Anti-folr1 immunoconjugate dosing regimen

Abstract

This article provides a method for administering an immunoconjugate that binds to FOLR1. The method comprises administering an anti-FOLR1 immunoconjugate to a person in need, such as a cancer patient, using a therapeutically effective dosing regimen that produces minimal side effects.

Description

[0001] This application is a divisional application of patent application No. 201480055444.3, filed on October 8, 2014, by Immunogen Corporation, entitled "Anti-FOLR1 Immunoconjugate Dosing Regimen". Invention Field The field of this invention generally relates to methods of administering anti-FOLR1 immunoconjugates for the treatment of diseases such as cancer. The methods provide dosing regimens that minimize unwanted side effects. Background of the Invention Cancer is one of the leading causes of death in developed countries, with more than one million people diagnosed with cancer and 500,000 deaths annually in the United States alone. Overall, it is estimated that more than one-third of people will develop some form of cancer in their lifetime. There are more than 200 different types of cancer, four of which—breast cancer, lung cancer, colorectal cancer, and prostate cancer—account for more than half of all new cases (Jemal et al., 2003). Cancer J. Clin. 53:5-26).

[0002] Folate receptor 1 (FOLR1) (also known as folate receptor-α or folate-binding protein) is an N-glycosylated protein expressed on the cell membrane. FOLR1 has a high affinity for folate and several reduced folate derivatives. FOLR1 mediates the delivery of physiological folate (5-methyltetrahydrofolate) into the cell.

[0003] FOLR1 is overexpressed in the vast majority of ovarian cancers and in many types of uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, lung cancer, and breast cancer. In normal tissues, however, FOLR1 expression is limited to the proximal tubules of the kidney, alveolar cells of the lung, bladder, testis, choroid plexus, and the apical membrane of epithelial cells in the thyroid gland (Weitman SD et al.). Cancer Res 52:3396-3401 (1992); Antony AC, Annu Rev Nutr 16: 501-521 (1996); Kalli KR wait, Gynecol Oncol 108: 619-626 (2008)). This expression pattern of FOLR1 makes it an ideal target for FOLR1-guided cancer therapy.

[0004] Because ovarian cancer is often asymptomatic before its advanced stages, it is frequently diagnosed at an advanced stage and has a poor prognosis when treated with currently available procedures (usually chemotherapy following surgical debulking). Wait, Cancer 112: 2221-2227 (2008); Ayhan A Wait, Am J Obstet Gynecol 196:81 e81-86 (2007); Harry VN Etc., Obstet Gynecol Surv 64: 548-560 (2009)). Therefore, there is a significant unmet medical need for more effective treatments for ovarian cancer.

[0005] Antibodies are emerging as a promising approach for treating this type of cancer. Furthermore, immunoconjugates containing antibodies conjugated to other compounds, such as cytotoxins, are being investigated as potential therapeutic agents. Specifically, immunoconjugates containing maytansinoids (a plant-derived antifungal and antitumor agent) have shown some beneficial activity. From *Maytansinus ovatus* (… Maytenus ovatus ) and Buchananmedenmu ( Maytenus buchananii The isolation of three ansa macrolides by alcoholic extracts of FOLR1 was first reported by SM Kupchan et al., and together with the demonstrated anti-leukemic activity in mouse models at doses in the microgram / kg range, is the subject of U.S. Patent No. 3,896,111. However, maytansine exhibits unacceptable toxicity, causing central and peripheral neuropathy and side effects: specifically nausea, vomiting, diarrhea, elevated liver function tests, and less commonly, asthenia and somnolence. This overall toxicity is mitigated to some extent by conjugating maytansine to antibodies, as the antibody-drug conjugate exhibits several orders of magnitude lower toxicity on antigen-negative cells compared to antigen-positive cells. However, specific dosage regimens for anti-FOLR1 immunoconjugates that are effective in human treatment while avoiding side effects still need to be identified. Invention Overview This document provides a method for administering an antiFOLR1 immunoconjugate using a therapeutically effective dosing regimen that minimizes unwanted side effects. As described in more detail below, administering the same dose of the antiFOLR1 immunoconjugate to different patients causes significant changes in the pharmacokinetics (e.g., Cmax and AUC) of the immunoconjugate. The inventors have discovered, and experimental evidence provided herein, that ocular toxicity is associated with high Cmax and high initial AUC values. However, high Cmax and initial AUC values ​​are undesirable for efficacy. Therefore, this document describes a method for treating a patient with cancer, the method comprising administering to the patient an effective dose of an antiFOLR1-binding immunoconjugate, wherein the immunoconjugate is administered at a dose of about 3.0 mg / kg to about 7.0 mg / kg, wherein the kilogram of body weight is adjusted to ideal body weight (IBW), lean body weight (LBW), or adjusted ideal body weight (ADJ or AIBW). The abbreviations “ADJ” and “AIBW” are used interchangeably to refer to adjusted ideal body weight. In some embodiments, kilograms are adjusted to AIBW (ADJ). Furthermore, this document describes a method for treating a patient with cancer, the method comprising administering to the patient an effective dose of an immunoconjugate binding to FOLR1, wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule (e.g., on days 1, 8, and 15 of the four-week schedule). This document also describes a method for treating a patient with cancer, the method comprising administering to the patient an effective dose of an immunoconjugate binding to FOLR1, wherein the immunoconjugate is administered at a dose of about 1 to about 7 mg / kg, wherein the kg is adjusted to IBW, LBW, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule (e.g., on days 1, 8, and 15 of the four-week schedule). The methods described herein may result in a reduction of toxicities (e.g., ocular toxicity).

[0006] Furthermore, this document describes a method for treating a patient with cancer, the method comprising administering to the patient an effective dose of an immunoconjugate binding to FOLR1, wherein the Cmax value and initial AUC value leading to toxicity are not exceeded. For example, in some embodiments, the administration produces a Cmax of approximately 90-160 µg / mL, and in some embodiments, the administration produces a Cmax of approximately 110-160 µg / mL. In some embodiments, the administration produces an AUC not exceeding 2785 hr•µg / mL. 0-24 In some implementations, administration produces an AUC not exceeding 2741 hr•µg / mL. 0-24 In some implementations, administration produces an AUC not exceeding 2700 hr•µg / mL. 0-24In some embodiments, the application produces a Cmax of no more than 160 µg / mL. In some embodiments, the application produces a Cmax of no more than 150 µg / mL.

[0007] In some implementations, administration produces an AUC of approximately 1000-3500 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-3000 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-2785 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-2741 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-2700 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-2500 hr•µg / mL. 0-24 In some implementations, the administration produces an AUC not exceeding 1500-3500 hr•µg / mL. 0-24 In some implementations, the administration produces an AUC not exceeding 1500-3000 hr•µg / mL. 0-24 In some implementations, administration produces an AUC not exceeding 1500-2785 hr•µg / mL. 0-24 In some implementations, administration produces an AUC not exceeding 1500-2741 hr•µg / mL. 0-24 In some implementations, the administration produces an AUC not exceeding 1500-2700 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1500-2500 hr•µg / mL. 0-24 .

[0008] In some embodiments, the application produces a Cmax of 110-160 µg / mL. In some embodiments, the application produces a Cmax of 110-150 µg / mL. In some embodiments, the application produces a Cmax of 110-140 µg / mL. In some embodiments, the application produces a Cmax of 120-160 µg / mL. In some embodiments, the application produces a Cmax of about 120-150 µg / mL. In some embodiments, the application produces a Cmax of about 120-140 µg / mL. In some embodiments, the application produces a Cmax of 90-160 µg / mL. In some embodiments, the application produces a Cmax of about 90-150 µg / mL. In some embodiments, the application produces a Cmax of about 90-140 µg / mL. In some embodiments, the application produces a Cmax of 100-160 µg / mL. In some embodiments, the application produces a Cmax of about 100-150 µg / mL. In some implementations, the application produces a Cmax of approximately 100-140 µg / mL.

[0009] The anti-FOLR1 immunoconjugate may include a charged linker. In some embodiments, the anti-FOLR1 immunoconjugate includes the antibody huMov19, the linker sulfonyl-SPDB, and maytanyl DM4.

[0010] In some embodiments, the immunoconjugate comprises an antibody or an antigen-binding fragment thereof that competitively inhibits the binding of an antibody having the variable region sequences of SEQ ID NO:3 and SEQ ID NO:5 to FOLR1. In some embodiments, the antibody or fragment thereof comprises the CDRs of huMOV19 (i.e., SEQ ID NO: 6-10 and 12 or SEQ ID NO: 6-9, 11 and 12). In some embodiments, the antibody or antigen-binding fragment thereof comprises the variable region sequences of huMOV19 (i.e., SEQ ID NO: 3 and 5). In some embodiments, the antibody or fragment does not comprise the six CDRs of mouse Mov19 (i.e., SEQ ID NO: 6-9, 16 and 12). In some embodiments, the antibody is huMov19. In some embodiments, the immunoconjugate comprises maytansine. In some embodiments, maytansine is DM4. In some embodiments, the immunoconjugate comprises a linker for sulfonyl-SPDB. In some embodiments, the immunoconjugate is IMGN853 (huMov19-sulfonyl-SPDB-DM4).

[0011] In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 1 to 7 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 1.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 1.1 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 1.5 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 1.8 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 2.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 2.5 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 2.8 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 3.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 3.3 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ).In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 3.75 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 4.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 4.1 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 4.2 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 5 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 5.5 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 5.6 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 6 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is administered at a dose of about 6.5 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 7 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, the kilogram body weight is adjusted to AIBW (ADJ).

[0012] According to the methods described herein, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) may be applied approximately every 4 weeks. In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is applied approximately every 3 weeks. In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is applied approximately every 2 weeks. In some embodiments, the anti-FOLR1 binder (e.g., huMov19-sulfon-SPDB-DM4) is applied approximately every 1 week.

[0013] In some embodiments, the immunoconjugate is administered once weekly for three weeks at a dose of about 1 to 7 mg / kg according to a four-week schedule. In some embodiments, the immunoconjugate is administered once weekly for three weeks at a dose of about 1.5 mg / kg to about 6 mg / kg according to a four-week schedule. In some embodiments, the immunoconjugate is administered once weekly for three weeks at a dose of about 1.5, 2.0, 2.5, 3, 3.75, 4.0, 4.1, 4.2, 5.0, 5.5, or 6.0 mg / kg according to a four-week schedule. In some embodiments, the immunoconjugate is administered once weekly for three weeks at a dose of about 1.1, 1.8, 2.5, 3.3, or 4.2 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of about 1.0 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 1.1 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 1.5 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 1.8 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 2 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 2.5 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 2.8 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 binder is administered once weekly for three weeks at a dose of approximately 3.0 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 3.3 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 3.75 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 binder is administered once weekly for three weeks at a dose of approximately 4.0 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 4.1 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 4.2 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 5 mg / kg according to a four-week schedule.In some embodiments, the anti-FOLR1 binder is administered once weekly for three weeks at a dose of approximately 5.5 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 5.6 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 6 mg / kg according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate is administered once weekly for three weeks at a dose of approximately 7 mg / kg according to a four-week schedule.

[0014] In some embodiments, the immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 1 to 7 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 1.5 mg / kg to about 6 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 1 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 1.1 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 1.5 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 1.8 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 2 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 2.5 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once a week for three weeks according to a four-week schedule.In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 2.8 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 3 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 3.3 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 3.75 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 4 mg / kg, wherein the kilogram is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 4.1 mg / kg, wherein the kilogram is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 4.2 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 5 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule.In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 5.5 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 5.6 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 6 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 6.5 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfonyl-SPDB-DM4) is administered at a dose of about 7 mg / kg, wherein the kg is adjusted to IBW, LBW, BSA, or AIBW (ADJ), and wherein the immunoconjugate is administered once weekly for three weeks according to a four-week schedule. In some implementations, kilograms are adjusted to AIBW (ADJ).

[0015] In some embodiments, the FOLR1 binder is applied to obtain the AUC obtained in Examples 1-6 and shown in Figures 1-2 and 7-12.

[0016] In some embodiments, the FOLR1 binder is applied to obtain the Cmax obtained in Examples 1-6 and shown in Figures 1-6 and 9-12.

[0017] In some implementations, the anti-FOLR1 binder (e.g., huMov19-sulfonyl-SPDB-DM4) is administered intravenously.

[0018] The methods described herein can be used to treat cancer. In some embodiments, the cancer is selected from the group consisting of: ovarian cancer, brain cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, kidney cancer (e.g., renal cell carcinoma), and lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, or bronchioloalveolar carcinoma (BAC)). In some embodiments, the cancer is ovarian cancer or lung cancer. In some embodiments, the cancer is epithelial ovarian cancer.

[0019] In some embodiments, the cancer expresses the FOLR1 peptide or nucleic acid. In some embodiments, the cancer has an increased FOLR1 peptide expression level, as measured by immunohistochemistry (IHC). For example, in some embodiments, the cancer expresses the FOLR1 peptide at a heterogeneous level of 1 or higher as measured by IHC. In some embodiments, the cancer expresses the FOLR1 peptide at a homogeneous level of 1 or higher as measured by IHC. In some embodiments, the cancer expresses the FOLR1 peptide at a heterogeneous level of 2 or higher as measured by IHC. In some embodiments, the cancer expresses the FOLR1 peptide at a homogeneous level of 2 or higher as measured by IHC. In some embodiments, the cancer expresses the FOLR1 peptide at a heterogeneous level of 3 or higher as measured by IHC. In some embodiments, the cancer expresses the FOLR1 peptide at a homogeneous level of 3 or higher as measured by IHC. In some embodiments, the cancer is lung cancer expressing the FOLR1 peptide at a heterogeneous level of 2 or higher as measured by IHC. In some embodiments, the cancer is lung cancer expressing the FOLR1 peptide at a heterogeneous level of 3 or higher as measured by IHC. In some embodiments, the cancer is epithelial ovarian cancer expressing FOLR1 peptide at a heterogeneous level of 2 or higher (e.g., platinum-resistant, relapsed, or refractory). In some embodiments, the cancer is epithelial ovarian cancer expressing FOLR1 peptide at a heterogeneous level of 3 or higher (e.g., platinum-resistant, relapsed, or refractory). In some embodiments, the cancer is endometrial cancer expressing FOLR1 peptide at a heterogeneous level of 1 or higher. In some embodiments, the cancer is endometrial cancer expressing FOLR1 peptide at a heterogeneous level of 2 or higher.

[0020] In some implementations, the method further includes administering a steroid to the patient. The steroid may be administered as pretreatment (i.e., prior to the administration of an anti-FOLR1 binder). The steroid may be dexamethasone.

