Dosage of antibody drug conjugate RINATABART SESUTECAN

Abstract

The present invention relates to a method of treating a solid tumor by administering to a human subject an antibody-drug conjugate (ADC) comprising an antibody directed against FOLR1 conjugated to avixetecan via a hydrophilic linker. The ADC is administered at a dose of from 40 mg / m2 to 200 mg / m2. In one embodiment, the ADC is a conjugate rinatabart sesutecan (Rina-S), and in one embodiment, the ADC is a conjugate rinatabart sesutecan (Rina-S). The ADC can reduce tumor size when administered at specific doses and schedules and is effective to treat cancers that are resistant to standard therapies, such as radiation therapy, chemotherapy, or immunotherapy. The ADC can be used in combination with other anti-cancer drugs.

Description

Technical Field

[0001] This disclosure generally relates to dosing schedules for antibody-drug conjugates (ADCs) for use in human subjects, and more particularly to dosing schedules for the ADC rinatabart sesutecan (Rina-S) for use in human subjects in the treatment of cancers such as solid tumors. This disclosure also relates to such ADCs for use in such dosing regimens. This disclosure further relates to combination therapies in which the ADC is used in combination with other anticancer drugs. Background Technology

[0002] Folate receptor 1 (FOLR1), also known as folate receptor-α (FRα) or folate-binding protein (FBP), is an N-glycosylated protein expressed on the cell membrane. FOLR1 is overexpressed in the vast majority of ovarian cancers, as well as many uterine cancers, endometrial cancers, pancreatic cancers, renal cancers, lung cancers, and breast cancers. However, FOLR1 expression in normal tissues is limited to the apical membrane of epithelial cells in the proximal tubules of the kidney, alveolar cells of the lungs, bladder, testes, choroid plexus, and thyroid gland (Weitman SD, et al., Cancer Res 52: 3396-3401 (1992); Antony AC, Annu Rev Nutr 16: 501-521 (1996); Kalli KR, et al., Gynecol Oncol 108: 619-626 (2008)). The antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S; formerly known as PRO1184) was developed to target FOLR1 and comprises a FOLR1 antibody and drug units, each drug unit comprising eczema linked to the antibody via a hydrophilic linker. Rina-S has been shown to induce cytotoxicity in cancer cells and exhibit antitumor activity both in vitro and in vivo. However, there remains a need for efficient methods of administering Rina-S to human subjects. Preferably, these methods include optimized dosing and administration schedules to maximize the efficacy of Rina-S for therapeutic use in human subjects and minimize its toxicity. There is also a need to provide combination therapies for the treatment of FOLR1-positive cancers. Summary of the Invention

[0003] In one aspect, the present invention provides a method for treating solid tumors, comprising administering to a human subject suffering from a solid tumor an antibody-drug conjugate (ADC) having the characteristics described herein, the ADC comprising an antibody against FOLR1 conjugated to the anticancer drug eczema via a hydrophilic linker. In any embodiment set forth herein, the ADC may be Rina-S.

[0004] This article provides methods and dosage schedules for administering Rina-S to human subjects in the treatment of cancers (such as, but not limited to, solid tumors).

[0005] In one aspect, the present invention provides a method for treating folate receptor 1 (FOLR1)-positive solid tumors, the method comprising administering an antibody-drug conjugate (ADC) to a human subject suffering from a solid tumor, wherein the ADC has a structure (Structure 1):

[0006]

[0007] The Ab is an antibody that binds to FOLR1 and contains a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region and VL region have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and where n is 8.

[0008] And the ADC was 40 mg / m 2 Up to 200 mg / m 2 For example, 60 mg / m 2 Up to 140 mg / m 2 The dosage is administered. In some embodiments, the human subject has ovarian cancer. In some embodiments, the human subject has endometrial cancer. In one aspect, the present invention provides a method for treating a human subject with cancer, including a FOLR1-positive solid tumor, the method comprising administering to the subject an ADC having structure 1, wherein the Ab is an antibody comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH and VL regions have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is administered at a dose of 40 mg / m 2 Up to 200 mg / m 2 For example, 60 mg / m 2 Up to 140 mg / m 2 The dosage is specified. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the ADC is administered at 100 mg / m². 2 The ADC is administered at a dose of 120 mg / m³. In some embodiments, the ADC is administered at a dose of 120 mg / m³. 2Dosage administration. In some embodiments, the ADC is administered once every three weeks. In some embodiments, the ADC has the structure of Structure 1, wherein the Ab is an antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC and LC have the amino acid sequences shown in SEQ ID NO: 6 and SEQ ID NO: 5, respectively, and wherein n is 8. In some embodiments, the HC and LC have the amino acid sequences shown in SEQ ID NO: 4 and SEQ ID NO: 5, respectively. In some embodiments, the ADC has the structure of Structure 1, wherein the Ab is an antibody comprising two HCs each having the amino acid sequence shown in SEQ ID NO: 6 and two LCs each having the amino acid sequence shown in SEQ ID NO: 5, and wherein n is 8. In some embodiments, each of the two HCs has the amino acid sequence shown in SEQ ID NO: 4, and each of the two LCs has the amino acid sequence shown in SEQ ID NO: 5.

[0009] One aspect of the invention relates to a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 40 mg / m². 2 Up to 200 mg / m 2 The dosage was administered, and the solid tumor was folate receptor 1 (FOLR1) positive.

[0010] In some embodiments of the invention, the solid tumor is selected from the group consisting of ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is platinum-resistant ovarian cancer (PROC). In some embodiments, the solid tumor is platinum-sensitive ovarian cancer (PSOC). In some embodiments, the solid tumor is ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the solid tumor is endometrial cancer. In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC). In some embodiments, the solid tumor is breast cancer, including HER2-negative breast cancer. In some embodiments, the solid tumor is pleural mesothelioma or peritoneal mesothelioma. In some embodiments, the solid tumor is localized or metastatic.

[0011] In some embodiments, another aspect of the invention relates to treatment using ADC Rina-S, wherein the ADC is administered at 60 mg / m². 2 Up to 180 mg / m 2 The ADC is administered at a dose of 140 mg / m³. In some embodiments, the ADC is administered at a dose of 140 mg / m³. 2The ADC is administered at a dose of 100 mg / m³. In some embodiments, the ADC is administered at a dose of 100 mg / m³. 2 Up to 140 mg / m 2 The ADC is administered at a dose of 100 mg / m³. In some embodiments, the ADC is administered at a dose of 100 mg / m³. 2 Up to 120 mg / m 2 The ADC is administered at a dose of approximately 100 mg / m³. 2 The ADC is administered at a dose of approximately 120 mg / m³. 2 Dosage administration.

[0012] Another aspect of the invention relates to a dosing schedule for the ADC Rina-S, wherein the ADC is administered to a human subject once or twice a week using a schedule selected from the following groups of cycles: (i) once a week; (ii) every other week; (iii) one week of treatment, followed by a two-, three-, or four-week break; (iv) two weeks of treatment, followed by a one-, two-, three-, or four-week break; (v) three weeks of treatment, followed by a one-, two-, three-, four-, or five-week break; (vi) four weeks of treatment, followed by a one-, two-, three-, four-, or five-week break; (vii) five weeks of treatment, followed by a one-, two-, three-, four-, or five-week break; and (viii) once a month. In some embodiments, the ADC dose is administered to a human subject once a week using a schedule selected from the following groups of cycles: (i) once a week; (ii) every other week; (iii) one week of treatment, followed by a two-, three-, or four-week break. In some embodiments, the ADC dose is administered to the human subject on day 1 of a 21-day treatment cycle. In some implementations, the ADC dose is administered to human subjects as an intravenous (IV) infusion over 30 minutes.

