RU2801307C1 - Anti-folr1 immunoconjugate application schemes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to a method of treating a human patient with FOLR1-expressing cancer which includes administering to the patient an immunoconjugate that binds to a FOLR1 polypeptide, the said immunoconjugate containing an antibody or its antigen-binding fragment containing a complementarity-determining region (CDR)-1 variable light chain (VL) according to SEQ ID NO: 6, CDR-2 VL according to SEQ ID NO: 7, CDR-3 VL according to SEQ ID NO: 8, Variable heavy chain (VH) CDR-1 according to SEQ ID NO: 9, CDR-2 VH according to SEQ ID NO: 11, CDR-3 VH according to SEQ ID NO: 12 and maytansinoid, wherein the said immunoconjugate is administered at a dose of 5 milligrams (mg) per kilogram (kg) of adjusted ideal body weight (AIBW) of a patient, also relates to a method of treating a human patient having FOLR1-expressing cancer comprising administering the composition to the patient containing immunoconjugates that bind to a FOLR1 polypeptide, the said immunoconjugates containing an average of 3–4 DM4 maytansinoid per antibody containing (i) a heavy chain containing the same amino acid sequence as the heavy chain amino acid sequence encoded by the plasmid deposited in the American Type Culture Collection (ATCC) number PTA-10772, and (ii) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited at ATCC number PTA-10774, wherein the DM4 maytansinoids are linked to the antibody via sulfo-SPDB, wherein the immunoconjugates are administered at a dose of 5 milligrams (mg) per kilogram (kg) of the patient's adjusted ideal body weight (AIBW) once every three weeks, and also relates to a method of treating a human patient having FOLR1-expressing cancer, comprising administering to a patient a composition containing immunoconjugates that bind to a FOLR1 polypeptide, the said immunoconjugates containing 3–4 DM4 maytansinoid per antibody containing (i) a heavy chain variable domain comprising SEQ ID NO: 3 and (ii) a light chain variable domain comprising SEQ ID NO: 5 wherein DM4 maytansinoids are bound to the antibody via sulfo-SPDB and the immunoconjugates are administered at a dose of 5 milligrams (mg) per kilogram (kg) of the patient's adjusted ideal body weight (AIBW) once every three weeks, and also applies to the uses of immunoconjugates that bind to a FOLR1 polypeptide in the treatment of FOLR1-expressing cancer.

EFFECT: group of inventions provides reduction of ophthalmic toxicity.

96 cl, 13 dwg, 3 tbl, 6 ex

Description

FIELD OF TECHNOLOGY

[001] The scope of the invention generally relates to methods of administering anti-FOLR1 immunoconjugates for the treatment of diseases such as cancer. The methods provide administration regimens that minimize unwanted side effects.

BACKGROUND OF THE INVENTION

[002] Cancer is one of the leading causes of death in the developed world, with more than one million people diagnosed with cancer in the United States alone, with 500,000 deaths each year. It is generally estimated that more than 1 in 3 people will develop some form of cancer during their lifetime. There are more than 200 different types of cancer, four of which - breast, lung, colon and rectum and prostate - account for more than half of all new cases (Jemal et al., 2003, Cancer J. Clin. 53:5-26).

[003] Folic acid receptor 1 (FOLR1), also known as folic acid receptor-alpha or folic acid-binding protein, is an N-glycosylated protein expressed on the plasma membrane of cells. FOLR1 has a high affinity for folic acid and some reduced folic acid derivatives. FOLR1 mediates the delivery of physiological folate, 5-methyltetrahydrofolate, to the interior of cells.

[004] FOLR1 is overexpressed in the vast majority of ovarian cancers, as well as in many cancers of the uterus, endometrium, pancreas, kidney, lung, and breast, while FOLR1 expression in normal tissues is limited to the apical membrane of epithelial cells in the proximal renal tubules, alveolar pneumocytes of the lung, bladder, testes, choroid plexus and thyroid gland (Weitman SD, et al. , Cancer Res 52 : 3396-3401 (1992); Antony AC, Annu Rev Nutr 16 : 501-521 (1996); Kalli KR, et al Gynecol Oncol 108 : 619-626 (2008)). This pattern of FOLR1 expression makes it a desirable target for FOLR1-targeted cancer therapy.

[005] Since ovarian cancer is usually asymptomatic until a late stage, it is often diagnosed at an advanced stage with a poor prognosis when treated with currently available techniques, usually chemotherapeutic drugs after surgical excision (von Gruenigen V et al., Cancer 112 : 2221- 2227 (2008); Ayhan A et al., Am J Obstet Gynecol 196 : 81 e81-86 (2007); Harry VN et al., Obstet Gynecol Surv 64 : 548-560 (2009)). Thus, there is a clear unmet medical need for more effective ovarian cancer therapy.

[006] Antibodies are increasingly recognized as a promising treatment for these cancers. In addition, immunoconjugates that contain an antibody conjugated to another compound, such as a cytotoxin, are also being explored as a potential therapy. In particular, immunoconjugates containing maytansinoids, which are antifungal and antitumor agents of plant origin, have shown certain beneficial activity. The isolation of three loop macrolides from ethanol extracts of Maytenus ovatus and Maytenus buchananii was first reported by SM Kupchan et al. and is the subject matter of US Pat. However, maytansinoids have unacceptable toxicity, causing both central and peripheral neuropathies and side effects, especially nausea, vomiting, diarrhea, elevated liver function tests, and, less commonly, weakness and lethargy. This general toxicity is reduced to some extent by conjugation of maytansinoids to antibodies, since the antibody conjugate has a toxicity several orders of magnitude lower against antigen negative cells compared to antigen positive cells. However, there is still a need to identify specific regimens for the administration of anti-FOLR1 immunoconjugates that are therapeutically effective in humans but avoid side effects.

BRIEF DESCRIPTION OF THE INVENTION

[007] Provided herein are methods for administering an anti-FOLR1 immunoconjugate in a therapeutically effective regimen that minimizes unwanted side effects. As described in more detail below, administration of the same dose of an anti-FOLR1 immunoconjugate to different patients results in significant variation in the pharmacokinetics of the immunoconjugate (eg, Cmax and AUC). The present inventors have found, and the experiments presented herein demonstrate, that ophthalmic toxicity correlates with high Cmax and high baseline AUC. However, high Cmax and initial AUC are not required to be effective. Accordingly, this document describes methods of treating a patient with cancer comprising administering to the patient an effective dose of an immunoconjugate that binds to FOLR1, wherein the immunoconjugate is administered at a dose of from about 3.0 mg/kg to about 7.0 mg/kg, with kg of body weight bodies are adjusted to ideal body weight (IBW), lean body weight (LBW), or adjusted ideal body weight (ADJ or AIBW). The abbreviations "ADJ" and "AIBW" may be used interchangeably to refer to adjusted ideal body weight. In some embodiments of the invention, kilograms result in AIBW (ADJ). Also described herein are methods of treating a patient with cancer comprising administering to the patient an effective dose of an immunoconjugate that binds to FOLR1, wherein the immunoconjugate is administered once a week for three weeks according to a four-week schedule (e.g., on days 1, 8, and 15 four-week schedule). Also described herein are methods of treating a patient with cancer, comprising administering to the patient an effective dose of an immunoconjugate that binds to FOLR1, wherein the immunoconjugate is administered at a dose of about 1.0 mg/kg to about 7.0 mg/kg, with kg of body weight lead to IBW, LBW, or AIBW (ADJ), and the immunoconjugate is administered once a week for three weeks in accordance with a four-week regimen (for example, on days 1, 8, and 15 of a four-week regimen). The methods described herein may result in reduced toxicity, such as ophthalmic toxicity.

[008] In addition, the methods described herein for the treatment of a patient with cancer, comprising administering to the patient an effective dose of an immunoconjugate that binds to FOLR1, characterized in that the Cmax and the initial value of AUC, which lead to intoxication, are not exceeded. For example, in some embodiments, the administration provides a Cmax of about 90-160 μg/ml, and in some embodiments, the administration provides a Cmax of about 110-160 μg/ml. In some embodiments, administration provides an AUC _0-24 of no more than 2785 h⋅μg/mL. In some embodiments of the invention, administration provides an AUC _{of 0-24} of no more than 2741 h⋅µg/mL. In some embodiments, administration provides an AUC _0-24 of no more than 2700 h⋅μg/mL. In some embodiments of the invention, the introduction provides a Cmax of no more than 160 µg/ml. In some embodiments of the invention, the introduction provides a Cmax of no more than 150 µg/ml.

[009] In some embodiments, administration provides an AUC _0-24 of about 1000-3500 h⋅µg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-3000 h⋅µg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2785 h⋅μg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2741 h⋅ug/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2700 h⋅μg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2500 h⋅μg/mL. In some embodiments of the invention, administration provides an AUC _0-24 of no more than 1500-3500 h⋅µg/mL. In some embodiments of the invention, administration provides an AUC _0-24 of no more than 1500-3000 h⋅µg/mL. In some embodiments, administration provides an AUC _0-24 of no more than 1500-2785 h⋅ug/mL. In some embodiments, administration provides an AUC _0-24 of no more than 1500-2741 h⋅μg/mL. In some embodiments of the invention, administration provides an AUC _0-24 of no more than 1500-2700 h⋅µg/mL. In some embodiments, administration provides an AUC _0-24 of about 1500-2500 h⋅µg/mL.

[0010] In some embodiments of the invention, the introduction provides Cmax 110-160 µg/ml. In some embodiments of the invention, the introduction provides Cmax 110-150 µg/ml. In some embodiments of the invention, the introduction provides Cmax 110-140 µg/ml. In some embodiments of the invention, the introduction provides Cmax 120-160 µg/ml. In some embodiments of the invention, the introduction provides a Cmax of about 120-150 µg/ml. In some embodiments of the invention, the introduction provides a Cmax of about 120-140 µg/ml. In some embodiments of the invention, the introduction provides Cmax 90-160 µg/ml. In some embodiments of the invention, the introduction provides a Cmax of about 90-150 µg/ml. In some embodiments of the invention, the introduction provides a Cmax of about 90-140 µg/ml. In some embodiments of the invention, the introduction provides Cmax 100-160 µg/ml. In some embodiments of the invention, the introduction provides a Cmax of about 100-150 µg/ml. In some embodiments of the invention, the introduction provides a Cmax of about 100-140 µg/ml.

[0011] The anti-FOLR1 immunoconjugate may contain a charged linker. In some embodiments, the anti-FOLR1 immunoconjugate comprises a huMov19 antibody, a sulfo-SPDB linker, and a DM4 maytansinoid.

[0012] In some embodiments, the immunoconjugate comprises an antibody or antigen-binding fragment thereof that competitively inhibits binding to FOLR1 of an antibody of SEQ ID NO: 3 and SEQ ID NO: 5. In some embodiments, the antibody or fragment thereof contains the huMov19 CDR ( i.e. SEQ ID NOs: 6-10 and 12 or SEQ ID NOs: 6-9, 11 and 12). In some embodiments, the antibody or antigen-binding fragment thereof contains a variable region of the huMOV19 sequence (ie, SEQ ID NOs: 3 and 5). In some embodiments, the antibodies or fragments do not contain the six CDRs of mouse Mov19 (ie, SEQ ID NOs: 6-9, 16, and 12). In some embodiments, the antibody is huMov19. In some embodiments, the immunoconjugate comprises a maytansinoid. In some embodiments, the maytansinoid is DM4. In some embodiments, the immunoconjugate contains a linker that is a sulfo-SPDB. In some embodiments, the immunoconjugate is IMGN853 (huMov19-sulfo-SPDB-DM4).

[0013] In some embodiments, an anti-FOLR1 binding agent (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1 to about 7.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA , or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.1 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.8 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 2.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 2.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 2.8 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ.) In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 3.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 3.3 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 3.75 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 4.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 4.1 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 4.2 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 5.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 5.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 5.6 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 6.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 6.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered at a dose of about 7.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, BSA, or AIBW (ADJ). In some embodiments of the invention, kilograms of body weight result in AIBW (ADJ).

[0014] According to the methods described herein, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) can be administered about once every 4 weeks. In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered about once every 3 weeks. In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered about once every 2 weeks. In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered about once per week.

[0015] In some embodiments of the invention, the immunoconjugate is administered at a dose of about 1 to 7 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate is administered at a dose of about 1.5 mg/kg to about 6.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments, the immunoconjugate is administered at a dose of about 1.5, 2.0, 2.5, 3, 3.75, 4.0, 4.1, 4.2, 5.0, 5.5, and 6, 0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the immunoconjugate is administered at a dose of about 1.1, 1.8, 2.5, 3.3, and 4.2 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 1.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 1.1 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 1.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 1.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 2.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 2.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 2.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 3.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 3.3 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate is administered at a dose of about 3.75 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate is administered at a dose of about 4.0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate is administered at a dose of about 4.1 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 4.2 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 5.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate is administered at a dose of about 5.5 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 5.6 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 6.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 6.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-FOLR1 immunoconjugate is administered at a dose of about 7.0 mg/kg once a week for three weeks in accordance with a four-week regimen.

[0016] In some embodiments, the immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1 to 7 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and The immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some embodiments, the immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.5 mg/kg to about 6 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and while the immunoconjugate is administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate is administered alone. once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.1 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.5 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and The immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 1.8 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 2 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate is administered alone. once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 2.5 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 2.8 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 3 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate is administered alone. once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 3.3 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 3.75 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 4 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate is administered alone. once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 4.1 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 4.2 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 5 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate is administered alone. once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 5.5 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 5.6 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 6 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate is administered alone. once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 6.5 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate administered once a week for three weeks in accordance with the four-week regimen. In some embodiments, the anti-FOLR1 immunoconjugate (e.g., huMov19-sulfo-SPDB-DM4) is administered at a dose of about 7 mg/kg, with kilograms resulting in IBW, LBW, BSA, or AIBW (ADJ), and the immunoconjugate is administered alone. once a week for three weeks in accordance with the four-week regimen. In some embodiments of the invention, kilograms result in AIBW (ADJ).

[0017] In some embodiments, anti-FOLR1 binding agents were administered to produce the AUCs obtained in Examples 1-6 and shown in Figures 1-2 and 7-12.

[0018] In some embodiments, anti-FOLR1 binding agents were administered to obtain the Cmax obtained in Examples 1-6 and are shown in Figures 1-6 and 9-12.

[0019] In some embodiments, an anti-FOLR1 binding agent (eg, huMov19-sulfo-SPDB-DM4) is administered intravenously.

[0020] The methods described herein can be used to treat cancer. In some embodiments, the cancer is selected from the group consisting of cancers of the ovary, brain, breast, uterus, endometrium, pancreas, kidney (e.g., renal cell carcinoma), and lung (e.g., non-small cell lung cancer or bronchioloalveolar carcinoma (BAC) ). In some embodiments, the cancer is ovarian cancer or lung cancer. In some embodiments, the cancer is epithelial ovarian cancer.

[0021] In some embodiments, the cancer expresses a FOLR1 polypeptide or nucleic acid. In some embodiments of the invention, the cancer is characterized by an increased level of expression of the FOLR1 polypeptide, as measured by immunohistochemistry (IHC). For example, in some embodiments, the cancer is a cancer that expresses a FOLR1 polypeptide at or above hetero 1 as measured by IHC. In some embodiments, the cancer is a cancer that expresses a FOLR1 polypeptide at homo level 1 or higher as measured by IHC. In some embodiments, the cancer is a cancer that expresses a FOLR1 polypeptide at or above hetero level 2 as measured by IHC. In some embodiments, the cancer is a cancer that expresses a FOLR1 polypeptide at homo level 2 or higher as measured by IHC. In some embodiments, the cancer is a cancer that expresses a FOLR1 polypeptide at or above hetero level 3 as measured by IHC. In some embodiments, the cancer is a cancer that expresses a FOLR1 polypeptide at or above homo 3 as measured by IHC. In some embodiments, the cancer is a lung cancer that expresses a FOLR1 polypeptide at or above hetero 2 as measured by IHC. In some embodiments, the cancer is a lung cancer that expresses a FOLR1 polypeptide at or above hetero 3 as measured by IHC. In some embodiments, the cancer is epithelial ovarian cancer (eg, platinum-resistant or relapsed or refractory) that expresses a FOLR1 polypeptide at or above hetero 2. In some embodiments, the cancer is an epithelial ovarian cancer (eg, platinum-resistant or relapsed or refractory) that expresses a FOLR1 polypeptide at or above hetero 3. In some embodiments, the cancer is an endometrial cancer that expresses a FOLR1 polypeptide at hetero 1 or higher. In some embodiments, the cancer is an endometrial cancer that expresses a FOLR1 polypeptide at hetero 2 or higher.

[0022] In some embodiments, the methods further comprise administering a steroid to the patient. The steroid may be administered as a pre-treatment, i. prior to administration of the anti-FOLR1 binding agent. The steroid may be dexamethasone.