[0021] The methods described herein can reduce tumor size. The methods described herein can reduce CA125 levels in patients with ovarian cancer. In one instance, CA125 levels in samples from ovarian cancer patients were measured once or multiple times before and after treatment, and a decrease in CA125 levels over time indicated treatment efficacy. The methods described herein can increase the time between cancer treatments. The methods described herein can increase progression-free survival (PFS). The methods described herein can increase disease-free survival (DFS). The methods described herein can increase overall survival (OS). The methods described herein can increase complete response (CR). The methods described herein can increase partial response (PR). The methods described herein can increase stable disease (SD). The methods described herein can increase the reduction in progressive disease (PD). The methods described herein can reduce time to progression (TTP).

[0022] Specifically, the dosing regimens provided herein achieve an optimal balance between efficacy (e.g., PR) and reduced toxicity, as illustrated, for example, in Examples 1-4 and Figures 1-7. Brief description of the attached diagram Figure 1A and 1B Pharmacokinetic data from administration of IMGN853 (0.15 mg / kg to 7.0 mg / kg) are provided as described in Example 1. Figure 1B Provided including from Figure 1A A summary of pharmacokinetic data from the data obtained from other patients will follow later.

[0023] Figures 2A-2C show the results for a series of Cmax and AUC. 0-24 and AUC 0-168 The patient's reaction and the occurrence of ocular toxicity under certain conditions.

[0024] Figure 3 The range of Cmax values ​​measured at different doses is shown.

[0025] Figure 4 The dependence of Cmax on patient weight is shown.

[0026] Figure 5 The Cmax and AUC related to alternative dosing methods are shown. 0-24 The changes.

[0027] Figure 6 The predicted dependence of Cmax on body weight is shown when using alternative dosing methods.

[0028] Figure 7The AUC observed in 24 patients who received 3.3, 5, or 7 mg / kg IMGN853 based on their total weight (actual) is shown. 0-24 The values ​​are plotted. These values ​​are compared to the projected values ​​for all patients treated with a total repetition dose of 5 mg / kg (TBW 5 mg / kg) and the projected values ​​for all patients treated with 5, 5.4, or 6 mg / kg (ADJ 5, 5.4, or 6) based on adjusted ideal body weight. Actual data for 7 patients treated with 5 mg / kg / adjusted ideal body weight (5 ADJ actual) are also shown. The percentage of patients with or expected to have AUC values ​​above the ocular toxicity threshold is shown in the table below the plot.

[0029] Figure 8 The AUC for all patients administered 3.3–7.0 mg / kg is shown. 0-24 Values. The TBW group is used to calculate the predicted AUC at the indicated dose level. 0-24 Values. Actual patient AUCs for the indicated doses were also plotted. 0-24 Data includes patients who have been treated to date in the 5.0 and 6.0 adjusted ideal body weight (AIBW) groups.

[0030] Figure 9 The antitumor activity, predicted plasma concentrations, and other pharmacokinetic parameters of IMGN853 in mice treated with a single dose of the immunoconjugate at 2.8 mg / kg, 5.6 mg / kg, or 8.5 mg / kg are shown.

[0031] Figure 10 The antitumor activity, predicted plasma concentrations, and other pharmacokinetic parameters of IMGN853 are shown in mice treated with a single dose of 8.5 mg / kg, three daily doses of 2.8 mg / kg, or three doses of 2.8 mg / kg every three days.

[0032] Figure 11 The antitumor activity, predicted plasma concentrations, and other pharmacokinetic parameters of IMGN853 in mice treated with a single daily dose of 5.6 mg / kg or 1.4 mg / kg for three consecutive days are shown.

[0033] Figure 12 The antitumor activity, predicted plasma concentrations, and other pharmacokinetic parameters of IMGN853 in mice treated with a single dose of 8.5 mg / kg or 2.8 mg / kg weekly for three weeks are shown. Invention Details This invention provides a novel dosing regimen for FOLR1-binding immunoconjugates.

[0034] I. Definition To aid in understanding this invention, some terms and phrases are defined below.

[0035] Unless otherwise specified, the terms “human folate receptor 1,” “FOLR1,” or “folate receptor α (FR-α)” as used herein refer to any naturally occurring human FOLR1. Therefore, all these terms may refer to the protein or nucleic acid sequence indicated herein. The term “FOLR1” encompasses “full-length” unprocessed FOLR1 as well as any form of FOLR1 produced by intracellular processing. The term also encompasses naturally occurring variants of FOLR1, such as splice variants, allelic variants, and isotypes. The FOLR1 polypeptide described herein may be isolated from a variety of sources, such as human tissue types, or from another source, or prepared by recombinant or synthetic methods. Examples of FOLR1 sequences include, but are not limited to, NCBI reference numbers P15328, NP_001092242.1, AAX29268.1, AAX37119.1, NP_057937.1, and NP_057936.1.

[0036] 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 thereof) by means of at least one antigen recognition site within the variable region of an immunoglobulin molecule. As used herein, the term "antibody" encompasses complete polyclonal antibodies, complete monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single-chain Fv (scFv) mutants, multispecific antibodies (such as bispecific antibodies derived from at least two complete antibodies), chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing the antigenic determinant of an antibody, and any other modified immunoglobulin molecule containing an antigen recognition site, provided that the antibody exhibits the desired biological activity. Antibodies can be any of the five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM (designated α, δ, ε, γ, and μ, respectively, based on the identification of their heavy chain constant regions), or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). 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.

[0037] "Blocking" antibodies or "antagonist" antibodies are antibodies that inhibit or reduce the biological activity of the antigen they bind to, such as FOLR1. In some embodiments, blocking or antagonist antibodies substantially or completely inhibit the biological activity of the antigen. The biological activity can be reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0038] The term "anti-FOLR1 antibody" or "FOLR1-binding antibody" refers to an antibody capable of binding to FOLR1 with sufficient affinity, making the antibody suitable as a diagnostic and / or therapeutic agent targeting FOLR1. The binding degree of an anti-FOLR1 antibody to unrelated non-FOLR1 proteins may be less than about 10% of the antibody binding to FOLR1, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the FOLR1-binding antibody has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM.

[0039] The term "antibody fragment" refers to a portion of a complete antibody and specifically to the antigenic determination 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, single-chain antibodies, and multispecific antibodies formed from antibody fragments.

[0040] "Monoclonal antibody" refers to a homogeneous group of antibodies involved in the highly specific recognition and binding of a single antigenic determinant or epitope. This contrasts with polyclonal antibodies, which typically contain different antibodies targeting different antigenic determinants. The term "monoclonal antibody" encompasses 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 portions, and any other modified immunoglobulin molecules containing antigen recognition sites. Furthermore, "monoclonal antibody" refers to such antibodies formed in any number of ways, including but not limited to hybridomas, phage selection, recombinant expression, and transgenic animals.

[0041] The term "humanized antibody" refers to a non-human (e.g., mouse) antibody form that contains a minimal non-human (e.g., mouse) sequence of specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof. Typically, a humanized antibody is a human immunoglobulin 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., 1986). Nature , 321:522-525; Riechmann et al., 1988, Nature, 332:323-327; Verhoeyen et al., 1988, Science In some cases, Fv framework region (FR) residues of human immunoglobulins are replaced by corresponding residues from antibodies derived from non-human species that have the desired specificity, affinity, and capability. Humanized antibodies can be further modified by substitution of additional residues within the Fv framework region and / or within the replaced non-human residues to improve and optimize antibody specificity, affinity, and / or capability. Generally, humanized antibodies will substantially contain at least all, and typically two or three, variable domains containing all or substantially all of the CDR regions corresponding to non-human immunoglobulins, and all or substantially all of the FR regions being those of the human immunoglobulin common sequence. Humanized antibodies may also contain at least a portion (Fc) of the immunoglobulin constant region or domain, typically a portion of the human immunoglobulin. Examples of methods for generating humanized antibodies are described in U.S. Patent 5,225,539. In some embodiments, a “humanized antibody” is a surface-reconstructed antibody.

[0042] The “variable region” of an antibody refers to the variable region of the antibody light chain, either alone or in combination, or the variable region of the antibody heavy chain. The variable regions of both the heavy and light chains are each composed of four frame regions (FRs) connected by three complementarity-determining regions (CDRs) (also known as hypervariable regions). The CDRs in each chain are tightly bound together by the FRs and, together with CDRs from the other chain, 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 variation (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md.)); and (2) methods based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al. (1997) J). Molec. Biol. 273:927-948). In addition, a combination of these two methods is sometimes used in the art to determine CDR.

[0043] When referring to residues in variable domains, the Kabat numbering system is typically used (approximately residues 1-107 in the light chain and residues 1-113 in the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0044] For example, the amino acid position number in Kabat refers to Kabat et al. , The heavy chain variable domain or light chain variable domain numbering system used for antibody compilation is described in *Sequences of Proteins of Immunological Interest, 5th Edition. Public Health Service, National Institutes of Health, Bethesda, Md.* (1991). Using this numbering system, the actual linear amino acid sequence may contain several or additional amino acids that correspond to a shortened or inserted FR or CDR of the variable domain. For example, the heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (according to Kabat residue 52a) and multiple inserted residues after heavy chain FR residue 82 (e.g., according to Kabat residues 82a, 82b, and 82c, etc.). For a given antibody, the Kabat number of the residue can be determined by comparing the antibody sequence at a homologous region with a sequence numbered according to the "standard" Kabat number. Chothia, on the other hand, refers to the location of the structural loop (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). When using the Kabat numbering rules, the end of the loop varies between H32 and H34 depending on the length of the Chothia CDR-H1 loop (this is because the Kabat numbering scheme inserts at H35A and H35B; if neither 35A nor 35B exists, the loop terminates at 32; if only 35A exists, the loop terminates at 33; if both 35A and 35B exist, the loop terminates at 34). The AbM hypervariable region represents a compromise between the Kabat CDR and the Chothia structural loop and is used by Oxford Molecular's AbM antibody modeling software. The term "human antibody" means an antibody produced by a human or an antibody prepared using any technique known in the art that has an amino acid sequence corresponding to an antibody produced by a human. This definition of human antibody includes full-length or complete antibodies, fragments thereof, and / or antibodies containing at least one human heavy chain and / or light chain polypeptide, such as antibodies containing a mouse light chain polypeptide and a human heavy chain polypeptide.

[0045] The term "chimeric antibody" refers to an antibody in which the amino acid sequence of an immunoglobulin molecule is derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody derived from one mammal (e.g., mouse, rat, rabbit, etc.) that have the desired specificity, affinity, and capacity, while the constant regions are homologous to the sequences in antibodies derived from another species (usually human) to avoid inducing an immune response in said species.

[0046] 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 by consecutive amino acids and non-consecutive amino acids juxtaposed by the ternary folding of a protein. Epitopes formed by consecutive amino acids are generally retained upon protein denaturation, while epitopes formed by ternary folding are generally lost upon protein denaturation. In a distinctive spatial conformation, an epitope typically contains at least three, and more usually at least five, or eight to ten amino acids.

[0047] "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity 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 can typically be represented by the dissociation constant (Kd). Affinity can be measured by commonly used 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 for longer periods. A variety of 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.

[0048] When used in this document to refer to binding affinity, "or better" means a stronger binding between the molecule and its binding partner. As used herein, "or better" means a stronger binding expressed as a smaller numerical value (Kd). For example, an antibody having an affinity of "0.6 nM or better" for an antigen, where the antibody's affinity for the antigen is <0.6 nM, i.e., 0.59 nM, 0.58 nM, 0.57 nM, etc., or any value less than 0.6 nM.

[0049] The term "specific binding" generally means that an antibody binds to an epitope via its antigen-binding domain, and that this binding requires some complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody can be said to "specifically bind" to an epitope when it binds to one epitope more readily than to a random, unrelated epitope. The term "specific" is used here to describe the relative affinity of an antibody for a given epitope. For example, antibody "A" can be considered to have higher specificity for a given epitope than antibody "B," or antibody "A" can be said to bind to epitope "C" with higher specificity than it does to related epitope "D."

[0050] The term "preferential binding" means that an antibody is more likely to specifically bind to an epitope than it would bind to a related, similar, homologous, or analogous epitope. Therefore, an antibody that "prefers binding" to a given epitope will be more likely to bind to that given epitope than to a related epitope, even if the antibody may cross-react with the related epitope.

[0051] If an antibody preferentially binds to a given epitope to the extent that it blocks the binding of a reference antibody to the epitope, then it can be said that it "competitively inhibits" the binding of the 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 epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0052] As used herein, the phrase "substantially similar" or "substantially identical" indicates a sufficiently high degree of similarity between two values ​​(typically one value associated with the antibody of the present invention and the other with a reference / comparison antibody) such that a person skilled in the art would consider the difference between the two values ​​to be little or no biologically and / or statistically significant in the context of the biological characteristics measured by said values ​​(e.g., Kd values). The difference between the two values ​​may be less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% as the value of the reference / comparison antibody varies.

[0053] The “isolated” polypeptides, antibodies, polynucleotides, vectors, cells, or compositions are polypeptides, antibodies, polynucleotides, vectors, cells, or compositions in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the point that they no longer exist in the form found in nature. In some embodiments, the isolated antibodies, polynucleotides, vectors, cells, or compositions are substantially pure.

[0054] 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.

[0055] 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 = anti-FOLR1 antibody or antibody fragment. Immunoconjugates can also be defined by the following general formula in reverse order: ALC.

[0056] The term "IMGN853" refers to the immunoconjugate described herein containing huMov19 antibody, sulfonated SPDB linker, and DM4 maytansine. The huMov19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:3 and a variable light chain having the amino acid sequence of SEQ ID NO:5.

[0057] A "connector" is any chemical moiety capable of stably and covalently linking a compound (typically a drug, such as maytansine) to a cell binder, such as an anti-FOLR1 antibody or a fragment thereof. Under conditions where the compound or antibody remains active, the connector may be susceptible to or substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage. Suitable connectors are well known in the art and include, for example, disulfide groups, thioether groups, acid-instable groups, light-instable groups, peptidase-instable groups, and esterase-instable groups. Connectors also include charged connectors as described herein and known in the art, and their hydrophilic forms.

[0058] The terms "cancer" and "cancerous" refer to or describe a physiological state in mammals in which a population of cells is characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, germ cell tumor, sarcoma, and leukemia. More specific examples of this type of cancer include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, and various types of head and neck squamous cell carcinoma. The cancers mentioned can be cancers expressing FOLR1.

