Item 6) The method according to item 1, wherein the immune complex is administered in combination with the anti-VEGF agent and the doxorubicin. (Item 7) The method according to item 1, wherein the immune complex is administered in combination with the platinum-based drug and the doxorubicin. (Item 8) The method according to any one of items 1 to 7, wherein the immune complex that binds to FOLR1 comprises an antibody or antigen-binding fragment thereof, comprising VH containing the sequence of SEQ ID NO: 3 and VL containing the sequence of SEQ ID NO: 5. (Item 9) The method according to item 8, wherein the antibody or antigen-binding fragment is huMov19. (Item 10) The method according to any one of items 1 to 9, wherein the immune complex comprises a cytotoxin, and the cytotoxin is a mytansinoid. (Item 11) The method according to item 10, wherein the mytansinoid is DM4. (Item 12) The method according to any one of items 1 to 11, wherein the immune complex comprises a linker, and the linker is a sulfo-SPDB. (Item 13) The method according to any one of items 1 to 12, wherein the immune complex is IMGN853. (Item 14) The method described in any one of items 1 to 13, wherein the administration is the first-line therapy. (Item 15) The method according to any one of items 1 to 14, wherein the immune complex is administered intravenously or intraperitoneally. (Item 16) The method according to any one of items 1 to 15, wherein the administration of the anti-VEGF agent, the platinum-based agent, the doxorubicin, or a combination thereof, and the immune complex produces a synergistic effect. (Item 17) The method according to any one of items 1, 2, 5, 6, and 8-16, wherein the administration of the immune complex and the anti-VEGF agent does not produce greater toxicity than the administration of the immune complex alone or the anti-VEGF agent alone. (Item 18) The method according to any one of items 1, 3, 5, and 8-16, wherein the administration of the immune complex and the platinum-based agent does not produce greater toxicity than the administration of the immune complex alone or the platinum-based agent alone. (Item 19) The method according to any one of items 1, 4, and 6-16, wherein the administration of the immune complex and the doxorubicin does not produce greater toxicity than the administration of the immune complex alone or the doxorubicin alone. (Item 20) The method according to any one of items 5 and 8-16, wherein the administration of the immune complex, the anti-VEGF agent, and the platinum-based agent does not produce greater toxicity than the administration of taxol, the anti-VEGF agent, and / or the platinum-based agent, and the platinum-based agent is carboplatin or cisplatin. (Item 21) The method according to any one of items 1 to 20, wherein the immune complex is administered once every three weeks or once every four weeks. (Item 22) The method according to any one of items 1 to 21, wherein the immune complex is administered at a dose of approximately 4 mg / kg adjusted ideal body weight (AIBW), at a dose of approximately 5 mg / kg AIBW, or at a dose of approximately 6 mg / kg AIBW. (Item 23) The method according to any one of items 1 to 20, wherein the immune complex is administered once a week. (Item 24) The method according to any one of items 1 to 20 and 23, wherein the immune complex is administered in a dose of approximately 1.1 mg / kg AIBW, approximately 1.8 mg / kg AIBW, approximately 2.0 mg / kg AIBW, or approximately 2.5 mg / kg AIBW. (Item 25) The method according to any one of items 1 to 20, wherein the immune complex is administered once every two weeks. (Item 26) The method according to any one of items 1 to 20 and 25, wherein the immune complex is administered in a dose of approximately 2.0 mg / kg AIBW, approximately 2.5 mg / kg AIBW, approximately 3.0 mg / kg AIBW, approximately 3.5 mg / kg AIBW, or approximately 4.0 mg / kg AIBW. (Item 27) The method according to 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) The method according to item 27, wherein the antibody or antigen-binding fragment that binds to VEGF is bevacizumab. (Item 29) The method according to 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) The method according to item 29, wherein the tyrosine kinase inhibitor is selected from the group consisting of cedilanib, pazopanib, axitinib, batalanib, semacsanib, sunitinib, sorafenib, ramucirumab, and aflibercept. (Item 31) The method according to any one of items 1, 2, 5, 6, 8-17, and 20-26, wherein the anti-VEGF agent comprises a soluble VEGF receptor. (Item 32) The method according to item 31, wherein the soluble VEGF receptor is VEGF-TRAP. (Item 33) The method according to 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) The method according to any one of items 1, 2, 5, 6, 8-17, and 20-34, wherein the anti-VEFG agent is administered in a dose of approximately 15 mg / kg, approximately 10 mg / kg, or approximately 7.5 mg / kg. (Item 35) The method according to item 28, wherein the bevacizumab is administered at a dose of 15 mg / kg once every three weeks. (Item 36) The method according to item 28, wherein the bevacizumab is administered at a dose of 10 mg / kg once every two weeks. (Item 37) The method according to any one of items 1, 3, 5, 7-16, 18, and 20-36, wherein the platinum-based drug is carboplatin. (Item 38) The method described in item 37, in which carboplatin is administered once every three weeks. (Item 39) The method according to item 37 or 38, wherein the carboplatin is administered in a dose that yields 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) The method according to any one of items 1, 3, 5, 7-16, 18, and 20-36, wherein the platinum-based drug is cisplatin. (Item 41) The method according to item 40, wherein cisplatin is administered every three weeks or once every four weeks. (Item 42) The aforementioned cisplatin is approximately 50-70 mg / m2, approximately 75-100 mg / m2 2 , or approximately 100 mg / m² 2 The method described in item 40 or 41, administered in the specified dose. (Item 43) The method according to any one of items 1, 4, 6-16, 19, and 21-42, wherein doxorubicin is pegylated doxorubicin, liposomal doxorubicin, or pegylated liposomal doxorubicin. (Item 44) The method according to any one of items 1, 4, 6-16, 19, and 21-43, wherein the doxorubicin is administered once every four weeks. (Item 45) The aforementioned doxorubicin is 30 mg / m². 2 , 35 mg / m² 2 , 40 mg / m² 2 , 45 mg / m²2 , or 50 mg / m² 2 The method described in any one of items 1, 4, 6-16, 19, and 21-44, administered in the specified dose. (Item 46) The method according to 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 immune complex is administered at a dose of 4 mg / kg AIBW once every three weeks. (Item 47) The method according to 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 immune complex is administered at a dose of 5 mg / kg AIBW once every three weeks. (Item 48) The method according to 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 immune complex is administered at a dose of 6 mg / kg AIBW once every three weeks. (Item 49) The method according to 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 immune complex is administered at a dose of 4 mg / kg AIBW once every four weeks. (Item 50) The method according to 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 immune complex is administered at a dose of 5 mg / kg AIBW once every four weeks. (Item 51) The method according to 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 immune complex is administered at a dose of 6 mg / kg AIBW once every four weeks. (Item 52) The method described in any one of items 46-50, wherein carboplatin is administered. (Item 53) The method described in item 52, in which carboplatin is administered once every three weeks. (Item 54) The method according to item 52 or 53, wherein the carboplatin is administered in a dose that yields 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) The method according to any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based drug is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 4 mg / ml·min, and the immune complex is administered once every three weeks at a dose of 4 mg / kg AIBW. (Item 56) The method according to any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based drug is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 4 mg / ml·min, and the immune complex is administered once every three weeks at a dose of 5 mg / kg AIBW. (Item 57) The method according to any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based drug is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 5 mg / ml·min, and the immune complex is administered once every three weeks at a dose of 5 mg / kg AIBW. (Item 58) The method according to any one of items 1, 3, 5, 7-16, 18, and 20, wherein the platinum-based drug is carboplatin, the carboplatin is administered once every three weeks to obtain an AUC of 5 mg / ml·min, and the immune complex is administered once every three weeks at a dose of 6 mg / kg AIBW. (Item 59) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is present in a concentration of approximately 30 mg / m². 2 The drug is administered once every four weeks at a dose of 4 mg / kg. The method according to any one of items 1, 4, 6-16, and 19, administered once every four weeks at the AIBW dose. (Item 60) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is present in a concentration of approximately 30 mg / m². 2 The drug is administered once every four weeks at a dose of 5 mg / kg. The method according to any one of items 1, 4, 6-16, and 19, administered once every four weeks at the AIBW dose. (Item 61) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is approximately 40 mg / m². 2 The method according to any one of items 1, 4, 6-16, and 19, wherein the immune complex is administered once every four weeks at a dose of 5 mg / kg AIBW. (Item 62) The doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is present in a concentration of approximately 40 mg / m². 2 The drug is administered once every four weeks at a dose of 6 mg / kg. The method according to any one of items 1, 4, 6-16, and 19, administered once every four weeks at the AIBW dose. (Item 63) The method according to any one of items 1 to 62, wherein the cancer is cancer of the ovary, peritoneum, fallopian tube, endometrium, or lung. (Item 64) The method according to item 63, wherein the cancer is ovarian cancer. (Item 65) The method according to item 64, wherein the ovarian cancer is epithelial ovarian cancer. (Item 66) The method according to item 64 or 65, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. (Item 67) The method according to any one of items 64 to 66, wherein the administration results in a reduction of CA125. (Item 68) The method according to item 63, wherein the peritoneal cancer is primary peritoneal cancer. (Item 69) The method according to item 63, wherein the endometrial cancer is serous endometrial cancer. (Item 70) The method according to 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) The method according to any one of items 1 to 70, wherein the cancer expresses FOLR1. (Item 72) The method according to item 71, wherein FOLR1 expression is measured by immunohistochemistry (IHC). (Item 73) The method according to 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. (Item 74) The method according to item 71, wherein at least 25%, at least 50%, or at least 75% of the cells in the sample obtained from the patient have an immunohistochemistry (IHC) score of at least 2. (Item 75) The method according to item 71, wherein at least 25%, at least 50%, or at least 75% of the cells in the sample obtained from the patient have an immunohistochemistry (IHC) score of at least 3. (Item 76) The method according to any one of items 1 to 75, further comprising administering a steroid to the patient. (Item 77) The method according to item 76, wherein the steroid is dexamethasone. (Item 78) The method according to any one of items 1 to 77, wherein the immune complex and the anti-VEGF agent, platinum-based agent, doxorubicin, or a combination thereof are administered in separate pharmaceutical compositions. (Item 79) The method according to any one of items 1-13 and 15-78, wherein the cancer has been previously treated with bevacuzimab. (Item 80) The method according to any one of items 1 to 78, wherein the cancer has not been previously treated with bevacuzimab. (Item 81) The method according to any one of items 1 to 80, wherein the cancer is primary platinum-refractory. (Item 82) The method according to any one of items 1 to 80, wherein the cancer is platinum-resistant. (Item 83) The method according to any one of items 1-65 and 67-80, wherein the cancer is platinum-sensitive. (Item 84) The method according to any one of items 1 to 83, wherein the cancer is metastatic or progressive. (Item 85) The method described in any one of items 1-13 and 15-84, wherein the administration is a second-line therapy. (Item 86) The method described in any one of items 1-13 and 15-84, wherein the administration is a third-line therapy. (Item 87) The method according to item 71, wherein at least 33% or at least 66% of the cells in the sample obtained from the patient have an immunohistochemistry (IHC) score of at least 2. (Item 88) The method according to item 71, wherein 33% or at least 66% of the cells in the 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, 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, as well as 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 drugs, or doxorubicin; and A kit comprising instructions for use for administering the immune complex with the anti-VEGF agent, the platinum-based agent, or doxorubicin. (Item 90) A method for providing instructions for use to a human subject with cancer, comprising providing instructions for use to receive cancer treatment using an immune complex that binds to FOLR1 and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof. (Item 91) The kit or method described in item 89 or 90, wherein the anti-VEGF agent is an anti-VEGF antibody. (Item 92) The kit or method described in item 91, wherein the anti-VEGF antibody is bevacizumab. (Item 93) The kit or method according to item 89 or 90, wherein the anti-VEGF agent is a tyrosine kinase inhibitor. (Item 94) The kit or method described in item 93, wherein the tyrosine kinase inhibitor is selected from the group consisting of cedilanib, pazopanib, axitinib, batalanib, semacsanib, sunitinib, sorafenib, ramucirumab, and aflibercept. (Item 95) The kit or method according to item 89 or 90, wherein the anti-VEGF agent is a soluble VEGF receptor. (Item 96) The kit or method described in item 95, wherein the soluble VEGF receptor is VEGF-TRAP. (Item 97) The kit or method described in any one of items 89 to 96, wherein the platinum-based drug is carboplatin or cisplatin. (Item 98) The kit or method according to any one of items 89 to 97, wherein the doxorubicin is pegylated liposome doxorubicin. (Item 99) The kit or method according to any one of items 89 to 98, wherein the immune complex is IMGN853. (Item 100) The method according to item 1, wherein the immune complex is IMGN853, the immune complex is administered once every three weeks at a dose of 6 mg / kg AIBW, and the anti-VEGF agent is bevacizumab, the bevacizumab is administered once every three weeks at a dose of 15 mg / kg. (Item 101) The method according to item 1, wherein the immune complex is IMGN853, the immune complex is administered once every three weeks at a dose of 6 mg / kg AIBW, and the anti-VEGF agent is bevacizumab, the bevacizumab is administered twice every four weeks at a dose of 10 mg / kg. (Item 102) The method according to item 1, wherein the immune complex is IMGN853, and the immune complex is administered once every three weeks at a dose of 6 mg / kg AIBW, and the platinum-based drug is carboplatin, and the carboplatin is administered once every three weeks to obtain an AUC of 5 mg / ml·min. (Item 103) The method according to item 1, wherein the immune complex is IMGN853, and the immune complex is administered once every three weeks at a dose of 6 mg / kg AIBW, and the platinum-based drug is carboplatin, and the carboplatin is administered once every three weeks to obtain an AUC of 6 mg / ml·min. (Item 104) The immune complex is IMGN853, and the immune complex is administered once every four weeks at a dose of 6 mg / kg AIBW, and the doxorubicin is pegylated liposomal doxorubicin (PLD), and the PLD is 40 mg / m² 2 The method described in item 1, administered once every four weeks at the specified dose. [Brief explanation of the drawing]