[0023] The methods described herein may result in a reduction in tumor size. The methods described herein may result in a decrease in CA125 levels in patients with ovarian cancer. In one example, CA125 levels are measured in a sample obtained from a patient with ovarian cancer before treatment and then once or more after treatment, with a decrease in CA125 levels over time indicating therapeutic efficacy. The methods described herein may result in an increase in the amount of time between cancer treatments. The methods described herein can lead to an increase in the duration of the period without progression (PFS). The methods described in this document may lead to an increase in the period of remission (DFS). The methods described herein may result in an increase in overall life expectancy (OS). The methods described herein may result in an increase in the complete response rate (CR). The methods described herein may result in an increased partial response (PR) rate. The methods described herein can lead to stable disease (SD). The methods described herein may result in a more pronounced reduction in the rate of disease progression (PD). The methods described herein can result in a reduction in time to disease progression (TTP).

[0024] In particular, the schemes of application presented herein provide an optimal balance between efficiency (eg, PR) and reduced toxicity, as demonstrated, for example, in examples 1-4 and figures 1-7.

BRIEF DESCRIPTION OF GRAPHICS / FIGURES

[0025] Figures 1A and B show the pharmacokinetic data obtained by administering IMGN853 (0.15 mg/kg to 7.0 mg/kg) as described in Example 1. Figure 1B shows the final pharmacokinetic data including data from FIG. 1A and additional data from additional patients.

[0026] Figures 2A-B show the reactions and occurrence of ophthalmic toxicity in patients with various Cmax and AUC _0-24 and AUC _0-168 .

[0027] Figure 3 shows the range of Cmax values measured at different doses.

[0028] Figure 4 shows Cmax as a function of patient weight.

[0029] Figure 5 shows the variance in Cmax and AUC _0-24 associated with alternative dosing approaches.

[0030] Figure 6 shows predicted Cmax versus body weight using alternative dosing approaches.

[0031] Figure 7 is a graph of AUC values _0-24 observed in 24 patients receiving 3.3, 5 or 7 mg/kg IMGN853 based on total body weight (actual). These values were compared with predicted values if all patients were treated with 5 mg/kg based on total body weight (TBW 5 mg/kg) and predicted values if all patients were treated with doses of 5, 5.4, or 6 mg/kg. based on adjusted ideal body weight (ADJ 5, 5.4, or 6). Evidence from 7 patients treated at doses of 5 mg/kg per adjusted ideal body weight (actually 5 ADJ) is also shown. The percentage of patients who have or will have predicted AUC values above the ocular toxicity threshold is shown in the table below the graph.

[0032] Figure 8 shows AUC values _{of 0-24} for all patients in the range of 3.3-7.0 mg/kg. The TBW group was used to calculate predicted AUC values _{of 0-24} at indicated doses. Actual AUC data _0-24 patients for the indicated doses are also displayed, including data from the group of patients dosed at 5.0 and 6.0 adjusted ideal body weight (AIBW).

[0033] Figure 9 shows the antitumor activity, predicted plasma concentration, and other pharmacokinetic parameters of IMGN853 in mice treated with single doses of 2.8 mg/kg, 5.6 mg/kg, or 8.5 mg/kg of the immunoconjugate.

[0034] Figure 10 shows the antitumor activity, predicted plasma concentration, and other pharmacokinetic parameters of IMGN853 in mice treated with single doses of 8.5 mg/kg, three daily doses of 2.8 mg/kg, or three doses of 2 .8 mg/kg every three days.

[0035] Figure 11 shows the antitumor activity, predicted plasma concentration and other pharmacokinetic parameters of IMGN853 in mice treated with single doses of 5.6 mg/kg or 1.4 mg/kg daily for three days.

[0036] Figure 12 shows the antitumor activity, predicted plasma concentration, and other pharmacokinetic parameters of IMGN853 in mice treated with single doses of 8.5 mg/kg or 2.8 mg/kg weekly for three weeks.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention provides novel administration regimens for immunoconjugates that bind to FOLR1.

I. Definitions

[0038] To facilitate understanding of the present invention, a number of terms and expressions are defined below.

[0039] The terms "human folate receptor 1", "FOLR1", or "folate receptor alpha (FR-α)", as used herein, refer to any native human FOLR1 unless otherwise indicated. Thus, all of these terms may refer to a protein or nucleic acid sequence as defined herein. The term "FOLR1" includes "full-length" unprocessed FOLR1, as well as any form of FOLR1 that results from processing within a cell. In addition, the term includes naturally occurring variants of FOLR1, such as splicing variants, allelic variants, and isoforms. The FOLR1 polypeptides described herein may be isolated from a variety of sources, such as various types of human tissue or other source, or obtained by recombinant or synthetic methods. Exemplary FOLR1 sequences include, without limitation, NCBI accession numbers P15328, NP_001092242.1, AAX29268.1, AAX37119.1, NP_057937.1, and NP_057936.1.

[0040] The term "antibody" means an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the above, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. . As used herein, the term "antibody" includes intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2 and Fv fragments), Fv single chain mutants (scFv), polyspecific antibodies, such as dual specificity antibodies generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, chimeric proteins containing an antigen recognition portion of an antibody, and any other modified immunoglobulin molecule containing an antigen recognition site, as long as as long as the antibodies exhibit the desired biological activity. An antibody can belong to any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavyweight constant domains. chains labeled alpha, delta, upsilon, gamma, and mu, respectively. Different classes of immunoglobulins contain different and well-known subunit structures and three-dimensional configurations. Antibodies may be unconjugated or conjugated to other molecules such as toxins, radioisotopes, and the like.

[0041] A "blocking" or "antagonist" antibody is one that inhibits or reduces the biological activity of the antigen to which it binds, such as FOLR1. In some embodiments of the invention, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen. Biological activity can be reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95% or even 100%.

[0042] The term "anti-FOLR1 antibody" or "antibody that binds to FOLR1" means an antibody that is capable of binding to FOLR1 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent for targeting FOLR1. The degree of binding of an anti-FOLR1 antibody to an extraneous non-FOLR1 protein may be less than about 10% of the antibody's binding to FOLR1 as determined by, for example, radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of an antibody that binds to FOLR1 is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, or ≤ 0.1 nM.

[0043] The term "antibody fragment" refers to a portion of an intact antibody and refers to the antigen-recognizing variable regions of an intact 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 polyspecific antibodies formed from antibody fragments.

[0044] "Monoclonal antibody" means a homogeneous population of antibodies involved in the highly specific recognition and binding of a single antigenic determinant or epitope. In contrast, polyclonal antibodies typically include different antibodies directed against different antigenic determinants. The term "monoclonal antibody" includes both intact and full-length monoclonal antibodies, as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single-stranded (scFv) mutants, chimeric proteins containing part of the antibody, and any other modified immunoglobulin molecule containing an antigen recognition site. In addition, "monoclonal antibody" means such antibodies obtained by any number of methods, including, but not limited to, using hybridoma, phage selection, recombinant expression, and transgenic animals.

[0045] The term "humanized antibody" refers to forms of non-human (eg, murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof containing minimal non-human (eg, murine) sequences. Typically, humanized antibodies are human immunoglobulins in which complementarity determining region (CDR) residues are replaced with CDR residues from non-human species (e.g., mouse, rat, rabbit, hamster) having the desired specificity, affinity, and valency (Jones et al., 1986, Nature , 321:522-525; Riechmann et al., 1988, Nature , 332:323-327; Verhoeyen et al., 1988, Science , 239:1534-1536). In some cases, Fv framework region (FR) residues of a human immunoglobulin are replaced by corresponding non-human antibody residues that have the desired specificity, affinity, and valency. A humanized antibody can be modified by substitution of additional residues within the Fv framework and/or within the modified non-human residues to refine and optimize the specificity, affinity and/or valency of the antibody. In general, a humanized antibody contains substantially all of at least one, and usually two or three, variable domains containing all or substantially all of the CDR regions that correspond to a non-human immunoglobulin, while all or substantially all of the FR regions originate from from the human immunoglobulin consensus sequence. The humanized antibody may comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically from a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in US Pat. No. 5,225,539. In some embodiments, a "humanized antibody" is a surface-modified antibody.

[0046] "Variable region" of an antibody refers to an antibody light chain variable region or an antibody heavy chain variable region, alone or in combination. Each heavy and light chain variable region consists of four framework regions (FRs) connected by three complementarity determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are held together in close proximity to the FR and, together with the CDRs from the other chain, participate in the formation of the antigen-binding site of antibodies. There are at least two methods for determining CDRs: (1) an approach based on interspecies sequence variability (i.e. Kabat et al., Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md .)); and (2) an approach based on crystallographic studies of antigen-antibody complexes ((Al-lazikani et al (1997) J. Molec. Biol. 273:927-948)). In addition, combinations of the two approaches are sometimes used in the art to determine CDRs.

[0047] The Kabat numbering system is generally used when specifying a residue in a variable domain (approximately light chain residues 1-107 and heavy chain residues 1-113) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0048] Kabat amino acid position numbering refers to the numbering system used for heavy chain variable domains or light chain variable domains when compiling antibodies in Kabat et al. , Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991). Using this numbering system, the actual linear amino acid sequence may contain fewer or more amino acids, which corresponds to a shortening or insertion in the FR or CDR of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion (residue 52a according to Kabat) after residue 52 H2 and inserted residues (eg residues 82a, 82b and 82c, etc. according to Kabat) after residue 82 FR of the heavy chain. The Kabat numbering of residues can be determined for a particular antibody by aligning the sequence homology regions of the antibody with a "standard" Kabat numbered sequence. Instead, Chothia refers to the arrangement of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The end of the loop of Chothia CDR-H1, when numbered according to the Kabat numbering convention, varies from H32 to H34, depending on the length of the loop (this is due to the Kabat numbering scheme placing inserts in H35A and H35B; if 35A and 35B are missing, the loop ends at 32; if only 35A is present, the loop ends at 33; if 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.

[0049] The term "human antibody" means an antibody produced by a human, or an antibody containing an amino acid sequence corresponding to an antibody produced by a human, obtained using any technology known in the art. This definition of a human antibody includes intact or full-length antibodies, fragments thereof, and/or antibodies containing at least one human heavy and/or light chain polypeptide, such as, for example, an antibody containing mouse light chain and human heavy chain polypeptides.

[0050] The term "chimeric antibodies" refers to antibodies in which the amino acid sequence of an immunoglobulin molecule is derived from two or more species. Typically, the variable region of both the light and heavy chains corresponds to the variable region of antibodies derived from a single mammalian species (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and valency, while the constant regions are sequence homologous antibodies derived from another species (usually a human) to avoid an immune response in said species.

[0051] The terms "epitope" or "antigenic determinant" are used interchangeably herein and refer to the portion of an antigen that a particular antibody can recognize and specifically bind to. If the antigen is a polypeptide, epitopes can be formed by both adjacent amino acids and non-adjacent amino acids that are brought together as a result of tertiary folding of the protein. Epitopes formed by contiguous amino acids are usually retained by protein denaturation, while epitopes formed by tertiary folding are usually lost by protein denaturation. An epitope usually contains at least 3 and more often at least 5 or 8-10 amino acids in a unique spatial conformation.

[0052] "Binding affinity" generally refers to the strength of the total amount of non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to intrinsic binding affinity, which represents a 1:1 interaction between members of a binding pair (eg, antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by general methods known in the art, including those described herein. Low affinity antibodies generally bind antigen slowly and tend to dissociate easily, while high affinity antibodies generally bind antigen faster and tend to bind longer. Many methods for measuring binding affinity are known in the art, and any of them can be used for the purposes of the present invention. Specific illustrative embodiments of the invention are described below.

[0053] "Or better", as used herein with reference to binding affinity, denotes a stronger binding between a molecule and its binding partner. "Or better" as used herein denotes a stronger bond, represented by a smaller Kd numerical value. For example, in the case of an antibody that has an affinity for an antigen of "0.6 nM or better", the affinity of the antibody for the antigen is <0.6 nM, i. 0.59 nM, 0.58 nM, 0.57 nM, etc., or any value less than 0.6 nM.

[0054] "Specifically binds" generally means that an antibody binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. Under this definition, an antibody is referred to as "specifically binding" to an epitope if it binds to that epitope through its antigen binding domain more readily than it would to a random, unrelated epitope. The term "specificity" is used herein to indicate the relative affinity with which a particular antibody binds to a particular epitope. For example, antibody "A" may be considered to have higher specificity for a given epitope than antibody "B", or it may be indicated that antibody "A" binds epitope "C" with higher specificity than cognate epitope "D". ".

[0055] By "preferential binding" is meant that an antibody specifically binds to an epitope more readily than it would bind to a related, similar, homologous, or analogous epitope. Thus, an antibody that "preferentially binds" to a given epitope will be more likely to bind to that epitope than to a related epitope, even though such an antibody may cross-react with the related epitope.

[0056] An antibody is referred to as "competitively inhibiting" the binding of a reference antibody to a given epitope if it preferentially binds to that epitope to the extent that it blocks, to some extent, 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. An antibody can be designated as competitively inhibiting binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0057] The phrase "substantially similar" or "substantially the same" as used herein refers to a sufficiently high degree of similarity between two numerical values (in general, one associated with an antibody of the invention and the other associated with reference antibody/comparator) such that one of skill in the art would consider the difference between the two values to be of little or no biological and/or statistical significance in the context of the biological characteristic measured from said values (e.g., Kd values). The difference between these two values may be less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% as a function of the reference antibody/comparator value.

[0058] An "isolated" polypeptide, antibody, polynucleotide, vector, cell, or composition is a polypeptide, antibody, polynucleotide, vector, cell, or composition that is in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those purified to the extent that they no longer exist in the form found in nature. In some embodiments, the isolated antibody, polynucleotide, vector, cell, or composition is substantially pure.

[0059] 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.

[0060] The term "immunoconjugate" or "conjugate", as used herein, refers to a compound or derivative thereof that is associated with a cell binding agent (i.e., an anti-FOLR1 antibody or fragment thereof) and is defined by the general formula: C-L-A, where C=cytotoxin, L=linker, and A=anti-FOLR1 antibody or antibody fragment. In addition, immunoconjugates can be defined by the general formula in reverse order: A-L-C.

[0061] The term "IMGN853" refers to the immunoconjugate described herein, which contains the huMov19 antibody, the sulfoSPDB linker, and the DM4 maytansinoid. The huMov19 antibody contains a heavy chain variable with the amino acid sequence of SEQ ID NO: 3 and a variable light chain with the amino acid sequence of SEQ ID NO: 5.

[0062] A "linker" is any chemical moiety that is capable of linking a compound, typically a drug, such as a maytansinoid, to a cell-binding agent, such as an anti-FOLR1 antibody or fragment thereof, in a stable, covalent form. Linkers may be sensitive or substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage under conditions in which the compound or antibody remains active. Suitable linkers are well known in the art and include, for example, disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, and esterase labile groups. In addition, linkers include charged linkers and their hydrophilic forms, as described herein and known in the art.

[0063] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals in which a population of cells is characterized by disordered cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal tract cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, carcinoma liver and various types of head and neck cancer. The cancer may be a cancer that expresses FOLR1.

[0064] "Tumor" and "neoplasm" refers to any mass of tissue that is the result of excessive growth or proliferation of cells, benign (noncancerous) or malignant (cancerous), including precancerous lesions.

[0065] The terms "cancer cell" "tumor cell" and their grammatical equivalents refer to the total population of cells derived from a tumor or precancerous lesion, including both non-tumorogenic cells, which constitute the bulk of the tumor cell population, and tumorigenic stem cells (cancer stem cells ). As used herein, the term "tumor cell" will be modified by the term "non-tumorogenic" to refer exclusively to those tumor cells that lack the ability to renew and differentiate to distinguish such tumor cells from cancer stem cells.

[0066] The term "subject" refers to any animal (eg, mammal), including, but not limited to, humans, non-human primates, rodents, and the like, that is intended to be the recipient of a particular treatment regimen. Generally, the terms "subject" and "patient" are used interchangeably herein with reference to a human subject.

[0067] The term "ideal body weight" (IBW) refers to a value that is not directly related to total body weight. IBW is an estimate of weight adjusted for height, sex, and additionally body type. 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 in cm.

[0068] The term "lean body weight" (LBW) refers to the value of the indicator, which takes into account the relative fat mass of the body (% BWT). LBW is equal to the total body weight minus the product of rel. ZhMT and masses. LBW can be calculated, for example, using the formulas LBW = 1.10 x weight in kg - 128([weight in kg] ² ∕ [100 x height in meters] ² ) (for men) and LBW = 1.07 x weight in kg - 148 ([weight in kg] ² ∕ [100 x height in meters] ² ) (for women).

[0069] The term "Adjusted Ideal Body Weight" (AIBW) or "Adjusted Ideal Weight" (ADJ) refers to an index value that takes into account gender, total body weight, and height. AIBW and ADJ are used interchangeably. AIBW (ADJ) can be calculated, for example, using the formula ADJ = IBW + 0.4 (weight in kg - IBW).