[0059] "Tumor" and "neoplasm" refer to any mass of tissue caused by excessive cell growth or proliferation, whether benign (non-cancerous) or malignant (cancerous), including precancerous lesions.

[0060] The terms “cancer cell,” “tumor cell,” and grammatically equivalents refer to the total cell population derived from a tumor or precancerous lesion, including both non-tumorigenic cells (including tumor cell masses) and tumorigenic stem cells (cancer stem cells). As used herein, the term “tumor cell” when referring only to those tumor cells lacking the capacity for renewal and differentiation will be modified by the term “non-tumorigenic” to distinguish those tumor cells from cancer stem cells.

[0061] The term "subject" refers to any animal (e.g., a mammal) that is to become a recipient of a specific treatment, including but not limited to humans, non-human primates, rodents, etc. Generally, the terms "subject" and "patient" are used interchangeably in this text when referring to human subjects.

[0062] The term "ideal body weight" (IBW) refers to a size descriptor that is independent of total weight. IBW is an estimate of weight adjusted for sex and height, and optionally for skeletal size. IBW can be calculated, for example, using the formulas IBW = 0.9H - 88 (for men) and IBW = 0.9H - 92 (for women), where H = height (cm).

[0063] The term "lean body mass" (LBW) refers to the mass of fat that can be considered (FM). frac The size descriptor for LBW is equal to the total weight minus FM. frac The product of weight and weight. For example, you can use the formula LBW = 1.10 × weight (kg) – 128([weight (kg)]). 2 / [100 × height (m)] 2(For males) and LBW = 1.07 × weight (kg) – 148 ([weight (kg)]) 2 / [100 × height (m)] 2 (For women) Calculate LBW.

[0064] The terms "Adjusted Ideal Body Weight" (AIBW) or "Adjusted Weight" (ADJ) refer to a size descriptor that takes into account sex, total weight, and height. AIBW and ADJ are used interchangeably throughout the instruction manual. AIBW (ADJ) can be calculated, for example, using the formula ADJ = IBW + 0.4(weight (kg) – IBW).

[0065] IBW, LBW, and AIBW (ADJ) are located in Green and Duffull. British Journal of Clinical Pharmacology 58 This is discussed in more detail in 119-133 (2004), which is incorporated herein by reference in its entirety.

[0066] "Combined" administration with one or more other therapeutic agents includes simultaneous (parallel) administration and sequential administration in any order.

[0067] The term "pharmaceutical formulation" refers to a formulation in which the biological activity of the active ingredient is permitted and which does not contain any additional components that would have unacceptable toxicity to a subject administering the formulation. The formulation may be sterile.

[0068] The “effective amount” of an antibody or immunoconjugate as disclosed herein is an amount sufficient to perform the stated purpose. Depending on the stated purpose, the “effective amount” may be determined empirically and in a conventional manner.

[0069] The term "therapeutic effective dose" refers to the amount of antibody 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; inhibit (i.e., to some extent slow down and, in one implementation, stop) the invasion of cancer cells into surrounding organs; inhibit (i.e., to some extent slow down and, in one implementation, stop) 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 increased progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), or in some cases, stable disease (SD), reduction in progressive disease (PD), reduction in time to progression (TTP), reduction in CA125 in the case of ovarian cancer, or any combination thereof.

[0070] See the definition of “treatment” in this document. It can be cytoseptic and / or cytotoxic, depending on the extent to which a drug prevents the growth of and / or kills existing cancer cells. In some embodiments, the identification of increased FOLR1 levels allows for the administration of a reduced dose of a FOLR1-targeted therapeutic agent to achieve the same therapeutic effect as seen at higher doses. “Prophylactic effective dose” refers to the amount required to effectively achieve the desired preventative outcome in terms of both dosage and duration. Typically, but not necessarily, because the prophylactic dose is administered to the subject before or in an early stage of the disease, the prophylactic effective dose will be less than the therapeutic effective dose.

[0071] The term "good response" generally refers to a favorable state in a subject. In the context of cancer treatment, this term refers to the provision of a therapeutic effect in a 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 assess the efficacy of anticancer treatments. Regarding tumor growth inhibition, according to NCI criteria, a T / C ≤ 42% is the minimum level of antitumor activity. A T / C < 10% is considered a high level of antitumor activity, where T / C (%) = median tumor volume of the treatment / median tumor volume of the control × 100. A favorable response can be assessed, for example, by the following: increased progression-free survival (PFS), disease-free survival (DFS) or overall survival (OS), complete response (CR), partial response (PR), or in some cases, stable disease (SD), reduction in progressive disease (PD), reduction in time to progression (TTP), reduction in CA125 in the case of ovarian cancer, or any combination thereof.

[0072] PFS, DFS, and OS can be measured using the standards set by the National Cancer Institute and the US Food and Drug Administration for the approval of new drugs. See Johnson et al., (2003) J. Clin. Oncol. 21(7):1404-1411.

[0073] Progression-free survival (PFS) refers to the time from recruitment to disease progression or death. PFS is typically measured using the Kaplan-Meier method and the RECIST 1.1 criteria. Generally, progression-free survival refers to the period during which a patient remains alive without cancer progression.

[0074] "Time to progression of tumor" (TTP) is defined as the time from recruitment to disease progression. TTP is typically measured using the RECIST 1.1 standard.

[0075] "Complete response," "complete remission," or "CR" indicates the disappearance of all symptoms of a tumor or cancer in response to treatment. This does not always mean that the cancer has been cured.

[0076] "Partial response" or "PR" refers to a reduction in the size or volume of one or more tumors or lesions or the degree of cancer in the body in response to treatment.

[0077] "Stable disease" refers to disease that does not progress or relapse. In stable disease, there is neither sufficient tumor shrinkage to qualify as a partial response nor sufficient tumor growth to be classified as a progressive disease.

[0078] "Progressive disease" refers to the appearance and / or clear progression of a new lesion or tumor on top of an existing non-target lesion. Progressive disease can also refer to tumor growth exceeding 20% ​​since the start of treatment due to treatment or spread of the tumor.

[0079] "Disease-free survival" (DFS) refers to the length of time a patient remains disease-free during or after treatment.

[0080] Overall survival (OS) refers to the time from patient recruitment to death or the last known date of survival. OS includes the extension of life expectancy relative to the original or untreated individual or patient. Overall survival refers to the duration of a patient's survival for a defined period, such as one year, five years, etc. (e.g., from diagnosis or treatment). A decrease in CA125 levels can be assessed according to the Gynecologic Cancer Group (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 relative to baseline levels is considered a decrease in CA125 levels.

[0081] Terms such as “treating,” “treatment,” “to treat,” “alleviating,” or “to alleviate” refer to therapeutic measures that cure, reduce, alleviate the symptoms of a diagnosed pathological condition or symptom, and / or prevent its progression. Therefore, those requiring treatment include those already diagnosed with or suspected of having the aforementioned condition. In some implementations, a subject is considered successfully “treated” for 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 size; 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; reduction of one or more symptoms associated with a specific cancer; a decrease in morbidity and mortality; an improvement in quality of life; a reduction in tumorigenicity, frequency of tumorigenicity, or tumorigenic capacity of the tumor; a reduction in the number or frequency of cancer stem cells in the tumor; differentiation of tumorigenic cells into a non-tumorigenic state; an increase in progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), reduction in progressive disease (PD), reduction in time to progression (TTP), a reduction in CA125 in the case of ovarian cancer, or any combination thereof.

[0082] Prophylactic or preventative measures refer to therapeutic actions that prevent and / or slow the development of a targeted pathological symptom or condition. Therefore, those requiring prophylactic or preventative measures include both those susceptible to the condition and those for which the condition needs to be prevented.

[0083] The terms “pre-treat” and “pre-treatment” refer to treatment measures that occur prior to the administration of an anti-FOLR1 treatment agent. For example, as described in more detail herein, prophylactic agents such as steroids may be administered approximately one week, five days, three days, two days, or one day or 24 hours before the administration of an anti-FOLR1 treatment agent. Prophylactic agents may also be administered on the same day as the anti-FOLR1 treatment agent, prior to the anti-FOLR1 treatment agent.

[0084] The term "maximum concentration" (Cmax) refers to the highest concentration of a drug in the blood measured after a drug dose.

[0085] The term "area under the curve" (AUC) refers to the total amount of drug in the bloodstream after a drug dose. AUC can be defined over a specific time period. Therefore, for example, AUC... 0-∞ It refers to the total amount of drug in the bloodstream over an indefinite period of time after a drug dose. In another instance, AUC...0-24 This refers to the total amount of drug in the bloodstream within a 24-hour period following a drug dose. In another example, AUC... 0-168 This refers to the total amount of drug in the bloodstream within a period of 168 hours (or one week) after the drug dose.

[0086] "The apparent volume distribution under steady state" (V) ss The total amount of drug in the body is the ratio of the concentration of drug in the blood plasma, or, if the total amount of drug in the body is at the same concentration as in the blood plasma, the "apparent" volume necessary for the total amount of drug contained in the body.

[0087] "Chemotherapy agents" are compounds used to treat cancer, regardless of their mechanism of action. Chemotherapy agents include, for example, CD20 antagonists such as rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, fludarabine, etoposide, methotrexate, lenalidomide, chlorambucil, betamustine, and / or modified forms of these chemotherapeutic agents.

[0088] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers having amino acids of any length. The polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acid groups. The term also covers amino acid polymers that have been naturally modified or modified by intervention; for example, disulfide bond formation, glycosylation, lipoylation, acetylation, phosphorylation, or any other operation or modification, such as coupling with a labeled component. Within the definition, there is also, for example, polypeptides containing one or more analogs of amino acids (including, for example, non-natural amino acids, etc.), and other modifications 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 be present as single-chain or associated chains.

[0089] In the context of two or more nucleic acids or polypeptides, the term "identical" or "percentage of identity" refers to the fact that, when comparing and aligning against the largest corresponding sequence (introducing gaps if necessary), two or more sequences or subsequences are identical or have the same specified percentage of nucleotide or amino acid residues, regardless of any conserved amino acid substitutions as part of sequence identity. The percentage of identity can be measured using sequence alignment software or algorithms or by visual inspection. Various algorithms and software available for obtaining alignments of amino acid or nucleotide sequences are known in the art. A non-limiting example of such a sequence alignment algorithm is found in Karlin et al., 1990. Proc. Natl. Acad. Sci. Described in , 87:2264-2268, in Karlin et al., 1993, Proc. Natl. Acad. Sci.Modifications were made in 90:5873-5877 and incorporated into the NBLAST and XBLAST programs (Altschul et al., 1991). Nucleic Acids Res. The algorithm in (25:3389-3402). In some implementations, it may be as in Altschul et al., 1997. Nucleic Acids Res. The Gapped BLAST is used as described in 25:3389-3402. BLAST-2, WU-BLAST-2 (Altschul et al., 1996, Methods in Enzymology (266:460-480), ALIGN, ALIGN-2 (Genentech, South San Francisco, California), or Megalign (DNASTAR) are other publicly available software programs that can be used for sequence alignment. 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 and vacancy weights of 40, 50, 60, 70, or 90 and length weights of 1, 2, 3, 4, 5, or 6). In some alternative embodiments, the Needleman and Wunsch algorithms are combined ( J. Mol. Biol. The GAP procedure in the GCG software package (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, 5). Alternatively, in some embodiments, the Myers and Miller algorithm (CABIOS, 4:11-17 (1989)) is used to determine the percentage of identity between nucleotide or amino acid sequences. For example, the ALIGN procedure (version 2.0) and PAM120 with a residue table, a vacancy length penalty of 12, and a vacancy penalty of 4 can be used to determine the percentage of identity. Appropriate parameters for achieving maximum alignment with 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 amino acid sequence and the second amino acid sequence is calculated as 100 × (Y / Z), where Y is the number of amino acid residues that score as a consistent match in the alignment of the first and second sequences (e.g., by visual inspection or a specific sequence alignment procedure), 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 greater than the identity percentage between the second and first sequences.

[0090] As a non-limiting example, in some implementations, the Bestfit program (Wisconsin sequence analysis package, Unix version 8, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, WI 53711) can be used to determine whether any particular polynucleotide has a certain percentage of sequence identity with a reference sequence (e.g., at least 80% identity, at least 85% identity, at least 90% identity, and in some implementations at least 95%, 96%, 97%, 98%, or 99% identity). Bestfit uses Smith and Waterman's local homology algorithm ( Advances in Applied Mathematics 2: 482 489 (1981)), to find the optimal fragment with homology between two sequences. When using Bestfit or any other sequence alignment program according to the invention to determine whether a particular sequence has, for example, 95% identity with a reference sequence, parameters are set such that the percentage of identity is calculated over the full length of the reference nucleotide sequence and allows for vacancies in homology up to 5% of the total number of nucleotides in the reference sequence.

[0091] In some embodiments, the two nucleic acids or polypeptides of the present invention are substantially identical, meaning that when compared and aligned against the maximum correspondence, as measured by sequence comparison algorithms or by visual inspection, 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. Identity can be present in regions of sequences of at least about 10, about 20, about 40 to about 60 residues or any integer value between therewith, and can be present in regions longer than 60 to 80 residues, for example, at least about 90 to 100 residues. In some embodiments, the sequences are substantially identical across the full length of the compared sequences (e.g., coding regions like nucleotide sequences).

[0092] "Conservative amino acid substitution" is a substitution in which one amino acid residue is replaced by another amino acid residue having a similar side chain. Families of amino acid residues having 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 sequence of the peptides and antibodies of the present invention does not eliminate the binding of the peptide or antibody containing the amino acid sequence to the antigen (i.e., FOLR1 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: 1180-1 187 (1993); Kobayashi et al. Protein Eng. 12(10):879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA 94:.412-417 (1997)).

[0093] Unless the context clearly specifies otherwise, the singular forms “a”, “an”, and “the” used in this disclosure and claims include the plural forms.

[0094] It should be understood that wherever the word “comprising” is used to describe an implementation scheme in this document, other similar implementation schemes are also provided to be described using the phrases “composed of” and / or “mainly composed of”.

[0095] The term "and / or" as used in phrases such as "A and / or B" herein is intended 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 cover 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).

[0096] II. FOLR1 binder The methods described herein provide for the administration of an agent (“FOLR1 binder”) that specifically binds to FOLR1 (e.g., an antibody or its antigen-binding fragment or peptide). In some embodiments, the FOLR1 binder is an antibody, an immunoconjugate, or a peptide. The amino acid and nucleotide sequences of human FOLR1 are known in the art and are also provided herein as shown by SEQ ID NO: 1 and SEQ ID NO: 2. Thus, in some embodiments, the FOLR1 binder may bind to the epitope found in SEQ ID NO: 1.