[0013] In some implementations, the ADC is administered to a human subject in cycles consisting of: (i) once a week for two weeks, followed by a two-, three-, or four-week break; (ii) once a week for three weeks, followed by a two-, three-, or four-week break; (iii) once a week for four weeks, followed by a two-, three-, or four-week break; (iv) once every other week for four weeks, followed by a two-, three-, or four-week break; and (v) once a week for five weeks, followed by a two-, three-, or four-week break.

[0014] In some embodiments, the ADC dose is administered to human subjects every three weeks. In some embodiments, the dose is 120 mg / m². 2 In some implementations, the ADC dose is administered as an intravenous infusion.

[0015] In another aspect of the invention, the treatment cycles are repeated 2, 4, 6, 8, 10, 12, 16, or 20 times. In one embodiment, treatment is continued as needed. In some embodiments, treatment is continued, for example, when the subject exhibits a reduction in tumor size or a stable tumor size (e.g., by RECIST v1.1 criteria), and / or a positive objective response duration (DOR), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and / or overall survival. Treatment with the ADC may continue, for example, until disease progression or unacceptable toxicity.

[0016] In another aspect of the invention, the human subject has previously been treated with at least one anticancer therapy. In some embodiments, the human subject has previously been treated with one to four anticancer therapies. In some embodiments, the at least one anticancer therapy includes treatment with a chemotherapeutic agent. In some embodiments, the at least one anticancer therapy includes treatment with at least one anticancer therapy selected from the group consisting of platinum-based chemotherapy, bevacizumab, poly-ADP-ribose polymerase (PARP) inhibitors, and mirvetuximab soravtansine. In some embodiments, the human subject failed to respond to at least one anticancer therapy prior to ADC treatment. In some embodiments, the human subject has previously been treated with soravtuximab. In some embodiments, the human subject does not meet the criteria for treatment with soravtuximab.

[0017] In another aspect of the invention, treatment with ADC Rina-S results in a reduction of at least 15%, at least 20%, at least 30%, at least 40%, or at least 50% in the size of a solid tumor.

[0018] In another aspect of the invention, the ADC is administered in combination with one or more treatment modalities selected from the group consisting of: unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, local radiotherapy, surgery, and interfering RNA therapy.

[0019] In another aspect of the invention, treatment with ADC Rina-S improves the outcome for the subject. In some embodiments, the improved treatment outcome is an objective response selected from disease stability, partial response, or complete response. In some embodiments, the improved treatment outcome is a reduction in tumor burden. In some embodiments, the improved treatment outcome is progression-free survival or disease-free survival. In some embodiments, the improved treatment outcome is improved overall survival.

[0020] This article has demonstrated that treatment with the ADC Rina-S provides clinical benefit in patients with tumors (across all FOLR1 expression levels), which generates the possibility of treating patients with Rina-S without establishing FOLR1 expression levels. Therefore, in another aspect, the present invention provides treatment of human subjects with solid tumors using Rina-S, wherein the FOLR1 expression level in the solid tumor has not been determined. In some embodiments, the human subject has ovarian cancer. In some embodiments, the human subject has been pretreated with other anticancer therapies, such as at least one, two, three, four, or more lines of therapy. In some embodiments, the human subject is given 100 mg / m². 2 Rina-S treatment at dose levels. In some implementations, human subjects were treated with 120 mg / m². 2 The Rina-S treatment is administered at dose levels. In some embodiments, the dose is administered to the human subject approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously, such as via intravenous infusion.

[0021] In another aspect, the present invention provides a combination therapy for a subject suffering from a solid tumor, comprising a method of combination therapy including administering Rina-S to the subject in combination with any one of a platinum-based chemotherapy, an anti-angiogenic agent, a PARP inhibitor, or a checkpoint inhibitor. In one embodiment, the combination therapy comprises a combination of Rina-S with a platinum-based chemotherapy such as carboplatin, cisplatin, or oxaliplatin. In one embodiment, the combination therapy comprises a combination of Rina-S with an anti-angiogenic agent such as an anti-VEGF antibody such as bevacizumab. In one embodiment, the combination therapy comprises a combination of Rina-S with a PARP inhibitor such as olaparib or niraparib. In one implementation, the combination therapy comprises Rina-S in combination with: checkpoint inhibitors, such as inhibitors of PD-1 or PD-L1 immune checkpoint proteins, such as anti-PD1 antibodies such as pembrolizumab, nivolumab, cimipril, dostarlimab, retinfanlimab, toripalimab, etc., or anti-PD-L1 antibodies such as atezolizumab, avelumab, durvalumab, etc. In some implementations, 100 mg / m² is used. 2 Subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2Subjects are treated with doses of Rina-S. In some embodiments, these doses are administered to the subject approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously. Dosing and administration regimens for other therapies in the combination of the invention are performed according to the approved label of the other corresponding therapy.

[0022] Therefore, the present invention provides various methods for treating cancer by administering Rina-S to a subject, optionally in combination with other anticancer drugs, as described above and below. Alternatively, the present invention also provides various aspects of the treatment methods according to the present invention, wherein Rina-S, optionally in combination with other anticancer drugs, is used for use in the treatment of cancer. In other alternative aspects, the present invention also provides various aspects of the treatment methods according to the present invention, wherein Rina-S, optionally in combination with other anticancer drugs, is used for the preparation of medicaments for the treatment of cancer. In a further aspect, the present invention further provides an agent for the treatment of cancer comprising Rina-S as an active agent, optionally in combination with other anticancer drugs. While the treatment methods are described herein, the present invention also provides corresponding products for use in the methods, and uses of the products for the preparation of medicaments for the methods, and vice versa.

[0023] In embodiments where two of the drugs described herein are mentioned for combined administration, the drugs may be administered, for example, simultaneously, separately, or sequentially. In one embodiment, combined administration of the drugs may mean that they are both administered using the provided method. The drugs may be administered in the same pharmaceutical composition. Alternatively, the drugs may be administered as separate compositions. When the regimen for administering Rina-S is listed herein, any other drug may be administered at the same time point but in a separate composition. In other embodiments, Rina-S and the second drug may be administered in the same composition. In a further embodiment, Rina-S may be administered according to the regimen described herein, but the second drug may be administered according to its own separate regimen.

[0024] Additional features will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following text and the accompanying drawings, or may be learned by the generation or operation of examples. The features of this disclosure can be realized and obtained by practice or by using various aspects of the methods, tools, and combinations described in the detailed examples discussed below. Attached Figure Description

[0025] This disclosure is further described with reference to exemplary embodiments. These exemplary embodiments are described in detail with reference to the accompanying drawings. It should be noted that the drawings are not drawn to scale. These embodiments are non-limiting exemplary embodiments, wherein similar reference numerals in several views of the drawings represent similar structures, and wherein:

[0026] Figure 1 This is a diagram illustrating the design of Study 1, which describes the drug dosage schedule for PRO1184-001.

[0027] Figure 2 This is a graph illustrating the change in tumor burden in the target lesion relative to baseline.

[0028] Figure 3 It is a graph illustrating the percentage change in tumor size over time at each dose level.

[0029] Figure 4 This is a graph illustrating the decrease in CA-125 (cancer antigen 125) levels in each subject.

[0030] Figure 5 This indicates that Rina-S 100 mg / m 2 Group and Rina-S 120 mg / m 2 A graph showing the number of adverse events (TEAEs) that occurred during treatment in the group.