[0070] IBW, LBW and AIBW (ADJ) are discussed in more detail in Green and Duffull, British Journal of Clinical Pharmacology 58 : 119-133 (2004), which is incorporated herein in its entirety by reference.

[0071] Administration "in combination with" one or more additional therapeutic agents includes simultaneous (competitive) and sequential administration in any order.

[0072] The term "pharmaceutical composition" means a formulation that is in a form that allows the biological activity of the active ingredient to be exhibited in an effective manner and does not contain additional components that would be unacceptably toxic to the subject to whom the formulation is administered. The composition may be sterile.

[0073] An "effective amount" of an antibody or immunoconjugate, as described herein, is an amount sufficient to achieve a specifically stated purpose. An "effective amount" can be determined in an empirical and formulaic way, relative to the stated purpose.

[0074] The term "therapeutically effective amount" means an amount of an antibody or other drug that is effective in "treating" a disease or disorder in a subject or mammal. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the size of the tumor; suppress (ie, slow down to some extent, and in some embodiment of the invention stop) the infiltration of cancer cells into peripheral organs; suppress (ie, slow down to some extent, and in a certain embodiment of the invention, stop) tumor metastasis; suppress, to some extent, tumor growth; alleviate, to some extent, one or more of the symptoms associated with cancer; and/or result in a favorable response, such as increased progression-free period (PFS), remission period (DFS), or overall life expectancy (OS), complete response rate (CR), partial response (PR), or, in some cases , stable disease (SD), reduced rate of disease progression (PD), decreased time to disease progression (TTP), decreased CA125 levels in ovarian cancer, or any combination thereof.

[0075] See the definition of "treatment" in this document. To the extent that a drug can prevent the growth and/or cause death of existing cancer cells, it can be cytostatic and/or cytotoxic. In some embodiments of the invention, the identification of elevated levels of FOLR1 allows the introduction of reduced amounts of FOLR1-targeting therapeutic agent to achieve the same therapeutic effect that is observed at higher doses. "Prophylactically effective amount" means an effective amount, at such doses and for such necessary periods of time, to achieve the desired prophylactic result. Typically, but not necessarily, as long as the prophylactic dose is administered to subjects before or at an earlier stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0076] The term "respond favorably" generally refers to the induction of a favorable state in a subject. With regard to the treatment of cancer, the term refers to providing a therapeutic effect in a subject. A positive therapeutic effect in cancer can be measured in a variety of ways ( see WA Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, tumor growth suppression, molecular marker expression, serum marker expression, and molecular imaging technologies can all be used to assess the therapeutic efficacy of an anticancer therapeutic agent. Regarding tumor growth inhibition, according to NCI standards, T/C ≤ 42% represents the minimum level of antitumor activity. T/C < 10% is considered high antitumor activity, where T/C (%) = Median volume of tumor treated / Median volume of control tumor x 100. A favorable response can be assessed, for example, by an increase in the length of the period without progression ( PFS), period of remission (DFS) or overall life expectancy (OS), complete response rate (CR), partial response (PR), or, in some cases, stable disease (SD), reduction in the rate of disease progression (PD), reduction time to disease progression (TTP), a decrease in CA125 levels in the case of ovarian cancer, or any combination thereof.

[0077] PFS, DFS and OS can be measured according to standards set by the National Cancer Institute and the US Food and Drug Administration for new drug approvals. See Johnson et al, (2003) J. Clin. oncol. 21(7):1404-1411.

[0078] "Progression free period" (PFS) refers to the period of time from registration to disease progression or death. PFS is generally measured using the Kaplan-Meier method and Response Evaluation Criteria in Standards for Solid Tumors (RECIST) 1.1. In general, a progression-free period refers to a situation in which the patient remains alive without the cancer getting worse.

[0079] "Time to tumor progression" (TTP) is defined as the time period from registration to disease progression. TTP is generally measured using the RECIST 1.1 criteria.

[0080] "Complete response" or "complete remission" or "CR" indicates the disappearance of all signs of tumor or cancer in response to treatment. This does not always mean that the cancer is cured.

[0081] "Partial response" or "PR" means a decrease in the size or volume of one or more tumors or lesions, or the prevalence of cancer in the body in response to treatment.

[0082] "Stable disease" means a disease without progression or relapse. In stable disease, there is neither sufficient shrinkage of the tumor to qualify it as a partial response, nor sufficient tumor enlargement to qualify it as a progressive disease.

[0083] "Progressive disease" refers to the appearance of new lesions or tumors and/or unambiguous progression of existing non-target lesions. In addition, progressive disease may mean that the tumor has grown by more than 20 percent since the start of treatment, as a result of an increase in the mass or spread of the tumor.

[0084] "Remission period" (DFS) refers to the period of time during and after treatment during which the disease is absent in the patient.

[0085] "Total life expectancy" (OS) refers to the time from patient registration to death or the date the patient was last seen alive. OS includes the extension of life expectancy compared to untreated or untreated individuals or patients. Total life expectancy refers to a situation in which a patient remains alive for a certain period of time, such as one year, five years, etc., for example, from the time of diagnosis or treatment.

[0086] "Reduction in CA125 levels" can be assessed according to the guidelines of the International Gynecologic Cancer Intergroup (GCIG). For example, CA125 levels may be measured prior to treatment to establish baseline CA125 levels. CA125 levels may be measured one or more times during or after treatment, and a decrease in CA125 levels over time from baseline is considered a decrease in CA125 levels.

[0087] Terms such as "therapy" or "treatment" or "treat" or "alleviate" or "alleviate" refer to therapeutic measures that cure, slow, reduce symptoms and/or stop the progress of a diagnosed condition or disease. Thus, those in need of treatment include those already diagnosed or suspected of having a disease. In some embodiments of the invention, the subject is successfully "treated" for cancer in accordance with the methods of the present invention, if the patient demonstrates one or more of the following: a decrease in the number or complete absence of cancer cells; reduction in tumor size; suppression or absence of infiltration of cancer cells into peripheral organs, including, for example, the spread of cancer into soft tissue and bone; suppression or absence of tumor metastases; suppression or absence of tumor growth; relief of one or more symptoms associated with a particular type of cancer; reducing morbidity and mortality; improving the quality of life; reduction of tumorigenicity, incidence of tumorigenicity, or tumorigenicity potential of the tumor; a decrease in the number or occurrence of cancer stem cells in the tumor; differentiation of tumorigenic cells to a nontumorogenic state; increase in progression-free period (PFS), remission period (DFS) or overall life expectancy (OS), complete response rate (CR), partial response (PR), stable disease (SD), decrease in disease progression rate (PD), decrease time to disease progression (TTP), a decrease in CA125 levels in the case of ovarian cancer, or any combination of these.

[0088] Prophylactic or prophylactic measures refer to therapeutic measures that prevent and/or delay the development of a target pathological condition or disorder. Thus, those in need of prophylactic or preventive measures include those who are prone to developing the disorder and those in whom the disorder should be prevented.

[0089] The terms "pretreatment" and "pretreatment" refer to therapeutic measures that are carried out before the introduction of a therapeutic agent anti-FOLR1. For example, as described in more detail herein, a prophylactic such as a steroid may be administered within about a week, about five days, about three days, about two days, or about one day or 24 hours prior to administration of the anti- FOLR1. The prophylactic agent may also be administered prior to administration of the anti-FOLR1 therapeutic on the same day as the anti-FOLR1 therapeutic.

[0090] The term "peak concentration (Cmax)" refers to the maximum concentration of a drug in the blood, which is measured after a dose of the drug.

[0091] The term "area under the pharmacokinetic curve" (AUC) refers to the total amount of a drug in the blood following a dose of the drug. AUC can be determined over a period of time. Thus, for example, AUC _0-∞ refers to the total amount of the drug in the bloodstream for an infinite period of time after a dose of the drug. In another example, AUC _0-24 refers to the total amount of the drug in the bloodstream within 24 hours after a dose of the drug. In another example, AUC _0-168 refers to the total amount of the drug in the bloodstream within 168 hours (or 1 week) after a dose of the drug.

[0092] "Apparent volume of distribution at steady state" (V _ss ) refers to the ratio of the total amount of drug in the body to the concentration of the drug in plasma, or the "apparent" volume necessary to include the entire volume of the drug, if the whole body drug is at the same concentration , as in plasma.

[0093] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of the mechanism of action. Chemotherapeutic agents include, for example, CD20 antagonists such as Rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, fludarabine, etoposide, methotrexate, lenalidomide, chlorambucil, bentamustine, and/or modified versions of such chemotherapeutic agents.

[0094] The terms "polypeptide", "peptide", and "protein" are used interchangeably herein to refer to amino acid polymers of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by amino acids. The terms also include an amino acid polymer that is naturally or artificially modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification such as conjugation to a label component. Also within the definition are, for example, polypeptides containing one or more analogs of amino acids (including, for example, non-natural amino acids, etc.), as well as other modifications known in the art. It should be understood that since the polypeptides of this invention are based on antibodies, in some embodiments of the invention, the polypeptides may exist as single chains or linked chains.

[0095] The terms “identical” or percent “identity”, in the context of two or more nucleic acids or polypeptides, means two or more sequences or subsequences that are the same or contain a specified percentage of nucleotides or amino acid residues that are the same when compared and aligned (if necessary , with gaps introduced) for maximum matching, not taking into account any conservative amino acid substitutions as part of sequence identity. Percent identity can be measured using sequence or algorithm comparison software or by visual inspection. Various algorithms and software are known in the art that can be used to achieve amino acid or nucleotide sequence alignment. One such non-limiting example of a sequence alignment algorithm is the algorithm described in Karlin et al, 1990, Proc. Natl. Acad. sci. , 87:2264-2268, modified in Karlin et al., 1993, Proc. Natl. Acad. sci. , 90:5873-5877, and embedded in the NBLAST and XBLAST programs (Altschul et al., 1991, Nucleic Acids Res. , 25:3389-3402). In some embodiments, Gapped BLAST may be used as described in Altschul et al., 1997, Nucleic Acids Res. 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, CA), or Megalign (DNASTAR) are additional, open source software that can be used to align sequences. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software (e.g., using the NWSgapdna.CMP matrix, a gap opening penalty of 40, 50, 60, 70, or 90, and a gap extension penalty of 1, 2, 3, 4, 5 or 6). In some alternative embodiments, the GAP program in the GCG software package in which the Needleman and Wunsch algorithm ( J. Mol. Biol. (48):444-453 (1970)) is embedded can be used to determine percent identity between two amino acid sequences (e.g. , using a Blossum 62 matrix or a PAM250 matrix, a gap opening penalty of 16, 14, 12, 10, 8, 6, or 4 and a gap extension penalty of 1, 2, 3, 4, 5). Alternatively, in some embodiments, percent identity between nucleotide or amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4:11-17 (1989)). For example, percent identity can be determined using the ALIGN program (version 2.0), using PAM120 with a residual table, a gap extension penalty of 12, and a gap opening penalty of 4. Suitable parameters for maximum alignment with a particular alignment software can be determined by one skilled in the art. this field of technology. In some embodiments of the invention, the default parameters used by the alignment software are used. In some embodiments of the invention, the percentage identity "X" of the first amino acid sequence of the second amino acid sequence is calculated as 100 x (Y/Z), where Y is the number of amino acid residues qualified as identical matches when the first and second sequences are aligned (when aligned with visual inspection or a specific sequence alignment program), and Z is the total number of residues in the second sequence. If the length of the first sequence is greater than the second sequence, the percent identity of the first sequence of the second sequence will be longer than the percent identity of the second sequence of the first sequence.

[0096] As a non-limiting example, any particular polynucleotide has a certain percentage of sequence identity (e.g., at least 80% identical, at least 85% identical, at least 90% identical, and in some embodiments at least 95%, 96%, 97%, 98%, or 99% identical) of the reference sequence can, in some embodiments, be determined using the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group , University Research Park, 575 Science Drive, Madison, WI 53711). Bestfit uses the local homology algorithm of Smith and Waterman, Advances in Applied Mathematics 2: 482 489 (1981), to find the best homology segment of two sequences. When using Bestfit or any other program to align sequences to determine if a particular sequence would be, for example, 95% identical to a reference sequence according to the present invention, the parameters are set such that percent identity is calculated for the full length reference nucleotide sequence and that will be resolved gaps in homology up to 5% of the total number of nucleotides in the reference sequence.

[0097] In some embodiments, two nucleic acids or polypeptides of the invention are substantially identical if they contain 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% identical nucleotides or amino acid residues, when compared and aligned for maximum match, as measured using a sequence comparison algorithm or visual checks. The identity may be present in a region of sequences at least about 10, about 20, about 40-60 residues, or any integer value in between, and may be present in a region longer than 60-80 residues, e.g., at least about 90-100 residues , and in some embodiments of the invention, the sequences are substantially identical throughout the compared sequences, such as, for example, the coding region of the nucleotide sequence.

[0098] A "conservative amino acid substitution" is one in which one amino acid residue is replaced with another amino acid residue with a similar side chain. Families of amino acid residues with similar side chains are defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine , glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (eg, threonine, valine, isoleucine), and aromatic side chains (eg tyrosine, phenylalanine, tryptophan, histidine). For example, replacing phenylalanine with tyrosine is a conservative substitution. In some embodiments of the invention, conservative substitutions in the sequences of the polypeptides and antibodies of the invention do not abolish the binding of the polypeptide or antibody containing the amino acid sequence to the antigen(s), i.e. FOLR1 to which the polypeptide or antibody binds. Methods for identifying conservative nucleotide and amino acid substitutions that do not abolish 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)).

[0099] As used herein and in the claims, words in the singular also mean the plural, unless the context clearly dictates otherwise.

[00100] It should be understood that in all cases where embodiments of the invention are described in this document using the expression "comprising (including)", other similar embodiments of the invention are also provided, described in terms of "consisting of" and / or "essentially consisting of".

[00101] The term "and/or" as used herein in phrases such as "A and/or B" includes "A and B", "A or B", and "A" and "B". In addition, the term "and/or" as used in phrases such as "A, B and/or C" includes each of the following: 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; (only) A; (only) B; and (only) C.

II. FOLR1 binding agents

[00102] The methods described herein provide methods for administering agents (eg, antibodies or antigen-binding fragments thereof or polypeptides) that specifically bind to FOLR1 ("FOLR1-binding agents"). In some embodiments, the FOLR1 binding agents are antibodies, immunoconjugates, or polypeptides. The amino acid and nucleotide sequences of human FOLR1 are known in the art and are also given herein as represented by SEQ ID NO: 1 and SEQ ID NO: 2. Thus, in some embodiments, FOLR1 binding agents can bind to an epitope found in within SEQ ID NO: 1.

[00103] Examples of therapeutically effective anti-FOLR1 antibodies can be found in US Application Publication No. 2012/0009181, which is incorporated herein by reference. An example of a therapeutically effective anti-FOLR1 antibody is huMov19 (M9346A). The polypeptides of SEQ ID NO: 3-5 comprise huMov19 heavy chain variable domain (M9346A) and light chain variable domain version 1.00, huMov19 light chain variable domain version 1.60, respectively. In some embodiments, the huMov19 anti-FOLR1 antibody comprises a heavy chain variable domain as set forth in SEQ ID NO:3 and a light chain variable domain as set forth in SEQ ID NO:5 (huMov19 version 1.60). In some embodiments, the huMov19 antibody (M9346A) is encoded by plasmids deposited on April 7, 2010 under the terms of the Budapest Treaty with the American Type Culture Collection (ATCC) located at 10801 University Boulevard, Manassas, Virginia 20110, accession numbers PTA-10772 and PTA-10773 or 10774. Examples of FOLR1 immunoconjugates useful in the therapeutic methods of the present invention are shown below.

[00104] In some embodiments, the FOLR1 binding agents are humanized antibodies or antigen binding fragments thereof. In some embodiments, the humanized antibody or fragment is a surface-modified antibody or antigen-binding fragment thereof. In other embodiments, the FOLR1 binding agent is a fully human antibody or antigen binding fragment thereof.

[00105] In some embodiments, FOLR1 binding agents cause one or more of the following effects: induce stable disease, suppress tumor cell proliferation, reduce tumorigenicity of the tumor, reduce the incidence of cancer stem cells in the tumor, suppress tumor growth, increase survival, initiate tumor cell death, differentiate tumorigenic cells to a non-tumorogenic state, or prevent metastasis of tumor cells.

[00106] In some embodiments, the FOLR1 binding agent is an antibody that has the property of inducing antibody-dependent cellular cytotoxicity (ADCC).

[00107] In some embodiments, FOLR1 binding agents are capable of shrinking tumor volume. The ability of a FOLR1 binding agent to reduce tumor volume can be assessed, for example, by measuring the %T/C value, which is the median tumor volume in treated subjects divided by the median tumor volume in control subjects. In some embodiments, immunoconjugates or other agents that specifically bind to human FOLR1 initiate cell death via a cytotoxic agent. For example, in some embodiments, an anti-human FOLR1 antibody is conjugated to a maytansinoid that is activated in tumor cells expressing the FOLR1 protein by internalization. In some embodiments, FOLR1 binding agents are capable of inhibiting tumor growth. In some embodiments, FOLR1 binding agents are capable of inhibiting tumor growth in vivo (eg, in a mouse xenograft model and/or in a human with cancer).

