Administration of anti-folate receptor α antibody drug conjugates

Abstract

To provide a method for treating individuals suffering from cancer. [Solution] A method is provided for treating subjects suffering from cancer that expresses folate receptor α using an anti-folate receptor α antibody drug conjugate.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Patent Application No. 63 / 774,402 filed on 19 March 2025, U.S. Provisional Patent Application No. 63 / 789,198 filed on 15 April 2025, U.S. Provisional Patent Application No. 63 / 808,880 filed on 20 May 2025, U.S. Provisional Patent Application No. 63 / 860,023 filed on 8 August 2025, U.S. Provisional Patent Application No. 63 / 887,654 filed on 25 September 2025, U.S. Provisional Patent Application No. 63 / 917,477 filed on 14 November 2025, and U.S. Provisional Patent Application No. 63 / 960,835 filed on 15 January 2026, all of which are incorporated herein by reference in their entirety.

[0002] (Sequence Listing) This application includes a sequence listing in XML format, created on January 14, 2026, with the filename txt_31461_WO and a file size of 2,601 bytes, which is incorporated herein by reference in its entirety. [Background technology]

[0003] This disclosure relates to a method for treating subjects with cancer expressing folate receptor α (FRα) using an anti-folate receptor α antibody drug conjugate (anti-FRα ADC). Folate receptor α (FRα) is generally expressed on the apical membrane side of polarized epithelial cells, particularly in the proximal tubular cells, choroid plexus, and glomerular endothelial cells of the kidney, but is absent in most other healthy tissues (Wu et al. Cancer Epidemiol Biomarkers Prev. 1999;8(9):775, Weitman et al. Cancer Res. 1992;52(23):6708). Non-malignant tissues have a limited distribution of FRα. However, various cancer types, including ovarian cancer, endometrial cancer, cervical cancer, triple-negative breast cancer, and lung cancer, are characterized by FRα overexpression, making this receptor a promising target for anticancer drugs (Yazaki et al. J Gynecol Oncol. 2022;33(6):e82, Scaranti et al. Nat Rev clin Concol. 2020;17(6):349, Cheung et al. Oncotarget. 2016;7(32):52553). Specifically, FRα expression as determined by IHC has been reported in up to 70%–90% of ovarian cancers, 80% of NSCLCs, 30%–40% of breast cancers (71%–86% of TNBCs), 20%–50% of endometrial cancers, 37%–80% of pancreatic cancers, and 30%–40% of colorectal cancers.FRα expression has also been found in metastases from these diseases (see The Human Protein Atlas website for ENSG00000110195-FOLR1, Yazaki et al. 2022, Norton et al. NPJ Breast Cancer 2020;6:4, Omote et al. Med Mol Morphol. 2018;51(4):237, Cai et al. Oncotarget. 2017;8(23):37646, Boogerd et al. Oncotarget. 2016;7(14):17442, O'Shannessy et al. Oncotarget. 2012;3(4):414), higher expression levels have been found in metastatic sites than in primary tumors in several histological examinations (Yazaki et al. 2022), and expression levels correlate with survival (Norton et al. 2020, Cai et al. 2017).

[0004] Currently, mirvetuximab soravtansine-gynx (Elahere®) (MIRV) is the only anti-FRα ADC approved for the treatment of FRα-positive, silver-resistant epithelial ovarian cancer, fallopian tube cancer, or peritoneal cancer. MIRV consists of a FRα-binding antibody, a cleavable linker, and the cytotoxic mytansionoid effector molecule DM4 (Mai et al. Front Immunol. 2023, 14:1254532). In a Phase 3 clinical trial (FORWARD I) comparing MIRV with chemotherapy in FRα-positive, platinum-resistant ovarian cancer, MIRV did not meet its primary endpoint of progression-free survival. When patient subgroups were analyzed, MIRVs benefited only patients with high FRα tumor expression, and MIRVs were inactive against low and negative FRα-expressing cells (Matulonis UA., et al., J Clin Oncol 2023;41:2436-45, Moore KN., et al., Ann Oncol 2021;32:757-765). Based on the results of subsequent SORAYA Phase 2 / 3 and MIRASOL Phase 3 trials, MIRVs demonstrated promising activity as monotherapy in patients with platinum-resistant epithelial ovarian cancer with tumors expressing high levels of FRα (Matulonis 2023, Moore 2023), but the toxicity profile demonstrated a high rate of ocular AEs, including blurred vision (40.8%) and keratopathy (32.1%) (Moore 2023).

[0005] Other anti-FRα ADCs currently in clinical development include, for example, Lardotutsugderuxtecan (Daiichi Sankyo & Merck & Co.), Rinatavertesestecan (Rina-S, Genmab A / S), Rubertamabutazevibrin (STRO-002 or Luvelta-Sutro Biopharma), Farretsuzumabecteribulin (MORAb-202-Eisai), AMT-151 (Multitude Therapeutics), PRO1184 (ProfoundBio), IMGN151 (Immunogen), AZD-5335 (Astrazeneca), IMGN-151 (Abbvie), ZW191 (Zymeworks), SYS604 (CSPC Megalith Biopharmaceutical), HMB9033 (Harbour Biomed), and BAT8006 (Bio-Thera Solutions).

[0006] Therefore, there is a need to develop therapies for treating FRα-positive cancers that have an improved treatment index for treating low and moderate FRα expression cancers in addition to high-FRα expression cancers, and that have a milder adverse event profile that allows for combination with early selective cytotoxic agents and immunotherapies. [Brief explanation of the drawing]

[0007] [Figure 1A] We compare the in vivo activity of both FRαADC and MIRV at 3 mg / kg over post-treatment days in various tumor models representing high (Figure 1A), moderate (Figures 1B and 1C), and low (Figure 1D) FRα expression levels. See Example 1. [Figure 1B] We compare the in vivo activity of both FRαADC and MIRV at 3 mg / kg over post-treatment days in various tumor models representing high (Figure 1A), moderate (Figures 1B and 1C), and low (Figure 1D) FRα expression levels. See Example 1. [Figure 1C]We compare the in vivo activity of both FRαADC and MIRV at 3 mg / kg over post-treatment days in various tumor models representing high (Figure 1A), moderate (Figures 1B and 1C), and low (Figure 1D) FRα expression levels. See Example 1. [Figure 1D] We compare the in vivo activity of both FRα ADCs and MIRVs at 3 mg / kg over post-treatment days in various tumor models representing high (Figure 1A), medium (Figures 1B and 1C), and low (Figure 1D) FRα expression levels. See Example 1. [Figure 2A] The in vivo efficacy of FRα ADCs at 1 mpk, 3 mpk, or 5 mpk in combination with bevacizumab in an OV-90 ovarian cancer model is shown (Figure 2A). Tumor volume was measured every 3-4 days and plotted as mean tumor volume (mm3) ± mean standard error (SEM) versus time on the y axis for each treatment group (n=5). Bev = bevacizumab, Mirv = mirbetuximab sorabtansine-gynx. See Study A in Example 2. [Figure 2B] The in vivo efficacy of FRα ADCs at 1 mpk, 3 mpk, or 5 mpk in combination with bevacizumab in an OV-90 ovarian cancer model is shown (Figure 2A). Tumor volume was measured every 3-4 days and plotted as mean tumor volume (mm3) ± mean standard error (SEM) versus time on the y axis for each treatment group (n=5). Body weight of each test animal in each test group was also monitored (Figure 2B). Bev = bevacizumab, Mirv = mirbetuximab sorabtansine-gynx. See Study A in Example 2. [Figure 3A]The in vivo efficacy of FRα ADCs at 1 mpk, 3 mpk, or 5 mpk in combination with cisplatin or cisplatin and bevacizumab in an OV-90 ovarian cancer model is shown (Figure 3A). Tumor volume was measured every 3-4 days and plotted as mean tumor volume (mm3) ± mean standard error (SEM) versus time on the y axis for each treatment group (n=5). Bev = bevacizumab, Mirv = mirbetuximab sorabtansine-gynx. See Study B in Example 2. [Figure 3B] The in vivo efficacy of FRα ADCs at 1 mpk, 3 mpk, or 5 mpk in combination with cisplatin or cisplatin and bevacizumab in an OV-90 ovarian cancer model is shown (Figure 3A). Tumor volume was measured every 3-4 days and plotted as mean tumor volume (mm3) ± mean standard error (SEM) versus time on the y axis for each treatment group (n=5). Body weight of each test animal in each test group was also monitored (Figure 3B). Bev = bevacizumab, Mirv = mirbetuximab sorabtansine-gynx. See Study B in Example 2. [Figure 4] This shows the Phase 1a clinical trial scheme for cases where CRC = colorectal cancer. DL = dose level, MIRV = milbetuximab sorabtansine-gynx, NSCLC = non-small cell lung cancer, and TNBC = triple-negative breast cancer. See Example 3. [Figure 5] The Phase 1b clinical trial scheme is shown, where CRC = colorectal cancer, NSCLC = non-small cell lung cancer, RP2D = recommended Phase 2 dose, and TNBC = triple-negative breast cancer. See Example 3. [Figure 6] This report presents patient disease evaluation results from Phase Ia monotherapy dose escalation in patients with high-grade serous ovarian cancer (HGSOC), separated by FRα expression levels at 2 mg / kg, 3 mg / kg, 4 mg / kg, and 6 mg / kg. ">" indicates ongoing treatment, and "*" indicates patients with prior MIRV treatment. See Example 3 and Tables 4 and 5. [Figure 7] The nM analyte concentrations of the free payload (exatecan), total FRα ADC, and total antibody at different doses (2 mg / kg, 3 mg / kg, 4 mg / kg, and 6 mg / kg) tested in Phase Ia are shown over time, measured in days. See Example 3 and Table 6. [Figure 8] This shows a Phase 3 study scheme for platinum-resistant ovarian cancer (PROC). BRCA = breast cancer gene, IHC = immunohistochemistry, MIRV = milbetuximabsorabtansine. See Example 5. [Figure 9] This shows a Phase 3 study scheme for platinum-sensitive ovarian cancer (PSOC). PLD = pegylated liposomal doxorubicin. See Example 5. [Figure 10] The revised Phase Ia trial scheme discussed in Example 3 is shown, and the revised Phase Ia trial scheme adds Cohort A6 dose optimization for endometrial cancer, and Cohort A6 dose optimization adds sub-studies Arm A, Arm B, and Arm C within Cohort A1. See Example 6. [Figure 11] This shows the research scheme cycle for the newly added drug-drug interaction sub-arm B in Cohort A1 of the revised Phase Ia clinical trial scheme. See Example 7. [Figure 12] The revised Phase Ib trial scheme discussed in Example 3 is shown below. The revised Phase Ib trial scheme modifies the Cohort B dose expansion and adds Cohorts B1, B2, B3, and B4. See Example 8. [Overview of the project] [Means for solving the problem]

[0008] The present invention describes a method of treating a subject suffering from a cancer that expresses folate receptor α (FRα) using an anti-folate receptor α antibody-drug conjugate (anti-FRα ADC).

[0009] Anchored to the cell membrane of non-malignant tissues, folate receptor alpha (FRα) is an internalizing target that is overexpressed in several solid tumors, including ovarian cancer, endometrial cancer, Non-Small Cell Lung Cancer (NSCLC), Triple-Negative Breast Cancer (TNBC), pancreatic cancer, and Colorectal Cancer (CRC). The FRα isoform has high affinity for folate and folic acid, and when folate binds to FRα, it results in internalization of clusters of the ligand-receptor complex within vesicles in the cell cytoplasm and release of folate. The interaction between folate and FRα has been associated with tumor progression. Since FRα is known to have minimal physiological roles in post-embryonic and non-malignant tissues, its overexpression in tumor cells makes FRα a promising candidate for targeting in anti-cancer therapy. In contrast to non-malignant cells, the differential expression of FRα on the surface of cancer cells in selected tumors enables the development of antibody-based therapeutic strategies including ADCs. These properties, together with the highly restricted expression of FRα in normal tissues and its very efficient internalization rate, provide a strong rationale for ADC targeting of the FRα receptor in several FRα-positive cancers.

[0010] An ADC is a selective drug delivery system that combines two classes of drugs with complementary properties, with the goal of increasing the therapeutic index of the payload and minimizing damage to normal tissues (Manzano and Ocana 2020). Emerging evidence indicates that the efficacy of ADCs depends on antibody-specific, linker-specific, and payload-specific factors, each of which is a function of the complex interactions between the ADC and various components of the tumor and the tumor microenvironment.

[0011] MIRV is the only approved ADC, which consists of a FRα-binding antibody, a cleavable linker, and the cytotoxic maytansinoid effector molecule DM4 (Mai et al. 2023). There are other anti-folate receptor alpha-antibody drug conjugates in clinical development, for example, refer to lardiratuzedruxtecan (Daiichi Sankyo & Merck & Co.), rinatabartsetecan (Rina-S, Genmab A / S), lubertamab tazevibrin (STRO-002 or Luvelta-Sutro Biopharma), farletuzumab ecteribulin (MORAb-202-Eisai), AMT-151 (Multitude Therapeutics), PRO1184 (ProfoundBio), IMGN151 (Immunogen), AZD-5335 (Astrazeneca), IMGN-151 (Abbvie), ZW191 (Zymeworks), SYS604 (CSPC Megalith Biopharmaceutical), HMB9033 (Harbour Biomed), and BAT8006 (Bio-Thera Solutions).

[0012] WO 2019 / 081455 describes the synthesis of linker L of the present Formula III, and is therefore incorporated by reference in its entirety. WO 2023 / 170247 describes synthesizing the dipeptide-based drug linker of the present Formula II, and conjugating the resulting drug linker to an antibody, for example, the anti-FRα antibody described herein, to generate the anti-folate receptor alpha-antibody drug conjugate (Formula I) of the present invention having a drug-antibody ratio (DAR) of 8, and is therefore incorporated herein by reference in its entirety.

