Therapeutic combinations comprising an anti-folr1 immunoconjugate

Abstract

Therapeutic combinations of immunoconjugates that bind to FOLR1 (e.g., IMGN853) with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin are provided. Methods of administering the combinations to treat cancer, e.g., ovarian cancer, with higher clinical efficacy and / or reduced toxicity are also provided.

Description

[0001] This application is a divisional application of patent application No. 201680053477.3, filed on September 16, 2016, by Immonogen Corporation, entitled "Therapeutic Combination Containing Anti-FOLR1 Immunoconjugate".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 220,028, filed September 17, 2015; U.S. Provisional Application No. 62 / 242,669, filed October 16, 2015; and U.S. Provisional Application No. 62 / 250,756, filed November 4, 2015, each of which is incorporated herein by reference in its entirety.

[0004] References to sequence lists submitted electronically via EFS-Web

[0005] The contents of the electronically submitted sequence list (name: 2921_077PC03_SL.txt; size: 19,451 bytes; and creation date: September 13, 2016) are incorporated herein by reference in their entirety. Invention Field

[0006] The field of this invention generally relates to combinations of antiFOLR1 immunoconjugates with antiVEGF agents, platinum-based agents and / or doxorubicin, and the use of said combinations in the treatment of cancers such as ovarian cancer. background

[0007] Cancer is one of the leading causes of death in developed countries, with more than one million people diagnosed with cancer and 500,000 dying each year in the United States alone. Overall, it is estimated that more than one in three people will develop some form of cancer in their lifetime.

[0008] Folate receptor 1 (FOLR1), also known as folate receptor-α (FRα) or folate-binding protein, is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein with a strong binding affinity for folate and its reduced 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 proximal tubules of the kidney, alveolar cells of the lung, bladder, testis, choroid plexus, and thyroid gland (Weitman SD et al., Cancer Res. 52:3396-3401 (1992); Antony AC, Ann. Rev. Nutr. 16:501-521 (1996); Kalli KR et al., Gynecol. Oncol. 108:619-626 (2008)). FOLR1 is overexpressed in tumors of epithelial origin, including ovarian tumors, uterine tumors, breast tumors, endometrial tumors, pancreatic tumors, kidney tumors, lung tumors, colorectal tumors, and brain tumors. This pattern of FOLR1 expression makes it an ideal target for FOLR1-targeted cancer therapy.

[0009] Vascular endothelial growth factor-A (VEGF), also known as vascular permeability factor (VPF), is a prototypical member of the VEGF protein family and a key regulator of angiogenesis (Hoeben et al., Pharmacol. Rev. 56:549-580 (2004); Ferrara et al., Nat. Med. 9:669-676 (2003)). Angiogenesis is the process by which new blood vessels develop from an existing vascular system and is important for wound healing, organ regeneration, and the female reproductive system (Hoeben et al., ibid.; Ferrara et al., ibid.). Angiogenesis is also important for several pathological processes, including tumor development, growth, and metastasis (Hoeben et al., ibid.; Ferrara et al., ibid.). VEGF is a pro-angiogenic factor highly expressed in normal lung, kidney, heart, adrenal gland, liver, spleen, and gastric mucosa tissues and is also highly expressed in many human tumors (Hoeben et al., ibid.). Its elevated and misexpressed levels in tumors and its pro-angiogenic function make VEGF an ideal target for targeted cancer therapy.

[0010] Cisplatin and carboplatin are platinum analogues and alkylating chemotherapeutic agents that have been used, alone or in combination with other agents, for decades to treat a variety of solid tumors (Lokich et al., Annals. Of Oncology 9:13-21 (1998)). Carboplatin has been reported to have less gastrointestinal side effects compared to cisplatin (Lokich et al.). However, carboplatin causes the negative side effect of myelosuppression (Lokich et al.). Therefore, there is a need to improve the efficacy and tolerability of cisplatin and carboplatin.

[0011] Doxorubicin, an anthracycline antibiotic chemotherapy agent, is used alone or in combination with other chemotherapy agents such as paclitaxel (a mitotic inhibitor chemotherapy agent, also known as...). The combination of Bristol Myers Squibb and [Bristol Myers Squibb] is used as a therapeutic agent for a variety of cancers; see also Gehl et al., Annals of Oncology, 7:687-639 (1996)). The efficacy of doxorubicin as a cancer therapeutic agent is limited by its toxicity, specifically its cardiotoxicity (see Tacar et al., J. of Pharmacy & Pharmacology, 65:157-170 (2013)). Therefore, there is a need to improve the therapeutic efficacy and tolerability of doxorubicin. Liposome encapsulation of doxorubicin hydrochloride (HCl) salts has also been developed. Liposome delivery of doxorubicin HCl improves drug penetration into tumors and reduces drug clearance, thereby increasing the duration of therapeutic action. Liposome formulations of doxorubicin also modulate toxicity, particularly the cardiotoxic effects commonly seen with anthracycline antitumor drugs.

[0012] The U.S. Food and Drug Administration (FDA) has approved bevacizumab (an anti-VEGF antibody, also known as...) (GENENTECH, INC.) Bevacizumab in combination with carboplatin and paclitaxel is a first-line treatment for advanced, recurrent non-squamous non-small cell lung cancer (NSCLC) (see Cohen et al., Oncologist 12:713-718 (2007)). The combination of carboplatin and paclitaxel (CP therapy) was previously a first-line treatment for NSCLC (Sandler et al., N. Engl. J. of Medicine 355:2542-2550 (2006)). However, while the addition of bevacizumab to CP therapy increased patient survival benefits, this triple combination (BV / CP) therapy resulted in increased treatment-related deaths and a higher incidence of non-hematologic and hematologic adverse events (Cohen et al., ibid., in Tables 4-5). In recent years, 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.

[0013] There is an unmet medical need for more effective therapies, such as combination therapies targeting tumor cells that express FOLR1 for the treatment of cancer. Invention Summary

[0014] This article provides a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. This article also provides methods for treating patients with cancer using said combinations. As described in more detail below, the use of an anti-FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can produce synergistic efficacy against tumors. For example, an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can enhance the efficacy of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and / or an anti-FOLR1 immunoconjugate (e.g., IMGN853) can enhance the efficacy of an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. The combined efficacy of antiFOLR1 immunoconjugates (e.g., IMGN853) with antiVEGF agents, platinum-based agents, and / or doxorubicin can be achieved, even when using smaller and / or lower frequency doses of the antiFOLR1 immunoconjugate (e.g., IMGN853) and / or antiVEGF agents, platinum-based agents, and / or doxorubicin. Furthermore, the combinations may produce toxicities not exceeding those of any one of the antiVEGF agent, platinum-based agent, and / or doxorubicin alone, the antiFOLR1 immunoconjugate (e.g., IMGN853) alone, and / or the antiVEGF agent, platinum-based agent, and / or doxorubicin or the antiFOLR1 immunoconjugate (e.g., IMGN853).

[0015] In one instance, a method for treating a patient with cancer, the method comprising administering to the patient in need: an immunoconjugate bound to FOLR1, wherein the immunoconjugate comprises an antibody or an antigen-binding fragment thereof containing: the heavy chain variable region (VH) complementarity-determining region (CDR) 1 sequence of SEQ ID NO:9, the VHCDR2 sequence of SEQ ID NO:10, and 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; and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

[0016] In one instance, a method of treating a patient with cancer includes administering to the patient in need: an immunoconjugate bound to FOLR1, wherein the immunoconjugate comprises an antibody or an antigen-binding fragment thereof containing: the VH CDR1 sequence of SEQ ID NO:19, the VH CDR2 sequence of SEQ ID NO:11, and the VH CDR3 sequence of SEQ ID NO:12, and 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; and an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

[0017] In one instance, the immunoconjugate (e.g., IMGN853) is administered in combination with an anti-VEGF agent (e.g., bevacizumab). In another instance, the immunoconjugate (e.g., IMGN853) is administered in combination with a platinum-based agent. In yet another instance, the immunoconjugate is administered in combination with doxorubicin.

[0018] In one instance, the immunoconjugate (e.g., IMGN853) is administered in combination with an anti-VEGF agent and a platinum-based agent. In another instance, the immunoconjugate (e.g., IMGN853) is administered in combination with an anti-VEGF agent and doxorubicin. In yet another instance, the immunoconjugate (e.g., IMGN853) is administered in combination with a platinum-based agent and doxorubicin.

[0019] In one instance, the immunoconjugate bound to FOLR1 comprises an antibody or an antigen-binding fragment thereof containing the sequence of SEQ ID NO:3 (VH) and the sequence of SEQ ID NO:5 (VL). In another instance, the antibody or antigen-binding fragment is huMov19.

[0020] In one case, the immunoconjugate (e.g., IMGN853) contains a cytotoxin, wherein the cytotoxin is a maytansine alkaloid. In another case, the maytansine alkaloid is DM4.

[0021] In one case, the immunoconjugate (e.g., IMGN853) contains a linker, wherein the linker is sulfonyl-SPDB.

[0022] In one case, the immunoconjugate is IMGN853.

[0023] In one case, the administration is a first-line therapy. In one case, the administration is a second-line therapy. In one case, the administration is a third-line therapy.

[0024] In one case, the immunoconjugate (e.g., IMGN853) is administered intravenously or intraperitoneally.

[0025] In one case, the administration of an immunoconjugate (e.g., IMGN853) produces a synergistic effect with the administration of an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

[0026] In one instance, the administration of an immunoconjugate (e.g., IMGN853) with an anti-VEGF agent does not produce greater toxicity than the administration of the immunoconjugate alone or the anti-VEGF agent alone. In one instance, the administration of an immunoconjugate (e.g., IMGN853) with a platinum-based agent does not produce greater toxicity than the administration of the immunoconjugate alone or the platinum-based agent alone. In one instance, the administration of an immunoconjugate (e.g., IMGN853), an anti-VEGF agent, and a platinum-based agent does not produce greater toxicity than the administration of paclitaxel, an anti-VEGF agent, or a platinum-based agent, wherein the platinum-based agent is carboplatin or cisplatin.

[0027] In one case, the immunoconjugate (e.g., IMGN853) is administered once every 3 or 4 weeks. In another case, the immunoconjugate (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.

[0028] In one case, the immunoconjugate (e.g., IMGN853) is administered weekly. In another case, the immunoconjugate (e.g., IMGN853) is administered at 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.

[0029] In one case, the immunoconjugate (e.g., IMGN853) is administered once every 2 weeks. In another case, the immunoconjugate (e.g., IMGN853) is administered at a dose of about 2.0 mg / kg AIBW, about 2.5 mg / kg AIBW, about 3.0 mg / kg AIBW, about 3.5 mg / kg AIBW, or about 4.0 mg / kg AIBW.

[0030] In one instance, the anti-VEGF agent comprises an antibody or antigen-binding fragment thereof that binds to VEGF or the VEGF receptor. In another instance, the antibody or antigen-binding fragment thereof that binds to VEGF is bevacizumab. In yet another instance, the antibody or antigen-binding fragment thereof that binds to VEGF is highly similar to bevacizumab and there are no clinically significant differences in safety and efficacy compared to bevacizumab (e.g., ABP 215 (Amgen), BCD-021 (Biocad)).

[0031] In one instance, the anti-VEGF agent comprises a tyrosine kinase inhibitor. In another instance, the tyrosine kinase inhibitor is selected from the group consisting of: cidinibub, pazopanib, axitinib, vastarabine, semasanib, sunitinib, sorafenib, ramucirumab, and aflibercept.

[0032] In one case, the anti-VEGF agent contains a soluble VEGF receptor. In another case, the soluble VEGF receptor is VEGF-TRAP.

[0033] In one case, the anti-VEGF agent is administered once every 3 weeks or every 2 weeks. In another case, the anti-VEGF agent is administered at a dose of about 15 mg / kg, about 10 mg / kg, or about 7.5 mg / kg.

[0034] In one case, bevacizumab was administered at a dose of 15 mg / kg every 3 weeks. In another case, bevacizumab was administered at a dose of 10 mg / kg every 2 weeks.

[0035] In one case, the platinum-based agent is carboplatin. In another case, carboplatin is administered once every 3 weeks. In yet another case, 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.

[0036] In one case, the platinum-based agent is cisplatin. In another case, cisplatin is administered every 3 or 4 weeks. In yet another case, cisplatin is administered at approximately 50-70 mg / m² or approximately 75-100 mg / m². 2 or approximately 100 mg / m 2 Dosage administration.

[0037] In one case, doxorubicin is PEGylated doxorubicin, liposomal doxorubicin, or PEGylated liposomal doxorubicin. In one case, doxorubicin is administered once every 4 weeks. In one case, doxorubicin is administered at a dose of 30 mg / m². 2 35mg / m 2 40mg / m 2 45mg / m 2 Or 50mg / m 2 Dosage administration.

[0038] In one scenario, the anti-VEGF agent is bevacizumab, administered at a dose of 15 mg / kg every 3 weeks, and an immunoconjugate (e.g., IMGN853) is administered at a dose of 4 mg / kg AIBW every 3 weeks. In another scenario, the anti-VEGF agent is bevacizumab, administered at a dose of 15 mg / kg every 3 weeks, and an immunoconjugate (e.g., IMGN853) is administered at a dose of 5 mg / kg AIBW every 3 weeks. In yet another scenario, the anti-VEGF agent is bevacizumab, administered at a dose of 15 mg / kg every 3 weeks, and an immunoconjugate (e.g., IMGN853) is administered at a dose of 6 mg / kg AIBW every 3 weeks.

[0039] In one scenario, the anti-VEGF agent is bevacizumab, administered at a dose of 10 mg / kg every 2 weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 4 mg / kg AIBW every 4 weeks. In another scenario, the anti-VEGF agent is bevacizumab, administered at a dose of 10 mg / kg every 2 weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 5 mg / kg AIBW every 4 weeks. In yet another scenario, the anti-VEGF agent is bevacizumab, administered at a dose of 10 mg / kg every 2 weeks, and the immunoconjugate (e.g., IMGN853) is administered at a dose of 6 mg / kg AIBW every 4 weeks.

[0040] In one case, carboplatin was administered in combination with bevacizumab and an immunoconjugate (IMGN853). In another case, carboplatin was administered every 3 weeks. In yet another case, carboplatin was administered at doses yielding the area under the curve (AUC) at 4 mg / ml·min, 5 mg / ml·min, 6 mg / ml·min, or 7 mg / ml·min.

[0041] In one case, the platinum-based agent is carboplatin, which is administered every 3 weeks to obtain an AUC of 4 mg / ml·min, and the immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of 4 mg / kg AIBW.

[0042] In one case, the platinum-based agent is carboplatin, which is administered every 3 weeks to obtain an AUC of 4 mg / ml·min, and the immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of 5 mg / kg AIBW.

[0043] In one case, the platinum-based agent is carboplatin, which is administered every 3 weeks to obtain an AUC of 5 mg / ml·min, and the immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of 5 mg / kg AIBW.

[0044] In one case, the platinum-based agent is carboplatin, which is administered every 3 weeks to obtain an AUC of 5 mg / ml·min, and the immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of 6 mg / kg AIBW.

[0045] In one case, doxorubicin is pegylated liposomal doxorubicin (PLD), with PLD at approximately 30 mg / m³. 2 The dosage is administered once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 weeks at a dose of 4 mg / kg AIBW.

[0046] In one case, doxorubicin was a PLD (partially administered dose), with the PLD dose at approximately 30 mg / m². 2 The dosage is administered once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 weeks at a dose of 5 mg / kg AIBW.

[0047] In one case, doxorubicin was a PLD (proton pump inhibitor), with a PLD concentration of approximately 40 mg / m³. 2 The dosage is administered once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 weeks at a dose of 5 mg / kg AIBW.

[0048] In one case, doxorubicin was a PLD (proton pump inhibitor), with a PLD concentration of approximately 40 mg / m³. 2 The dosage is administered once every 4 weeks, and the immunoconjugate (e.g., IMGN853) is administered once every 4 weeks at a dose of 6 mg / kg AIBW.

[0049] In one case, the cancer is ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer.

[0050] In one case, the cancer is ovarian cancer. In another case, the ovarian cancer is epithelial ovarian cancer. In yet another case, the ovarian cancer is platinum-resistant, recurrent, or refractory.

[0051] In one case, the cancer is platinum-refractory. In another case, the cancer is primary platinum-refractory. In yet another case, the cancer is platinum-sensitive.

[0052] In one case, the cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0053] In one case, the cancer was ovarian cancer and the administration caused a decrease in CA125. In one case, the peritoneal cancer was primary peritoneal cancer. In one case, the endometrial cancer was serous endometrial cancer. In one case, the lung cancer was selected from the group consisting of: non-small cell lung cancer (NSCLC), adenocarcinoma, and bronchioloalveolar carcinoma.

[0054] In one case, the cancer had previously been treated with bevacizumab. In another case, the cancer had not previously been treated with bevacizumab (i.e., the patient was "not treated with bevacizumab").

[0055] In one case, the cancer is metastatic or advanced.

[0056] In one instance, the cancer expresses FOLR1. In one instance, FOLR1 expression is measured by immunohistochemistry (IHC). In one instance, the IHC score has at least one heterologous, at least one homologous, at least two heterologous, at least two homologous, or at least three heterologous staining scores. In one instance, at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of the cells in the sample obtained from the patient have at least two IHC staining scores (moderate). In one instance, at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of the cells in the sample obtained from the patient have at least three IHC staining scores.

[0057] In one instance, the method further includes administering a steroid to the patient. In one instance, the steroid is dexamethasone. In one instance, the steroid is administered as eye drops. In one instance, the eye drops are preservative-free lubricating eye drops.

[0058] In one case, the immunoconjugate (e.g., IMGN853) is administered in separate pharmaceutical compositions with an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof.

[0059] This document also provides a kit. In one embodiment, the kit comprises an immunoconjugate bound to FOLR1, wherein the immunoconjugate comprises an antibody or an antigen-binding fragment thereof containing: the VH CDR1 sequence of SEQ ID NO:9, the VH CDR2 sequence of SEQ ID NO:10, and the VH CDR3 sequence of SEQ ID NO:12, and the VL CDR1 sequence of SEQ ID NO:6, the VL CDR2 sequence of SEQ ID NO:7, and the VL CDR3 sequence of SEQ ID NO:8; and an anti-VEGF agent, a platinum-based agent, or doxorubicin; and instructions for administering the immunoconjugate with the anti-VEGF agent, platinum-based agent, or doxorubicin. In one embodiment, the anti-VEGF agent is an anti-VEGF antibody. In one embodiment, the anti-VEGF antibody is bevacizumab. In one embodiment, the anti-VEGF agent is a tyrosine kinase inhibitor. In one instance, the tyrosine kinase inhibitor is selected from the group consisting of: cidinibub, pazopanib, axitinib, vatalanib, semasanib, sunitinib, sorafenib, ramucirumab, and aflibercept. In one instance, the anti-VEGF agent is a soluble VEGF receptor. In one instance, the soluble VEGF receptor is VEGF-TRAP. In one instance, the platinum-based agent is carboplatin or cisplatin. In one instance, doxorubicin is PEGylated liposomal doxorubicin. In one instance, the immunoconjugate is IMGN853.

[0060] This article also provides methods for guiding subjects with cancer. In one instance, the method includes providing instructions for receiving cancer treatment with an immunoconjugate bound to FOLR1 (e.g., IMGN853) in combination with an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof. In one instance, the anti-VEGF agent is an anti-VEGF antibody. In one instance, the anti-VEGF antibody is bevacizumab. In one instance, the anti-VEGF agent is a tyrosine kinase inhibitor. In one instance, the tyrosine kinase inhibitor is selected from the group consisting of: cidinibub, pazopanib, axitinib, vatalanib, semasanib, sunitinib, sorafenib, ramucirumab, and aflibercept. In one instance, the anti-VEGF agent is a soluble VEGF receptor. In one instance, the soluble VEGF receptor is VEGF-TRAP. In one instance, the platinum-based agent is carboplatin or cisplatin. In one instance, the doxorubicin is polyethylene glycol-modified liposomal doxorubicin. In one case, the immunoconjugate is IMGN853. Brief description of the attached diagram

[0061] Figure 1The antitumor activity of IMGN853 (5 mg / kg), pegylated liposomal doxorubicin (PLD) (4 mg / kg), and the combination therapy of IMGN853+PLD was demonstrated in an epithelial ovarian cancer tumor model.

[0062] Figure 2A The antitumor activity of IMGN853 (5 mg / kg), bevacizumab (5 mg / kg), and IMGN853 + bevacizumab combination therapy in a serous ovarian cancer tumor model was demonstrated.

[0063] Figure 2B 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 was demonstrated.

[0064] Figure 3 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 was demonstrated.

[0065] Figure 4 The antitumor activity of IMGN853 (5 mg / kg), bevacizumab (5 mg / kg), and IMGN853 + bevacizumab combination therapy in an epithelial ovarian cancer tumor model was demonstrated.

[0066] Figure 5 The antitumor activity of IMGN853 (5 mg / kg), paclitaxel (10 mg / kg), bevacizumab (5 mg / kg), paclitaxel + bevacizumab combination therapy, and IMGN853 + bevacizumab combination therapy in an epithelial ovarian cancer tumor model was demonstrated.

[0067] Figure 6 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 was demonstrated.

[0068] Figure 7The antitumor activity of 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) in a non-small cell lung cancer tumor model was demonstrated.

[0069] Figure 8 The antitumor activity of IMGN853 (2.5 mg / kg), sildenafil (1.5 mg / kg), and the combination therapy of IMGN853 and sildenafil was demonstrated in a serous ovarian cancer tumor model.