[0059] [Figure 1] This study demonstrates the antitumor activity of IMGN853 (5 mg / kg), pegylated liposomal doxorubicin (PLD) (4 mg / kg), and IMGN853 + PLD combination therapy in epithelial ovarian cancer tumor models. [Figure 2A]This study demonstrates 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] This study demonstrates 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] This study demonstrates 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] This study demonstrates the antitumor activity of IMGN853 (5 mg / kg), bevacizumab (5 mg / kg), and IMGN853 + bevacizumab combination therapy in epithelial ovarian cancer tumor models. [Figure 5] This study demonstrates 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 epithelial ovarian cancer tumor models. [Figure 6] This study demonstrates 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 non-small cell lung cancer tumor models. [Figure 7] This study demonstrates the antitumor activity of the following combination therapies in non-small cell lung cancer tumor models: IMGN853 (5 mg / kg) + carboplatin (100 mg / kg), IMGN853 (5 mg / kg) + carboplatin (100 mg / kg) + bevacizumab (5 mg / kg), paclitaxel (10 mg / kg) + carboplatin (100 mg / kg), and paclitaxel (100 mg / kg) + carboplatin (100 mg / kg) + bevacizumab (5 mg / kg). [Figure 8]This study demonstrates the antitumor activity of IMGN853 (2.5 mg / kg), cediranib (1.5 mg / kg), and IMGN853 + cediranib combination therapy in a serous ovarian cancer model. [Figure 9A] This shows the effects on IGROV-1 cells and proliferation treated with graded concentrations of IMGN853, carboplatin, or both. The combination coefficient (CI) was calculated using median effect analysis. Data from two independent experiments are shown, determining the drug concentration range, with an efficacy rate (Fa) of 0.4–0.7. Data points below the dotted line represent synergistic effects between drug pairs. [Figure 9B] The images show IGROV-1 cells treated with carboplatin (20 μM) or IMGN853 (8 nM) for 6 hours, both alone and in combination. The cells were washed, and the cell cycle distribution was determined after 24 hours of culture in drug-free medium. [Figure 9C] The images show IGROV-1 cells exposed to carboplatin (40 μM) or IMGN853 (16 nM), either alone or in combination, for 6 hours, followed by incubation in drug-free medium for a further 18 hours. Cell extracts were immunoblotted for γH2AX or actin (loading control) as shown. [Figure 9D] This study describes the antitumor activity of IMGN853 (2.5 mg / kg) or carboplatin (80 mg / kg) alone and in combination (n=7 mice / group) in xenografts (PDX) derived from platinum-sensitive ovarian cancer patients established in SCID mice. Data are presented as the mean and standard error of the mean (SEM) for each time point. [Figure 9E] The antitumor activity of two consecutive weekly doses of the vehicle—carboplatin (80 mg / kg, intraperitoneal) plus paclitaxel (10 mg / kg), carboplatin plus PLD (4 mg / kg), or carboplatin plus IMGN853 (5 mg / kg)—in mice with platinum-sensitive PDX tumors (n=7 mice / group) is demonstrated. [Figure 10A]This shows the effects on IGROV-1 cells treated with gradually increasing concentrations of IMGN853, doxorubicin, or both, and their proliferation. The combination confidence interval (CI) was calculated using median effect analysis. Data from three independent experiments are shown, with data points below the dotted line representing synergistic effects between drug pairs. [Figure 10B] The images show IGROV-1 cells treated with doxorubicin (200 nM) or IMGN853 (8 nM) for 6 hours, both alone and in combination. The cells were washed, and the cell cycle distribution was determined after 24 hours of culture in drug-free medium. [Figure 10C] This study describes the antitumor activity in established platinum-resistant ovarian cancer PDX in SCID mice using two consecutive weekly doses of IMGN853 (5 mg / kg) and PLD (4 mg / kg) alone or in combination (n=8 mice / group). Data are presented as mean and SEM for each time point. [Figure 10D] This shows the body weight of mice, measured twice a week. The mean value is plotted against the vehicle control. [Figure 11A] The antitumor activity of IMGN853 (3 mg / kg) alone or in combination with bevacizumab, administered as a single dose of 5 mg / kg or as a dose of 2.5 mg / kg (QW×2) once every two consecutive weeks, was demonstrated in mice (n=7 mice / group) with established OV-90 xenografts. [Figure 11B] This shows tumor volume measured at the end of a study in mice with platinum-resistant ovarian cancer PDX who received bevacizumab (5 mg / kg) once every two consecutive weeks, either alone or in combination with paclitaxel (10 mg / kg) or IMGN853 (5 mg / kg), and individual tumor size plotted according to treatment group. Tumor growth was monitored up to 102 days. *P=0.011;**P<0.018;ns, no significant difference (Wilcoxon test, unadjusted). [Figure 12A]This image shows mice with OV-90 tumors treated with a single dose of vehicle, IMGN853 (2.5 mg / kg), bevacizumab (5 mg / kg), or IMGN853 plus bevacizumab, and tumors collected 4 days later. Histological staining (H&E) revealed the presence of a large central necrotic area in the tumors of the combination-treated mice. Original magnification, 4x; scale bar, 2 mm (600 μm for the combination panel). [Figure 12B] The tumor extracts immunoblotted against γH2AX or actin (loading control) are shown as indicated. [Figure 12C] This shows the immunohistochemical evaluation of CD31 expression (upper panel) and mytansin detection (anti-MAY; lower panel) in tumor tissue on day 4. For each group, a representative micrograph from one of the three tumors is shown. Original magnification, 20x; scale bar, 200 μm. [Modes for carrying out the invention]

[0060] The present invention provides anti-FOLR1 immune complexes, anti-VEGF agents, platinum-based drugs, doxorubicin, or combinations thereof, and the use of such combinations in the treatment of cancer.

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

[0062] As used herein, the term "FOLR1" refers to any undenatured 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 the "full-length" unprocessed FOLR1 polypeptide, 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 allele variants. The FOLR1 polypeptides described herein may be isolated from various sources, such as human tissue types or other origins, or prepared by recombinant or synthetic methods. Where specifically indicated, "FOLR1" can be used to represent the nucleic acid encoding the FOLR1 polypeptide. Human FOLR1 sequences are publicly known, including, for example, the sequence published under UniProtKB accession number P15328 (including the isotype). As used herein, the term "human FOLR1" refers to FOLR1 containing the sequence of Sequence ID No. 1.

[0063] The term "VEGF," as used herein, refers to any undenatured human VEGF polypeptide unless otherwise specified. 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 allele variants. The VEGF polypeptides described herein may be isolated from various sources, including human tissue types or other origins, or prepared by recombinant or synthetic methods. Where specifically indicated, "VEGF" may be used to represent the nucleic acid encoding the VEGF polypeptide. Human VEGF sequences are publicly known, including, for example, the sequences published under UniProtKB accession number P15692 (including isotypes).

[0064] The term “antibody” means an immunoglobulin molecule that recognizes and specifically binds to a target, e.g., a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination thereof, 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, antibody-containing fusion proteins, and any other modified immunoglobulin molecules as 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 of their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) based on the identity of their heavy chain constant domains, referred to as alpha, delta, epsilon, gamma, and mu, respectively. Different classes of immunoglobulins have different known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated with other molecules such as toxins or radioisotopes.

[0065] The term "antibody fragment" refers to a portion of an intact antibody. "Antigen-binding fragment" refers to a portion of an intact antibody that binds to an antigen. Antigen-binding fragments may contain the antigen-determining variable region of an 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" antibody or "antagonistic" antibody inhibits or reduces the biological activity of the antigen to which it binds, such as FOLR1 or VEGF. In some embodiments, the 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 "FOLR1-binding antibody" refer to an antibody that can bind to FOLR1 with sufficient affinity to be useful as a diagnostic and / or therapeutic agent in targeting FOLR1 (e.g., huMov19(M9346A) antibody). The degree of binding of an anti-FOLR1 antibody to unrelated non-FOLR1 proteins may be less than 10% of the antibody binding to FOLR1, as measured, for example, by radioimmunoassay (RIA).

[0068] The term "anti-VEGF agent" refers to a drug that can inhibit 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 Holash et al., PNAS 99(17)11393-11398 (2002)).

[0069] The terms “anti-VEGF antibody” or “VEGF-binding antibody” refer to an antibody that can bind to VEGF with sufficient affinity to be useful as a therapeutic agent in targeting VEGF (e.g., bevacizumab). The degree of binding of an anti-VEGF antibody to unrelated non-VEGF proteins 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 that binds to VEGF or its antigen-binding fragment is bevacizumab. In certain embodiments, the antibody that binds to VEGF or its antigen-binding fragment is very similar to bevacizumab and does not have clinically significant differences in terms of 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 containing an antigen-binding complementarity-determining region derived from mouse 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 terms "paclitaxel" or "PAC" refer 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 thought to be a mitotic inhibitor chemotherapeutic agent that binds to tubulin, inhibits microtubule degradation, prevents cell division, and induces apoptosis.

[0072] The term "platinum-based drugs" refers to chemotherapeutic agents that are based on platinum. Platinum-based drugs include cisplatin, carboplatin, and oxaliplatin.

[0073] The term "cisplatin" refers to the compound associated with CAS registry number 15663-27-1. Cisplatin is the active ingredient in PLATINOL® (Bristol-Myers Company) and is also known as "cisplatinum." Cisplatin is thought to be a platinum-containing alkylating chemotherapeutic agent that binds to nucleophilic groups in DNA, causing intra- and inter-strand DNA crosslinking, as well as DNA-protein crosslinking, which leads to apoptosis and inhibition of cell growth.

[0074] The terms "carboplatin" or "carbo" refer to the compound associated with 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 ammonia groups and a cyclobutane-dicarboxyl residue. This agent is activated in cells to form reactive platinum complexes that bind to nucleophiles such as GC-rich sites in DNA, thereby inducing intra- and inter-strand DNA crosslinking as well as DNA-protein crosslinking. These carboplatin-induced DNA and protein effects result in apoptosis and inhibition of cell growth. This agent has similar tumor-killing activity to 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 known as "hydroxydaunorubicin" or "doxorubicin hydrochloride." Doxorubicin is the active ingredient in "Adriamycin" and "Rubex." Liposomal doxorubicin (i.e., doxorubicin encapsulated in lipid globules or liposomes) is the active ingredient in MYOCET® (Cephalon UK, Ltd.). Pegylated liposomal doxorubicin (PLD) (liposomal doxorubicin with polyethylene glycol polymer attached) is the active ingredient in DOXIL® (Liposom Technology, Inc.) and "Caelyx® (Janssen)." Doxorubicin is thought to be an anthracycline antibiotic chemotherapeutic agent that intercalates between base pairs in the DNA helix to prevent DNA replication. In addition, doxorubicin inhibits topoisomerase II, which leads to an increased and stabilized cleavable enzyme-DNA binding complex during DNA replication, and subsequently prevents nucleotide chain ligation after double-strand breaks. Doxorubicin also forms oxygen free radicals, resulting in cytotoxicity following lipid peroxidation of cell membrane lipids.

[0076] The terms “treatment options” or “treatment options” refer to a treatment regimen that may include, but is not limited to, surgery, radiotherapy, chemotherapy, differentiation induction therapy, biological therapy, immunotherapy, or the administration of one or more anticancer agents (e.g., cytotoxic agents, antiproliferative compounds, and / or angiogenesis inhibitors).

[0077] The terms “first-line treatment,” “first-line therapy,” and “frontline treatment” refer to preferred, standard initial treatments for a particular condition, e.g., a given type and stage of cancer. These treatments are distinct from “second-line” therapies, which are attempted when first-line therapy is ineffective. “Third-line” therapies are attempted when first-line and second-line therapies are ineffective.

[0078] For example, the combination of the anti-FOLR1 immune conjugate provided herein (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as first-line therapy, second-line therapy (e.g., in patients with platinum-sensitive or platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer), or 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 the FOLR1 immune conjugate provided herein (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as one of 0, 1, 2, 3, 4, 5, 6, or more treatment options in patients who have received treatment with the combination of the FOLR1 immune conjugate provided herein (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin described herein. The combination of the FOLR1 immune complex provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as one treatment option in patients who have received at least one, at least two, or at least three treatment options prior to treatment with the combination of the FOLR1 immune complex provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In some embodiments, the combination of the FOLR1 immune complex provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as one treatment option in patients who have received one or fewer, two or fewer, three or fewer, four or fewer, five or fewer, or six or fewer treatment options. In certain embodiments, the combination of the FOLR1 immune complex provided herein (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can be administered as adjuvant therapy or neoadjuvant therapy.

[0079] The term "adjuvant therapy" refers to systemic therapy administered after surgery. In its broadest sense, adjuvant therapy is a procedure administered in addition to primary therapy to kill any potentially spreading cancer cells, even if their spread cannot be detected by radiological or clinical examinations.

[0080] The term "neoadjuvant therapy" refers to systemic therapy administered before surgical intervention.

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

[0082] A “monoclonal” antibody or its antigen-binding fragment represents a homogeneous group of antibodies or antigen-binding fragments involved in the highly specific recognition and binding of a single antigenic determinant, i.e., an epitope. This is in contrast to polyclonal antibodies, which typically contain different antibodies directed toward different antigenic determinants. The term “monoclonal” antibody or its antigen-binding fragment 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 antibody moieties, and any other modified immunoglobulin molecules containing antigen recognition sites. Furthermore, “monoclonal” antibodies or their antigen-binding fragments represent antibodies or their antigen-binding fragments produced in any number of ways, including but not limited to those by hybridomas, phage selection, recombinant expression, and transgenic animals.

[0083] The term “humanized” antibody or its antigen-binding fragment refers to a form of non-human (e.g., mouse) antibody or its antigen-binding fragment that contains a minimal non-human (e.g., mouse) sequence, specifically a particular immunoglobulin chain, chimeric immunoglobulin, or fragment thereof. Typically, a humanized antibody or its antigen-binding fragment is a human immunoglobulin in which residues from the complementarity-determining region (CDR) are replaced with residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) that possess the desired specificity, affinity, and capability ("CDR graft") (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 cases, the Fv framework region (FR) residues of human immunoglobulin are replaced with corresponding residues in an antibody or fragment from a non-human species having the desired specificity, affinity, and capability. Humanized antibodies or their antigen-binding fragments can be further modified by substitution of additional residues in the Fv framework region and / or within the replaced non-human residues to refine and optimize the specificity, affinity, and / or capability of the antibody or its antigen-binding fragment. Generally, a humanized antibody or its antigen-binding fragment will contain substantially all of at least one, typically two or three, variable domains, including all or substantially all of the CDR region corresponding to the non-human immunoglobulin, while all or substantially all of the FR region is from the consensus sequence of the human immunoglobulin. Humanized antibodies or their antigen-binding fragments may also contain at least a portion of the immunoglobulin constant region or domain (Fc), typically from human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Patent 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, the "humanized antibody" is a resurfaced antibody.

[0084] The “variable region” of an antibody refers to either a variable region of the antibody’s light chain or a variable region of the antibody’s heavy chain, either alone or in combination. Each variable region of the heavy or light chain consists of four framework regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions. The CDRs within each chain are bound in close proximity by 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, which are: (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 methods may be used in this field to determine the CDR.

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

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

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

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

[0089] The terms “epitope” or “antigenic determinant” are used interchangeably herein and refer to a portion of an antigen that can be recognized and specifically bound by a particular antibody. When the antigen is a polypeptide, epitopes can be formed from both consecutive amino acids and discontinuous amino acids juxtaposed by the tertiary folding of the protein. Epitopes formed from consecutive amino acids are typically retained during protein denaturation, while epitopes formed by tertiary folding are typically lost during protein denaturation. Epitopes typically contain at least three, more commonly at least five or eight to ten, amino acids in a unique spatial conformation.

[0090] "Binding affinity" generally represents the strength of the combined 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 endogenous binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be expressed by its dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally tend to bind slowly to antigens and dissociate easily, while high-affinity antibodies generally tend to bind more quickly to antigens and remain bound for longer. Various methods for measuring binding affinity are known in the art, and any of them can be used for the purposes of this invention. Specific exemplary embodiments are described below.