[0013] Ovarian cancer is the leading cause of cancer death among gynecological malignancies worldwide, ranking third after cervical and uterine cancer. Tumor debulking surgery and platinum-based chemotherapy are the standard treatment options for early-stage cancer. The most commonly used platinum combinations are carboplatin plus paclitaxel or cisplatin plus paclitaxel, each of which has similar efficacy but different safety profiles. Cisplatin tends to have more renal, GI, and metabolic toxicity, while carboplatin causes more thrombocytopenia and granulocytopenia (du Bois et al. J Natl Cancer Inst. 2003;95(17):1320, Ozols et al. J Clin Oncol. 2003;21(17):3194, Neijt et al. J Clin Oncol. 2000;18(17):3084). While platinum therapy as the first-line treatment has a high response rate, the majority of patients experience disease relapse (Wang et al. Signal Transduct Target Ther. 2020;5(1):137).

[0014] Bevacizumab is a cancer-targeted therapy developed for VEGF-A. Two randomized studies, GOG-0218 and ICON7, showed improved PFS when bevacizumab was added to carboplatin plus paclitaxel and continued as maintenance therapy until progression (Oza et al. Lancet Oncol. 2015;16(8):928, Burger et al. N Engl J Med. 2011;365:2473). However, no survival benefit was observed in either study. Addition of bevacizumab to platinum doublets increases VEGFR-driven toxicities, such as bleeding, hypertension, proteinuria, wound dehiscence, GI perforation, and thromboembolism.

[0015] Endometrial cancer is one of the few malignant conditions, and both its incidence and mortality rates are currently on the rise. By 2040, endometrial cancer is projected to be the third most common cancer and the fourth leading cause of cancer death among women (Siegel, RL, et al., CA Cancer J clin 2023;73:17-48). Standard first-line chemotherapy, including paclitaxel plus carboplatin, is used to treat patients with advanced or recurrent endometrial cancer.

[0016] Pembrolizumab, also known as Keytruda®, is an immunotherapy drug that targets PD-1 and blocks the PD-1 receptor in T cells. As a result of the Phase III KEYNOTE-868 / NRG-GY018 clinical trial, pembrolizumab was approved for the treatment of primary advanced or recurrent endometrial cancer as monotherapy or in combination with carboplatin and paclitaxel (see Eskander, R. et al., N Engl J Med 388;23 June 8, 2023).

[0017] Itraconazole (ITZ) is a p-glycoprotein (P-gp) inhibitor, and P-gp inhibitors are commonly used in drug-drug interaction (DDI) studies as cytochrome P450 3A (CYP3A4) inhibitors because CYP3A4 is an enzyme involved in the metabolism of many drugs, meaning that CYP3A4 can increase the levels of other drug therapies in the body of the subject, potentially leading to an increased risk of side effects. It is approved as an antifungal drug used to treat and prevent fungal infections.

[0018] To overcome resistant or recurrent diseases and to mitigate the toxicity observed with known treatments, the methods of the present invention using the FRα ADCs described herein are used to treat ovarian cancer, endometrial cancer, and other FRα-positive cancers both as monotherapy and in the combinations described herein. [Modes for carrying out the invention]

[0019] Embodiments of the method of the present invention include, but are not limited to, the following.

[0020] A method for treating a subject with folate receptor alpha-positive cancer, comprising administering an anti-folate receptor alpha-antibody drug conjugate in a drug regimen comprising an intravenous (IV) infusion at a dose of approximately 1.0 mg / kg to approximately 10.0 mg / kg for at least two cycles on day 1 (Q3W) of every 21-day cycle, wherein the anti-folate receptor alpha-antibody drug conjugate has the chemical structure of formula I, Ab-(LD) p A method having (I), wherein p is 1 to 8. In another embodiment, in the above method, the anti-folate receptor alpha-antibody drug conjugate has the chemical structure of formula (II),

[0021] [ka] The formula has the following characteristics, where Ab is an anti-folate receptor alpha antibody, k is 2-20, and p is 1-8.

[0022] In another embodiment, the above method administers the above anti-folate receptor alpha-antibody drug conjugate in a dosing regimen of approximately 1.0 mg / kg to approximately 2.0 mg / kg, or approximately 2.0 mg / kg to approximately 3.0 mg / kg, or approximately 3.0 mg / kg to approximately 4.0 mg / kg, or approximately 4.0 mg / kg to approximately 5.0 mg / kg, or approximately 5.0 mg / kg to approximately 6.0 mg / kg, or approximately 6.0 mg / kg to approximately 7.0 mg / kg, or approximately 7.0 mg / kg to approximately 8.0 mg / kg, or approximately 8.0 mg / kg to approximately 9.0 mg / kg, or approximately 9.0 mg / kg to approximately 10.0 mg / kg, or approximately 1 mg / kg to approximately 4 mg / kg, or approximately 4 mg / kg to approximately 10 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of each 21-day cycle. In another embodiment, the above method administers the above anti-folate receptor alpha-antibody drug conjugate in a dosing regimen of approximately 1.0 mg / kg to approximately 2.0 mg / kg, or approximately 2.0 mg / kg to approximately 3.0 mg / kg, or approximately 3.0 mg / kg to approximately 4.0 mg / kg, or approximately 4.0 mg / kg to approximately 5.0 mg / kg, or approximately 5.0 mg / kg to approximately 6.0 mg / kg, or approximately 6.0 mg / kg to approximately 7.0 mg / kg, or approximately 7.0 mg / kg to approximately 8.0 mg / kg, or approximately 8.0 mg / kg to approximately 9.0 mg / kg, or approximately 9.0 mg / kg to approximately 10.0 mg / kg, or approximately 1 mg / kg to approximately 4 mg / kg, or approximately 4 mg / kg to approximately 10 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q4W) of each 28-day cycle. In another embodiment, the method described herein involves administering the above-mentioned anti-folate receptor alpha-antibody drug conjugate in a dosing regimen comprising doses of approximately 1.0 mg / kg, or approximately 1.5 mg / kg, or approximately 2.0 mg / kg, or approximately 2.5 mg / kg, or approximately 3.0 mg / kg, or approximately 3.5 mg / kg, or approximately 4.0 mg / kg, or approximately 4.5 mg / kg, or approximately 5.0 mg / kg, or approximately 5.5 mg / kg, or approximately 6.0 mg / kg, or approximately 7.0 mg / kg, or approximately 8.0 mg / kg, or approximately 9.0 mg / kg, or approximately 10.0 mg / kg, as intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of each 21-day cycle.In yet another embodiment, the method herein involves administering the above-described anti-folate receptor alpha-antibody drug conjugate in a dosing regimen comprising doses of approximately 1.0 mg / kg, or approximately 1.5 mg / kg, or approximately 2.0 mg / kg, or approximately 2.5 mg / kg, or approximately 3.0 mg / kg, or approximately 3.5 mg / kg, or approximately 4.0 mg / kg, or approximately 4.5 mg / kg, or approximately 5.0 mg / kg, or approximately 5.5 mg / kg, or approximately 6.0 mg / kg, or approximately 7.0 mg / kg, or approximately 8.0 mg / kg, or approximately 9.0 mg / kg, or approximately 10.0 mg / kg, as intravenous (IV) infusion for at least two cycles on day 1 (Q4W) of each 28-day cycle. The doses disclosed herein are calculated based on the actual body weight of the subject on day 1 of treatment.

[0023] In another embodiment, with respect to the doses used as discussed above, such doses are administered as intravenous (IV) infusions during at least two, or at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight, or at least nine, or at least ten, or at least eleven, or at least twelve, or at least thirteen, or at least thirteen, or at least fourteen, or at least fifteen, or at least sixteen, or at least seventeen, or at least eighteen, or at least nineteen, or at least twenty, or at least twenty-one, or at least twenty-two cycles on day one (Q3W) of each 21-day cycle. In yet another embodiment, with respect to the doses used as considered above, such doses are administered as intravenous (IV) infusions over at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelf, thirteen, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or twenty-two cycles on day one (Q4W) of each 28-day cycle. The number of cycles may continue until disease exacerbation or unacceptable toxicity occurs, as assessed by the healthcare provider.

[0024] In one embodiment, in any of the methods discussed above, the anti-FRα antibody Ab of formula I may be, for example, an FRα antibody, particularly as described in International Publication Nos. 2005 / 080431, 2008 / 031577, 2009 / 132081, 2011 / 106528, 2012 / 033987, 2014 / 087863, 2018 / 071597, and The FRα antibody may be one of those disclosed in Publication No. 2019 / 177854, International Publication No. 2019 / 177372, International Publication No. 2020 / 016661, International Publication No. 2020 / 127224, International Publication No. 2022 / 223784, International Publication No. 2022 / 109010, International Publication No. 2023 / 178451, International Publication No. 2023 / 169896, International Publication No. 2023 / 066866, or International Publication No. 2023 / 116911. In another embodiment, in the method considered above, the anti-FRα antibody Ab of formula I considered above may further include Fc silencing mutations. Such Fc silencing mutations may include, for example, L234A and L235A according to the EU numbering scheme.

[0025] In another embodiment, in any of the methods discussed above, the anti-FRα antibody Ab of formula I or formula II comprises a variable heavy (VH) domain containing the amino acid sequence of SEQ ID NO: 1 and a variable light (VL) domain containing the amino acid sequence of SEQ ID NO: 2. In another embodiment, in the method discussed above, the anti-FRα antibody Ab of formula I or formula II discussed herein may further comprise Fc silencing mutations. Such Fc silencing mutations may include, for example, L234A and L235A according to the EU numbering scheme. In a further embodiment, in the method discussed above, the anti-FRα antibody comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 3 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 4. In another embodiment, in the method described herein, the anti-FRα antibody comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 3 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 4, where in Formula II, k is 10 and p is 8.

[0026] In one embodiment, in any of the methods discussed above, D in formula I is a topoisomerase I inhibitor, and the topoisomerase I inhibitor includes, but is not limited to, a camptothesine analog, an indolocarbazole analog, a phenanthidine analog, a fluoroquinolone analog, a quinoxaline, an evodiamine, an acridine, a naphthyridine, a deoxynibomycin analog, an angustin analog, a stilbentiazole analog, a pyrroloquinazolinoquinoline alkaloid, or an indenoisoquinoline analog, and such a topoisomerase I inhibitor may be selected from the group consisting of camptothesine and its analogs, which include, but is not limited to, irinotecan, topotecan, camptothesine, SN-38, exatecan, DXd, silatecan, cocitecan, lulutotecan, gimatecan, berotecan, or rubitecan.

[0027] In another embodiment, in any of the methods discussed above, L in formula I is polysarcosine of formula (III),

[0028] [ka] In the formula, k is an integer between 2 and 50, or 4 and 30, or 2 and 20, or 2 and 10. In another embodiment, in formula III, k is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In yet another embodiment, in formula III, R6 is OH or NH2. In yet another embodiment, in the method considered above, L in formula I or II is a polyethylene glycol moiety (PEG) containing 2 to 50 ethylene glycol moieties. In yet another embodiment, L in formula I is a severable linker having an optional stretcher unit linked to Ab and a severable portion linked to D.

[0029] In one embodiment, in any of the methods considered above, p in formula I or formula II is 1-8, or 1-4, or 2-6, or 2-8, or 6-8. In another embodiment, in the method considered above, p in formula I or formula II is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0030] In one embodiment, in any of the methods considered above, FRα-positive cancer is characterized as a very low / ultra-low FRα-expressing tumor, a low FRα-expressing tumor, a medium FRα-expressing tumor, or a high FRα-expressing tumor, as measured by immunohistochemistry (IHC) as defined herein. Detection of FRα expression may be determined, for example, by immunohistochemistry or any of the FDA-approved available tests for measuring FRα expression, the tests of which may, non-limitingly, include the Ventana FOLR1 (FOLR-2.1)RxDx assay (Ventana Medical Systems, Inc.).

[0031] In one embodiment, in any of the methods considered above, FRα-positive cancer is selected from the group consisting of ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), pancreatic cancer, primary peritoneal cancer, and colorectal cancer (CRC). In a further embodiment, ovarian cancer includes epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, is platinum-resistant, and the subject has received at least one prior platinum-based treatment regimen. In an additional embodiment, epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is platinum-sensitive, and the subject has received at least one prior platinum-based treatment regimen and a PARP inhibitor.

[0032] The FRα-positive ovarian cancers discussed above may be, for example, epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. The FRα-positive ovarian cancers discussed above may also be high-grade serous ovarian cancer (HGSOC), low-grade serous ovarian cancer (LGSOC), high-grade ovarian endometrioid carcinoma, ovarian carcinosarcoma, uterine serous carcinoma, mucinous ovarian carcinoma, epithelial ovarian carcinoma, borderline epithelial ovarian tumor, or ovarian clear cell adenocarcinoma. Further embodiments of the FRα-positive ovarian cancers discussed above may also be malignant cord-stromal ovarian tumors or malignant germ cell ovarian tumors. In another embodiment, the FRα-positive ovarian cancers discussed above may be platinum-sensitive in any of the methods discussed above. In yet another embodiment, the FRα-positive ovarian cancers discussed above may be resistant to previous platinum treatments.

[0033] The FRα-positive endometrial cancers discussed above may, but are not limited to, primary advanced endometrial cancer, recurrent endometrial cancer, endometrial stromal sarcoma, endometrial leiomyosarcoma, endometrial adenocarcinoma, or endometrioid carcinoma. In one embodiment, the endometrial cancer to be treated is a TP53 variant. In another embodiment, the endometrial cancer to be treated is TP53-wildtype. In yet another embodiment, the endometrial cancer may harbor a deficient mismatch repair (dMMR) mutation, a proficient mismatch repair (pMMR) mutation, a microsatellite instability-high (MSI-H) mutation, or a p53 mutation. In yet another embodiment, the FRα-positive endometrial cancers discussed herein may be platinum-sensitive in any of the methods discussed above. In yet another embodiment, the FRα-positive endometrial cancers discussed herein may be resistant to previous platinum treatments.

[0034] In one embodiment, in any of the methods discussed above, the FRα-positive cancer is metastatic. In another embodiment, in any of the methods discussed above, the FRα-positive cancer is recurrent.