[0031] Figure 6 This is a graph illustrating the optimal changes in target lesions (optimal changes in the sum of tumor diameters relative to baseline) in patients with ovarian cancer and endometrial cancer.

[0032] Figure 7 This indicates the use of Rina 100 mg / m² 2 Or Rina-S 120 mg / m 2 A graph showing the optimal change in target lesions (optimal change in the sum of tumor diameters relative to baseline) in treated ovarian cancer patients.

[0033] Figure 8 This indicates the use of Rina 100 mg / m² 2 Or Rina-S 120 mg / m 2 A graph showing the treatment response over time in patients with ovarian cancer. 120 mg / m² 2 One patient in the cohort with prior somituximab administration was not evaluable for response. Reasons for discontinuation included elevated alanine aminotransferase (n=1; treatment-independent), decreased neutrophil count (n=1; treatment-independent), small bowel perforation (n=1; treatment-independent), and rectal bleeding (n=1; treatment-independent). CR: Complete response, MIRV: Somituximab, OC: Ovarian cancer, PD: Disease progression, PR: Partial response, Rina-S: Rinatabart sesutecan, SD: Stable disease, tx: Treatment.

[0034] Figure 9This indicates that Rina-S 100 mg / m² was administered according to the FRα PS2+ state. 2 Or Rina-S 120 mg / m 2 A graph showing the optimal changes in target lesions (optimal changes in sum of tumor diameters relative to baseline) in treated ovarian cancer patients. FRα: folate receptor, OC: ovarian cancer, PS: positive staining, SoD: sum of diameters, Rina-S: rinatabart sesutecan.

[0035] Figure 10A This is a graph showing the cell viability and drug concentration of human ovarian cancer cell line OVCAR-8 treated with Rina-S alone, carboplatin alone, or a combination of both. Figure 10B This is a graph showing the cell viability and drug concentration of human endometrial cancer cell line HEC-1-A after treatment with Rina-S alone, olaparib alone, or a combination of the two drugs.

[0036] Figure 11 shows a graph of various markers after treatment with eczema or Rina-S on KB cells (a subline of human HeLa cells) or 3LL-FR-α cells (FR-α-expressing mouse Lewis lung cancer cells). Figures 11A to 11C The results of KB cells treated with eczema or Rina-S are shown, where the biomarker measured is extracellular ATP ( Figure 11A ), % of cells positive for calreticulin ( Figure 11B ) and HMGB1 level ( Figure 11C ). Figures 11D to 11F The corresponding results for 3LL-FR-α cells are shown.

[0037] Figure 12 provides a graph of tumor volume in mouse tumor models treated with Rina-S alone or in combination with various other cancer-care drugs, namely carboplatin (“+carbo”), bevacizumab (“+Bev”), olaparib (“+PARP”), and CS1003 (anti-PD-1 antibody, “+IO”). Results for PBS controls are also included in each figure. The xenograft cancer involved in each model is the ovarian cancer cell line OVCAR-8 ( Figure 12A and Figure 12B ), human endometrial cancer cell line HEC-1-A ( Figure 12C ), mouse 3LL-FR-α Lewis lung cancer cells ( Figure 12D ) and mouse colon adenocarcinoma cell line MC-38-FR-α ( Figure 12E ). Detailed Implementation

[0038] The following description is presented to enable any person skilled in the art to make and use this disclosure, and is provided in the context of a particular application and its requirements. Various modifications to the disclosed embodiments will be apparent to those skilled in the art, and the general principles defined herein can be applied to other embodiments and applications without departing from the spirit and scope of this disclosure. Therefore, this disclosure is not limited to the embodiments shown, but should be accorded the widest scope consistent with the claims.

[0039] The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be restrictive. As used herein, the singular forms “a,” “an,” and “the” may also be intended to include the plural forms unless the context clearly indicates otherwise. It will be further understood that, when used in this specification, the terms “comprises,” “comprising,” “includes,” and / or “including” specify the presence of the stated feature, integer, step, operation, element, and / or component, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0040] The operational methods, functions, and manufacturing economics of these and other features and characteristics of this disclosure, as well as combinations of related structural elements and components, become more apparent when considered in conjunction with the accompanying drawings, all of which form part of this specification. However, it should be clearly understood that the drawings are for illustrative and descriptive purposes only and are not intended to limit the scope of this disclosure. It should be understood that the drawings are not drawn to scale.

[0041] For convenience, certain terms in the specification, examples, and claims are defined herein. Unless otherwise stated or implied by context, the following terms and phrases have the meanings provided below. These definitions are provided to aid in describing particular embodiments and are not intended to limit the claimed invention, as the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0042] As used herein, unless otherwise stated, the terms “a” and “an” mean “one,” “at least one,” or “one or more.” Unless the context requires otherwise, singular terms used herein shall include the plural, and plural terms shall include the singular.

[0043] Unless the context explicitly requires otherwise, throughout the specification and claims, the terms "comprise," "comprising," etc., should be interpreted in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is, in the sense of "including but not limited to." When using "comprises," "comprising," or similar wording to describe embodiments, the present invention also provides embodiments that "consist substantially of the described content." The present invention further provides embodiments that "consist of the described content."

[0044] The terms “decreased,” “reduce,” “reduced,” “reduction,” “decrease,” and “inhibit” are generally used in this article to refer to a statistically significant reduction relative to a reference.

[0045] The terms “increased,” “increase,” “enhancement,” or “activation” are used in this document to generally refer to a statistically significant increase relative to a reference.

[0046] The term "about" may, for example, allow for up to 10% variation in the described content. In some embodiments, it may allow up to 5% variation. In some embodiments, it may allow up to 2% variation. In some embodiments, it may allow up to 1% variation. In some embodiments using the term "about," embodiments with precise description of the described content are also provided.

[0047] As used herein, the terms “protein” and “peptide” are used interchangeably to designate a series of amino acid residues, each linked to each other by peptide bonds between adjacent α-amino and carboxyl groups. The terms “protein” and “peptide” also refer to polymers of amino acids, including modified amino acids (e.g., phosphorylated, glycosylated, etc.) and amino acid analogs, regardless of their size or function. “Protein” and “peptide” are generally used to refer to relatively large peptides, while the term “peptide” is generally used to refer to small peptides; however, the usage of these terms overlaps in the art. When referring to encoded gene products and fragments thereof, the terms “protein” and “peptide” are used interchangeably herein. Thus, exemplary peptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments, and other equivalents, variants, fragments, and analogs described above.

[0048] FOLR1, or folate receptor α, is a cell surface protein that binds to folate and reduced folate derivatives and mediates the delivery of 5-methyltetrahydrofolate and folate analogues into the cell. It is also known as FRα, adult folate-binding protein, FBP, folate receptor 1, folate receptor-adult, KB cell FBP, and ovarian tumor-associated antigen MOv18. Human FOLR1 polypeptides include, but are not limited to, those having the amino acid sequence shown by the UniProt identifier P15328-1; this sequence is incorporated herein by reference.

[0049] Antibody-drug conjugates (ADCs) contain an antibody conjugated to a drug. The antibody and drug can be conjugated via any suitable means. This can be done via a linker. Alternatively, the antibody and drug can be conjugated directly to each other. The ADCs discussed herein contain an anticancer drug as the drug component of the ADC.