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

[0092] "Specifically binding" generally means that an antibody binds to an epitope via its antigen-binding domain, and that this binding results in some complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to "specifically bind" to an epitope if, via its antigen-binding domain, it binds to that epitope 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 a particular epitope. For example, antibody "A" may be considered to have higher specificity for a given epitope than antibody "B", or antibody "A" may be said to bind to epitope "C" with higher specificity than it has for the related epitope "D".

[0093] "Preferential binding" means that an antibody specifically binds to a particular epitope more easily than it binds to related, similar, homologous, or analogous epitopes. Therefore, an antibody that "preferentially binds" to a given epitope is more likely to bind to that epitope than to related epitopes, even if the antibody could cross-react with related epitopes.

[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 a duplicate epitope to such an extent that it interferes to some degree with the binding of the reference antibody to that epitope. Competitive inhibition can be determined by any method known in the art, for example, a competitive ELISA assay. An antibody may 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 terms “substantially similar” or “substantially identical” mean a sufficiently high degree of similarity between two numerical values ​​(typically one relating to the antibody of the present invention and the other to a reference / comparative antibody) such that a person skilled in the art would consider the difference between the two values ​​to be of little or no biological and / or statistical significance within the range of the biological characteristics measured by the said value (e.g., the Kd value). The difference between the two values ​​may 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 / comparative antibody.

[0096] "Isolated" polypeptides, antibodies, polynucleotides, vectors, cells, or compositions are polypeptides, antibodies, polynucleotides, vectors, cells, or compositions in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to a degree that they are no longer found in nature. In some embodiments, isolated antibodies, polynucleotides, vectors, cells, or compositions are substantially pure.

[0097] As used herein, “substantially pure” means a substance that is at least 50% pure (i.e., free of impurities), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0098] As used herein, the terms “immune complex” or “complex” refer to a compound or derivative thereof that is linked to a cell-binding agent (i.e., an anti-FOLR1 antibody or a fragment thereof) and is defined by the general formula: CLA, where C = cytotoxin, L = linker, and A = antibody or its antigen-binding fragment, e.g., an anti-FOLR1 antibody or antibody fragment. An immune complex may also be defined by the general formula: ALC in the reverse order.

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

[0100] The terms "cancer" and "cancerous" describe or indicate a physiological condition in mammals in which a population of cells is characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinomas, blastomas, and sarcomas. 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 cancer (PPC), hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer (including epithelial ovarian cancer (EOC) and advanced EOC), liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial cancer (or uterine carcinoma), salivary gland carcinoma, non-clear renal cell carcinoma, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, various types of head and neck cancers, and cancers of the bone, pituitary gland, testes, and brain (see, for example, U.S. Patent No. 8,709,432; U.S. Patent No. 8,834,877; Zwicke et al., Nano Reviews 3:18496-18506 (2012)). Cancer can be a cancer that expresses FOLR1 ("FOLR1-expressing cancer" or "FRα-positive" cancer).

[0101] The terms “cancer cells,” “tumor cells,” and their synonyms refer to the entire population of cells derived from a tumor or precancerous lesion, including both non-tumorogenic cells and oncogenic stem cells (cancer stem cells), which constitute the majority of the tumor cell population. Where used herein, the term “tumor cells” will be modified by the term “non-tumorogenic” to distinguish such tumor cells from cancer stem cells, if they simply refer to tumor cells that lack the ability to regenerate and differentiate.

[0102] "Advanced" cancer is cancer that has spread outside of its site or organ of origin, either through local invasion or metastasis. The term "advanced" cancer encompasses both locally progressive and metastatic diseases.

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

[0104] "Refractory" cancers are those that progress even when cancer patients are receiving antitumor treatment, such as chemotherapy. One example of a refractory cancer is platinum-resistant cancer.

[0105] A patient is considered "platinum-refractory" if they do not respond to platinum-based therapy and their disease progresses during the course of treatment or within four weeks after the last dose. "Platinum-resistant" patients progress within six months of platinum-based therapy. "Partially platinum-sensitive" patients progress between six and twelve months of platinum-based therapy. "Platinum-sensitive" patients progress within a period exceeding twelve months.

[0106] "Recurrent" cancer is cancer that grows again, either at the original site or 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 is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein when referring to human subjects.

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

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

[0110] Combination therapy provides a "synergistic effect," and a "synergistic" effect can be demonstrated, that is, the effect achieved when the active ingredients are used together is greater than the sum of the effects obtained by using the compounds separately. A synergistic effect can be achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in an integrated unit dosage form; (2) delivered sequentially, alternately, or in parallel as separate formulations; or (3) by several other regimens. When delivered in alternating therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes.

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

[0112] The “effective amount” of the antibodies, immune complexes, or other drugs disclosed herein is an amount sufficient to perform the specifically presented purpose. The “effective amount” can be determined empirically and in a conventional manner with respect to the presented purpose.

[0113] The term “therapeutic dose” refers to the amount of an antibody, immune complex, or other drug that is effective in “treating” a disease or disorder in a subject or mammal. In the case of cancer, a therapeutic dose of a drug may reduce the number of cancer cells, reduce tumor size or volume, inhibit (i.e., delay to some extent, and in certain embodiments, halt) the invasion of cancer cells into peripheral organs, inhibit (i.e., delay to some extent, and in certain embodiments, halt) tumor metastasis, inhibit tumor growth to some extent, alleviate one or more of the symptoms associated with cancer to some extent, and / or result in a favorable response such as an increase in progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), or, in some cases, disease stability (SD), a decrease in disease progression (PD), a shortening of time to progression (TTP), a decrease in CA125 in the case of ovarian cancer, or any combination thereof. See the specified definition of “treating.” A drug can be cell proliferation inhibitory and / or cytotoxic insofar as it can prevent growth and / or kill existing cancer cells. The “prophylactic effective dose” represents the amount effective in achieving the desired prophylactic outcome at the required dosage and duration. Typically, though not always, prophylactic administration is used in a subject before or at the early stages of the disease, so the prophylactic effective dose will be less than the therapeutic effective dose.

[0114] The term "favorably responds" generally refers to causing a beneficial state in the subject. In the context of cancer treatment, this term refers to providing a therapeutic effect to the subject. Positive therapeutic effects in cancer can be measured in several ways (see WA 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 anticancer drugs. 10 Cell Kill (LCK) can be used to quantify tumor cell death. 10Cell Kill (LCK) is given by the formula LCK = (TC) / T d Calculated using ×3.32, where (TC) (i.e., tumor growth retardation (TGD)) is the median time (days) for tumors in the treatment and control groups to reach a predetermined size (tumor-free survivors are excluded). 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 cell doubling rate per logarithmic cell growth. The ability to reduce tumor volume may be evaluated, for example, by measuring the %T / C value, which is the median tumor volume of the treated subject divided by the median tumor volume of the control subject. Regarding tumor growth inhibition, according to NCI criteria, a T / C of 42% or less is considered the minimum level of antitumor activity. A T / C of less than 10% is considered to be a high level of antitumor activity, and T / C (%) = median tumor volume of the treated subject / median tumor volume of the control × 100. A favorable response can be evaluated, 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, disease stability (SD), reduced disease progression (PD), shortened time to progression (TTP), reduced CA125 in the case of ovarian cancer, or any combination thereof.

[0115] PFS, DFS, and OS can be measured according to 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) represents the time from registration to disease progression or death. PFS is generally measured using the Kaplan-Meier procedure and the RECIST 1.1 criteria for evaluating the effectiveness of treatment for solid tumors. Generally, progression-free survival represents the period during which a patient continues to live without their cancer worsening.

[0117] The "time without progression" (TTP) is defined as the period from registration to disease progression. TTP is generally measured using the RECIST 1.1 criteria.

[0118] "Complete response," "complete remission," or "CR" indicates that all signs of the tumor or cancer have disappeared in response to treatment. This does not necessarily mean that the cancer is cured.

[0119] "Partial response" or "PR" indicates 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] "Disease stability" refers to a disease that does not progress or recur. In disease stability, there is neither a tumor reduction sufficient to be considered a partial response, nor a tumor increase sufficient to be considered disease progression.

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

[0122] Disease-free survival (DFS) represents the length of time during and after a procedure in which a patient remains disease-free.

[0123] Overall survival (OS) represents the period from patient registration to death or censorship on the last confirmed survival date. OS includes an extension of life expectancy compared to untreated or unmedicated individuals or patients. Overall survival represents the situation in which a patient continues to live for a predetermined period, such as one year or five years, from the time of diagnosis or treatment.

[0124] "Extended survival" or "increased survivability" means that the PFS and / or OS in the treated subjects are increased compared to the untreated subjects or compared to a control treatment protocol, such as that used in standard treatment for a particular type of cancer.

[0125] "Reduction in CA125 levels" can be evaluated 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 once or multiple times during or after treatment, and a decrease in CA125 levels over time compared to the baseline level is considered a reduction in CA125 levels.

[0126] The terms “increased expression” or “overexpression” of FOLR1 in a particular tumor, tissue, or cell sample refer to the presence of FOLR1 (FOLR1 polypeptide or nucleic acid encoding such polypeptide) at a higher level than that present in healthy or non-infected (undenatured, wild-type) tissue or cells of the same type or origin. Such increased or overexpression may be caused, for example, by mutation, gene amplification, increased transcription, increased translation, or increased protein stability.

[0127] Terms such as “to treat,” “treatment,” “to treat,” “to alleviate,” or “to alleviate” refer to therapeutic means that cure, delay, relieve, and / or halt the progression of the symptoms of the diagnosed condition or disorder. Therefore, persons in need of treatment include those who have already been diagnosed with the disorder or those suspected of having the disorder. In certain embodiments, a patient is considered to have successfully undergone cancer “treatment” according to the method of the present invention if the patient exhibits one or more of the following: a reduction or complete absence of the number of cancer cells; a reduction in tumor volume; inhibition or absence of invasion of cancer cells into peripheral organs, including, for example, the spread of cancer into soft tissue and bone; inhibition or absence of tumor metastasis; inhibition or absence of tumor growth; relief of one or more symptoms associated with a particular cancer; a reduction in morbidity and mortality; an improvement in quality of life; a reduction in the tumor’s tumorigenicity, tumorigenicity frequency, or tumorigenic capacity; a reduction in the number or frequency of cancer stem cells within the tumor; differentiation from tumorigenic cells to non-tumoric states; 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); a reduction in CA125 in the case of ovarian cancer; or any combination thereof.

[0128] Protective or preventive measures refer to means that prevent and / or delay the onset of a targeted disease or disorder. Therefore, those who require protective or preventive measures include those who are prone to the disorder and those for whom the disorder should be prevented.

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

[0130] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to represent polymers of amino acids of any length. Polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. This term also encompasses amino acid polymers that are modified naturally or by intervention; for example, by any other operation or modification such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or conjugation with labeling components. Furthermore, polypeptides containing, for example, one or more analogues of amino acids (including, for example, non-natural amino acids), as well as other modifications known in the art, are also included in this definition. Since the polypeptides of the present invention are antibody-based, it should be understood that in certain embodiments, polypeptides may arise as single-chain or associated chains.

[0131] In the context of two or more nucleic acids or polypeptides, the terms “identical” or “percent “identical” refer to two or more sequences or subsequences that, when compared and aligned (with gaps introduced if necessary) for maximum matching, have the same nucleotide or amino acid residues, or a certain percentage (%) of the same nucleotide or amino acid residues, without considering any conserved amino acid substitutions as part of sequence identity. Percential identity can be measured using sequence comparison software or algorithms, or by visual inspection. Various algorithms and software available for obtaining amino acid or nucleotide sequence alignments are publicly known in the art. One such non-exclusive example of a sequence alignment algorithm is described in Karlin et al, Proc. Natl. Acad. Sci., 87:2264-2268 (1990), modified in Karlin et al., Proc. Natl. Acad. Sci., 90:5873-5877 (1993), and is part of the NBLAST and XBLAST programs (Altschul et al. This algorithm is 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 for sequence alignment. In certain embodiments, the percentage identity between two nucleotide sequences is determined using the GAP program of the GCG software (e.g., using the NWSgapdna.CMP matrix and gap weights of 40, 50, 60, 70, or 90, and length weights of 1, 2, 3, 4, 5, or 6). In certain alternative embodiments, the percentage identity between two amino acid sequences can be determined using the GAP program of the GCG software package incorporating the algorithm of Needleman and Wunsch (J. Mol. Biol. (48): 444-453 (1970)) (e.g., using the Blossum 62 matrix or PAM250 matrix and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, or 5). Alternatively, in certain embodiments, the percentage identity between nucleotide or amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4: 11-17 (1989)). For example, percentage identity can be determined using the ALIGN program (version 2.0), as well as using PAM120 with residue tables, gap length penalty 12, and gap penalty 4. The appropriate parameters for maximum alignment with specific alignment software can be determined by those skilled in the art.In certain embodiments, predefined parameters of alignment software are used. In certain embodiments, the percentage identity "X" of the first amino acid sequence to the amino acids of the second sequence is calculated as 100 × (Y / Z), where Y is the number of amino acid residues that were scored as a perfect match (by visual inspection or sequence comparison by a specific sequence alignment program) in the alignment of the first and second sequences, and Z is the total number of residues in the second sequence. If the length of the first sequence is longer than that of the second sequence, the percentage identity of the first sequence to the second sequence will be longer than the percentage identity of the second sequence to the first sequence.

[0132] As a non-limiting example, whether any particular polynucleotide has a certain percentage (%) of sequence identity with respect to a reference sequence (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) can be determined in certain embodiments by the Bestfit program (Wisconsin Sequence Analysis Package, Unix® version 8, Genetics). This can be determined using the 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 homology segment between two sequences. When using Bestfit or any other sequence alignment program to determine whether a particular sequence is 95% identical to, for example, a reference sequence according to this invention, the parameters are set such that the percentage of identity (%) is calculated over the entire length of the reference nucleotide sequence, and that a gap in homology is 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 present invention are substantially identical, i.e., they have nucleotide or amino acid residue identity of 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%, and 99%, when compared and aligned for maximum match using a sequence comparison algorithm or by visual inspection. The identity can exist over regions of sequences with residue lengths of at least about 10, about 20, about 40–60, or any integer value in between, and can also extend over regions longer than 60–80 residues, for example, at least about 90–100 residues, and in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared, such as the coding region of a nucleotide sequence.

[0134] A "conservative amino acid substitution" is a substitution in which one amino acid residue is replaced by another amino acid residue having a similar side chain. Families of amino acid residues with similar side chains are defined in the art and include basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), non-charged 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, the substitution of tyrosine with phenylalanine is a conservative substitution. In some embodiments, the conserved substitutions in the polypeptide and antibody sequences of the present invention do not invalidate the 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 conserved nucleotide and amino acid substitutions that do not exclude antigen binding are well known in the art (see, for example, Brummell et al., Biochem. 32:1180-1 187 (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] When used in this disclosure and in the claims, the singular forms "a," "an," and "the" are plural unless the context explicitly indicates otherwise.