[0070] Figure 9A The effects of treatment with gradient concentrations of IMGN853, carboplatin, or both on IGROWV-1 cells and their proliferation are shown. The combination index (CI) was calculated using median effect analysis. Data from two independent experiments are shown, determined for a range of drug concentrations and fractional effect (Fa) values ​​from 0.4 to 0.7. Data points below the dashed lines indicate synergistic effects between drug pairs.

[0071] Figure 9B IGROWV-1 cells were treated with carboplatin (20 μM) or IMGN853 (8 nM) alone and in combination for 6 hours. Cell cycle distribution was determined after washing the cells and culturing them in drug-free medium for 24 hours.

[0072] Figure 9C IGROWV-1 cells were exposed alone or in combination to carboplatin (40 μM) or IMGN853 (16 nM) for 6 hours followed by incubation in drug-free medium for 18 hours. Cell extracts were immunoblotted against γH2AX or actin (loading control) as shown.

[0073] Figure 9D The antitumor activity of IMGN853 (2.5 mg / kg) or carboplatin (80 mg / kg) alone and in combination (n = 7 mice / group) in platinum-sensitive ovarian cancer patient-derived xenografts (PDX) established in SCID mice is shown. Data are presented as mean and standard error of mean (SEM) for each time point.

[0074] Figure 9EThe antitumor activity of two consecutive weekly doses of the mediators, carboplatin (80 mg / kg, ip) plus paclitaxel (10 mg / kg), carboplatin plus PLD (4 mg / kg), or carboplatin plus IMGN853 (5 mg / kg), was demonstrated in mice (n = 7 mice / group) with platinum-sensitive PDX tumors.

[0075] Figure 10A The effects of treatment with progressively increasing concentrations of IMGN853, doxorubicin, or both on IGROWV-1 cells and their proliferation are shown. The combination index (CI) was calculated using median effect analysis. Data from three independent experiments are shown, with points below the dashed lines representing synergistic effects between drug pairs.

[0076] Figure 10B IGROWV-1 cells were treated with doxorubicin (200 nM) or IMGN853 (8 nM) alone and in combination for 6 hours. Cell cycle distribution was determined after washing the cells and culturing them in drug-free medium for 24 hours.

[0077] Figure 10C The antitumor activity of two consecutive weekly doses of IMGN853 (5 mg / kg) and PLD (4 mg / kg), alone or in combination (n = 8 mice / group), in platinum-resistant ovarian cancer PDX established in SCID mice is shown. Data are presented as mean and SEM for each time point.

[0078] Figure 10D The mouse body weights measured twice weekly are shown. The averages are plotted against a mediator control.

[0079] Figure 11A The antitumor activity of IMGN853 (3 mg / kg) alone or in combination with bevacizumab at a single dose of 5 mg / kg or at two consecutive weekly doses of 2.5 mg / kg (QWx2) in mice (n = 7 mice / group) with established OV-90 xenografts was demonstrated.

[0080] Figure 11B Tumor volume measured at the end of the study and individual tumor size plotted against the treatment group in mice with platinum-resistant ovarian cancer PDX who received two consecutive weekly doses of bevacizumab (5 mg / kg) alone or in combination with paclitaxel (10 mg / kg) or IMGN853 (5 mg / kg). Tumor growth was monitored for up to 102 days. *P = 0.011; **P = 0.018; ns, not significant (Wilcoxon test, unadjusted).

[0081] Figure 12AMice with OV-90 tumors treated with a single dose of the mediator, IMGN853 (2.5 mg / kg), bevacizumab (5 mg / kg), or IMGN853 plus bevacizumab, and tumors collected 4 days later are shown. Histological staining (H&E) revealed large central necrotic areas in the tumors from mice receiving the combination treatment. Initial magnification, 4X; scale bar, 2 mm (600 μm for the combination image).

[0082] Figure 12B Tumor extracts were immunoblotted against γH2AX or actin (sample control) as shown.

[0083] Figure 12C Immunohistochemical assessment of CD31 expression in tumor tissue on day 4 (top panel) and maytansine detection (anti-MAY; bottom panel) is shown. For each group, a representative micrograph from one of the three tumors is shown. Initial magnification, 20X; scale bar, 200 μm. Invention Details

[0084] This invention provides a combination of an anti-FOLR1 immunoconjugate with an anti-VEGF agent, a platinum-based agent, doxorubicin, or a combination thereof, and the use of said combination in cancer treatment.

[0085] I. Definition

[0086] To facilitate understanding of this invention, many terms and expressions are defined as follows.

[0087] Unless otherwise indicated, the term “FOLR1” as used herein refers to any naturally occurring human FOLR1 polypeptide. FOLR1 is also known as “human folate receptor 1,” “folate receptor α (FR-α),” and “FRα.” The term “FOLR1” includes “full-length,” unprocessed FOLR1 polypeptides, and any form of FOLR1 polypeptide produced by intracellular processing. The term also includes naturally occurring FOLR1 variants, such as those encoded by splice variants and allelic variants. The FOLR1 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. When specifically indicated, “FOLR1” may be used to refer to the nucleic acid encoding the FOLR1 polypeptide. Human FOLR1 sequences are known and include publicly available sequences, for example, under UniProtKB registry number P15328 (including isoforms). As used herein, the term “human FOLR1” refers to FOLR1 containing the sequence SEQ ID NO:1.

[0088] Unless otherwise indicated, the term “VEGF” as used herein refers to any naturally occurring human VEGF polypeptide. VEGF is also known as vascular endothelial growth factor-A, VEGF-A, vascular permeability factor, and VPF. The term “VEGF” includes “full-length”, unprocessed VEGF polypeptides, and any form of VEGF polypeptide produced by cellular processing. The term also includes naturally occurring VEGF variants, such as those encoded by splice variants and allelic variants. The VEGF polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or other sources, or prepared by recombinant or synthetic methods. When specifically indicated, “VEGF” may be used to refer to the nucleic acid encoding the VEGF polypeptide. Human VEGF sequences are known and include publicly available sequences, for example, under UniProtKB registry number P15692 (including isotypes).

[0089] The term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of the above via at least one antigen recognition site within the variable region of an immunoglobulin molecule. As used herein, the term "antibody" includes complete polyclonal antibodies, complete monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, antibody-containing fusion proteins, and any other modified immunoglobulin molecules, provided that the antibody exhibits the desired biological activity. Antibodies can be any of the five major immunoglobulin classes: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), designated α, δ, ε, γ, and μ based on the identity of their heavy chain constant domains, respectively. Different classes of immunoglobulins have different and well-known subunit structures and three-dimensional conformations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.

[0090] The term "antibody fragment" refers to a portion of a complete antibody. "Antigen-binding fragment" refers to a portion of a complete antibody that binds to an antigen. Antigen-binding fragments may contain the antigen-determining variable region of the complete 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.

[0091] "Blocking" or "antagonistic" antibodies are antibodies that inhibit or reduce the biological activity of the antigen they bind to (such as FOLR1 or VEGF). In some embodiments, blocking or antagonistic antibodies substantially or completely inhibit the biological activity of the antigen. The biological activity may be reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0092] The term "anti-FOLR1 antibody" or "FOLR1-bound antibody" refers to an antibody that binds to FOLR1 with sufficient affinity to make the antibody suitable for use as a diagnostic and / or therapeutic agent targeting FOLR1 (e.g., huMov19 (M9346A) antibody). The binding degree of anti-FOLR1 antibodies to unrelated, non-FOLR1 proteins may be less than approximately 10%, as measured by, for example, radioimmunoassay (RIA) of antibody binding to FOLR1.

[0093] The term "anti-VEGF agent" refers to an agent 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., sildenafil or...). (IPR Pharmaceuticals Inc.), see Nikolinakos et al., J. Thoracic Oncology 3(6) Supplement 2: S131-S134 (2008)), and soluble VEGF receptors (e.g., VEGF-Trap; see, for example, Holash et al., PNAS 99(17) 11393-11398 (2002)).

[0094] The term "anti-VEGF antibody" or "VEGF-bound antibody" refers to an antibody capable of binding to VEGF with sufficient affinity to make the antibody suitable as a therapeutic agent targeting VEGF (e.g., bevacizumab). The binding degree of an anti-VEGF antibody to unrelated, non-VEGF proteins may be less than approximately 10% of the antibody-VEGF binding as measured by, for example, radioimmunoassay (RIA). In some embodiments, the VEGF-bound antibody has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. In some embodiments, the VEGF-bound antibody or its antigen-binding fragment is bevacizumab. In some embodiments, the VEGF-bound antibody or its antigen-binding fragment is highly similar to bevacizumab and has no clinically significant differences in safety and efficacy compared to bevacizumab (e.g., ABP 215 (Amgen), BCD-021 (Biocad)).

[0095] 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 the murine anti-VEGF monoclonal antibody A.4.6.1 (see, Presta et al., Cancer Res. 57:4593-4599 (1997); US Patent 6,054,297; US Patent 7,365,166; US Patent 7,622,115; US Patent 8,778,340). Bevacizumab is... The active ingredient in (Genentech, Inc.)(Id.).

[0096] The term "paclitaxel" or "PAC" refers to the compound associated with CAS registry number 33069-62-4. Paclitaxel is... (Bristol-Myers Squibb Company), Onxol and The active ingredient in (Abraxis Bioscience, LLC). Paclitaxel is believed to be a mitotic inhibitory chemotherapeutic agent that binds to tubulin and inhibits microtubule degradation to prevent cell division and induce apoptosis.

[0097] The term "platinum-based" refers to platinum-based chemotherapy agents. Platinum-based agents include cisplatin, carboplatin, and oxaliplatin.

[0098] The term "cisplatin" refers to the compound associated with CAS registry number 15663-27-1. Cisplatin is... The active ingredient in (Bristol-Myers Company) cisplatin is also known as "cisplatinum". Cisplatin is believed to be a platinum-containing alkylating chemotherapeutic agent that binds to nucleophilic groups in DNA and causes intra- and inter-strand DNA crosslinks as well as DNA-protein crosslinks, thereby causing apoptosis and inhibiting cell growth.

[0099] The term "carboplatin" refers to the compound associated with CAS registry number 41575-94-4. Carboplatin is... The active ingredient in Bristol-Myers Squibb Co., Corp., is carboplatin. Carboplatin contains platinum atoms complexed with two amino groups and a cyclobutane-dicarboxyl residue. This agent is activated intracellularly to form reactive platinum complexes that bind to nucleophilic groups, such as GC-rich sites in DNA, thereby inducing intra- and inter-strand DNA crosslinks and DNA-protein crosslinks. These carboplatin-induced DNA and protein effects result in apoptosis and cell growth inhibition. This agent exhibits tumor-killing activity similar to its parent compound, cisplatin, but is more stable and less toxic.

[0100] 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 "doxorubicin" and "Rubex." Liposome doxorubicin (i.e., doxorubicin encapsulated in liposomes or liposomes) is... The active ingredient in Cephalon UK, Ltd. Polyethylene glycol-modified liposomal doxorubicin (PLD) (polyethylene glycol polymer-linked liposomal doxorubicin) is... (Liposom Technology, Inc.) and " Doxorubicin is the active ingredient in "(Janssen)". It is believed to be an anthracycline antibiotic chemotherapeutic agent that inserts between base pairs in the DNA helix to prevent DNA replication. Additionally, doxorubicin inhibits topoisomerase II, which produces an increased and stable cleavable enzyme-DNA linker complex during DNA replication and subsequently prevents the linking of nucleotide chains after double-strand breaks. Doxorubicin also forms oxygen free radicals, causing cytotoxicity secondary to lipid peroxidation of cell membrane lipids.

[0101] The term “treatment line” or “therapeutic line” refers to treatment options that may include, but are not limited to, surgery, radiation therapy, chemotherapy, differentiation therapy, biotherapy, immunotherapy, or administration of one or more anticancer agents (e.g., cytotoxic agents, antiproliferative compounds, and / or angiogenesis inhibitors).

[0102] The terms "first-line treatment," "first-line therapy," and "primary therapy" refer to the preferred and standard initial treatment for a specific condition, such as cancer of a given type and stage. These treatments differ from "second-line" therapy, which is attempted when first-line therapy is insufficient. "Third-line" therapy is attempted when both first-line and second-line therapy are insufficient.

[0103] For example, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin as described herein may be administered as first-line, second-line (e.g., in patients with platinum-sensitive or platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer), or third-line (e.g., in patients with platinum-sensitive or platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer). The combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin as described herein may be administered as a line of therapy in patients who have received 0, 1, 2, 3, 4, 5, 6, or more lines of therapy prior to treatment with the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin as described herein. The combination of FOLR1 immunoconjugates (e.g., IMGN853) with the anti-VEGF agents, platinum-based agents, and / or doxorubicin described herein may be administered as a first-line therapy in patients who have received at least one, two, or three lines of therapy prior to treatment with the combination of FOLR1 immunoconjugates (e.g., IMGN853) with the anti-VEGF agents, platinum-based agents, and / or doxorubicin described herein. In some embodiments, the combination of FOLR1 immunoconjugates (e.g., IMGN853) with the anti-VEGF agents, platinum-based agents, and / or doxorubicin described herein may be administered as a first-line therapy in patients who have received no more than one, two, three, four, five, or six lines of therapy. In some embodiments, the combination of FOLR1 immunoconjugates (e.g., IMGN853) with the anti-VEGF agents, platinum-based agents, and / or doxorubicin described herein may be administered as adjuvant or neoadjuvant therapy.

[0104] The term "adjuvant therapy" refers to systemic treatment given after surgery. In a broader sense, adjuvant therapy is any treatment given in addition to the primary therapy to kill any cancer cells that may have spread, even if the spread cannot be detected by radiation or laboratory tests.

[0105] The term "neoadjuvant therapy" refers to systemic therapy administered prior to surgery.

[0106] The term "IMGN853" refers to the immunoconjugate described herein containing the huMov19 (M9346A) antibody, the sulfonated SPDB linker, and the DM4 maytansine alkaloid. The huMov19 (M9346A) antibody is an anti-FOLR1 antibody containing the variable heavy chain sequence SEQ ID NO:3 and the variable light chain sequence SEQ ID NO:5. DM4 refers to N2'-deacetylated-N2'-(4-mercapto-4-methyl-1-oxopentyl) maytansine. "Sulfonated SPDB" refers to the 4-(2-pyridyldithio)-2-sulfobutyric acid N-succinimide linker.

[0107] "Monoclonal" antibodies or their antigen-binding fragments refer to a group of homologous antibodies or antigen-binding fragments that participate in highly specific recognition and binding to a single antigenic determinant or epitope. This contrasts with polyclonal antibodies, which typically consist of different antibodies targeting different antigenic determinants. The term "monoclonal" antibody or its antigen-binding fragment includes full-length and complete monoclonal antibodies, as well as antibody fragments (such as 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 refer to such antibodies and their antigen-binding fragments prepared in, but not limited to, by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0108] The term "humanized" antibody or its antigen-binding fragment refers to a non-human (e.g., murine) antibody or antigen-binding fragment that is a specific immunoglobulin chain, a chimeric immunoglobulin, or a fragment containing a minimal non-human (e.g., murine) sequence. Typically, humanized antibodies or their antigen-binding fragments are human immunoglobulins in which residues from the complementarity-determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) with the desired specificity, affinity, and ability (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 immunoglobulins are replaced by corresponding residues from antibodies or fragments of non-human species with the desired specificity, affinity, and ability. Humanized antibodies or their antigen-binding fragments may be further modified by substitution of additional residues within non-human residues in the Fv framework region and / or by substitution to improve and optimize the specificity, affinity, and / or ability of the antibody or its antigen-binding fragment. Typically, humanized antibodies or their antigen-binding fragments will contain substantially all at least one, and typically two or three, variable domains containing all or substantially all CDR regions corresponding to non-human immunoglobulins, and all or substantially all FR regions being those regions of the common sequence of human immunoglobulins. Humanized antibodies or their antigen-binding fragments may also contain at least a portion of immunoglobulin constant regions or domains (Fc), typically at least a portion of human immunoglobulins. Examples of methods for generating humanized antibodies are described in U.S. Patent 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 implementations, "humanized antibody" refers to surface-reconstructed antibody.

[0109] The “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable regions of both the heavy and light chains are each composed of four framework regions (FRs) connected by three complementarity-determining regions (CDRs, also known as hypervariable regions). The CDRs of each chain are tightly bound by the FRs and, together with the CDRs of other chains, contribute to the formation of the antigen-binding site of the antibody. At least two techniques exist for determining CDRs: (1) methods based on cross-species 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) methods based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., J. Molec. Biol. 273:927-948 (1997)). Additionally, combinations of these two methods are sometimes used in the art to determine CDRs.

[0110] When referring to residues in the variable domain (approximately residues 1-107 of the light chain and approximate residues 1-113 of the heavy chain), the Kabat numbering system is generally used (e.g., Kabat et al., Sequences of Immunological Interest. (5th ed., 1991, National Institutes of Health, Bethesda, Md.) (“Kabat”).

[0111] The amino acid positions numbered in Kabat refer to the numbering system used for antibody editing of heavy chain or light chain variable domains in Kabat et al. (Sequences of Immunological Interest. (5th edition, 1991, National Institutes of Health, Bethesda, Md.) "Kabat"). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids, corresponding to shortened or inserted fragments of the FR or CDR of the variable domain, respectively. For example, the heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (according to residue 52a in Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c in Kabat). The Kabat number of residues can be determined for a given antibody by comparing the sequence homologous regions of the given antibody with the sequence of "standard" Kabat numbering. Chothia, on the other hand, refers to the position of the structural loop (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). When numbered using the Kabat numbering convention, the end of the Chothia CDR-H1 loop varies between H32 and H34, depending on the loop length (this is because the Kabat numbering scheme places the inserts at H35A and H35B; if neither 35A nor 35B is present, the loop terminates at 32; if only 35A is present, the loop terminates at 33; if both 35A and 35B are present, the loop terminates at 34). The AbM hypervariable region represents a compromise between the Kabat CDR and the Chothia structural loop and is used through Oxford Molecular's AbM antibody modeling software.

[0112]

[0113] The term "human" antibody or antigen-binding fragment thereof means an antibody or antigen-binding fragment thereof produced by a person having an amino acid sequence corresponding to an antibody or antigen-binding fragment thereof produced by a person using any technique known in the art. This definition of human antibody or antigen-binding fragment thereof includes complete or full-length antibodies and fragments thereof.

[0114] The term "chimeric" antibody or its antigen-binding fragment refers to an antibody or its antigen-binding fragment whose amino acid sequence originates from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of antibodies or their antigen-binding fragments derived from one species of mammal (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and ability, while the constant regions are homologous to sequences in antibodies or their antigen-binding fragments derived from another (usually human) to avoid evoking an immune response in that species.

[0115] The terms “epitope” or “antigenic determinant” are used interchangeably herein and refer to the portion of an antigen that can be recognized and specifically bound by a particular antibody. When the antigen is a polypeptide, an epitope can be formed from consecutive amino acids and non-consecutive amino acids arranged side-by-side through the ternary folding of a protein. Epitopes formed from consecutive amino acids are generally retained after protein denaturation, while epitopes formed through ternary folding are generally lost after protein denaturation. Epitopes typically consist of at least three, and more usually, at least five or eight to ten amino acids in a distinctive spatial conformation.

[0116] "Binding affinity" generally refers to the total strength of the non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise stated, "binding affinity" as used herein refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y is typically expressed by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies typically bind antigens slowly and tend to dissociate easily, while high-affinity antibodies typically bind antigens more quickly and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which may be used for the purposes of this invention. Specific illustrative embodiments are described below.

[0117] When used in this text to refer to binding affinity, "or better" means a stronger binding between the molecule and its binding partner. "Or better" in this text refers to a stronger binding, expressed as a smaller Kd value. For example, when an antibody has an affinity of "0.6 nM or better" for an antigen, the antibody's affinity for the antigen is <0.6 nM, which is 0.59 nM, 0.58 nM, 0.57 nM, etc., or any value less than 0.6 nM.

[0118] "Specific binding" generally refers to an antibody binding to an epitope via its antigen-binding domain, and this binding requires a certain complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to "specifically bind" to an epitope when it binds to it more readily via its antigen-binding domain than to a random, unrelated epitope. The term "specificity" is used herein to identify the relative affinity of an antibody to a given epitope. For example, antibody "A" may be considered to have higher specificity to a given epitope than antibody "B," or antibody "A" may be said to bind to epitope "C" with higher specificity than to its associated epitope "D."

[0119] "Preferred binding" means that an antibody specifically binds to an epitope more readily than to a related, similar, homologous, or analogous epitope. Therefore, an antibody that "preferentially binds" to a given epitope is more likely to bind to that epitope than to a related epitope, even though such an antibody may cross-react with the related epitope.

[0120] An antibody is considered to "competitively inhibit" the binding of a reference antibody to a given epitope or overlapping epitope such that it partially blocks the binding of a reference antibody to the epitope. Competitive inhibition can be determined by any method known in the art, such as a competitive ELISA assay. It can be said that the antibody competitively inhibits the binding of the reference antibody to the given antibody by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0121] As used herein, the phrases “substantially similar” or “substantially identical” indicate a sufficiently high degree of similarity between two values ​​(generally one relating to the antibody of the present invention and the other to a reference / comparison 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 context of the biological characteristics measured by said values ​​(e.g., Kd values). The difference between said 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 / comparison antibody.

[0122] "Isolated" peptides, antibodies, polynucleotides, vectors, cells, or compositions are peptides, antibodies, polynucleotides, vectors, cells, or compositions in forms not found in nature. Isolated peptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the point that they no longer appear in their naturally occurring forms. In some embodiments, the isolated antibodies, polynucleotides, vectors, cells, or compositions are substantially pure.