[00108] FOLR1-binding molecules can be antibodies or antigen-binding fragments that specifically bind to FOLR1, which contain a huMov19 (M9346A) CDR containing up to four (i.e., 0, 1, 2, 3, or 4) conservative amino acid substitutions on a CDR, for example, where the antibodies or fragments do not contain the six CDRs of mouse Mov19 (ie, SEQ ID NOs: 6-9, 16, and 12). The polypeptides may contain one of the individual variable light chains or variable heavy chains described herein. Antibodies and polypeptides may contain both a variable light chain and a variable heavy chain.

[00109] In some embodiments, the FOLR1 binding molecule is an antibody or antigen binding fragment comprising the sequences of SEQ ID NO: 6-10 and the sequence of SEQ ID NO: 12. In some embodiments, the FOLR1 binding molecule is an antibody or an antigen binding fragment containing the sequences of SEQ ID NOs: 6-9 and the sequences of SEQ ID NOs: 11 and 12.

[00110] Further provided are polypeptides that include 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 includes 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 comprising the amino acid sequence of SEQ ID NO: 3; and/or (b) a polypeptide comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5. In some embodiments, the polypeptide is an antibody and/or a polypeptide that specifically binds to FOLR1. In some embodiments, the polypeptide is a murine, chimeric, or humanized antibody that specifically binds to FOLR1. In some embodiments, a polypeptide having a certain percentage of sequence identity with SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5 differs from SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5 only conservative amino acid substitutions.

[00111] The polypeptides may contain one of the individual light chains or heavy chains described herein. Antibodies and polypeptides may contain both a light chain and a heavy chain.

[00112] Monoclonal antibodies can be generated using hybridoma techniques such as those described by Kohler and Milstein (1975) Nature 256:495. In the case of the hybridoma method, a mouse, hamster, or other suitable host animal is immunized as described above to cause the lymphocytes to produce antibodies that will specifically bind to the immunizing antigen. Lymphocytes can be immunized in vitro . After immunization, the lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol to obtain hybridoma cells, which can then be separated from non-fused lymphocytes and myeloma cells. Hybridomas that produce monoclonal antibodies specifically directed against a selected antigen, as determined by immunoprecipitation, immunoblotting, or in vitro binding assays (eg, radioimmunoassay (RIA); enzyme-linked immunosorbent assay (ELISA)), can then be cultured in vitro using standard methods. (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, 1986) or in vivo as ascitic tumors in an animal. Subsequently, monoclonal antibodies can be purified from the culture medium or ascitic fluid, as described for polyclonal antibodies above.

[00113] Alternatively, monoclonal antibodies can be generated using DNA recombination techniques as described in US Pat. No. 4,816,567. oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using conventional techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into appropriate expression vectors such that, upon transfection, host cells such as E. coli cells, monkey COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, which themselves do not produce immunoglobulin protein for themselves, monoclonal antibodies are generated by host cells. In addition, recombinant monoclonal antibodies or fragments thereof from the desired species can be isolated from phage display libraries expressing the CDRs of the desired species, as described (McCafferty et al., 1990, Nature, 348:552-554; Clackson et al., 1991 , Nature, 352:624-628 and Marks et al., 1991, J. Mol. Biol., 222:581-597).

[00114] The polynucleotide(s) encoding(e) a monoclonal antibody can be further modified in many different ways using recombinant DNA technology to generate alternative antibodies. In some embodiments, the constant domains of light and heavy chains, e.g., a mouse monoclonal antibody, can be replaced 1) for such regions, for example, a human antibody, to create a chimeric antibody, or 2) for a non-immunoglobulin polypeptide, to create a chimeric antibody. In some embodiments, the constant regions are truncated or removed to create the desired monoclonal antibody fragment. Site directed mutagenesis or high variable region density mutagenesis can be used to optimize specificity, affinity, and the like. monoclonal antibody.

[00115] In some embodiments, the anti-human FOLR1 monoclonal antibody is a humanized antibody. In some embodiments, the humanized antibody is a surface modified antibody. In some embodiments, such antibodies are used therapeutically to reduce antigenicity and HAMA (human anti-mouse antibody) responses when administered to a human subject. Humanized antibodies can be obtained using various methods known in the art. In some alternative embodiments, the anti-FOLR1 antibody is a human antibody.

[00116] Human antibodies can be directly obtained using various methods known in the art. Immortalized human B-lymphocytes, immunized in vitro or isolated from an immunized individual, can be obtained that produce an antibody directed against the target antigen (see, for example, Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p 77 (1985), Boemer et al., 1991, J. Immunol., 147(1):86-95, and US Patent 5,750,373). In addition, the human antibody can be selected from a phage library, where such a phage library expresses human antibodies, as described, for example, in Vaughan et al., 1996, Nat. Biotech., 14:309-314, Sheets et al., 1998, Proc. Nat'l. Acad. Sci., 95:6157-6162, Hoogenboom and Winter, 1991, J. Mol. Biol., 227:381, and Marks et al., 1991, J. Mol. Biol., 222:581). Additionally, methods for creating and using antibody phage libraries are described in US Pat. Nos. 5,969,108; 6,172,197; 6544731; 6555313; 6582915; 6593081; 6300064; 6653068; 6706484; and 7264963; and Rothe et al., 2007, J. Mol. Bio., doi:10.1016/j.jmb.2007.12.018 (each incorporated by reference in its entirety). Affinity maturation strategies and strand shuffling strategies (Marks et al., 1992, Bio/Technology 10:779-783, incorporated by reference in its entirety) are known in the art and can be used to generate high affinity human antibodies.

[00117] Humanized antibodies can be generated from transgenic mice carrying a human immunoglobulin locus that are capable of producing the full spectrum of human antibodies after immunization in the absence of endogenous immunoglobulin production. This approach is described in US patents 5545807; 5545806; 5569825; 5625126; 5633425; and 5661016.

[00118] The present invention also includes dual specific antibodies that specifically recognize FOLR1. Dual specificity antibodies are antibodies that are able to specifically recognize and bind to at least two different epitopes. Different epitopes can be found within the same molecule (e.g., the same FOLR1) or on different molecules, such that both of them, e.g., antibodies can specifically recognize and bind to FOLR1, and also, for example, 1) an effector molecule on a leukocyte such as a T cell receptor (eg CD3) or an Fc receptor (eg CD64, CD32 or CD16) or 2) a cytotoxic agent, as detailed below.

[00119] The polypeptides of the present invention may be recombinant polypeptides, natural polypeptides, or synthetic polypeptides containing a human anti-FOLR1 antibody or fragment thereof.

[00120] Polypeptides and analogs can be further modified to contain additional chemical moieties not normally part of a protein. Such derivatizing fragments can improve the solubility, biological half-life or absorption of the protein. In addition, fragments can reduce or eliminate any desirable side effects of proteins and the like. A review of such fragments can be found in REMINGTON'S PHARMACEUTICAL SCIENCES, 20th ed., Mack Publishing Co., Easton, PA (2000).

[00121] Methods known in the art for purifying antibodies and other proteins further include, for example, those described in US Patent Publication Nos. by reference in its entirety.

III. Immunoconjugates

[00122] Methods for administering conjugates containing anti-FOLR1 antibodies, antibody fragments, and functional equivalents thereof, as described herein, linked or conjugated to a drug or prodrug (also referred to herein as immunoconjugates) are also described herein. Suitable drugs or prodrugs are known in the art. Drugs or prodrugs may be cytotoxic agents. The cytotoxic agent used in the cytotoxic conjugate of the present invention may be any compound that causes or induces cell death or reduces cell viability in any way, and includes, for example, maytansinoids and maytansinoid analogs. Other suitable cytotoxic agents are e.g. cisplatin, carboplatin, daunorubicin, doxorubicin, vincristine, vinblastine, melphalan, mitomycin C, chlorambucil, and morpholinodoxorubicin.

[00123] Such conjugates can be prepared using a linker group to connect the drug or prodrug to the antibody or functional equivalent. Suitable linker groups are well known in the art and include, for example, disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, and esterase labile groups.

[00124] The drug or prodrug may, for example, be linked to an anti-FOLR1 antibody or fragment thereof via a disulfide bond. The linker molecule or crosslinker contains a reactive chemical group that can react with an anti-FOLR1 antibody or fragment thereof. Reactive chemical groups for reaction with the cell-binding agent may be N -succinimidyl ethers and N -sulfosuccinimidyl ethers. Additionally, the linker molecule contains a reactive chemical group, which may be a dithiopyridyl group and may react with the drug to form a disulfide bond. Linker molecules include, for example, N- succinimidyl-3-(2-pyridylthio)propionate (SPDP) (see, for example, Carlsson et al., Biochem. J. , 173: 723-737 (1978)), N -succinimidyl -4-(2-pyridylthio)-butanoate (SPDB) (see, for example, US patent No. 4563304), N -succinimidyl-4-(2-pyridylthio)-2-sulfobutanoate (sulfo-SPDB) (see US Publication No. 20090274713), N -succinimidyl-4-(2-pyridylthio)-pentanoate (SPP) (see, for example, CAS registration number 341498-08-6), 2-iminothiolane or acetylsuccinic anhydride. For example, an antibody or cell-binding agent can be modified with cross-linking reagents, and the thus obtained antibody or cell-binding agent containing free or protected thiol groups is further reacted with a disulfide- or thiol-containing maytansinoid to obtaining a conjugate. The conjugate can be purified by chromatography, including but not limited to HPLC, size exclusion, adsorption, ion exchange and affinity capture, dialysis, or tangential flow filtration.

[00125] In another aspect of the present invention, an anti-FOLR1 antibody is linked to a cytotoxic drug via a disulfide bond and a polyethylene glycol spacer to increase the activity, solubility, or potency of the immunoconjugate. Such cleavable hydrophilic linkers are described in WO 2009/0134976. An additional advantage of this linker design is the desirable high monomer ratio and minimal aggregation of the antibody-drug conjugate. Specifically included in this aspect are conjugates of cell-binding agents and drugs linked via a disulfide group (-SS-) bearing polyethylene glycol spacers ((CH ₂ CH ₂ O) _n=1-14 ) with a narrow drug loading range of 2-8 , which are described as exhibiting high biological activity against cancer cells and having the desirable biochemical properties of high conjugate yield and high monomer ratio with minimal protein aggregation.

[00126] Optionally, an antibody-maytansinoid conjugate with non-cleavable linkers can be prepared. Such crosslinkers are described in the art (see US Publication No. 20050169933) and include, but are not limited to, N- succinimidyl-4-(maleimidomethyl)-cyclohexanecarboxylate (SMCC). In some embodiments, the antibody is modified with cross-linking reagents such as succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC), sulfo-SMCC, maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), sulfo -MBS or succinimidyl iodoacetate as described in the literature to introduce 1-10 reactive groups (Yoshitake et al, Eur. J. Biochem., 101:395-399 (1979); Hashida et al, J. Applied Biochem., 56-63 (1984); and Liu et al, Biochem., 18:690-697 (1979)). Next, the modified antibody is reacted with a thiol-containing maytansinoid derivative to obtain a conjugate. The conjugate can be purified by gel filtration through a Sephadex G25 column or by dialysis or tangential flow filtration. The modified antibodies are treated with a thiol-containing maytansinoid (1-2 molar equivalents/maleimido group) and the antibody-maytansinoid conjugate is purified by gel filtration through a Sephadex G-25 column, chromatography on a ceramic hydroxyapatite column, dialysis, or tangential flow filtration, or a combination of these methods. Usually, on average, 1-10 maytansinoids are associated with an antibody. One method is to modify antibodies with succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) to introduce maleimido groups, followed by reacting the modified antibody with a thiol-containing maytansinoid to produce a thioether-linked conjugate. Conjugates are again formed containing 1-10 drug molecules per antibody. Maytansinoid-antibody conjugates, antibody fragments, and other proteins are prepared in the same manner.

[00127] In another aspect of the invention, the anti-FOLR1 antibody is linked to the drug via a non-cleavable bond through an intermediate PEG spacer. Suitable cross-linking reagents containing hydrophilic PEG chains that form linkers between the drug and the anti-FOLR1 antibody or fragment are also well known in the art or commercially available (eg, from Quanta Biodesign, Powell, Ohio). In addition, suitable PEG-containing crosslinkers can be synthesized from commercially available PEGs themselves using standard chemical synthesis methods known to those skilled in the art. Drugs may be reacted with PEG-containing bifunctional crosslinkers to give compounds of the following formula, ZX _l -(-CH ₂ -CH ₂ -O-) _n -Y _p -D, by methods detailed in US Patent Publication 20090274713 and WO2009/0134976, which can then be reacted with a cell binding agent to obtain a conjugate. Alternatively, cell binding can be modified with a bifunctional PEG crosslinker to introduce a thiol-reactive group (such as maleimide or haloacetamide) which can then be treated with a thiol-containing maytansinoid to form a conjugate. In another method, cell binding can be modified with a bifunctional PEG crosslinker to introduce a thiol moiety, which can then be treated with a thiol-reactive maytansinoid (such as a maytansinoid bearing maleimide or haloacetamide) to form a conjugate.

[00128] Examples of suitable PEG-containing linkers include linkers containing an N- succinimidyl ether or N- sulfosuccinimidyl ether moiety for reaction with an anti-FOLR1 antibody or fragment thereof, as well as a maleimido or haloacetyl moiety for reaction with a compound. The PEG spacer can be incorporated into any crosslinker known in the art by the methods described herein.

[00129] In some embodiments, the linker is a linker containing at least one charged group, as described, for example, in US Patent Publication No. 2012/0282282, the contents of which are incorporated herein by reference in its entirety. In some embodiments, charged or pro-charged crosslinkers are agents containing sulfonate, phosphate, carboxyl, or quaternary amine substituents that substantially increase the solubility of the modified cell-binding agent and cell-drug-binding agent conjugates, especially for monoclonal drug-binding agent conjugates. drug-antibody with 2-20 linked drug/antibody molecules. Conjugates are prepared based on linkers containing a pro-charged fragment, which gives one or more charged fragments after the conjugate is metabolized in the cell. In some embodiments, the linker is selected from the group consisting of: N-succinimidyl 4-(2-pyridylthio)-2-sulfopentanoate (sulfo-SPP) and N-succinimidyl-4-(2-pyridylthio)-2-sulfobutanoate (sulfo -SPDB).

[00130] Many of the linkers described herein are detailed in US Pat. the contents of which are incorporated herein in their entirety by reference.

[00131] The present invention includes aspects in which about 2 to about 8 drug molecules ("drug loading"), such as maytansinoid, are associated with an anti-FOLR1 antibody or fragment thereof. "Drug loading" as used herein refers to the number of drug molecules (eg, maytansinoid) that can be attached to a cell binding agent (eg, anti-FOLR1 antibody or fragment thereof). In one aspect, the number of drug molecules that can be attached to a cell binding agent can average from about 2 to about 8 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3 , 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3 .6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 , 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6 .1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 , 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1). N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1) and N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) can be used ).

[00132] Thus, in one aspect, the immunoconjugate contains 1 maytansinoid per antibody. In another aspect, the immunoconjugate contains 2 maytansinoids per antibody. In another aspect, the immunoconjugate contains 3 maytansinoids per antibody. In another aspect, the immunoconjugate contains 4 maytansinoids per antibody. In another aspect, the immunoconjugate contains 5 maytansinoids per antibody. In another aspect, the immunoconjugate contains 6 maytansinoids per antibody. In another aspect, the immunoconjugate contains 7 maytansinoids per antibody. In another aspect, the immunoconjugate contains 8 maytansinoids per antibody.

[00133] In one aspect, the immunoconjugate contains from about 1 to about 8 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 2 to about 7 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 2 to about 6 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 2 to about 5 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 3 to about 5 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 3 to about 4 maytansinoids per antibody.

[00134] In one aspect, a composition containing immunoconjugates contains an average of about 2 to about 8 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 , 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3 .8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 , 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6 .3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5 , 7.6, 7.7, 7.8, 7.9, 8.0, 8.1) of attached drug molecules (eg, maytansinoids) per antibody. In one aspect, a composition containing immunoconjugates contains an average of about 1 to about 8 drug molecules (eg, maytansinoids) per antibody. In one aspect, a composition containing immunoconjugates contains an average of about 2 to about 7 drug molecules (eg, maytansinoids) per antibody. In one aspect, a composition containing immunoconjugates contains an average of about 2 to about 6 drug molecules (eg, maytansinoids) per antibody. In one aspect, a composition containing immunoconjugates contains an average of about 2 to about 5 drug molecules (eg, maytansinoids) per antibody. In one aspect, a composition containing immunoconjugates contains an average of about 3 to about 5 drug molecules (eg, maytansinoids) per antibody. In one aspect, a composition containing immunoconjugates contains an average of about 3 to about 4 drug molecules (eg, maytansinoids) per antibody.