[0097] Examples of therapeutically effective antiFOLR1 antibodies can be found in U.S. Patent Application Publication No. US 2012 / 0009181, which is incorporated herein by reference. An example of a therapeutically effective antiFOLR1 antibody is huMov19 (M9346A). The polypeptides of SEQ ID NO: 3-5 comprise a variable domain of the heavy chain of huMov19 (M9346A) and variable domain light chains of huMov19, type 1.00 and type 1.60, respectively. In some embodiments, the huMov19 antiFOLR1 antibody comprises a variable domain heavy chain represented by SEQ ID NO: 3 and a variable domain light chain (type 1.60 of huMov19) represented by SEQ ID NO: 5. In some embodiments, the huMov19 (M9346A) antibody is encoded by a plasmid registered on April 7, 2010, under the terms of the Budapest Treaty at the American Collection of Type Cultures (ATCC) (10801 University Boulevard, Manassas, VA 20110) with ATCC registration numbers PTA-10772 and PTA-10773 or 10774. Examples of FOLR1 immunoconjugates suitable for the therapeutic methods of this invention are provided below.

[0098] In some embodiments, the FOLR1 binder is a humanized antibody or its antigen-binding fragment. In some embodiments, the humanized antibody or fragment is a surface-reconstructed antibody or its antigen-binding fragment. In other embodiments, the FOLR1 binder is a fully human antibody or its antigen-binding fragment.

[0099] In some embodiments, the FOLR1 binder has one or more of the following effects: inducing disease stabilization, inhibiting tumor cell proliferation, reducing tumorigenicity by decreasing the frequency of cancer stem cells in the tumor, inhibiting tumor growth, increasing survival, inducing cell death in tumor cells, differentiating tumorigenic cells into a non-tumorigenic state, or preventing tumor cell metastasis.

[0100] In some implementations, the FOLR1 binder is an antibody with antibody-dependent cytotoxic (ADCC) activity.

[0101] In some embodiments, the FOLR1 binder can reduce tumor volume. The ability of the FOLR1 binder to reduce tumor volume can be assessed, for example, by measuring the %T / C value, which is the median tumor volume of the treated subject divided by the median tumor volume of the control subject. In some embodiments, an 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 with maytansine, which is activated in FOLR1-expressing tumor cells via protein internalization. In some embodiments, the FOLR1 binder can inhibit tumor growth. In some embodiments, the FOLR1 binder can inhibit tumor growth in vivo (e.g., in xenograft mouse models and / or in people with cancer).

[0102] FOLR1 binding molecules can be antibodies or antigen-binding fragments that specifically bind to FOLR1, said antibody or antigen-binding fragment containing a CDR of uMov19 (M9346A), each CDR having up to four (i.e., 0, 1, 2, 3, or 4) conserved amino acid substitutions, for example, said antibody or fragment does not contain the six CDRs of mouse Mov19 (i.e., SEQ ID NO: 6-9, 16, and 12). Peptides may contain one of the single variable light chains or variable heavy chains described herein. Antibodies and peptides may also contain variable light chains and variable heavy chains.

[0103] 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.

[0104] Also provided are polypeptides comprising a polypeptide having 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 the polypeptide specifically binds to FOLR1. In some embodiments, the polypeptide is a mouse, chimeric, or humanized antibody that specifically binds to FOLR1. In some embodiments, the peptides that have a certain percentage of sequence identity with SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 differ from SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 only in the conserved amino acid substitutions.

[0105] Peptides may contain either a single light chain or a heavy chain as described herein. Antibodies and peptides may also contain both light and heavy chains.

[0106] Monoclonal antibodies can be prepared using hybridoma methods (such as those described by Kohler and Milstein (1975) Nature 256:495). Using these 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, which can then be selected from unfused lymphocytes and myeloma cells. Hybridomas that produce monoclonal antibodies specifically against the selected antigen can then be propagated in vitro in cultures or in vivo in animals as ascites tumors using standard methods (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, 1986). The monoclonal antibody can then be purified from the culture medium or ascites as described for polyclonal antibodies.

[0107] Alternatively, monoclonal antibodies can be prepared using a recombinant DNA method as described in U.S. Patent 4,816,567. Polynucleotides encoding monoclonal antibodies are isolated from mature B cells or hybridoma cells, such as by RT-PCR 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, which, 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), produces monoclonal antibodies from the host cells. In addition, recombinant monoclonal antibodies or fragments thereof of the desired species can be isolated from phage display libraries expressing the desired species' CDRs, 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).

[0108] Recombinant DNA technology can be used to further modify polynucleotides encoding monoclonal antibodies in many different ways to produce alternative antibodies. In some embodiments, (e.g.) the constant domains of the light and heavy chains of a mouse monoclonal antibody can be replaced with: 1) (e.g.) those regions of a human antibody to produce a chimeric antibody or 2) a non-immunoglobulin polypeptide to produce a fusion antibody. In some embodiments, the constant regions are truncated or removed to produce the desired antibody fragment of the monoclonal antibody. Site-directed or high-density mutagenesis of variable regions can be used to optimize the specificity, affinity, etc., of the monoclonal antibody.

[0109] 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, when administered to a human subject, such antibodies are therapeutically used to reduce antigenicity and HAMA (human anti-mouse antibody) responses. Various techniques known in the art can be used to generate humanized antibodies. In some alternative embodiments, the antibody against FOLR1 is a human antibody.

[0110] Human antibodies can be prepared directly using a variety of techniques known in the art. Immortalized human B lymphocytes that have been immunized in vitro or isolated from an immune individual that produces antibodies against the target antigen can be generated (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). Furthermore, the human antibody may be selected from a phage library expressing a human antibody, as described, for example, in the following: 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 the generation and use of 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.

[0111] Humanized antibodies can also be prepared in transgenic mice containing human immunoglobulin loci, which, upon immunization, produce the full lineage of human antibodies without producing endogenous immunoglobulins. 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.

[0112] This invention also covers bispecific antibodies that specifically recognize FOLR1. A bispecific antibody is an antibody capable of specifically recognizing and binding to at least two different epitopes. The different epitopes may be within the same molecule (e.g., the same FOLR1) or on different molecules, such that (e.g.) both antibodies can specifically recognize and bind to FOLR1 and, for example, 1) effector molecules on leukocytes such as T-cell receptors (e.g., CD3) or Fc receptors (e.g., CD64, CD32, or CD16) or 2) cytotoxic agents as described in detail below.

[0113] The polypeptides of the present invention may be recombinant polypeptides, natural polypeptides or synthetic polypeptides, including antibodies against human FOLR1 or fragments thereof.

[0114] Peptides and analogues can be further modified to include additional chemical moieties that are not the usual parts of proteins. These derived moieties can improve protein solubility, biological half-life, or absorption. The moieties can also reduce or eliminate any desired side effects of the protein. A review of these moieties can be found in REMINGTON'S PHARMACEUTICAL SCIENCES, 20th edition, Mack Publishing Co., Easton, PA (2000).

[0115] Methods known in the art for purifying antibodies and other proteins include, for example, those described in U.S. Patent Publications 2008 / 0312425, 2008 / 0177048, and 2009 / 0187005, each of which is hereby incorporated herein by reference in its entirety.

[0116] III. Immunoconjugates This document also describes methods for administering conjugates (also referred to herein as immunoconjugates) comprising an anti-FOLR1 antibody, antibody fragment, or functional equivalent thereof, as disclosed herein, linked or conjugated to a drug or prodrug. Suitable drugs or prodrugs are known in the art. Drugs or prodrugs may be cytotoxic agents. Cytotoxic agents used in the cytotoxic conjugates of this invention may be any compound that causes or induces cell death or reduces cell viability in some way, and include, for example, maytandemin and maytandemin analogues. Other suitable cytotoxic agents include, for example, benzodiazepines, taxanes, CC-1065 and CC-1065 analogs, bacitracin and bacitracin analogs, enediyne derivatives (such as chazim), dolalastatin and dolalastatin analogs (including orlistatin), tomatine derivatives, leptomycin derivatives, methotrexate, cisplatin, carboplatin, daunorubicin, doxorubicin, vincristine, vinblastine, melphalan, mitomycin C, chlorambucil, and morpholino doxorubicin.

[0117] Such conjugates can be prepared by using a linker to link a drug or prodrug to an antibody or functional equivalent. Suitable linkers are well known in the art and include, for example, disulfide, thioether, acid-instable, light-instable, peptidase-instable, and esterase-instable groups.

[0118] The drug or prodrug may, for example, be linked to an antiFOLR1 antibody or a fragment thereof via a disulfide bond. The linker molecule or crosslinker includes 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 binder may be... N -Succinimide ester and N -Sulfosuccinimide ester. Furthermore, the linker molecule contains a reactive chemical group, which can be a dithiopyridyl group capable of reacting with the drug to form a disulfide bond. Linker 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-sulfonobutyric acid N -Succinimide ester (sulfonyl-SPDB) (see US Publication No. 20090274713) 4-(2-pyridyldithio)valerate N-succinyl ether amine esters (SPP) (see, for example, CAS Registry No. 341498-08-6), 2-iminothione, or acetylsuccinic anhydride. For example, antibodies or cell binders can be modified with a cross-linking agent and then the resulting antibody or cell binder containing free or protected thiol groups can be reacted with maytansine containing disulfide bonds or thiol groups to produce conjugates. The 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.

[0119] In another aspect of the invention, an anti-FOLR1 antibody is linked to a cytotoxic drug via a disulfide bond and a polyethylene glycol spacer, thereby enhancing the potency, solubility, or efficacy of the immunoconjugate. Such cleavable hydrophilic linkers are 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. Specifically, this includes conjugates of cell-binding agents and drugs linked via a disulfide group (-SS-) with a polyethylene glycol spacer ((CH2CH2O)). n=1-14 The study describes a narrow range of drug loadings from 2 to 8 that exhibit relatively potent bioactivity against cancer cells and possess the desired biochemical properties of high conjugation yield and high monomer ratio, while exhibiting minimal protein aggregation.

[0120] Antibody-matenine conjugates with non-cleavable linkers can also be prepared. Such crosslinking agents are described in the art (see US Publication No. 20050169933) and include, but are not limited to, 4-(maleimidemethyl)cyclohexanecarboxylic acid. N- Succinimide ester (SMCC). In some embodiments, as described in the literature, the antibody is modified with a cross-linking agent such as 4-(N-maleimidemethyl)-cyclohexane-1-carboxylic acid succinimide ester (SMCC), sulfon-SMCC, maleimide benzoyl-N-hydroxysuccinimide ester (MBS), sulfon-MBS, or iodoacetic acid succinimide ester 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 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. Modified antibodies are treated with thiol-containing maytandemin (1 to 2 molar equivalents / maleimide group), and the antibody-matenimin conjugates are purified by gel filtration via a Sephadex G-25 column, ceramic hydroxyapatite column chromatography, dialysis or tangential flow filtration, or a combination of these methods. Typically, each antibody is linked to an average of 1-10 maytandemin groups. 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 thiol-containing maytandemin to obtain a thioether-linked conjugate. This again yields conjugates containing 1 to 10 drug molecules per antibody molecule. Maytandemin conjugates of antibodies, antibody fragments, and other proteins are prepared in the same manner.

[0121] In another aspect of the invention, the FOLR1 antibody is linked to the drug via an indestructible bond through the intermediate nature of the PEG spacer group. Suitable crosslinking agents comprising the hydrophilic PEG chain forming the linker between the drug and the antiFOLR1 antibody or fragment are also known in the art or 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 crosslinking agent containing bifunctional PEG by the methods described in U.S. Patent Publication 20090274713 and WO2009 / 0134976 to yield a compound of the following formula: Z–X l –(–CH2–CH2–O–) n –Y p–D, the compound can then be reacted with a cell-binding agent to provide a conjugate. Alternatively, the cell-binding agent can be modified with a bifunctional PEG crosslinking agent to introduce a thiol-reactive group (such as maleimide or haloacetamide), which can then be treated with a thiol-containing maytansine to provide a conjugate. In another approach, the cell-binding agent can be modified with a bifunctional PEG crosslinking agent to introduce a thiol moiety, which can then be treated with a thiol-reactive maytansine (such as maytansine carrying maleimide or haloacetamide) to provide a conjugate.

[0122] Suitable examples of 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-based moiety for reaction with compounds. PEG spacer groups can be incorporated into any crosslinking agent known in the art by the methods described herein.

[0123] In some embodiments, the connector is a connector containing at least one charged group, such as that 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 pre-charged crosslinking agent is one containing sulfonate, phosphate, carboxyl, or quaternary ammonium substituents, which significantly increase the solubility of the modified cell binder and cell binder-drug conjugate, particularly for monoclonal antibody-drug conjugates linked with 2 to 20 drugs / antibodies. Conjugates prepared from connectors containing pre-charged portions will produce one or more charged portions after the conjugate is metabolized in cells. In some embodiments, the connector is selected from the group consisting of 4-(2-pyridyldithio)-2-sulfopenic acid. N -Succinimide ester (sulfon-SPP) and 4-(2-pyridyldithio)-2-sulfonbutyric acid N - Succinimide ester (sulfonyl-SPDB).

[0124] Many of the connectors disclosed herein are described in detail in U.S. Patent Publications 2005 / 0169933, 2009 / 0274713, and 2012 / 0282282, as well as in WO2009 / 0134976, the contents of which are incorporated herein by reference in their entirety.

[0125] This invention includes aspects in which about 2 to about 8 drug molecules (“drug load”) (e.g., maytandemin) 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., maytandemin) that can be linked to a cell binder (e.g., an anti-FOLR1 antibody or a fragment thereof). In one aspect, the number of drug molecules that can be linked to a cell binder may average about 2 to about 8 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, ...). 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1). N2'-deacetylated N2'-(3-mercapto-1-oxopropyl)-maytansin (DM1) and N2'-deacetylated N2'-(4-mercapto-4-methyl-1-oxopentyl)maytansin (DM4) can be used.

[0126] Therefore, on one hand, the immunoconjugate contains 1 maytansine per antibody. On the other hand, the immunoconjugate contains 2 maytansine per antibody. On another hand, the immunoconjugate contains 3 maytansine per antibody. On another hand, the immunoconjugate contains 4 maytansine per antibody. On another hand, the immunoconjugate contains 5 maytansine per antibody. On another hand, the immunoconjugate contains 6 maytansine per antibody. On another hand, the immunoconjugate contains 7 maytansine per antibody. On another hand, the immunoconjugate contains 8 maytansine per antibody.