[0123] As used herein, “substantially pure” means material that is at least 50% pure (i.e., free of contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0124] As used herein, the term "immunoconjugate" or "conjugate" refers to a compound or derivative thereof linked to a cell binder (i.e., an anti-FOLR1 antibody or a fragment thereof) and defined by the following general formula: CLA, where C = cytotoxin, L = linker, and A = antibody or an antigen-binding fragment thereof, for example, an anti-FOLR1 antibody or an antibody fragment. Immunoconjugates can also be defined by the following general formula in reverse order: ALC.

[0125] A "connector" is any chemical part capable of stably covalently linking a compound, a common drug (such as maytansine alkaloids), to a cell binding agent (such as an anti-FOLR1 antibody or a fragment thereof). A connector may be susceptible to, for example, disulfide bond cleavage or substantially resistant to disulfide bond cleavage, provided the compound or antibody remains active. Suitable connectors are well known in the art and include, for example, disulfide and thioether groups.

[0126] The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinomas, germ cell tumors, and sarcomas. More specific examples of the cancers mentioned include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer including primary peritoneal carcinoma (PPC), hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer (including epithelial ovarian cancer (EOC) and advanced EOC), liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial cancer (or uterine carcinoma), salivary gland cancer, non-clear cell kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, various types of head and neck cancer, bone cancer, pituitary cancer, testicular cancer, and brain cancer (see, for example, U.S. Patent 8,709,432; U.S. Patent 8,834,877; Zwicke et al., Nano Reviews 3:18496-18506 (2012)). Cancer can be FOLR1-expressing cancer ("FOLR1-expressing cancer" or "FRα-positive cancer").

[0127] The terms “cancer cell,” “tumor cell,” and their grammatical equivalents refer to the total cell population derived from a tumor or precancerous lesion, including non-tumorigenic cells (which constitute the majority of the tumor cell population) and tumorigenic stem cells (cancer stem cells). As used herein, the term “tumor cell” will be modified by the term “non-tumorigenic” when it refers only to those tumor cells that lack the capacity for renewal and differentiation to distinguish them from cancer stem cells.

[0128] "Late-stage" cancer is cancer that has spread beyond its site of origin or organ through local invasion or metastasis. The term "late-stage" cancer includes both locally advanced and metastatic disease.

[0129] Metastatic cancer refers to cancer that has spread from one part of the body to another.

[0130] "Refractory" cancer is cancer that continues to progress despite the administration of anti-tumor treatments such as chemotherapy. An example of refractory cancer is platinum-resistant cancer.

[0131] A patient is considered "platinum-refractory" if they do not respond to platinum-based therapy and show progression during treatment or within 4 weeks after the last dose. "Platinum-resistant" patients progress within 6 months of platinum-based therapy. "Partially platinum-sensitive" patients progress between 6 and 12 months of platinum-based therapy. "Platinum-sensitive" patients progress within an interval exceeding 12 months.

[0132] "Recurrent" cancer is cancer that regenerates at the initial site or a distant site after a response to initial therapy.

[0133] The term "subject" refers to any animal (e.g., a mammal), including but not limited to humans, non-human primates, rodents, etc., that will be the recipient of a particular treatment. Generally, the terms "subject" and "patient" are used interchangeably in this document in relation to human subjects.

[0134] A "relapsed" patient is someone who has developed signs or symptoms of cancer after a period of remission. Optionally, a patient may relapse after adjuvant or neoadjuvant therapy.

[0135] Administration in combination with one or more other therapeutic agents includes simultaneous (parallel) or sequential administration in any order.

[0136] Combination therapies can provide a “synergistic effect” and are demonstrated to be “synergistic,” meaning that the combined effect of the active ingredients is greater than the sum of the effects of the compounds used alone. The synergistic effect can be obtained when the active ingredients are subjected to: (1) co-formulated and administered or delivered in combined unit dose formulations; (2) delivered sequentially, alternately, or simultaneously as separate formulations; or (3) by some other protocol. When delivered in alternating therapies, the synergistic effect can be obtained when the compounds are administered or delivered, for example, by sequential injections in separate syringes.

[0137] The term "pharmaceutical formulation" refers to a formulation in which the biological activity of the active ingredient is clearly demonstrated and which does not contain any other components that would have unacceptable toxicity to the subject administering the formulation. The formulation may be sterile.

[0138] The “effective amount” of antibodies, immunoconjugates, or other drugs disclosed herein is an amount sufficient for the purpose specifically stated. An “effective amount” may be determined empirically and in a conventional manner in relation to the stated purpose.

[0139] The term “therapeutic effective dose” refers to the amount of an antibody, immune conjugate, or other drug that effectively “treats” a disease or condition in a subject or mammal. In the case of cancer, a therapeutically effective dose of a drug may: reduce the number of cancer cells; reduce tumor size or burden; inhibit (i.e., to some extent slow down and, in one implementation, halt) cancer cell infiltration into surrounding organs; inhibit (i.e., to some extent slow down and, in one implementation, halt) tumor metastasis; inhibit tumor growth to some extent; alleviate one or more symptoms associated with cancer to some extent; and / or produce a favorable response, such as prolonging progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), or, in some cases, stable disease (SD), reduction in progressive disease (PD), shortening time to progression (TTP), a decrease in CA125 in the case of ovarian cancer, or any combination thereof. See the definition of “therapeutic” in this document. If a drug can prevent the growth and / or kill existing cancer cells, it may be cytoseptic and / or cytotoxic. A “preventive effective dose” refers to the amount that effectively achieves the desired preventive outcome at the necessary dose and time period. Usually, but not always, the preventative dose is used before or in the early stages of a patient's illness, so the effective preventative dose is generally less than the effective therapeutic dose.

[0140] The term "good response" generally refers to a beneficial state produced in a subject. In the context of cancer treatment, this term refers to the therapeutic effect delivered to the subject. Positive therapeutic effects in cancer can be measured in many 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 agents. 10 Cell Kill (LCK) can be used to quantify tumor cell killing. Log 10 Cell killing (LCK) is calculated using the following formula: LCK = (TC) / T d x 3.32, where (TC) (or tumor growth delay (TGD)) is the median time (in days) for tumors to reach the predetermined size in the treatment and control groups (excluding those without tumor survival). T d3.32 is the tumor doubling time (estimated by fitting a nonlinear exponential curve to the median daily growth of control tumors), and 3.32 is the number of cell doublings per log cell growth. The ability to reduce tumor volume can be evaluated, for example, by measuring the %T / C value, which is the median tumor volume of the treated subject divided by the median tumor volume of the control subject. Regarding tumor growth inhibition, according to NCI criteria, T / C ≤ 42% is the minimum level of antitumor activity. T / C < 10% is considered a high level of antitumor activity, where T / C (%) = median tumor volume of the treated subject / median tumor volume of the control subject x 100. Favorable responses can be evaluated, for example, by 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, stable disease (SD), a reduction in progressive disease (PD), a shortened time to progression (TTP), a decrease in CA125 in the case of ovarian cancer, or any combination thereof.

[0141] PFS, DFS, and OS can be measured using the standards set by the National Cancer Institute and the Food and Drug Administration for new drug approval. See Johnson et al., J. Clin. Oncol. 21(7):1404-1411 (2003).

[0142] Progression-free survival (PFS) refers to the time from recruitment to disease progression or death. PFS is generally measured using the Kaplan-Meier method and the response evaluation criteria in RECIST 1.1. In general, progression-free survival means that a patient remains alive without the cancer progressing.

[0143] "Time to Tumor Progression" (TTP) is defined as the time from recruitment to disease progression. The RECIST 1.1 standard is generally used to measure TTP.

[0144] "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 has been cured.

[0145] "Partial response" or "PR" refers to the reduction in size or volume of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment.

[0146] "Stable disease" refers to disease that does not progress or relapse. In stable disease, there is neither sufficient tumor shrinkage to be classified as a partial response nor sufficient tumor increase to be classified as progressive disease.

[0147] "Progressive disease" refers to the appearance of a new lesion or tumor and / or a clear progression of an existing non-target lesion. Progressive disease can also refer to tumor growth exceeding 20% ​​since the start of treatment due to mass enlargement or tumor spread.

[0148] "Disease-free survival" (DFS) refers to the duration during and after treatment when a patient remains disease-free.

[0149] Overall survival (OS) refers to the time from patient recruitment to the last date of death or examination indicating that the patient is known to be alive. OS includes the extension of life expectancy compared to the original or untreated individual or patient. Overall survival refers to the survival of a patient over a defined period of time (e.g., 1 year, 5 years, etc.) since diagnosis or treatment.

[0150] "Prolonged survival" or "increased likelihood of survival" means an increase in PFS and / or OS in treated subjects relative to untreated subjects or relative to control treatment regimens (such as standard care for a type of cancer).

[0151] A decrease 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 baseline CA125 levels. CA125 levels can be measured once or multiple times during or after treatment, and a decrease in CA125 levels over time compared to baseline levels is considered a decrease in CA125 levels.

[0152] The term "increased expression" or "overexpression" of FOLR1 in a specific tumor, tissue, or cell sample refers to the presence of FOLR1 (the FOLR1 polypeptide or the nucleic acid encoding said polypeptide) at a higher level than is present in healthy or disease-free (natural, wild-type) tissues or cells of the same type or origin. This increased expression or overexpression can be caused, for example, by mutation, gene amplification, increased transcription, increased translation, or improved protein stability.

[0153] Terms such as “treating,” “treatment,” “to treat,” “to alleviate,” or “to alleviate” refer to therapeutic measures that cure, slow down, alleviate the symptoms of a diagnosed pathological condition or symptom, and / or stop its progression. Therefore, those requiring treatment include those who have been diagnosed with or are suspected of having the condition. In some implementations, a subject is considered successfully “treated” with cancer according to the method of the invention if the patient exhibits one or more of the following: a reduction or complete absence of cancer cells; a reduction in tumor burden; inhibition or absence of cancer cell infiltration into surrounding organs (including, for example, cancer spread to 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 specific cancer; a reduction in morbidity and mortality; an improvement in quality of life; a reduction in tumorigenicity, frequency, or capacity for tumorigenicity; a reduction in the number or prevalence of cancer stem cells in the tumor; differentiation of tumorigenic cells into a non-tumorigenic state; an extension of progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS); a reduction in complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD); a shortened time to progression (TTP); a decrease in CA125 in the case of ovarian cancer; or any combination thereof.

[0154] Preventive or preventative measures refer to actions taken to prevent and / or slow the development of a target pathological condition or ailment. Therefore, those requiring preventative or preventative measures include both those predisposed to the condition and those with conditions requiring prevention.

[0155] The term "guidance" refers to providing instructions on applicable therapies, medications, treatments, treatment plans, etc., in any way, such as in written form, like package inserts or other written promotional materials.

[0156] The terms “polypeptide,” “peptide,” and “protein” are generally used interchangeably herein to refer to amino acid polymers of any length. Polymers may be linear or branched, may contain modified amino acids, and may intercalate non-amino acids. The term also includes amino acid polymers, whether naturally occurring or modified through intervention; for example, disulfide bond formation, glycosylation, lipoylation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeled component. This definition also includes, for example, one or more analogues of amino acids (including, for example, non-natural amino acids) and other modified polypeptides known in the art. It should be understood that because the polypeptides of the present invention are antibody-based, in some embodiments, the polypeptides may exist as single chains or related chains.

[0157] In the context of two or more nucleic acids or polypeptides, the term "identity" or "percentage of identity" refers to the fact that two or more sequences or subsequences are identical or have a specific percentage of identical nucleotide or amino acid residues when compared or aligned (with vacancies introduced where necessary and without regard to any conserved amino acid substitutions as part of sequence identity). The percentage of identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are known in the art and can be used to obtain alignments of amino acid or nucleotide sequences. One such non-limiting example of a sequence alignment algorithm is the algorithm described in Karlin et al., Proc. Natl. Acad. Sci., 87:2264-2268 (1990), modified as in Karlin et al., Proc. Natl. Acad. Sci., 90:5873-5877 (1993), and incorporated into the NBLAST and XBLAST procedures (Altschul et al., Nucleic Acids Res., 25:3389-3402 (1991)). In some implementations, Gapped BLAST may 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 additional publicly available software programs that can be used to align sequences. In some embodiments, the percentage of identity between two nucleotide sequences is determined using the GAP procedure in GCG software (e.g., using the NWSgapdna.CMP matrix with vacancy weights of 40, 50, 60, 70, or 90 and length weights of 1, 2, 3, 4, 5, or 6). In some alternative implementations, the GAP procedure in the GCG software package, incorporating the algorithm of Needleman and Wunsch (J. Mol. Biol. (48): 444-453 (1970)), can be used to determine the percentage of identity between two amino acid sequences (e.g., using a Blossum 62 matrix or a PAM250 matrix, with vacancy weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, or 5). Alternatively, in some implementations, the percentage of identity between nucleotide or amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4: 11-17 (1989)).For example, the identity percentage can be determined using the ALIGN program (version 2.0) and PAM120 (with a residue table, a vacancy length penalty of 12, and a vacancy penalty of 4). Appropriate parameters for the maximum alignment using specific alignment software can be determined by those skilled in the art. In some embodiments, the default parameters of the alignment software are used. In some embodiments, the identity percentage "X" between the first and second amino acid sequences is calculated as 100x(Y / Z), where Y is the number of identical matching amino acid residues assessed in the alignment of the first and second sequences (e.g., by visual inspection or a specific sequence alignment program) and Z is the total number of residues in the second sequence. If the first sequence is longer than the second sequence, then the identity percentage between the first and second sequences will be longer than the identity percentage between the second and first sequences.

[0158] As a non-limiting example, whether any particular polynucleotide has a certain percentage of sequence identity with a reference sequence (e.g., at least 80%, at least 85%, at least 90%, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99%) can be determined in some embodiments using the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics 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 optimal homologous regions between two sequences. When using Bestfit or any other sequence alignment program to determine whether a particular sequence is, for example, 95% identical to a reference sequence according to the invention, parameters are set to calculate the percentage of identity over the full length of the reference nucleotide sequence and to allow vacancies in the homology comparison to not exceed 5% of the total number of nucleotides in the reference sequence.

[0159] In some embodiments, the two nucleic acids or polypeptides of the present invention are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid residue identity when compared and aligned for maximum similarity, such as by using sequence comparison algorithms or by visual inspection. Identity may be present in sequence regions of at least about 10, about 20, about 40-60 residues or any integer value between them, and may be present in regions longer than 60-80 residues, for example at least about 90-100 residues. In some embodiments, the sequences are substantially identical across the full-length sequences being compared (e.g., coding regions of nucleotide sequences).

[0160] "Conservative amino acid substitution" is a situation where 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, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, replacing tyrosine with phenylalanine is a conservative substitution. In some embodiments, the conservative substitution in the peptide and antibody sequences of the present invention does not eliminate the binding of the peptide or antibody containing the amino acid sequence to one or more antigens (i.e., FOLR1 or VEGF to which the peptide or antibody binds). Methods for identifying conserved substitutions of nucleotides and amino acids that do not eliminate antigen binding are well known in the art (see, for example, Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94:.412-417 (1997)).

[0161] Unless otherwise clearly stated herein, the singular forms “a,” “an,” and “the” as used in this disclosure and claims include a plurality of forms.

[0162] It should be understood that when an implementation is described herein with the word "comprising", other similar implementations described as "consisting of" and / or "substantially consisting of" are also provided.

[0163] The term "and / or" as used in phrases such as "A and / or B" is intended herein to include "A and B", "A or B", "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).

[0164] II. Anti-FOLR1 Immunoconjugate

[0165] This document describes a method for administering an immunoconjugate (e.g., IMGN853) that specifically binds to FOLR1. These reagents are referred to herein as “FOLR1 immunoconjugates or anti-FOLR1 immunoconjugates”. The amino acid and nucleotide sequences of human FOLR1 are known in the art and are also provided herein as SEQ ID NO:1 and SEQ ID NO:2, respectively.

[0166] SEQ ID NO:1-Human Folic Acid Receptor 1

[0167] MAQRMTTQLLLLLVWVAVVGEAQTRIAWARTELLNVCMNAKHHKEKPGPEDKLHEQCRPWRKNACCSTNTSQEAHKDVSYLYRFNWNHCGEMAPACKRHFIQDTCLYECSPNLGPWIQQVDQSWRKER VLNVPLCKEDCEQWWEDCRTSYTCKSNWHKGWNWTSGFNKCAVGAACQPFHFYFPTPTVLCNEIWTHSYKVSNYSRGSGRCIQMWFDPAQGNPNEEVARFYAAAMSGAGPWAAWPFLLSLALMLLWLLS

[0168] SEQ ID NO:2 - Human folate receptor 1 nucleic acid sequence

[0169] atggctcagcggatgacaacacagctgctgctccttctagtgtgggtggctgtagtaggggaggctcagacaaggattgcatgggccaggactgagcttctcaatgtctgcatgaacgccaagcaccacaaggaaaagccaggccccgaggacaagttgcatgagcagtgtcgaccctggaggaagaatgcctgctgttctaccaacaccagccaggaagcccataaggatgtttcctacctatatagattcaactggaaccactgtggagagatggcacctgcctgcaaacggcatttcatccaggacacctgcctctacgagtgctcccccaacttggggccctggatccagcaggtggatcagagctggcgcaaagagcgggtactgaacgtgcccctgtgcaaagaggactgtgagcaatggtgggaagattgtcgcacctcctacacctgcaagagcaactggcacaagggctggaactggacttcagggtttaacaagtgcgcagtgggagctgcctgccaacctttccatttctacttccccacacccactgttctgtgcaatgaaatctggactcactcctacaaggtcagcaactacagccgagggagtggccgctgcatccagatgtggttcgacccagcccagggcaaccccaatgaggaggtggcgaggttctatgctgcagccatgagtggggctgggccctgggcagcctggcctttcctgcttagcctggccctaatgctgctgtggctgctcagc

[0170] The anti-FOLR1 immunoconjugate contains a cell binder linked to a cytotoxin. The cell binder may be an anti-FOLR1 antibody or an antigen-binding fragment thereof. Examples of therapeutically effective anti-FOLR1 antibodies can be found in U.S. Patent Application Publication No. US 2012 / 0009181, which is incorporated herein by reference. One example of a therapeutically effective anti-FOLR1 antibody is huMov19 (M9346A) (containing the sequences of SEQ ID NO:3 and SEQ ID NO:5). The peptides of SEQ ID NO:3-5 respectively contain a variable domain of the heavy chain of huMov19 (M9346A), a light chain of huMov19 with a variable domain (type 1.00), and a light chain of huMov19 with a variable domain (type 1.60). In some embodiments, the huMov19 anti-FOLR1 antibody comprises a heavy chain with a variable domain represented by SEQ ID NO:3 and a light chain with a variable domain represented by SEQ ID NO:5 (type 1.60 of huMov19). In some implementations, 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 terms of the Budapest Agreement, with ATCC accession numbers PTA-10772 and PTA-10773 or PTA-10774.

[0171] The amino acid sequence of huMov19 is provided in Tables 1-4 below:

[0172] Table 1: CDR amino acid sequence of variable heavy chain

[0173]

[0174] Table 2: Amino acid sequences of variable light chain CDR

[0175]

[0176] Table 3: Anti-FOLR1 variable chain amino acid sequence

[0177]

[0178] Figure 4 Full-length heavy and light chain amino acid sequences

[0179]

[0180] In some embodiments, the anti-FOLR1 immunoconjugate comprises a humanized antibody or an antigen-binding fragment thereof. In some embodiments, the humanized antibody or fragment is a surface-reconstructed antibody or an antigen-binding fragment thereof. In other embodiments, the anti-FOLR1 immunoconjugate comprises a fully human antibody or an antigen-binding fragment thereof.

[0181] In some implementations, the anti-FOLR1 immunoconjugate has one or more of the following effects: inhibiting tumor cell proliferation, reducing tumorigenicity by decreasing the presence of cancer stem cells in the tumor, inhibiting tumor growth, increasing patient survival, triggering cell death of tumor cells, differentiating tumorigenic cells into a non-tumorigenic state, or preventing or reducing tumor cell metastasis.

[0182] In some embodiments, the antiFOLR1 immunoconjugate contains an antibody having antibody-dependent cytotoxic (ADCC) activity.

[0183] In some embodiments, the antiFOLR1 immunoconjugate can reduce tumor volume. The ability of the antiFOLR1 immunoconjugate to reduce tumor volume can be evaluated, for example, by measuring the %T / C value, which is the median tumor volume of a treated subject divided by the median tumor volume of a control subject. In some embodiments, the immunoconjugate or other agent that specifically binds to human FOLR1 triggers cell death via a cytotoxic agent. For example, in some embodiments, an antibody against human FOLR1 is conjugated to a maytansine alkaloid, which is activated in FOLR1-expressing tumor cells via protein internalization. In some embodiments, the antiFOLR1 immunoconjugate can inhibit tumor growth. In some embodiments, the antiFOLR1 immunoconjugate can inhibit tumor growth in vivo (e.g., in xenograft mouse models and / or in people with cancer). In some embodiments, the antiFOLR1 immunoconjugate can reduce CA125 in patients with ovarian cancer.

[0184] FOLR1-binding molecules may be antibodies or antigen-binding fragments that specifically bind to FOLR1, containing a CDR of huMov19 (M9346A), wherein each CDR has up to 4 (i.e., 0, 1, 2, 3, or 4) conserved amino acid substitutions, for example, wherein the antibody or fragment does not contain the 6 CDRs of murine Mov19 (i.e., SEQ ID NO: 6-9, 16, and 12). Peptides may contain one of the various variable light chains or variable heavy chains described herein. Antibodies and peptides may also contain both variable light chains and variable heavy chains.