[00135] In one aspect, a composition containing immunoconjugates contains 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 attached drug molecules (eg, maytansinoids) per antibody. In one aspect, a composition containing immunoconjugates contains an average of about 3.5 ± 0.5 drug molecules (eg, maytansinoids) per antibody.

[00136] An anti-FOLR1 antibody, or fragment thereof, can be modified by reacting a bifunctional cross-linking reagent with an anti-FOLR1 antibody, or fragment thereof, thereby providing a covalent attachment of a linker molecule to the anti-FOLR1 antibody, or fragment thereof. As used herein, a "bifunctional cross-linking reagent" is any chemical moiety that covalently binds a cell-binding agent and a drug, such as the drugs described herein. In another method, a portion of the linker moiety is provided with a drug. In such a case, the drug contains a linker moiety, which is part of a larger linker molecule used to connect the cell-binding agent to the drug. For example, to obtain maytansinoid DM1, the side chain at the C-3 hydroxyl group of maytansine is modified to contain a free sulfhydryl group (SH). This thiolated form of maytansine can be reacted with a modified cell binding agent to form a conjugate. Thus, the final linker is assembled from two components, one of which provides a cross-linking reagent, while the other is provided by the side chain of DM1.

[00137] In addition, drug molecules can be linked to antibody molecules via an intermediate carrier molecule, such as serum albumin.

[00138] As used herein, the expression "associated with a cell binding agent" or "associated with an anti-FOLR1 antibody or fragment" means a conjugate molecule containing at least one drug derivative associated with a cell binding agent with an anti-FOLR1 antibody or a moiety via a suitable linker group, or a precursor thereof. Exemplary linker groups are SPDB or sulfo-SPDB.

[00139] In some embodiments, the cytotoxic agents used in accordance with the present invention are maytansinoids and maytansinoid analogs. Examples of suitable maytansinoids include maytansinol esters and maytansinol analogues. Any drugs that inhibit microtubule formation and are highly toxic to mammalian cells are included, such as maytansinol and maytansinol analogs.

[00140] Examples of suitable maytansinol esters include those containing a modified aromatic ring and those containing modifications at other positions. Such suitable maytansinoids are described in US Pat. Nos. 4,424,219; 4256746; 4294757; 4307016; 4313946; 4315929; 4331598; 4361650; 4362663; 4364866; 4450254; 4322348; 4371533; 5208020; 5416064; 5475092; 5585499; 5846545; 6333410; 7276497 and 7473796.

[00141] In some embodiment, the immunoconjugates of the invention use a thiol-containing maytansinoid (DM1), formally named N ² '-deacetyl- N ² '-(3-mercapto-1-oxopropyl)-maytansine, as a cytotoxic agent. DM1 is represented by the following structural formula (I):

[00142] In another embodiment, the conjugates of the present invention use a thiol-containing maytansinoid, N ² '-deacetyl- N ² ' (4-methyl-4-mercapto-1-oxopentyl)-maytansine (for example, DM4), in as a cytotoxic agent. DM4 is represented by the following structural formula (II):

[00143] Another maytansinoid containing a side chain that contains a sterically hindered thiol bond is N ^2' -deacetyl- N - ² '(4-mercapto-1-oxopentyl)-maytansine (named DM3) represented by the following structural formula ( III):

[00144] Each of the maytansinoids described in US Pat. Nos. 5,208,020 and 7,276,497 can additionally be used in the conjugate of the present invention. With this in mind, the full description of 5208020 and 7276697 is incorporated into this document by reference.

[00145] Many positions on maytansinoids can serve as the position of chemical bonding to the linker moiety. For example, the C-3 position containing a hydroxyl group, the C-14 position modified with hydroxymethyl, the C-15 position modified with hydroxy, and the C-20 position containing a hydroxy group would be useful. In some embodiments, the C-3 position serves as the chemical bonding position to the linker moiety, and in certain specific embodiments, the C-3 position of the maytansinoid serves as the chemical bonding position to the linker moiety.

[00146] The structural representation of some of the conjugates is shown below:

[00147] Also included in the present invention are any stereoisomers and mixtures thereof for any compounds or conjugates represented by any of the structures above.

[00148] Several descriptions of the preparation of such antibody-maytansinoid conjugates are provided in US Pat.

[00149] In general, an aqueous buffer solution of an antibody can be incubated with a molar excess of maytansinoids containing a disulfide moiety that carries a reactive group. The reaction mixture can be quenched by adding an excess of an amine (such as ethanolamine, taurine, etc.). The maytansinoid-antibody conjugate can then be purified by gel filtration.

[00150] The number of maytansinoid molecules associated with an antibody molecule can be determined by spectrophotometric determination of the ratio of optical density at a wavelength of 252 nm and 280 nm. The average number of maytansinoid molecules/antibody may be, for example, 1-10 or 2-5. The average number of maytansinoid molecules/antibody may be, for example, from about 3 to about 4. The average number of maytansinoid molecules/antibody may be about 3.5.

[00151] Antibody conjugates with maytansinoid or other drugs can be evaluated for their ability to inhibit the proliferation of various undesirable cell lines in vitro . For example, cell lines such as the Daudi human lymphoma cell line and the Ramos human lymphoma cell line can readily be used to evaluate the cytotoxicity of such compounds. The cells to be evaluated can be exposed to the compounds for 4-5 days, and fractions of surviving cells are measured in direct assays by known methods. Further, IC ₅₀ values can be calculated based on the results of the analysis.

[00152] Immunoconjugates may, in some embodiments described herein, be taken up by cells. Thus, an immunoconjugate may have a therapeutic effect if it is captured or taken up by a FOLR1-expressing cell. In some specific embodiments, the immunoconjugate comprises an antibody, antibody fragment, or polypeptide coupled to a cytotoxic agent by a cleavable linker, wherein the cytotoxic agent is cleaved from the antibody, antibody fragment, or polypeptide upon uptake by a FOLR1-expressing cell.

[00153] In some embodiments of the invention, immunoconjugates are able to reduce tumor volume. For example, in some embodiments, immunoconjugate treatment results in a %T/C value that is less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. In some specific embodiments, the immunoconjugates can reduce tumor size in a KB, OVCAR-3, IGROV-1 and/or OV-90 xenograft model. In some embodiments, the immunoconjugates are capable of suppressing metastases.

III. Routes of Administration for FOLR1 Binding Agents

[00154] The FOLR1 binding agents (including antibodies, immunoconjugates, and polypeptides) of the 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 useful for suppressing tumor growth, inducing differentiation, suppressing metastases, shrinking tumor volume, and/or reducing tumorigenicity. The methods of administration may be in vivo methods.

[00155] According to the methods described herein, FOLR1-binding agents can be administered at specific doses. For example, FOLR1 binding agents (e.g., IMGN853) can be administered at a dose of about 0.15 mg/kg to about 7 mg/kg, with kg of body weight resulting in ideal body weight (IBW), lean body weight (LBW) , or adjusted ideal body weight (ADJ or AIBW). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at a dose of about 3.0 mg/kg to about 6.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at a dose of about 3.3 mg/kg to about 6.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 0.15 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 0.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 1.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 1.1 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 1.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 1.8 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 2.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 2.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 2.8 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 3.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 3.3 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 3.75 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 4.2 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 4.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 4.8 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 5.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 5.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 5.6 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.1 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.2 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.3 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.4 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.5 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.6 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.7 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.8 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 6.9 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 7.0 mg/kg, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments of the invention, kilograms of body weight result in AIBW (ADJ).

[00156] In addition, FOLR1 binding agents can be administered in a specific dosage range. For example, FOLR1 binding agents can be administered from about four times per week to about once every four weeks. Thus, in some embodiments of the invention, FOLR1-binding agents are administered once every three weeks. In some embodiments of the invention, FOLR1-binding agents are administered about 1 time in two and a half weeks. In some embodiments of the invention, FOLR1-binding agents are administered about 1 time in two weeks. In some embodiments of the invention, FOLR1-binding agents are administered about 1 time in ten days. In some embodiments of the invention, FOLR1-binding agents are administered about 1 time per week.

[00157] FOLR1 binding agents can be administered in a cycle of about 3 weeks (i.e., about 21 days). For example, FOLR1 binding agents can be administered twice over a period of about 3 weeks. Thus, in some embodiments of the invention, FOLR1 binding agents can be administered on days around 1 and 8 of a 21 day cycle. In other embodiments of the invention, FOLR1-binding agents can be administered three times over a period of about 3 weeks. Thus, in some embodiments of the invention, FOLR1 binding agents can be administered on days around 1, 8 and 15 of a 21 day cycle.

[00158] FOLR1 binding agents can be administered in a cycle of about 4 weeks (i.e., about 28 days). For example, FOLR1 binding agents can be administered three times over about 4 weeks. Thus, in some embodiments of the invention, FOLR1 binding agents can be administered on days around 1, 8 and 15 of a 28 day cycle.

[00159] According to the methods described herein, FOLR1-binding agents can be administered at specific doses. In some embodiments, FOLR1 binding agents (eg, IMGN853) may be administered at a dose of about 0.15 mg/kg to about 7 mg/kg once a week for three weeks on a four week schedule. In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at a dose of about 3.0 mg/kg to about 6.0 mg/kg once a week for three weeks on a four-week schedule. In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at a dose of about 3.3 mg/kg to about 6.0 mg/kg once a week for three weeks on a four-week schedule. In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 0.15 mg/kg once a week for three weeks on a four week schedule. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 0.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 1.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 1.1 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 1.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 1.8 mg/kg once a week for three weeks on a four week schedule. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 2.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 2.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 2.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 3.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 3.3 mg/kg once a week for three weeks on a four week schedule. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 3.75 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 4.2 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 4.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 4.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 5.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 5.5 mg/kg once a week for three weeks on a four week schedule. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 5.6 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.1 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.2 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.3 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.4 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.6 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.7 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, FOLR1 binding agents (eg, IMGN853) are administered at about 6.9 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments, FOLR1 binding agents (eg, IMGN853) are administered at about 7.0 mg/kg once a week for three weeks on a four week schedule.

[00160] In accordance with the methods described herein, FOLR1 binding agents (for example, IMGN853) can be administered at a dose of from about 0.15 mg/kg to about 7 mg/kg once a week for three weeks in accordance with four-week regimen, with kg of body weight resulting in ideal body weight (IBW), lean body weight (LBW), or adjusted ideal body weight (ADJ or AIBW). In some embodiments of the invention, FOLR1 binding agents (e.g., IMGN853) are administered at a dose of about 3.0 mg/kg to about 6.0 mg/kg once a week for three weeks in accordance with a four-week regimen, with kilograms body weights result in IBW, LBW, or AIBW (ADJ). In some embodiments of the invention, FOLR1 binding agents (e.g., IMGN853) are administered at a dose of about 3.3 mg/kg to about 6.0 mg/kg once a week for three weeks in accordance with a four-week regimen, with kilograms body weights result in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at a dose of about 0.15 mg/kg once a week for three weeks in accordance with a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 0.5 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 1.0 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 1.1 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 1.5 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 1.8 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 2.0 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 2.5 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 2.8 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 3.0 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 3.3 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 3.75 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 4.2 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 4.5 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 4.8 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 5.0 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 5.5 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments of the invention, FOLR1 binding agents (e.g., IMGN853) are administered at about 5.6 mg/kg once a week for three weeks according to a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.0 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.1 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.2 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.3 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.4 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.5 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.6 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.7 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.8 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 6.9 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments, FOLR1 binding agents (e.g., IMGN853) are administered at about 7.0 mg/kg once a week for three weeks on a four-week regimen, with kilograms of body weight resulting in IBW, LBW, or AIBW (ADJ ). In some embodiments of the invention, kilograms of body weight result in AIBW (ADJ).

[00161] In some embodiments of the invention, FOLR1 binding agents can be administered at a dose that results in a specific Cmax. For example, in some embodiments, FOLR1 binding agents are administered at a dose that results in a Cmax of about 110 to about 160 μg/mL. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 110 to about 150 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 110 to about 140 µg/mL. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 120 to about 160 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 120 to about 150 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 120 to about 140 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 90 to about 160 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 90 to about 150 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 90 to about 140 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 100 to about 160 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 100 to about 150 μg/ml. In some embodiments, the FOLR1 binding agents are administered at a dose that results in a Cmax of about 100 to about 140 μg/ml.

[00162] In some embodiments, FOLR1 binding agents can be administered at a dose that results in a particular AUC. For example, in some embodiments of the invention, FOLR1 binding agents can be administered at a dose that results in an AUC _0-24 of no more than 2785 h⋅µg/mL. In some embodiments, FOLR1 binding agents may be administered at a dose that results in an AUC _0-24 of no more than 2741 h⋅μg/mL. In some embodiments, the FOLR1 binding agents may be administered at a dose that results in an AUC _0-24 of no more than 2700 h⋅μg/mL. In some embodiments, the administration provides an AUC _0-24 of about 1000-3500 ppmg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-3000 ppmkg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2785 h⋅μg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2741 h⋅ug/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2700 h⋅μg/mL. In some embodiments, administration provides an AUC _0-24 of about 1000-2500 h⋅μg/mL. In some embodiments of the invention, administration provides an AUC _0-24 of no more than 1500-3500 h⋅µg/mL. In some embodiments of the invention, administration provides an AUC _0-24 of no more than 1500-3000 h⋅µg/mL. In some embodiments, administration provides an AUC _0-24 of no more than 1500-2785 h⋅ug/mL. In some embodiments, administration provides an AUC _0-24 of no more than 1500-2741 h⋅μg/mL. In some embodiments of the invention, administration provides an AUC _0-24 of no more than 1500-2700 h⋅µg/mL. In some embodiments, administration provides an AUC _0-24 of about 1500-2500 h⋅µg/mL.

[00163] In certain embodiments, the disease being treated with a FOLR1 binding agent or antagonist (eg, an anti-FOLR1 antibody) is cancer. In certain embodiments, the cancer is characterized by FOLR1-expressing cells to which a FOLR1-binding agent (eg, antibody) binds. In certain embodiments of the invention, the tumor overexpresses human FOLR1.

[00164] The present invention provides methods for treating cancer comprising administering a therapeutically effective amount of a FOLR1 binding agent to a subject (eg, a subject in need of treatment). Cancers that can be treated by the methods included in the present invention include, but are not limited to, neoplasms, tumors, metastases, or any disease or disorder characterized by uncontrolled cell growth. The cancer may be primary or metastatic cancer. Specific examples of cancers that can be treated with the methods included in the present invention include, but are not limited to, ovarian cancer, lung cancer, colon and rectal cancer, pancreatic cancer, liver cancer, breast cancer, brain cancer, kidney cancer. , prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, and head and neck cancer. In certain embodiments of the invention, the cancer is ovarian cancer. In certain embodiments of the invention, the cancer is endometrial cancer. In certain embodiments of the invention, the cancer is lung cancer. In certain embodiments of the invention, the cancer is small cell lung cancer. In certain embodiments, the non-small cell lung cancer is lung adenocarcinoma.

[00165] In some embodiments, the cancer is a cancer that expresses FOLR1 (polypeptide or nucleic acid). In some embodiments, a FOLR1 binding agent is administered to a patient with elevated levels of FOLR1 expression, such as as described in US Published Application No. 2012/0282175 or International Published Application WO 2012/135675, both of which are incorporated herein by reference in their entirety. . Thus, in some embodiments of the invention, FOLR1 expression is measured immunohistochemically (IHC) to provide staining intensity scores and/or staining uniformity scores compared to a control (e.g., a calibrated control) showing a certain score (e.g., an intensity score of 3 is assigned to the test sample). if the intensity is comparable to level 3 of the calibrated control, or intensity 2 is assigned to the test sample if the intensity is comparable to level 2 of the calibrated control). Uniformity of staining, which is patchy or uniform, also indicates increased expression of FOLR1. Stain intensity and stain uniformity scores may be used alone or in combination (eg, 2 homo, 2 hetero, 3 homo, 3 hetero, etc.). In another example, an increase in FOLR1 expression can be determined by detecting an increase of at least 2-fold, at least 3-fold, or at least 5-fold) relative to control values (e.g., the level of expression in a tissue or cell of a subject having cancer no or present cancer in which FOLR1 values do not increase).

[00166] In some embodiments, the cancer is a cancer that expresses FOLR1 at hetero level 1 or higher as measured by IHC. In some embodiments, the cancer is a cancer that expresses FOLR1 at or above hetero level 2 as measured by IHC. In some embodiments, the cancer is a cancer that expresses FOLR1 at or above hetero 3 as measured by IHC. In some embodiments, the cancer is a lung cancer that expresses FOLR1 at or above hetero level 2 as measured by IHC. In some embodiments, the cancer is a lung cancer that expresses FOLR1 at or above hetero 3 as measured by IHC. In some embodiments, the cancer is an ovarian cancer that expresses FOLR1 at or above hetero level 2 as measured by IHC. In some embodiments, the cancer is an ovarian cancer that expresses FOLR1 at or above hetero 3 as measured by IHC. In some embodiments, the cancer is an endometrial cancer that expresses FOLR1 at or above hetero 1 as measured by IHC. In some embodiments, the cancer is endometrial cancer that expresses FOLR1 at or above hetero level 2 as measured by IHC.