[0127] On one hand, the immunoconjugate contains approximately 1 to approximately 8 maytandynes per antibody. On the other hand, the immunoconjugate contains approximately 2 to approximately 7 maytandynes per antibody. On the other hand, the immunoconjugate contains approximately 2 to approximately 6 maytandynes per antibody. On the other hand, the immunoconjugate contains approximately 2 to approximately 5 maytandynes per antibody. On the other hand, the immunoconjugate contains approximately 3 to approximately 5 maytandynes per antibody. On the other hand, the immunoconjugate contains approximately 3 to approximately 4 maytandynes per antibody.

[0128] On the one hand, compositions containing immunoconjugates have an average of about 2 to about 8 antibodies linked to each 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, ...). 4.8, 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) drug molecules (e.g., maytandem). On one hand, the composition containing the immunoconjugate has an average of about 1 to about 8 drug molecules per antibody (e.g., maytandem). On another hand, the composition containing the immunoconjugate has an average of about 2 to about 7 drug molecules per antibody (e.g., maytandem). On yet another hand, the composition containing the immunoconjugate has an average of about 2 to about 6 drug molecules per antibody (e.g., maytandem). On one hand, the composition containing the immunoconjugate has an average of about 2 to about 5 drug molecules per antibody (e.g., maytanyl). On the other hand, the composition containing the immunoconjugate has an average of about 3 to about 5 drug molecules per antibody (e.g., maytanyl). On the other hand, the composition containing the immunoconjugate has an average of about 3 to about 4 drug molecules per antibody (e.g., maytanyl).

[0129] 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., maytandem) linked to each antibody. On the other hand, compositions containing immunoconjugates have an average of about 3.5 ± 0.5 drug molecules (e.g., maytandem) linked to each antibody.

[0130] Anti-FOLR1 antibodies or fragments thereof can be modified by reacting a bifunctional crosslinking agent with said anti-FOLR1 antibody or fragment thereof, resulting in a linker molecule covalently linked 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 DM1, the side chain at the C-3 hydroxyl group of maytansine is modified to have a free thiol group (SH). This thiolated 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.

[0131] Drug molecules can also be linked to antibody molecules via intermediate carrier molecules such as serum albumin.

[0132] As used herein, the expression "linked to a cell binder" or "linked to an anti-FOLR1 antibody or a fragment thereof" refers to a conjugate molecule comprising at least one drug derivative or precursor thereof bound to a cell binder, an anti-FOLR1 antibody or a fragment thereof, via a suitable linker. An exemplary linker is SPDB or sulfonyl-SPDB.

[0133] In some embodiments, the cytotoxic agents useful in this invention are maytansine and maytansine analogues. Suitable examples of maytansine include esters of maytanol and maytanol analogues. This includes any drug that inhibits microtubule formation and is highly toxic to mammalian cells, such as maytanol and maytanol analogues.

[0134] Examples of suitable maytanol esters include those with modified aromatic rings and those with modifications at other positions. Suitable maytenin of this type is 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.

[0135] In some embodiments, the immunoconjugate of the present invention utilizes maytansine (DM1) containing thiols (formally known as...). N2’ -Deacetylated- N 2’ DM1 (-(3-mercapto-1-oxopropyl)-matansine) is used as a cytotoxic agent. DM1 is represented by the following structural formula (I): (I) In another embodiment, the coupling compound of the present invention utilizes maytannin containing thiols. N 2’ -Deacetylated- N 2’ (4-Methyl-4-mercapto-1-oxopentyl)-maytansin (e.g., DM4) is used as a cytotoxic agent. DM4 is represented by the following structural formula (II): (II) Another type of maytannin 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): (III) Each maytenin taught in U.S. Patent Nos. 5,208,020 and 7,276,497 may also be used in the conjugates of the present invention. In this regard, the entire disclosure of 5,208,020 and 7,276,697 is incorporated herein by reference.

[0136] Many positions on maytanyl alcohol can be used as sites for chemically linking 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 is used as the site for chemically linking the linker, and in some specific embodiments, the C-3 position of maytanyl alcohol is used as the site for chemically linking the linker.

[0137] The following shows the structural representations of some couplings: The present invention also includes any stereoisomers of any compound or coupling compound and mixtures thereof described by any of the above structures.

[0138] Some descriptions of the production of such antibody-maydenine 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.

[0139] Generally, the antibody solution in aqueous buffer can be incubated with a molar excess of maytansine carrying the reactive disulfide moiety. The reaction mixture can be quenched by adding an excess of an amine (such as ethanolamine or taurine). The maytansine-antibody conjugate can then be purified by gel filtration.

[0140] The number of maytandyne molecules bound by each antibody molecule can be determined by measuring the ratio of absorbance at 252 nm and 280 nm using spectrophotometry. The average maytandyne molecule / antibody ratio can be, for example, 1-10 or 2-5. The average maytandyne molecule / antibody ratio can be, for example, about 3 to about 4. The average maytandyne molecule / antibody ratio can be about 3.5.

[0141] For antibody conjugates with maytansine or other drugs, their ability to inhibit the proliferation of various unwanted cell lines can be evaluated 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 can be exposed to the compound for 4 to 5 days, and the cell survival fraction can be measured directly using known methods. The IC50 can then be calculated from the results of said assay. 50 value.

[0142] According to some embodiments described herein, the immunoconjugate can be internalized into cells. Therefore, when the immunoconjugate is absorbed or internalized by cells expressing FOLR1, it can exert a therapeutic effect. In some specific embodiments, the immunoconjugate comprises an antibody, antibody fragment, or peptide linked to a cytotoxic agent via a cleavable linker, and the cytotoxic agent is cleaved from the antibody, antibody fragment, or peptide, wherein it is internalized by cells expressing FOLR1.

[0143] In some embodiments, the immunoconjugate can reduce tumor volume. For example, in some embodiments, treatment with the immunoconjugate produces a %T / C of less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. In some specific embodiments, the 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.

[0144] III. Method of applying FOLR1 binder The FOLR1 binders (including antibodies, immunoconjugates, and peptides) of the present invention are useful in a variety of applications, including but not limited to therapeutic treatments such as cancer treatment. In some embodiments, the agents are suitable for inhibiting tumor growth, inducing differentiation, inhibiting metastasis, reducing tumor volume, and / or reducing tumorigenicity. The method of use may be an in vivo method.

[0145] According to the methods described herein, the FOLR1 binder can be administered in specific doses. For example, the FOLR1 binder (e.g., IMGN853) can be administered at doses from about 0.15 mg / kg to about 7 mg / kg, wherein the kilogram body weight is adjusted to ideal body weight (IBW), lean body weight (LBW), or adjusted ideal body weight (AIBW or ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at doses from about 3.0 mg / kg to about 6.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at doses from about 3.3 mg / kg to about 6.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 0.15 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 0.5 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 1.0 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 1.1 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 1.5 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 1.8 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 2.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 2.5 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 2.8 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ).In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 3.0 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 3.3 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 3.75 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 4.2 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 4.5 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 4.8 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 5.0 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 5.5 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 5.6 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.0 mg / kg, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.1 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.2 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.3 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ).In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.4 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.5 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.6 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.7 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at about 6.8 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at approximately 6.9 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered at approximately 7.0 mg / kg, wherein the kilogram body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the kilogram body weight is adjusted to AIBW (ADJ).

[0146] Furthermore, the FOLR1 binder can be administered at specific dosage intervals. For example, the FOLR1 binder can be administered from about four times a week to about once every four weeks. Thus, in some embodiments, the FOLR1 binder is administered about once every three weeks. In some embodiments, the FOLR1 binder is administered about once every two and a half weeks. In some embodiments, the FOLR1 binder is administered about once every two weeks. In some embodiments, the FOLR1 binder is administered about once every ten days. In some embodiments, the FOLR1 binder is administered about once a week.

[0147] The FOLR1 binder can also be administered over a period of approximately 3 weeks (i.e., approximately 21 days). For example, the FOLR1 binder can be administered twice over approximately 3 weeks. Therefore, in some embodiments, the FOLR1 binder can be administered approximately on day 1 and day 8 of a 21-day cycle. In other embodiments, the FOLR1 binder can be administered three times over approximately 3 weeks. Therefore, in some embodiments, the FOLR1 binder can be administered approximately on day 1, day 8, and day 15 of a 21-day cycle.

[0148] The FOLR1 binder can also be applied over a period of approximately 4 weeks (i.e., approximately 28 days). For example, the FOLR1 binder can be applied three times over approximately 4 weeks. Therefore, in some embodiments, the FOLR1 binder can be applied approximately on day 1, day 8, and day 15 of a 28-day period.

[0149] According to the methods described herein, the FOLR1 binder can be administered in specific doses. For example, the FOLR1 binder (e.g., IMGN853) can be administered once weekly for three weeks at a dose of about 0.15 mg / kg to about 7 mg / kg according to a four-week schedule. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a dose of about 3.0 mg / kg to about 6.0 mg / kg according to a four-week schedule. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a dose of about 3.3 mg / kg to about 6.0 mg / kg according to a four-week schedule. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a dose of about 0.15 mg / kg according to a four-week schedule. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a dose of about 0.5 mg / kg according to a four-week schedule. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 1.0 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 1.1 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 1.5 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 1.8 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 2.0 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 2.5 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 2.8 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 3.0 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 3.3 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 3.75 mg / kg.In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 4.2 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 4.5 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 4.8 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 5.0 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 5.5 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 5.6 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.0 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.1 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.2 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.3 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.4 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.5 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.6 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.7 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.8 mg / kg. In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule of approximately 6.9 mg / kg.In some implementations, the FOLR1 binder (e.g., IMGN853) is administered once a week for three weeks according to a four-week schedule at approximately 7.0 mg / kg.

[0150] According to the methods described herein, the FOLR1 binder (e.g., IMGN853) may be administered once weekly for three weeks at a dose of about 0.15 mg / kg to about 7 mg / kg according to a four-week schedule, wherein the body weight is adjusted to ideal body weight (IBW), lean body weight (LBW), or adjusted ideal body weight (AIBW or ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) may be administered once weekly for three weeks at a dose of about 3.0 mg / kg to about 6.0 mg / kg according to a four-week schedule, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) may be administered once weekly for three weeks at a dose of about 3.3 mg / kg to about 6.0 mg / kg according to a four-week schedule, wherein the body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 0.15 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 0.5 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 1.0 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 1.1 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 1.5 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 1.8 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 2.0 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ).In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 2.5 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 2.8 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 3.0 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 3.3 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 3.75 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 4.2 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 4.5 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 4.8 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 5.0 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 5.5 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 5.6 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ).In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.0 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.1 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.2 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.3 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.4 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.5 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.6 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.7 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.8 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 6.9 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, the FOLR1 binder (e.g., IMGN853) is administered once weekly for three weeks at a four-week schedule at approximately 7.0 mg / kg, wherein body weight is adjusted to IBW, LBW, or AIBW (ADJ). In some embodiments, body weight is adjusted to AIBW (ADJ).

[0151] In some embodiments, the FOLR1 binder can be administered at a specific dose to produce a Cmax. For example, in some embodiments, the FOLR1 binder is administered at a dose to produce a Cmax of about 110 to about 160 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose to produce a Cmax of about 110 to about 150 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose to produce a Cmax of about 110 to about 140 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose to produce a Cmax of about 120 to about 160 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose to produce a Cmax of about 120 to about 150 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose to produce a Cmax of about 120 to about 140 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose to produce a Cmax of about 90 to about 160 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose that produces a Cmax of about 90 to about 150 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose that produces a Cmax of about 90 to about 140 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose that produces a Cmax of about 100 to about 160 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose that produces a Cmax of about 100 to about 150 µg / mL. In some embodiments, the FOLR1 binder is administered at a dose that produces a Cmax of about 100 to about 140 µg / mL.

[0152] In some embodiments, the FOLR1 binder can be administered at a specific AUC. For example, in some embodiments, the FOLR1 binder is used to produce an AUC not exceeding 2785 hr•µg / mL. 0-24 The dosage is administered. In some embodiments, the FOLR1 binder is used to produce an AUC not exceeding 2741 hr•µg / mL. 0-24 The dosage is administered. In some embodiments, the FOLR1 binder is used to produce an AUC not exceeding 2700 hr•µg / mL. 0-24 The dosage is administered. In some embodiments, administration produces an AUC of approximately 1000-3500 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-3000 hr•µg / mL. 0-24In some implementations, administration produces an AUC of approximately 1000-2785 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-2741 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-2700 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1000-2500 hr•µg / mL. 0-24 In some implementations, the administration produces an AUC not exceeding 1500-3500 hr•µg / mL. 0-24 In some implementations, the administration produces an AUC not exceeding 1500-3000 hr•µg / mL. 0-24 In some implementations, administration produces an AUC not exceeding 1500-2785 hr•µg / mL. 0-24 In some implementations, administration produces an AUC not exceeding 1500-2741 hr•µg / mL. 0-24 In some implementations, the administration produces an AUC not exceeding 1500-2700 hr•µg / mL. 0-24 In some implementations, administration produces an AUC of approximately 1500-2500 hr•µg / mL. 0-24 .

[0153] In some embodiments, the disease treated with a FOLR1 binder or antagonist (e.g., an anti-FOLR1 antibody) is cancer. In some embodiments, the cancer is characterized by FOLR1-expressing cells to which the FOLR1 binder (e.g., an antibody) binds. In some embodiments, the tumor overexpresses human FOLR1.

[0154] This invention provides a method for treating cancer, the method comprising administering a therapeutically effective amount of a FOLR1 binder to a subject (e.g., a subject requiring treatment). Cancers treatable by the methods covered by this invention include, but are not limited to, growths, tumors, metastases, or any disease or condition characterized by uncontrolled cell growth. The cancer may be primary or metastatic. Specific examples of cancers treatable by the methods covered by this invention include, but are not limited to, ovarian cancer, lung cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, brain cancer, kidney cancer, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, endometrial cancer, and head and neck cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is lung adenocarcinoma.