[0185] In some embodiments, the FOLR1 binding molecule is an antibody or antigen-binding fragment comprising the sequences of SEQ ID NO:6-10 and SEQ ID NO:12. In some embodiments, the FOLR1 binding molecule is an antibody or antigen-binding fragment comprising the sequences of SEQ ID NO:6-9 and SEQ ID NO:11 and 12. In some embodiments, the FOLR1 binding molecule is an antibody or antigen-binding fragment thereof comprising the sequences of SEQ ID NO:6-8, 19, 11, and 12.

[0186] Also provided are polypeptides comprising at least about 90% sequence identity with SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. In some 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 with SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. Thus, in some embodiments, the polypeptide comprises (a) a polypeptide having at least about 95% sequence identity with SEQ ID NO:3 and / or (b) a polypeptide having at least about 95% sequence identity with SEQ ID NO:4 or SEQ ID NO:5. In some 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 some embodiments, the polypeptide is an antibody and / or polypeptide that specifically binds to FOLR1. In some embodiments, the polypeptide is a murine, chimeric, or humanized antibody that specifically binds to FOLR1. In some 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 only by conserved amino acid substitutions.

[0187] Peptides may contain one of the various light or heavy chains described herein. Antibodies and peptides may also contain both light and heavy chains.

[0188] Monoclonal antibodies can be prepared using hybridoma methods (such as those described by Kohler and Milstein (1975) Nature 256:495). Using hybridoma methods, mice, hamsters, or other suitable host animals are immunized as described above to induce lymphocytes to produce antibodies that specifically bind to the immunoantigen. Lymphocytes can also be immunized in vitro. Following immunization, the lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol to form hybridoma cells. The hybridoma cells can then be selected to avoid unfused lymphocytes and myeloma cells. Hybridomas that produce monoclonal antibodies specifically against the selected antigen can then be proliferated in vitro or in vivo as ascites tumors in animals using standard methods (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, 1986). Monoclonal antibodies can then be purified from the culture medium or ascites as described above for polyclonal antibodies.

[0189] Alternatively, monoclonal antibodies can also be manufactured using recombinant DNA methods as described in U.S. Patent 4,816,567. For example, by RT-PCR, polynucleotides encoding monoclonal antibodies are isolated from mature B cells or hybridoma cells using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequences are determined using standard procedures. The isolated polynucleotides encoding the heavy and light chains are then cloned into a suitable expression vector, and when transfected into host cells that do not additionally produce immunoglobulins, such as *E. coli* cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, the host cells produce monoclonal antibodies. Furthermore, recombinant monoclonal antibodies or fragments thereof of the desired species can be isolated from phage display libraries expressing the CDR of the desired species as described (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).

[0190] The polynucleotides encoding monoclonal antibodies can be further modified in many 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 mouse monoclonal antibodies can be replaced by: 1) regions such as those of human antibodies to generate chimeric antibodies; or 2) non-immunoglobulin polypeptides to generate fusion antibodies. In some embodiments, constant regions are truncated or removed to generate desired antibody fragments of monoclonal antibodies. Site-directed or high-density mutagenesis of variable regions can be used to optimize the specificity, affinity, etc., of monoclonal antibodies.

[0191] In some embodiments, the monoclonal antibody against human FOLR1 is a humanized antibody. In some embodiments, the humanized antibody is a surface-reconstructed antibody. In some embodiments, such an antibody is used therapeutically to reduce antigenicity and HAMA (human anti-mouse antibody) response when administered to a human subject. Humanized antibodies can be produced using various techniques known in the art. In some alternative embodiments, the antibody against FOLR1 is a human antibody.

[0192] Human antibodies can be prepared directly using a variety of techniques known in the art. Immortalized human B lymphocytes can be generated, which are either immunized in vitro or isolated from immunized individuals who produce antibodies against the target antigen (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 5,750,373). Human antibodies can also be selected from phage libraries that express human antibodies, such as those described in Vaughan et al., 1996, Nat. Biotech., 14:309-314; Sheets et al., 1998, Proc. Nat'l. Acad. Sci., 95:6157-6162; Hoogenboom and Winter, 1991, J. Mol. Biol., 227:381; and Marks et al., 1991, J. Mol. Biol., 222:581. Techniques for generating and using antibody phage libraries are also described in U.S. Patent Nos. 5,969,108; 6,172,197; 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915; 6,593,081; 6,300,064; 6,653,068; 6,706,484; and 7,264,963; and Rothe et al., 2007, J.Mol.Bio., doi:10.1016 / j.jmb.2007.12.018 (each of which is incorporated herein by reference in its entirety). Affinity maturation and chain shuffling strategies (Marks et al., 1992, Bio / Technology 10:779-783, incorporated herein by reference in its entirety) are known in the art and can be used to generate high-affinity human antibodies.

[0193] Humanized antibodies can also be produced in transgenic mice containing human immunoglobulin loci, which, once immunized, can produce all components of human antibodies 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.

[0194] The polypeptides of the present invention may be recombinant polypeptides, natural polypeptides or synthetic polypeptides containing an antibody against human FOLR1 or a fragment thereof.

[0195] Peptides and analogues can be further modified to contain additional chemical moieties that are not normally part of a protein. These derived moieties can improve protein solubility, biological half-life, or absorption. They can also reduce or eliminate any desired side effects of proteins and their analogues. An overview of these moieties can be found in REMINGTON'S PHARMACEUTICAL SCIENCES, 20th edition, Mack Publishing Co., Easton, PA (2000).

[0196] It also includes methods known in the art for purifying antibodies and other proteins, such as those described in U.S. Patent Publications 2008 / 0312425, 2008 / 0177048 and 2009 / 0187005, each of which is incorporated herein by reference in its entirety.

[0197] Suitable drugs or prodrugs are known in the art. Drugs or prodrugs may be cytotoxic agents. The cytotoxic agents used in the cytotoxic conjugates of the present invention may be any compound that causes or induces cell death or reduces cell viability in a certain manner, including, for example, maytansine alkaloids and maytansine alkaloid analogues.

[0198] Such conjugates can be prepared by using a linker group to link a drug or prodrug to an antibody or functional equivalent. Suitable linker groups are known in the art and include, for example, disulfide groups, thioether groups, acid-labile groups, light-labile groups, peptidase-labile groups, and esterase-labile groups.

[0199] The drug or prodrug may be linked, for example, to an antiFOLR1 antibody or a fragment thereof via a disulfide bond. The linker molecule or crosslinker contains a reactive chemical group that can react with the antiFOLR1 antibody or a fragment thereof. The reactive chemical group used for reaction with the cell binding agent may be N-succinimidyl ester or N-sulfosuccinimidyl ester. Alternatively, the linker molecule contains a reactive chemical group, which may be a dithiopyridyl group, that can react with the drug to form a disulfide bond. Connector molecules include, for example, 3-(2-pyridyldithio)propionic acid N-succinimide ester (SPDP) (see, for example, Carlsson et al., Biochem.J., 173:723-737 (1978)), 4-(2-pyridyldithio)butyric acid N-succinimide ester (SPDB) (see, for example, U.S. Patent No. 4,563,304), 4-(2-pyridyldithio)2-sulfonylbutyric acid N-succinimide ester (sulfon-SPDB) (see U.S. Publication No. 20090274713), 4-(2-pyridyldithio)valerate N-succinimide ester (SPP) (see, for example, CAS Registry No. 341498-08-6), 2-iminothiacyclopentane, or acetylsuccinic anhydride. For example, antibodies or cell binders can be modified with cross-linking agents, and the resulting antibodies or cell binders containing free or protected thiol groups can then be reacted with maytansine alkaloids containing disulfides or thiols to produce conjugates. Conjugates can be purified by chromatography, including but not limited to HPLC, size exclusion adsorption, ion exchange and affinity trapping, dialysis, or tangential flow filtration.

[0200] In another aspect of the invention, the anti-FOLR1 antibody is linked to a cytotoxic drug via a disulfide bond and a polyethylene glycol spacer to enhance the potency, solubility, or efficacy of the immunoconjugate. This cleavable hydrophilic linker is described in WO2009 / 0134976. An additional benefit of this linker design is the desired high monomer ratio and minimal aggregation of the antibody-drug conjugate. Particular consideration is given in this regard for the cell binder and drug being linked via a polyethylene glycol spacer ((CH2CH2O)). n＝1-14 The disulfide (-SS-)-linked conjugates of 2-8 are described, which exhibit relatively high bioactivity against cancer cells and possess the desired biochemical properties of high conjugation yield and high monomer ratio with minimal protein aggregation.

[0201] Antibody-matenidine alkaloid conjugates with non-cleavable linkers 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-succinimide-4-(maleimide-methyl)cyclohexanecarboxylate (SMCC). In some embodiments, the antibody is modified with crosslinking agents such as 4-(N-maleimidemethyl)-cyclohexane-1-carboxylic acid succinimide (SMCC), sulfon-SMCC, maleimide benzoyl-N-hydroxysuccinimide (MBS), sulfon-MBS, or succinimide-iodoacetate, as described in the literature, to introduce 1-10 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 maytansine alkaloid derivative to produce a conjugate. The conjugates can be purified by gel filtration via a Sephadex G25 column or by dialysis or tangential flow filtration. The modified antibody is treated with a thiol-containing maytandemin alkaloid (1 to 2 molar equivalents / maleimide group), and the antibody-maytandemin alkaloid conjugate is purified by gel filtration via a Sephadex G-25 column, chromatography on a ceramic hydroxyapatite column, dialysis, or tangential flow filtration, or a combination of these methods. Typically, each antibody is linked to an average of 1–10 maytandemin alkaloids. One method involves modifying the antibody with 4-(N-maleimidemethyl)-cyclohexane-1-carboxylic acid succinimide ester (SMCC) to introduce maleimide groups, followed by reaction of the modified antibody with a thiol-containing maytandemin alkaloid to yield a thioether-linked conjugate. This again produces conjugates containing 1 to 10 drug molecules per antibody molecule. Maytandemin alkaloid conjugates for antibodies, antibody fragments, and other proteins are prepared in the same manner.

[0202] In another aspect of the invention, the FOLR1 antibody is linked to the drug via an indestructible bond mediated by a PEG spacer. Suitable crosslinking agents comprising a hydrophilic PEG chain (which forms a linker between the drug and the antiFOLR1 antibody or fragment) are also known in the art or are commercially available (e.g., from Quanta Biodesign, Powell, Ohio). Suitable PEG-containing crosslinking agents can also be synthesized from commercially available PEG itself using standard synthetic chemistry techniques known to those skilled in the art. The drug can be reacted with a bifunctional PEG-containing crosslinking agent to give a compound of the following formula: Z–X l –(–CH2–CH2–O–) n –Y p–D, as described in detail in U.S. Patent Publications 20090274713 and WO2009 / 0134976, the method may subsequently react with a cell binder to form a conjugate. Alternatively, the cell binder may be modified with a bifunctional PEG crosslinking agent to introduce a thiol-reactive group (such as maleimide or haloacetamide), and subsequently treated with a thiol-containing maytandemin alkaloid to form a conjugate. In another method, the cell binder may be modified with a bifunctional PEG crosslinking agent to introduce a thiol moiety, and subsequently treated with a thiol-reactive maytandemin alkaloid (such as a maytandemin alkaloid containing maleimide or haloacetamide) to form a conjugate.

[0203] Examples of suitable PEG-containing linkers include linkers having an N-succinimide or N-sulfosuccinimide moiety for reaction with anti-FOLR1 antibodies or fragments thereof; and a maleimide or haloacetyl moiety for reaction with compounds. PEG spacer groups can be incorporated into any crosslinking agent known in the art by the methods described herein.

[0204] In some embodiments, the linker is a linker containing at least one charged group, as described, for example, in U.S. Patent Publication No. 2012 / 0282282, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the charged or pro-charged crosslinking agent is one containing sulfonate, phosphate, carboxyl, or quaternary ammonium substituents, which significantly improve the solubility of modified cell binders and cell binder-drug conjugates, particularly for monoclonal antibody-drug conjugates linked with 2 to 20 drugs / antibodies. Conjugates prepared from linkers containing a pre-charged moiety will produce one or more charged moieties after the conjugate is metabolized in cells. In some embodiments, the linker is selected from the group consisting of: 4-(2-pyridyldithio)-2-sulfovaleric acid N-succinimide ester (sulfon-SPP) and 4-(2-pyridyldithio)-2-sulfobutyric acid N-succinimide ester (sulfon-SPDB).

[0205] Many of the connectors disclosed herein are described in detail in U.S. Patent Publications 2005 / 0169933, 2009 / 0274713, 2012 / 0282282, and WO2009 / 0134976, the contents of which are incorporated herein by reference in their entirety.

[0206] This invention includes aspects in which about 2 to about 8 drug molecules (“drug load”), such as maytansine alkaloids, are linked to an anti-FOLR1 antibody or a fragment thereof. As used herein, “drug load” refers to the number of drug molecules (e.g., maytansine alkaloids) that can be linked to a cell binder (e.g., an anti-FOLR1 antibody or a fragment thereof). On one hand, the number of drug molecules that can be linked to a cell binder may be an average of about 2 to about 8 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4...). 6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1). N2'-deacetylated-N2'-(3-mercapto-1-oxopropyl)-maytansin (DM1) and N2'-deacetylated-N2'-(4-mercapto-4-methyl-1-oxopentyl)maytansin (DM4) can be used.

[0207] Therefore, on one hand, the immunoconjugate contains 1 maytansine alkaloid per antibody. On the other hand, the immunoconjugate contains 2 maytansine alkaloids per antibody. On another hand, the immunoconjugate contains 3 maytansine alkaloids per antibody. On another hand, the immunoconjugate contains 4 maytansine alkaloids per antibody. On another hand, the immunoconjugate contains 5 maytansine alkaloids per antibody. On another hand, the immunoconjugate contains 6 maytansine alkaloids per antibody. On another hand, the immunoconjugate contains 7 maytansine alkaloids per antibody. On another hand, the immunoconjugate contains 8 maytansine alkaloids per antibody.

[0208] On one hand, each immunoconjugate (e.g., an immunoconjugate containing the linker SPDB and the maytansine alkaloid DM4) contains about 1 to about 8 maytansine alkaloids. On the other hand, each immunoconjugate (e.g., an immunoconjugate containing the linker SPDB and the maytansine alkaloid DM4) contains about 2 to about 7 maytansine alkaloids. On the other hand, each immunoconjugate (e.g., an immunoconjugate containing the linker SPDB and the maytansine alkaloid DM4) contains about 2 to about 6 maytansine alkaloids. On the other hand, each immunoconjugate (e.g., an immunoconjugate containing the linker SPDB and the maytansine alkaloid DM4) contains about 2 to about 5 maytansine alkaloids. On the other hand, each immunoconjugate (e.g., an immunoconjugate containing the linker SPDB and the maytansine alkaloid DM4) contains about 3 to about 5 maytansine alkaloids. On the other hand, immunoconjugates (e.g., immunoconjugates containing linker SPDB and maytansine alkaloid DM4) contain about 3 to about 4 maytansine alkaloids per antibody.

[0209] On the one hand, compositions containing immunoconjugates have an average of about 2 to about 8 antibodies linked per antibody (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. The composition containing the immunoconjugate has an average of about 1 to about 8 drug molecules (e.g., maytandemin alkaloids) per antibody. On one hand, the composition containing the immunoconjugate has an average of about 2 to about 7 drug molecules (e.g., maytandemin alkaloids) per antibody. On the other hand, the composition containing the immunoconjugate has an average of about 2 to about 6 drug molecules (e.g., maytandemin alkaloids) per antibody. On one hand, compositions containing immunoconjugates have an average of about 2 to about 5 drug molecules per antibody (e.g., maytandemin alkaloids). On the other hand, compositions containing immunoconjugates have an average of about 3 to about 5 drug molecules per antibody (e.g., maytandemin alkaloids). On the other hand, compositions containing immunoconjugates have an average of about 3 to about 4 drug molecules per antibody (e.g., maytandemin alkaloids).

[0210] On one hand, compositions containing immunoconjugates have an average of 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 drug molecules (e.g., maytandemin alkaloids) linked per antibody. On the other hand, compositions containing immunoconjugates have an average of about 3.5 ± 0.5 drug molecules (e.g., maytandemin alkaloids) linked per antibody.

[0211] Anti-FOLR1 antibodies or fragments thereof can be modified by reacting with a bifunctional crosslinking agent, thereby creating a covalent linker molecule to the anti-FOLR1 antibody or fragment thereof. As used herein, a “bifunctional crosslinking agent” is any chemical part that covalently links a cell binder to a drug (such as the drug described herein). In another approach, a portion of the linker portion is provided by the drug. In this respect, the drug comprises a linker portion as part of a larger linker molecule for linking the cell binder to the drug. For example, to form maytansine alkaloid DM1, the side chain at the C-3 hydroxyl group of maytansine is modified to have a free thiol group (SH). This thiolized form of maytansine can react with the modified cell binder to form a conjugate. Thus, the final linker is assembled from two components, one provided by the crosslinking agent and the other by the side chain from DM1.

[0212] Drug molecules can also be linked to antibody molecules via intermediate carrier molecules such as serum albumin.

[0213] As used herein, the expressions “linked to a cell binder” or “linked to an antiFOLR1 antibody or fragment” mean that a conjugated molecule comprising at least one drug derivative is bound to a cell binder, antiFOLR1 antibody, or fragment via a suitable linker group or its precursor. An exemplary linker group is SPDB or sulfonyl-SPDB.

[0214] In some embodiments, the cytotoxic agents suitable for use in this invention are maytansine alkaloids and maytansine alkaloid analogs. Examples of suitable maytansine alkaloids include esters of maytansine alcohol and maytansine alcohol analogs. This includes any drug that inhibits microtubule formation and is highly toxic to mammalian cells, such as maytansine alcohol and maytansine alcohol analogs.

[0215] Examples of suitable maytanyl esters include those with modified aromatic rings and those with modifications at other positions. Such suitable maytansine alkaloids are disclosed in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866; 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.

[0216] In one embodiment, the immunoconjugate of the present invention utilizes a thiol-containing maytansine alkaloid (DM1), formally known as N 2’ -Deacetylated-N 2’ -(3-Mercapto-1-oxopropyl)-Maytansin, used as a cytotoxic agent. DM1 is represented by the following structural formula (I):

[0217]

[0218] In another embodiment, the conjugate of the present invention utilizes the thiol-containing maytansine alkaloid N. 2’ -Deacetylated-N 2’ -(4-Mercapto-4-methyl-1-oxopentyl)matansin (e.g., DM4) is used as a cytotoxic agent. DM4 is represented by the following structural formula (II):

[0219]

[0220] Another maytansine alkaloid containing a side chain with a sterically hindered thiol bond is N. 2’ -Deacetylated-N- 2’ (4-Mercapto-1-oxopentyl)-Maytansine (referred to as DM3) is represented by the following structural formula (III):

[0221]

[0222] Each of the maytansine alkaloids taught in U.S. Patent Nos. 5,208,020 and 7,276,497 may also be used in the conjugates of the present invention. For this purpose, the entire disclosure of 5,208,020 and 7,276,697 is incorporated herein by reference.

[0223] Many positions on the maytansine alkaloid can serve as sites for the chemical attachment of the linker. For example, the C-3 position with a hydroxyl group, the C-14 position modified with a hydroxymethyl group, the C-15 position modified with a hydroxyl group, and the C-20 position with a hydroxyl group are all considered useful. In some embodiments, the C-3 position serves as the site for the chemical attachment of the linker, and in some specific embodiments, the C-3 position of maytansine serves as the site for the chemical attachment of the linker.

[0224] The structural diagrams of some conjugates are shown below:

[0225]

[0226]

[0227]

[0228] The present invention also includes any stereoisomers of any compound or conjugate described by any of the above structures, and mixtures thereof.

[0229] Several descriptions of the preparation of such antibody-matentin alkaloid conjugates are provided in U.S. Patent Nos. 6,333,410; 6,441,163; 6,716,821 and 7,368,565, each of which is incorporated herein by reference in its entirety.

[0230] Typically, the antibody solution in an aqueous buffer is incubated with a molar excess of maytansine alkaloids containing a disulfide moiety with a reactive group. The reaction mixture can be quenched by adding an excess of an amine (such as ethanolamine, taurine, etc.). The maytansine alkaloid-antibody conjugate can then be purified by gel filtration.

[0231] The number of maytansine alkaloid molecules bound to each antibody molecule can be determined by spectrophotometric measurement of the absorbance ratio at 252 nm and 280 nm. The average maytansine alkaloid molecule / antibody ratio can be, for example, 1-10 or 2-5. The average maytansine alkaloid molecule / antibody ratio can be, for example, about 3 to about 4. The average maytansine alkaloid molecule / antibody ratio can be about 3.5.

[0232] Antibody conjugates with maytansine alkaloids 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 lines Daudi and Ramos can be readily used to assess the cytotoxicity of these compounds. Cells to be evaluated are exposed to the compound for 4 to 5 days, and the cell viability fraction is measured in a direct assay using known methods. The IC50 can then be calculated from the assay results. 50 value.

[0233] According to some embodiments described herein, the immunoconjugate can be internalized into cells. Therefore, the immunoconjugate can exert a therapeutic effect when it is taken up or internalized by cells expressing FOLR1. In some specific embodiments, the immunoconjugate comprises an antibody, antibody fragment, or peptide linked to a cytotoxic agent via a cleavable linker, and cleaves the cytotoxic agent from the antibody, antibody fragment, or peptide, wherein it is internalized by cells expressing FOLR1.

[0234] In some embodiments, the immunoconjugate can reduce tumor volume. For example, in some embodiments, treatment with the immunoconjugate produces the following %T / C values: less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. In some specific embodiments, the immunoconjugate can reduce tumor size in KB, OVCAR-3, IGROW-1, and / or OV-90 xenograft models. In some embodiments, the immunoconjugate can inhibit metastasis.