[0035] In one embodiment, in any of the methods considered above, the subject has been unable to respond to at least one other therapy prior to treatment with an anti-folate receptor alpha-antibody drug conjugate. In another embodiment, the subject has been previously treated with MIRV or its biosimilar. In another embodiment, if the subject is a platinum-resistant ovarian cancer (PROC) patient and has been previously treated with MIRV or its biosimilar, the subject may be treated with two or fewer, three or fewer, four or fewer, five or fewer, or six or fewer lines of therapy before receiving the methods of the present invention considered herein. In another embodiment, the subject has never been previously treated with MIRV or its biosimilar (MIRV naive). In another embodiment, the subject has never been previously treated with a topoisomerase I inhibitor. In another embodiment, if the subject is a platinum-resistant ovarian cancer (PROC) patient, the subject has been previously treated with three or fewer lines of therapy. In another embodiment, the subject has been previously treated with fewer than three lines of therapy in a platinum-resistant situation, or the subject has been previously treated with three or more lines of therapy in a platinum-resistant situation. In another embodiment, if the subject is a platinum-sensitive ovarian cancer (PSOC) subject in any of the methods discussed above, the subject may have been previously treated with two or more lines of therapy. In yet another embodiment, the subject has been previously treated with a PARP inhibitor. In a further embodiment, the subject has not been previously treated with a PARP inhibitor (PARPi naive).

[0036] In one embodiment, the subjects in any of the methods discussed above are 65 years of age or older.

[0037] In one embodiment, in any of the methods discussed above, the subject does not have platinum-refractory disease, or has no evidence of keratopathy confirmed in baseline ocular evaluation prior to the treatment, or has no history of corneal transplantation prior to the treatment.

[0038] In one embodiment, in any of the methods discussed above, the anti-folate receptor alpha-antibody drug conjugate is administered as monotherapy. In another embodiment, in any of the methods discussed above, the anti-folate receptor alpha-antibody drug conjugate monotherapy is administered to a subject with platinum-resistant ovarian cancer (PROC).

[0039] In one embodiment, for platinum-sensitive ovarian cancer (PSOC) patients, the treatment further includes administering an anti-VEGF antibody in any of the methods discussed above. In another embodiment, the anti-VEGF antibody is bevacizumab. In a further embodiment, the anti-VEGF antibody is a biosimilar of bevacizumab. In such cases, bevacizumab or its biosimilar is administered after administration of an anti-folate receptor alpha-antibody drug conjugate, and the dosing regimen for bevacizumab or its biosimilar is administered at a dose of approximately 15 mg / kg on day 1 (Q3W) of every 21-day cycle for up to 22 cycles. In another embodiment, the combination with bevacizumab or its biosimilar is for treating metastatic disease as first-line therapy, or for treating platinum-sensitive disease as second-line therapy, or for treating BRCAwt patients in first-line maintenance status. In another embodiment, in any of the methods discussed above, the combination with bevacizumab or its biosimilar is used as first-line or second-line maintenance therapy in patients with relapsed PSOC.

[0040] In one embodiment, in any of the methods considered above, the treatment further comprises administering an immuno-oncology (IO) therapeutic agent in combination with an anti-folate receptor alpha-antibody drug conjugate. In another embodiment, the IO therapeutic agent is an anti-PD-1 antibody. In another embodiment, the anti-PD1 antibody is pembrolizumab or its biosimilar. When the method administers pembrolizumab or its biosimilar, it is administered to the subject after administration of the anti-folate receptor alpha-antibody drug conjugate. Furthermore, when the method administers pembrolizumab or its biosimilar, the dosing regimen is administered at a dose of approximately 200 mg / kg on day 1 of every 21-day cycle (Q3W) or at a dose of approximately 400 mg / kg on day 1 of every 6 weeks (Q6W). In another embodiment, the anti-PD1 antibody is dostallimab or its biosimilar. In another embodiment, the anti-PD1 antibody is cemiprimab or its biosimilar. In yet another embodiment, the anti-PD-1 antibody is nivolumab or its biosimilar. In yet another embodiment, the IO therapeutic agent is an anti-PD-L1 antibody. In yet another embodiment, the anti-PD-L1 antibody is atezolizumab or its biosimilar. In yet another embodiment, the anti-PD-L1 antibody is durvalumab or its biosimilar. In yet another embodiment, the anti-PD-L1 antibody is avelumab or its biosimilar. In yet another embodiment, the subject being treated has folate receptor alpha-positive endometrial cancer, to the extent that the method comprises administering a combination of the anti-folate receptor alpha-antibody drug conjugate of the present invention and pembrolizumab or its biosimilar. In yet another embodiment, the subject being treated has folate receptor alpha-positive endometrial cancer that is primary, advanced or recurrent. In further embodiments, the patient being treated has folate receptor alpha-positive endometrial cancer, which is defined as primary advanced endometrial cancer, recurrent endometrial cancer, endometrial stromal sarcoma, endometrial leiomyosarcoma, endometrial adenocarcinoma, or endometrioid cancer. In one embodiment, the patient being treated has endometrial cancer with a TP53 mutation.In another embodiment, the patient to be treated has endometrial cancer with TP53 wild-type. In yet another embodiment, the patient to be treated has endometrial cancer harboring a dummy mismatch repair (dMMR) mutation, a proficient mismatch repair (pMMR) mutation, a high-frequency microsatellite instability (MSI-H) mutation, or a p53 mutation. In yet another embodiment, in any of the methods discussed above, the patient to be treated has platinum-sensitive FRα-positive endometrial cancer. In yet another embodiment, the patient to be treated has platinum-resistant FRα-positive endometrial cancer.

[0041] In one embodiment, in any of the methods considered above, the treatment further includes administering a chemotherapeutic agent. In non-limiting examples, such chemotherapeutic agents may include paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan. In another embodiment, the chemotherapeutic agent is a platinum-containing compound. In yet another embodiment, the platinum-containing compound is carboplatin or cisplatin, which is administered after the administration of an anti-folate receptor alpha-antibody drug conjugate, and the dosing regimen for carboplatin or cisplatin is administered on day 1 (Q3W) of each 21-day cycle at AUC 4. In a further embodiment, if the chemotherapeutic agent is carboplatin, the anti-folate receptor alpha-antibody drug conjugate is administered on day 1 (Q4W) of each 28-day cycle and not on Q3W. In yet another embodiment, carboplatin or cisplatin is administered for up to 6 cycles as described herein. In further embodiments, carboplatin or cisplatin is administered after administration of an anti-folate receptor alpha-antibody drug conjugate. In another embodiment, the combination with carboplatin or cisplatin is for treating metastatic diseases as first-line therapy. Alternatively, the combination with carboplatin or cisplatin is for treating platinum-sensitive diseases as second-line therapy. Other platinum-containing compounds include oxaliplatin, nedaplatin, or dicycloplatin, which may be used in the methods described herein.

[0042] In another embodiment, in any of the methods described above, the treatment further comprises administering a poly ADP-ribose polymerase (PARP) inhibitor. In a non-limiting example, such a PARP inhibitor may include, for example, olaparib, lucaparib, talazoparib, or niraparib. If the method intends to perform combination therapy with a PARP inhibitor, the PARP inhibitor is administered to the subject after administration of an anti-folate receptor alpha-antibody drug conjugate.

[0043] In one embodiment, an anti-folate receptor alpha-antibody drug conjugate as described above for use in combination with, separately from, or sequentially with, an anti-VEGF antibody in the treatment of the above-mentioned FRα-positive cancer. In another embodiment, the anti-VEGF antibody is bevacizumab or its biosimilar, and bevacizumab or its biosimilar is administered separately after the anti-folate receptor alpha-antibody drug conjugate has been administered. In another embodiment, bevacizumab or its biosimilar is administered after the anti-folate receptor alpha-antibody drug conjugate, but within day 1. In such cases, the administration regimen for bevacizumab or its biosimilar is administered at a dose of approximately 15 mg / kg on day 1 (Q3W) of every 21-day cycle for a maximum of 22 cycles. In another embodiment, a combination of bevacizumab or its biosimilar is for (a) treating metastatic disease as first-line therapy, or (b) treating platinum-sensitive disease as second-line therapy, including treating subjects with known germline or somatic BRCA mutations who have previously received PARP inhibitor therapy, or (c) treating BRCAwt patients in first-line maintenance status.

[0044] In one embodiment, an antifolate receptor alpha-antibody drug conjugate as described above for use in concurrent, separate, or sequential combination with a chemotherapeutic agent in the treatment of the above-mentioned FRα-positive cancer. In another embodiment, the chemotherapeutic agent is administered separately, after the antifolate receptor alpha-antibody drug conjugate has been administered. In a non-limiting example, such a chemotherapeutic agent may include paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan. In another embodiment, the chemotherapeutic agent is a platinum-containing compound. In yet another embodiment, the platinum-containing compound is carboplatin or cisplatin, which is administered after the administration of the antifolate receptor alpha-antibody drug conjugate, and the administration regimen for carboplatin or cisplatin is administered on day 1 (Q3W) of every 21-day cycle for up to 6 cycles. In another embodiment, the combination with carboplatin or cisplatin is for treating metastatic diseases as first-line therapy. Alternatively, the combination with carboplatin or cisplatin is for treating platinum-sensitive diseases as second-line therapy. Other platinum-containing compounds include oxaliplatin, nedaplatin, or dicycloplatin, which may be used in the methods described herein.

[0045] In one embodiment, the anti-folate receptor alpha-antibody drug conjugate described in any of the methods discussed above is administered as a second-line treatment. In another embodiment, the anti-folate receptor alpha-antibody drug conjugate described in any of the methods discussed above is administered as a third-line treatment. In another embodiment, the anti-folate receptor alpha-antibody drug conjugate described in any of the methods discussed above is administered as a fourth-line treatment. In another embodiment, the anti-folate receptor alpha-antibody drug conjugate described in any of the methods discussed above is administered as a fifth-line treatment. In another embodiment, the anti-folate receptor alpha-antibody drug conjugate described in any of the methods discussed above is administered as a sixth-line treatment.

[0046] In one embodiment, in any of the methods discussed above, pulmonary toxicity is not observed in the subject as a result of treatment, and / or ocular toxicity is not observed in the subject as a result of treatment, and / or neuropathy is not observed in the subject as a result of treatment, and / or alopecia is not observed in the subject as a result of treatment. In a further embodiment, in any of the methods discussed above, major drug-drug interactions are not observed in the subject as a result of treatment.

[0047] In one embodiment, as a result of any of the methods considered above, the ORR observed in the subject as a result of treatment is 30% or more at 2 mg / kg, 31% or more at 2 mg / kg, 32% or more at 2 mg / kg, 33% or more at 2 mg / kg, 35% or more at 2 mg / kg, 40% or more at 2 mg / kg, 45% or more at 2 mg / kg, 50% or more at 2 mg / kg, 25% or more at 3 mg / kg, 30% or more at 3 mg / kg, 35% or more at 3 mg / kg, 36% or more at 3 mg / kg, 37% or more at 3 mg / kg, and 38% or more at 3 mg / kg. The percentages are above average, with 39% or more at 3 mg / kg, 40% or more at 3 mg / kg, 45% or more at 3 mg / kg, 50% or more at 3 mg / kg, 55% or more at 3 mg / kg, 60% or more at 3 mg / kg, 30% or more at 4 mg / kg, 35% or more at 4 mg / kg, 40% or more at 4 mg / kg, 45% or more at 4 mg / kg, 50% or more at 4 mg / kg, 55% or more at 4 mg / kg, 60% or more at 4 mg / kg, 61% or more at 4 mg / kg, 50% or more at 6 mg / kg, 55% or more at 6 mg / kg, and 56% or more at 6 mg / kg.

[0048] In one embodiment, when FRα-positive cancer is characterized as a high-FRα-expressing tumor as measured by immunohistochemistry (IHC) in any of the methods discussed above, the ORR observed as a result of treatment in the subject is 50% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg. In another embodiment, when FRα-positive cancer is characterized as a moderate-FRα-expressing tumor as measured by immunohistochemistry (IHC) in any of the methods discussed above, the ORR observed as a result of treatment in the subject is 40% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg. In yet another embodiment, when FRα-positive cancer is characterized as a low-FRα-expressing tumor as measured by immunohistochemistry (IHC) in any of the methods discussed above, the ORR observed as a result of treatment in the subject is 40% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg. In another embodiment, in any of the methods discussed above, when FRα-positive cancer is characterized as a very low FRα-expressing tumor as measured by immunohistochemistry (IHC), the ORR observed as a result of treatment in the subject is 40% or greater at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg.

[0049] In one embodiment, in any of the methods considered above, the ORR observed in the subject as a result of treatment is 40% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject was previously treated with MIRV. In another embodiment, in any of the methods considered above, the ORR observed in the subject as a result of treatment is 45% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject was previously treated with MIRV. In another embodiment, in any of the methods considered above, the ORR observed in the subject as a result of treatment is 50% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject was previously treated with MIRV. In another embodiment, in any of the methods considered above, the ORR observed in the subject as a result of treatment is 55% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject was previously treated with MIRV. In further embodiments, in any of the methods discussed above, the ORR observed in the subject as a result of treatment is 60% or greater at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject was previously treated with MIRV.

[0050] In one embodiment, in any of the methods considered above, the ORR observed as a result of treatment in the subject is 20% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject has not been previously treated for MIRV (MIRV naive). In another embodiment, in any of the methods considered above, the ORR observed as a result of treatment in the subject is 30% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject has not been previously treated for MIRV (MIRV naive). In one embodiment, in any of the methods considered above, the ORR observed as a result of treatment in the subject is 35% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject has not been previously treated for MIRV (MIRV naive). In one embodiment, in any of the methods discussed above, the ORR observed as a result of treatment in the subject is 40% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject has not been previously treated for MIRV (MIRV naive). In one embodiment, in any of the methods discussed above, the ORR observed as a result of treatment in the subject is 45% or more at 2 mg / kg, 3 mg / kg, 4 mg / kg, or 6 mg / kg when the subject has not been previously treated for MIRV (MIRV naive).