[0050] Antibodies and antibody-drug conjugates (ADCs)

[0051] In one embodiment, the present invention provides a method for treating solid tumors, comprising administering to a human subject suffering from a tumor an antibody-drug conjugate (ADC) having the characteristics described herein, the ADC comprising an antibody against FOLR1 conjugated to the drug eczema via a hydrophilic linker, wherein the ADC is administered at a dose of 40 mg / m². 2 Up to 200 mg / m 2 The dosage is administered. In some embodiments, the dosage is 60 mg / m². 2 Up to 140 mg / m 2 In some implementations, the dose is 100 mg / m². 2 In some implementations, the dose is 120 mg / m². 2 In any of the embodiments described herein, the tumor may be a solid tumor. In any of the embodiments set forth herein, the ADC used may be Rina-S as detailed herein. As used herein, the term "Rina-S" encompasses embodiments of the ADC described herein, including biosimilars of Rina-S.

[0052] Rinatabart sesutecan (Rina-S; sometimes also referred to as PRO1184), as used herein, is an antibody-drug conjugate (ADC) comprising an antibody against FOLR1 and an eczemacon drug unit, each drug unit being linked to the antibody via a hydrophilic linker. In some embodiments, Rina-S has the following structure (Structure 1):

[0053] ,

[0054] Ab is an antibody that binds to FOLR1 and comprises a heavy chain and a light chain. The heavy chain comprises three CDRs having the amino acid sequence shown in SEQ ID NO: 1 (the corresponding CDRs underlined in the sequences shown below), and the light chain comprises three CDRs having the amino acid sequence shown in SEQ ID NO: 2 (the corresponding CDRs underlined in the sequences shown below). In some embodiments, Ab is an antibody comprising a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 2. In some embodiments, Ab is an IgG1 antibody. In some embodiments, Ab is an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 6 (or optionally further comprising an amino acid sequence with an additional C-terminal lysine (K), i.e., a heavy chain having the amino acid sequence shown in SEQ ID NO: 4) and a light chain having the amino acid sequence shown in SEQ ID NO: 5. In structure 1, n is p load , which is the average drug load (e.g., the ratio of drug to antibody; or DAR). In some embodiments, n is 8.

[0055] In some embodiments, the ADC comprises an antibody component containing an Fc domain or region having one or more amino acid substitutions that weaken IgG Fc receptor (FcγR) binding (compared to the IgG1 constant region having the amino acid sequence shown in SEQ ID NO: 3), such as substitutions at positions 234 and 235 of the Fc region (EU numbers of the residues). In some embodiments, according to the Kabat EU number, the substitution is L234A and L235A (LALA). In some alternative forms, according to the Kabat EU number, the Fc domain may contain D265A and / or P329G in an Fc region derived from the human IgG1 Fc region. In some embodiments, according to the Kabat EU number, the substitution is L234A, L235A, and P329G in an Fc region derived from the human IgG1 Fc region (LALA-PG). (See, for example, WO 2012 / 130831). In some embodiments, according to the Kabat EU designation, the substitution is derived from L234A, L235A, and D265A (LALA-DA) in the Fc region of the human IgG1 Fc region. In some embodiments, the Ab contains a constant region of the κ isotype light chain.

[0056] In some embodiments, the ADC is a biosimilar of Rina-S. As used herein, a “biosimilar” (e.g., of an approved reference product / biologic) refers to a biologic product similar to a reference product based on data from: (a) analytical studies demonstrating a high degree of similarity between the biologic product and the reference product, despite minor differences in clinically inactive components; (b) animal studies (including toxicity assessments); and / or (c) one or more clinical studies (including assessments of immunogenicity and pharmacokinetic or pharmacodynamics) sufficient to demonstrate safety, purity, and potency under appropriate conditions for use where one or more reference products are approved and intended for use and for which approval is sought (e.g., there are no clinically significant differences between the biologic product and the reference product in terms of safety, purity, and potency). In some embodiments, for the conditions of use specified, recommended, or suggested in the proposed label, the biosimilar biologic product and the reference product use the same mechanism of action, but only to the extent that the mechanism of action of the reference product is known. In some embodiments, one or more conditions of use specified, recommended, or suggested in the proposed label for the biologic product have previously been approved for use in the reference product. In some implementations, the route of administration, dosage form, and / or potency of the bioproduct are the same as those of the reference product. Biosimilars may be, for example, currently known antibodies having the same primary amino acid sequence as the marketed antibody, but may be prepared in different cell types or through different production, purification, or formulation methods. Biosimilar ADCs are generally structurally highly similar to the reference product, including the antibody moiety, cytotoxic payload, and linker, but may be produced via slightly different manufacturing processes.

[0057] SEQ ID NO: 1 F131 VH amino acid sequence (where three CDRs are underlined):

[0058] EVQLLESGGGVVQPGRSLRLSCAASGFTFS SYGMH WVRQAPGKGLEWVA VISYDGSNKYYADSVKG RFTISRANSKNTLYLQMNSLRAEDTAVYYCAR PRAYYGAYGSSFDY WGQGTQVTVSS

[0059] SEQ ID NO: 2 F131 VL amino acid sequence (where three CDRs are underlined):

[0060] EIVMTQSPSSVSASVGDRVAITC RASQGISSWLA WYQQKPGKAPKLLIY AASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPLT FGGGTKVDIK

[0061] SEQ ID NO: 3 Human IgG1 heavy chain constant region UniProt P01857-1:

[0062] ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKPKDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGKEYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQPENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK

[0063] SEQ ID NO: 4 F131 heavy chain amino acid sequence (including C-terminal K):

[0064] EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRANSKNTLYLQMNSLRAEDTAVYYCARPRAYYGAYGSSFDYWGQGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0065] SEQ ID NO: 5 Amino acid sequence of the light chain of F131:

[0066] EIVMTQSPSSVSASVGDRVAITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0067] SEQ ID NO: 6 Amino acid sequence of the heavy chain of F131 (without C-terminal K):

[0068] EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRANSKNTLYLQMNSLRAEDTAVYYCARPRAYYGAYGSSFDYWGQGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0069] In some embodiments, the heavy chain of the antibody component of Rina-S described herein is free of a C-terminal lysine at the C-terminus of the CH3 region (i.e., the C-terminal lysine corresponding to position 453 of SEQ ID NO: 4 or position 330 of SEQ ID NO: 3). The C-terminal lysine-free heavy chain of SEQ ID NO: 4 is provided as SEQ ID NO: 6. The C-terminal lysine can be removed, for example, by engineering the heavy chain to be C-terminal lysine-free, or by removing the C-terminal lysine (e.g., with a carboxypeptidase, for example, during antibody production or processing). Thus, in some embodiments, the heavy chain of the antibody component of Rina-S has the amino acid sequence of SEQ ID NO: 6. For any aspect and embodiment of the invention, the heavy chain of the antibody component may therefore comprise either SEQ ID NO: 6 or SEQ ID NO: 4.

[0070] In some embodiments, the antibody component of Rina-S is the F131 antibody of PCT application WO / 2022 / 217022. WO / 2022 / 217022 is incorporated herein by reference in its entirety. WO / 2022 / 217022 is also incorporated herein specifically with respect to the antibody disclosed therein, and particularly with respect to F131 and related antibodies.

[0071] In some implementations, the average DAR (drug-antibody ratio) of Rina-S is approximately 8.

[0072] In various embodiments, the present invention relates to the treatment of cancer with the ADC provided herein. In some embodiments, the ADC comprises an antibody or antibody fragment having a VH region and a VL region having the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2. The ADC comprises a pharmaceutical unit (ecientecan). The ADC comprises a linker for attaching the pharmaceutical unit to the antibody or antibody fragment. In some embodiments, the linker comprises a polar unit having the following structure (structure 2):

[0073]

[0074] In some implementations, the connector is derived from a connector compound having the following structure (structure 3):

[0075]

[0076] The H on the benzyl OH group is optionally replaced by a bond with one of the pharmaceutical units (ethitecan).