[0155] In some embodiments, the cancer is a cancer that expresses FOLR1 (a polypeptide or nucleic acid). In some embodiments, the FOLR1 binder is administered to a patient with increased FOLR1 expression levels, as described, for example, in U.S. Publication Application No. 2012 / 0282175 or International Publication Application No. WO 2012 / 135675, both of which are incorporated herein by reference in their entirety. Thus, in some embodiments, FOLR1 expression is measured by immunohistochemistry (IHC) and a staining intensity score and / or staining homogeneity score is given by comparison with a control (e.g., a calibrated control) that displays a defined score (e.g., an intensity score of 3 is given to the test sample if the intensity is equivalent to a grade 3 calibrated control, or an intensity score of 2 is given to the test sample if the intensity is equivalent to a grade 2 calibrated control). Heterogeneous or homogeneous staining homogeneity also indicates increased FOLR1 expression. Staining intensity and staining homogeneity scores may be used alone or in combination (e.g., 2 homogeneous, 2 heterogeneous, 3 homogeneous, 3 heterogeneous, etc.). In another instance, an increase in FOLR1 expression can be determined by detecting an increase of at least 2, 3, or 5 times relative to a control (e.g., the expression level in tissues or cells from subjects who do not have cancer or have cancer with no elevated FOLR1 values).

[0156] In some embodiments, the cancer is cancer expressing FOLR1 at a heterogeneous level of 1 or higher as determined by IHC. In some embodiments, the cancer is cancer expressing FOLR1 at a heterogeneous level of 2 or higher as determined by IHC. In some embodiments, the cancer is cancer expressing FOLR1 at a heterogeneous level of 3 or higher as determined by IHC. In some embodiments, the cancer is lung cancer expressing FOLR1 at a heterogeneous level of 2 or higher as determined by IHC. In some embodiments, the cancer is lung cancer expressing FOLR1 at a heterogeneous level of 3 or higher as determined by IHC. In some embodiments, the cancer is ovarian cancer expressing FOLR1 at a heterogeneous level of 2 or higher as determined by IHC. In some embodiments, the cancer is ovarian cancer expressing FOLR1 at a heterogeneous level of 3 or higher as determined by IHC. In some embodiments, the cancer is endometrial cancer expressing FOLR1 at a heterogeneous level of 1 or higher as determined by IHC. In some embodiments, the cancer is endometrial cancer expressing FOLR1 at a heterogeneous level of 2 or higher as determined by IHC.

[0157] In some embodiments, the method of inhibiting tumor growth includes administering a therapeutically effective amount of the FOLR1 binder to a subject. In some embodiments, the subject is a human being. In some embodiments, the subject has a tumor or the tumor has been removed.

[0158] Furthermore, the present invention provides a method for reducing the tumorigenicity of a tumor in a subject, the method comprising administering a therapeutically effective amount of a FOLR1 binder to the subject. In some embodiments, the tumor comprises cancer stem cells. In some embodiments, the frequency of cancer stem cells in the tumor is reduced by administering the agent.

[0159] The present invention also provides pharmaceutical compositions comprising one or more FOLR1 binders described herein. In some embodiments, the pharmaceutical compositions further comprise a pharmaceutically acceptable mediator. These pharmaceutical compositions can be used to inhibit tumor growth and treat cancer in human patients.

[0160] In some embodiments, formulations are prepared for storage and use by combining the purified antibodies or agents of the present invention with pharmaceutically acceptable mediators (e.g., carriers, excipients) (Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000). Suitable pharmaceutically acceptable mediators include, but are not limited to, non-toxic buffers such as phosphoric acid, citric acid, and other organic acids; salts such as sodium chloride; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzyl methylammonium chloride; benzyl ethoxymmonium chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight peptides (e.g., less than about 10). (Amino acid residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and nonionic surfactants such as TWEEN or polyethylene glycol (PEG).

[0161] The pharmaceutical compositions described herein can be administered in any manner for local or systemic treatment. Administration can be local (e.g., to mucous membranes, including vaginal and rectal delivery), such as transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders; pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal, epidermal, and transdermal); oral; or parenteral, including intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. In some specific embodiments, administration is intravenous.

[0162] In drug combination formulations or dosing regimens, antibodies or immunodrug conjugates may be combined with a second compound as a combination therapy. In some embodiments, the second compound is a steroid. In some embodiments, the method encompasses the administration of a steroid and an immunodrug conjugate, resulting in a reduction in headache compared to administration of the immunodrug conjugate alone.

[0163] Steroids may be administered concurrently with, before, and / or after the administration of an immunodrug conjugate. 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 immunodrug conjugate. In some embodiments, the steroid is administered within one day of the administration of the immunodrug conjugate. 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 immunodrug conjugate. Steroids may be administered in any manner, including, for example, topical, pulmonary, oral, parenteral, or intracranial administration. In some embodiments, administration is oral. In some embodiments, administration is intravenous. In some embodiments, administration is both oral and intravenous.

[0164] In combination drug formulations or dosing regimens, antibodies or immunodrug conjugates may also be combined with analgesics or other agents for the prevention or treatment of headaches as a combination therapy. For example, acetaminophen and / or diphenhydramine may be administered in addition to the antibody or immunodrug conjugate. The analgesic may be administered before, simultaneously with, or after the administration of the immunodrug conjugate and may be administered via any suitable route of administration. In some embodiments, the analgesic is administered orally.

[0165] In some embodiments, the method includes administering a first compound as an antibody or immunoconjugate, a second compound as a steroid, and a third compound as an analgesic. In some embodiments, the method includes administering a first compound as IMGN388, a second compound as dexamethasone, and a third compound as acetaminophen and / or diphenhydramine.

[0166] In drug combination formulations or dosing regimens, antibodies or immunodrug conjugates may be combined with a second compound having anticancer properties as a combination therapy. The second compound in the drug combination formulation or dosing regimen may have complementary activity to the combined ADCs so that they do not adversely affect each other. Pharmaceutical compositions comprising a FOLR1 binder and a second anticancer agent are also provided.

[0167] *** The embodiments of this disclosure can be further defined by referring to 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 practiced without departing from the scope of this disclosure.

[0168] Example It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations thereof are to be suggested to those skilled in the art and are included within the spirit and scope of this application.

[0169] Example 1 IMGN853 dosing trial in human cancer patients IMGN853 is an antibody-drug conjugate (ADC) comprising a folate receptor 1 (FOLR1) binding antibody and a potent maytansine DM4. IMGN853 has been previously described in international publications WO 2011 / 106528, WO 2012 / 135675, and WO2012 / 138749, and in U.S. publications 2012 / 0009181, 2012 / 0282175, and 2012 / 0282282, each of which is incorporated herein by reference in its entirety. IMGN853 is huMov19-sSPDB-DM4, and the huMov19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:3 and a variable light chain having the amino acid sequence of SEQ ID NO:5. FOLR1 protein is expressed at elevated levels in many solid tumors, particularly epithelial ovarian cancer (EOC), endometrial cancer, non-small cell lung cancer (NSCLC), and clear cell renal cell carcinoma.

[0170] Studies will begin to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IMGN853, as well as to assess its safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. These studies will consist of two components: an accelerated dose titration component, in which IMGN853 immunoconjugate is administered to patients with any type of FOLR1-expressing refractory solid tumor, including epithelial ovarian cancer (EOC) and other FOLR1-positive solid tumors; and a dose escalation component.

[0171] For the accelerated titration portion of the study, IMGN853 was administered intravenously (IV) on day 1 of each 21-day (3-week) cycle. Twenty-nine patients have been recruited in the accelerated portion of the clinical trial at seven dose levels ranging from 0.15 to 7.0 mg / kg IMGN853, and safety data are currently available for 23 patients. No study drug-related adverse events of any grade were reported in patients treated in the initial four dose groups. At doses up to 5.0 mg / kg, IMGN853-related adverse events were mild to moderate. Ocular toxicity was reported in 4 out of 10 patients at the 5.0 and 7.0 mg / kg dose levels, and in 5 out of 5 patients, respectively.

[0172] Table 1: Recruitment by Tumor Type Drug exposure was measured in 23 patients and a linear increase was found overall, among whom... > At a dose of 2.0 mg / kg, it has a half-life of approximately 5 days. One patient with serous endometrial cancer also had a CA125 response and an unconfirmed partial response at 5 mg / kg. Three patients with ovarian cancer reported confirmed CA125 responses (one at 7 mg / kg, one at 5 mg / kg, and one at 3.3 mg / kg). Patients receiving IMGN853 at doses greater than or equal to 5.0 mg / kg received dexamethasone, 10 mg IV (or a similar steroid equivalent), 30 to 60 minutes prior to administration of the anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0173] Pharmacokinetic (PK) parameters are reported for cycle 1 of the IMGN853 phase 1 trial (the first cycle of dosing for each patient only). Figure 1A and 1BThe clearance of IMGN853 was rapid at low doses (CL = 1.1 mL / hr / kg), with a half-life of approximately 35.4 hours or 1.5 days. Clearance decreased at higher doses (CL = 0.4 mL / hr / kg), and the half-life increased to approximately 4 days or approximately 5 days at doses ≥ 2.0 mg / kg. Exposure (AUC) and Cmax also generally increased at higher doses.

[0174] At a dose of 7.0 mg / kg, all 5 patients experienced ocular toxicity. One patient was reported to have grade 3 dose-limited punctate keratitis and grade 2 blurred vision, which were considered definitively related to the study treatment. Additionally, one patient had grade 3, 2, and 1 blurred vision individually; all events were considered probable or definitively related to IMGN853 treatment. Therefore, the maximum tolerated dose according to this dosing schedule (i.e., every three weeks) was considered to exceed the 7.0 mg / kg dose level, and all patients maintained at the 7.0 mg / kg dose level were dosed back to the previous dose level (5.0 mg / kg), and 7 additional patients were evaluated at a dose of 5 mg / kg. Together with the 3 previously treated patients, 10 patients were treated at a dose of 5 mg / kg. Of the total 10 patients at the 5 mg / kg level, 3 had blurred vision, including 1 patient with grade 3 blurred vision, and 2 patients had corneal changes. Other relevant grade 3 adverse events included elevated alkaline phosphatase and grade 3 hypophosphatemia. In addition, patients were recruited to a 3.3 mg / kg dose level to further explore and confirm the safety profile observed in the three patients initially assigned to this dose. Safety reviews are currently underway in six additional patients treated at 3.3 mg / kg, and IMGN853 is well tolerated. To date, three of the nine patients treated at the 3.3 mg / kg dose level have reported IMGN853-related adverse events, including grade 2 peripheral neuropathy (1 patient), grade 2 nausea, fatigue, and elevated AST (1 patient), and one patient experienced grade 2 vomiting.

[0175] Once the MTD is determined, the study will proceed to the dose escalation phase. Three escalation groups will evaluate patients with positive FOLR1 protein in (1) platinum-resistant epithelial ovarian cancer; (2) recurrent or refractory epithelial ovarian cancer; and (3) recurrent or refractory non-small cell lung cancer (NSCLC). Groups 2 and 3 will be assessed for IMGN853 PD by pre- and post-dose tumor biopsy and / or by FLT-PET imaging, respectively. IMGN853 will be administered at a dose of at least 3.3 mg / kg and may include doses of 5.0 mg / kg or up to 6.0 mg / kg or even 7.0 mg / kg. Initially, IMGN853 should be administered at a rate of 1 mg / min; after 30 minutes, if well tolerated, the rate may be increased to 3 mg / min. If well tolerated after 30 minutes at 3 mg / min, the rate may be increased to 5 mg / min. Subsequent infusions may be delivered at a tolerated rate.

[0176] For all IMGN853 administrations at 3.3 mg / kg or higher, prophylactic steroid therapy will be incorporated using the regimen described in Example 2 (e.g., steroid therapy will be incorporated 30 to 60 minutes prior to the required IMGN853 administration with 10 mg dexamethasone IV (or a similar steroid equivalent), and prophylactic diphenhydramine HCl and acetaminophen are recommended prior to IMGN853 administration). The cycle will be repeated until (i) the patient's disease worsens, (ii) the patient experiences unacceptable toxicity, (iii) the patient withdraws informed consent, (iv) the patient develops comorbidities that will prevent further investigational treatment, or (v) the patient discontinues treatment due to non-compliance or administrative reasons.

[0177] Response was assessed using RECIST and Gynecologic Cancer Group (GCIG) criteria (where appropriate).

[0178] Example 2 For the prevention of infusion reactions using IMGN853-based steroids To reduce the likelihood of infusion reactions, any of the following steroid-based preventative measures can be used.

[0179] (1) Patients receive dexamethasone, 10 mg IV (or a similar steroid equivalent) 30 to 60 minutes prior to administration of an anti-FOLR1 immunoconjugate (e.g., IMGN853).

[0180] (2) Patients should receive dexamethasone, 10 mg IV (or a similar steroid equivalent), and diphenhydramine HCl (25-50 mg IV or PO), with or without acetaminophen (325-650 mg IV or PO), 30 to 60 minutes prior to administration of an anti-FOLR1 immunoconjugate (e.g., IMGN853). This prophylactic regimen is recommended and subject to investigator's discretion.

[0181] (3) The patient receives dexamethasone 8 mg (or a similar steroid equivalent) by oral BID the day prior to administration of the anti-FOLR1 immunodrug (e.g., IMGN853). On the day prior to administration of the anti-FOLR1 immunodrug (e.g., IMGN853), 30–60 minutes before administration, the patient receives dexamethasone 10 mg IV (or a similar steroid equivalent), diphenhydramine HCl (25–50 mg IV or PO), with or without acetaminophen (325–650 mg IV or PO).

[0182] (4) Administer orally within 24 hours prior to infusion of steroids (e.g., dexamethasone).

[0183] Example 3 The relationship between IMGN853 exposure and ocular toxicity For each patient treated with the IMGN853 regimen described in Examples 1 and 2, plasma concentrations of IMGN853 were measured at different time points within each cycle, beginning at the end of infusion and continuing until day 21. Pharmacokinetic (PK) parameter analysis identified a clear association between Cmax and the occurrence of ocular toxicity, characterized by corneal deposition and loss of visual acuity. This was achieved, as indicated by the area under the curve (AUC) in the first 24 hours. 0-24 Statistically significant associations were also observed at early exposure levels. (See Figures 2A-2C.) In the 3.3 to 7.0 mg / kg groups, the Cmax value was at or above 147.7. Ocular toxicity was observed in 9 / 10 patients with Cmax values ​​below 147.7 µg / ml, indicated by the dashed line in Figure 2A. No ocular toxicity developed in patients with Cmax values ​​below 147.7 µg / ml. AUC 0-24 At or above 2785 hr* All (9 / 9) patients (indicated by dashed lines in Figure 2B) with an active concentration of ≥ 3.3 μg / ml developed ocular toxicity, while none with concentrations below this level experienced any ocular toxicity. An efficacy signal was observed at doses ≥ 3.3 mg / kg and was not associated with reports of ocular toxicity. The lowest Cmax value among patients exhibiting an active signal was 91.25 µg / ml.