[0051] In one embodiment, as a result of any of the methods discussed above, the disease control rate observed in the subject as a result of treatment is The DCR (Diagnosis Rate) is 80% or higher at 2 mg / kg, 81% or higher at 2 mg / kg, 82% or higher at 2 mg / kg, 83% or higher at 2 mg / kg, 84% or higher at 2 mg / kg, 85% or higher at 2 mg / kg, 80% or higher at 3 mg / kg, 81% or higher at 3 mg / kg, 82% or higher at 3 mg / kg, 80% or higher at 4 mg / kg, 81% or higher at 4 mg / kg, 82% or higher at 4 mg / kg, 83% or higher at 4 mg / kg, 85% or higher at 4 mg / kg, 70% or higher at 6 mg / kg, 71% or higher at 6 mg / kg, 72% or higher at 6 mg / kg, 73% or higher at 6 mg / kg, 74% or higher at 6 mg / kg, and 75% or higher at 6 mg / kg.

[0052] In one embodiment, as a result of any of the methods discussed above, the mPFS efficacy for platinum-resistant ovarian cancer is approximately 5 to 6 months at an HR of 0.75 or less, or approximately 5 to 7 months at an HR of 0.65 or less, or approximately 5 to 7 months at an HR of 0.70 or less, or approximately 5 to 6 months at an HR of 0.65 or less. In another embodiment, as a result of any of the methods discussed above, the mOS efficacy for platinum-resistant ovarian cancer is approximately 14 to 15 months at an HR of 0.80 or less, or approximately 16 to 17 months at an HR of 0.70 or less, or approximately 17 to 18 months at an HR of 0.70 or less.

[0053] In one embodiment, as a result of any of the methods considered above, the mPFS efficacy for platinum-sensitive ovarian cancer is approximately 6 to 7 months for an HR of 0.70 or less, or approximately 7 to 8 months for an HR of 0.70 or less, or approximately 8 to 9 months for an HR of 0.70 or less, or approximately 9 to 10 months for an HR of 0.70 or less, or approximately 10 to 11 months for an HR of 0.70 or less, or approximately 11 to 12 months for an HR of 0.70 or less, or approximately 11 to 12 months for an HR of 0.70 or less, or approximately 12 to 13 months for an HR of 0.75 or less, or approximately 12 to 13 months for an HR of 0.70 or less, or approximately 13 to 14 months for an HR of 0.75 or less, or approximately 13 to 14 months for an HR of 0.65 or less, or approximately 15 to 16 months for an HR of 0.65 or less. In another embodiment, as a result of any of the methods discussed above, the mOS efficacy for platinum-sensitive ovarian cancer is approximately 37 to 38 months at an HR of ≤0.80, or approximately 42 to 43 months at an HR of ≤0.70.

[0054] One embodiment is the anti-folate receptor alpha-antibody drug conjugate described above for use in the treatment of folate receptor alpha-positive cancer in the subjects described above. Another embodiment is the anti-folate receptor alpha-antibody drug conjugate described above for use in the treatment of folate receptor alpha-positive cancer in the subjects described above, wherein the anti-folate receptor alpha-antibody drug conjugate is administered in a drug regimen comprising an intravenous (IV) infusion of approximately 1.0 mg / kg to approximately 10.0 mg / kg for at least two cycles on day 1 (Q3W) of each 21-day cycle. Another embodiment is the anti-folate receptor alpha-antibody drug conjugate described above for use in the treatment of folate receptor alpha-positive cancer in the subjects described above, wherein the anti-folate receptor alpha-antibody drug conjugate is administered in a dosing regimen comprising a dose of approximately 1.0 mg / kg to approximately 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q4W) of every 28-day cycle. Another embodiment is the anti-folate receptor alpha-antibody drug conjugate described above for use in a method for treating folate receptor alpha-positive cancer in the subjects described above, wherein the method comprises administering the anti-folate receptor alpha-antibody drug conjugate in a dosing regimen comprising a dose of approximately 1.0 mg / kg to approximately 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of every 21-day cycle. Another embodiment is the above-described anti-folate receptor alpha-antibody drug conjugate for use in a method of treating folate receptor alpha-positive cancer in the above-described subjects, wherein the method comprises administering the anti-folate receptor alpha-antibody drug conjugate in a dosing regimen comprising a dose of about 1.0 mg / kg to about 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q4W) of every 28-day cycle.Another embodiment is the use of the above anti-folate receptor alpha-antibody drug conjugate in the manufacture of a pharmaceutical for treating folate receptor alpha-positive cancer in the above subjects. Another embodiment is the use of the above anti-folate receptor alpha-antibody drug conjugate in the manufacture of a pharmaceutical for treating folate receptor alpha-positive cancer in the above subjects, wherein the pharmaceutical is formulated for administration in a dosing regimen including a dose of about 1.0 mg / kg to about 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of every 21-day cycle. Another embodiment is the use of the above anti-folate receptor alpha-antibody drug conjugate in the manufacture of a pharmaceutical for treating folate receptor alpha-positive cancer in the above subjects, wherein the pharmaceutical is formulated for administration in a dosing regimen including a dose of about 1.0 mg / kg to about 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q4W) of every 28-day cycle. Another embodiment is the use of the above anti-folate receptor alpha-antibody drug conjugate for the manufacture of a pharmaceutical product for treating folate receptor alpha-positive cancer in the above subjects, wherein the anti-folate receptor alpha-antibody drug conjugate is administered in a dosing regimen comprising a dose of approximately 1.0 mg / kg to approximately 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of every 21-day cycle. Another embodiment is the use of the above anti-folate receptor alpha-antibody drug conjugate for the manufacture of a pharmaceutical product for treating folate receptor alpha-positive cancer in the above subjects, wherein the anti-folate receptor alpha-antibody drug conjugate is administered in a dosing regimen comprising a dose of approximately 1.0 mg / kg to approximately 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q4W) of every 28-day cycle.

[0055] Additional embodiments of the present invention also include the following:

[0056] Embodiment 1: A method for treating a subject having folate receptor alpha-positive cancer, the method comprising administering an anti-folate receptor alpha-antibody drug conjugate in a drug regimen comprising a dose of approximately 1.0 mg / kg to approximately 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of each 21-day cycle, wherein the anti-folate receptor alpha-antibody drug conjugate has the chemical structure of formula II.

[0057] [ka] A method comprising the formula, wherein Ab is an anti-FRα antibody, k is 2 to 20, and p is 1 to 8.

[0058] Embodiment 2: The method according to Embodiment 1, wherein the anti-FRα antibody comprises a variable heavy chain (VH) domain containing the amino acid sequence of SEQ ID NO: 1 and a variable light chain (VL) domain containing the amino acid sequence of SEQ ID NO: 2.

[0059] Embodiment 3: The method according to Embodiment 1, wherein the anti-FRα antibody further comprises an Fc silencing mutation.

[0060] Embodiment 4: The method according to Embodiment 3, wherein the Fc silencing mutations are L234A and L235A.

[0061] Embodiment 5: The method according to Embodiment 1 or 2, wherein the anti-FRα antibody comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 3 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 4.

[0062] Embodiment 6: The method according to any one of Embodiments 2 to 5, wherein k is 10 and p is 8.

[0063] Embodiment 7: The method according to any one of Embodiments 1 to 6, wherein the dose is approximately 3.0 mg / kg to approximately 4.0 mg / kg.

[0064] Embodiment 8: The method according to Embodiment 7, wherein the dose is approximately 3.0 mg / kg.

[0065] Embodiment 9: The method according to any one of Embodiments 1 to 8, wherein the FRα-positive cancer is characterized as a low-FRα-expressing tumor as measured by immunohistochemistry (IHC).

[0066] Embodiment 10: The method according to any one of Embodiments 1 to 8, wherein FRα-positive cancer is characterized as a medium-FRα-expressing tumor as measured by immunohistochemistry (IHC).

[0067] Embodiment 11: The method according to any one of Embodiments 1 to 8, wherein FRα-positive cancer is characterized as a high-FRα-expressing tumor as measured by immunohistochemistry (IHC).

[0068] Embodiment 12: The method according to any one of Embodiments 1 to 11, wherein the FRα-positive cancer is selected from the group consisting of ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), pancreatic cancer, and colorectal cancer (CRC).

[0069] Embodiment 13: The method according to Embodiment 12, wherein the ovarian cancer is epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, and high-grade endomethriod ovarian cancer, low-grade serous ovarian cancer (LGSOC), and high-grade serous ovarian cancer (HGSOC).

[0070] Embodiment 14: The method according to Embodiment 12 or 13, wherein the ovarian cancer is resistant to previous platinum therapy (PROC).

[0071] Embodiment 15: The method according to Embodiment 12 or 13, wherein the ovarian cancer is platinum-sensitive (PSOC).

[0072] Embodiment 16: The method according to any one of Embodiments 1 to 15, wherein the subject has been previously treated with milbetuximab sorabtansine-gynx or its biosimilar.

[0073] Embodiment 17: The method according to any one of Embodiments 1 to 14 or 16, wherein the subject has been previously treated with three or fewer lines of therapy.

[0074] Embodiment 18: The method according to Embodiment 16, wherein the subject has been previously treated with four or fewer lines of therapy.

[0075] Embodiment 19: The method according to any one of Embodiments 1-13 and 15-16, wherein the subject has been previously treated with two or more lines of therapy.

[0076] Embodiment 20: The method according to Embodiment 19, wherein the subject has not been previously treated with a poly-ADP-ribose polymerase (PARP) inhibitor.

[0077] Embodiment 21: The method according to any one of Embodiments 1 to 20, wherein the subject had previously failed to respond to at least one other therapy prior to treatment with an anti-folate receptor alpha-antibody drug conjugate.

[0078] Embodiment 22: The method according to any one of Embodiments 1 to 21, wherein the subject is 65 years of age or older.

[0079] Embodiment 23: The method according to any one of Embodiments 1 to 22, wherein the FRα-positive cancer is metastatic.

[0080] Embodiment 24: The method according to any one of Embodiments 1 to 12 or 14 to 19, wherein the subject does not have a platinum-intractable disease.

[0081] Embodiment 25: The method according to any one of Embodiments 1 to 24, wherein the subject does not have evidence of corneal disease confirmed by baseline ocular evaluation.

[0082] Embodiment 26: The method according to any one of Embodiments 1 to 25, wherein the subject does not have a history of corneal transplantation.

[0083] Embodiment 27: The method according to any one of Embodiments 1-14, 16-18, and 22-26, wherein an anti-folate receptor alpha-antibody drug conjugate is administered as monotherapy.

[0084] Embodiment 28: The method according to any one of Embodiments 1-14, 16-18, and 22-26, wherein the treatment further comprises administering an anti-VEGF antibody.

[0085] Embodiment 29: The method according to Embodiment 28, wherein the anti-VEGF antibody is bevacizumab or a biosimilar thereof.

[0086] Embodiment 30: The method according to Embodiment 29, wherein bevacizumab or its biosimilar is administered after administration of an anti-folate receptor alpha-antibody drug conjugate.

[0087] Embodiment 31: The method according to Embodiment 29 or 30, wherein the dosing regimen for bevacizumab or its biosimilar is administered at a dose of approximately 15 mg / kg on day 1 (Q3W) of every 21-day cycle for a maximum of 22 cycles.

[0088] Embodiment 32: The method according to any one of Embodiments 29 to 31, wherein bevacizumab or a combination thereof is used to treat metastatic disease as a first-line therapy.

[0089] Embodiment 33: The method according to any one of Embodiments 29 to 31, wherein bevacizumab or a combination thereof is used to treat platinum-sensitive diseases as a second-line therapy.

[0090] Embodiment 34: The method according to any one of Embodiments 29 to 32, wherein bevacizumab or a combination thereof is used to treat BRCAwt patients in a first-line maintenance condition.

[0091] Embodiment 35: The method according to any one of Embodiments 1-14, 16-18, and 22-26, further comprising administering an anti-PD-1 antibody or an anti-PD-L1 antibody as treatment.

[0092] Embodiment 36: The method according to Embodiment 35, wherein the anti-PD-1 antibody is pembrolizumab or a biosimilar thereof.

[0093] Embodiment 37: The method according to Embodiment 36, wherein pembrolizumab or its biosimilar is administered after administration of an anti-folate receptor alpha-antibody drug conjugate.

[0094] Embodiment 38: The method according to Embodiment 36 or 37, wherein the dosing regimen for pembrolizumab or its biosimilar is administered at a dose of approximately 200 mg on day 1 of every 21-day cycle (Q3W) or at a dose of approximately 400 mg on day 1 of every 6 weeks (Q6W).

[0095] Embodiment 39: The method according to any one of Embodiments 35 to 38, wherein the FRα-positive cancer is endometrial cancer.

[0096] Embodiment 40: The method according to Embodiment 39, wherein the endometrial cancer is primary, advanced, or recurrent.

[0097] Embodiment 41: The method according to any one of Embodiments 1-14, 16-18, and 22-26, wherein the treatment further comprises administering carboplatin, and an anti-folate receptor alpha-antibody drug conjugate is administered on day 1 (Q4W) of each 28-day cycle.

[0098] Embodiment 42: The method according to Embodiment 41, wherein carboplatin is administered on day 1 (Q3W) of each 21-day cycle at an AUC of 4.

[0099] Embodiment 43: The method according to Embodiment 42, wherein carboplatin is administered after administration of an anti-folate receptor alpha-antibody drug conjugate.

[0100] Embodiment 44: The method according to Embodiment 43, wherein the target is ovarian cancer and is platinum-sensitive.

[0101] Embodiment 45: The method according to any one of Embodiments 1 to 44, wherein pulmonary toxicity is not observed in the subject as a result of treatment.

[0102] Embodiment 46: The method according to any one of Embodiments 1 to 45, wherein neuropathy is not observed in the subject as a result of treatment.

[0103] Embodiment 47: The method according to any one of Embodiments 1 to 46, wherein ocular toxicity is not observed in the subject as a result of treatment.

[0104] Embodiment 48: The method according to any one of Embodiments 1 to 47, wherein no major drug-drug interactions are observed as a result of treatment in the subject.