[00167] In some embodiments, a method for inhibiting tumor growth comprises administering to a subject a therapeutically effective amount of a FOLR1 binding agent. In some embodiments of the invention, the subject is a human. In some embodiments, the subject has a tumor or the tumor has been removed.

[00168] In addition, the present invention provides a method of reducing the tumorigenicity of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a FOLR1 binding agent. In some embodiments of the invention, the tumor contains cancer stem cells. In some embodiments of the invention, the frequency of occurrence of cancer stem cells in a tumor is reduced by administering an agent.

[00169] The present invention further provides pharmaceutical compositions containing one or more of the FOLR1 binding agents described herein. In some embodiments of the invention, the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier. Such pharmaceutical compositions find use in the suppression of tumor growth and the treatment of cancer in human patients.

[00170] In some embodiments, formulations are prepared for storage and use by combining the purified antibody or agent of the present invention with a pharmaceutically acceptable carrier (e.g., carrier, excipient) (Remington, The Science and Practice of Pharmacy 20th Edition Mack Publishing, 2000 ). Suitable pharmaceutically acceptable carriers include, but are not limited to, non-toxic buffering agents such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (for example, octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzalkonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (eg, 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 dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (eg Zn-protein complexes); and non-ionic surfactants such as Tween or polyethylene glycol (PEG).

[00171] The pharmaceutical compositions described herein can be administered in any number of ways, for local or systemic treatment. Application may be topical (eg, to mucous membranes, including vaginal and rectal administration), for example, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders; inhalation (for example, by inhalation or insufflation of powders or aerosols, including using a nebulizer; intratracheal, intranasal, epidermal and transdermal); oral; or parenteral, including intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (eg, intrathecal or intraventricular) administration. In some specific embodiments of the invention, the administration is performed intravenously.

[00172] The antibody or immunoconjugate may be combined in a pharmaceutical combination formulation or regimen, in the form of a combination therapy, with a second compound. In some embodiments, the second compound is a steroid. In some embodiments, the methods include administering a steroid and an immunoconjugate that results in a reduction in headaches compared to administering the immunoconjugate alone.

[00173] The steroid can be administered simultaneously with the immunoconjugate, before the administration of the immunoconjugate, and/or after the administration of the immunoconjugate. In some embodiments, the steroid is administered within about a week, about five days, about three days, about two days, or about one day, or 24 hours prior to administration of the immunoconjugate. In some embodiments of the invention, the steroid is administered within one day of the administration of the immunoconjugate. In some embodiments of the invention, the steroid is administered multiple times. In some embodiments, the steroid is administered from about one day prior to the administration of the immunoconjugate and on the same day as the immunoconjugate. The steroid can be administered by any number of routes, including, for example, topical, inhalation, oral, parenteral, or intracranial administration. In some embodiments of the invention, the introduction is carried out orally. In some embodiments of the invention, the administration is carried out intravenously. In some embodiments of the invention, the administration is carried out both orally and intravenously.

[00174] Additionally, the antibody or immunoconjugate may be combined in a pharmaceutical combination formulation or regimen, in the form of combination therapy, with an analgesic or other therapeutic agents that prevent or treat headaches. For example, acetaminophine and/or defenhydramine may be administered in addition to administration of the antibody or immunoconjugate. The analgesic may be administered simultaneously with or after administration of the immunoconjugate, and this may be by any suitable route of administration. In some embodiments of the invention, the pain reliever is administered orally.

[00175] In some embodiments, the methods include administering a first compound that is an antibody or immunoconjugate, a second compound that is a steroid, and a third compound that is an analgesic. In some embodiments, the methods include administering a first compound that is IMGN388, a second compound that is dexamethasone, and a third compound that is acetaminophine and/or diphenhydramine.

[00176] The antibody or immunoconjugate may be combined in a pharmaceutical combination composition or administration schedule, in the form of a combination therapy, with a second compound having anti-cancer properties. The second compound in a pharmaceutical combination composition or administration schedule may have complementary activity to the ADC combination such that they do not adversely affect each other. Additionally, pharmaceutical compositions containing a FOLR1 binding agent and a second anticancer agent are provided.

[00177]

***

[00178] Embodiments of the invention in accordance with this document can be further defined with reference to the following non-limiting examples, which describe in detail the production of some antibodies of the present invention and methods of using the antibodies of the present invention. Those skilled in the art will appreciate that many modifications to materials and methods can be made without departing from the scope of the present invention.

Examples

[00179] It is to be understood that the examples and embodiments of the invention described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be proposed by those skilled in the art and should be considered as being within the scope of the present invention.

Example 1

Dose trial of IMGN853 in human patients with cancer.

[00180] IMGN853 is an antibody drug conjugate (ADC) containing a folic acid receptor 1 (FOLR1) binding antibody and a highly active maytansinoid, DM4. IMGN853 has previously been described in International Published Applications WO 2011/106528, WO 2012/135675 and WO 2012/138749, and US Published Application Nos. 2012/0009181, 2012/0282175 and 2012/0282282, each of which is incorporated herein by reference in in full. IMGN853 is huMov19-sSPDB-DM4, wherein the huMov19 antibody contains a variable heavy chain with the amino acid sequence of SEQ ID NO: 3 and a variable light chain with the amino acid sequence of SEQ ID NO: 5. The FOLR1 protein is expressed at elevated levels in many solid tumors, especially epithelial ovarian cancer (EOC), endometrial cancer, non-small cell lung cancer (NSCLC) and clear cell kidney cancer.

[00181] A study was initiated to determine the maximum tolerated dose (MTD) and phase 2 recommended doses (RP2D), as well as to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of IMGN853. The study included two components: an accelerated dose titration component, in which the IMGN853 immunoconjugate was administered to patients with any type of FOLR1-expressing refractory solid tumors, including epithelial ovarian cancer (EOC) and other FOLR1-expressing solid tumors, and a drug-at-dose component reached during the phase of increasing the dose of the drug to the maximum tolerated.

[00182] In the accelerated titration portion of the study, IMGN853 was administered intravenously (IV) on Day 1 of each 21-day cycle (3 weeks). Twenty-nine patients were enrolled in the study to obtain seven dose levels ranging from 0.15 to 7.0 mg/kg IMGN85 in the accelerated portion of the clinical drug trial and robust data currently available for 23 patients. There are no studies of adverse effects associated with drugs of any grade in the first 4 groups of patients. Adverse events associated with IMGN853 at a dose of 5.0 mg/kg were mild to moderate. At doses of 5.0 and 7.0 mg/kg, 4 out of 10 and 5 out of 5 patients, respectively, experienced ophthalmic toxicity.

Table 1: Study enrollment by tumor type

Inclusion in the study and expression of FOLR1 by tumor type
N=29 Diagnosis FOLR1 expression level 2 Hetero 2 Homo 3 Hetero 3 Homo Other Total Ovarian cancer Serous Transitional cell
Clear cell carcinosarcoma 2
1 ¹
1 2
1
1 7
6 ¹
1 ² 4
3
1 1
1 ⁴ 16
10
1
3
1 Endometrial Serous Endometrioid Adenosquamous Mixed 2
2 0 5
3 ³
1
1 1
1 0 8
4
2
1
1 Adenocarcinoma NSCLC 1 1 Renal cell
Light cell 0 2
2 25 ^_
25 4
4 ¹ CA125 response in 1 patient for every 3.3 mg/kg, 5.0 mg/kg and 7.0 mg/kg
² Confirmed partial response
³ Unconfirmed partial response and confirmed CA125 response in 1 patient at a dose of 5.0 mg/kg
⁴ Focal
⁵ Negative

[00183] The area under the pharmacokinetic curve of the drug was measured in 23 patients, and found that, in general, it increases linearly, with a half-life at doses ≥ 2.0 mg/kg of about 5 days. One patient with serous endometrial cancer also had a CA125 response and an unconfirmed partial response to 5 mg/kg. Three patients with ovarian cancer had a confirmed CA125 response (one each at 7 mg/kg, 5 mg/kg, and one at 3.3 mg/kg). Patients treated with IMGN853 at doses greater than or equal to 5.0 mg/kg received dexamethasone 10 mg IV (or similar steroid equivalent) 30-60 minutes prior to administration of an anti-FOLR1 immunoconjugate (eg, IMGN853).

[00184] Pharmacokinetic (PK) parameters are shown for Cycle 1 (only the first administration cycle for each patient) of the IMGN853 Phase 1 trial (Figures 1A and B). Clearance of IMGN853 has been shown to be rapid at low doses (CL = 1.1 ml/hour/kg) with a half-life of about 35.4 hours or 1.5 days. Clearance decreases (CL = 0.4 ml/hour/kg) at higher doses, and at doses ≥ 2.0 mg/kg, the elimination half-life increases to about 4 days or about 5 days. It is shown that the area under the pharmacokinetic curve (AUC) and Cmax at higher doses, in general, also increase.

[00185] For the 7.0 mg/kg dose, all 5 patients experienced ophthalmic toxicity. One patient presented with dose-limiting grade 3 punctate keratitis and grade 2 blurred vision, which are considered to be definitely related to study treatment. Additionally, grade 3, grade 2, and grade 1 blurred vision was recorded, 1 patient for each; all cases are considered to be possibly or definitely related to IMGN853 treatment. As a result, the maximum tolerated dose for this dosing regimen (i.e. once every three weeks) was considered to be exceeded at the 7.0 mg/kg dose level, and for all patients who received the 7.0 mg/kg dose , the dose was reduced to the previous level (5.0 mg/kg) and 7 other patients were evaluated at a dose of 5 mg/kg. Together with 3 previously treated patients, 10 patients were treated at a dose of 5 mg/kg. In total, of 10 patients at the 5 mg/kg dose level, 3 had blurred vision, including 1 patient with grade 3 blurred vision, and 2 patients had corneal changes. Other associated grade 3 adverse events included elevated alkaline phosphatase and grade 3 hypophosphatemia. Other patients were included in the study at the 3.3 mg/kg dose level to further confirm the safety profile seen in the 3 patients initially assigned to this dose. Safety analysis of another 6 patients currently on treatment at 3.3 mg/kg and IMGN853 is well tolerated. To date, three out of nine patients treated at 3.3 mg/kg have experienced adverse events associated with IMGN853, including grade 2 peripheral neuropathy (1 patient), grade 2 nausea, fatigue, and increased AST (1 patient ), and 1 patient with grade 2 vomiting.

[00186] Once the MTD is determined, the study will move into the therapy phase with the drug at the dose reached during the escalation phase of the drug to the maximum tolerated dose. The three treatment arms at the dose reached during the escalation phase to the maximum tolerated dose will evaluate patients with FOLR1 protein-positive (1) platinum-resistant epithelial ovarian cancer; (2) relapsed or refractory epithelial ovarian cancer, and (3) relapsed or refractory non-small cell lung cancer (NSCLC). Groups 2 and 3 will include assessment of IMGN853 PD by pre- and post-dose tumor biopsy and/or FLT-PET imaging, respectively. IMGN853 will be administered at a dose of at least 3.3 mg/kg and possibly 5.0 mg/kg, or even as high as 6.0 mg/kg or even 7.0 mg/kg will be included. Initially, IMGN853 should be administered at a rate of 1 mg/min; after 30 minutes the rate may be increased to 3 mg/min if well tolerated. If well tolerated, after 30 minutes of administration at a rate of 3 mg/min, the rate may be increased to 5 mg/min. Subsequent infusions can be given at a tolerable rate.

[00187] For all doses of IMGN853 at or above 3.3 mg/kg, prophylactic steroid treatment using the protocols described in Example 2 would be included (e.g., steroid treatment at 10 mg IV dexamethasone (or equivalent) would be required). steroid) 30-60 minutes prior to IMGN853 administration, and prophylactic administration of diphenhydramine HCl and acetaminophen prior to IMGN853 administration is recommended). Cycles are repeated until (i) the patient's disease worsens, (ii) the patient develops unacceptable toxicity, (iii) the patient withdraws consent, (iv) the patient develops a comorbid condition that precludes further study treatment. , or (v) the patient's participation in the study will not be terminated due to non-compliance with physician orders or for administrative reasons.

[00188] Response is assessed using RECIST and Gynecological Cancer International Intergroup (GCIG) criteria (as applicable).

Example 2

Prevention of infusion reaction to IMGN853 based steroid

[00189] In order to reduce the likelihood of an infusion reaction, any of the following steroid-based prophylaxis protocols may be used.

[00190] (1) Patients receive dexamethasone, 10 mg IV (or the equivalent of a similar steroid), 30-60 minutes prior to administration of an anti-FOLR1 immunoconjugate (eg, IMGN853).

[00191] (2) Patients receive dexamethasone, 10 mg IV (or the equivalent of a similar steroid) and diphenhydramine HCl (25-50 mg IV or PO), with acetaminophen (325-650 mg IV or PO). /o) or without it, 30-60 minutes prior to administration of the anti-FOLR1 immunoconjugate (eg, IMGN853). This prophylactic protocol is recommended and remains at the discretion of each investigator.

[00192] (3) Patients receive 8 mg (or the equivalent of a similar steroid) dexamethasone orally 2 times a day the day before administration of the anti-FOLR1 immunoconjugate (eg, IMGN853). On the day of administration of the anti-FOLR1 immunoconjugate (eg, IMGN853), 30-60 minutes prior to administration of the anti-FOLR1 immunoconjugate (eg, IMGN853), patients receive dexamethasone, 10 mg IV (or an equivalent steroid), diphenhydramine HCl (25- 50 mg IV or PO), with or without acetaminophen (325–650 mg IV or PO).

(4) Steroids (eg, dexamethasone) are administered orally within 24 hours prior to infusion.

Example 3

Relationship between area under the pharmacokinetic curve (AUC) of IMGN853 and ophthalmic toxicity

[00193] For each patient treated with IMGN853 according to the protocol described in Examples 1 and 2, the plasma concentration of IMGN853 was measured at different time points for each cycle, at the beginning and at the end of the infusion, and continued to be measured for 21 days. Analysis of pharmacokinetic parameters (PK) revealed an obvious relationship between Cmax and the occurrence of ophthalmic toxicity, which is characterized by deposits in the cornea and loss of visual acuity. A statistically significant correlation was also observed at baseline exposure levels, as measured by area under the curve during the first 24 hours (AUC _0-24 ). (See figures 2A-2B).

[00194] In the 3.3 to 7.0 mg/kg groups, ophthalmic toxicity was observed in 9 of 10 patients with Cmax values at or above 147.7 μg/mL, indicated by the dotted line in Figure 2A. There were no patients with Cmax values below 147.7 μg / ml with detected ophthalmic toxicity. All (9/9) patients with AUC _0-24 at or above 2785 h*mcg/mL, marked with a dotted line in Figure 2B, had ophthalmic toxicity, while no patient below the dotted line had ophthalmic toxicity. . An effect was observed at doses ≥ 3.3 mg/kg and did not correlate with reports of ophthalmic toxicity. The lowest value of Cmax in patients in whom the effect was noted was 91.25 μg / ml.

[00195] In 24 patients treated with either 3.3 mg/kg, 5.0 mg/kg, or 7.0 mg/kg IMGN853, Cmax values above cut-off correlate with (reversible) ophthalmic toxicity using Fisher's exact test , p = 0.00004. AUC _0-24 values above the cut-off level of 2.741 h*mcg/mL also correlate with (reversible) ophthalmic toxicity using Fisher's exact test, p = 0.00001. Based on these results and calculations using nominal time and concentration values, it was found that in patients with a Cmax of more than about 150 μg / ml or an AUC _0-24 value of more than 2785 h * μg / ml, an increase in the incidence of ophthalmic toxicity, and patients in whom the effect was noted had a Cmax level of at least about 90 μg / mg. Strategies have been developed to modify drug regimens in order to reduce apparent variability within each dose level and achieve Cmax levels with optimal efficacy and minimal toxicity for any patient weight.

Example 4

Alternative applications for IMGN853

[00196] As described above in Example 3, a correlation between Cmax values greater than 150 μg/ml or AUC _0-24 values greater than 2785 h*μg/ml and the incidence of ophthalmic toxicity was observed across all dose levels. In addition, the initial analysis of pharmacokinetic parameters showed that although Cmax increases in proportion to the dose of IMGN853, there is a significant variation in Cmax, AUC _0-24 and volume of distribution within acceptable doses (figure 3).

[00197] Changes in Cmax are especially noticeable in the 5 mg/kg group, where PK was analyzed in 10 patients. There were no apparent changes in Cmax in the same patient across cycles, and infusion times were similar between patients and were not associated with a change in Cmax. Covariance analysis showed a correlation between mass and Cmax. (figure 4).