[0136] In any case where an embodiment is described herein with the word “including”, it should be understood that other similar embodiments described with respect to “consisting of” and / or “essentially consisting of” are also provided.

[0137] In this specification, the term "and / or" as used 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 include 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 Methods for administering immune complexes (e.g., IMGN853) that specifically bind to FOLR1 are described herein. 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 provided herein as SEQ ID NO: 1 and SEQ ID NO: 2, respectively. SEQ ID NO: 1 - Human folate receptor 1 MAQRMTTQLLLLLVWVAVVGEAQTRIAWARTELLNVCMNAKHHKEKPGPEDKLHEQCRPWRKNACCSTNTSQEAHKDVSYLYRFNWNHCGEMAACKRHFIQDTCLYECSPNLGPWIQQVDQSWRKER VLNVPLCKEDCEQWWEDCRTSYTCKSNWHKGWNWTSGFNKCAVGAACQPFHFYFPTPTVLCNEIWTHSYKVSNYSRGSGRCIQMWFDPAQGNPNEEVARFYAAAMSGAGPWAAWPFLLSLALMLLWLLS Sequence ID No. 2 - Human folate receptor 1 nucleic acid sequence atggctcagcggatgacaacacagctgctgctccttctagtgtgggtggctgtagtaggggaggctcagacaaggattgcatgggccaggactgagcttctcaatgtctgcatgaacgccaagcaccacaaggaaaagccaggccccgaggacaagttgcatgagcagtgtcgaccctggaggaagaatgcctgctgttctaccaacaccagccaggaagcccataaggatgtttcctacctatatagattcaactggaaccactgtggagagatggcacctgcctgcaaacggcatttcatccaggacacctgcctctacgagtgctcccccaacttggggccctggatccagcaggtggatcagagctggcgcaaagagcgggtactgaacgtgcccctgtgcaaagaggactgtgagcaatggtgggaagattgtcgcacctcctacacctgcaagagcaactggcacaagggctggaactggacttcagggtttaacaagtgcgcagtgggagctgcctgccaacctttccatttctacttccccacacccactgttctgtgcaatgaaatctggactcactcctacaaggtcagcaactacagccgagggagtggccgctgcatccagatgtggttcgacccagcccagggcaaccccaatgaggaggtggcgaggttctatgctgcagccatgagtggggctgggccctgggcagcctggcctttcctgcttagcctggccctaatgctgctgtggctgctcagc

[0139] The anti-FOLR1 immune complex contains a cell-binding agent linked to a cytotoxin. The cell-binding agent may be an anti-FOLR1 antibody or its antigen-binding fragment. An example of a therapeutically effective anti-FOLR1 antibody can be found in U.S. Patent Publication No. US2012 / 0009181, which is incorporated herein by reference. An example of a therapeutically effective anti-FOLR1 antibody is huMov19(M9346A) (containing the sequences of SEQ ID NOs. 3 and 5). The polypeptides of SEQ ID NOs. 3-5 each contain 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 consists of the variable domain heavy chain represented by SEQ ID NOs. 3 and the variable domain light chain represented by SEQ ID NOs. 5 (version 1.60 of huMov19). In a particular embodiment, the huMov19(M9346A) antibody is encoded by a plasmid deposited on April 7, 2010, at the American Type Culture Collection (ATCC) located at 10801 University Boulevard, Manassas, VA 20110, under the provisions of the Budapest Convention, with ATCC deposit numbers PTA-10772 and PTA-10773 or 10774.

[0140] The amino acid sequences of huMov19 are 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 its antigen-binding fragment. In some embodiments, the humanized antibody or fragment is a surface-reconstituted antibody or its antigen-binding fragment. In other embodiments, the anti-FOLR1 immune complex comprises a fully human antibody or its antigen-binding fragment.

[0142] In certain embodiments, the anti-FOLR1 immune complex has one or more of the following effects: inhibition of tumor cell proliferation, reduction of tumor tumorigenic potential by decreasing the frequency of cancer stem cells in the tumor, inhibition of tumor growth, increase of patient survival, induction of tumor cell death, differentiation of tumorigenic cells into a non-tumoric state, or prevention or reduction of tumor cell metastasis.

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

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

[0145] The FOLR1-binding molecule may be an antibody or antigen-binding fragment that specifically binds to FOLR1 containing a CDR of huMov19(M9346A) with up to four (i.e., 0, 1, 2, 3, or 4) conserved amino acid substitutions per CDR, for example, here 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 may contain one of the individual variable light chains or variable heavy chains described herein. The antibody and polypeptide may also contain 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 containing the sequences of SEQ ID NOs. 6-10 and SEQ ID NO. 12. In some embodiments, the FOLR1-binding molecule is an antibody or antigen-binding fragment containing the sequences of SEQ ID NOs. 6-9 and SEQ ID NOs. 11 and 12. In some embodiments, the FOLR1-binding molecule is an antibody or antigen-binding fragment containing the sequences of SEQ ID NOs. 6-8, 19, 11, and 12.

[0147] Polypeptides are also provided that have 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 mouse, chimeric, or humanized antibody that specifically binds to FOLR1. In certain embodiments, a polypeptide having a certain percentage (%) of sequence identity with SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5 is different from SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5 solely by conservative amino acid substitutions.

[0148] A polypeptide may contain one of the individual light chains or heavy chains described herein. Antibodies and polypeptides may also contain both light chains and heavy chains.

[0149] Monoclonal antibodies can be prepared using hybridoma methods, such as those described in Kohler and Milstein (1975) Nature 256:495. Using hybridoma methods, mice, hamsters, or other suitable host animals are immunized as described above to induce the production of antibodies by lymphocytes that will specifically bind to the immune 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 that produce monoclonal antibodies specifically targeted to a selected antigen, as determined by immunoprecipitation, immunoblotting, or in vitro binding assays (e.g., radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA)), can then be propagated either in vitro 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 antibody are isolated from mature B cells or hybridoma cells by RT-PCR using oligonucleotide primers that specifically amplify, for example, the genes encoding the heavy and light chains of the antibody, 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 would otherwise not produce immunoglobulin proteins, such as E. coli cells, monkey COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, thereby generating the monoclonal antibody by the host cells. Alternatively, recombinant monoclonal antibodies or fragments of the desired species can be isolated from phage display libraries expressing the CDR 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 numerous 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 mouse monoclonal antibody can be replaced with 1) a region of a human antibody to generate a chimeric antibody, or 2) a non-immunoglobulin polypeptide to generate a fusion antibody. In some embodiments, the constant region is cleaved or removed to generate a desired antibody fragment of the monoclonal antibody. Site-directed or high-density mutagenesis of the variable region 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 surface-reconstituted antibody. In certain embodiments, such an antibody is used therapeutically to reduce antigenicity and HAMA (human anti-mouse antibody) reaction when administered to a human subject. Humanized antibodies can be manufactured 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 various techniques known in the art. Immortalized human B lymphocytes that produce antibodies against target antigens can be generated in vitro from immunized individuals or isolated from immunized individuals (see, for example, 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). Furthermore, as described in, for example, 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), human antibodies can be selected from a phage library, in which case the phage library expresses human antibodies. Techniques for generating and using antibody phage libraries are also described in U.S. Patents 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 in Rothe et al., 2007, J.Mol.Bio., doi:10.1016 / j.jmb.2007.12.018 (each of these is incorporated herein by reference in its entirety). Affinity maturation strategies and chain shuffling strategies (Marks et al., 1992, Bio / Technology 10:779-783, the entire text of which is incorporated by reference) are known in the field and can be employed to generate high-affinity human antibodies.

[0154] Humanized antibodies can also be produced in transgenic mice containing human immunoglobulin loci, which can generate a repertoire of human antibodies upon immunization in the absence of endogenous immunoglobulin production. This method is described in U.S. Patents 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016.

[0155] The polypeptide of the present invention may be a recombinant polypeptide, a natural polypeptide, or a synthetic polypeptide, comprising an antibody against human FOLR1 or a fragment thereof.

[0156] Polypeptides and analogs can be further modified to contain additional chemical moieties that are not normally part of the protein. These derivatized moieties can improve the protein's solubility, biological half-life, or absorption. These moieties can also reduce or eliminate any desired side effects of the protein. An overview 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, for example, those described in U.S. Patent Publications 2008 / 0312425, 2008 / 0177048, and 2009 / 0187005, each of which is incorporated herein by reference in whole.

[0158] Suitable drugs or prodrugs are known in the art. The drug or prodrug may be a cytotoxic agent. The cytotoxic agent used in the cytotoxin complex of the present invention may be any compound that causes or induces cell death or reduces the viability of cells in any way, and includes, for example, mytansinoids and mytansinoid analogs.

[0159] Such a complex can be prepared by using a linking group to link a drug or prodrug to an 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 an anti-FOLR1 antibody or a fragment thereof, for example, through a disulfide bond. The linker molecule or crosslinking agent comprises a reactive chemical group capable of reacting with the anti-FOLR1 antibody or a fragment thereof. The reactive chemical group for reaction with a cell binding agent can be N-succinimidyl ester and N-sulfosuccinimidyl ester. In addition, the linker molecule comprises a reactive chemical group, which can be a dithiopyridyl group that can react with a 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. Patent 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 Number 341498-08-6), 2-iminothiolane, or acetylsuccinic anhydride. For example, an antibody or cell binding agent can be modified with a crosslinking reagent, and the antibody or cell binding agent containing free or protected thiol groups thus obtained is then reacted with a maytansinoid containing a disulfide or thiol to form a complex. The complex 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 aspect of the present invention, the 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 WO2009 / 0134976. An additional advantage of this linker design is the desired high monomer ratio and minimal aggregation of the antibody-drug conjugate. In this aspect, with a narrow drug loading range of 2 to 8, the polyethylene glycol spacer ((CH2CH2O) n=1-14 conjugates of cell binding agents and drugs linked via a disulfide group (-S-S-) having ) are specifically contemplated, which exhibit relatively potent biological activity against cancer cells and have the desired biochemical properties of high conjugation yield and high monomer ratio, along with minimal protein aggregation.

[0162] Antibody-mytansinoid complexes having an uncleavable linker can also be prepared. Such crosslinking agents 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, the antibody is modified with a crosslinking reagent such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC), sulfo-SMCC, maleimidobenzoyl-N-hydroxysuccinimid ester (MBS), sulfo-MBS, or succinimidyl-iodoacetic acid, as described in the literature, to introduce 1 to 10 reactive groups (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 mytansinoid derivative to form a complex. The complex can be purified by gel filtration through a Sephadex G25 column, or by dialysis or tangential flow filtration. Modified antibodies are treated with thiol-containing mytansinoids (1-2 molar equivalents / maleimide group), and the antibody-mytansinoid complexes are purified by gel filtration through a Sephadex G-25 column, chromatography on a ceramic hydroxyapatite column, dialysis, tangential flow filtration, or a combination of these methods. Typically, on average, 1-10 mytansinoids are linked per antibody molecule. One method involves modifying the antibody with succinimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) to introduce a maleimide group, and then reacting the modified antibody with a thiol-containing mytansinoid to obtain a thioether-linked complex. Again, a complex with 1-10 drug molecules per antibody molecule is produced. Mytansinoid complexes of antibodies, antibody fragments, and other proteins are prepared in the same manner.

[0163] In another aspect of the present invention, the FOLR1 antibody is linked to the drug via an indestructible bond mediated by a PEG spacer. Suitable crosslinking 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., Quanta Biodesign, Powell, Ohio). Suitable PEG-containing crosslinkers can also be synthesized from commercially available PEG itself using standard synthetic chemical techniques known to those skilled in the art. The drug is reacted with a bifunctional PEG-containing crosslinker to form a crosslinker of the following formula, ZX l -(-CH2-CH2-O-) n -Y p Compound -D can be obtained by the method detailed in U.S. Patent Publication No. 20090274713 and WO2009 / 0134976, and then reacted with a cell binder to provide a complex. Alternatively, the cell binder can be modified with a bifunctional PEG crosslinker to introduce a thiol reactive group (such as maleimide or haloacetamide), and then treated with a thiol-containing mytansinoid to provide a complex. In another method, the cell binder can be modified with a bifunctional PEG crosslinker to introduce a thiol moiety, and then treated with a thiol-reactive mytansinoid (such as a mytansinoid having maleimide or haloacetamide) to provide a complex.

[0164] Examples of suitable PEG-containing linkers include linkers having an N-succinimidyl ester or N-sulfosuccinimidyl ester moiety for reaction with anti-FOLR1 antibodies or fragments thereof, and a maleimide or haloacetyl moiety for reaction with compounds. The PEG spacer can be incorporated into any crosslinking agent known to those skilled in the art by the method described herein.

[0165] In some embodiments, the linker is a linker containing at least one charged group, which is described, for example, in U.S. Patent Publication 2012 / 0282282, the contents of which are incorporated herein by reference in whole. In some embodiments, the charged or pro-charged crosslinker contains a sulfonate, phosphate, carboxyl, or quaternary amine substituent that significantly increases the solubility of the modified cell-binding agent and cell-binding agent-drug complex, particularly for monoclonal antibody-drug complexes linked with 2 to 20 drug / antibody units. Complexes prepared from a linker containing a pro-charged moiety will generate one or more charged moieties after the complex is metabolized intracellularly. 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 Publications 2005 / 0169933, 2009 / 0274713, and 2012 / 0282282, and WO2009 / 0134976; the contents thereof are incorporated herein by reference in whole.

[0167] The present invention includes embodiments in which about 2 to about 8 drug molecules ("drug load"), for example, mytansinoids, are ligated to an anti-FOLR1 antibody or a fragment thereof. "Drug load," as used herein, refers to the number of drug molecules (e.g., mytansinoids) that can adhere to a cell binder (e.g., an anti-FOLR1 antibody or a fragment thereof). In one embodiment, the number of drug molecules that can adhere to the cell binder 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) can be used. N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-mytansine (DM1) and N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)mytansine (DM4) can be used.

[0168] Therefore, in one embodiment, the immune complex contains one mytansinoid per antibody. In another embodiment, the immune complex contains two mytansinoids per antibody. In another embodiment, the immune complex contains three mytansinoids per antibody. In another embodiment, the immune complex contains four mytansinoids per antibody. In another embodiment, the immune complex contains five mytansinoids per antibody. In another embodiment, the immune complex contains six mytansinoids per antibody. In another embodiment, the immune complex contains seven mytansinoids per antibody. In another embodiment, the immune complex contains eight mytansinoids per antibody.