[0105] Embodiment 49: A method for treating a subject having folate receptor alpha-positive cancer, the method comprising administering an anti-folate receptor alpha-antibody drug conjugate in a drug regimen comprising a dose of 3.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of each 21-day cycle, wherein the anti-folate receptor alpha-antibody drug conjugate has the chemical structure of formula II.

[0106] [ka] It has, In the formula, Ab is an anti-FRα antibody comprising a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 3 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 4, k is 10, p is 8, the FRα-positive cancer is platinum-resistant ovarian cancer (PROC), and the subject has received three or fewer prior elective systemic cytotoxic therapies, or four or fewer if MIRV was one of the previous line therapies.

[0107] Embodiment 50: A method for treating a subject having folate receptor alpha-positive cancer, comprising a drug regimen comprising administering an anti-folate receptor alpha-antibody drug conjugate in combination with bevacizumab or a biosimilar thereof as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of every 21-day cycle, wherein the bevacizumab or biosimilar is administered in a drug regimen that is administered after the administration of the anti-folate receptor alpha-antibody drug conjugate, wherein the anti-folate receptor alpha-antibody drug conjugate has the chemical structure of formula II.

[0108] [ka] It has, The method wherein Ab is an anti-FRα antibody comprising a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 3 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 4, k is 10, p is 8, the FRα-positive cancer is platinum-sensitive ovarian cancer (PSOC), the subject has received two or fewer prior elective systemic cytotoxic therapies, and has experienced disease progression either during or within six months of completion of treatment with a poly(ADP-ribose) polymerase inhibitor (PARPi).

[0109] array In one embodiment, the amino acid sequence of the anti-FRα antibody containing the FRα ADC of the present invention is as follows.

[0110] [Table 1]

[0111] definition As used herein, the term “adverse event” or “AE” means any undesirable medical event in a participant administered the investigational product that is not necessarily causally related to the treatment. Therefore, an AE may be any undesirable, unintended sign, symptom, or disease that is temporarily related to the use of the investigational product, whether or not it is considered to be related to the investigational product. The severity of each AE may be graded using NCI CTCAE v5.0. For AE events for which a grading scale does not exist, the AE may be classified as mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening / debilitating (grade 4), or fatal (grade 5).

[0112] As used herein, the term “antibody” refers to an isolated immunoglobulin molecule that specifically binds to an antigen, such as a tumor antigen. Embodiments of an antibody include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, bispecific or multispecific antibodies, or conjugate antibodies. Unless otherwise specified, an antibody may be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0113] The VH and VL regions can be further subdivided into hypervariable regions called Complementarity Determining Regions (CDRs), which contain scattered, more conserved regions called Framework Regions (FRs). CDRs are exposed on the protein surface and are crucial regions of the antibody for antigen-binding specificity. Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this specification, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." CDRs contain the majority of the residues that form specific interactions with the antigen.The assignment of amino acid residues to CDRs may be carried out according to schemes well known to those skilled in the art, such as Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987), Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international This includes those listed in the ImMunoGeneTics database (available at www.imgt.org, see Lefranc et al., Nucleic Acids Res. 1999;27:209-212).

[0114] As used herein, the term “antibody drug conjugate” (ADC) refers to a class of compounds comprising (a) an antibody or antibody fragment, (2) a payload, such as a cytotoxic agent, an immunomodulator, or a therapeutic peptide, and (3) a linker that conjugates the antibody to the payload.

[0115] As used herein, the term “ASCO / CAP HER2 trial guidelines” refers to the HER2 trial guidelines in breast cancer designed to ensure that patients receive appropriate HER2-targeted therapy. See Wolff AC, Somerfield MR, Dowsett M, et al. Human epidermal growth factor receptor 2 testing in breast cancer: ASCO-CAP guideline update [published online June 7, 2023]. Arch Pathol Lab Med. 2023.

[0116] As used herein, the term "BRCAwt" means FRα-positive cancer identified by a null mutation signature for germline BRCA mutation (gBRCAm), mutation in BRCA1-Interacting Protein 1 (mBRIP1), or mutation in the DNA repair protein Radiation Sensitive Protein 51 (mRAD51).

[0117] As used herein, the term “disease control rate (DCR)” refers to the proportion of patients who achieve and maintain tumor palliative care (PR + CR) and disease stabilization after treatment, for the minimum duration requirement. Specifically, DCR includes patients with tumors maintained in disease stabilization, and DCR = CR + PR + disease stabilization. The ability of tumors to be controlled for an extended period in disease stabilization is also one of the effective performance characteristics of drug therapy.

[0118] As used herein, the term “Fc silencing mutation” includes mutations in the amino acid sequence of the Fc region of an antibody that cause the human Fc gamma receptor on effector cells to bind to the antibody. These mutations reduce or eliminate effector function while maintaining binding to the neonatal Fc receptor, which is important for normal antibody pharmacokinetics. See Strohl, WR, Curr Opin Biotech 2009, 20:685-91 and Saunders, KO, Frontiers Immunol., June 2019, vol.10:1296.

[0119] As used herein, the terms “folate receptor alpha” or “FRα” refer to human folate receptor alpha encoded by the human FOLR1 gene, which is represented as P15328 in UniprotKB.

[0120] As used herein, the terms “anti-folate receptor alpha antibody,” “anti-FRα antibody,” or “FRα antibody” all mean an antibody that specifically binds to the human folate receptor alpha. Non-limiting examples of such FRα antibodies include, for example, International Publication Nos. 2005 / 080431, 2008 / 031577, 2009 / 132081, 2011 / 106528, 2012 / 033987, 2014 / 087863, 2018 / 071597, and 2019 / 177854. It is disclosed in International Publication Nos. 2019 / 177372, 2020 / 016661, 2020 / 127224, 2022 / 223784, 2022 / 109010, 2023 / 178451, 2023 / 169896, 2023 / 066866, and 2023 / 116911.

[0121] As used herein, the term "FRα ADC" refers to the chemical structure of formula I, Ab-(LD) pA specific anti-folate receptor alpha-antibody drug conjugate having (I), wherein Ab is an anti-FRα antibody comprising a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 3 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 4, and (LD) p However, we describe an anti-folate receptor alpha-antibody drug conjugate having the chemical structure of formula (II).

[0122] [ka] FRα ADC is also known by its generic name, sofeta bartimipitecan. FRα ADC may also be found, non-exclusively, disclosed in International Publication No. 2023 / 170247.

[0123] As used herein, the terms “folate receptor alpha-positive cancer,” “FRα-positive cancer,” or “FRα+ cancer” mean any human cancer having detectable overexpression of folate receptor alpha protein compared to normal tissue. Detection of FRα expression may be determined, for example, by immunohistochemistry or any of the FDA-approved available tests for measuring FRα expression, which may, non-limitingly, include the Ventana FOLR1(FOLR-2.1)RxDx assay (Ventana Medical Systems, Inc.). Non-limiting examples of FRα-positive cancers include, for example, ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung cancer (NSCLC), breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, gastrointestinal cancer, kidney cancer, melanoma, adenocarcinoma, brain cancer, e.g., glioma or glioblastoma, mesothelioma, head and neck cancer, oral squamous cell carcinoma, and colorectal cancer (CRC). FRα+ ovarian cancer may include, for example, epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, high-grade serous ovarian cancer (HGSOC), high-grade endomethriod ovarian cancer, platinum-sensitive ovarian cancer (PSOC), platinum-resistant ovarian cancer (PROC), ovarian carcinosarcoma, uterine serous cancer, or ovarian clear cell adenocarcinoma.

[0124] As used herein, the terms “high FRα expression” or “high FRα expression” mean that, in subjects with FRα-positive cancer, the level of FRα expression in the cancer is such that, when assessed by immunohistochemistry and scored using the PS2+ scoring method, 75% or more of the surviving tumor cells have moderate [2+] or strong [3+] staining intensity (intensity 2+ or greater). Detection of FRα expression may be determined, for example, by immunohistochemistry or any of the FDA-approved tests for measuring FRα expression, the tests may, but are not limited to, the Ventana FOLR1 (FOLR-2.1)RxDx assay (Ventana Medical Systems, Inc.).

[0125] As used herein, the terms “medium FRα expression” or “medium FRα expression” mean that, in subjects with FRα-positive cancer, the level of FRα expression in the cancer is such that, when assessed by immunohistochemistry and scored using the PS2+ scoring method, it is found in 50% to over 74% of surviving tumor cells with moderate [2+] or strong [3+] staining intensity (intensity 2+ or greater). Detection of FRα expression may be determined, for example, by immunohistochemistry or any of the FDA-approved tests for measuring FRα expression, the tests may, but are not limited to, the Ventana FOLR1 (FOLR-2.1)RxDx assay (Ventana Medical Systems, Inc.).

[0126] As used herein, the terms “low FRα expression” or “low FRα expression” mean that, in subjects with FRα-positive cancer, the level of FRα expression in the cancer is such that, when assessed by immunohistochemistry and scored using the PS2+ scoring method, 25% to 49% of surviving tumor cells have moderate [2+] or strong [3+] staining intensity (intensity 2+ or higher). Detection of FRα expression may be determined, for example, by immunohistochemistry or any of the FDA-approved tests for measuring FRα expression, the tests may, but are not limited to, the Ventana FOLR1 (FOLR-2.1)RxDx assay (Ventana Medical Systems, Inc.).

[0127] As used herein, the terms “very low or extremely low FRα expression” or “very low or extremely low FRα expression” mean that, in subjects with FRα-positive cancer, the level of FRα expression in the cancer is less than 25% of surviving tumor cells with moderate [2+] or strong [3+] staining intensity (intensity 2+ or higher), as assessed by immunohistochemistry and scored using the PS2+ scoring method. Detection of FRα expression may be determined, for example, by immunohistochemistry or any of the FDA-approved tests for measuring FRα expression, which may include, but are not limited to, the Ventana FOLR1 (FOLR-2.1)RxDx assay (Ventana Medical Systems, Inc.).

[0128] As used herein, the term “major drug-drug interaction” means an interaction between two or more drugs that results in an unexpected side effect, such as an adverse event or reduced efficacy.

[0129] As used herein, the terms “metastatic” or “metastatic” mean that a human cancer, including FRα-positive cancer as defined herein, spreads from its site of origin to another part of the human body.

[0130] As used herein, the term “NCI-ODWG criteria” is an abbreviation for the National Cancer Institute Organ Dysfunction Working Group, and refers to criteria used to classify the severity of hepatic dysfunction based on serum biomarkers, such as aspartate aminotransferase (AST) and total bilirubin levels. For example, (a) mild hepatic dysfunction means total bilirubin less than ULN and AST greater than ULN, or total bilirubin greater than 1 to 1.5 × ULN and either AST; (b) moderate hepatic dysfunction means total bilirubin greater than 1.5 to 3 × ULN and either AST; and (c) severe hepatic dysfunction means total bilirubin greater than 3 × ULN and either AST.

[0131] As used herein, the term “ocular toxicity” means adverse events in the eye of a subject after treatment by the method of the present invention. For example, ocular toxicity may include adverse events found in the cornea and / or retina. In non-limiting examples, ocular toxicity may include visual impairment, keratopathy, dry eyes, photophobia, eye pain, and / or uveitis.

[0132] As used herein, the term "pulmonary toxicity" means adverse effects on the lungs of a subject after treatment by the method of the present invention. In non-limiting examples, pulmonary toxicity may include cytokine-driven interstitial lung disease (ILD).

[0133] The term ORR is defined as the proportion of efficacy-evaluable participants who achieved a confirmed BOR (Best Bystander) according to RECIST v1.1, specifically a complete response (CR) or partial response (PR). BOR is defined as the best response recorded from the start of the investigational treatment to the earliest objective disease progression or the initiation of a new anticancer therapy. It provides a corresponding 95% accurate CI. DOR is defined as the time from the date of the first described response (CR or PR) to the date of the first occurrence of either the first disease progression or death at either cause, as assessed by the investigator according to RECIST v1.1. The DOR curve is estimated using the Kaplan-Meier method. Kaplan-Meier estimates with 95% CIs calculated using the Brookmeyer-Crowley method are provided for the DOR time quartiles. ORR is an index that directly measures the antitumor activity of a drug and is the most common endpoint based on tumor measurements.

[0134] As used herein, the terms "Overall Survival" (OS) and "median Overall Survival" (mOS) refer to measures of time from randomization to death as endpoints used in clinical trials.

[0135] As used herein, the term “prior PD-1 / PD-L1 blockade” means any approved therapeutic agent that inhibits the PD-1 and / or PD-L1 pathway. Examples include, but are not limited to, pembrolizumab, dostallimab, semiprimab, nivolumab, atezolizumab, durvalumab, or avelumab. Biosimilars of the aforementioned are also intended.

[0136] As used herein, the term “platinum-sensitive ovarian cancer (PSOC)” means ovarian cancer that has responded to previous first-line platinum-based treatment and subsequently recurs at least six months after the last platinum-based treatment, but responds to subsequent platinum-based treatment in the event of such recurrence.

[0137] As used herein, the term “platinum-resistant ovarian cancer (PROC)” means ovarian cancer that has responded to previous first-line platinum-based treatment and subsequently recurs at least six months after the last platinum-based treatment and / or other chemotherapy treatment, but becomes resistant to such subsequent treatment.

[0138] As used herein, the term “platinum-containing compound” refers to a platinum-based anti-cancer drug or chemotherapeutic agent that contains a platinum compound that damages DNA and is used to treat cancer. Non-limiting examples include cisplatin, carboplatin, and oxaliplatin.

[0139] As used herein, the terms “Progression-Free Survival” (PFS) and “median Progression-Free Survival” (mPFS) are defined as the time from the initial dose date (or randomization date for dose-optimized cohorts) to the date of the first occurrence of either the first described disease progression or death due to either cause, as assessed according to RECIST v1.1. PFS curves are estimated using the Kaplan-Meier method; Kaplan-Meier estimates with 95% CI calculated using the Brookmeyer-Crowley method.

[0140] As used herein, the terms “relapse” or “recurrent” refer to the resumption of a disease, such as a human cancer including folate receptor alpha-positive cancer as defined herein, after successful treatment. The term “recurrence” is synonymous with “relapse.”