[00198] The volume of distribution (V _ss ) is a measure of blood plasma volume for biologics and does not increase linearly with weight. When the Cmax values were normalized to Vss, the spread was reduced. These data suggest that by investigating other alternative routes of administration, other than approaches based on total body weight, more uniform dosing can be achieved across the group. To this end, Cmax values were determined using alternative dosing calculations for all patients treated by groups at doses of 3.3 (n=3), 5.0 (n=10) and 7 mg/kg (n=5) . Calculated Cmax values were adjusted to a dose of 5 mg/kg and compared with Cmax values derived from total body weight (TBW) dosages. Body surface area (BSA) was also considered, however, Cmax values based on BSA dosing decreased and variability was minimally affected and still showed a positive correlation between weight and Cmax, albeit to a lesser extent. Three more alternative formulas were also evaluated: (1) ideal body weight (IBW), lean body weight (LBW), and adjusted body weight (ADJ). The formula for each IBW, LBW, ADJ and BSA is given below:

Ideal body weight (IBW)

IBW (male) = 0.9H-88

IBW (female) = 0.9H-92

(where H=height in cm)

Lean body weight (LBW)

Men = 1.10 x weight in kg - 128([weight in kg] ² ∕ [100 x height in meters] ² )

Women = 1.07 x weight in kg - 148([weight in kg] ² ∕ [100 x height in meters] ² )

Adjusted ideal body weight (AIBW or ADJ)

IBW + 0.4 (actual weight in kg - IBW)

Body Surface Area (BSA) - Mosteller Formula

BSA (m ² ) = (height (cm) x weight (kg) / 3600) ^½

Body surface area (BSA) - Boyd's formula

BSA ( ^m2 ) = (0.0003207 x height(cm) ^0.3 x mass(g) ^{(0.7285 - ( 0.0188 x log(g)} )]

[00199] Mean Cmax values were 93.06, 82.72, 110.77 and 137.46 μg/ml for IBW, LBW, AIBW (ADJ) and TBW, respectively. In addition, all three alternative measures reduced the standard deviation in Cmax (21.7, 20.5, 22.9 vs. 33.7 µg/mL for TBW). (See figure 5).

[00200] As mentioned above, a positive correlation was found between TBW and Cmax. The graph shows that the correlation analysis revealed a negative correlation between IBW and LBW with mass. Dosing by body weight AIBW (ADJ) had a lower dependence on body weight (see figure 6) similar to BSA, but with less PK variability.

[00201] IBW, LBW, or AIBW (ADJ) dosing results in the least weight dependency compared to TBW dosing. Based on current data, dosing by weight IBW (ADJ) results in a smaller dispersion of Cmax.

[00202] AUC values _{of 0-24} were observed in 24 patients who received 3.3, 5, or 7 mg/kg IMGN853 based on total body weight (see FIG. 7 "actual TBW"). In addition, AUC values _{of 0-24} were observed in 7 patients who received 5 mg/kg IMGN853 in terms of adjusted ideal body weight (see Fig. 7 "5 actual ADJ"). These actual values from 24 patients were compared to predicted values from the same patients if they were treated at 5 mg/kg based on total body weight (Fig. 7 "TBW 5 mg/kg") or if they were treated at 5, 5.4, or 6 mg/kg in terms of adjusted ideal body weight (Figure 7 "ADJ 5 mg/kg", "ADJ 5.4 mg/kg" and "ADJ 6 mg/kg"). kg") As shown in the table in Figure 7, administration of 5 mg/kg of IMGN853 in terms of AIBW (ADJ) minimizes the number of patients predicted to exceed the AUC threshold of _0-24 2741 h⋅μg/mL associated with ophthalmic toxicity. In addition, only 14% of 7 patients who received 5 mg/kg IMGN853 in terms of AIBW (ADJ) achieved an AUC _0-24 greater than 2741 h⋅µg/mL, while 38% of patients who received 3.3 , 5 or 7 mg/kg IMGN853 in terms of TBW, exceeded this level. Analysis of AUC _0-24 determined that the use of nominal time and concentration values resulted in a value of 2785 h⋅μg/mL. When converted using real time, there is little change in AUC _0-24 and the cut-off value is 2741 h⋅µg/mL.

[00203] Patients then received treatment with either 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. In FIG. 8 ("Actual") shows the AUC values observed in these patients _0-24 and these values were compared with the predicted values ("predicted") that would be obtained if all these patients were treated with 5 mg/kg in terms of 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. Dosage based on adjusted ideal body weight reduced variability at baseline exposure levels and reduced ophthalmic adverse events as shown in Table 2 below. In particular, only one patient who received 5 mg/kg adjusted ideal body weight experienced abnormalities. grade 1 vision and three patients who received 6 mg/kg adjusted ideal body weight experienced grade 1-2 ophthalmic toxicity. In contrast, doses of 5 mg/kg or more based on total body weight were associated with more patients with ophthalmic adverse events and grade 3 ophthalmic side effects.

Table 2: Reported ocular adverse events (AEs) with dosages based on adjusted ideal body weight (all reversible)

IMGN853 (mg/kg normalized to ideal body weight) Group size Patients with different degrees of AIE ONYA DLT 1-2 degrees 3 degrees ¹ 5.0 7 1 1 ² 0 0 6.0 7 3 5 ³ 0 0

¹ Side effects 4 degrees.

² One patient reported visual impairment.

³ 2nd degree blurred vision and punctate keratitis in 1 patient; 2nd degree retinopathy in one patient; and 1st degree blurred vision and floating "flies" in 1 patient.

Example 5

Alternative mode of administration IMGN853

[00204] A population pharmacokinetic model was developed based on the maximum and minimum values (derivatives of the maximum and minimum) of the concentration-time profiles of IMGN853 with a dosing regimen every 3 weeks (with increasing dose). The pharmacokinetics of IMGN853, as noted above, appear to be linear over the dose range studied.

[00205] This model has been applied to simulate the steady state concentration of IMGN853 in the following suitable application patterns:

1 to 2.5 mg/kg every week (10 dose levels in 0.15 mg/kg increments).

2 to 5 mg/kg once every two weeks (10 dose levels in 0.3 mg/kg increments).

1 to 2.5 mg/kg once a week for four weeks, then once every other week for four weeks (10 dose levels in increments of 0.15 mg/kg).

1 to 2.5 mg/kg once a week for three weeks according to a four-week regimen (10 dose levels in 0.15 mg/kg increments).

[00206] The once weekly regimen for four weeks and then once every other week for four weeks resulted in the lowest accumulation over time (i.e. accumulation index was 1), while the application regimen drug once a week resulted in the largest accumulation (i.e. accumulation index was 1.97). Once a week for three weeks in accordance with the four-week regimen in general allowed to increase the area under the pharmacokinetic curve up to ~3 times, limiting Cmax below the level at which ophthalmic toxicity is observed (table 3).

Table 3

Application mode Dose (mg/kg) Сmax (µg/ml) Cmin (µg/ml) Cavg (mcg/ml) AUC _{12 weeks} (h⋅mg/mL) once every three weeks 4.2 112 7.8 thirty 32 once every two weeks 4.1 119 18 44 84 Once a week for three weeks in accordance with the four-week regimen 3.3 119 20 52 105

[00207] A population pharmacokinetic model was also used to simulate a hypothetical population of 500 patients using the Monte Carlo method. Descriptive statistics were obtained in order to determine dosing regimens in the proportion of subjects with C _max < 150 μg/ml to optimize the safety profile of IMGN853. In a once-a-week regimen for three weeks in accordance with a four-week regimen, doses of 1.5, 2.0, and 2.5 mg/kg resulted in 99%, 95%, and 90% of the sample members to C _max < 150 µg/ml, respectively.

Example 6

Antitumor activity in vivo and predicted pharmacokinetics of repeated administration of IMGN853

[00208] Plasma concentration of intact IMGN853 conjugate administered intravenously at a dose of 10 mg/kg to female CD-1 mice was determined by enzyme immunoassay at various time points after injection. Pharmacokinetic (PK) analyzes were performed using standard algorithms in a model-independent pharmacokinetic method using (201) WinNonlin Professional version 6.1 (Pharsight, Mountain View, CA). The maximum concentration (Cmax), total area under the concentration-time curve (AUC _0-∞ ), terminal elimination half-life (t _1/2 ), systemic clearance (CL), and volume of distribution at steady state (Vss) were determined. First order rate constant values to determine the half-life (t _1/2 ) of the conjugate were evaluated using concentration data from days 1 to 28 after administration. First order rate constant values to determine the half-life (t _1/2 ) of the antibody were evaluated using concentration data from days 1 to 28 post-administration. Based on the measurement results obtained at a dose of 10 mg/kg, pharmacokinetic models were created in WinNonlin using various doses in both single and multi-dose regimens. The obtained parameters were evaluated in comparison with the antitumor activity of IMGN853 at various doses and regimens of administration in NCI-H2110 (non-small cell lung cancer, NSCLC) xenografts in female mice with severe combined immunodeficiency.

[00209] When IMGN853 was administered as a single injection, a dose-dependent antitumor activity was observed in the NCI-H2110 model. All doses (2.8, 5.6 and 8.5 mg/kg) showed high activity at T/C values <10%, but with an increased dose of IMGN853, the number of complete tumor regressions (CR) increased. The predicted plasma pharmacokinetic parameters also showed a dose-dependent increase in Cmax (maximum serum concentration), Cavg (mean serum concentration) and area under the pharmacokinetic curve (AUC _0-540 h). Thus, the predictive, based on plasma PK parameters, and dose-dependent pattern of the intensity of action of single doses of IMGN853 is shown, as depicted in Figure 9.

[00210] In contrast to the activity of a single dose, multi-dose regimens of IMGN853 administration showed that the activity is independent of Cmax (figure 10). Administration of IMGN853 at 2.8 mg/kg x 3 daily or every 3 days of the regimen (total dose was 8.4 mg/kg) had similar activity with a single administration of IMGN853 at 8.5 mg/kg. Interestingly, the total area under the pharmacokinetic curve (AUC) and the mean serum concentration (Cavg) of the conjugate were comparable among the study groups, while Cmax was highest in the group that used a single dose of 8.5 mg/kg. The activity observed with multiple therapeutic exposures indicates that this dosing method has a greater activity, since there were animals remaining without tumors at the end of the study, compared with the absence of animals without tumors in the group with a single administration of the drug.

[00211] Additionally, IMGN853 dose rates and application regimens were evaluated for activity against NCI-H2110 xenografts, with results consistently demonstrating that multi-dose regimens are equivalent or more potent in effect than single-dose IMGN853 preparation. The predicted mean serum concentration of IMGN853 given as a single dose of 5.6 mg/kg IMGN853 was comparable to a daily dose of 1.4 mg/kg for 3 days. Despite the presence of a lower total dose (4.2 mg/kg), Cmax and area under the pharmacokinetic curve (AUC _0-540 ), administration of the drug at a dose of 1.4 mg/kg for 3 days was comparable to in vivo antitumor activity ( figure 11). These results suggest that maintaining a certain minimum plasma concentration is critical to drug activity.

[00212] With a weekly regimen of IMGN853, consistent with a total dose of one high dose of IMGN853, comparable in vivo activity was found (Figure 12). Again, maintaining mean plasma concentrations above the minimum threshold required for drug activity with a single dose of IMGN853 (8.5 mg/kg) resulting in slightly higher Cavg and AUC, but comparable to total potency. The key difference in the predicted pharmacokinetic parameters with a single therapeutic exposure compared to the multi-dose regimen is a sharp decrease in Cmax. The Cmax with a weekly regimen of the drug is predicted to be almost 60% lower than the Cmax with a single therapeutic exposure to IMGN853. Since there is no apparent benefit from achieving a higher Cmax, avoidance of higher plasma concentrations may be beneficial in reducing toxicity.

[00213] It should be understood that the "Detailed Description" section and the "Summary" and "Abstract" sections are for interpretation of the claims. The Summary and Abstract sections set forth one or more, but not all, exemplary embodiments of the present invention as envisioned by the inventor(s), and thus are not intended to limit the present invention and the appended claims in any way. - either way.

[00214] The present invention has been described above in terms of functional building blocks illustrating the performance of these functions and their relationships. The boundaries of these functional building blocks are herein arbitrarily defined for convenience of description. Other boundaries may be defined, as long as these functions are properly performed and their relationship respected.

[00215] The foregoing description of specific embodiments will so fully disclose the general nature of the invention that others will be able, using the knowledge of one of ordinary skill in the art, to easily modify and/or adapt such specific embodiments for various uses, without undue experimentation, without going beyond scope of the present invention. Thus, such adaptations and modifications are within the scope of the invention and the range of equivalents of the disclosed embodiments of the invention, based on the presentation and guidance provided herein. It is to be understood that the phraseology or terminology in this document is used for the purpose of description and not limitation, such that the terminology or phraseology of this document is to be interpreted by a qualified person in light of the presentation and guidance.

[00216] The scope and context of the present invention should not be limited by any of the above-described exemplary embodiments of the invention, but should be defined only in accordance with the following claims and their equivalents.

--->

SEQUENCE LIST

<110> IMMUNOGEN, INC.

LUTZ, ROBERT J

PONTE, JOSE

<120> ANTI-FOLR1 IMMUNOCONJUGATE APPLICATION REGIMENS

<130> 2921.055PC04/EKS/CLD

<150> 61/888365

<151> 2013-10-08

<150> 61/888337

<151> 2013-10-08

<150> 61/948363

<151> 2014-03-05

<150> 62/004.815

<151> 2014-05-29

<160> 16

<170> PatentIn version 3.5

<210> 1

<211> 257

<212> Protein

<213> Homo sapiens

<400> 1

Met Ala Gln Arg Met Thr Thr Gln Leu Leu Leu Leu Leu Val Trp Val

1 5 10 15

Ala Val Val Gly Glu Ala Gln Thr Arg Ile Ala Trp Ala Arg Thr Glu

20 25 30

Leu Leu Asn Val Cys Met Asn Ala Lys His His Lys Glu Lys Pro Gly

35 40 45

Pro Glu Asp Lys Leu His Glu Gln Cys Arg Pro Trp Arg Lys Asn Ala

50 55 60

Cys Cys Ser Thr Asn Thr Ser Gln Glu Ala His Lys Asp Val Ser Tyr

65 70 75 80

Leu Tyr Arg Phe Asn Trp Asn His Cys Gly Glu Met Ala Pro Ala Cys

85 90 95

Lys Arg His Phe Ile Gln Asp Thr Cys Leu Tyr Glu Cys Ser Pro Asn

100 105 110

Leu Gly Pro Trp Ile Gln Gln Val Asp Gln Ser Trp Arg Lys Glu Arg

115 120 125

Val Leu Asn Val Pro Leu Cys Lys Glu Asp Cys Glu Gln Trp Trp Glu

130 135 140

Asp Cys Arg Thr Ser Tyr Thr Cys Lys Ser Asn Trp His Lys Gly Trp

145 150 155 160

Asn Trp Thr Ser Gly Phe Asn Lys Cys Ala Val Gly Ala Ala Cys Gln

165 170 175

Pro Phe His Phe Tyr Phe Pro Thr Pro Thr Val Leu Cys Asn Glu Ile

180 185 190

Trp Thr His Ser Tyr Lys Val Ser Asn Tyr Ser Arg Gly Ser Gly Arg

195 200 205

Cys Ile Gln Met Trp Phe Asp Pro Ala Gln Gly Asn Pro Asn Glu Glu

210 215 220

Val Ala Arg Phe Tyr Ala Ala Ala Met Ser Gly Ala Gly Pro Trp Ala

225 230 235 240

Ala Trp Pro Phe Leu Leu Ser Leu Ala Leu Met Leu Leu Trp Leu Leu

245 250 255

Ser

<210> 2

<211> 771

<212> DNA

<213> Homo sapiens

<400> 2

atggctcagc ggatgacaac acagctgctg ctccttctag tgtgggtggc tgtagtaggg 60

gaggctcaga caaggattgc atgggccagg actgagcttc tcaatgtctg catgaacgcc 120

aagcaccaca aggaaaagcc aggccccgag gacaagttgc atgagcagtg tcgaccctgg 180

aggaagaatg cctgctgttc taccaacacc agccaggaag cccataagga tgtttcctac 240

ctatatagat tcaactggaa ccactgtgga gagatggcac ctgcctgcaa acggcatttc 300

atccaggaca cctgcctcta cgagtgctcc cccaacttgg ggccctggat ccagcaggtg 360

gatcagagct ggcgcaaaga gcgggtactg aacgtgcccc tgtgcaaaga ggactgtgag 420

caatggtggg aagattgtcg cacctcctac acctgcaaga gcaactggca caagggctgg 480

aactggactt cagggtttaa caagtgcgca gtgggagctg cctgccaacc tttccatttc 540

tacttcccca cacccactgt tctgtgcaat gaaatctgga ctcactccta caaggtcagc 600

aactacagcc gaggggagtgg ccgctgcatc cagatgtggt tcgacccagc ccagggcaac 660

cccaatgagg aggtggcgag gttctatgct gcagccatga gtggggctgg gccctgggca 720

gcctggcctt tcctgcttag cctggcccta atgctgctgt ggctgctcag c 771

<210> 3

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vHC

<400> 3

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Phe Met Asn Trp Val Lys Gln Ser Pro Gly Gln Ser Leu Glu Trp Ile