[0235] III. Anti-VEGF agents

[0236] This article describes a method for administering an anti-FOLR1 immunoconjugate such as IMGN853 in combination with an agent that specifically binds to VEGF (e.g., bevacizumab) or the VEGF receptor. Anti-VEGF agents include, for example, anti-VEGF or anti-VEGFR antibodies (e.g., bevacizumab), tyrosine kinase inhibitors (TKIs) (e.g., sildenafil), and soluble VEGF receptors (e.g., VEGF-Trap). Anti-VEGF agents are known in the art, and certain examples are provided in Meadows and Hurwitz, Cold Spring Harbor Perspectives in Medicine 2:a006577 (2012), which is incorporated herein by reference in its entirety.

[0237] In some embodiments, the anti-VEGF agent can inhibit tumor growth. In some embodiments, the anti-VEGF agent can inhibit tumor growth in vivo (e.g., in xenograft mouse models and / or in people with cancer). In some embodiments, the anti-VEGF agent can inhibit angiogenesis.

[0238] In some implementations, the anti-VEGF agent is an anti-VEGF or anti-VEGFR antibody or its antigen-binding fragment.

[0239] The full-length amino acid sequence of human VEGF-A is provided under UniProtKB accession number P15692 and is provided herein as SEQ ID NO:17:

[0240] MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIG EMSFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVYVGARCCLMPWSLPGPHPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR(SEQ ID NO:17), and its signal sequence is MNFLLSWVHWSLALLLYLHHAKWSQA (SEQ ID NO:18).

[0241] Therefore, in some embodiments, the anti-VEGF antibody or its antigen-binding fragment binds to the epitope in SEQ ID NO:17 or the epitope in the mature form of SEQ ID NO:17 (i.e., SEQ ID NO:17 lacking the signal sequence).

[0242] Anti-VEGF antibodies and their antigen-binding fragments may comprise polypeptides containing the variable light chains or variable heavy chains described herein. Anti-VEGF antibodies and polypeptides may also comprise both variable light chains and variable heavy chains. Anti-VEGF antibodies and their variable light and heavy chains are described at least in U.S. Patents 6,884,879; 6,054,297; 7,169,901; 7,365,166; 7,060,269; 7,622,115; 8,778,340; and 7,297,334, all of which are incorporated herein by reference in their entirety.

[0243] 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.

[0244] 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.

[0245] In some embodiments, the anti-VEGF agent is a tyrosine kinase inhibitor. The tyrosine kinase inhibitor may inhibit, for example, VEGFR1, VEGFR2, and / or VEGFR3. In some embodiments, the tyrosine kinase inhibitor is sildenafil. 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 valtarabine. In some embodiments, the tyrosine kinase inhibitor is semasanib. 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.

[0246] In some embodiments, the anti-VEGF agent is a soluble VEGF receptor protein. The soluble VEGF receptor protein may include the extracellular ligand-binding domain of VEGFR1. The soluble VEGF receptor protein may include the extracellular ligand-binding domain of VEGFR2. The soluble VEGF receptor protein may include the extracellular ligand-binding domains of both VEGFR1 and VEGFR2. In some embodiments, the soluble VEGF receptor is VEGF-Trap (aflibercept), i.e., a fusion protein combining the Fc moiety of human IgG1 with the major extracellular ligand-binding domains of human VEGFR1 and VEGFR2.

[0247] IV. Platinum-based agents

[0248] This article describes a method for administering an anti-FOLR1 immunoconjugate such as IMGN853 in combination with a platinum-based agent (e.g., cisplatin, carboplatin, or oxaliplatin).

[0249] Cisplatin is a platinum-based alkylated chemotherapeutic agent that produces DNA adducts and is therefore cytotoxic to cells lacking cleavage repair (see Huang et al., PNAS 91:10394-10398 (1994)). Cisplatin is the parent compound of carboplatin. Similar to cisplatin, carboplatin produces DNA adducts that are cytotoxic to cells lacking cleavage repair. Exemplary cisplatins include Platinol and Platinol-AQ.

[0250] Carboplatin is considered a therapeutic equivalent of cisplatin (demonstrating efficacy in the same and other tissues compared to cisplatin), but with a very different (better) toxicity profile (Lokich et al., Annals. Of Oncology 9:13-21 (1998)). Exemplary carboplatin includes paraplatin.

[0251] Oxaliplatin is a third-generation platinum-based drug. Exemplary oxaliplatin includes...

[0252] Combining platinum-based agents with anti-FOLR1 immunoconjugates (such as IMGN853) can reduce the amount and / or frequency of platinum-based agents required to achieve the same efficacy, thereby reducing the toxicity of the therapy. Combining platinum-based agents with anti-FOLR1 immunoconjugates (such as IMGN853) can also enhance the efficacy of the therapy.

[0253] In some embodiments, the platinum base is cisplatin, carboplatin, or oxaliplatin. In some embodiments, the platinum base is cisplatin or carboplatin. In some embodiments, the platinum base is cisplatin. In some embodiments, the platinum base is carboplatin.

[0254] V. Dorothy Star

[0255] This article describes a method for administering an anti-FOLR1 immunoconjugate, such as IMGN853, in combination with doxorubicin.

[0256] Doxorubicin is an anthracycline antibiotic chemotherapeutic agent that binds to DNA-related enzymes such as topoisomerase and can insert into DNA base pairs, thereby producing a series of cytotoxic effects and ultimately causing apoptosis (Tacar et al., J. of Pharmacy & Pharmacology, 65:157-170 (2013)).

[0257] In some implementations, doxorubicin is polyethylene glycol-modified. In other implementations, doxorubicin is not polyethylene glycol-modified.

[0258] In some embodiments, doxorubicin is liposomes. In some embodiments, doxorubicin is not liposomes.

[0259] In some implementations, doxorubicin is polyethylene glycol-modified, liposomal doxorubicin.

[0260] Exemplary Dorubi stars include (Cephalon UK, Ltd.)), DOX-NP (Avanti Polar Lipids, Inc.), (Janssen) and (Liposom Technology, Inc.).

[0261] Combining doxorubicin with an anti-FOLR1 immunoconjugate (e.g., IMGN853) can reduce the amount and / or frequency of doxorubicin required to achieve the same efficacy, thereby reducing the toxicity of the therapy. Combining doxorubicin with an anti-FOLR1 immunoconjugate (e.g., IMGN853) can also enhance the efficacy of the therapy.

[0262] VI. Pharmaceutical Compositions and Kits

[0263] As described in this article, anti-FOLR1 immunoconjugates (e.g., IMGN853) can be combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin for the treatment of cancer.

[0264] In some embodiments, an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab) are contained in the same pharmaceutical composition. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the anti-VEGF agent (e.g., bevacizumab) are contained in two separate pharmaceutical compositions within a single kit. In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and instructions for administering both the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the anti-VEGF agent (e.g., bevacizumab). In other embodiments, the kit includes an anti-VEGF agent (e.g., bevacizumab) and instructions for administering both the anti-VEGF agent (e.g., bevacizumab) and the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0265] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and a platinum-based agent are contained within the same pharmaceutical composition. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and a platinum-based agent are contained in two separate pharmaceutical compositions within a single kit. In other embodiments, the kit includes the anti-FOLR1 immunoconjugate (e.g., IMGN853) and instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the platinum-based agent. In other embodiments, the kit includes the platinum-based agent and instructions for administering the platinum-based agent and the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0266] In some embodiments, an anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are contained within the same pharmaceutical composition. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are contained within two separate pharmaceutical compositions in a single kit. In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin. In other embodiments, the kit includes doxorubicin and instructions for administering a platinum-based agent and the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0267] In some embodiments, an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and a platinum-based agent are contained in the same pharmaceutical composition. In some embodiments, an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and a platinum-based agent are contained in two or three separate pharmaceutical compositions in a single kit.

[0268] In other embodiments, the kit includes instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and a platinum-based agent. In other embodiments, the kit includes instructions for administering an anti-VEGF agent (e.g., bevacizumab), an anti-FOLR1 immunoconjugate (e.g., IMGN853), and a platinum-based agent. In other embodiments, the kit includes instructions for administering a platinum-based agent, an anti-VEGF agent (e.g., bevacizumab), and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0269] In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), as well as instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), the anti-VEGF agent (e.g., bevacizumab), and the platinum-based agent. In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and a platinum-based agent, as well as instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), the platinum-based agent, and the anti-VEGF agent (e.g., bevacizumab). In other embodiments, the kit includes an anti-VEGF agent (e.g., bevacizumab) and a platinum-based agent, as well as instructions for administering the anti-VEGF agent (e.g., bevacizumab), the platinum-based agent, and the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0270] In other embodiments, the kit includes instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), and doxorubicin. In other embodiments, the kit includes instructions for administering an anti-VEGF agent (e.g., bevacizumab), an anti-FOLR1 immunoconjugate (e.g., IMGN853), and doxorubicin. In other embodiments, the kit includes doxorubicin and instructions for administering doxorubicin, an anti-VEGF agent (e.g., bevacizumab), and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0271] In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), as well as instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), the anti-VEGF agent (e.g., bevacizumab), and doxorubicin. In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin, as well as instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), doxorubicin, and the anti-VEGF agent (e.g., bevacizumab). In other embodiments, the kit includes an anti-VEGF agent (e.g., bevacizumab) and doxorubicin, as well as instructions for administering the anti-VEGF agent (e.g., bevacizumab), doxorubicin, and the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0272] In other embodiments, the kit includes instructions for administering an anti-FOLR1 immunoconjugate (e.g., IMGN853), a platinum-based agent, and doxorubicin. In other embodiments, the kit includes instructions for administering a platinum-based agent, an anti-FOLR1 immunoconjugate (e.g., IMGN853), and doxorubicin. In other embodiments, the kit includes instructions for administering doxorubicin, a platinum-based agent, and an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0273] In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and a platinum-based agent, along with instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), the platinum-based agent, and doxorubicin. In other embodiments, the kit includes an anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin, along with instructions for administering the anti-FOLR1 immunoconjugate (e.g., IMGN853), doxorubicin, and a platinum-based agent. In other embodiments, the kit includes a platinum-based agent and doxorubicin, along with instructions for administering the platinum-based agent, doxorubicin, and the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0274] In some embodiments, the pharmaceutical compositions provided herein comprise an anti-FOLR1 immunoconjugate (e.g., IMGN853), an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent and / or doxorubicin, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions also comprise a preservative. These pharmaceutical compositions are used in human patients to inhibit tumor growth and treat cancer.

[0275] The pharmaceutical compositions used as described herein can be administered in many ways for local or systemic treatment. Administration can be local, such as through transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders; pulmonary (e.g., inhalation or blowing in powders or aerosols, including via nebulizers; intratracheal, intranasal, epidermal, and percutaneous); oral; or parenteral, including intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. In some embodiments, the pharmaceutical composition is formulated for intravenous (iv) administration. In some embodiments, the pharmaceutical composition is formulated for intraperitoneal (ip) administration.

[0276] VII. Instructions for Use

[0277] As described in this article, anti-FOLR1 immunoconjugates (e.g., IMGN853) can be combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin for the treatment of cancer.

[0278] VII.A. Cancer Selection

[0279] Cancers treatable by the methods include, but are not limited to, growths, tumors, metastases, or any disease or condition characterized by uncontrolled cell growth. The cancer can be primary or metastatic. Specific examples of cancers treatable by the methods covered by this invention include, but are not limited to, ovarian cancer, peritoneal cancer, fallopian tube cancer, lung cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, brain cancer, uterine cancer, non-clear cell renal cell carcinoma, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, endometrial cancer, and head and neck cancer.

[0280] More specific examples of the cancer include ovarian cancer, epithelial ovarian cancer, primary peritoneal ovarian cancer, or ovarian-fallopian tube cancer. In some embodiments, the subject has previously untreated ovarian cancer. In some embodiments, the subject has newly diagnosed, previously untreated ovarian cancer (e.g., not previously treated with an anti-VEGF antibody (e.g., bevacizumab) (“not bevacizumab-treated”)). In other embodiments, the subject has previously treated ovarian cancer (e.g., previously treated with an anti-VEGF antibody (e.g., bevacizumab)). In some embodiments, the subject has newly diagnosed, previously untreated (e.g., not previously treated with an anti-VEGF antibody (e.g., bevacizumab) (“not bevacizumab-treated”), stage III (suboptimal and grossly optimal volume reduction), and stage IV epithelial ovarian-fallopian tube cancer. In other embodiments, the subject has previously treated (e.g., previously treated with an anti-VEGF antibody (e.g., bevacizumab)) stage III (suboptimal and grossly best volume reduction) and IV epithelial ovarian primary peritoneal or fallopian tube cancer. In some embodiments, the subject has platinum-sensitive recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In other embodiments, the subject has platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

[0281] In some embodiments, a combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is given to patients diagnosed with or having ovarian cancer, epithelial ovarian cancer, primary ovarian peritoneal cancer, or ovarian fallopian tube cancer who have not previously received anti-VEGF antibody (e.g., bevacizumab) treatment. In other embodiments, a combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is given to patients diagnosed with or having ovarian cancer, epithelial ovarian cancer, primary ovarian peritoneal cancer, or ovarian fallopian tube cancer who have received anti-VEGF antibody (e.g., bevacizumab) treatment. In some aspects of the above embodiments, the cancer is platinum-resistant, platinum-sensitive, platinum-sensitive relapsed, platinum-resistant relapsed, platinum-refractory, primary platinum-refractory, or relapsed.

[0282] A combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin may be administered to patients who have previously been treated with bevacizumab. In some embodiments, bevacizumab is administered as a single agent in prior treatment. In some embodiments, bevacizumab is administered as part of a combination therapy in prior treatment.

[0283] FOLR1 immunoconjugates (e.g., IMGN853) can be administered to patients who have not previously been treated with bevacizumab (i.e., patients who are “bevacizumab-naïve”) in combination with anti-VEGF agents, platinum-based agents and / or doxorubicin.

[0284] In some implementations, the cancer is ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer. An anti-FOLR1 immunoconjugate (e.g., IMGN853) combined with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin may be administered to ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer as first-line, second-line, third-line, or fourth-line or later-line therapy. An anti-FOLR1 immunoconjugate (e.g., IMGN853) combined with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin may be administered to ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, or lung cancer as adjuvant or neoadjuvant therapy.

[0285] In some implementations, the cancer is ovarian cancer. In some implementations, the ovarian cancer is epithelial ovarian cancer (EOC). In some implementations, the ovarian cancer (e.g., EOC) is platinum-resistant, relapsed, or refractory. An anti-FOLR1 immunoconjugate (e.g., IMGN853) combined with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin may be administered to the EOC (e.g., platinum-resistant, relapsed, or refractory EOC) as first-line, second-line, third-line, or fourth-line or later-line therapy. An anti-FOLR1 immunoconjugate (e.g., IMGN853) combined with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin may be administered to the EOC (e.g., platinum-resistant, relapsed, or refractory EOC) as adjuvant or neoadjuvant therapy.

[0286] In some implementations, the cancer is peritoneal cancer. In some implementations, the peritoneal cancer is primary peritoneal cancer. Primary peritoneal cancer may be treated with a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as first-line, second-line, third-line, or fourth-line or later-line therapy. Primary peritoneal cancer may also be treated with a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as adjuvant or neoadjuvant therapy.

[0287] In some implementations, the cancer is endometrial cancer. In some implementations, the endometrial cancer is serous endometrial cancer. Serous endometrial cancer may be treated with a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as first-line, second-line, third-line, or fourth-line or later-line therapy. Serous endometrial cancer may be treated with a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) and an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as adjuvant or neoadjuvant therapy.

[0288] In some implementations, the cancer is lung cancer. In some implementations, the lung cancer is non-small cell lung cancer (NSCLC). In some implementations, the lung cancer is adenocarcinoma or bronchioloalveolar carcinoma. Anti-FOLR1 immunoconjugates (e.g., IMGN853) combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin may 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. Anti-FOLR1 immunoconjugates (e.g., IMGN853) combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin may be administered to lung cancer (e.g., NSCLC, adenocarcinoma, or bronchioloalveolar carcinoma) as adjuvant or neoadjuvant therapy.

[0289] In some implementations, the cancer is platinum-refractory. In some implementations, the cancer is primary platinum-refractory. Anti-FOLR1 immunoconjugates (e.g., IMGN853) combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin can be administered to platinum-refractory or primary platinum-refractory cancers as first-line, second-line, third-line, or fourth-line or later-line therapy. Anti-FOLR1 immunoconjugates (e.g., IMGN853) combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin can be administered to platinum-refractory or primary platinum-refractory cancers as adjuvant or neoadjuvant therapy.

[0290] In some implementations, the cancer is platinum-sensitive. Anti-FOLR1 immunoconjugates (e.g., IMGN853) can be administered to platinum-sensitive cancers in combination with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin as first-line, second-line, third-line, or fourth-line or later-line therapy. Anti-FOLR1 immunoconjugates (e.g., IMGN853) can also be administered to platinum-sensitive cancers in combination with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin as adjuvant or neoadjuvant therapy.

[0291] In some implementations, the cancer is metastatic or advanced. Anti-FOLR1 immunoconjugates (e.g., IMGN853) combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, 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. Anti-FOLR1 immunoconjugates (e.g., IMGN853) combined with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin can also be administered to metastatic or advanced cancer as adjuvant or neoadjuvant therapy.

[0292] The administration of anti-FOLR1 immunoconjugates (e.g., IMGN853) in combination with anti-VEGF agents (e.g., bevacizumab), platinum-based agents, and / or doxorubicin as “second-line” therapy includes the following administrations: where the first-line therapy is, for example, the administration of a single agent; or the administration of a combination of agents, surgery, radiation, or a combination thereof.

[0293] The administration of an anti-FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as "third-line" therapy includes the following administrations: where the first-line therapy is, for example, the administration of a single agent; the administration of a combination of agents, surgery, radiation, or a combination thereof, and where the second-line therapy is, for example, the administration of a single agent; the administration of a combination of agents, surgery, radiation, or a combination thereof. Therefore, the administration of an anti-FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as "third-line" therapy includes, for example, administration according to first-line therapy (i.e., administration of a single agent) and second-line therapy (i.e., administration of a combination of agents). The administration of an anti-FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as "third-line" therapy also includes, for example, administration according to first-line therapy (i.e., administration of a combination of agents) and second-line therapy (i.e., administration of a single agent). The administration of an anti-FOLR1 immunoconjugate (e.g., IMGN853) in combination with an anti-VEGF agent (e.g., bevacizumab), a platinum-based agent, and / or doxorubicin as "third-line" therapy also includes, for example, administration based on first-line therapy (i.e., the combination of administered agents) and second-line therapy (i.e., the combination of administered agents).

[0294] In some embodiments, the cancer is a cancer that expresses FOLR1 (a peptide or nucleic acid). In some embodiments, a combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is administered to a patient with increased FOLR1 expression levels, as described, for example, in published U.S. Application No. 2012 / 0282175 or published International Application No. WO 2012 / 135675, both of which are incorporated herein by reference in their entirety. Exemplary antibodies, assays, and kits for detecting FOLR1 are provided in WO 2014 / 036495 and WO 2015 / 031815, both of which are incorporated herein by reference in their entirety. Therefore, in some embodiments, FOLR1 protein expression is measured by immunohistochemistry (IHC) and assigned a staining intensity score and / or staining homogeneity score by comparison with a control (e.g., a calibration control) exhibiting a defined score (e.g., assigning an intensity score to test sample 3 if the intensity is comparable to a grade 3 calibration control, or assigning an intensity (moderate) score to test sample 2 if the intensity is comparable to a grade 2 calibration control). Staining homogeneity that is “non-uniform” (i.e., at least 25% versus less than 75% cell staining) or “uniform” (i.e., at least 75% cell staining) rather than “focal” (i.e., greater than 0% versus less than 25% cell staining) also indicates increased FOLR1 expression. Staining intensity and staining homogeneity scores can be used alone or in combination (e.g., 2 identical, 2 different, 3 identical, 3 different, etc.). In another instance, an increase in FOLR1 expression can be determined by detecting an increase of at least 2, at least 3, or at least 5-fold relative to a control value (e.g., the expression level in tissues or cells from cancer-free tissues or cells with cancers that do not have elevated FOLR1 values). In some implementations, staining uniformity is scored based on the percentage of stained cells.

[0295] In some embodiments, the cancer is cancer expressing FOLR1 at one or higher level (as measured by IHC). In some embodiments, the cancer is cancer expressing FOLR1 at two or higher levels (as measured by IHC). In some embodiments, the cancer is cancer expressing FOLR1 at three or higher levels (as measured by IHC). In some embodiments, the cancer is lung cancer expressing FOLR1 at two or higher levels (as measured by IHC). In some embodiments, the cancer is lung cancer expressing FOLR1 at three or higher levels (as measured by IHC). In some embodiments, the cancer is ovarian cancer expressing FOLR1 at two or higher levels (as measured by IHC). In some embodiments, the cancer is ovarian cancer expressing FOLR1 at three or higher levels (as measured by IHC). In some embodiments, the cancer is endometrial cancer expressing FOLR1 at two or higher levels (as measured by IHC). In some implementations, the cancer is periosteal carcinoma of the uterus expressing FOLR1 at an unequal or higher level (as determined by IHC).

[0296] In some embodiments, at least one cell in the sample obtained from the patient has a FORL1 score of at least 1. In some embodiments, at least one cell in the sample obtained from the patient has a FORL1 score of at least 2 (moderate). In some embodiments, at least one cell in the sample obtained from the patient has a FORL1 score of at least 3.

[0297] In some embodiments, at least 25% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 1. In some embodiments, at least 33% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 1. In some embodiments, at least 50% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 1. In some embodiments, at least 66% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 1. In some embodiments, at least 75% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 1.