[0141] As used herein, the term “refractory” means that a disease, such as FRα-positive cancer as defined herein, is unable to respond to medical treatment from the initiation of treatment. A synonym for refractory is “resistant.” A refractory disease, such as refractory cancer, is different from a recurrent disease, such as recurrent cancer, as defined above.

[0142] The term "Serious Adverse Event" or "SAE" refers to any adverse medical event that, at any dose, (a) results in death, (b) is life-threatening, (c) requires hospitalization or extension of existing hospitalization, (d) results in disability / incapacity, (e) results in a birth defect / birth defect, or (f) is a significant medical event.

[0143] As used herein, the term "TP53" refers to a gene whose mutation status in human cancers, such as endometrial cancer, can be associated with invasive histological subtypes and poor prognosis compared to the wild type (see The Cancer Genome Atlas Research Network, Nature 497, 67-73; 2013).

[0144] As used herein, the terms “to treat” or “to cure” in the context of a disease mean reducing the severity and / or frequency of one or more symptoms, eliminating one or more symptoms and / or their underlying causes, reducing the frequency or likelihood of one or more symptoms and / or their underlying causes, slowing, preventing and / or slowing the progression of a disease and / or disorder, and improving or curing damage directly or indirectly caused by a disease and / or disorder. For clarity, treating a disease is separate from preventing a disease.

[0145] The term "Treatment-Emergent Adverse Event" (TEAE) is defined as an AE with an onset date or a pre-existing AE that worsens over a period from after the first dose of the investigational drug to 30 days after the last dose of the investigational drug.

[0146] As used herein, the term “Time to Response (TTR)” is defined as the time from the first dose date (or randomization date for dose-optimized cohorts) to the date of the first described response, e.g., complete response (CR) or partial response (PR). TTR is measured only in participants who have a confirmed CR or PR. [Examples]

[0147] Example 1: In vivo efficacy in a cancer xenograft model Four-to-five-week-old female CB-17 severe combined immunodeficiency (SCID) mice were obtained and isolated for seven days before the start of the study. The mice were then resuspended in PBS with 5-10 × 10¹⁶ cells of the following cancer cells: KB (human cervical cancer cell line, ATCC CCL-17), IGROV1 (drug-resistant human ovarian cancer cell line, MilliporeSigma number SCC203), OV-90 (oncogenic epithelial ovarian cancer cell line, ATCC CRL-3585), and SW-620 (adherent colorectal cancer cell line, ATCC CRL-227). 6 Individual cells, or 50% BD Matrigel (Corning®) in PBS, were subcutaneously seeded. The average tumor volume was approximately 120-150 mm². 3When reached, mice were randomized (about 7 mice per group) and treated with a single intravenous injection of PBS (negative control), 3 mg / kg FRα ADC, or 3 mg / kg mirvetuximab soravtansine (Mirvetuximab soravtansine, Mirve sorav) as a comparator. Tumor volume was measured every 3 to 5 days using a caliper device (length × width) for at least 30 days, and calculated using the following formula: V=4 / 3×π×R3, where R represents the radius. Tumor volume of 1500 mm 3 When exceeded, or in case of tumor ulceration, the mice were sacrificed.

[0148] Antitumor activity was confirmed across a large collection of cell lines with low, medium, and high FRα expression and patient-derived tumor xenografts (Figures 1A to 1D). FRα ADC showed improved in vivo activity over MIRV, especially in medium (Figures 1B and 1C) and low (Figure 1D) FRα-expressing tumor models.

[0149] Example 2: Combination with cisplatin and / or bevacizumab in ovarian xenografts The objective was to demonstrate the potential that the activity of FRα ADC in combination with the standard therapeutic agents cisplatin, bevacizumab, or the combination of cisplatin plus bevacizumab in the ovarian cancer model OV-90 xenograft is enhanced compared to FRα ADC alone. Mirvetuximab soravtansine (MIRV), a folate receptor-targeted ADC with a maytansine payload, was used as a comparator.

[0150] OV-90 (CRL-3585 ATCC), a human ovarian cancer cell line, was unilaterally implanted on the right flank of female immunocompromised mice (Envigo RMS, Hsd:Athymic Nude-Foxn1 nu ) at a concentration of 5.0×10 6 OV-90 cells). When the tumor volume reached approximately 200 to 300 mm 3When the tumor volume reached a certain point, animals were randomized to either the control or treatment group as described in Tables 2 and 3, based on tumor volume and body weight, and medication was initiated. Medication was discontinued after 4 weeks in Study A and after 6 weeks in Study B, and tumor regrowth measurements were continued until the completion of the study. Abbreviations in Tables 2 and 3: N / A = Not applicable, IV = Intravenous, IP = Intraperitoneal, Q7D × 4 = 7 times a day for 4 days.

[0151] [Table 2]

[0152] [Table 3]

[0153] The tumor volume is calculated using the formula v = l × w 2 Estimates were made using ×0.536, where l = the larger of the measured diameters and w = the smaller of the vertical diameters. The following termination criteria were applied to individual animals regardless of experimental status: (a) 2000 mm 3 (b) an excessive tumor volume (unilateral), (c) an animal having an ulcerated cutaneous penetrating tumor, (d) a weight loss of 20% or more or 15% or more in three consecutive measurements, and (e) severe functional impairment of the general condition (apathy, pain, significant reduction in feed and water intake, respiratory distress, abnormal constitution, or behavior).

[0154] Tumor volume was converted to a log10 scale to equalize variance over time and treatment. Log10 volume and body weight were analyzed separately using a two-way repeated measures analysis of variance (RM ANOVA) model consisting of time, treatment, and the interaction between time and treatment, using the MIXED procedure in the SAS software package (version 9.4). Spatial power covariance structures were used to model the correlation of observations over time for the same subjects. Kenward-Roger (1997) denominator degrees of freedom (DDFM) calculations were used for fixed-effects testing. Post-hoc pairwise t-tests were used to compare tumor volume and body weight in the treatment group with the control group and on the summary day, with a p-value ≤ 0.05 considered statistically significant.

[0155] In Study A, tumor growth inhibition and combination effect analyses were calculated on day 46. In this study, FRα ADC as a monotherapy demonstrated dose-dependent tumor growth inhibition activity at dose levels of 1, 3, and 5 mg / kg. See Figure 2A. The combination of FRα ADC at each of these dose levels with a single 5 mg / kg dose of bevacizumab resulted in a greater antitumor effect than FRα ADC or bevacizumab alone, with more pronounced effects observed at 1 and 3 mg / kg and at later time points (Figure 2A). Additionally, FRα ADC plus bevacizumab showed superior activity compared to the standard treatment of cisplatin plus bevacizumab (Figure 2A). Administration of FRα ADC at dose levels of 3 and 5 mg / kg resulted in a greater antitumor effect than milbetuximab sorabtansine, the approved comparator ADC at 5 mg / kg, either as monotherapy or in combination with bevacizumab (Figure 2A).

[0156] In Study B, FRα ADC was further evaluated in combination with cisplatin or cisplatin plus bevacizumab. Tumor growth inhibition and combination therapy effects were determined on days 69 and 89. The combination of FRα ADC at a single dose of 1 or 5 mg / kg every 7 days with 4 mg / kg cisplatin showed increased activity compared to either FRα ADC or cisplatin alone (Figure 3A). The triple combination of FRα ADC, 4 mg / kg Q7D cisplatin plus a single dose of 5 mg / kg bevacizumab also resulted in a significant increase in antitumor activity compared to monotherapy or the cisplatin and bevacizumab dual combination therapy (Figure 3A). These increases were determined to be additive or greater than additive compared to monotherapy or the standard combination of cisplatin and bevacizumab. Furthermore, the 5 mg / kg FRα ADC triple combination therapy achieved a more sustained antitumor effect than either the FRα ADC plus cisplatin or the cisplatin and bevacizumab combination with the approved ADC comparator, milbetuximab sorabtansine (Figure 3A). The triple combination regimen also demonstrated good tolerability based on the absence of observed significant animal weight loss in any of the treatment groups (Figure 3B).

[0157] In summary, FRα ADCs demonstrate promising antitumor efficacy in ovarian cancer, both as monotherapy and in combination with standard therapeutic agents such as cisplatin, bevacizumab, or cisplatin plus bevacizumab.

[0158] Example 3: Phase 1a / 1b Clinical Trial This was a Phase 1a / 1b multicenter, open-label, first-in-human clinical trial to evaluate the safety, efficacy, and pharmacokinetics of FRα ADCs in participants with ovarian cancer, endometrial cancer, cervical cancer, NSCLC, TNBC, pancreatic cancer, and colorectal cancer. The trial consisted of two phases (see Figures 4 and 5). Phase 1a included a monotherapy dose-escalation cohort (Cohort A1), a dose-optimization cohort (Cohort A2), a monotherapy cohort (Cohort A3) in participants with high FRα expression (≥75% of surviving tumor cells with staining intensity ≥2+) who were mirbetuximab sorabtansine-gynx (Elahere®; MIRV), a combination therapy cohort with bevacizumab (Cohort A4), and a combination therapy dose-escalation cohort with carboplatin (Cohort A5). Dose escalation evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of FRα ADC in participants with advanced ovarian cancer, endometrial cancer, cervical cancer, NSCLC, TNBC, pancreatic cancer, and CRC to determine the Recommended Phase 2 Dose (RP2D) for Phase 1b.

[0159] To support the decision for RP2D for Phase 1b, dose optimization (Cohort A2) further evaluated the safety, tolerability, PK, preliminary efficacy, and patient-reported outcomes of FRα ADCs at two or more dose levels (DL) in participants with platinum-resistant ovarian cancer (progression / recurrence within 6 months of the last platinum dose). Participants in Cohort A2 were randomized across at least two DLs, stratified by prior MIRV treatment (with vs. without) and the number of previous lines of therapy in the platinum-resistant situation (<3 vs. ≥3).

[0160] In the enrichment cohort A3, participants with platinum-resistant ovarian cancer and high FRα expression (≥75% with a strength of ≥2+) who had not been previously treated with MIRV were enrolled at doses deemed safe in cohort A1. The combination dose cohort A4 evaluated the safety, tolerability, PK, and preliminary efficacy of FRα ADCs in combination with bevacizumab. The dose escalation cohort A5 evaluated the safety, tolerability, PK, and preliminary efficacy of FRα ADCs in combination with carboplatin in participants with platinum-sensitive ovarian cancer. Approximately 160 participants were recruited for monotherapy and combination dose escalation, approximately 20 participants were recruited for (a) the monotherapy enrichment cohort and (b) the combination cohort, and approximately 60 participants were recruited for the dose optimization cohort. See Figure 4.

[0161] Phase 1b dose expansion was initiated after near completion of Phase 1a dose randomization (Cohort A2), which established the optimal dose of FRα ADC RP2D as monotherapy. Phase 1b dose expansion included four dose expansion cohorts to evaluate FRα ADC at the RP2D dose as monotherapy (see Figure x). These were participants with platinum-resistant ovarian cancer with high and moderate / low FRα expression (Cohorts B1 and B2, respectively), and basket cohorts for all other solid tumors with high and moderate / low FRα expression (endometrial cancer, cervical cancer, NSCLC, TNBC, pancreatic cancer, and CRC) (Cohorts C1 and C2, respectively). FRα expression levels were determined in tumor tissue by immunohistochemistry using central studies. For Cohorts B1 and B2, available local FRα results were used and confirmed for cohort assignment. For cohorts C1 and C2, a central trial of FRα expression levels guided enrollment due to lower FRα expression levels in assessed histological examinations and the lack of conventional FRα testing compared to ovarian cancer. For cohorts C1 and C2, each histological examination was limited to 5 patients. For the dose expansion cohort, approximately 20-30 participants were recruited, bringing the total to a maximum of 100 participants.

[0162] Inclusion Criteria: Participants must be 18 years of age or older, or higher according to local regulations, at the time of registration, and must have a history of diagnosis of locally advanced or metastatic solid tumors / malignancies as defined below for each specific cohort.

[0163] Cohort A1 (dose escalation): Histological diagnosis of ovarian cancer (epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer), endometrial cancer, cervical cancer, NSCLC, TNBC, pancreatic cancer, or CRC.

[0164] Cohort A2 (Dose Optimization): Histological diagnosis of ovarian cancer (epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer) that is resistant to previous platinum therapy (recurrence or progression within 6 months of the last platinum dose). Individuals with platinum-refractory disease (i.e., progression in first-line platinum-based chemotherapy, or progression within 3 months of completion of first-line treatment) are ineligible.

[0165] Cohort A3 (Enrichment Cohort): Histological diagnosis of ovarian cancer (epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer) with high FRα expression (75% or more with a strength of 2+ or higher), no prior treatment for MIRV, and resistance to prior platinum therapy (recurrence or progression within 6 months of the last platinum dose).

[0166] Cohort A4 (bevacizumab combination cohort): Histological diagnosis of ovarian cancer (epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer) that is responsive to prior platinum therapy (CR / PR or recurrence / progression-free survival more than 6 months after the last platinum dose).

[0167] Cohort A5 (dose-escalation combination with carboplatin): Histological diagnosis of ovarian cancer (epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer) that is responsive to previous platinum therapy (CR / PR or recurrence / progression-free interval of more than 6 months from the last platinum dose). Participants enrolled in this Cohort A5 must receive prophylactic granulocyte-colony-stimulating factor (GCSF) support at the start of treatment.

[0168] Cohorts B1 and B2 (dose escalation): Histological diagnosis of ovarian cancer (epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer) that is resistant to previous platinum therapy (recurrence or progression within 6 months of the last platinum dose). Individuals with platinum-refractory disease (i.e., progression in first-line platinum-based chemotherapy, or progression within 3 months of completion of first-line treatment) are ineligible. Measurable disease must be present according to RECIST v1.1.

[0169] Cohorts C1 and C2 (dose expansion): Histological or cytological diagnosis of endometrial cancer, cervical cancer, NSCLC, TNBC, CRC, or pancreatic cancer. Must have a measurable disease according to RECIST v1.1.