[0077] In some embodiments, the ADC of the present invention has an average DAR of about 4, about 6, or about 8. In some embodiments, the ADC has an average DAR of about 8.

[0078] In various embodiments, the present invention relates to the treatment of cancer with Rina-S or other ADCs as described above or disclosed in PCT applications WO2023280227 and WO2022217022. Both are disclosed in their entirety and specifically with respect to Rina-S and ADCs.

[0079] In any of the embodiments described herein, the preferred ADC is Rina-S or a biosimilar thereof. In a particularly preferred embodiment, Rina-S (or a biosimilar thereof) has the following structure:

[0080] ,

[0081] Ab is an antibody comprising a heavy chain and a light chain, the heavy chain and the light chain having the amino acid sequences shown in SEQ ID NO: 6 and SEQ ID NO: 5, respectively, and wherein n is 8. In one embodiment, Ab has two such heavy chains as in SEQ ID NO: 6 and two such light chains as in SEQ ID NO: 5. In some embodiments, Rina-S may replace the heavy chain sequence shown in SEQ ID NO: 6 and comprise the heavy chain sequence shown in SEQ ID NO: 4 (i.e., having an additional C-terminal lysine). In some embodiments, Rina-S (or a biosimilar thereof) is formulated into a pharmaceutical composition according to the invention that can be administered to a subject, and the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0082] Patients and Cancer Types

[0083] In various embodiments, the present invention relates to a method of treating cancer, such as, but not limited to, solid tumors; the method comprising administering ADC Rina-S to a human subject, wherein the ADC is at a concentration of 40 mg / m². 2 Up to 200 mg / m 2 Administer at the prescribed dosage. Here, "m" 2 "(square meters) is a measurement of the patient's body surface area (BSA)."

[0084] In some embodiments, the method of the present invention can be used to treat solid tumors. In some embodiments, the subject has multiple solid tumors. In some embodiments, the subject has multiple solid tumors because the cancer has metastasized. In some embodiments, the solid tumor is a primary tumor. In some embodiments, the solid tumor is a secondary tumor. In some embodiments, the subject has multiple solid tumors, including both primary and secondary solid tumors. In some embodiments, the solid tumor is present in a subject with cancer selected from the group consisting of: ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is platinum-resistant ovarian cancer (PROC). In some embodiments, the solid tumor is platinum-sensitive ovarian cancer (PSOC). In some embodiments, the solid tumor can be ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the solid tumor can be primary peritoneal cancer. In some embodiments, the solid tumor can be fallopian tube cancer. In some embodiments, the solid tumor can be endometrial cancer. In some embodiments, the solid tumor can be lung cancer, such as non-small cell lung cancer (NSCLC). In some embodiments, the solid tumor may be breast cancer, including HER2-negative breast cancer. In some embodiments, the solid tumor may be mesothelioma. In some embodiments, the solid tumor may be pleural mesothelioma or peritoneal mesothelioma. In some embodiments, the method of the present invention can be used to treat FOLR1-positive cancers (e.g., solid tumors). As used herein, a tumor being “FOLR1-positive” means that at least a portion of the tumor cells express FOLR1 protein that can be detected by standard methods such as immunohistochemistry (IHC); cells being “FOLR1-positive” means that the cells express FOLR1 protein that can be detected by standard methods such as IHC. In some embodiments, FOLR1 expression in the tumor is determined by applying a regulatory-approved test (e.g., the FDA-approved Ventana FOLR1-2.1 RxDx Assay or its local equivalent) to the tumor sample. In some embodiments, at least 10%, 15%, 20%, 25%, 30%, 40%, or 50% of the cells in the sample from the tumor are FOLR1-positive. In some embodiments, at least 25% of the cancer cells in a sample of a solid tumor from a human subject are FOLR1 positive. In some embodiments, at least 75% of the cancer cells in a sample of a solid tumor from a human subject are FOLR1 positive. In some embodiments, less than 75% of the cancer cells in a sample of a solid tumor from a human subject are FOLR1 positive. In some embodiments, less than 25% of the cancer cells in a sample of a solid tumor from a human subject are FOLR1 positive.In some embodiments, tumors in human subjects exhibit high FOLR1 expression, identified in IHC assays such as the Ventana FOLR1 (FOLR1-2.1) RxDx Assay as an FRα membrane staining intensity ≥2+ (“PS2+”) in ≥75% of tumor cells. In some embodiments, tumors in human subjects exhibit moderate FOLR1 expression, identified in IHC assays such as the Ventana FOLR1 (FOLR1-2.1) RxDx Assay as an FRα membrane staining intensity ≥1+ (“PS1+”) in ≥25% of tumor cells and PS2+ in <75% of tumor cells. In some embodiments, tumors in human subjects exhibit low FOLR1 expression, identified in IHC assays such as the Ventana FOLR1 (FOLR1-2.1) RxDx Assay as PS1+ in <25% of tumor cells. In some embodiments, the human subject is treated with Rina-S according to the invention before the percentage of FOLR1-positive cancer cells in a solid tumor sample of the human subject has been determined; in some embodiments, the human subject has ovarian cancer.

[0085] In some embodiments, the method of the present invention can be used to treat localized cancers (e.g., solid tumors). In some embodiments, the method of the present invention can be used to treat metastatic cancers (e.g., solid tumors). In some embodiments, the patient has an advanced solid tumor. In some embodiments, the patient has a locally advanced tumor. In some embodiments, the tumor has spread, causing the patient to have a secondary solid tumor in addition to the primary tumor. In some embodiments, the tumor is not surgically removable, i.e., the tumor is unresectable. In some embodiments, the tumor has both of the following characteristics: it has spread (the cancer is metastatic) and at least one unresectable solid tumor is present.

[0086] In some implementations, the subject may have high-grade epithelial ovarian cancer. In some implementations, the subject may have high-grade serous ovarian cancer.

[0087] In some embodiments described herein, the subject may have a platinum-resistant tumor. In some embodiments, the subject may have high-grade serous or endometrioid EOC (epithelial ovarian cancer), primary peritoneal cancer, or fallopian tube cancer that is resistant to platinum-based chemotherapy. In a preferred embodiment, the subject has platinum-resistant ovarian cancer. Alternatively, the subject may have a platinum-sensitive tumor. In some embodiments, the subject may have platinum-sensitive ovarian cancer.

[0088] In some implementations, the subject to treatment has a histologically or cytologically confirmed metastatic or unresectable solid malignancy. In some implementations, the subject has ovarian cancer, including epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some implementations, the subject has endometrial cancer. In some implementations, the subject has non-small cell lung cancer (NSCLC). In some implementations, the subject has EGFR-mutant NSCLC. In some implementations, the subject has breast cancer. In some implementations, the subject has hormone receptor-positive, HER2-negative, or triple-negative breast cancer. In some implementations, the subject has mesothelioma. In one implementation, the cancer is selected from histologically or cytologically confirmed metastatic or unresectable solid malignancies, including ovarian cancer (must be epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer), endometrial cancer, non-small cell lung cancer, epidermal growth factor receptor (EGFR)-mutant NSCLC, breast cancer (hormone receptor-positive, HER2-negative, and triple-negative), and mesothelioma.