[0298] In some embodiments, at least 25% of the cells in the sample obtained from the patient have a FORR1 IHC score of at least 2 (moderate). In some embodiments, at least 33% of the cells in the sample obtained from the patient have a FORR1 IHC score of at least 2 (moderate). In some embodiments, 25-75% of the cells in the sample obtained from the patient have a FORR1 IHC score of at least 2 (moderate). In some embodiments, at least 50% of the cells in the sample obtained from the patient have a FORR1 IHC score of at least 2 (moderate). In some embodiments, at least 66% of the cells in the sample obtained from the patient have a FORR1 IHC score of at least 2 (moderate). In some embodiments, at least 75% of the cells in the sample obtained from the patient have a FORR1 IHC score of at least 2 (moderate).

[0299] In some embodiments, at least 25% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 3. In some embodiments, at least 33% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 3. In some embodiments, at least 50% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 3. In some embodiments, at least 66% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 3. In some embodiments, at least 75% of the cells in the sample obtained from the patient have a FORL1 IHC score of at least 3.

[0300] In one implementation, immunoassay of FOLR1 (by immunohistochemistry) is performed using an H-score. The H-score combines a staining intensity score (e.g., a score from 0 to 3, where 0 represents no staining and 3 represents strong staining) with the percentage of cells that are positive for membrane staining (i.e., homogeneous). The H-score can be calculated as follows: H-score = [0 * (percentage of cells with staining intensity 0)] + [1 * (percentage of cells with staining intensity 1)] + [2 * (percentage of cells with staining intensity 2)] + [3 * (percentage of cells with staining intensity 3)]. Therefore, the H-score can range from 0 (no cell membrane staining) to 300 (staining intensity 3 for all cell membranes).

[0301] VII.B. Administration

[0302] As provided herein, antiFOLR1 immunoconjugates (e.g., IMGN853) may be administered at specific doses and / or at specific time intervals. Administration of antiFOLR1 immunoconjugates (e.g., IMGN853) may be, for example, intravenous or intraperitoneal. Dosage regimens for antiFOLR1 immunoconjugates (e.g., IMGN853) are provided in, for example, WO 2014 / 186403, WO 2015 / 054400 and WO 2015 / 149018, each of which is incorporated herein by reference in its entirety.

[0303] For example, anti-FOLR1 immunoconjugates (e.g., IMGN853) can be administered at doses from about 0.15 mg / kg to about 7 mg / kg, wherein body weight in kilograms is adjusted to ideal body weight (IBW), lean body weight (LBW), body surface area (BSA), or adjusted ideal body weight (AIBW). Anti-FOLR1 immunoconjugates (e.g., IMGN853) can also be administered at doses from about 1 mg / kg to about 6 mg / kg of IBW, LBW, BSA, or AIBW. Anti-FOLR1 immunoconjugates (e.g., IMGN853) can also be administered at doses from about 3 mg / kg to about 6 mg / kg of IBW, LBW, BSA, or AIBW. Anti-FOLR1 immunoconjugates (e.g., IMGN853) can also be administered using divided doses.

[0304] Anti-FOLR1 immunoconjugates (e.g., IMGN853) can be administered at doses of about 0.15 mg / kg to about 7 mg / kg based on total body weight (TBW). Anti-FOLR1 immunoconjugates (e.g., IMGN853) can also be administered at doses of about 1 mg / kg to about 6 mg / kg TBW. Anti-FOLR1 immunoconjugates (e.g., IMGN853) can also be administered at doses of about 3 mg / kg to about 6 mg / kg TBW.

[0305] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every 3 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 5 mg / kg AIBW every 3 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every 3 weeks.

[0306] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every 4 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 5 mg / kg AIBW every 4 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every 4 weeks.

[0307] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 2 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 2.0 mg / kg AIBW every 2 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 2.5 mg / kg AIBW every 2 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 3 mg / kg AIBW every 2 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 3.5 mg / kg AIBW every 2 weeks. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every 2 weeks.

[0308] In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered weekly. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered weekly at a dose of approximately 1.1 mg / kg AIBW. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered weekly at a dose of approximately 1.8 mg / kg AIBW. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered weekly at a dose of approximately 2.0 mg / kg AIBW. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered weekly at a dose of approximately 2.5 mg / kg AIBW.

[0309] In some implementations, anti-FOLR1 immunoconjugates (e.g., IMGN853) are administered weekly for 3 weeks based on a 4-week regimen (e.g., on days 1, 8, and 15 of a 28-day cycle).

[0310] As provided herein, anti-VEGF agents can be administered at specific doses and / or at specific time intervals. Anti-VEGF agents (e.g., bevacizumab) can also be administered in divided doses. Administration of anti-VEGF agents (e.g., bevacizumab) can be, for example, intravenous.

[0311] In some implementations, the anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks. In some implementations, the anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks. In some implementations, the anti-VEGF agent (e.g., bevacizumab) is administered twice every 4 weeks (e.g., on days 1 and 15 of a 28-day cycle).

[0312] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of about 15 mg / kg. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of about 10 mg / kg. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of about 7.5 mg / kg.

[0313] In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of approximately 15 mg / kg every 3 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of approximately 10 mg / kg every 2 weeks. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered twice every 4 weeks at a dose of approximately 10 mg / kg each time. In some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered at a dose of approximately 7.5 mg / kg every 2 weeks.

[0314] 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 2 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 2 weeks.

[0315] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered at a dose of approximately 15 mg / kg every 3 weeks, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered at a dose of approximately 15 mg / kg every 3 weeks, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every 3 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered at a dose of approximately 15 mg / kg every 3 weeks, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 5 mg / kg AIBW every 3 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered at a dose of approximately 15 mg / kg every 3 weeks, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 6 mg / kg AIBW every 3 weeks.

[0316] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 4 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 6 mg / kg AIBW.

[0317] As provided herein, platinum-based preparations may be administered at specific doses and / or at specific time intervals. Administered platinum-based preparations may be, for example, intravenous. Platinum-based preparations may be, for example, carboplatin or cisplatin.

[0318] As provided herein, carboplatin can be administered at specific doses and / or at specific time intervals. Carboplatin can be administered, for example, intravenously.

[0319] In some implementations, carboplatin is administered every 3 weeks.

[0320] The dose can be calculated using the formula based on the patient’s glomerular filtration rate (GFR in mL / min) and the target area of ​​carboplatin injection on the concentration-time curve (AUC in mg / mL·min): Total dose (mg) = (target AUC) × (GFR + 25).

[0321] 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.

[0322] In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 4 mg / mL·min. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 5 mg / mL·min. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 6 mg / mL·min. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL·min.

[0323] In some implementations, carboplatin is administered every 4 weeks.

[0324] In some implementations, carboplatin is used at 360 mg / m². 2 The dosage is as follows. In some embodiments, carboplatin is administered at approximately 300 mg / m². 2 Dosage administration.

[0325] In some implementations, carboplatin is used at 360 mg / m². 2 The dosage is administered every 4 weeks. In some implementations, carboplatin is given at approximately 300 mg / m². 2 The dosage is administered every 4 weeks.

[0326] As provided in this article, cisplatin can be administered at specific doses and / or at specific time intervals. Cisplatin can be administered, for example, intravenously.

[0327] In some implementations, cisplatin is administered every 4 weeks. In other implementations, cisplatin is administered every 3 weeks.

[0328] In some implementations, cisplatin is used at approximately 100 mg / m². 2The dosage is as follows. In some implementations, cisplatin is administered at approximately 75-100 mg / m². 2 The dosage is as follows. In some implementations, cisplatin is administered at approximately 50-70 mg / m². 2 The dosage is as follows. In some implementations, cisplatin is administered at approximately 20 mg / m². 2 Dosage administration.

[0329] In some implementations, cisplatin is used at approximately 100 mg / m². 2 The dosage is administered every 4 weeks. In some implementations, cisplatin is given at approximately 75-100 mg / m². 2 The dosage is administered every 4 weeks.

[0330] In some implementations, cisplatin is used at approximately 50-70 mg / m². 2 The dosage is administered every 3 weeks.

[0331] In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 4 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0332] In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 4 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0333] In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 4 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0334] In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 4 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 5 mg / kg AIBW. In some embodiments, carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 6 mg / kg AIBW.

[0335] 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 producing an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. 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 producing an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 4 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, carboplatin is administered every 3 weeks at a dose producing an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 5 mg / kg AIBW. In some implementations, 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 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 6 mg / kg AIBW.

[0336] 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 producing an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. 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 producing an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 4 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, carboplatin is administered every 3 weeks at a dose producing an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 5 mg / kg AIBW. In some implementations, an anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 15 mg / kg, carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0337] 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 producing an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. 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 producing an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 4 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, carboplatin is administered every 3 weeks at a dose producing an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 5 mg / kg AIBW. In some implementations, 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 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 6 mg / kg AIBW.

[0338] 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 producing an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks. 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 producing an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 4 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, carboplatin is administered every 3 weeks at a dose producing an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of approximately 5 mg / kg AIBW. In some implementations, an anti-VEGF agent (e.g., bevacizumab) is administered every 3 weeks at a dose of about 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 immunoconjugate (e.g., IMGN853) is administered every 3 weeks at a dose of about 6 mg / kg AIBW.

[0339] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every 3 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 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 4 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 6 mg / kg AIBW.

[0340] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every 3 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 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 5 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 6 mg / kg AIBW.

[0341] In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every 3 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 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 5 mg / kg AIBW. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 6 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 6 mg / kg AIBW.

[0342] In some implementations, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks. In some embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 4 mg / kg AIBW, and carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min. In other embodiments, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), and carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 5 mg / kg AIBW. In some implementations, an anti-VEGF agent (e.g., bevacizumab) is administered every 2 weeks at a dose of about 10 mg / kg or about 7.5 mg / kg, or twice every 4 weeks at a dose of about 10 mg / kg each time (e.g., on days 1 and 15 of a 28-day cycle), carboplatin is administered every 3 weeks at a dose that produces an AUC of 7 mg / mL·min, and an anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of about 6 mg / kg AIBW.

[0343] As provided herein, doxorubicin can be administered at specific doses and / or at specific time intervals. Doxorubicin (e.g., pegylated liposomal doxorubicin (PLD)) can be administered, for example, intravenously.

[0344] In some implementations, doxorubicin (e.g., PLD) is administered every 4 weeks.

[0345] In some implementations, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m². 2 Doxorubicin (e.g., PLD) is administered at a dose of approximately 35 mg / m². 2 Doxorubicin (e.g., PLD) is administered at a dose of approximately 40 mg / m². 2 Doxorubicin (e.g., PLD) is administered at a dose of approximately 45 mg / m². 2Doxorubicin (e.g., PLD) is administered at a dose of approximately 50 mg / m². 2 Dosage administration.

[0346] In some implementations, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m². 2 The dosage is administered every 4 weeks. In some implementations, doxorubicin (e.g., PLD) is administered at approximately 35 mg / m². 2 The dosage is administered every 4 weeks. In some implementations, doxorubicin (e.g., PLD) is administered at approximately 40 mg / m². 2 The dosage is administered every 4 weeks. In some implementations, doxorubicin (e.g., PLD) is administered at approximately 45 mg / m². 2 The dosage is administered every 4 weeks. In some implementations, doxorubicin (e.g., PLD) is administered at approximately 50 mg / m². 2 The dosage is administered every 4 weeks.

[0347] In some implementations, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m². 2 The dose is administered every 4 weeks, along with an anti-FOLR1 immunoconjugate (e.g., IMGN853) every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m². 2 The dose is administered every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at a dose of approximately 30 mg / m². 2 The dosage is administered every 4 weeks, and anti-FOLR1 immunoconjugates (e.g., IMGN853) are administered at approximately 5 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 30 mg / m². 2 The dose is administered every 4 weeks and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of approximately 6 mg / kg AIBW.

[0348] In some implementations, doxorubicin (e.g., PLD) is administered at approximately 35 mg / m². 2 The dose is administered every 4 weeks, along with an anti-FOLR1 immunoconjugate (e.g., IMGN853) every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 35 mg / m². 2 The dosage is administered every 4 weeks, and anti-FOLR1 immunoconjugates (e.g., IMGN853) are administered at approximately 4 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 35 mg / kg AIBW. 2The dosage is administered every 4 weeks, and anti-FOLR1 immunoconjugates (e.g., IMGN853) are administered at approximately 5 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 35 mg / kg AIBW. 2 The dose is administered every 4 weeks and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of approximately 6 mg / kg AIBW.

[0349] In some implementations, doxorubicin (e.g., PLD) is administered at approximately 40 mg / m². 2 The dose is administered every 4 weeks, along with an anti-FOLR1 immunoconjugate (e.g., IMGN853) every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 40 mg / m². 2 The dose is administered every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at approximately 4 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 40 mg / kg AIBW. 2 The dosage is administered every 4 weeks, and anti-FOLR1 immunoconjugates (e.g., IMGN853) are administered at approximately 5 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 40 mg / kg AIBW. 2 The dose is administered every 4 weeks and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of approximately 6 mg / kg AIBW.

[0350] In some implementations, doxorubicin (e.g., PLD) is administered at approximately 45 mg / m². 2 The dose is administered every 4 weeks, along with an anti-FOLR1 immunoconjugate (e.g., IMGN853) every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 45 mg / m². 2 The dose is administered every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at approximately 4 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 45 mg / kg AIBW. 2 The dose is administered every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at approximately 5 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 45 mg / kg AIBW. 2 The dose is administered every 4 weeks and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of approximately 6 mg / kg AIBW.

[0351] In some implementations, doxorubicin (e.g., PLD) is administered at approximately 50 mg / m². 2The dose is administered every 4 weeks, along with an anti-FOLR1 immunoconjugate (e.g., IMGN853) every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 50 mg / m². 2 The dose is administered every 4 weeks, and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered at a dose of approximately 4 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 50 mg / m². 2 The dosage is administered every 4 weeks, and anti-FOLR1 immunoconjugates (e.g., IMGN853) are administered at approximately 5 mg / kg AIBW every 4 weeks. In some embodiments, doxorubicin (e.g., PLD) is administered at approximately 50 mg / kg AIBW. 2 The dose is administered every 4 weeks and the anti-FOLR1 immunoconjugate (e.g., IMGN853) is administered every 4 weeks at a dose of approximately 6 mg / kg AIBW.

[0352] In one case, the FOLR1-binding immunoconjugate (e.g., IMGN853) and the anti-VEGF agent are administered simultaneously. In another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the anti-VEGF agent are administered in separate pharmaceutical compositions. In yet another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the anti-VEGF agent are administered in the same pharmaceutical composition. In yet another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the anti-VEGF agent are administered sequentially. In this case, a platinum-based agent or doxorubicin may optionally be administered simultaneously (in the same pharmaceutical composition or separate pharmaceutical compositions) with the anti-FOLR1 immunoconjugate (e.g., IMGN853). Alternatively, a platinum-based agent or doxorubicin may also optionally be administered simultaneously (in the same pharmaceutical composition or separate pharmaceutical compositions) with the anti-VEGF agent. Alternatively, a platinum-based agent or doxorubicin may optionally be administered sequentially with the anti-FOLR1 immunoconjugate (e.g., IMGN853) and / or the anti-VEGF agent in any order.

[0353] In one case, the FOLR1-binding immunoconjugate (e.g., IMGN853) and the platinum-based agent are administered simultaneously. In another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the platinum-based agent are administered in separate pharmaceutical compositions. In yet another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the platinum-based agent are administered in the same pharmaceutical composition. In yet another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and the platinum-based agent are administered sequentially. In this case, the anti-VEGF agent or doxorubicin may optionally be administered simultaneously (in the same pharmaceutical composition or separate pharmaceutical compositions) with the anti-FOLR1 immunoconjugate (e.g., IMGN853). The anti-VEGF agent or doxorubicin may also optionally be administered simultaneously (in the same pharmaceutical composition or separate pharmaceutical compositions) with the platinum-based agent. The anti-VEGF agent or doxorubicin may also optionally be administered sequentially with the anti-FOLR1 immunoconjugate (e.g., IMGN853) and / or the platinum-based agent.

[0354] In one case, the FOLR1-binding immunoconjugate (e.g., IMGN853) and doxorubicin are administered simultaneously. In another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are administered in separate pharmaceutical compositions. In yet another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are administered in the same pharmaceutical composition. In yet another case, the anti-FOLR1 immunoconjugate (e.g., IMGN853) and doxorubicin are administered sequentially. In this case, an anti-VEGF agent or platinum-based agent may optionally be administered simultaneously with the anti-FOLR1 immunoconjugate (e.g., IMGN853) (in the same pharmaceutical composition or separate pharmaceutical compositions). An anti-VEGF agent or platinum-based agent may also optionally be administered simultaneously with doxorubicin (in the same pharmaceutical composition or separate pharmaceutical compositions). An anti-VEGF agent or platinum-based agent may also optionally be administered sequentially with the anti-FOLR1 immunoconjugate (e.g., IMGN853) and / or doxorubicin.

[0355] VII.C. Assessment and Monitoring

[0356] In some embodiments, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is suitable for inhibiting tumor growth. In some embodiments, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is suitable for inducing tumor cell differentiation. In some embodiments, the combination of an anti-FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin is suitable for reducing tumor volume.

[0357] For example, in some implementations, combination therapy with FOLR1 immunoconjugates (e.g., IMGN853) and anti-VEGF agents, platinum-based agents, and / or doxorubicin produces the following %T / C values: less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%.

[0358] In some specific embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with 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, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can reduce tumor size in ST088, OV90, and / or IGROW-1 xenograft models. In some specific embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can reduce tumor size in the H2110 xenograft model.

[0359] In some embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can inhibit metastasis. In some embodiments, the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin can reduce tumorigenicity. The method of use may be in vivo.

[0360] In some embodiments, the FOLR1 immunoconjugate (e.g., IMGN853) produces a synergistic effect in combination with anti-VEGF agents, platinum-based agents, and / or doxorubicin. For example, the combination of an anti-VEGF agent (e.g., bevacizumab) and the FOLR1 immunoconjugate (e.g., IMGN853) can be synergistic because the anti-VEGF agent (e.g., bevacizumab) enhances or strengthens the tumor localization or activity of IMGN853. Therefore, in some embodiments, the anti-VEGF agent (e.g., bevacizumab) is administered prior to the administration of the FOLR1 immunoconjugate (e.g., IMGN853).

[0361] In some embodiments, the combined administration of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin does not produce greater toxicity than the administration of an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In some embodiments, the combined administration of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin does not produce greater toxicity than the administration of an anti-FOLR1 immunoconjugate. In some embodiments, the combined administration of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin does not produce greater toxicity than the administration of an anti-FOLR1 immunoconjugate or an anti-VEGF agent, a platinum-based agent, and / or doxorubicin.

[0362] Each of the above aspects may also include monitoring for cancer recurrence in the subject. Monitoring may be achieved, for example, by assessing progression-free survival (PFS), overall survival (OS), target response rate (ORR), complete response (CR), and partial response (PR). In one implementation, PFS is assessed after treatment initiation. In some implementations, PFS is extended 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, or approximately 3 years compared to the control. In one implementation, PFS is extended by approximately 2.9 months to 3.8 months compared to the control with a treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In one implementation, PFS is extended by at least approximately 3.8 months compared to the control with a treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. In another embodiment, the treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin prolonged PFS by approximately 2.3 months compared to the control. In one embodiment, the treatment regimen combining a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin prolonged PFS by approximately 6 months compared to the control.

[0363] VII.D. Additional Therapies

[0364] In addition to the combination of FOLR1 immunoconjugates (e.g., IMGN853) with anti-VEGF agents, platinum-based agents, and / or doxorubicin, steroids may also be administered. In some embodiments, the administration of steroids in addition to the combination of FOLR1 immunoconjugates (e.g., IMGN853) with anti-VEGF agents, platinum-based agents, and / or doxorubicin results in a reduction of headache compared to the administration of FOLR1 immunoconjugates (e.g., IMGN853) alone with anti-VEGF agents, platinum-based agents, and / or doxorubicin.

[0365] Steroids may be administered concurrently with, before, and / or after the administration of the immunoconjugate. In some embodiments, the steroid is administered approximately one week, five days, three days, two days, one day, or 24 hours before the administration of the immunoconjugate. In some embodiments, the steroid is administered within one day of the administration of the immunoconjugate. In some embodiments, the steroid is administered multiple times. In some embodiments, the steroid is administered approximately one day before and on the same day as the administration of the immunoconjugate. Steroids may be administered via a variety of routes, including, for example, local, pulmonary, oral, parenteral, or intracranial administration. In some embodiments, administration is oral. In some embodiments, administration is intravenous. In some embodiments, administration is both oral and intravenous.

[0366] In some implementations, the steroid is administered as eye drops. In some implementations, the eye drops are preservative-free lubricating eye drops.

[0367] In addition to the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin, another analgesic or other medication for the prevention or treatment of headache may be administered. For example, acetaminophen and / or dephenhydramine may be administered in addition to the combination of a FOLR1 immunoconjugate (e.g., IMGN853) with an anti-VEGF agent, a platinum-based agent, and / or doxorubicin. The analgesic may be administered before, simultaneously with, or after the administration of the immunoconjugate and may be administered via any suitable route of administration. In some embodiments, the analgesic is administered orally.

[0368] The embodiments of this disclosure may also be limited by the following non-limiting examples, which describe in detail 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 the materials and methods can be made without departing from the scope of this disclosure. Example

[0369] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations thereof will be apparent to those skilled in the art and are included within the spirit and scope of this application.

[0370] Example 1

[0371] Combination therapy with IMGN853+PLD is superior to either IMGN853 monotherapy or PLD monotherapy in ST088 epithelial ovarian cancer. It is more active in tumor models.