[0170] Phase 1b Dose Expansion: Individuals with FRα expression levels determined by immunohistochemistry using the anti-FOLR1 antibody clone FOLR1-2.1, performed in accordance with local guidelines including but not limited to compliance with the In Vitro Diagnostic Regulation (IVDR), may be enrolled in Clinical Laboratory Improvement Amendments (CLIA), the International Organization for Standardization / Independent Ethics Committee (ISO / IEC), the College of American Pathologists (CAP), or similarly accredited laboratories, while central trials are pending. They must have a measurable disease according to RECIST v1.1. See Figure 5.

[0171] The patient has an ECOG performance status of 1 or less or a Karnovsky performance status of 80% or higher. The researcher determines that the patient has a life expectancy of more than 12 weeks. The patient must have adequate organ function, including bone marrow, liver, and kidney function.

[0172] Exclusion Criteria: History of known or suspected active central nervous system (CNS) complications; history of carcinomatous meningitis; any unresolved toxicity from previous therapy; or a serious pre-existing medical condition that would prevent participation in this study, including interstitial lung disease, bowel obstruction, or severe dyspnea at rest.

[0173] Significant cardiovascular disease, for example, significant cardiovascular disease defined as either unstable angina or acute coronary syndrome within the past two months; a history of myocardial infarction within six months prior to the planned initiation of the investigational treatment; heart failure, uncontrolled or symptomatic arrhythmias of grade 3 or higher on the New York Heart Association functional classification system; heart failure, uncontrolled or symptomatic arrhythmias of grade 3 or higher on the New York Heart Association functional classification system.

[0174] During screening, the corrected QT interval by Fridericia (QTcF) is extended by more than 470 milliseconds. QTcF is given by Fridericia's formula: QTcF = QT / (RR 0.33 It is calculated using ).

[0175] Participants with the following known infections are excluded: active, uncontrolled systemic bacterial, viral, fungal, or parasitic infections; active hepatitis B virus (HBV); HBsAg-positive and HBV DNA-positive (detectable) participants; active hepatitis C virus (HCV), active HIV infection, or active cytomegalovirus infection.

[0176] Unless the patient is in remission and has an average life expectancy of more than two years, they are considered to have active secondary cancer.

[0177] Cohort A2 (dose optimization), and B1 and B2 (dose expansion): ovarian cancer as determined by mucinous or clear cell histological examination.

[0178] Cohort A2 (dose optimization), and B1 and B2 (dose expansion): characterized by ovarian cancer and the presence of hypoalbuminemia (≤3.5 g / dL), malnutrition and weight loss (grade 2 or higher), or ascites requiring the placement of an indwelling drainage catheter or frequent drainage procedures (more than twice in the last 28 days).

[0179] Previous / combination therapy: Cytotoxic therapy: shorter than 14 days or half-life of 5 or less. Treatment monoclonal antibody: 14 days or less. Radiation therapy: 7 days or less or 21 days or less. Major surgery: 28 days or less.

[0180] The patient is currently undergoing an interventional anti-cancer treatment trial in the therapeutic phase. They have a history of prior treatment with FRα ADCs containing a topoisomerase I inhibitor.

[0181] Cohort A2 (dose optimization), and B1 and B2 (dose expansion): Patients with a history of receiving five or more prior elective systemic therapies in a platinum-resistant condition.

[0182] Tumor Measurement: Evaluate the tumor according to the SOA and imaging manual. Evaluation of both measurable and unmeasurable disease, either by evaluating according to tumor type using RECIST v1.1, or by evaluating in a location-dependent manner using an equivalent evaluation method.

[0183] Response Assessment: Imaging studies (CT or MRI scans, including spiral CT of the chest, abdomen, and pelvis) will be performed locally at baseline for all participants. Abdominal and pelvic CT imaging should be performed with IV contrast whenever possible. The CT portion of a PET-CT scan may be used as a method of response assessment if the facility can describe that the CT is of the same diagnostic quality as diagnostic CT (with IV and oral contrast). PET scans alone or as part of a PET-CT scan may be performed as part of routine clinical care, but they cannot be used to assess response according to RECIST v1.1.

[0184] Summary of Results: Initial clinical data were consistent with preclinical findings, demonstrating that FRα ADCs were well-tolerated and active in HGSOC patients, including those with FRα expression levels below 75%, and in patients previously treated with MIRVs. See Figure 6. Specifically, no ocular or pulmonary toxicity or neuropathy was observed. Table 4 summarizes the complete response (CR) / partial response (PR) rates and whether or not there was prior MIRV treatment in evaluated HGSOC patients, separated by FRα expression levels.

[0185] [Table 4]

[0186] Table 4A summarizes the overall response rate (ORR) for 104 patients with evaluable high-grade serous ovarian cancer from Phase I dose escalation (Cohort A1) and dose optimization (Cohort A2).

[0187] [Table 5]

[0188] Table 4A shows that FRα ADCs were well-tolerated and demonstrated sustained clinical efficacy in patients with severely previously treated HGSOC, regardless of FRα expression levels or prior MIRV treatment.

[0189] Table 5 below: Patients eligible for efficacy evaluation are those who have had at least one baseline-post-response assessment or who have discontinued treatment before the first baseline-post-response assessment. Patients are shown in both the dose-escalation and dose-optimization cohorts. ORR in Table 5 includes patients with unconfirmed and confirmed CR and PR.

[0190] [Table 6]

[0191] Summary: As shown in Table 5, FRα ADC demonstrated promising efficacy across all dose levels in patients with HGSOC.

[0192] Table 5A below presents a recent data analysis of 106 efficacy-evaluable PROC patients with measurable disease at baseline who received at least one dose of FRα ADC. uORR=(CR+unconfirmed CR+PR+unconfirmed PR), cORR=(CR+PR), and DCR=(CR+uCR+PR+uPR+disease stability).

[0193] [Table 7]

[0194] Summary: In Table 5A, FRα ADC demonstrated clinically meaningful efficacy in patients with severely previously treated PROC. Overall, tumor responses were observed across all doses evaluated, with the highest uORR / cORR and DCR observed for 3 mg / kg and 4 mg / kg doses. Notably, tumor responses were observed regardless of FRα expression levels and in participants previously treated for MIRV.

[0195] A patient subgroup evaluation was performed in 47 patients aged 65 years or older with PROC, a median of four prior lines of therapy including prior treatment for MIRV, and FRα expression <75%, who were treated with 2, 3, 4, or 6 mg / kg of FRα ADC. The ORR for this patient subgroup was 51%. Separately, another evaluation was performed in 17 patients aged 65 years or older with PSOC, who were treated with 4 mg / kg of FRα ADC in combination with bevacizumab. These patients had a median of two prior lines of therapy including prior treatment for MIRV, and FRα expression <75%. The ORR for this patient subgroup was 29%. These combined patient subgroup data for PROC and PSOC demonstrate promising efficacy of FRα ADCs in adults aged 65 years or older, who constitute nearly half of all patients diagnosed with ovarian cancer.

[0196] Plasma concentrations of FRα ADC, total antibody, and total unconjugated exatecan were measured after Cycle 1 at the tested doses of 2 mg / kg, 3 mg / kg, 4 mg / kg, and 6 mg / kg. Please refer to Figure 7, where the data shown are the geometric mean and standard deviation (SD). This indicates that plasma FRα ADC concentrations were stable at the minimum accumulation prior to subsequent doses (6.5–8 days payload gomean half-life). Table 6 summarizes the comparison of FRα ADC and exatecan payload PK parameters.

[0197] [Table 8]

[0198] Table 6 demonstrates that the pharmacokinetics (PKs) of FRα ADC and exatecan were dose-proportional, ranging from 2 mg / kg to 6 mg / kg. The overall PK profile of FRα ADC supports dosing at Q3W.

[0199] Table 7 shows the Phase I efficacy results, which are calculated using ORR%, and ORR% is divided by the patient's tumor FRα expression level, where known.

[0200] [Table 9]

[0201] The results demonstrate that FRα ADCs possess clinical activity across all FRα expression levels, regardless of prior MIRV treatment.

[0202] Example 4: Translational PK / PD Modeling Understanding the PK / PD characteristics of FRα ADCs is crucial for optimizing their treatment window and predicting clinical outcomes. This study evaluated how preclinical PK and efficacy endpoints of FRα ADCs are translated to human patients.

[0203] FRα ADC non-human primate PK data were modeled using a two-compartment model for total antibody / conjugate ADCs and a one-compartment model for exatecan. Human PK was predicted using body weight-based allometric scaling from non-human primates, and human PK was used to estimate the minimum effective dose required to match the exposure needed for over 80% tumor regression in xenograft and PDX-bearing Tg32 mice, e.g., as demonstrated in Examples 1 and 2. The predictive accuracy of the human PK / efficacy model was evaluated by comparing it with observed clinical data, such as those described in Example 3.

[0204] Preclinical PK models accurately predicted human PK and therapeutic indices for FRα ADC and non-conjugated payloads within a 0.8–1.25 fold (see Table 8). Slower deconjugation of exatecan in patients resulted in lower plasma payload levels and long-term FRα ADC stability, which agreed the PSAR linker platform DAR stability results between preclinical and clinical studies. Preclinical and emerging clinical PKPD data suggest a broader therapeutic index for FRα ADC, supporting clinical efficacy and safety across a 2–3 fold dose range from Phase I trials (Example 3).

[0205] [Table 10]

[0206] Preclinical evaluations of PSAR-linked exatecan ADCs, combined with translational modeling, provided crucial data regarding payload release rate, half-lives of FRα ADCs (and their components), predicted effective doses and dosing regimens, and human PK / PD characteristics, supporting the design of a Phase I clinical trial of FRα ADCs.

[0207] Example 5: Phase 3 Clinical Trial This Phase 3 study aims to evaluate FRα ADC in the treatment of patients with advanced ovarian cancer, including high-grade serous ovarian cancer (HGSOC), high-grade endomethiodic ovarian cancer, primary peritoneal cancer, and fallopian tube cancer. The study consists of three independent parts, each dealing with a different patient population: Part A: platinum-resistant ovarian cancer (PROC), Part B: platinum-sensitive ovarian cancer (PSOC), and Part C: PARP inhibitor-naive PSOC. The primary endpoint for Parts A, B, and C is investigator-assessed progression-free survival (PFS) according to RECIST v1.1. The key secondary endpoint is to evaluate efficacy as measured by overall survival (OS) (a) FRα ADC monotherapy versus control in Part A, or (b) FRα ADC plus bevacizumab versus control in Parts B and C.

[0208] Part A: FRα ADC as monotherapy at 3 mg / kg versus 80 mg / m² 2 Paclitaxel, 40 mg / m² 2 Pegylated liposomal doxorubicin (PLD), 800-1000 mg / m² 2 Gemcitabine, 4 mg / m² 2 Evaluation of the control arm for selection of topotecan or MIRV in a 6 mg / kg AIBW (for MIRV-naive participants with FRα positivity [more than 75% of viable tumor cells with staining intensity of 2+ or higher] according to the local product label, if approved and marketed). See Table 9.

[0209] Participants with a PROC defined as a radiographic exacerbation less than 6 months prior to the last dose of platinum therapy, and who have previously received up to three prior elective systemic cytotoxic therapies (or up to four if MIRVs are included), will be enrolled in Part A. Participants will be randomly assigned in a 1:1 ratio to receive either FRα ADC or a control. Participant randomization will be stratified as follows: (a) high FRα expression (≥75% of viable tumor cells with staining intensity ≥2+): yes vs. no, (b) prior MIRV use: yes vs. no, and (c) investigator's choice of therapy: paclitaxel vs. other chemotherapy vs. MIRV. See Figure 8.

[0210] The exclusion criteria for Part A (PROC) may include the following types of patients: 1. The patient has received 1.5 or more prior elective systemic cytotoxic therapies. a. Neo-adjuvant + / - adjuvant therapy is considered a single line of therapy if the neo-adjuvant or adjuvant corresponds to a single, fully predefined regimen. b. Maintenance therapy should be considered as part of the preceding line of therapy and not counted independently. c. Changes in malignant tumor drugs due to toxicity should not be considered as a new line of therapy. d. If MIRV was not included in the prior selection, only three prior selection systemic cytotoxic therapies are acceptable. 2. The patient has a primary platinum-refractory disease, defined as a disease that has progressed to less than 3 months since the last dose of first-line platinum-containing chemotherapy. 3. The patient has previously received an ADC with a topoisomerase inhibitor payload.

[0211] Part B: In participants with PSOC, FRα ADC at 3 mg / kg versus platinum-based doublet chemotherapy in combination with bevacizumab at 15 mg / kg: (a) carboplatin at AUC of 5-6 mg / mL / min and 175 mg / m² 2 (b) Paclitaxel plus bevacizumab at 15 mg / kg, (b) Carboplatin and 800-1000 mg / m² at AUC of 4 mg / mL / min2 Evaluation of the control arm for the choice between gemcitabine plus 10 mg / kg of bevacizumab or carboplatin / pegylated liposomal doxorubicin plus 10 mg / kg of bevacizumab. See Table 10.

[0212] Participants with PSOC who have been subjected to up to two previous elective systemic cytotoxic therapies and whose condition has progressed either during or within 6 months of completion of treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor will be enrolled in Part B. Participants will be treated in a 1:1 ratio with either FRα ADC plus bevacizumab or a platinum-based doublet chemotherapy of the investigator's choice: (a) carboplatin at an AUC of 5–6 mg / mL / min and 175 mg / m² 2 (b) Paclitaxel plus bevacizumab at 15 mg / kg, (c) Carboplatin and gemcitabine at 4 mg / mL / min AUC and 800-1000 mg / m2 plus bevacizumab at 10 mg / kg, or (d) Carboplatin and 30 mg / m2 at 5 mg / mL / min AUC. 2 Participants will be randomly assigned to receive pegylated liposomal doxorubicin plus bevacizumab at 10 mg / kg. Randomization will be stratified as follows: (a) platinum-free period: <12 months vs. >12 months, (b) disease relapse: 1st vs. 2nd, and (c) carboplatin-based doublet of investigator's choice: carboplatin plus paclitaxel vs. gemcitabine vs. pegylated liposomal doxorubicin (PLD). See Figure 9.