[0169] In one embodiment, the immune complex (e.g., an immune complex containing linker SPDB and mytansinoid DM4) contains about 1 to about 8 mytansinoids per antibody. In another embodiment, the immune complex (e.g., an immune complex containing linker SPDB and mytansinoid DM4) contains about 2 to about 7 mytansinoids per antibody. In another embodiment, the immune complex (e.g., an immune complex containing linker SPDB and mytansinoid DM4) contains about 2 to about 6 mytansinoids per antibody. In another embodiment, the immune complex (e.g., an immune complex containing linker SPDB and mytansinoid DM4) contains about 2 to about 5 mytansinoids per antibody. In another embodiment, the immune complex (e.g., an immune complex containing linker SPDB and mytansinoid DM4) contains about 3 to about 5 mytansinoids per antibody. In another embodiment, the immune complex (e.g., an immune complex containing the linker SPDB and the mytansinoid DM4) contains approximately 3 to 4 mytansinoids per antibody.

[0170] In one embodiment, the composition containing immune complexes comprises, on average, about 2 to about 8 per antibody (for example, 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) It has 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., mytansinoids). In one embodiment, the composition containing the immune complex has, on average, about 1 to about 8 drug molecules (e.g., mytansinoids) per antibody. In another embodiment, the composition containing the immune complex has, on average, about 2 to about 7 drug molecules (e.g., mytansinoids) per antibody. In one embodiment, the composition containing the immune complex has, on average, about 2 to about 6 drug molecules (e.g., mytansinoids) per antibody. In another embodiment, the composition containing the immune complex has, on average, about 2 to about 5 drug molecules (e.g., mytansinoids) per antibody. In another embodiment, the composition containing the immune complex has, on average, about 3 to about 5 drug molecules (e.g., mytansinoids) per antibody. In yet another embodiment, the composition containing the immune complex has, on average, about 3 to about 4 drug molecules (e.g., mytansinoids) per antibody.

[0171] In one embodiment, the composition containing the immune complex 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., mytansinoids) per antibody. In another embodiment, the composition containing the immune complex has, on average, about 3.5 ± 0.5 drug molecules (e.g., mytansinoids) per antibody.

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

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

[0174] As used herein, the expressions “linked to a cell binder” or “linked to an anti-FOLR1 antibody or fragment” refer to a complex molecule comprising at least one drug derivative linked to a cell binder, an anti-FOLR1 antibody or fragment via a suitable linking group or its precursor. Exemplary linking groups are SPDB or sulfo-SPDB.

[0175] In certain embodiments of the present invention, useful cytotoxic agents are mytansinoids and mytansinoid analogs. Examples of suitable mytansinoids include mytansinol and esters of mytansinol analogs. This includes any drug that inhibits microtubule formation and is highly toxic to mammalian cells, such as mytansinol and mytansinol analogs.

[0176] Suitable examples of mytansinol esters include those having a modified aromatic ring and those having modifications at other positions. Such suitable mytansinoids are 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; and This information is disclosed in Patent 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 immune complex of the present invention is a thiol-containing mytansinoid (DM1), formally known as N 2’ -deacetyl-N 2’ -(3-mercapto-1-oxopropyl)-mytansin is used as a cytotoxic agent. DM1 has the following structural formula (I): [ka] It is represented by (I).

[0178] In another embodiment, the complex of the present invention is a thiol-containing mytansinoid N 2’ -deacetyl-N 2’ (4-methyl-4-mercapto-1-oxopentyl)-mytansin (e.g., DM4) is used as a cytotoxic agent. DM4 has the following structural formula (II): [ka] This is represented by (II).

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

Chemical Structure

[0180] Each of the maytansinoids taught in U.S. Patent Nos. 5,208,020 and 7,276,497 can also be used in the conjugate 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 positions for chemical attachment 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 hydroxyl group are all expected to be useful. In some embodiments, the C-3 position serves as the position for chemical attachment to the linking moiety, and in some specific embodiments, the C-3 position of maytansinol serves as the position for chemical attachment to the linking moiety.

[0182] Structural representations of some conjugates are shown below:

Chemical Structure

Chemical Structure

Chemical Structure

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

[0184] Several descriptions for the generation of such antibody-mytansinoid complexes are provided in U.S. Patents 6,333,410, 6,441,163, 6,716,821, and 7,368,565, each of which is incorporated herein by reference in whole.

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

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

[0187] Antibodies and mytansinoids or other drugs can be evaluated for their ability to inhibit the proliferation of various undesirable cell lines in vitro. 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 toxic effects of these compounds. The cells to be evaluated are exposed to the compound for 4-5 days, and cell viability can be measured by direct assays using known methods. 50 The value can then be calculated from the assay results.

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

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

[0190] III. Anti-VEGF agents This specification describes a method of administering an anti-FOLR1 immune complex, such as IMGN853, in combination with an agent that specifically binds to VEGF (e.g., bevacizumab) or an agent that specifically binds to the 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 This is provided in Medicine 2:a006577(2012), which is incorporated herein by reference in its entirety.

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

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

[0193] The full-length amino acid sequence of human VEGF-A is available in UniProtKB accession number P15692 and, as specified herein, in sequence number 17:

[0194] Provided as MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVYVGARCCLMPWSLPGPHPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR (SEQ ID NO: 17), this signal sequence is MNFLLSWVHWSLALLLYLHHAKWSQA (SEQ ID NO: 18).

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

[0196] Anti-VEGF antibodies and their antigen-binding fragments may include polypeptides containing a variable light chain or a variable heavy chain as described herein. Anti-VEGF antibodies and polypeptides may also contain both a variable light chain and a variable heavy chain. 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 whole.

[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 its antigen-binding fragment binds to VEGFR1, VEGFR2, or VEGFR3. In some embodiments, the anti-VEGF receptor antibody or its antigen-binding fragment 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. A tyrosine kinase inhibitor can inhibit, for example, VEGFR1, VEGFR2, and / or VEGFR3. In some embodiments, the tyrosine kinase inhibitor is cedilanib. 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 batalanib. In some embodiments, the tyrosine kinase inhibitor is semacsanib. 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 may contain the extracellular ligand-binding domain of VEGFR1. The soluble VEGF receptor protein may contain the extracellular ligand-binding domain of VEGFR2. The soluble VEGF receptor protein may contain the extracellular ligand-binding domains of both 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 This specification describes a method for administering an anti-FOLR1 immune conjugate, such as IMGN853, in combination with a platinum-based drug, such as cisplatin, carboplatin, or oxaliplatin.

[0202] Cisplatin is a platinum-based, alkylating chemotherapeutic agent that generates DNA adducts and is therefore cytotoxic to cells with insufficient excision and repair (see Huang et al., PNAS 91:10394-10398 (1994)). Cisplatin is the parent compound of carboplatin. Like cisplatin, carboplatin generates DNA adducts that are cytotoxic to cells with insufficient excision and 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 (better) toxicity profile (Lokich et al., Annals. Of Oncology 9:13-21 (1998)). Exemplary carboplatins include paraplatin.

[0204] Oxaliplatin is a third-generation platinum-based drug. An example of oxaplatin is Eloxatin®.

[0205] The administration of platinum-based drugs in combination with anti-FOLR1 immune complexes (e.g., IMGN853) can reduce the amount and / or frequency of platinum-based drugs required to achieve the same efficacy, thereby reducing the toxicity of the treatment. The administration of platinum-based drugs in combination with anti-FOLR1 immune complexes (e.g., IMGN853) can also increase the efficacy of the treatment.

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

[0207] V. Doxorubicin This specification describes a method for administering an anti-FOLR1 immune complex, such as IMGN853, in combination with doxorubicin.

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

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

[0210] In some embodiments, doxorubicin is a liposome. In some embodiments, doxorubicin is not a liposome.

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

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

[0213] Doxorubicin administration in combination with an anti-FOLR1 immune complex (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. Doxorubicin administration in combination with an anti-FOLR1 immune complex (e.g., IMGN853) can also increase the efficacy of the treatment.

[0214] VI. Pharmaceutical Compositions and Kits As provided herein, anti-FOLR1 immune complexes (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 complex (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 complex (e.g., IMGN853) and the anti-VEGF agent (e.g., bevacizumab) are contained within two separate pharmaceutical compositions in a single kit. In other embodiments, the kit includes instructions for use for administering the anti-FOLR1 immune complex (e.g., IMGN853) and the anti-VEGF agent (e.g., bevacizumab). In other embodiments, the kit includes instructions for use for administering the anti-VEGF agent (e.g., bevacizumab) and the anti-FOLR1 immune complex (e.g., IMGN853).

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

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

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

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

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

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

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

[0223] In other embodiments, the kit includes an anti-FOLR1 immune complex (e.g., IMGN853) and instructions for use for administering the anti-FOLR1 immune complex (e.g., IMGN853), a platinum-based drug, and doxorubicin. In other embodiments, the kit includes an anti-FOLR1 immune complex (e.g., IMGN853) and instructions for use for administering the platinum-based drug, a platinum-based drug, and doxorubicin. In other embodiments, the kit includes doxorubicin and instructions for use for administering doxorubicin, a platinum-based drug, and an anti-FOLR1 immune complex (e.g., IMGN853).

[0224] In other embodiments, the kit includes instructions for use for administering an anti-FOLR1 immune complex (e.g., IMGN853) and a platinum-based drug, as well as instructions for use for administering the anti-FOLR1 immune complex (e.g., IMGN853), a platinum-based drug, and doxorubicin. In other embodiments, the kit includes instructions for use for administering an anti-FOLR1 immune complex (e.g., IMGN853) and doxorubicin, as well as instructions for use for administering the anti-FOLR1 immune complex (e.g., IMGN853), doxorubicin, and a platinum-based drug. In other embodiments, the kit includes instructions for use for administering a platinum-based drug and doxorubicin, as well as instructions for use for administering the platinum-based drug, doxorubicin, and an anti-FOLR1 immune complex (e.g., IMGN853).

[0225] In certain embodiments, the pharmaceutical compositions provided herein include an anti-FOLR1 immune complex (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin, as well as a pharmaceutically acceptable vehicle. In certain embodiments, the pharmaceutical compositions further include a preservative. These pharmaceutical compositions are used for inhibiting tumor growth and treating cancer in human patients.

[0226] Pharmaceutical compositions for use as described herein may be administered by any means for either topical or systemic treatment. Administration may include topical administration, e.g., transdermal patches, ointments, lotions, creams, gels, infusions, suppositories, sprays, solutions and powders; transpulmonary administration (e.g., by inhalation or blowing of powders or sprays, including nebulizers; intratracheal, intranasal, epidermal and transdermal); oral administration; or parenteral administration, e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial administration (e.g., intrathecal or intraventricular). 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 immune complexes (e.g., IMGN853) can be used in combination with anti-VEGF agents (e.g., bevacizumab), platinum-based drugs, and / or doxorubicin to treat cancer.

[0228] VII.A. Cancer Treatment Options Cancers that can be treated by this method include, but are not limited to, any disease or disorder characterized by neoplasms, tumors, metastases, or uncontrolled cell growth. Cancers can be primary or metastatic cancers. 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 renal cell 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, subjects have previously untreated ovarian cancer. In some embodiments, subjects have newly diagnosed, previously untreated ovarian cancer (e.g., not previously treated with an anti-VEGF antibody, e.g., bevacizumab ("bevacizumab naive")). In other embodiments, subjects have previously treated ovarian cancer (e.g., previously treated with an anti-VEGF antibody, e.g., bevacizumab). In some embodiments, subjects have 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 reduced), and stage IV epithelial ovarian primary peritoneal or fallopian tube cancer. In other embodiments, subjects have previously treated (e.g., previously treated with an anti-VEGF antibody, e.g., bevacizumab) stage III (suboptimally and macroscopically optimally reduced) and IV epithelial ovarian primary peritoneal or fallopian tube cancer. In some embodiments, subjects have platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. In other embodiments, subjects have platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.

[0230] In certain embodiments, the combination of the FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is administered to patients who have been diagnosed with or have ovarian cancer, epithelial ovarian cancer, primary ovarian peritoneal cancer, or ovarian / fallopian tube cancer, and who have not been previously treated with an anti-VEGF antibody, such as bevacizumab ("bevacizumab-naive"). In other embodiments, the combination of the FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is administered to patients who have been diagnosed with or have ovarian cancer, epithelial ovarian cancer, primary ovarian peritoneal cancer, or ovarian / fallopian tube cancer, and who have been previously treated with an anti-VEGF antibody, such as 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] A combination of a FOLR1 immune complex (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 monotherapy in the prior treatment. In some embodiments, bevacuzimab was administered as part of a combination therapy in the prior treatment.

[0232] A combination of FOLR1 immune complexes (e.g., IMGN853) and anti-VEGF agents, platinum-based drugs, and / or doxorubicin can be administered to patients who have not been previously treated with bevacizumab (i.e., the patient is "bevacizumab-naive").

[0233] In certain embodiments, the cancer is ovarian, peritoneal, fallopian tube, endometrial, or lung cancer. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to ovarian, peritoneal, fallopian tube, endometrial, or lung cancer as first-line, second-line, third-line, or fourth-line or later-line therapy. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to ovarian, peritoneal, fallopian tube, endometrial, or lung cancer as 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 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to EOC, e.g., platinum-resistant, recurrent, or refractory EOC, as first-line, second-line, third-line, or fourth-line or later-line therapy. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to EOC, e.g., platinum-resistant, recurrent, or refractory EOC, as adjuvant therapy 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 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to primary peritoneal cancer as first-line, second-line, third-line, or fourth-line or later-line therapy. Doxorubicin combinations can be administered as adjuvant therapy 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. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to serous endometrial cancer as first-line, second-line, third-line, or fourth-line or later-line therapy. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to serous endometrial cancer as 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 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to lung cancer, e.g., NSCLC, adenocarcinoma, or bronchioloalveolar carcinoma, as first-line, second-line, third-line, or fourth-line or later-line therapy. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to lung cancer, e.g., 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. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to platinum-refractory cancer or primary platinum-refractory cancer as first-line, second-line, third-line, or fourth-line or later-line therapy. A combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin can be administered to platinum-refractory cancer or primary platinum-refractory cancer as adjuvant therapy or neoadjuvant therapy.

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

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

[0241] Administration of a combination of an anti-FOLR1 immune complex (e.g., IMGN853) and 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, monotherapy, combination therapy, surgery, radiation, or a combination thereof.

[0242] Administration of a combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin as a "third-line" therapy includes administrations where the first-line therapy was, for example, monotherapy, combination therapy, surgery, radiation, or a combination thereof, and the second-line therapy was, for example, monotherapy, combination therapy, surgery, radiation, or a combination thereof. Therefore, administration of a combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin as a "third-line" therapy includes administrations following, for example, first-line therapy which was monotherapy and second-line therapy which was combination therapy. The administration of a combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin as a "third-line" therapy includes, for example, administration after a first-line therapy which was a combination of drugs and a second-line therapy which was a monotherapy. The administration of a combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based drug, and / or doxorubicin as a "third-line" therapy includes, for example, administration after a first-line therapy which was a combination of drugs and a second-line therapy which was a combination of drugs. The administration of a combination of an anti-FOLR1 immune complex (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as a "third-line" therapy includes, for example, administration after first-line therapy which was the administration of the drug combination and surgery, and second-line therapy which was the administration of the drug combination.