35 40 45

Gly Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Lys Phe

50 55 60

Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala His

65 70 75 80

Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Phe Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Tyr Asp Gly Ser Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 4

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vLCv1.00

<400> 4

Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala

20 25 30

Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Asn Ile Ser

65 70 75 80

Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105 110

<210> 5

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vLCv1.60

<400> 5

Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala

20 25 30

Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105 110

<210> 6

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vLC CDR1

<400> 6

Lys Ala Ser Gln Ser Val Ser Phe Ala Gly Thr Ser Leu Met His

1 5 10 15

<210> 7

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vLC CDR2

<400> 7

Arg Ala Ser Asn Leu Glu Ala

15

<210> 8

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vLC CDR3

<400> 8

Gln Gln Ser Arg Glu Tyr Pro Tyr Thr

15

<210> 9

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vHC CDR1

<400> 9

Gly Tyr Phe Met Asn

15

<210> 10

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vHC CDR2 - determined by Kabat

<400> 10

Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Lys Phe Gln

1 5 10 15

gly

<210> 11

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vHC CDR2 - Determined by Abm

<400> 11

Arg Ile His Pro Tyr Asp Gly Asp Thr Phe

1 5 10

<210> 12

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 vHC CDR3

<400> 12

Tyr Asp Gly Ser Arg Ala Met Asp Tyr

15

<210> 13

<211> 448

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 HC

<400> 13

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Phe Met Asn Trp Val Lys Gln Ser Pro Gly Gln Ser Leu Glu Trp Ile

35 40 45

Gly Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Lys Phe

50 55 60

Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala His

65 70 75 80

Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Phe Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Tyr Asp Gly Ser Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 14

<211> 218

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 LCv1.00

<400> 14

Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala

20 25 30

Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Asn Ile Ser

65 70 75 80

Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 15

<211> 218

<212> Protein

<213> Artificial sequence

<220>

<223> huMov19 LCv1.60

<400> 15

Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala

20 25 30

Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 16

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<223> muMov19 vHC CDR2 - determined by Kabat

<400> 16

Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Asn Phe Lys

1 5 10 15

asp

<---

Claims (96)

1. A method of treating a human patient having a FOLR1-expressing cancer, comprising administering to the patient an immunoconjugate that binds to a FOLR1 polypeptide, said immunoconjugate comprising an antibody or antigen-binding fragment thereof containing a complementarity-determining region (CDR)-1 of the variable light chain (VL) according to SEQ ID NO: 6, CDR-2 VL according to SEQ ID NO: 7, CDR-3 VL according to SEQ ID NO: 8, CDR-1 variable heavy chain (VH) according to SEQ ID NO: 9, CDR-2 VH according to SEQ ID NO: 11, CDR-3 VH according to SEQ ID NO: 12, and maytansinoid, said immunoconjugate being administered at a dose of 5 milligrams (mg) per kilogram (kg) of adjusted ideal body weight (AIBW) of the patient. 2. The method according to p. 1, characterized in that VH-CDR-2 contains the amino acid sequence according to SEQ ID NO: 10. 3. The method according to p. 1 or p. 2, characterized in that the immunoconjugate is administered once every three weeks. 4. The method according to any one of paragraphs. 1-3, characterized in that said antibody or its antigen-binding fragment contains a heavy chain variable domain containing SEQ ID NO: 3, and a light chain variable domain containing SEQ ID NO: 4 or SEQ ID NO: 5. 5. The method according to any one of paragraphs. 1-4, characterized in that the antibody or its antigen-binding fragment contains a heavy chain variable domain containing SEQ ID NO: 3, and a light chain variable domain containing SEQ ID NO: 5. 6. The method according to any one of paragraphs. 1-5, characterized in that the specified antibody contains (i) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATCC) under the number PTA-10772, and ( ii) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited with ATCC under the number PTA-10774. 7. The method according to any one of paragraphs. 1-6, characterized in that the immunoconjugate contains 1-10 maytansinoid molecules. 8. The method according to any one of paragraphs. 1-7, characterized in that the immunoconjugate contains 2-5 maytansinoid molecules. 9. The method according to any one of paragraphs. 1-8, characterized in that the immunoconjugate contains 3-4 maytansinoid molecules. 10. The method according to any one of paragraphs. 1-9, characterized in that the maytansinoid is DM4. 11. The method according to any one of paragraphs. 1-10, characterized in that the immunoconjugate contains a sulfo-SPDB linker. 12. The method according to any one of paragraphs. 1-11, characterized in that the immunoconjugate contains DM4 and an antibody containing (i) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATCC) under the number PTA- 10772, and (ii) a light chain containing the same amino acid sequence as the light chain amino acid sequence encoded by the plasmid deposited at ATCC under the number PTA-10774, and wherein DM4 is linked to the antibody via sulfo-SPDB. 13. The method according to any one of paragraphs. 1-5, characterized in that the immunoconjugate contains DM4 and an antibody containing (i) a heavy chain containing the amino acid sequence according to SEQ ID NO: 13, and (ii) a light chain containing the amino acid sequence according to SEQ ID NO: 15, and when this DM4 is associated with the antibody through sulfo-SPDB. 14. The method according to any one of paragraphs. 1-13, characterized in that the immunoconjugate is intended for intravenous administration. 15. The method according to any one of paragraphs. 1-14, characterized in that the cancer is ovarian cancer. 16. The method of claim 15 wherein the ovarian cancer is an epithelial ovarian cancer. 17. The method of claim 16, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. 18. The method according to any one of paragraphs. 1-14, characterized in that said cancer is a cancer of the peritoneum. 19. The method according to any one of paragraphs. 1-14, characterized in that the cancer is endometrial cancer. 20. The method according to any one of paragraphs. 1-14, characterized in that the cancer is uterine cancer. 21. The method according to any one of paragraphs. 1-20, characterized in that the sample obtained from the patient's body shows the expression of FOLR1 as measured by the immunohistochemical method (IHC). 22. The method of claim. 21, characterized in that the sample has a staining intensity of at least 1 hetero. 23. The method according to claim 21, characterized in that the sample has a staining intensity of at least 1 homo. 24. The method of claim. 21, characterized in that the sample has a staining intensity of at least 2 hetero. 25. The method according to p. 21, characterized in that the sample has a staining intensity of at least 2 homo. 26. The method according to p. 21, characterized in that the sample has a staining intensity of at least 3 hetero. 27. The method according to p. 21, characterized in that the sample has a staining intensity of at least 3 homo. 28. The method according to any one of paragraphs. 1-27, further comprising administering a steroid to the patient. 29. The method of claim 28, wherein the steroid is dexamethasone. 30. The method according to any one of paragraphs. 1-17 and 21-29, characterized in that the cancer is ovarian cancer, and the introduction leads to a decrease in the level of CA125. 31. The method according to any one of paragraphs. 1-30, characterized in that the introduction leads to a decrease in toxicity. 32. The method of claim 31, wherein the toxicity is ophthalmic toxicity. 33. Use of an immunoconjugate that binds to a FOLR1 polypeptide in the treatment of FOLR1-expressing cancer, said immunoconjugate comprising an antibody or antigen-binding fragment thereof comprising a variable light chain (VL) complementarity determining region (CDR)-1 according to SEQ ID NO: 6, CDR -2 VL according to SEQ ID NO: 7, CDR-3 VL according to SEQ ID NO: 8, CDR-1 variable heavy chain (VH) according to SEQ ID NO: 9, CDR-2 VH according to SEQ ID NO: 11, CDR- 3 VH according to SEQ ID NO: 12 and maytansinoid, said immunoconjugate being administered at a dose of 5 milligrams (mg) per kilogram (kg) of the patient's corrected ideal body weight (AIBW). 34. Use according to claim 33, characterized in that VH-CDR-2 contains the amino acid sequence according to SEQ ID NO: 10. 35. Application according to paragraphs. 33 or 34, characterized in that the immunoconjugate is administered once every three weeks. 36. Application according to any one of paragraphs. 33-35, characterized in that said antibody or its antigen-binding fragment contains a heavy chain variable domain containing SEQ ID NO: 3, and a light chain variable domain containing SEQ ID NO: 4 or SEQ ID NO: 5. 37. Application according to any one of paragraphs. 33-36, characterized in that said antibody or antigen-binding fragment thereof contains a heavy chain variable domain containing SEQ ID NO: 3 and a light chain variable domain containing SEQ ID NO: 5. 38. Application according to any one of paragraphs. 33-37, characterized in that the specified antibody contains (i) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATCC) under the number PTA-10772, and ( ii) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited with ATCC under the number PTA-10774. 39. Application according to any one of paragraphs. 33-38, characterized in that the immunoconjugate contains 1-10 maytansinoid molecules. 40. Application according to any one of paragraphs. 33-39, characterized in that the immunoconjugate contains 2-5 maytansinoid molecules. 41. Application according to any one of paragraphs. 33-40, characterized in that the immunoconjugate contains 3-4 maytansinoid molecules. 42. Application according to any one of paragraphs. 33-41, wherein the maytansinoid is DM4. 43. Application according to any one of paragraphs. 33-42, characterized in that the immunoconjugate contains a sulfo-SPDB linker. 44. Application according to any one of paragraphs. 33-43, characterized in that the immunoconjugate contains DM4 and an antibody containing (i) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATCC) under the number PTA- 10772, and (ii) a light chain containing the same amino acid sequence as the light chain amino acid sequence encoded by the plasmid deposited at ATCC under the number PTA-10774, and wherein DM4 is linked to the antibody via sulfo-SPDB. 45. Application according to any one of paragraphs. 33-37, characterized in that the immunoconjugate contains DM4 and an antibody containing (i) a heavy chain containing the amino acid sequence according to SEQ ID NO: 13, and (ii) a light chain containing the amino acid sequence according to SEQ ID NO: 15, and when this DM4 is associated with the antibody through sulfo-SPDB. 46. Application according to any one of paragraphs. 33-45, characterized in that the immunoconjugate is intended for intravenous administration. 47. Application according to any one of paragraphs. 33-46, characterized in that said cancer is ovarian cancer. 48. Use according to claim 47, wherein the ovarian cancer is epithelial ovarian cancer. 49. Use according to claim 48, characterized in that the ovarian cancer is platinum-resistant, recurrent or refractory. 50. Application according to any one of paragraphs. 33-46, characterized in that said cancer is peritoneal cancer. 51. Application according to any one of paragraphs. 33-46, wherein the cancer is endometrial cancer. 52. Application according to any one of paragraphs. 33-46, characterized in that the cancer is uterine cancer. 53. Application according to any one of paragraphs. 33-52, characterized in that the sample obtained from the patient's body shows the expression of FOLR1 as measured by immunohistochemical method (IHC). 54. Use according to claim 53, characterized in that the sample has a staining intensity of at least 1 hetero. 55. Use according to claim 53, characterized in that the sample has a staining intensity of at least 1 homo. 56. Use according to claim 53, characterized in that the sample has a staining intensity of at least 2 hetero. 57. Use according to claim 53, characterized in that the sample has a staining intensity of at least 2 homo. 58. Use according to claim 53, characterized in that the sample has a staining intensity of at least 3 hetero. 59. Use according to claim 53, characterized in that the sample has a staining intensity of at least 3 homo. 60. Application according to any one of paragraphs. 33-59, further comprising administering a steroid to the patient. 61. Use according to claim 60, characterized in that the steroid is dexamethasone. 62. Application according to any one of paragraphs. 33-49 and 53-61, wherein the cancer is ovarian cancer, wherein the administration results in a decrease in the level of CA125. 63. Application according to any one of paragraphs. 33-62, characterized in that the introduction leads to a decrease in toxicity. 64. Use according to claim 63, characterized in that the toxicity is ophthalmic toxicity. 65. A method of treating a human patient having FOLR1-expressing cancer, comprising administering to the patient a composition containing immunoconjugates that bind to a FOLR1 polypeptide, said immunoconjugates containing an average of 3-4 DM4 maytansinoid per antibody containing (i) a heavy chain containing the same amino acid sequence as the heavy chain amino acid sequence encoded by the plasmid deposited with the American Type Culture Collection (ATCC) under the number PTA-10772, and (ii) a light chain containing the same amino acid sequence as the light chain amino acid sequence, encoded by a plasmid deposited at ATCC under the number PTA-10774, wherein the DM4 maytansinoids are linked to the antibody via sulfo-SPDB, and the immunoconjugates are administered at a dose of 5 milligrams (mg) per kilogram (kg) of the patient's corrected ideal body weight (AIBW) , once every three weeks. 66. The method of claim 65, wherein the patient sample exhibits at least 2 hetero FOLR1 expression as measured by immunohistochemistry (IHC). 67. The method according to claim 65 or 66, wherein said cancer is ovarian cancer. 68. The method of claim 67 wherein the ovarian cancer is an epithelial ovarian cancer. 69. The method of claim 68, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. 70. The method according to claim 65 or 66, wherein the cancer is peritoneal cancer. 71. The method according to claim 65 or 66, wherein the cancer is endometrial cancer. 72. The method according to claim 65 or 66, wherein the cancer is uterine cancer. 73. Use of immunoconjugates that bind to a FOLR1 polypeptide in the treatment of FOLR1-expressing cancer, said immunoconjugates containing an average of 3-4 DM4 maytansinoid per antibody containing (i) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain , encoded by the plasmid deposited with the American Type Culture Collection (ATCC) under the number PTA-10772, and (ii) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited with the ATCC under the number PTA-10774 , wherein the DM4 maytansinoids are bound to the antibody via sulfo-SPDB, and said immunoconjugates are designed to be administered at a dose of 5 milligrams (mg) per kilogram (kg) of the patient's adjusted ideal body weight (AIBW), once every three weeks. 74. Use according to claim 73, characterized in that the sample obtained from the patient shows the expression of FOLR1 at least 2 hetero as measured by immunohistochemistry (IHC). 75. Use according to claim 73 or 74, characterized in that said cancer is ovarian cancer. 76. Use according to claim 75, wherein the ovarian cancer is epithelial ovarian cancer. 77. Use according to claim 76, characterized in that the ovarian cancer is platinum-resistant, recurrent or refractory. 78. Use according to claim 73 or 74, characterized in that the cancer is a cancer of the peritoneum. 79. Use according to claim 73 or 74, wherein the cancer is endometrial cancer. 80. Use according to claim 73 or 74, characterized in that the cancer is uterine cancer. 81. A method of treating a human patient having FOLR1-expressing cancer, comprising administering to the patient a composition containing immunoconjugates that bind to a FOLR1 polypeptide, said immunoconjugates containing 3-4 DM4 maytansinoid per antibody containing (i) a heavy chain variable domain containing SEQ ID NO: 3, and (ii) a light chain variable domain comprising SEQ ID NO: 5, wherein the DM4 maytansinoids are linked to the antibody via sulfo-SPDB and the immunoconjugates are administered at a dose of 5 milligrams (mg) per kilogram ( kg) of the patient's adjusted ideal body weight (AIBW), once every three weeks. 82. The method of claim 81, wherein the patient sample exhibits at least 2 hetero FOLR1 expression as measured by immunohistochemistry (IHC). 83. The method of claim 81 or 82, wherein said cancer is ovarian cancer. 84. The method of claim 83, wherein the ovarian cancer is epithelial ovarian cancer. 85. The method of claim 84, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. 86. The method according to claim 81 or 82, wherein the cancer is peritoneal cancer. 87. The method according to claim 81 or 82, wherein the cancer is endometrial cancer. 88. The method according to claim 81 or 82, wherein the cancer is uterine cancer. 89. Use of immunoconjugates that bind to a FOLR1 polypeptide in the treatment of FOLR1-expressing cancer, said immunoconjugates containing an average of 3-4 DM4 maytansinoid per antibody containing (i) a heavy chain variable domain containing SEQ ID NO: 3, and ( ii) a light chain variable domain comprising SEQ ID NO: 5, wherein the DM4 maytansinoids are linked to the antibody via sulfo-SPDB, and said immunoconjugates are intended to be administered at a dose of 5 milligrams (mg) per kilogram (kg) of corrected ideal weight body (AIBW) patient, once every three weeks. 90. Use according to claim 89, characterized in that the sample obtained from the patient shows the expression of FOLR1 at least 2 hetero as measured by immunohistochemistry (IHC). 91. Use according to claim 89 or 90, characterized in that said cancer is ovarian cancer. 92. Use according to claim 91, wherein the ovarian cancer is epithelial ovarian cancer. 93. Use according to claim 92, characterized in that the ovarian cancer is platinum-resistant, recurrent or refractory. 94. Use according to claim 89 or 90, characterized in that the cancer is a cancer of the peritoneum. 95. Use according to claim 89 or 90, wherein the cancer is endometrial cancer. 96. Use according to claim 89 or 90, characterized in that the cancer is uterine cancer.

Images