[0089] In some implementations, subjects to be treated are selected from those with high-grade severe ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (specifically excluding those with endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma, low-grade carcinoma, and those with sarcoma or neuroendocrine elements).

[0090] In one embodiment, the patient's FRα expression status has been determined, for example using the Ventana FOLR1-2.1RxDx Assay. In one embodiment, the patient has high FRα expression (i.e., FRα expression ≥75% PS2+), for example as measured using the Ventana FOLR1-2.1 RxDx Assay. In another embodiment, the patient does not have high FRα expression, and specifically has FRα expression <75% PS2+, for example as measured using the Ventana FOLR1-2.1 RxDx Assay. In yet another embodiment, the patient has FRα expression <25% PS2+, for example as measured using the Ventana FOLR1-2.1RxDx Assay. In some embodiments, the patient's FRα expression status has not been determined. In such embodiments, the patient can be treated with Rina-S according to the invention without a pre-determined FRα expression status (e.g., in patients with ovarian cancer).

[0091] In some embodiments, the method of the present invention may include the step of determining whether a tumor expresses FOLR1. In other embodiments, it may include the step of determining the expression level of FOLR1. In other embodiments, it may exclude any of those steps. In some embodiments, the human subject has ovarian cancer. In some embodiments, the patient has been pretreated with other therapies targeting the tumor, such as at least one, two, three, four, or more lines of therapy. In some embodiments, at 100 mg / m²... 2 Patients are treated with ADCs (especially Rina-S) at dose levels that are appropriate for their condition. In some implementations, the dose is 120 mg / m². 2 The patient is treated with an ADC (especially Rina-S) at a dose level. In some embodiments, the dose is administered to the patient approximately every three weeks (Q3W). In some embodiments, the ADC (especially Rina-S) is administered intravenously.

[0092] In some implementations, the presence or absence of FOLR1 expression is not determined beyond the determination of the presence or absence of any FOLR1 expression. In some implementations, the level of FOLR1 expression in the solid tumor is not determined at all prior to treatment. For example, since most ovarian cancers exhibit FOLR1 expression, a subject with ovarian cancer can be treated according to the invention without certainty about the presence or absence or level of FOLR1 expression, because there is a high chance that the tumor will express FOLR1, and also because the exact level of FOLR1 expression may be less important for Rina-S than for other cancer drugs.

[0093] In one embodiment, a patient with one of the cancer types described herein is treated without any determination of whether the solid tumor exhibits FOLR1 expression. In some embodiments, the human subject has ovarian cancer. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least one, two, three, four, or more lines of therapy. In some embodiments, a dose level of 100 mg / m² is used. 2 ADCs (especially Rina-S) were used to treat human subjects. In some implementations, at 120 mg / m²... 2 The human subjects are treated with an ADC (particularly Rina-S) at dose levels. In some embodiments, the dose is administered to the human subject approximately every three weeks (Q3W). In some embodiments, the ADC (particularly Rina-S) is administered intravenously.

[0094] Dosage, dosing regimen, route of administration and patient assessment

[0095] In some embodiments, the dose range of the ADC (e.g., Rina-S) for treating cancer (e.g., solid tumors) in this invention can be 40 mg / m². 2 Up to 200 mg / m 2 In some implementations, the dosage range can be 60 mg / m². 2 Up to 180 mg / m 2 In some implementations, the dose is 40 mg / m². 2 60 mg / m 2 100 mg / m 2 120 mg / m 2 140 mg / m 2 Or 180 mg / m 2 In some implementations, the dose may be 60 mg / m². 2 -180 mg / m 2 100 mg / m 2 -140 mg / m 2 100mg / m 2 -120 mg / m 2 In some implementations, the ADC is at 140 mg / m³. 2 The dosage is administered. In some embodiments, the dosage is approximately 60 mg / m². 2 In some implementations, the dosage is approximately 100 mg / m². 2 In some implementations, the dosage is approximately 120 mg / m². 2 In mg / m 2 The dose expressed is based on the patient's body surface area (BSA), which can be calculated using the Mosteller equation (in m²). 2 The calculated BSA is √(height (cm)). Weight(kg) / 3600))

[0096] In some implementations, the ADC (e.g., Rina-S) may be administered once a week, twice a week, or every other week. Dosing schedules may include the following treatment cycles: two consecutive weeks of therapy followed by one, two, three, or four weeks of rest; or alternating therapy and rest weeks; or one week of therapy followed by two, three, or four weeks of rest; or three weeks of therapy followed by one, two, three, or four weeks of rest; or four weeks of therapy followed by one, two, three, or four weeks of rest; or five weeks of therapy followed by one, two, three, four, or five weeks of rest; or administration every two weeks, every three weeks, or monthly. Treatment can be extended to any number of cycles, such as at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 16, or at least 20 cycles (e.g., 2-20 cycles, 2-16 cycles, 2-10 cycles, 2-4 cycles, 4-20 cycles, 4-16 cycles, 4-10 cycles, 6-20 cycles, 6-16 cycles, 6-10 cycles, 8-20 cycles, 8-16 cycles, 8-10 cycles, 10-20 cycles, 10-16 cycles, 10-20 cycles, 12-16 cycles, or 16-20 cycles or more than 20 cycles). In some embodiments, the ADC dose is administered to the human subject on day 1 of a 21-day treatment cycle. In some embodiments, the ADC is administered every 2 to 4 weeks. In some embodiments, the ADC is administered approximately every 3 weeks. In some embodiments, the ADC is administered every 3 weeks. Dosing every 3 weeks can also be called Q3W.

[0097] In some implementations, the ADC dose is administered to human subjects as an intravenous (IV) infusion over 10, 20, 30, 40, 50, or 60 minutes. In some implementations, the ADC dose is administered to human subjects as an intravenous (IV) infusion over 30 minutes.

[0098] In some embodiments, treatment with an ADC results in a reduction of at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50% in the size of the solid tumor. In some embodiments, treatment with an ADC results in a reduction of at least 15% in the size of the solid tumor. In some embodiments, treatment with an ADC results in a reduction of at least 20% in the size of the solid tumor. In some embodiments, treatment with an ADC results in a reduction of at least 25% in the size of the solid tumor. In some embodiments, treatment with an ADC results in a reduction of 15%-90%, such as 15%-75%, 15%-50%, 15%-40%, 15%-30%, 30%-90%, 30%-75%, 30%-50%, 30%-40%, 40%-90%, 40%-75%, 40%-50%, 50%-90%, or 50-75% in the size of the solid tumor. General technicians will recognize that a number of factors can be considered in selecting the optimal dose of an ADC, such as age, general health, specific organ function or weight, and the effects of previous therapies on specific organ systems, and that the dose and / or frequency of administration can be increased or decreased during treatment.

[0099] In some embodiments, the treatment of the present invention results in an improved treatment outcome for the subject. This is especially true when the subject has previously failed treatment. In some embodiments, the improved treatment outcome is an objective response selected from disease stabilization, partial response, or complete response. In some embodiments, the improved treatment outcome is disease stabilization, indicating that the progression of the solid tumor has stopped. In some embodiments, the improved treatment outcome is a partial response. In some embodiments, a partial response indicates that the solid tumor size has decreased by at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. In some embodiments, a partial response indicates that the solid tumor size has decreased by at least 30%. As further discussed below, the RECIST version 1.1 criteria can be used to assess tumor size, and in one embodiment, a partial response indicates that the solid tumor size has decreased by at least 20%, at least 25%, at least 30%, at least 40%, or at least 50% according to those criteria. In one embodiment, it has decreased by at least 30% according to those criteria. In some embodiments, the improved treatment outcome is a complete response. In some embodiments, a complete response indicates the absence of detectable cancer. In some embodiments, the improved treatment outcome is a reduced tumor burden. In some embodiments, a reduction in tumor burden indicates a reduction in solid tumor size of at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. In some embodiments, an improved treatment outcome is progression-free survival or disease-free survival. In some embodiments, progression-free survival or disease-free survival is assessed after 1, 2, 3, 4, 5, or 10 years.