[0243] In some embodiments, the cancer is a cancer that expresses FOLR1 (a polypeptide or nucleic acid). In some embodiments, a combination of an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is administered to a patient with elevated FOLR1 expression levels, for example, as described in U.S. Publication Application 2012 / 0282175 or International Publication Application WO2012 / 135675, both of which are incorporated herein by reference in whole. Exemplary antibodies, assays, and kits for the detection of FOLR1 are provided in WO2014 / 036495 and WO2015 / 031815, both of which are incorporated herein by reference in whole. Therefore, in some embodiments, FOLR1 protein expression is measured by immunohistochemistry (IHC), and staining intensity scores and / or staining uniformity scores are given by comparison with a control (e.g., a calibration control) exhibiting a specified score (e.g., an intensity score of 3 is given to the test sample if the intensity corresponds to a level 3 calibration control, or an intensity of 2 (moderate) is given to the test sample if the intensity corresponds to a level 2 calibration control). "Homogeneous" staining uniformity (i.e., at least 75% of cells stained) instead of "heterogeneous" (i.e., at least 25% and less than 75% of cells stained) or "localized" (i.e., more 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 twofold, at least threefold, or at least fivefold compared to a control value (e.g., the expression level in tissues or cells from a subject with cancer that does not have cancer or whose 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 heterogeneous level of 1 or higher by IHC. In some embodiments, the cancer is a cancer that expresses FOLR1 at a heterogeneous level of 2 or higher by IHC. In some embodiments, the cancer is a cancer that expresses FOLR1 at a heterogeneous level of 3 or higher by IHC. In some embodiments, the cancer is a lung cancer that expresses FOLR1 at a heterogeneous level of 2 or higher by IHC. In some embodiments, the cancer is a lung cancer that expresses FOLR1 at a heterogeneous level of 3 or higher by IHC. In some embodiments, the cancer is an ovarian cancer that expresses FOLR1 at a heterogeneous level of 2 or higher by IHC. In some embodiments, the cancer is an ovarian cancer that expresses FOLR1 at a heterogeneous level of 3 or higher by IHC. In some embodiments, the cancer is an endometrial cancer that expresses FOLR1 at a heterogeneous level of 2 or higher by IHC. In some embodiments, the cancer is an endometrioid carcinoma that expresses FOLR1 at heterogeneous or higher levels due to IHC.

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

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

[0247] In some embodiments, at least 25% of the 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 the cells in a sample obtained from a patient have a FOLR1 IHC score of at least 2 (moderate). In some embodiments, 25–75% of the 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 the 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 the 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 the 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 a sample obtained from a patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 33% of the cells in a sample obtained from a patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 50% of the cells in a sample obtained from a patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 66% of the cells in a sample obtained from a patient have a FOLR1 IHC score of at least 3. In some embodiments, at least 75% of the cells in a sample obtained from a 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. The H-score combines a staining intensity score (e.g., a score of 0 to 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 intensity 0 (%)) + [1 * (Percentage of cells stained with intensity 1 (%)) + [2 * (Percentage of cells stained at intensity 2 (%)) + [3 * (Percentage of cells stained with intensity 3 (%)). Therefore, the H-score can 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 immune complexes (e.g., IMGN853) can be administered in specific doses and / or at specific time intervals. Administration of anti-FOLR1 immune complexes (e.g., IMGN853) may be, for example, intravenous or intraperitoneal. Dosing regiments for anti-FOLR1 immune complexes (e.g., IMGN853) are provided, for example, in WO2014 / 186403, WO2015 / 054400, and WO2015 / 149018, each of which is incorporated herein by reference in whole.

[0251] For example, anti-FOLR1 immune complexes (e.g., IMGN853) can be administered in doses of approximately 0.15 mg / kg to approximately 7 mg / kg, where the 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). Anti-FOLR1 immune complexes (e.g., IMGN853) can also be administered in doses of approximately 1 mg / kg to approximately 6 mg / kg for IBW, LBW, BSA, or AIBW. Anti-FOLR1 immune complexes (e.g., IMGN853) can also be administered in doses of approximately 3 mg / kg to approximately 6 mg / kg for IBW, LBW, BSA, or AIBW. Anti-FOLR1 immune complexes (e.g., IMGN853) can also be administered using divided doses.

[0252] Anti-FOLR1 immune complexes (e.g., IMGN853) can be administered in doses of approximately 0.15 mg / kg to approximately 7 mg / kg based on total body weight (TBW). Anti-FOLR1 immune complexes (e.g., IMGN853) can also be administered in doses of approximately 1 mg / kg to approximately 6 mg / kg TBW. Anti-FOLR1 immune complexes (e.g., IMGN853) can also be administered in doses of approximately 3 mg / kg to approximately 6 mg / kg TBW.

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

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

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

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

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

[0258] As provided herein, anti-VEGF agents may be administered in specific doses and / or at specific time intervals. Anti-VEGF agents (e.g., bevacizumab) may also be administered using divided doses. Administration of anti-VEGF agents (e.g., bevacizumab) may 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 day 1 and day 15 of a 28-day cycle).

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

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

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

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

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

[0265] As provided herein, platinum-based drugs can be administered in specific doses and / or at specific time intervals. Administration of platinum-based drugs may be, for example, intravenous. Platinum-based drugs may be, for example, carboplatin or cisplatin.

[0266] As provided herein, carboplatin may be administered in specific doses and / or at specific time intervals. The administration of carboplatin may, for example, be intravenous.

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

[0268] The formula for calculating the dosage can be used, based on the patient's glomerular filtration rate (GFR in mL / min) and carboplatin injection target area under a concentration-for-time curve (AUC in mg / mL·min): 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 three weeks. In some embodiments, carboplatin is administered at a dose that produces an AUC of 5 mg / mL·min every three weeks. In some embodiments, carboplatin is administered at a dose that produces an AUC of 6 mg / mL·min every three weeks. In some embodiments, carboplatin is administered at a dose that produces an AUC of 7 mg / mL·min every three weeks.

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

[0272] In some embodiments, carboplatin is 360 mg / m². 2 It is administered in the following doses. In some embodiments, carboplatin is administered at approximately 300 mg / m². 2 It is administered in the following dosage.

[0273] In some embodiments, carboplatin is administered at 360 mg / m² every four weeks. 2It is administered in the following doses. In some embodiments, carboplatin is administered at approximately 300 mg / m² every four weeks. 2 It is administered in the following dosage.

[0274] As provided herein, cisplatin may be administered in specific doses and / or at specific time intervals. Administration of cisplatin may, for example, be 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 approximately 100 mg / m². 2 It is administered in the following doses. In some embodiments, cisplatin is administered at approximately 75-100 mg / m². 2 It is administered in the following doses. In some embodiments, cisplatin is administered at approximately 50-70 mg / m². 2 It is administered in the following dose. In some embodiments, cisplatin is approximately 20 mg / m². 2 It is administered in the following dosage.

[0277] In some embodiments, cisplatin is administered at approximately 100 mg / m² every four weeks. 2 It is administered in the following doses. In some embodiments, cisplatin is administered at approximately 75-100 mg / m² every four weeks. 2 It is administered in the following dosage.

[0278] In some embodiments, cisplatin is administered at approximately 50-70 mg / m² every three weeks. 2 It is administered in the following dosage.

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

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

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

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

[0283] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 4 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks. The drugs are administered in AIBW doses. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 4 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 4 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 6 mg / kg AIBW.

[0284] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 4 mg / kg The drugs are administered in AIBW doses. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 6 mg / kg AIBW.

[0285] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 6 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 6 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 4 mg / kg The drugs are administered in doses equal to AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 6 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 6 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 6 mg / kg AIBW.

[0286] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 7 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every three weeks at a dose of approximately 15 mg / kg, carboplatin is administered every three weeks at a dose that produces an AUC of 7 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every three weeks at a dose of approximately 4 mg / kg The drugs are administered in AIBW doses. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of approximately 15 mg / kg, carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and an anti-FOLR1 immune complex (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of approximately 15 mg / kg, and carboplatin is administered every 3 weeks The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose that generates an AUC of 7 mg / mL·min with each dose, and approximately 6 mg / kg AIBW every three weeks.

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

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

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

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

[0291] As provided herein, doxorubicin can be administered in specific doses and / or at specific time intervals. Doxorubicin (e.g., pegylated liposomal doxorubicin (PLD)) may be administered, for example, intravenously.

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

[0293] In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m². 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is approximately 35 mg / m². 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is approximately 40 mg / m². 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is approximately 45 mg / m². 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is approximately 50 mg / m². 2 It is administered in the following dosage.

[0294] In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m² every four weeks. 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 35 mg / m² every four weeks. 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 40 mg / m² every four weeks. 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 45 mg / m² every four weeks. 2 It is administered in the following doses. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 50 mg / m² every four weeks. 2 It is administered in the following dosage.

[0295] In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m² every four weeks. 2The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 30 mg / m² every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 30 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 5 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 30 mg / m² every four weeks. 2 The drug is administered at the above dose, and the anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every four weeks.

[0296] In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 35 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 35 mg / m² every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 35 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 35 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 5 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 35 mg / m² every four weeks. 2 The drug is administered at the above dose, and the anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every four weeks.

[0297] In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 40 mg / m² every four weeks. 2The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 40 mg / m² every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 40 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 40 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 5 every 4 weeks. It is administered at a dose of mg / kg AIBW. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 40 mg / m² every 4 weeks. 2 The drug is administered at the above dose, and the anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every four weeks.

[0298] In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 45 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 45 mg / m² every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 45 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 45 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 5 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 45 mg / m² every four weeks. 2 The drug is administered at the above dose, and the anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every four weeks.

[0299] In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 50 mg / m² every four weeks. 2The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 50 mg / m² every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 50 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 50 mg / m² every four weeks. 2 The anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 5 mg / kg AIBW every four weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 50 mg / m² every four weeks. 2 The drug is administered at the above dose, and the anti-FOLR1 immune complex (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every four weeks.

[0300] In one example, an immune complex that binds to FOLR1 (e.g., IMGN853) and an anti-VEGF agent are administered simultaneously. In another example, an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent are administered in separate pharmaceutical compositions. In yet another example, an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent are administered in the same pharmaceutical composition. In yet another example, an anti-FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent are administered sequentially. In such examples, a platinum-based drug or doxorubicin may be administered simultaneously with the anti-FOLR1 immune complex (e.g., IMGN853) (in the same pharmaceutical composition or in separate pharmaceutical compositions) at the discretion of the patient. A platinum-based drug or doxorubicin may also be administered simultaneously with an anti-VEGF agent (in the same pharmaceutical composition or in separate pharmaceutical compositions) at the discretion of the patient. Platinum-based drugs or doxorubicin may also be administered in any order and of any choice with anti-FOLR1 immune complexes (e.g., IMGN853) and / or anti-VEGF agents.

[0301] In one example, an immune complex that binds to FOLR1 (e.g., IMGN853) and a platinum-based drug are administered simultaneously. In another example, an anti-FOLR1 immune complex (e.g., IMGN853) and a platinum-based drug are administered in separate pharmaceutical compositions. In yet another example, an anti-FOLR1 immune complex (e.g., IMGN853) and a platinum-based drug are administered in the same pharmaceutical composition. In yet another example, an anti-FOLR1 immune complex (e.g., IMGN853) and a platinum-based drug are administered sequentially. In such an example, an anti-VEGF agent or doxorubicin may be administered simultaneously with the anti-FOLR1 immune complex (e.g., IMGN853) (in the same pharmaceutical composition or in separate pharmaceutical compositions) at an optional rate. An anti-VEGF agent or doxorubicin may also be administered simultaneously with a platinum-based drug (in the same pharmaceutical composition or in separate pharmaceutical compositions) at an optional rate rate. Anti-VEGF agents or doxorubicin may also be optionally administered sequentially with anti-FOLR1 immune complexes (e.g., IMGN853) and / or platinum-based agents.

[0302] In one example, an immune complex that binds to FOLR1 (e.g., IMGN853) and doxorubicin are administered simultaneously. In another example, an anti-FOLR1 immune complex (e.g., IMGN853) and doxorubicin are administered in separate pharmaceutical compositions. In yet another example, an anti-FOLR1 immune complex (e.g., IMGN853) and doxorubicin are administered in the same pharmaceutical composition. In yet another example, an anti-FOLR1 immune complex (e.g., IMGN853) and doxorubicin are administered sequentially. In such an example, an anti-VEGF agent or platinum-based agent may be administered simultaneously with the anti-FOLR1 immune complex (e.g., IMGN853) (in the same pharmaceutical composition or in separate pharmaceutical compositions) at an optional rate. An anti-VEGF agent or platinum-based agent may also be administered simultaneously with doxorubicin (in the same pharmaceutical composition or in separate pharmaceutical compositions) at an optional rate rate. Anti-VEGF agents or platinum-based agents may also be optionally administered sequentially with anti-FOLR1 immune complexes (e.g., IMGN853) and / or doxorubicin.

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

[0304] For example, in some embodiments, treatment using a combination of a FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin results in %T / C values ​​of less than approximately 50%, less than approximately 45%, less than approximately 40%, less than approximately 35%, less than approximately 30%, less than approximately 25%, less than approximately 20%, less than approximately 15%, less than approximately 10%, or less than approximately 5%.

[0305] In some specific embodiments, a combination of the FOLR1 immune complex (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 some specific embodiments, a combination of the FOLR1 immune complex (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 some specific embodiments, a combination of the FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can reduce tumor size in H2110 xenograft models.

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

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

[0308] In certain embodiments, administration of a combination of FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based drug, and / or doxorubicin does not produce stronger toxicity than administration of an anti-VEGF agent, a platinum-based drug, and / or doxorubicin alone. In some embodiments, administration of a combination of FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based drug, and / or doxorubicin does not produce stronger toxicity than administration of an anti-FOLR1 immune complex. In some embodiments, administration of a combination of FOLR1 immune complex (e.g., IMGN853) and an anti-VEGF agent, a platinum-based drug, and / or doxorubicin does not produce stronger toxicity than administration of an anti-FOLR1 immune complex or any of the anti-VEGF agent, a platinum-based drug, and / or doxorubicin alone.

[0309] Each of the above embodiments further includes monitoring the subject for cancer recurrence. Monitoring can be achieved, for example, by evaluating progression-free survival (PFS), overall survival (OS), objective response (ORR), complete response (CR), and partial response (PR). In one embodiment, PFS is evaluated after the start of treatment. In some embodiments, PFS is extended compared to the control by approximately 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, approximately 2 years, approximately 3 years, etc. In one embodiment, PFS is extended compared to the control by approximately 2.9 to 3.8 months with a treatment regimen combining a FOLR1 immune complex (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In one embodiment, PFS is extended by at least approximately 3.8 months compared to a control with a treatment regimen combining a FOLR1 immune complex (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In another embodiment, PFS is extended by approximately 2.3 months compared to a control with a treatment regimen combining a FOLR1 immune complex (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In one embodiment, PFS is extended by approximately 6 months compared to a control with a treatment regimen combining a FOLR1 immune complex (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin.