[0184] Following treatment with IMGN853 at doses of 3.3 mg / kg, 5.0 mg / kg, or 7.0 mg / kg in 24 patients, Fisher's exact test was used to determine that Cmax values ​​above the threshold were associated with ocular toxicity (inversely), p = 0.00004. Fisher's exact test was also used to determine AUC values ​​above the threshold level of 2,741 hr*µg / ml. 0-24 The value was also correlated with ocular toxicity (inversely), p = 0.00001. Based on these results and calculations using calibration time and concentration values, the determined Cmax was greater than approximately 150 µg / ml or AUC. 0-24 Patients with values ​​greater than 2785 hr*µg / ml are most likely to have an increased rate of ocular toxicity, and patients with an active signal have a Cmax level of at least approximately 90 µg / mg. Strategies are being developed to modify dosing to reduce the variability observed at each dose level and to achieve a Cmax level for optimal efficacy and minimal toxicity at each patient's body weight.

[0185] Example 4 IMGN853 Alternative Dosage Methods As described above in Example 3, Cmax values ​​above 150 µg / ml and AUC values ​​above 2785 hr*µg / ml were observed at all dose levels. 0-24 The correlation between values ​​and the occurrence of ocular toxicity. Furthermore, initial PK parameter analysis demonstrated that although Cmax increased proportionally with the dose of IMGN853, there were variations in Cmax and AUC within the dose level. 0-24 and significant changes in distribution volume ( Figure 3 ).

[0186] Changes in Cmax were particularly significant in the 5 mg / kg group, with pharmacokinetic (PK) analyzed in 10 patients. No significant changes in Cmax were observed in patients throughout the cycle, and infusion time was similar among patients and not associated with changes in Cmax. Covariate analysis demonstrated an association between weight and Cmax. Figure 4 ).

[0187] Volume distribution (V) ssThe plasma volume of the biologic agent is indicated and does not increase linearly with weight. The change is reduced when the Cmax value is normalized by Vss. These data suggest that exploring alternative dosing methods other than total body weight can produce more uniform dosing within groups. For this purpose, Cmax values ​​were estimated using alternative dosing calculations for all patients treated in the 3.3 (n=3), 5.0 (n=10), and 7 mg / kg (n=5) dose groups. The calculated Cmax values ​​were normalized to the 5 mg / kg dose level and compared with Cmax values ​​obtained from dosing based on total body weight (TBW). Body surface area (BSA) was also considered; however, Cmax values ​​based on BSA decreased Cmax, but the change was minimal and a positive correlation between body weight and Cmax was still observed, but to a lesser extent. Three additional alternative formulations were evaluated: (1) ideal body weight (IBW), lean body weight (LBW), and adjusted body weight (ADJ). Formulations for each of IBW, LBW, ADJ, and BSA are provided below: Ideal body weight (IBW) IBW (male) = 0.9H-88 IBW (female) = 0.9H-92 (Where H = height (cm)) Lean body mass (LBW) Male = 1.10 × weight (kg) – 128 ([weight (kg)]) 2 / [100 × height (m)] 2 ) Female = 1.07 × weight (kg) – 148 ([weight (kg)]) 2 / [100 × height (m)] 2 ) Adjusted ideal weight (AIBW or ADJ) IBW + 0.4 (Actual weight (kg) – IBW) Body Surface Area (BSA) – Mosteller Formula BSA (m 2 = (Height (cm) × Weight (kg) / 3600) ½ Body surface area (BSA) – Boyd Formula BSA (m 2 ) = (0.0003207 × height (cm) 0.3 × weight (grams) (0.7285 - ( 0.0188 x LOG(克) )] The mean Cmax values ​​for IBW, LBW, AIBW (ADJ), and TBW were 93.06, 82.72, 110.77, and 137.46 µg / ml, respectively. Furthermore, all three alternative measures reduced the standard deviation of Cmax (21.7, 20.5, 22.9 vs. 33.7 µg / ml for TBW). (See also...) Figure 5 。 ) As mentioned above, a positive correlation was observed between TBW and Cmax. Correlation analysis of IBW and LBW on weight curves confirmed a negative correlation with weight. AIBW administration (ADJ) showed a small weight-dependent effect on weight (see [link]). Figure 6 It is similar to BSA but has fewer PK variations.

[0188] IBW, LBW, or AIBW administration (ADJ) produces lower weight dependence compared to TBW administration. Based on current data, AIBW administration (ADJ) produces the smallest change in Cmax.

[0189] Based on total weight (see Figure 7 An AUC was observed in 24 patients who received 3.3, 5, or 7 mg / kg IMGN853 (TBW Real). 0-24 Value. Additionally, based on an adjusted ideal weight (see...) Figure 7 An AUC was observed in 7 patients who received 5 mg / kg IMGN853 (“5 ADJ Reality”). 0-24 Values. These actual values ​​obtained in the case of 24 patients will be compared with those in those same patients who have all been based on a total repetition of 5 mg / kg ( Figure 7 In cases of treatment with “TBW 5 mg / kg” or with 5, 5.4 or 6 mg / kg (which are all based on adjusted ideal body weight) Figure 7 The predicted values ​​obtained from treatment with "ADJ 5 mg / kg", "ADJ 5.4 mg / kg", and "ADJ 6 mg / kg" will be compared. For example, in... Figure 7 As shown in the table, administration of 5 mg / kg IMGN853 based on AIBW (ADJ) resulted in an expected AUC exceeding the ocular toxicity-related AUC. 0-24 The number of patients with a threshold level of 2741 hr*µg / ml was minimized. Furthermore, only 14% of the 7 patients receiving 5 mg / kg IMGN853 based on AIBW (ADJ) achieved an AUC higher than 2741 hr*µg / ml. 0-24 The levels were higher in 38% of patients receiving 3.3, 5, or 7 mg / kg IMGN853 based on TBW, while these levels were higher in 38% of patients. AUC was calculated using calibration time and concentration values. 0-24The original analysis yielded a value of 2785 hr* µg / ml. When recalculated using actual time, the result was for AUC. 0-24 Slight modifications to the determination of the value and the threshold of 2741 hr* µg / ml.

[0190] Patients were subsequently treated with 5 mg / kg based on adjusted ideal body weight, 6 mg / kg based on adjusted ideal body weight, 5 mg / kg based on total body weight, or 7 mg / kg based on total body weight. The AUC observed in these patients... 0-24 Value at Figure 8 The values ​​are shown in the “Actual” section and compared to the predicted values ​​(“Proj”) that would have been obtained if all these patients had been treated with 5 mg / kg based on adjusted ideal body weight, 6 mg / kg based on adjusted ideal body weight, 5 mg / kg based on total body weight, or 7 mg / kg based on total body weight. Dosing based on adjusted ideal body weight reduced variability in early exposure levels and reduced ocular adverse events, as shown in Table 2 below. Specifically, only one patient receiving 5 mg / kg based on adjusted ideal body weight experienced Grade 1 visual impairment, and three patients receiving 6 mg / kg based on adjusted ideal body weight experienced Grade 1–2 ocular toxicity. In contrast, doses based on total body weight of 5 mg / kg or more were associated with more patients experiencing ocular adverse events and with the occurrence of Grade 3 ocular adverse events.

[0191] Table 2: Reported ocular adverse events (OAEs) under drug administration based on adjusted ideal body weight (all reversible) 1 There were no Level 4 adverse events.

[0192] 2 A patient reported visual impairment.

[0193] 3 One patient had grade 2 blurred vision and punctate keratitis; one patient had grade 2 retinopathy; and one patient had grade 1 blurred vision and floaters.

[0194] Example 5 IMGN853 Replacement Plan Population PK models were generated based on the rich and sparse (peak and trough) concentration-time profiles of IMGN853 after Q3W dosing (incremental dose). As described above, the PK of IMGN853 appears to be linear over the studied dose range.

[0195] This model is used to stimulate steady-state exposure of IMGN853 for the following candidate schemes: 1 to 2.5 mg / kg QW (10 dose levels in 0.15 mg / kg increments) 2 to 5 mg / kg Q2W (10 dose levels in 0.3 mg / kg increments) 1 to 2.5 mg / kg QWx4 followed by Q2Wx4 (10 dose levels in 0.15 mg / kg increments) 1 to 2.5 mg / kg QWx3 over 4 weeks (10 dose levels in 0.15 mg / kg increments) The QWx4 dosing regimen followed by the Q2Wx4 dosing regimen produced the least accumulation over time (i.e., an accumulation index of 1), while the QW dosing regimen produced the highest accumulation (i.e., an accumulation index of 1.97). In 4W, QWx3 allowed for an increase in overall exposure of approximately 3-fold, while limiting Cmax to levels below those observed in ocular toxicity cases (Table 3).

[0196] Table 3 The population pharmacokinetic model was also used to stimulate a hypothetical population of 500 patients via Monte Carlo resampling. Descriptive statistics were generated to determine the population with Cp. max The dosing regimen was optimized to suit the safety profile of IMGN853 in cases where the percentage of subjects had a concentration of <150 µg / ml. For the 4-week regimen with QWx3, dose levels of 1.5, 2.0, and 2.5 mg / kg produced 99%, 95%, and 90% of the populations, respectively, with C max < 150 µg / ml.

[0197] Example 6 In vivo antitumor activity and predicted pharmacokinetics of multiple doses of IMGN853 Plasma concentrations of the intact IMGN853 conjugate administered intravenously at a dose of 10 mg / kg were determined by ELISA at different time points following injection in female CD-1 mice. Pharmacokinetic (PK) analysis was performed using the standard algorithm WinNonlin, Professional version 6.1 (Pharsight, Mountain View, CA) of the non-compartmental pharmacokinetic analysis program (201). The maximum concentration (Cmax) and the area under the concentration-time curve (AUC) were estimated. 0-∞ ), the half-life (t) in the terminal elimination period 1 / 2 Total blood clearance (CL) and volume of distribution at steady state (Vss) were used to evaluate the efficacy of the conjugate t. 1 / 2The value of the first-order rate constant was evaluated using concentration data from days 1 to 28 post-administration for the determination of antibody t. 1 / 2 The value of the first-order rate constant. Based on measurements generated at a dose of 10 mg / kg, PK stimulation with WinNonlin was performed at different dose levels in both single-dose and multi-dose schedules. Parameters were compared with those obtained from evaluating the antitumor activity of IMGN853 in NCI-H2110 (non-small cell lung cancer, NSCLC) xenografts in female SCID mice under different dose levels and schedules.

[0198] When IMGN853 was administered as a single injection, dose-dependent antitumor activity was observed in the NCI-H2110 model. High activity was observed at all dose levels (2.8, 5.6, and 8.5 mg / kg) with T / C values ​​<10%, but an increase in the number of complete tumor regressions (CRs) was observed with increasing IMGN853 doses. This predicted plasma pharmacokinetic parameter also showed Cmax (maximum plasma concentration), Cavg (mean plasma concentration), and exposure (AUC). 0-540 The dose-dependent increase (within hours) is observed. Therefore, the activity of a single dose of IMGN853 is shown to be dose-dependent and predictable based on plasma PK parameters, such as... Figure 9 As shown in the image.

[0199] Compared to single-dose activity, the multi-dose schedule for IMGN853 shows that activity is independent of Cmax ( Figure 10 IMGN853 administered at a daily or 3-day schedule at a dose of 2.8 mg / kg x 3 (total dose of 8.4 mg / kg) showed similar activity to a single dose of IMGN853 at 8.5 mg / kg. Interestingly, the total exposure (AUC) and mean plasma concentration (Cavg) of the conjugate were comparable between the treatment groups, while Cmax was highest in the 8.5 mg / kg single-dose group. The activity observed using a multi-dose schedule suggests greater activity with this administration method, as the presence of tumor-free animals at the end of the study was observed in the single high-dose group.

[0200] Additional IMGN853 dose levels and schedules were used to assess the activity of NCI-H2110 xenografts, with results consistently demonstrating that multiple doses were equivalent in activity or had better activity than a single dose of IMGN853. The predicted mean plasma concentration of IMGN853 as a single dose of 5.6 mg / kg was comparable to the mean plasma concentration of 1.4 mg / kg daily for 3 days. Despite the lower total dose (4.2 mg / kg), Cmax, and exposure (AUC)... 0-540However, 1.4 mg / kg qd x3 exhibits considerable in vivo antitumor activity. Figure 11 These results indicate that maintaining a specific minimum plasma concentration is crucial for activity.

[0201] A weekly regimen of IMGN853 with a total dose matched to a single high dose of IMGN853 was also found to have comparable in vivo activity. Figure 12 Again, maintaining a mean plasma concentration above the minimum threshold is necessary for activity, with a single dose of IMGN853 (8.5 mg / kg) producing slightly higher Cavg and AUC but with comparable overall activity. A key difference in predicted pharmacokinetic parameters using a single-dose versus multi-dose schedule is the significant reduction in Cmax. Weekly dosing was predicted to result in a Cmax that was almost 60% lower than that of a single dose of IMGN853. Since there is no significant activity benefit from achieving a higher Cmax, avoiding high plasma concentrations may be beneficial in reducing toxicity.

[0202] **** It should be understood that the detailed description, rather than the summary and abstract, is intended to interpret the claims. The summary and abstract present one or more, but not all, exemplary embodiments of the invention as conceived by the inventors, and are therefore not intended to limit the invention and the appended claims in any way.

[0203] The invention has been described above by way of functional components illustrating the implementation of specified functions and their relationships. The boundaries of these functional components have been arbitrarily defined herein for the sake of descriptive convenience. Alternative boundaries may be defined provided that the specified functions and their relationships are properly performed.

[0204] The foregoing description of the specific embodiments so fully reveals the general nature of the invention that others can readily modify and / or adapt such specific embodiments for different applications without departing from the overall concept of the invention and without excessive experimentation, by applying knowledge of the art. Therefore, based on the teachings and guidance presented herein, such modifications and adaptations are intended to be in the sense and scope of equivalents to the disclosed embodiments. It should be understood that the wording or terminology herein is for descriptive rather than limiting purposes, and that the terminology or terminology of this specification should be interpreted by those skilled in the art based on the teachings and guidance presented.

[0205] The breadth and scope of this invention should not be limited to any of the exemplary embodiments described above, but should be defined only by the following claims and their equivalents.