[0100] Any appropriate method can be used to assess the tumor and treatment. In some implementations, treatment is assessed according to RECIST v1.1. In implementations where the cancer is pleural mesothelioma, treatment can be assessed using mRECIST v1.1. The RECIST version 1.1 criteria, published by Eisenhauer et al. in the European Journal of Cancer (2009) 228-247, can be used to define the degree of response. Eisenhauer et al. have incorporated this in its entirety and specifically address the RECIST version 1.1 criteria. In some implementations, the best overall response (BOR) can be assessed. In some implementations, the overall response rate (ORR) can be assessed. In some implementations, the disease control rate (DCR) can be assessed. In some implementations, progression-free survival (PFS) can be assessed. In some implementations, overall survival can be assessed. In some implementations, the duration of objective response (DOR) can be assessed.

[0101] The optimized dosage and administration schedule disclosed in this paper demonstrated unexpectedly superior efficacy and reduced toxicity in human subjects, which could not be predicted from animal model studies. This superior efficacy allows for the treatment of tumors previously found to be resistant to one or more standard anticancer therapies.

[0102] Typically, the dose of an ADC (e.g., Rina-S) administered to human subjects can vary depending on factors such as the patient's age, weight, height, sex, general medical condition, and prior medical history. As mentioned above, the dose of Rina-S can be as low as 40 mg / m². 2 Up to 200 mg / m 2 60 mg / m 2 Up to 180 mg / m 2 100 mg / m 2 -140 mg / m 2 100 mg / m 2 -120 mg / m 2 or approximately 60 mg / m 2 or approximately 100 mg / m 2 or approximately 120 mg / m 2 Variations. In some implementations, Rina-S is administered IV on day 1 of a 21-day cycle and may continue until disease progression, unacceptable toxicity, or other reasons for treatment discontinuation. At 140 mg / m² 2 and 180 mg / m 2Dose-limiting toxicities were observed at dose levels, all of which were hematologic cytopenias. Administration schedules may include weekly or twice-weekly administration in cycles selected from the following groups: (i) weekly; (ii) every other week; (iii) one week of treatment followed by a two-, three-, or four-week break; (iv) two weeks of treatment followed by a one-, two-, three-, or four-week break; (v) three weeks of treatment followed by a one-, two-, three-, four-, or five-week break; (vi) four weeks of treatment followed by a one-, two-, three-, four-, or five-week break; (vii) five weeks of treatment followed by a one-, two-, three-, four-, or five-week break; and (viii) monthly. This cycle may be repeated 2, 4, 6, 8, 10, 12, 16, or 20 times. Treatment with the ADC resulted in a reduction in the size of the solid tumor by at least 15%, at least 20%, at least 30%, at least 40%, or at least 50%.

[0103] In some embodiments, subjects treated with the ADC Rina-S according to the invention have previously been treated with other lines of therapy (e.g., 1, 2, 3, 4, 5, 6, or 7 other prior cancer therapies). In some embodiments, subjects with ovarian cancer treated with the ADC Rina-S according to the invention have previously been treated with one or more of bevacizumab, PARP inhibitors, platinum-based chemotherapy (e.g., cisplatin, carboplatin, oxaliplatin), and / or somituximab. In some embodiments, subjects with endometrial cancer treated with the ADC Rina-S according to the invention have previously been treated with a PD-1 inhibitor (e.g., pembrolizumab).

[0104] In one embodiment, the present invention provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² from approximately every three weeks (Q3W) to approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the solid tumor was folate receptor 1 (FOLR1) positive.

[0105] In one embodiment of this method, these doses are administered every 3 weeks (Q3W). In another embodiment, they are administered every 4 weeks (Q4W). In another embodiment, they are administered every 5 weeks (Q5W). In yet another embodiment, they are administered every 6 weeks (Q6W).

[0106] In one embodiment, the present invention provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² from approximately every three weeks (Q3W) to approximately every six weeks (Q6W). 2 The dosage was administered, and the solid tumor was folate receptor 1 (FOLR1) positive.

[0107] In another embodiment, the present invention provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² every three weeks (Q3W) to every six weeks (Q6W). 2 The dosage was administered, and the solid tumor was folate receptor 1 (FOLR1) positive.

[0108] In one embodiment, the present invention provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the solid tumor was folate receptor 1 (FOLR1) positive.

[0109] In one embodiment, the present invention provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the solid tumor was folate receptor 1 (FOLR1) positive.

[0110] These regimens can be specifically administered to subjects with ovarian cancer. In one embodiment, they can be administered to subjects with platinum-resistant ovarian cancer. In an alternative embodiment, they can be administered to subjects with platinum-sensitive ovarian cancer. In yet another embodiment, they can be administered to subjects with endometrial cancer.

[0111] In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² from approximately every three weeks (Q3W) to approximately every six weeks (Q6W).2 Up to 120 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0112] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0113] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0114] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0115] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0116] In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0117] In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0118] In one embodiment, the present invention provides a method of treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0119] In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0120] In other implementations, administration is typically once every 3 weeks (Q3W) in the treatment of breast cancer. Therefore, alternative implementations of Q3W in relation to breast cancer are described below.

[0121] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² from approximately every three weeks (Q3W) to approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0122] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0123] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0124] In other implementations, non-small cell lung cancer (NSCLC) is treated with dosing approximately every 3 weeks (Q3W). Therefore, alternative implementations of Q3W in the treatment of NSCLC are described below.

[0125] In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² from approximately every three weeks (Q3W) to approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0126] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0127] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0128] In other embodiments, administration is performed approximately every 3 weeks (Q3W) in the treatment of mesothelioma. Therefore, alternative embodiments of Q3W in the treatment of mesothelioma are described below.

[0129] In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² from approximately every three weeks (Q3W) to approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0130] In one embodiment, the present invention provides a method of treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0131] In one embodiment, the present invention provides a method of treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every three weeks (Q3W). 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0132] Combination therapy

[0133] In some embodiments of the method of the present invention, the ADC can be used alone or as a combination therapy with one or more therapeutic modalities selected from the group consisting of: unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, local radiotherapy, surgery, and interfering RNA therapy.

[0134] In one embodiment, when an ADC is used in combination with other drugs, they can be administered simultaneously, or the ADC and the other drug can be administered simultaneously, separately, or sequentially. In one embodiment, they can be administered in the same pharmaceutical composition. In an alternative embodiment, the ADC and the other drug can be administered in separate compositions. In one embodiment, although the ADC and the other drug are administered separately, they can be packaged together, for example, in the form of a kit containing both. In one embodiment, an ADC is provided for use in the methods described herein. In an alternative embodiment, the present invention provides for use in the methods described herein with an additional drug, wherein the ADC is also administered. Various regimens involving the administration of the ADC as described herein are listed herein, and the present invention provides such regimens in which a second drug is administered as part of that regimen. For example, the second drug can be administered at the same time as the ADC. Alternatively, the additional drug can be administered according to a standard regimen of the drug. The present invention also provides a regimen of alternating administration of the ADC with other drugs.