[0310] Additional treatments for VII.D. Steroids can be administered in addition to a combination of FOLR1 immune complexes (e.g., IMGN853) and anti-VEGF agents, platinum-based drugs, and / or doxorubicin. In some embodiments, administration of steroids in addition to a combination of FOLR1 immune complexes (e.g., IMGN853) and anti-VEGF agents, platinum-based drugs, and / or doxorubicin results in a reduction of headache compared to administration of FOLR1 immune complexes (e.g., IMGN853) and anti-VEGF agents, platinum-based drugs, and / or doxorubicin alone.

[0311] Steroids can be administered at the same time as immune complexes, before the administration of immune complexes, and / or after the administration of immune complexes. In some embodiments, steroids are administered about 1 week, about 5 days, about 3 days, about 2 days, or about 1 day or within 24 hours before the administration of immune complexes. In some embodiments, steroids are administered within 1 day of the administration of immune complexes. In some embodiments, steroids are administered multiple times. Several embodiments In terms of form, steroids are administered approximately one day before and on the same day as the administration of immune complexes. Steroids can be administered by any number of methods, including, for example, topical, transpulmonary, 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 as eye drops. In some embodiments, the eye drops are preservative-free, lubricating eye drops.

[0313] Other analgesics or other pharmaceuticals for preventing or treating headaches may also be administered in addition to the FOLR1 immune complex (e.g., IMGN853) and the combination of anti-VEGF agents, platinum-based drugs, and / or doxorubicin. For example, acetaminophin and / or dephenhydramine may be administered in addition to the FOLR1 immune complex (e.g., IMGN853) and the combination of anti-VEGF agents, platinum-based drugs, and / or doxorubicin. The analgesic may be administered before, simultaneously with, or after the administration of the immune complex, and may be administered via any suitable route of administration. In some embodiments, the analgesic is administered orally.

[0314] Embodiments of this disclosure can be further defined by reference to the following non-limiting examples detailing the preparation of certain antibodies of this disclosure and methods for using the antibodies of this disclosure. It will be apparent to those skilled in the art that many modifications to both substances and methods are possible without departing from the scope of this disclosure. [Examples]

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

[0316] Example 1 IMGN853 + PLD combination therapy is more active than IMGN853 monotherapy 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 carrying tumor xenografts derived from ST088 human epithelial ovarian cancer patients. CB17 SCID mice were randomized into groups (n=8 per group) based on tumor volume and subsequently administered the drugs. The groups included a control group administered IMGN853 buffer solution (vehicle) ("Control" in Figure 1), an IMGN853 monotherapy group administered 5 mg / kg once every 7 days (weeks) for 2 weeks (QW x 2) ("IMGN853" in Figure 1), a PLD monotherapy group administered 4 mg / kg QW x 2 ("PLD" in Figure 1), and an IMGN853 + PLD combination group administered 5 mg / kg QW x 2 doses of IMGN853 in combination with 4 mg / kg QW x 2 doses of PLD ("IMGN853 + PLD" in Figure 1).

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

[0318] IMGN853 administered at 5 mg / kg QW x 2 was active as monotherapy (T / C 31%, 0 / 8 partial response (PR), and 0 / 8 complete response (CR)). Furthermore, IMGN853 monotherapy was well-tolerated, and no significant weight loss was observed. PLD administered 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 weight loss (BWL) of 19% at its lowest point (15 days post-administration). The IMGN853 + PLD combination was highly active, 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 that of PLD monotherapy (16% at its lowest point). See Figure 1. Therefore, combination therapy using IMGN853 and PLD increased efficacy without increasing toxicity.

[0319] Example 2 IMGN853 (5 mg / kg) plus 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 carrying OV90 serous ovarian tumor xenografts, both as monotherapy and in combination with the anti-VEGF antibody bevacizumab. Mice were randomized into groups (n=6 per group) based on tumor volume, and then administered 14 days after inoculation. The groups included a control group that received a single dose (1X) of IMGN853 buffer ("Vehicle" in Figure 2A), an IMGN853 monotherapy group that received 5 mg / kg 1X ("IMGN853" in Figure 2A), a bevacizumab monotherapy group that received 5 mg / kg 1X ("Bevacizumab" in Figure 2A), and an IMGN853 + bevacizumab combination group that received 5 mg / kg 1X IMGN853 in combination with 5 mg / kg 1X bevacizumab ("IMGN853 + Bevacizumab" in Figure 2A).

[0320] Tumor volume was measured in three dimensions using calipers once or twice a week. Tumor volume was expressed in mm using the formula V = length × width × height × 1 / 2. 3 The values ​​were expressed in units (Tomayko and Reynolds, Cancer Chemother. Pharmacol. 24:148-54 (1989)). Body weight was measured twice per week as an indicator of toxicity. Activity was evaluated as described in Bissery et al. (1991). Figure 2A shows the results.

[0321] At 5 mg / kg, a single dose of IMGN853 was active as monotherapy (T / C 36%, 1 / 5 CR, and 0 / 5 tumor-free survival (TFS)). At 5 mg / kg, a single dose of bevacizumab was also active as monotherapy (T / C 37%, 0 / 6 CR, and 0 / 6 TFS). The IMGN853 + bevacizumab combination (5 mg / kg each) was highly active, more active than both IMGN853 monotherapy 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. Therefore, combination therapy with IMGN853 and bevacizumab increased efficacy without increasing toxicity.

[0322] Example 3 IMGN853 (2.5 mg / kg) plus bevacizumab combination therapy is more active than IMGN853 monotherapy and bevacizumab monotherapy in the OV90 ovarian cancer tumor model. The antitumor activity of IMGN853 was evaluated in female SCID mice carrying OV90 serous ovarian tumor xenografts, both as monotherapy and in combination with the anti-VEGF antibody bevacizumab. Mice were randomized into groups (n=6 per group) based on tumor volume, and then administered 14 days after inoculation. The groups included a control group that received a single dose (1X) of IMGN853 buffer ("Vehicle" in Figure 2B), an IMGN853 monotherapy group that received 2.5 mg / kg 1X ("IMGN853" in Figure 2B), a bevacizumab monotherapy group that received 5 mg / kg 1X ("Bevacizumab" in Figure 2B), and an IMGN853 + bevacizumab combination group that received 2.5 mg / kg 1X IMGN853 in combination with 5 mg / kg 1X bevacizumab ("IMGN853 + Bevacizumab" in Figure 2B).

[0323] Tumor volume was measured in three dimensions using calipers once or twice a week. Tumor volume was expressed in mm using the formula V = length × width × height × 1 / 2. 3 The values ​​were expressed in units (Tomayko 1989). Body weight was measured twice a week as an indicator of toxicity. Activity was measured using Bisery The evaluation was performed as described in et al. (1991). Figure 2B shows the results.

[0324] At a dose of 2.5 mg / kg, a single dose of IMGN853 was active as monotherapy (T / C 36%, 0 / 6 CR, and 0 / 6 TFS). At a dose of 5.0 mg / kg, a single dose of bevacizumab was active (T / C 31%, 0 / 6 CR, and 0 / 6 TFS). As monotherapy, bevacizumab exhibited comparable antitumor activity to IMGN853 at these dose levels; however, neither drug induced sustained tumor growth inhibition or tumor regression. In stark contrast, the combination of IMGN853 plus bevacizumab resulted in strong 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 monotherapy 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 tolerable, and no significant weight loss was observed in any treatment group. Therefore, combination therapy with IMGN853 and bevacizumab increased efficacy without increasing toxicity.

[0325] Next, the effects of divided bevacizumab administration were examined. For this purpose, animals were administered bevacizumab as either a single dose of 5 mg / kg or two doses of 2.5 mg / kg (QW x 2), both as monotherapy and in combination with 3 mg / kg IMGN853 (Figure 11A). Divided dosing did not affect the efficacy of bevacizumab, and a similar (moderate) growth inhibitory effect was observed after treatment with IMGN853 monotherapy. 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 in all 7 animals (Figure 11A). Again, the combination treatment of IMGN853 and bevacizumab was well tolerable.

[0326] Finally, the efficacy of IMGN853 in combination with bevacizumab was evaluated in the same platinum-resistant PDX model, as shown in Figure 11B. Unlike the moderate activity observed with IMGN853 monotherapy, monotherapy with bevacizumab (5 mg / kg, administered twice a week) extended the control of growth in these invasive tumors (data not shown), but no complete response (CR) was observed over the 102-day trial period. Consistent with the OV-90 results, the combination of IMGN853 and bevacizumab (both 5 mg / kg, twice a week) was superior to either monotherapy and induced tumor regression in all mice. CR was observed in 7 / 8 animals. In fact, analysis of tumor volume at the end of the trial revealed a significant reduction in tumor volume in the combination treatment group compared to 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 provided by adding IMGN853 to anti-angiogenic agents is functionally specific to ADC molecules.

[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, in combination with bevacizumab, was evaluated in female SCID mice carrying OV90 serous ovarian tumor xenografts. Mice were randomized into groups (n=8 per group) based on tumor volume, and then administered 14 days after inoculation. All treatments consisted of a single dose (1X). The groups included a control group administered with IMGN853 buffer solution ("Vehicle" in Figure 3), an IMGN853 monotherapy group administered at 1.25 mg / kg 1X ("IMGN853-1.25" in Figure 3), a paclitaxel monotherapy group administered at 10 mg / kg 1X ("Paclitaxel-10" in Figure 3), a bevacizumab monotherapy group administered at 5 mg / kg 1X ("Bevacizumab-5" in Figure 3), IMGN853 + bevacizumab combination groups administered at 1.25 mg / kg 1X and 5 mg / kg 1X respectively ("IMGN853+BEV" in Figure 3), and a paclitaxel + bevacizumab combination group administered at 10 mg / kg 1X and 5 mg / kg 1X respectively ("PAC+BEV" in Figure 3).

[0328] Tumor volume was measured in three dimensions using calipers once or twice a week. Tumor volume was expressed in mm³ using the formula V = length × width × height × 1 / 2 (Tomayko 1989). Body weight was measured twice a week as an indicator of toxicity. Activity was measured using Bisery The evaluation was performed as described in et al. (1991). Figure 3 shows the results.

[0329] At 1.25 mg / kg, a single dose of IMGN853 was active as monotherapy (T / C 37%, 0 / 7 CR, and 0 / 7 TFS). Paclitaxel monotherapy was inactive (T / C 94%, 0 / 6 CR, and 0 / 6 TFS). A single dose of 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, more active than all monotherapy and the paclitaxel + bevacizumab combination (T / C 5%, 5 / 8 CR, and 0 / 8 TFS). See Figure 3. All treatments were well tolerable. Therefore, the combination of bevacizumab and IMGN853 was more effective than the combination of bevacizumab with another treatment.

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

[0331] Tumor volume was measured in three dimensions using calipers once or twice a week. Tumor volume is expressed in mm using the formula V = length × width × height × 1 / 2. 3The values ​​were expressed in units (Tomayko 1989). Body weight was measured twice per week as an indicator of toxicity. Activity was evaluated as described in 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 plus bevacizumab combination therapy was highly active and 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. Therefore, combination therapy with IMGN853 and bevacizumab increased efficacy without increasing toxicity.

[0333] Example 6 IMGN853 plus bevacizumab combination therapy 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 carrying tumor xenografts derived from ST088 human epithelial ovarian cancer (EOC) patients. CB17 SCID mice were randomized into groups (n=8 per group) based on tumor volume and then administered the drug. The groups included a control group (vehicle) administered with IMGN853 buffer solution ("Control" in Figure 5), an IMGN853 monotherapy group administered at 5 mg / kg QW x 2 ("IMGN853" in Figure 5), a bevacizumab monotherapy group administered at 5 mg / kg QW x 2 ("Bev" in Figure 5), and an IMGN853 + bevacizumab combination group administered at 5 mg / kg QW x 2 of IMGN853 and 5 mg / kg QW x 2 of bevacizumab ("IMGN853 + Bev" in Figure 5).

[0334] For comparison, mice in one group were administered paclitaxel at 10 mg / kg QW x 2, and mice in another group were administered a combination of paclitaxel at 10 mg / kg QW x 2 and bevacizumab at 5 mg / kg QW x 2.

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

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

[0337] Example 7 IMGN853 plus bevacizumab combination therapy is more active than IMGN853 monotherapy 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 carrying H2110 non-small cell lung cancer (NSCLC) tumor xenografts. Mice were randomized into groups (n=6-10 per group) based on tumor volume, and then administered 7 days after inoculation. All treatments consisted of a single dose (1X). The groups included a control group administered with IMGN853 buffer ("Vehicle" in Figure 6), an IMGN853 monotherapy group administered at 3 mg / kg ("IMGN853 3 mg / kg" in Figure 6), an IMGN853 monotherapy group administered at 1.5 mg / kg ("IMGN853 1.5 mg / kg" in Figure 6), a bevacizumab monotherapy group administered at 5 mg / kg ("Bevacizumab 5 mg / kg" in Figure 6), and an IMGN853 + bevacizumab combination group administered at 5 mg / kg of bevacizumab and 3 mg / kg of IMGN853 ("IMGN853 3 mg / kg + Bevacizumab" in Figure 6). This included the group receiving 5 mg / kg of bevacizumab, as well as the IMGN853 + bevacizumab combination group ("IMGN853 1.5 mg / kg + Bev 5 mg / kg" in Figure 6), which received 5 mg / kg of bevacizumab and 1.5 mg / kg of IMGN853.

[0338] Tumor volume was measured in three dimensions using calipers once or twice a week. Tumor volume was expressed in mm using the formula V = length × width × height × 1 / 2. 3 The values ​​were expressed in units (Tomayko 1989). Body weight was measured twice per week as an indicator of the toxicity of the test drug. Activity was evaluated as described in Bissery et al. (1991). Figure 6 shows the results.

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

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

[0341] Tumor volume was measured in three dimensions using calipers once or twice a week. Tumor volume was expressed in mm using the formula V = length × width × height × 1 / 2. 3 The values ​​were expressed in units (Tomayko 1989). Body weight was measured twice a week as an indicator of toxicity. Activity was measured using Bisery The evaluation was performed as described in et al. (1991). Figure 7 shows the results.

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

[0343] The triple combination of paclitaxel, carboplatin, and bevacizumab resulted in significantly greater weight loss (BWL) at the lowest point (6.9%) compared to the triple combination of IMGN853, carboplatin, and bevacizumab (2.9% BWL). The BWL at the lowest point of the IMGN853 + carboplatin combination (12.9%) was comparable to the BWL at the lowest point of paclitaxel + carboplatin treatment (11.1%). Therefore, the triple combination therapy using IMGN853, carboplatin, and bevacizumab increased efficacy while reducing toxicity compared to the triple combination therapy using paclitaxel, carboplatin, and bevacizumab.