[0206] sequence SEQ ID NO:1 – Human folate receptor 1 SEQ ID NO:2 – Human folate receptor 1 nucleic acid sequence SEQ ID NO:3 - huMov19 vHC SEQ ID NO:4 - huMov19 vLCv1.00 SEQ ID NO:5 - huMov19 vLCv1.60 SEQ ID NO:10 - huMov19 vHC CDR2 – Kabat Definition SEQ ID NO:11 – huMov19 vHC CDR2 – Abm definition SEQ ID NO:12 - huMov19 vHC CDR3 SEQ ID NO:13 - huMov19 HC amino acid sequence SEQ ID NO:15 - huMov19 LCv1.60 SEQ ID NO:16 – muMov19 vHC CDR2 – Kabat definition

Claims

1. A method for treating a human patient with cancer expressing FOLR1, the method comprising administering an immunoconjugate conjugate to the patient, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 mg per kilogram (kg) of the patient’s body weight, wherein the patient’s body weight is adjusted to an adjusted ideal body weight (AIBW).

2. The method of claim 1, wherein the application produces a Cmax of about 90-160 µg / mL.

3. The method of claim 2, wherein the application produces a Cmax of about 90-150 µg / mL.

4. The method according to any one of claims 1-3, wherein the application produces an area under the curve (AUC) not exceeding 2700 hr•µg / mL. 0-24 .

5. The method of any one of claims 1-4, wherein the immunoconjugate is administered at a dose of about 5.0 mg / kg.

6. The method of any one of claims 1-4, wherein the immunoconjugate is administered at a dose of about 6.0 mg / kg.

7. The method of any one of claims 1-4, wherein the immunoconjugate is administered at a dose of about 6.5 mg / kg.

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

9. The method of any one of claims 1-4, wherein the immunoconjugate is administered once weekly.

10. A method for treating a human patient with cancer expressing FOLR1, the method comprising administering an immunoconjugate binding a FOLR1 peptide to the patient, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 mg per kilogram (kg) of the patient's body weight, and wherein the administration produces a Cmax of about 110-160 µg / mL.

11. The method of claim 10, wherein the application produces a Cmax of about 110-150 µg / mL.

12. A method for treating a human patient with cancer expressing FOLR1, the method comprising administering an immunoconjugate conjugate binding to the patient, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 mg per kilogram (kg) of the patient's body weight, and wherein the administration produces an AUC not exceeding 2700 hr•µg / mL. 0-24 .

13. The method of any one of claims 1-12, wherein the immunoconjugate comprises an antibody or an antigen-binding fragment thereof, said antibody or antigen-binding fragment comprising the CDR of SEQ ID NO: 6-9, 11 and 12.

14. The method of claim 13, wherein the antibody is huMov19.

15. The method of any one of claims 1-14, wherein the immunoconjugate comprises maytansin.

16. The method of claim 15, wherein the maytenin is DM4.

17. The method of any one of claims 1-16, wherein the immunoconjugate comprises a linker sulfonyl-SPDB.

18. The method of any one of claims 1-17, wherein the immunoconjugate is IMGN853.

19. The method of any one of claims 1-18, wherein the immunoconjugate is administered intravenously.

20. The method of any one of claims 1-19, wherein the cancer is selected from the group consisting of: ovarian cancer, brain cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, kidney cancer, and lung cancer.

21. The method of claim 20, wherein the lung cancer is non-small cell lung cancer.

22. The method of claim 21, wherein the non-small cell lung cancer is adenocarcinoma.

23. The method of claim 20, wherein the ovarian cancer is epithelial ovarian cancer.

24. The method of claim 23, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory.

25. The method of claim 20, wherein the cancer is endometrial cancer.

26. The method of any one of claims 1-25, wherein the sample obtained from the patient exhibits FOLR1 expression, as measured by immunohistochemistry (IHC).

27. The method of claim 26, wherein the sample has at least two heterogeneous staining intensities.

28. The method of claim 26, wherein the sample has at least two homogeneous staining intensities.

29. The method of claim 26, wherein the sample has at least 3 heterogeneous staining intensities.

30. The method of claim 26, wherein the sample has at least 3 homogeneous staining intensities.

31. The method of any one of claims 1-30, further comprising administering a steroid to the patient.

32. The method of claim 31, wherein the steroid is dexamethasone.

33. The method of any one of claims 1-32, wherein the application causes a reduction in tumor size.

34. The method of any one of claims 1-20, 23, 24 and 26-33, wherein the cancer is ovarian cancer and wherein the administration causes a decrease in CA125.

35. The method of any one of claims 1-34, wherein the application causes a reduction in toxicity.

36. The method of claim 35, wherein the toxicity is ocular toxicity.

37. The method of any one of claims 1-36, further comprising administering a second compound having anticancer properties.

38. The method of any one of claims 1-3, 5-11, and 13-37, wherein the administration produces an AUC not exceeding 2785 hr•µg / mL. 0-24 .

39. The method according to any one of claims 1-3, 5-11 and 13-37, wherein the administration produces an AUC not exceeding 2741 hr•µg / mL. 0-24 .

40. A method for treating a human patient with cancer expressing FOLR1, the method comprising administering to the patient an effective dose of an immunoconjugate binding a FOLR1 peptide, wherein the administration produces an AUC not exceeding 2741 hr•µg / mL. 0-24 .

41. The method of claim 40, wherein the application produces a Cmax of not more than 160 µg / mL.

42. The method of claim 41, wherein the application produces a Cmax of not more than 150 µg / mL.

43. The method of any one of claims 40-42, wherein the immunoconjugate comprises an antibody or an antigen-binding fragment thereof, said antibody or antigen-binding fragment comprising the CDR of SEQ ID NO: 6-9, 11 and 12.

44. The method of claim 43, wherein the antibody is huMov19.

45. The method of any one of claims 40-44, wherein the immunoconjugate comprises maytansin.

46. ​​The method of claim 45, wherein the maytenin is DM4.

47. The method of any one of claims 40-46, wherein the immunoconjugate comprises a linker sulfonyl-SPDB.

48. The method of any one of claims 40-47, wherein the immunoconjugate is IMGN853.

49. The method of any one of claims 40-48, wherein the immunoconjugate is administered intravenously.

50. The method of any one of claims 40-49, wherein the cancer is selected from the group consisting of: ovarian cancer, brain cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, kidney cancer, and lung cancer.

51. The method of claim 50, wherein the lung cancer is non-small cell lung cancer.

52. The method of claim 51, wherein the non-small cell lung cancer is adenocarcinoma.

53. The method of claim 50, wherein the ovarian cancer is epithelial ovarian cancer.

54. The method of claim 53, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory.

55. The method of claim 50, wherein the cancer is endometrial cancer.

56. The method of any one of claims 40-55, wherein the sample obtained from the patient exhibits FOLR1 expression, as measured by immunohistochemistry (IHC).

57. The method of claim 56, wherein the sample has at least two heterogeneous staining intensities.

58. The method of claim 56, wherein the sample has at least two homogeneous staining intensities.

59. The method of claim 56, wherein the sample has at least 3 heterogeneous staining intensities.

60. The method of claim 56, wherein the sample has at least 3 homogeneous staining intensities.

61. The method of any one of claims 40-60, further comprising administering a steroid to the patient.

62. The method of claim 61, wherein the steroid is dexamethasone.

63. The method of any one of claims 40-62, wherein the application causes a reduction in tumor size.

64. The method of any one of claims 40-50, 53, 54 and 56-63, wherein the cancer is ovarian cancer and wherein the administration causes a decrease in CA125.

65. The method of any one of claims 40-64, wherein the application causes a reduction in toxicity.

66. The method of claim 65, wherein the toxicity is ocular toxicity.

67. The method of any one of claims 40-66, further comprising administering a second compound having anticancer properties.

68. A method for treating a human patient with cancer expressing FOLR1, the method comprising administering to the patient an immunoconjugate binding to a FOLR1 peptide, wherein the immunoconjugate is administered once a week for three weeks according to a four-week schedule.

69. The method of claim 68, wherein the immunoconjugate is administered on days 1, 8, and 15 of the four-week schedule.

70. The method of claim 68 or 69, wherein the application produces a Cmax of about 90-160 µg / mL.

71. The method of claim 70, wherein the application produces a Cmax of about 90-150 µg / mL.

72. The method of claim 68 or 69, wherein the application produces a Cmax of about 110-160 µg / mL.

73. The method of claim 72, wherein the application produces a Cmax of about 110-150 µg / mL.

74. The method of any one of claims 68-73, wherein the administration produces an AUC not exceeding 2700 hr•µg / mL. 0-24 .

75. The method of any one of claims 68-74, wherein the immunoconjugate is administered at a dose of about 1.5 to about 6 mg / kg.

76. The method of claim 75, wherein the immunoconjugate is administered at a dose of about 1.5, 2.0, 2.5, 3, 3.3, 4.0, 4.1, 4.2, 5.0, 5.5 or 6.0 mg / kg.

77. The method of any one of claims 68-76, wherein the immunoconjugate comprises an antibody or an antigen-binding fragment thereof, the antibody or the antigen-binding fragment thereof comprising the CDR of SEQ ID NO: 6-9, 11 and 12.

78. The method of claim 77, wherein the antibody is huMov19.

79. The method of any one of claims 68-78, wherein the immunoconjugate comprises maytansin.

80. The method of claim 79, wherein the maytenin is DM4.

81. The method of any one of claims 68-80, wherein the immunoconjugate comprises a linker sulfonyl-SPDB.

82. The method of any one of claims 68-81, wherein the immunoconjugate is IMGN853.

83. The method of any one of claims 68-82, wherein the immunoconjugate is administered intravenously.

84. The method of any one of claims 68-83, wherein the cancer is selected from the group consisting of: ovarian cancer, brain cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, kidney cancer, and lung cancer.

85. The method of any one of claims 68-84, further comprising administering a steroid to the patient.

86. The method of claim 85, wherein the steroid is dexamethasone.

87. The method of any one of claims 68-86, wherein the application causes a reduction in tumor size.

88. The method of any one of claims 68-87, wherein the cancer is ovarian cancer and wherein the administration causes a decrease in CA125.

89. The method of any one of claims 68-88, wherein the application causes a reduction in toxicity.

90. The method of claim 89, wherein the toxicity is ocular toxicity.

91. The method of any one of claims 68-90, further comprising administering a second compound having anticancer properties.

92. A method for treating a human patient with cancer expressing FOLR1, the method comprising administering an immunoconjugate binding to a FOLR1 peptide to the patient, wherein the immunoconjugate is administered at a dose of about 1 to about 7 mg per kilogram (kg) of the patient's body weight, wherein the patient's body weight is adjusted to an adjusted ideal body weight and wherein the immunoconjugate is administered once a week for three weeks according to a four-week schedule.

93. The method of claim 92, wherein the immunoconjugate is administered on days 1, 8, and 15 of the four-week schedule.

94. The method of claim 92 or 93, wherein the immunoconjugate is administered at a dose of about 1.1 mg / kg.

95. The method of claim 92 or 93, wherein the immunoconjugate is administered at a dose of about 1.8 mg / kg.

96. The method of claim 92 or 93, wherein the immunoconjugate is administered at a dose of about 2.5 mg / kg.

97. The method of claim 92 or 93, wherein the immunoconjugate is administered at a dose of about 3.3 mg / kg.

98. The method of any one of claims 92-97, wherein the application produces a Cmax of about 90-160 µg / mL.

99. The method of claim 98, wherein the application produces a Cmax of about 90-150 µg / mL.

100. The method of any one of claims 92-99, wherein the application produces a Cmax of about 110-160 µg / mL.

101. The method of claim 100, wherein the application produces a Cmax of about 110-150 µg / mL.

102. The method of any one of claims 92-101, wherein the administration produces an AUC not exceeding 2700 hr•µg / mL. 0-24 .

103. The method of any one of claims 92-102, wherein the immunoconjugate comprises an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising a CDR of SEQ ID NO: 6-9, 11 and 12.

104. The method of claim 103, wherein the antibody is huMov19.

105. The method of any one of claims 92-104, wherein the immunoconjugate comprises maytansin.

106. The method of claim 105, wherein the maytenin is DM4.

107. The method of any one of claims 92-106, wherein the immunoconjugate comprises a linker sulfonyl-SPDB.

108. The method of any one of claims 92-107, wherein the immunoconjugate is IMGN853.

109. The method of any one of claims 92-108, wherein the immunoconjugate is administered intravenously.

110. The method of any one of claims 92-109, wherein the cancer is selected from the group consisting of: ovarian cancer, brain cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, kidney cancer, and lung cancer.

111. The method of claim 110, wherein the lung cancer is non-small cell lung cancer.

112. The method of claim 111, wherein the non-small cell lung cancer is adenocarcinoma.

113. The method of claim 110, wherein the ovarian cancer is epithelial ovarian cancer.

114. The method of claim 113, wherein the epithelial ovarian cancer is platinum-resistant, recurrent, or refractory.

115. The method of claim 110, wherein the cancer is endometrial cancer.

116. The method of any one of claims 92-115, wherein the sample obtained from the patient exhibits FOLR1 expression, as measured by immunohistochemistry (IHC).

117. The method of claim 116, wherein the sample has at least two heterogeneous staining intensities.

118. The method of claim 116, wherein the sample has at least two homogeneous staining intensities.

119. The method of claim 116, wherein the sample has at least 3 heterogeneous staining intensities.

120. The method of claim 116, wherein the sample has at least 3 homogeneous staining intensities.

121. The method of any one of claims 92-120, further comprising administering a steroid to the patient.

122. The method of claim 121, wherein the steroid is dexamethasone.

123. The method of any one of claims 92-122, wherein the application causes a reduction in tumor size.

124. The method of any one of claims 92-110, 113, 114 and 116-123, wherein the cancer is ovarian cancer and wherein the administration causes a decrease in CA125.

125. The method of any one of claims 92-124, wherein the application causes a reduction in toxicity.

126. The method of claim 125, wherein the toxicity is ocular toxicity.

127. The method of any one of claims 92-126, further comprising administering a second compound having anticancer properties.

128. The method of any one of claims 92, 93 and 98-127, wherein the immunoconjugate is administered at a dose of about 2.8 mg / kg.

129. The method of any one of claims 92, 93 and 98-127, wherein the immunoconjugate is administered at a dose of about 3.0 mg / kg.

130. The method of any one of claims 92, 93 and 98-127, wherein the immunoconjugate is administered at a dose of about 3.75 mg / kg.

131. The method according to any one of claims 92-101 and 103-130, wherein the administration produces an AUC not exceeding 2785 hr•µg / mL. 0-24 .

132. The method according to any one of claims 92-101 and 103-130, wherein the administration produces an AUC not exceeding 2741 hr•µg / mL. 0-24 .

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