[0213] The exclusion criteria for Part B (PSOC) may include the following types of patients: 1. The patient has received three or more prior elective systemic cytotoxic therapies. The number of prior elective anti-tumor regimens should be counted as follows: a. Neo-adjuvant + / - adjuvant therapy is considered a single line of therapy if the neo-adjuvant or adjuvant corresponds to a single, fully predefined regimen. b. Maintenance therapy should be considered as part of the preceding line of therapy and not counted independently. c. Changes in malignant tumor drugs due to toxicity should not be considered as a new line of therapy. 2. If a participant has clinically significant proteinuria and a urine test strip result of 3+ or higher, they should complete a 24-hour urine collection and must provide a result of 1g or less of protein during the 24-hour period to be eligible. 3. The patient has previously received an ADC with a topoisomerase inhibitor payload.

[0214] In both Part A and Part B, FRα ADC is administered by intravenous (IV) infusion on day 1 (Q3W) of the 21-day cycle. The dose is based on actual body weight on day 1 of each cycle. FRα ADC should be administered before bevacizumab in Part B. Bevacizumab is administered IV on day 1 (Q3W) of the 21-day cycle, as indicated on the product label. See Tables 9 and 10.

[0215] [Table 11]

[0216] [Table 12]

[0217] Part C will be added to a Phase 3 study including approximately 550 patients with PARP inhibitor naiveté and PSOC to compare the efficacy of FRα ADC at 3 mg / kg in combination with bevacizumab at 15 mg / kg or its biosimilar in this patient group to a control arm of investigator's choice platinum-carboplatin doublets, each in combination with bevacizumab or its biosimilar: (i) carboplatin / paclitaxel, (ii) carboplatin / gemcitabine, or (iii) carboplatin / pegylated liposomal doxorubicin. Participants with PSOC who have previously received up to two prior elective systemic cytotoxic therapies will be enrolled in Part C. The control arm of Part C includes (i) carboplatin / paclitaxel, (ii) carboplatin / gemcitabine, or (iii) carboplatin / pegylated liposomal doxorubicin in combination with bevacizumab or its biosimilar, as selected by the investigator before randomization. Participant randomization in Part C will be stratified as follows: (a) high FRα expression (≥75% of cells with staining intensity ≥2+) - present vs. absent, (b) platinum-free period: <12 months vs. >12 months, (c) disease relapse - 1st vs. 2nd, and (d) the investigator's choice of platinum-carboplatin doublet: (i) carboplatin / paclitaxel, (ii) carboplatin / gemcitabine, or (iii) carboplatin / pegylated liposomal doxorubicin.

[0218] Inclusion criteria for Part C-PSOC: (a) Must have relapsed after first-line platinum-based chemotherapy and have platinum-sensitive disease as defined by radiographic exacerbation more than 6 months after the last dose in a participant in platinum therapy; (b) Must be a candidate for subsequent treatment with platinum doublets and bevacizumab or their biosimilars as defined above; and (c) Must have previously received more than one but less than two prior elective systemic cytotoxic chemotherapy regimens.

[0219] Exclusion criteria for Part C-PSOC: Participants should complete 24-hour urine collection and provide a result of ≤1 g of protein over a 24-hour period to be eligible. (a) A history of three or more prior elective systemic cytotoxic chemotherapy treatments, (b) a history of prior treatment with a PARP inhibitor, and (c) clinically significant proteinuria with a urine test strip result greater than 3+.

[0220] For Part A PROC, and Parts B and C PSOC, administer FRα ADC until radiographic exacerbation, unacceptable toxicity, or other discontinuation criteria are met.

[0221] Example 6: Phase Ia dose optimization combination in endometrial cancer As a supplement to the Phase Ia study disclosed in Example 3, the optimal dose and antitumor activity of the FRα ADC plus pembrolizumab combination will be investigated in participants with endometrial cancer in a newly added cohort A6. Approximately 60 participants in cohort A6 will be randomized over at least two dose levels and stratified by TP53 status (mutant vs. wild-type) and prior PD-1 / PD-L1 blockade (with vs. without). FRα ADC will be administered first, followed by pembrolizumab. FRα ADC will be administered at 3 mg / kg and 4 mg / kg. Pembrolizumab will be administered intravenously (IV) on day 1 (Q6W) of a 21-day cycle, as indicated on the product packaging. Pembrolizumab will be conferred for up to two years or until disease progression. See Figure 10.

[0222] The inclusion criteria for Cohort A6 may include, but are not limited to, (a) a histological diagnosis of master mismatch repair (pMMR) / microsatellite stability (MSS) endometrial cancer that has progressed within 12 months of the last dose of platinum-taxane chemotherapy, and (b) participants must have a measurable disease in accordance with RECIST v1.1.

[0223] Exclusion criteria for Cohort A6 may include, but are not limited to, (a) participants receiving prednisone (or its equivalent) at doses greater than 10 mg / day are ineligible for enrollment; (b) participants with endometrial stromal sarcoma, leiomyosarcoma, or adenosarcoma are ineligible; and (c) participants whom the attending physician considers unsuitable for pembrolizumab, e.g., due to autoimmune disease, a history of interstitial lung disease, or interstitial pneumonia.

[0224] Example 7: Phase Ia Sub-study In the Phase Ia study described in Example 3, a new sub-study will be conducted in dose-escalation cohort A1 to evaluate the safety and PK properties of FRα ADC in (a) participants with moderate hepatic impairment (Arm A), (b) participants in a drug-drug interaction (DDI) study with a potent CYP3A4 inhibitor (Arm B), and (c) participants in an evaluation of the comparability of early-to-late-phase formulations (Arm C). See Figure 10.

[0225] Cohort A1, Arm A: Evaluate the safety and pharmacokinetics (PK) of FRα ADC monotherapy at 2 mg / kg in 8-10 eligible participants with gynecological cancers, such as ovarian cancer, cervical cancer, or endometrial cancer, and moderate hepatic impairment (total bilirubin greater than 1.5 to 3 × Upper Limit of Normal (ULN) and either aspartate aminotransferase (AST) based on NCI-ODWG criteria). The analysis will use a population PK model, evaluating liver function as a covariate in PK parameters, including, but not limited to, AUC and Cmax. Inclusion criteria for Arm A may include a histological diagnosis of gynecological cancer, which may include, for example, ovarian cancer, endometrial cancer, or cervical cancer in individuals with moderate hepatic impairment. For Arm A, acceptable liver function is determined using NCI-ODWG criteria, where total bilirubin is greater than 1.5 to 3 × upper limit of normal (ULN), and AST can be any type of AST.

[0226] Cohort A1, Arm B: A DDI study of FRα ADCs with itraconazole will be conducted in participants with gynecological cancers (ovarian cancer, cervical cancer, endometrial cancer, etc.). Itraconazole will be administered according to its product label. The sub-study is an open-label, fixed-sequence sub-study designed to evaluate the effects of itraconazole, a potent CYP3A4 inhibitor, on the PK and safety of the exatecan payload and FRα ADCs in eligible participants. The sub-study enrolled approximately 12–16 participants and included treatment periods in cycles 2 and 3: (a) In cycle 2, participants received a single dose of 2 mg / kg FRα ADC on day 1, then on day 15, and itraconazole at a dose of 200 mg twice daily, once at the clinic and once at home; (b) Starting on day 16 of cycle 2, participants received 200 mg orally once daily at home over 15 days of cycle 3 (a total of approximately 21 days); and (c) On day 1 of cycle 3, participants received a single dose of 2 mg / kg FRα ADC. See Figure 11. Blood samples for PK analysis of the exatecan payload, including but not limited to AUC and Cmax, were collected at specified time points. PK samples of itraconazole and hydroxyitraconazole were collected to ensure steady-state concentrations of itraconazole. Safety and tolerability, including adverse events (AEs), vital signs, ECG, and laboratory parameters, will be monitored throughout the substudy, including weekly laboratory examinations during Cycle 3. Initiating in Cycle 4, the FRα ADC dose may be increased after consideration and approval by the medical monitor if the attending physician believes the participant will benefit from the dose increase. Inclusion criteria for Arm B may include a histological diagnosis of gynecological cancer, which may include, for example, ovarian cancer, endometrial cancer, or cervical cancer. Exclusion criteria may include (a) individuals who are unable to receive itraconazole orally, or who have any medical condition, medical history, or are taking any drug therapy that is contraindicated in the itraconazole prescribing information, and (b) individuals with hearing loss requiring the use of assistive devices, such as hearing aids.

[0227] To support the transition from early to late phases in Cohort A1, Arm C, appropriate comparability assessments will be conducted to demonstrate that the pre- and post-change clinical materials do not reveal any clinically significant differences in product quality and safety profiles. Pharmacokinetics will be compared in participants treated with either the early phase material (dose escalation cohort A1 and dose optimization cohort A2) or the late phase material (Cohort A1: Arm C sub-study) at 3 mg / kg. Approximately 12–16 participants with ovarian cancer, cervical cancer, endometrial cancer, NSCLC, and TNBC will be enrolled in Cohort A1: Arm C. Comparability between the early and late phase clinical materials will be demonstrated using non-compartmental or pop-PK analysis with AUC and Cmax as PK parameters for FRα ADC. Where necessary, propensity score matching techniques are also considered to maintain a balance of disease characteristics between these two groups. Inclusion criteria may include histological diagnoses of ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung cancer, and triple-negative breast cancer.

[0228] Example 8: Phase Ib dose expansion As an amendment to Phase Ib described in Example 3, an additional cohort will be added to Cohort B. This study will evaluate FRα ADC monotherapy in participants with low-grade serous ovarian cancer, cervical cancer, NSCLC, and TNBC, and each cohort will be treated with FRα ADC at the recommended Phase 2 dose (RP2D) determined by Phase Ia. See Figure 12. Up to approximately 100 eligible participants will be added to the four new cohorts, each of which will have approximately 25 participants.

[0229] The Cohort B1 dose expansion will enroll eligible participants who have previously received platinum-containing therapy, have a histological or cytological diagnosis of low-grade serous ovarian cancer, and have measurable disease according to RECIST v1.1.

[0230] The Cohort B2 dose expansion will enroll eligible participants with a histological diagnosis of squamous cell carcinoma, adenocarcinoma, ground-glass cell carcinoma, or cervical adenosquamous cell carcinoma and a measurable disease according to RECIST v1.1. Participants must have received prior platinum-containing chemotherapy.

[0231] The Cohort B3 dose expansion enrolls eligible participants with a histological or cytological diagnosis of lung adenocarcinoma and measurable disease according to RECIST v1.1, participants must have previously received PD-1 / PD-L1 inhibitor therapy, and participants with activating oncogenic mutations must have previously received approved mutation-based thymidine kinase inhibitor (TKI) therapy; prior PD-1 / PD-L1 is not a requirement for participants with oncogenic drivers.

[0232] The Cohort B4 dose expansion will enroll eligible participants with a histological diagnosis of triple-negative breast cancer (TNBC) and measurable disease according to RECIST v1.1. Triple-negative receptor status is defined as estrogen and progesterone receptor expression of ≤10% and human epidermal growth factor receptor 2 (HER2) negative according to the ASCO / CAP HER2 trial guidelines.

Claims

1. A method for treating a subject having folate receptor alpha-positive cancer, the method comprising administering an anti-folate receptor alpha-antibody drug conjugate in a drug regimen comprising a dose of approximately 1.0 mg / kg to approximately 10.0 mg / kg as an intravenous (IV) infusion for at least two cycles on day 1 (Q3W) of each 21-day cycle, wherein the anti-folate receptor alpha-antibody drug conjugate has the chemical structure of formula II. 【Chemistry 1】 It has, A method in which Ab is an anti-FRα antibody, k is 2 to 20, and p is 1 to 8.

2. The method according to claim 1, wherein the anti-FRα antibody comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 3 and a light chain (LC) containing the amino acid sequence of SEQ ID NO:

4.

3. The method according to claim 2, wherein k is 10 and p is 8.

4. The method according to claim 3, wherein the dose is approximately 3.0 mg / kg.

5. The method according to claim 1 or 4, wherein the FRα-positive cancer is selected from the group consisting of ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), pancreatic cancer, and colorectal cancer (CRC).

6. The method according to claim 5, wherein the ovarian cancer is epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, and high-grade endomethriod ovarian cancer, low-grade serous ovarian cancer (LGSOC), and high-grade serous ovarian cancer (HGSOC).

7. The method according to claim 5, wherein the ovarian cancer is resistant to previous platinum therapy (PROC).

8. The method according to claim 5, wherein the ovarian cancer is platinum-sensitive (PSOC).

9. The method according to claim 7, wherein the subject has been previously treated with milbetuximab sorabtansine-gynx or a biosimilar thereof.

10. The method according to claim 7, wherein the subject has been previously treated with three or fewer lines of therapy.

11. The method according to claim 9, wherein the subject has been previously treated with four or fewer lines of therapy.

12. The method according to claim 8, wherein the subject has been previously treated with two or more lines of therapy.

13. The method according to claim 7 or 8, wherein the subject is 65 years of age or older.

14. The method according to claim 7, wherein the anti-folate receptor alpha-antibody drug conjugate is administered as monotherapy.

15. The method according to claim 12, wherein the treatment further comprises administering bevacizumab or a biosimilar thereof, the bevacizumab or biosimilar being administered after the administration of the anti-folate receptor alpha-antibody drug conjugate.

16. The method according to claim 15, wherein a drug regimen for bevacizumab or its biosimilar is administered at a dose of approximately 15 mg / kg on day 1 (Q3W) of every 21-day cycle for a maximum of 22 cycles.

17. The method according to claim 16, wherein the combination of bevacizumab or a biosimilar thereof is for treating platinum-sensitive diseases as a second-line therapy.

18. The method according to claim 14 or 16, wherein pulmonary toxicity is not observed as a result of treatment in the subject.

19. The method according to claim 14 or 16, wherein neuropathy is not observed in the subject as a result of treatment.

20. The method according to claim 14 or 16, wherein ocular toxicity is not observed in the subject as a result of treatment.

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