[0344] Example 9 IMGN853 plus cediranib combination therapy is more active than IMGN853 monotherapy and cediranib monotherapy in the OV90 ovarian tumor model. The antitumor activity of IMGN853 in combination with the anti-VEGF agent cediranib was evaluated in female SCID mice bearing OV90 serous ovarian tumor xenografts. Mice were randomized into groups (n=6 per group) by tumor volume, then dosed on day 14 after inoculation. The 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 once ("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×5) ("Cediranib 1.5 mg / kg qd×5" in Figure 8), and 2.5 mg / kg an IMGN853 + cediranib combination therapy group dosed with 1× IMGN853 and 1.5 mg / kg qd×5 cediranib ("IMGN853 + cediranib" in Figure 8).

[0345] Tumor volume was measured 1 to 2 times per week in three dimensions using calipers. Tumor volume is expressed in 3 units using the formula V = length × width × height × 1 / 2 (Tomayko 1989). Body weight was measured twice per week as an indicator of test article toxicity. Activity was evaluated as described in 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 / 6 PR). Cediranib monotherapy was inactive (T / C 80%, T-C 4 days, LCK 0.1, and 0 / 6 PR). The combination of IMGN853 + cediranib was active (T / C 13% with 1 / 6 PR), and T-C (47) and LCK (1.7) were greater than those of either IMGN853 or cediranib monotherapy. See Figure 8. All treatments were well tolerated, and the observed weight loss was minimal.

[0347] Example 10 Clinical trial evaluating the combination of IMGN853 with bevacizumab, carboplatin, and / or doxorubicin. Results from preclinical studies evaluating the activity of IMGN853 as a monotherapy and in combination with bevacizumab, carboplatin, or PLD in the ovarian cancer xenograft model described above indicate 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 recurrent and upfront settings. A Phase Ib 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 trial will consist of two components: a dose-setting component to determine the maximum tolerated dose (MTD) and recommended dose for the combinations of IMGN853 + bevacizumab, IMGN853 + carboplatin, and IMGN853 + PLD; and a dose-expansion component. The dose-expansion component will evaluate two expanded cohorts: (1) the IMGN853 + bevacizumab combination in patients who have not previously received treatment with bevacizumab ("bevacizumab-naive") and (2) the IMGN853 + bevacizumab combination in patients who have previously received treatment with bevacizumab. Further potential cohorts include: (1) IMGN853 + carboplatin combination in patients who have not previously received treatment with bevacizumab ("bevacizumab-naive"), (2) IMGN853 + PLD combination in patients who have not previously received treatment with bevacizumab ("bevacizumab-naive"), (3) a triple combination of IMGN853 + bevacizumab + PLD in patients who have not previously received treatment with bevacizumab ("bevacizumab-naive"), or (4) a triple combination of IMGN853 + bevacizumab + carboplatin in patients who have not previously received treatment with bevacizumab ("bevacizumab-naive"); (5 (6) IMGN853 + carboplatin combination in patients who have previously received treatment with bevacizumab, (7) IMGN853 + PLD combination in patients who have previously received treatment with bevacizumab, or (8) IMGN853 + bevacizumab + carboplatin combination in patients who have previously received treatment with bevacizumab; (9) IMGN853 + bevacizumab + carboplatin combination; and / or (10) IMGN853 + bevacizumab + PLD combination.The response to combination therapy will be assessed (where appropriate) using RECIST and Gynecologic Cancer InterGroup (GCIG) criteria.

[0348] Example 11 The combination of IMGN853 and carboplatin promotes synergistic growth inhibition 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 for EOC patients in the first-line adjuvant setting. To investigate whether IMGN853 co-treatment can improve carboplatin activity in EOC, the combined effect of IMGN853 and carboplatin exposure on inhibiting the growth of the platinum-sensitive ovarian carcinoma cell line IGROV-1 was evaluated. IGROV-1 cells were treated in vitro with escalating concentrations of IMGN853, carboplatin, or both, and the combined activity was evaluated using median effect analysis (Figure 9A). The combination was synergistic, indicating that IMGN853 enhanced the effect of platinum compounds in these ovarian tumor cells.

[0349] Cell cycle analysis revealed that carboplatin exposure resulted in the accumulation of IGROV-1 cells in both the S and G2 / M phases (Figure 9B), an effect previously reported to precede drug-induced cell death in ovarian cell lines. Treatment with IMGN853 alone resulted in cell enrichment in the G2 / M phase, according to the well-established antimitotic activity of the mytansinoid. Consistent with these results, co-treatment with both drugs resulted in the accumulation of nearly half of the viable cells in the G2 / M phase. We also examined changes in the expression of the phosphorylated form of histone H2AX (γH2AX), an indicator of susceptibility to DNA damage resulting from mitotic or mitotic cell death. Treatment with IMGN853 alone induced γH2AX expression in IGROV-1 cells to a higher level than that observed after carboplatin exposure alone. Combination treatment increased the degree of γH2AX upregulation, which indicates enhanced DNA damage and is consistent with a destructive phenotype (Figure 9C).

[0350] To investigate whether these in vitro cellular effects translate to improved efficacy in vivo, mice carrying patient-derived xenografts (PDX) from individuals with EOC were treated with IMGN853 and carboplatin, both as monotherapy and in combination (Figure 9D). It had been previously determined that IMGN853 exhibited strong monotherapy activity in this platinum-sensitive PDX model (data not shown); therefore, a suboptimal dose of IMGN853 was selected to allow evaluation of potential combination improvements in efficacy. Animals received a single dose of either 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 described above, concurrent treatment with both drugs 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 demonstrated good tolerance, with no toxicity or weight loss observed throughout the course of the study.

[0351] The combination benefit of IMGN853 / carboplatin treatment was compared with clinically evident chemotherapy combinations in the same PDX model. Animals with tumors were administered two consecutive weekly doses (QW×2) of carboplatin (80 mg / kg, intraperitoneal) in combination with intravenous paclitaxel (10 mg / kg), PLD (4 mg / kg), or IMGN853 (5 mg / kg). As expected, the carboplatin-paclitaxel dual treatment was effective in this platinum-sensitive model (Figure 9E). Carboplatin and PLD combination treatment was generally shown in platinum-sensitive relapse settings and was also active in suppressing tumor growth. In particular, IMGN853 plus carboplatin combination therapy induced the greatest degree of tumor growth inhibition, including complete regression (CR) in 6 out of 7 tumor-bearing mice. In contrast, only two complete response (CR) was observed in the carboplatin / PLD combination, while none were observed in the carboplatin / paclitaxel treatment group. Carboplatin-paclitaxel dual therapy was well tolerated in this model, although some delayed toxicity was observed in animals from the PLD / carboplatin and IMGN853 / carboplatin treatment groups (data not shown). The high incidence of CR strongly suggests superior sustained response for the combination, and overall, the data further support the IMGN853 and carboplatin combination for improved response to platinum therapy in endocrinology (EOC).

[0352] Example 12 Combination therapy with IMGN853 and PLD yields superior therapeutic activity in platinum-resistant PDX tumors. In clinical practice, PLD is a widely used second-line treatment for relapsed 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+G2 / M cell cycle delay (Figure 10B).

[0353] To extend in vitro observation, the combination of IMGN853 and PLD was tested in a platinum-resistant EOC PDX model (Figure 10C). Vehicle-treated animals showed rapid progression, with tumors reaching 1500–2000 mm. 3 The sample was removed from the test when it reached an intermediate volume. QW×2 dosing of IMGN853 (5 mg / kg) inhibited tumor growth by 81% at day 49, while a similar degree of inhibition (83%) was observed when PLD (4 mg / kg) was administered using the same regimen. Even at these effective dose levels, the combination therapy resulted in an improved and sustained antitumor response, complete suppression of tumor growth in this invasive model of EOC. Importantly, all regimens were well tolerable, and the addition of IMGN853 to PLD did not result in further toxicity or weight changes compared to PLD therapy alone (Figure 10D). Thus, for platinum-resistant disease, the combination of IMGN853 and PLD resulted in superior and sustained efficacy compared to the monotherapy activity of either compound alone.

[0354] This trial further supports the finding that the synergistic improvement in antitumor activity observed with the IMGN85 / PLD combination in vitro translates to improved sustained efficacy compared to each monotherapy in platinum-resistant PDX models, and, importantly, exhibits good tolerability. In preclinical EOC models, the combined benefit of PLD with another FRα-targeting compound, vintafolide, has been previously reported, prompting later clinical evaluation of that combination in subsequent Phase II and Phase III human trials. While not theoretical, IMGN853 possesses a broader spectrum of viability compared to vintafolide, including a more potent payload, longer circulation time, and "bystander cytotoxicity," i.e., the ability to eradicate adjacent FRα-negative or low-expression tumor cells. Therefore, these findings provide a rationale for the IMGN853 and PLD combination in EOC patients with relapsed disease.

[0355] Example 13 The IMGN853-bevacizumab combination induces rapid microvascular disruption and extensive necrotic injury in OV-90 xenografts. To further understand the mechanism of 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 a combination of the two, collected 4 days after administration, and examined (Figures 12A-12C). It is noteworthy that, as measured by changes in tumor volume, the combination therapy completely halted tumor growth at this early stage, in contrast to the corresponding monotherapy which only showed delay (see, e.g., Figure 2B). Histological (H&E) staining revealed that tumors from combination-treated mice structurally contained a large necrotic core surrounded by a smaller margin of viable cells at the periphery (Figure 12A). This degree of cellular disruption was not observed in any of the other treatment groups, which is consistent with the rapid tumor stabilization provided by the drug regimen. Next, as a pharmacodynamic readout, tumor γH2AX levels were measured by immunoblotting (Figure 12B). As expected, γH2AX expression was minimal in tumors from vehicle-treated mice, but was strongly induced after IMGN853 monotherapy. Consistent with the observed improvement in antitumor activity, the addition of bevacizumab to IMGN853 resulted in a further increase in γH2AX levels compared to IMGN853 monotherapy.

[0356] Interestingly, γH2AX upregulation was observed in tumors after bevacizumab exposure alone, although to a lower degree than in IMGN853 (Figure 12B). While genotoxic damage is the primary inducer of γH2AX, accumulation of this protein can also occur in response to hypoxia. This result therefore indicates that increased hypoxia resulting from bevacizumab-induced vascular disruption contributed to the amplified DNA damage profile. To examine treatment-related effects on microvessels, immunohistochemical staining was performed using the endothelial cell marker CD31 (Figure 12C, upper panel). Tumors from control and IMGN853-treated mice had numerous large vessels, which decreased in size and showed loss of luminal integrity after bevacizumab treatment. In particular, double administration of IMGN853 and bevacizumab resulted in significant changes in the tumor microvascular system. These included a clear reduction in the number of large branched vascular structures, and smaller CD31-stained regions lacked distinct lumens and were primarily localized in the peripheral rim region. Further staining of corresponding tissue samples with anti-mytansin antibodies confirmed tumor-specific delivery of IMGN853 in mice treated with an ADC-containing regimen (Figure 12C, lower panel).

[0357] While not adhering strictly to theory, the presence of bevacizumab may promote better tumor penetration and exposure to ADCs, potentially leading to more effective eradication of tumor cells. In this regard, it is well established that bevacizumab treatment can induce normalization of tumor vascular structure, which has been shown to result in reduced interstitial pressure and improved drug delivery. However, there are preclinical and clinical observations of decreased tumor uptake of both chemotherapeutic agents and antibodies after anti-angiogenic therapy. ***

[0358] The sections on modes for carrying out the invention, rather than the summary and abstract of the invention, should be understood as being intended for use in interpreting the claims. The summary and abstract sections describe one, but not all, exemplary embodiments of the invention as contemplated by the inventor(s) and are therefore not intended to limit the invention and the appended claims in any way.

[0359] The present invention has been described above by utilizing functional components that illustrate the implementation of specific functions and their relationships. The boundaries of these functional components are arbitrarily defined herein for explanatory purposes. Alternative boundaries may be defined, provided that the specific functions and their relationships are adequately implemented.

[0360] The foregoing description of specific embodiments is intended to fully illustrate the general nature of the invention, and by applying knowledge within the scope of the art, such specific embodiments can be readily modified and / or adapted for various applications without departing from the general concept of the invention, without requiring excessive experimentation. Therefore, such adaptations and modifications are intended to be included within the meaning and scope of the equivalent embodiments disclosed herein, based on the teachings and guidance presented herein. Expressions or terms herein are for illustrative purposes only, not limitation, and therefore, it should be understood that terms or expressions herein are to be interpreted by those skilled in the art in consideration of the teachings and guidance.

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

Claims

1. A composition comprising an immune complex that binds to folate receptor 1 (FOLR1) for use in cancer treatment in patients requiring cancer treatment, (a) The immune complex is 【Chemistry 1】 The formula includes, where Ab is an IgG antibody that binds to FOLR1, and M ＋ is H ＋ or Na ＋ or other pharmaceutically acceptable cations, and the antibody that binds to FOLR1 includes the heavy chain variable region (VH) complementarity-determining region (CDR) 1 sequence of SEQ ID NO: 9 or 19, the VH CDR 2 sequence of SEQ ID NO: 10 or 11, and the VH CDR 3 sequence of SEQ ID NO: 12, and the light chain variable region (VL) CDR 1 sequence of SEQ ID NO: 6, the VL CDR 2 sequence of SEQ ID NO: 7, and the VL CDR 3 sequence of SEQ ID NO: 8, and (b) The composition is (i) An anti-VEGF antibody comprising the heavy chain variable region (VH) of SEQ ID NO: 26 and the light chain variable region (VL) of SEQ ID NO: 27, which 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 containing the heavy chain variable region (VH) of SEQ ID NO: 26 and the 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. A composition administered together with [something].

2. The composition according to claim 1, which is administered in combination with the anti-VEGF antibody.

3. The composition according to claim 1, which is administered in combination with the platinum-based drug.

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

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

5.

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

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

15.

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

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

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

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

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

13. The composition according to claim 12, wherein the carboplatin is administered in a dose such that an area under the curve (AUC) of 4 mg / ml is obtained.

14. The composition according to claim 12, wherein the carboplatin is administered in a dose such that an AUC of 5 mg / ml is obtained.

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

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

17. - The antibody that binds to FOLR1 includes VH containing the sequence of SEQ ID NO: 3 and VL containing the sequence of SEQ ID NO: 5 - The aforementioned immune complex is administered intravenously once every three weeks. - The aforementioned platinum-based drug is carboplatin. - The carboplatin is administered once every three weeks. The composition according to claim 3.

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

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

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

21. The composition according to any one of claims 17 to 20, wherein the carboplatin is administered in a dose such that an AUC of 5 mg / ml is obtained.

22. The composition according to any one of claims 17 to 20, wherein the carboplatin is administered in a dose such that an AUC of 4 mg / ml is obtained.

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

24. The composition according to any one of claims 1 to 22, wherein it is administered together with a steroid, and optionally the steroid is dexamethasone.

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

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

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

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

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

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

33. A composition according to any one of claims 1 to 30 or 32, administered as a first-line therapy.

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

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

36. A composition according to any one of claims 1 to 32, administered as a fourth-line therapy.

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

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