[0372] The antitumor activity of IMGN853 as monotherapy and in combination with pegylated liposomal doxorubicin (PLD) was evaluated in female SCID mice with ST088 human epithelial ovarian cancer xenografts. CB17SCID mice were randomly assigned to groups (n = 8 mice / group) based on tumor volume and subsequently administered the drug. These groups included a control group administered IMGN853 formulation buffer (the medium). Figure 1 The "control" group in the text, and the IMGN853 single-dose group administered 5 mg / kg every seven days (one week) for two weeks (QWx2). Figure 1 The "IMGN853" in the text), and the PLD single-dose group administered at 4 mg / kg QWx2 ( Figure 1 The group referred to as “PLD” in the text, and the IMGN853+PLD combination group, which was administered with a dose of 5 mg / kg QWx2 and a dose of 4 mg / kg QWx2 of PLD. Figure 1 (IMGN853+PLD in the text).

[0373] Tumor volume was measured in three dimensions using calipers twice weekly. Body weight was measured twice weekly as an indicator of test reagent toxicity. Activity was assessed as described in Bissery et al., Cancer Res. 51:4845-4852 (1991). Figure 1 The results were described.

[0374] IMGN853 administered at 5 mg / kg twice daily (QWx2) was active as monotherapy (T / C 31%, 0 / 8 partial response (PR) and 0 / 8 complete response (CR)). Furthermore, IMGN853 monotherapy was well tolerated, with no significant weight loss observed. PLD administered at 4 mg / kg twice daily (QWx2) was also active as monotherapy (T / C 21%, 0 / 8 PR and 0 / 8 CR). PLD monotherapy produced a minimum median weight loss (BWL) of 19% (day 15). The IMGN853+PLD combination was highly active and more active than IMGN853 and PLD monotherapy (T / C 10%, 0 / 8 PR and 0 / 8 CR). The combination therapy of IMGN853 and PLD produced a weight loss comparable to PLD monotherapy (minimum 16%). See also Figure 1 Therefore, the combination therapy of IMGN853 and PLD improves efficacy without increasing toxicity.

[0375] Example 2

[0376] Combination therapy with IMGN853 (5 mg / kg) and bevacizumab is superior to IMGN853 monotherapy and anti-bevacizumab monotherapy. It is more active in the OV90 ovarian cancer tumor model.

[0377] The antitumor activity of IMGN853 as a monotherapy and in combination with the anti-VEGF antibody bevacizumab was evaluated in female SCID mice with OV90 serous ovarian tumor xenografts. Mice were randomly assigned to groups (n = 6 mice / group) based on tumor volume and subsequently administered the drug on day 14 post-grafting. These groups included a control group receiving a single dose (1X) of IMGN853 formulation buffer. Figure 2A The "mediator" in the text), the IMGN853 single-dose group administered at 5 mg / kg 1X ( Figure 2A The “IMGN853” in the text, and the bevacizumab single-dose group administered at 5 mg / kg 1X ( Figure 2A The group receiving IMGN853 (5 mg / kg 1X dose) and the IMGN853+bevacizumab combination group (5 mg / kg 1X dose) received IMGN853 and IMGN853+bevacizumab combination group (5 mg / kg 1X dose). Figure 2A (IMGN853+bevacizumab).

[0378] Measure the tumor volume in three dimensions using calipers once or twice a week. Tumor volume is calculated using the formula V = length x width x height x 1 / 2 in mm. 3 (Tomayko and Reynolds, Cancer Chemother. Pharmacol. 24:148-54 (1989)). Body weight was measured twice weekly as a toxicity index. Activity was assessed as described by Bissery et al. (1991). Figure 2A The results were described.

[0379] 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)). A single dose of bevacizumab was also active as monotherapy at 5 mg / kg (T / C 37%, 0 / 6 CR, and 0 / 6 TFS). The combination of IMGN853 and bevacizumab (5 mg / kg each) was highly active and more active than either IMGN853 monotherapy or bevacizumab monotherapy alone (T / C 9%, 6 / 6 CR, 1 / 6 TFS). See also Figure 2A All treatments were well tolerated, and no significant weight loss was observed in any treatment group. Therefore, the combination therapy of IMGN853 and bevacizumab improves efficacy without increasing toxicity.

[0380] Example 3

[0381] Combination therapy with IMGN853 (2.5 mg / kg) and bevacizumab is superior to IMGN853 monotherapy and bevacizumab monotherapy. It is more active in the OV90 ovarian cancer tumor model.

[0382] The antitumor activity of IMGN853 as a monotherapy and in combination with the anti-VEGF antibody bevacizumab was evaluated in female SCID mice with OV90 serous ovarian tumor xenografts. Mice were randomly assigned to groups (n = 6 mice / group) based on tumor volume and subsequently administered the drug on day 14 post-grafting. These groups included a control group receiving a single dose (1X) of IMGN853 formulation buffer. Figure 2B The "mediator" in the text), the IMGN853 single-dose group administered at 2.5 mg / kg 1X ( Figure 2B The “IMGN853” in the text, and the bevacizumab single-dose group administered at 5 mg / kg 1X ( Figure 2B The group receiving IMGN853 (bevacizumab) and the IMGN853+bevacizumab combination group (2.5 mg / kg 1X dose) and IMGN853+bevacizumab combination (5 mg / kg 1X dose) received bevacizumab. Figure 2B (IMGN853+bevacizumab).

[0383] Measure the tumor volume in three dimensions using calipers once or twice a week. Tumor volume is calculated using the formula V = length x width x height x 1 / 2 in mm. 3 (Tomayko 1989). Body weight was measured twice weekly as a toxicity index. Activity was assessed as described by Bissery et al. (1991). Figure 2B The results were described.

[0384] At 2.5 mg / kg, a single dose of IMGN853 was active as a monotherapy (T / C 36%, 0 / 6CR, and 0 / 6TFS). At 5.0 mg / kg, a single dose of bevacizumab was active (T / C 31%, 0 / 6CR, and 0 / 6TFS). As monotherapy, bevacizumab showed comparable antitumor activity to IMGN853 at these dose levels; however, neither agent induced sustained tumor growth inhibition or tumor regression. In stark contrast, the combination of IMGN853 and bevacizumab resulted in robust tumor regression in all animals. Figure 2B The combination of IMGN853 and bevacizumab (2.5 mg / kg IMGN853 + 5 mg / kg bevacizumab) was more active than either IMGN853 monotherapy or bevacizumab monotherapy alone (T / C 17%, 6 / 6 CR, and 0 / 6 TFS). See also Figure 2B Clearly, similar combination benefits were achieved when the dose of IMGN853 was further reduced to 1.25 mg / kg. Figure 3 All treatments were well tolerated, and no significant weight loss was observed in any treatment group. Therefore, the combination therapy of IMGN853 and bevacizumab improves efficacy without increasing toxicity.

[0385] Next, the effects of fractionated bevacizumab dosing were examined in animals as a monotherapy and in combination with 3 mg / kg IMGN853, by administering a single dose of 5 mg / kg or two doses of 2.5 mg / kg (QWx2) of bevacizumab. Figure 11A Separate administration did not affect the efficacy of bevacizumab, and a similar (moderate) growth-inhibiting effect was observed after treatment with a single dose of IMGN853. Exposure to both combination regimens resulted in rapid tumor stabilization and significant regression (up to 38% within 10 days of treatment), particularly in the IMGN853 plus 5 mg / kg bevacizumab group, where dual therapy cured all seven animals. Figure 11A Once again, the combination of IMGN853 and bevacizumab was well tolerated.

[0386] Finally, the combination of IMGN853 and bevacizumab was evaluated. Figure 11B The efficacy in the same platinum-resistant PDX model is shown. Unlike the moderate activity seen with IMGN853 monotherapy, single-dose bevacizumab exposure (5 mg / kg, QWx2) resulted in prolonged growth control of these aggressive tumors (data not shown), although no CR was observed during the 102-day study. Consistent with the OV-90 results, the combination of IMGN853 and bevacizumab (5 mg / kg each, QWx2) was superior to either single-dose regimen 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 study revealed a significant reduction in tumor burden in the combination therapy group compared to animals treated with bevacizumab alone. Figure 11B Furthermore, this effect was not summarized in animals treated with a combination of bevacizumab and paclitaxel (10 mg / kg), suggesting that the therapeutic benefits obtained by adding IMGN853 to an anti-angiogenic agent are functionally specific to the ADC molecule.

[0387] Example 4

[0388] Combination therapy with IMGN853 (1.25 mg / kg) and bevacizumab is superior to IMGN853 monotherapy or bevacizumab monotherapy. The combination of bevacizumab and paclitaxel therapy was more active in the OV90 ovarian cancer tumor model.

[0389] The antitumor activity of the combination of IMGN853 and bevacizumab was evaluated in female SCID mice with OV90 serous ovarian tumor xenografts. Mice were randomly assigned to groups (n = 8 mice / group) based on tumor volume and subsequently administered the drug on day 14 post-grafting. All treatments consisted of a single dose (1X). These groups included a control group administered IMGN853 formulation buffer. Figure 3 The "mediator" in the text), the IMGN853 single-dose group administered at 1.25 mg / kg 1X ( Figure 3 The “IMGN853-1.25” in the text, and the paclitaxel single-dose group administered at 10 mg / kg 1X ( Figure 3 The "paclitaxel-10" in the formula, and the bevacizumab single-dose group administered at 5 mg / kg 1X ( Figure 3 The combination of bevacizumab-5 (presumably referring to a specific drug or ingredient) and IMGN853+bevacizumab (presumably referring to a specific drug or ingredient) administered at 1.25 mg / kg 1X and 5 mg / kg 1X, respectively. Figure 3 The “IMGN853+BEV” group, and the paclitaxel + bevacizumab combination group administered at 10 mg / kg 1X and 5 mg / kg 1X, respectively. Figure 3 (PAC+BEV in the text).

[0390] 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 x width x height x 1 / 2 (Tomayko 1989). Body weight was measured twice a week as a toxicity index. Activity was assessed as described by Bissery et al. (1991). Figure 3 The results were described.

[0391] 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 combination of paclitaxel and bevacizumab was active (T / C 12%, 0 / 8 CR, and 0 / 8 TFS). The combination of IMGN853 and bevacizumab was highly active and more active than all monotherapy treatments and the paclitaxel and bevacizumab combination therapy (T / C 5%, 5 / 8 CR, and 0 / 8 TFS). See also Figure 3 All treatments were well tolerated. Therefore, the combination of bevacizumab and IMGN853 was more effective than the combination of bevacizumab and another therapy.

[0392] Example 5

[0393] Combination therapy with IMGN853 and bevacizumab is superior to IMGN853 monotherapy and bevacizumab monotherapy in IGROW-1 It is more active in epithelial ovarian tumor models.

[0394] The antitumor activity of IMGN853 as a monotherapy and in combination with bevacizumab was evaluated in female SCID mice with IGROW-1 ovarian tumor xenografts. Mice were randomly assigned to groups (n = 6 mice / group) based on tumor volume and subsequently administered the drug on day 14 post-grafting. All treatments consisted of a single dose (1X). These groups included a control group administered IMGN853 formulation buffer. Figure 4The "mediator" in the text), the IMGN853 single-dose group administered at 5 mg / kg 1X ( Figure 4 The “IMGN853-5” in the sample, and the bevacizumab single-dose group administered at 5 mg / kg 1X ( Figure 4 The combination of IMGN853 and bevacizumab (5 mg / kg of IMGN853 and 5 mg / kg of bevacizumab) is described in the text. Figure 4 (IMGN853+BEV in the text).

[0395] Measure the tumor volume in three dimensions using calipers once or twice a week. Tumor volume is calculated using the formula V = length x width x height x 1 / 2 1 / 2 in mm 3 (Tomayko 1989). Body weight was measured twice weekly as a toxicity index. Activity was assessed as described by Bissery et al. (1991). Figure 4 The results were described.

[0396] IMGN853 is active as a monotherapy (T / C 20%, 0 / 4 CR, and 0 / 4 TFS). Bevacizumab is inactive as a monotherapy (T / C 51%, 0 / 4 CR, and 0 / 4 TFS). The combination therapy of IMGN853 and bevacizumab is highly active and more active than IMGN853 and bevacizumab monotherapy (T / C 5%, 3 / 6 CR, and 0 / 6 TFS). See also Figure 4 All treatments were well tolerated, and no significant weight loss was observed in any treatment group. Therefore, the combination therapy of IMGN853 and bevacizumab improves efficacy without increasing toxicity.

[0397] Example 6

[0398] Combination therapy with IMGN853 and bevacizumab is superior to IMGN853 monotherapy, bevacizumab monotherapy, and combination therapy with taxanes. The combination of alcohol and bevacizumab therapy was more active in the ST088 epithelial ovarian cancer tumor model.

[0399] The antitumor activity of IMGN853 as monotherapy and in combination with bevacizumab was evaluated in female SCID mice with tumor xenografts derived from ST088 human epithelial ovarian cancer (EOC) patients. CB17 SCID mice were randomly assigned to groups (n = 8 mice / group) based on tumor volume and subsequently administered the drug. These groups included a control group administered IMGN853 formulation buffer (the medium). Figure 5 The "control" group and the IMGN853 single-dose group administered 5 mg / kg QWx2 (in the text) Figure 5 The “IMGN853” in the text, and the bevacizumab single-dose group administered at 5 mg / kg QWx2 ( Figure 5The “Bev” in the text), and the IMGN853 + bevacizumab combination group administered with 5 mg / kg QWx2 of IMGN853 and 5 mg / kg QWx2 of bevacizumab ( Figure 5 (IMGN853+Bev in the text).

[0400] For comparison, another group of mice was administered paclitaxel at 10 mg / kg QWx2, and yet another group of mice was administered a combination of paclitaxel at 10 mg / kg QWx2 and bevacizumab at 5 mg / kg QWx2.

[0401] Tumor volume was measured in three dimensions twice weekly using calipers. Body weight was measured twice weekly as an indicator of toxicity. Activity was assessed as described by Bissery et al. (1991). Figure 5 The results were described.

[0402] IMGN853 administered at 5 mg / kg QWx2 as monotherapy was active (T / C 31%) and showed no regression (0 / 8 PR and 0 / 8 CR). Bevacizumab administered at 5 mg / kg QWx2 as monotherapy was highly active (T / C 6%); however, no regression was observed (0 / 8 PR and 0 / 8 CR). Paclitaxel administered at 10 mg / kg QWx2 was inactive (T / C 71%, 0 / 8 PR and 0 / 8 CR). The combination therapy of paclitaxel and bevacizumab was highly active (T / C 6%, 6 / 8 PR and 0 / 8 CR). The combination therapy of IMGN853 and bevacizumab was also highly active (T / C 3%, 7 / 8 PR and 0 / 8 CR). On the last day of the study (37 vs 463 mm), 3 On day 109 post-drug administration, the median tumor volume in the group treated with the IMGN853 + bevacizumab combination was smaller than that in the group treated with the paclitaxel + bevacizumab combination. See also Figure 5 All treatments were well tolerated, and no significant weight loss was observed in any treatment group.

[0403] Example 7

[0404] The combination of IMGN853 and bevacizumab therapy is superior to IMGN853 monotherapy and bevacizumab monotherapy in H2110 non- It is more active in small cell lung cancer tumor models.

[0405] The antitumor activity of IMGN853 as monotherapy and in combination with bevacizumab was evaluated in female SCID mice with H2110 non-small cell lung cancer (NSCLC) tumor xenografts. Mice were randomly assigned to groups (n = 6–10 mice / group) based on tumor volume and subsequently administered the drug on day 7 post-grafting. All treatments consisted of a single dose (1X). These groups included a control group administered IMGN853 formulation buffer. Figure 6The "mediator" in the text), the IMGN853 single-dose group administered at 3 mg / kg ( Figure 6 The “IMGN853 3 mg / kg” in the text, and the IMGN853 single-dose group administered at 1.5 mg / kg ( Figure 6 The "IMGN8531.5mg / kg" in the text, and the bevacizumab single-dose group administered at 5mg / kg ( Figure 6 The text mentions "bevacizumab 5 mg / kg" and the IMGN853+bevacizumab combination group (administered with 5 mg / kg bevacizumab and 3 mg / kg IMGN853). Figure 6 The "IMGN853 3mg / kg + Bev 5mg / kg" combination, and the IMGN853 + bevacizumab combination group administered with 5mg / kg bevacizumab and 1.5mg / kg IMGN853 ( Figure 6 (The "IMGN8531.5mg / kg+Bev 5mg / kg" in the text).

[0406] Measure the tumor volume in three dimensions using calipers once or twice a week. Tumor volume is calculated using the formula V = length x width x height x 1 / 2 in mm. 3 (Tomayko 1989). Body weight was measured twice weekly as a toxicity index for the test agent. Activity was assessed as described in Bissery et al. (1991). Figure 6 The results were described.

[0407] 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). A single dose of bevacizumab at 5 mg / kg 1X was also active as monotherapy (T / C 22%, 0 / 6 PR, 0 / 6 CR, and 0 / 6 TFS). The combination of 3 mg / kg 1X IMGN853 + 5 mg / kg 1X bevacizumab showed high activity (T / C 0%, 10 / 10 PR, 6 / 10 CR, and 4 / 10 TFS). The combination of 1.5 mg / kg 1X IMGN853 + 5 mg / kg 1X bevacizumab also showed high activity (T / C 9%, 3 / 10 PR, 1 / 10 CR, and 0 / 10 TFS). Significant weight loss was observed. Because the vector treatment group experienced an 11% decrease in weight relative to baseline by day 25 post-vaccination, the weight loss is believed to be disease-related. The IMGN853 3 mg / kg monotherapy group experienced a 9% weight loss by day 42 post-vaccination, while the IMGN853 1.5 mg / kg monotherapy group experienced an 8% weight loss by day 25 post-vaccination. The bevacizumab monotherapy group experienced a 9% weight loss by day 49 post-vaccination. See also Figure 6 The combination therapy of IMGN853 and bevacizumab was well tolerated, and no significant weight loss was observed. Therefore, the combination therapy of IMGN853 and bevacizumab improves efficacy while reducing toxicity.

[0408] Example 8

[0409] The combination of IMGN853 and carboplatin therapy was more effective than the combination of paclitaxel and carboplatin therapy in the OV90 ovarian cancer tumor model. sex.

[0410] The antitumor activity of IMGN853 in combination with carboplatin and in triple combination therapy with carboplatin and bevacizumab was evaluated in female SCID mice with OV90 ovarian tumor xenografts. Mice were randomly assigned to groups (n = 6 mice / group) based on tumor volume and subsequently administered the drug on day 14 post-grafting. All treatments consisted of a single dose (1X). These groups included a control group administered IMGN853 formulation buffer. Figure 7 The "mediator" in the text), the IMGN853 + carboplatin combination group administered at 5 mg / kg 1X and 100 mg / kg 1X respectively ( Figure 7 The "CARBO+IMGN853" combination, administered at 5 mg / kg 1X, 100 mg / kg 1X, and 5 mg / kg 1X respectively, and the IMGN853+carboplatin+bevacizumab triple combination group ( Figure 7The “CARBO+IMGN853+Bev” group and the paclitaxel + carboplatin combination group, administered at 10 mg / kg 1X and 100 mg / kg 1X respectively ( Figure 7 The “CARBO+PAC” combination, and the paclitaxel + carboplatin + bevacizumab triple combination group administered at 10 mg / kg 1X, 100 mg / kg 1X and 5 mg / kg 1X respectively ( Figure 7 (CARBO+PAC+Bev in the text).

[0411] Measure the tumor volume in three dimensions using calipers once or twice a week. Tumor volume is calculated using the formula V = length x width x height x 1 / 2 in mm. 3 (Tomayko 1989). Body weight was measured twice weekly as a toxicity index. Activity was assessed as described by Bissery et al. (1991). Figure 7 The results were described.

[0412] The combination of IMGN853 and carboplatin is highly active (T / C 10%, 3 / 6 CR, and 0 / 6 TFS). The combination of paclitaxel and carboplatin is inactive (45% T / C, 0 / 6 CR, and 0 / 6 TFS). The triple combination of IMGN853, carboplatin, and bevacizumab is highly active (5% T / C, 6 / 6 CR, and 0 / 6 TFS). The triple combination of paclitaxel, carboplatin, and bevacizumab is active (16% T / C, 1 / 6 CR, and 0 / 6 TFS). The combination therapy of IMGN853 and carboplatin, and the triple combination of IMGN853, carboplatin, and bevacizumab, are more active than their equivalent paclitaxel-containing regimens (i.e., more active than paclitaxel + carboplatin and more active than paclitaxel + carboplatin + bevacizumab). See also Figure 7 .

[0413] The triple combination of paclitaxel, carboplatin, and bevacizumab resulted in slightly greater weight loss (BWL, minimum 6.9%) compared to the triple combination of IMGN853, carboplatin, and bevacizumab (2.9% BWL). The minimum BWL of the IMGN853 + carboplatin combination (12.9%) was comparable to that of paclitaxel + carboplatin treatment (11.1%). Therefore, the triple combination therapy of IMGN853, carboplatin, and bevacizumab improves efficacy while reducing toxicity compared to the triple combination therapy of paclitaxel, carboplatin, and bevacizumab.

[0414] Example 9

[0415] Combination therapy with IMGN853 and sildenafil is superior to IMGN853 monotherapy and sildenafil monotherapy in OV90 ovarian function. It is more active in tumor models.

[0416] The antitumor activity of IMGN853 in combination with the anti-VEGF agent sildenafil was evaluated in female SCID mice with OV90 serous ovarian tumor xenografts. Mice were randomly assigned to groups (n = 6 mice / group) based on tumor volume and subsequently administered the drug on day 14 post-grafting. These groups included a control group administered IMGN853 formulation buffer. Figure 8 The "mediator" in the text), the IMGN853 single-dose group administered at 2.5 mg / kg 1x ( Figure 8 The "IMGN853 2.5mg / kg" in the text, and the sildenafil single-dose group administered 1.5mg / kg once daily for 5 days (qdx5) ( Figure 8 The treatment group included "sildenafil 1.5 mg / kg qdx5" and the IMGN853 + sildenafil combination therapy group, which received 2.5 mg / kg 1x IMGN853 and 1.5 mg / kg qdx5 sildenafil. Figure 8 (IMGN853+Sildinibu).

[0417] Measure the tumor volume in three dimensions using calipers once or twice a week. Tumor volume is calculated using the formula V = length x width x height x 1 / 2 in mm. 3 (Tomayko 1989). Body weight was measured twice weekly as a toxicity index for the test agent. Activity was assessed as described in Bissery et al. (1991). Figure 8 The results were described.

[0418] IMGN853 monotherapy was active (T / C 31%, TC 13 days, LCK 0.5, and 0 / 6 PR). Sildirib monotherapy was inactive (T / C 80%, TC 4 days, LCK 0.1, and 0 / 6 PR). The combination of IMGN853 and sildirib was active (T / C 13% and 1 / 6 PR), but TC (47) and LCK (1.7) were greater than those of IMGN853 or sildirib monotherapy. See also Figure 8 All treatments were well tolerated, with minimal weight loss observed.

[0419] Example 10

[0420] Clinical studies evaluating the combination of IMGN853 with bevacizumab, carboplatin, and / or doxorubicin.

[0421] Preclinical studies evaluating the activity of IMGN853 as a single agent and in combination with bevacizumab, carboplatin, or PLD in the aforementioned ovarian cancer xenograft models suggest that the combination of IMGN853 with bevacizumab, carboplatin, and / or PLD is a promising approach for evaluation in clinical trials of epithelial ovarian cancer (EOC) in both recurrent and preclinical settings.

[0422] A phase 1b clinical trial was conducted to evaluate dual combinations of IMGN853 with bevacizumab, carboplatin, and / or PLD in patients with FRα-positive ovarian cancer. The study comprised two parts: a dose-finding part to determine the maximum tolerated dose (MTD) and recommended dose for combinations of IMGN853+bevacizumab, IMGN853+carboplatin, and IMGN853+PLD; and a dose-expansion part. In the dose-expansion part, two expansion groups were evaluated: (1) the combination of IMGN853+bevacizumab in patients who had not previously received bevacizumab treatment (“bevacizumab-naïve”), and (2) the combination of IMGN853+bevacizumab in patients who had previously received bevacizumab treatment. Other possible groups include: (1) the combination of IMGN853 and carboplatin in patients who have not previously received bevacizumab treatment (“bevacizumab-free”); (2) the combination of IMGN853 and PLD in patients who have not previously received bevacizumab treatment (“bevacizumab-free”); (3) the triple combination of IMGN853, bevacizumab, and PLD in patients who have not previously received bevacizumab treatment (“bevacizumab-free”); or (4) the triple combination of IMGN853, bevacizumab, and carboplatin in patients who have never previously received bevacizumab treatment (“bevacizumab-free”). (5) The combination of IMGN853 and carboplatin in patients previously treated with bevacizumab; (6) The combination of IMGN853 and PLD in patients previously treated with bevacizumab; (7) The triple combination of IMGN853, bevacizumab, and PLD in patients previously treated with bevacizumab; or (8) The triple combination of IMGN853, bevacizumab, and carboplatin in patients previously treated with bevacizumab; (9) The triple combination of IMGN853, bevacizumab, and carboplatin; and / or (10) The triple combination of IMGN853, bevacizumab, and PLD. Response to combination therapy was assessed using RECIST and Gynecologic Cancer Intergroup (GCIG) criteria (where appropriate).

[0423] Example 11

[0424] The combination of IMGN853 and carboplatin promotes synergistic growth inhibition and cell cycle perturbation in vitro, and IMGN853 Enhance the antitumor activity of carboplatin in vivo.

[0425] The combination of carboplatin and paclitaxel represents the standard of care for patients with endocrine disorders (EOC) in first-line adjuvant therapy. To test whether co-treatment with IMGN853 could improve the activity of carboplatin in EOC, the combined effect of IMGN853 and carboplatin exposure on inhibiting the growth of the platinum-sensitive ovarian cancer cell line IGROWV-1 was evaluated. IGROWV-1 cells were treated in vitro with escalating concentrations of IMGN853, carboplatin, or both, and the combined activity was assessed using a median effect analysis. Figure 9AThe combination is synergistic, indicating that IMGN853 enhances the effects of platinum compounds in these ovarian tumor cells.

[0426] Cell cycle analysis revealed that carboplatin exposure caused the accumulation of IGROW-1 cells in the S and G2 / M phases. Figure 9B The effects were reported prior to cell death induced by the agent in the ovarian lineage. Based on the well-established antimitotic activity of maytansine alkaloids, treatment with IMGN853 alone resulted in enrichment of cells in G2 / M. Consistent with these results, co-treatment with both agents resulted in accumulation in almost half of all viable cells in G2 / M. Changes in the expression of phosphorylated histone H2AX (γH2AX) were also examined. γH2AX is a sensitive indicator of DNA damage in response to alkylating agents or as a result of mitotic catastrophe. Single-dose IMGN853 treatment induced γH2AX expression in IGROV-1 cells to levels higher than those seen after carboplatin exposure alone. Combination therapy enhanced the degree of γH2AX upregulation, indicating enhanced DNA damage and consistent with a catastrophic phenotype. Figure 9C ).

[0427] To examine whether these in vitro cellular effects translate to improved efficacy in vivo, mice with patient-derived xenografts (PDX) obtained from individuals with endocrine disorders (EOC) were treated with IMGN853 and carboplatin as single agents and in combination. Figure 9D Previously established, IMGN853 demonstrated robust single-dose activity in this platinum-sensitive PDX model (data not shown); therefore, a suboptimal dose of IMGN853 was selected to evaluate potential combined efficacy improvements. Animals received single administration of IMGN853 (2.5 mg / kg) or carboplatin (80 mg / kg), with each regimen inhibiting tumor growth as monotherapy (T / C values ​​of 43% and 20%, respectively, on day 39). Consistent with the in vitro results above, concomitant treatment with both agents resulted in a considerable increase in antitumor activity, while tumor growth was inhibited by 97% (i.e., T / C value of 3%). Importantly, the combination of IMGN853 and platinum-based therapy was well tolerated, and no toxicity or weight loss was observed during the study.

[0428] The combined benefits of IMGN853 / carboplatin treatment were compared with clinically relevant chemotherapy combinations in the same PDX model. Animals with tumors received two consecutive weekly doses (QWx2) of carboplatin (80 mg / kg, ip) in combination with paclitaxel (10 mg / kg), PLD (4 mg / kg), or IMGN853 (5 mg / kg) iv. As expected, dual therapy with carboplatin and paclitaxel was effective in this platinum-sensitive model. Figure 9ECombination therapy with carboplatin and PLD (typically shown in the context of platinum-sensitive relapse) also showed activity in inhibiting tumor growth. Clearly, the combination therapy of IMGN853 plus carboplatin induced maximal tumor growth inhibition, including complete remission (CR), in 6 out of 7 tumor-bearing mice. In contrast, only CR was observed in 2 mice with the carboplatin / PLD combination, and none were observed in the carboplatin / paclitaxel treatment group. The carboplatin-paclitaxel dual therapy was well tolerated in this model, although some delayed toxicities were observed in animals in the PLD / carboplatin and IMGN853 / carboplatin treatment groups (data not shown). The higher incidence of CR strongly suggests a more durable response to the combination, and the overall data further support that the combination of IMGN853 and carboplatin improves the response to platinum therapy in EOC.

[0429] Example 12

[0430] Combination therapy with IMGN853 and PLD showed excellent therapeutic activity in platinum-resistant PDX tumors.

[0431] In clinical practice, PLD is a widely used second-line treatment for relapsed and / or platinum-resistant EOC, demonstrating excellent tolerability to doxorubicin. Similar to what has been observed with carboplatin, the combination of IMGN853 and doxorubicin exhibits synergistic antiproliferative activity in the IGROWV-1 cell line in vitro. Figure 10A And it causes a more pronounced S plus G2 / M cell cycle delay ( Figure 10B ).

[0432] To prolong in vitro observation, the combination of IMGN853 and PLD was examined in a platinum-resistant EOC PDX model. Figure 10C When the tumor volume reaches 1500-2000 mm... 3 During this period, the animal undergoing vector therapy progressed rapidly and was removed from the study. IMGN853, administered twice daily (5 mg / kg), inhibited tumor growth by 81% on day 49, and a similar degree of inhibition (83%) was observed when PLD was administered according to the same regimen (4 mg / kg). Even at these effective dose levels, the combination therapy resulted in an improved and sustained antitumor response in this aggressive EOC model, leading to complete elimination of tumor growth. Importantly, all regimens were well tolerated, and the addition of IMGN853 to PLD did not confer additional toxicity or weight changes compared to PLD treatment alone. Figure 10D Therefore, in the context of platinum-resistant diseases, the combination of IMGN853 and PLD results in superior and sustained efficacy compared to the single-agent activity of either compound.

[0433] This study further supports the findings that the synergistic improvement in in vitro antitumor activity observed in the IMGN85 / PLD combination is explained as improved and durable efficacy compared to the corresponding single-agent therapy, and importantly, good tolerability in a platinum-resistant PDX model. Previous reports have described the combination benefit of PLD with another FRα-targeting compound, vintafolide, in a preclinical EOC model, suggesting a late-stage clinical evaluation of that combination in subsequent Phase II and III human trials. Without being bound by theory, IMGN853 possesses a broader spectrum of biological activity relative to vintafolide, including a larger effective payload, longer circulation time, and “bystander cytotoxicity,” i.e., the ability to eradicate adjacent FRα-negative or low-expressing tumor cells. Therefore, these results provide a compelling rationale for the combination of IMGN853 and PLD in EOC patients with relapsed disease.

[0434] Example 13

[0435] The IMGN853-bevacizumab combination induced rapid microvascular destruction and extensive [various adverse events] in OV-90 xenografts. Necrosis

[0436] To enhance our understanding of the mechanisms underlying the superior in vivo efficacy of IMGN853 in the presence of bevacizumab, OV-90 tumors were collected and examined from animals treated with IMGN853 (2.5 mg / kg), bevacizumab (5 mg / kg), or a combination thereof 4 days after administration. Figures 12A-12C It is noteworthy that the combination therapy completely halted tumor growth at this early point in time, as measured by changes in tumor volume, in contrast to the delays observed with the corresponding single-dose administration (e.g., see [reference needed]). Figure 2B H&E staining of the tissue revealed that tumors from combination-treated mice were structurally composed of a large necrotic core surrounded by a smaller edge of living cells at the periphery. Figure 12A This level of cell destruction was not observed in any of the other treatment groups, and this is consistent with the rapid tumor stabilization induced by the dosing regimen. The tumor γH2AX level was then measured by immunoblotting as a pharmacodynamic readout. Figure 12B As expected, γH2AX expression was negligible in tumors from mice treated with the vector, but was strongly induced after single-dose IMGN853 treatment. Consistent with the improvements observed in antitumor activity, the addition of bevacizumab to IMGN853 resulted in a further increase in γH2AX levels relative to those seen with IMGN853 monotherapy.

[0437] Interestingly, upregulation of γH2AX was also observed in tumors after bevacizumab exposure alone, although to a lesser extent than that observed with IMGN853. Figure 12BAlthough genotoxic damage is the primary inducer of γH2AX, the accumulation of this protein can also occur in response to hypoxia. Therefore, this result suggests that increased hypoxia resulting from bevacizumab-induced vascular rupture promotes the amplified distribution of DNA damage. To examine the therapeutically relevant effects on microvessels, immunohistochemical staining with endothelial cell marker CD31 was performed. Figure 12C (See above image). Tumors from control and IMGN853-treated mice exhibited numerous large vessels, which shrank in size and showed loss of luminal integrity after bevacizumab treatment. Clearly, dual administration of IMGN853 with bevacizumab caused significant alterations in the tumor microvascular system. These included a marked reduction in the number of large branching vascular structures, with smaller CD31-stained areas lacking clear lumens and primarily localized in peripheral regions. Further staining of the corresponding tissue samples with anti-maytansin antibody confirmed tumor-directed delivery of IMGN853 in mice treated with an ADC-containing regimen. Figure 12C (See the image below).

[0438] Without being bound by theory, it is possible that the presence of bevacizumab promotes better tumor penetration and exposure to ADCs, resulting in more effective tumor cell eradication. In this regard, bevacizumab treatment has been well-established to induce normalization of the tumor vascular system, i.e., an effect shown to cause reduced interstitial pressure and improved drug delivery. However, there are preclinical and clinical observations of reduced tumor uptake of both chemotherapeutic drugs and antibodies following anti-angiogenic therapy.

[0439] ***

[0440] It should be understood that the detailed description section, not the summary and abstract section, is intended to interpret the claims. The summary and abstract section may list one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors, and therefore is not intended to limit the invention or the appended claims in any way.

[0441] The invention has been illustrated above with diagrams showing the performance of specified functions and their relationships among functional building blocks. For ease of explanation, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined, provided that the specific functions and their relationships are performed appropriately.

[0442] The foregoing description of the specific embodiments fully discloses the general nature of the invention, enabling others to readily improve and / or modify various applications of these specific embodiments by applying knowledge in the art, without excessive experimentation and without departing from the general conception of the invention. Therefore, based on the teachings and guidance provided herein, such improvements and modifications are intended to be covered within the equivalent meaning and scope of the disclosed embodiments. It should be understood that the wording or terminology herein is for descriptive purposes only and not restrictive; thus, the terminology or terminology in this specification should be interpreted by those skilled in the art based on the teachings and guidance.

[0443] The breadth and scope of this invention should not be limited by any of the above exemplary embodiments, but should be defined only by the appended claims and their equivalents.

[0444] Biological Preservation Information:

[0445] Accession Number: PTA-10772 Institution: American Center for Type Culture Collection (ATCC) Address: Manassas, Virginia, USA Date of Accession: 2010-04-07

[0446] Classification and nomenclature: Recombinant plasmid DNA, phMov19HCv1.0CTK

[0447] Accession Number: PTA-10773 Institution: American Center for Type Culture Collection (ATCC) Address: Manassas, Virginia, USA Date of Accession: 2010-04-07

[0448] Classification and nomenclature: Recombinant plasmid DNA, phMov19LCv1.0

[0449] Accession Number: PTA-10774 Institution: American Center for Type Culture Collection (ATCC) Address: Manassas, Virginia, USA Date of Accession: 2010-04-07

[0450] Classification and nomenclature: Recombinant plasmid DNA, phMov19 LCv1.6.

Claims

1. The use of a combination of a folic acid receptor 1 (FOLR1) immunoconjugate and an anti-VEGF antibody for the manufacture of a medicament for the treatment of patients with ovarian cancer, peritoneal cancer, fallopian tube cancer, and non-small cell lung cancer, wherein (a) the immunoconjugate comprises Ab is an anti-FOLR1 antibody, which contains 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, and M + It is H + Or Na + Or other pharmaceutically acceptable cations, and (b) The anti-VEGF antibody is bevacizumab; and (c) wherein the cancer expresses FOLR1.

2. The use of claim 1, wherein the antiFOLR1 antibody or its antigen-binding fragment comprises VH of the sequence shown in SEQ ID NO:3 and VL of the sequence shown in SEQ ID NO:

5.

3. The use of claim 2, wherein the immunoconjugate is administered once every three weeks at a dose of 6 mg / kg adjusted ideal body weight (AIBW).

4. The use of claim 2, wherein the immunoconjugate is administered once every three weeks at a dose of 5 mg / kg AIBW.

5. The use of claim 2, wherein the anti-VEGF antibody is administered at a dose of 15 mg / kg every 3 weeks.

6. The use according to claim 2, wherein the immunoconjugate is administered intravenously every three weeks at a dose of 6 mg / kg adjusted to ideal body weight (AIBW), and wherein the anti-VEGF antibody is administered every three weeks at a dose of 15 mg / kg.

7. The use according to claim 2, wherein the immunoconjugate is administered intravenously every three weeks at a dose of 5 mg / kg adjusted to ideal body weight (AIBW), and wherein the anti-VEGF antibody is administered every three weeks at a dose of 15 mg / kg.

8. Use according to any one of claims 1-7, wherein the antiFOLR1 antibody comprises (i) a heavy chain comprising an amino acid sequence identical to that encoded by plasmid PTA-10772 deposited at the American Type Culture Collection (ATCC), and (ii) a light chain comprising an amino acid sequence identical to that encoded by plasmid PTA-10774 deposited at the ATCC.

9. Use according to any one of claims 1-7, wherein the cancer is ovarian cancer.

10. Use according to any one of claims 1-7, wherein the expression of said FOLR1 is measured by immunohistochemistry (IHC).

11. The use of claim 10, wherein at least 25% of the cells obtained from the sample of said cancer have an IHC score of at least 2.

12. The use of claim 11, wherein at least 50% of the cells obtained from the sample of said cancer have an IHC score of at least 2.

13. The use of claim 12, wherein at least 75% of the cells obtained from the sample of said cancer have an IHC score of at least 2.

14. Use according to any one of claims 1-7, wherein the cancer has been previously treated with bevacizumab.

15. Use according to any one of claims 1-7, wherein the cancer has not been previously treated with bevacizumab.

16. Use according to any one of claims 1-7, wherein the immunoconjugate comprises 3 to 4 maytansine alkaloids per antibody.

17. The use according to any one of claims 1-7, wherein the cancer is a primary platinum-resistant cancer.

18. Use according to any one of claims 1-7, wherein said cancer is platinum resistant.

19. The use according to any one of claims 1-7, wherein the cancer is platinum sensitive.

20. The use according to any one of claims 1-7, wherein the drug is used as a first-line, second-line, third-line, fourth-line, or fifth-line therapy.

21. Use of a combination of a folic acid receptor 1 (FOLR1) immunoconjugate and an anti-VEGF antibody and a platinum-based agent for the manufacture of a medicament for the treatment of patients with ovarian cancer, peritoneal cancer, fallopian tube cancer, and non-small cell lung cancer, wherein (a) the immunoconjugate comprises Ab is an anti-FOLR1 antibody, which contains 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, 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, and M + It is H + Or Na + Or other pharmaceutically acceptable cations, and (b) The anti-VEGF antibody is bevacizumab. (c) wherein the cancer expresses FOLR1, and (d) wherein the platinum-based agent is carboplatin, cisplatin or oxaliplatin.

22. The use of claim 21, wherein the antiFOLR1 antibody or its antigen-binding fragment comprises the VH of the sequence of SEQ ID NO:3 and the VL of the sequence of SEQ ID NO:

5.

23. The use of claim 22, wherein the immunoconjugate is administered once every three weeks at a dose of 6 mg / kg adjusted ideal body weight (AIBW).

24. The use of claim 22, wherein the immunoconjugate is administered once every three weeks at a dose of 5 mg / kg AIBW.

25. The use of claim 22, wherein the anti-VEGF antibody is administered at a dose of 15 mg / kg every 3 weeks.

26. The use according to claim 22, wherein the immunoconjugate is administered intravenously once every three weeks at a dose of 6 mg / kg adjusted ideal body weight (AIBW), and wherein the anti-VEGF antibody is administered once every three weeks at a dose of 15 mg / kg.

27. The use according to claim 22, wherein the immunoconjugate is administered intravenously every three weeks at a dose of 5 mg / kg adjusted to ideal body weight (AIBW), and wherein the anti-VEGF antibody is administered every three weeks at a dose of 15 mg / kg.

28. The use according to any one of claims 21-27, wherein the antiFOLR1 antibody comprises (i) a heavy chain comprising the same amino acid sequence as the heavy chain encoded by plasmid PTA-10772 deposited at the American Center for Type Culture Collection (ATCC), and (ii) a light chain comprising the same amino acid sequence as the light chain encoded by plasmid PTA-10774 deposited at ATCC.

29. The use of any one of claims 21-27, wherein the platinum-based agent is carboplatin.

30. The use of claim 29, wherein the carboplatin is administered at a dose to obtain an area under the curve (AUC) of 4 mg / ml·min.

31. The use according to claim 29, wherein the carboplatin is administered at a dose of 5 mg / ml·min to obtain an AUC.

32. The use of claim 29, wherein carboplatin is administered once every three weeks.

33. Use according to any one of claims 21-27, wherein the cancer is ovarian cancer.

34. The use of any one of claims 21-27, wherein the expression of said FOLR1 is measured by immunohistochemistry (IHC).

35. The use of claim 34, wherein at least 25% of the cells obtained from the sample of said cancer have an IHC score of at least 2.

36. The use of claim 35, wherein at least 50% of the cells obtained from the sample of said cancer have an IHC score of at least 2.

37. The use of claim 35, wherein at least 75% of the cells obtained from the sample of said cancer have an IHC score of at least 2.

38. Use according to any one of claims 21-27, wherein the cancer has been previously treated with bevacizumab.

39. Use according to any one of claims 21-27, wherein the cancer has not been previously treated with bevacizumab.

40. Use according to any one of claims 21-27, wherein the immunoconjugate comprises from 3 to 4 maytansine alkaloids per antibody.

41. The use according to any one of claims 21-27, wherein the cancer is primary platinum-resistant cancer.

42. Use according to any one of claims 21-27, wherein said cancer is platinum resistant.

43. The use according to any one of claims 21-27, wherein the cancer is platinum sensitive.

44. The use according to any one of claims 21-27, wherein the drug is used as a first-line, second-line, third-line, fourth-line, or fifth-line therapy.

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