[0135] In some implementations, ADCs can be used in combination with platinum-based chemotherapy agents. Examples of such agents include cisplatin, carboplatin, and oxaliplatin. In some implementations, ADCs can be used in combination with carboplatin.

[0136] In some implementations, the ADC can be used in combination with a drug that is a VEGF inhibitor. In some implementations, the ADC is used in combination with bevacizumab.

[0137] In some embodiments, the ADC may be used in combination with immuno-oncology agents. In some embodiments, the ADC may be used in combination with a drug that inhibits PD-1. Non-limiting examples of drugs that inhibit PD-1 include pembrolizumab, nivolumab, nofalimab, and cimiprimab. In some embodiments, the ADC may be used in combination with pembrolizumab. In some embodiments, the ADC may be used in combination with nofalimab. In some embodiments, the ADC may be used in combination with pembrolizumab. In some embodiments, the ADC may be used in combination with a drug that inhibits PD-L1. Non-limiting examples of drugs that inhibit PD-1 include atezolizumab, avelumab, and durvalumab.

[0138] In some implementations, the ADC can be used in combination with a drug that is a PARP inhibitor. In some implementations, the ADC is used in combination with olaparib.

[0139] In a preferred embodiment, the ADC can be used to treat cancers that are unresponsive to standard therapies, such as ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. More preferably, the combination of the ADC with other treatment modalities is more effective than the individual or sum of the effects of the individual treatments. In one embodiment, the combination is synergistic.

[0140] In one embodiment, the ADC as described herein can be used in combination with olaparib. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has endometrial adenocarcinoma. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0141] In one embodiment, the ADC as described herein can be used in combination with carboplatin. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has endometrial adenocarcinoma. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0142] In one embodiment, the ADC as described herein can be used in combination with carboplatin in the treatment of ovarian cancer. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0143] In one embodiment, the ADC as described herein can be used in combination with bevacizumab. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has endometrial adenocarcinoma. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0144] In one embodiment, the ADC as described herein can be used in combination with bevacizumab to treat ovarian cancer. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has endometrial adenocarcinoma. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0145] In one embodiment, the ADC as described herein may be used in combination with immunotherapy. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has endometrial adenocarcinoma. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0146] In one embodiment, the ADC as described herein can be used in combination with immunotherapy. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has ovarian cancer. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0147] In one embodiment, the ADC as described herein can be used in combination with an anti-PD-1 antibody. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has endometrial adenocarcinoma. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least 1, 2, 3, 4 or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0148] In one embodiment, the ADC as described herein can be used in combination with an anti-PD-1 antibody to treat ovarian cancer. In one embodiment, the ADC is Rina-S. In some embodiments, the human subject has been pretreated with other therapies targeting the tumor, such as with at least one, two, three, four, or more lines of therapy. In some embodiments, 100 mg / m² is used. 2 Human subjects were treated with Rina-S at dose levels. In some embodiments, 120 mg / m² was used. 2 Rina-S is administered to human subjects at dose levels. In some embodiments, the dose is administered to human subjects approximately every three weeks (Q3W). In some embodiments, Rina-S is administered intravenously.

[0149] Patient group and medical history

[0150] The subject has previously been treated with at least one anticancer therapy. In one embodiment, the subject may have previously been treated with at least one anticancer therapy that was ineffective in treating cancer. In another embodiment, the subject may have previously been treated with at least one anticancer therapy that was initially effective but has now diminished or ceased to be effective. In some embodiments, the subject may have developed resistance to the prior therapy when administered alone.

[0151] In some implementations, the human subject had previously received one to four anticancer therapies. In some implementations, at least one anticancer therapy included treatment with a chemotherapy agent. In some implementations, at least one anticancer therapy included treatment with at least one anticancer therapy selected from the group consisting of: platinum-based chemotherapy, bevacizumab, a poly-ADP-ribose polymerase (PARP) inhibitor, and somituximab. The human subject had failed to respond to at least one anticancer therapy prior to ADC treatment.

[0152] In some implementations, the subjects to be treated are selected from those with high-grade, severe ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (specifically excluding endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma, low-grade carcinoma, and those with sarcoma or neuroendocrine elements). In some implementations, the subjects are selected from those with such solid tumors, and the subjects have received 1 to 3 lines of therapy with different anticancer therapies (a prior induction plus maintenance regimen is considered one line of therapy, even if the treatment regimen, induction, or maintenance portion was interrupted and / or resumed at a later date without disease progression while on active therapy—a switch / change in regimen solely due to toxicity or participant preference rather than disease progression is not considered a separate line of therapy). In some implementations, when the cancer is ovarian cancer, it is platinum-resistant / refractory ovarian cancer. In some implementations, the subjects have previously received bevacizumab. In some implementations, the subjects have breast cancer with a known or suspected harmful germline BRCA mutation or somatic BRCA mutation (e.g., as determined by an FDA-approved test) and have been treated with a poly-ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the subject has an FRα status based on an FDA-approved test (e.g., the Ventana FOLR1 RxDx Assay)—FRα-positive subjects may have previously received somituximab (MIRV). In some embodiments, the subject is FRα-positive but does not qualify for treatment with MIRV, for example, because FRα expression is too low. In some embodiments, the subject is treated according to the invention when the FRα expression level of the tumor in the subject has not yet been determined by a regulatory (e.g., FDA-approved) test. In some embodiments, it is not determined whether the tumor expresses FRα. For example, a high proportion of the cancer may express FRα, so it is considered unnecessary to determine the presence of FRα or at least not necessary to determine the level of FRα expression. In one embodiment, the cancer in such an embodiment is ovarian cancer.

[0153] In some implementations, the subject has platinum-sensitive ovarian cancer (PSOC) and has received one to three prior lines of therapy, particularly when the prior lines of therapy were platinum-based chemotherapy agents.

[0154] In some implementations, the subject will have platinum-resistant or platinum-refractory cancer. In some implementations, the subject will have high-grade serous or endometrioid EOC, primary peritoneal cancer, or fallopian tube cancer resistant to platinum-based chemotherapy. In some implementations, the subject will have platinum-resistant or platinum-refractory cancer in which the subject has previously received platinum-based chemotherapy. In some implementations, the subject will have received one to two prior lines of such therapy. In some implementations, the subject will have endometrial cancer, and specifically, any subtype of endometrial cancer excluding sarcoma. In some implementations, the subject will have such endometrial cancer and has received prior platinum-based chemotherapy for recurrent or advanced disease. In some implementation schemes, any subject mentioned in this paragraph will not have any of the following: (i) other malignancies within the past 3 years; (ii) active central nervous system (CNS) metastases (including treated, stable CNS metastases); (iii) uncontrolled grade 3 or higher infection within 2 weeks of starting treatment; (iv) a positive test for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV); (v) a history of steroid-required (non-infectious) interstitial lung disease (ILD) / pneumonia within the past 2 years, currently have ILD / pneumonia, or be unable to rule out suspected ILD / pneumonia by imaging at screening; (v) use of a strong CYP3A inhibitor (dose escalation only) within 14 days; or (vi) prior therapy with an antibody-drug conjugate based on a topoisomerase 1 inhibitor.

[0155] In one implementation, the subject will have histologically or cytologically confirmed high-grade serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In one implementation, such subjects will have received 1 to 4 prior lines of treatment. In a preferred implementation, the patient will have received at least one of the following:

[0156] a) Platinum-based chemotherapy

[0157] b) Obevacizumab, unless the patient has a documented contraindication.

[0158] c) Poly(ADP-ribose) polymerase (PARP) inhibitors (for patients with known or suspected harmful germline or somatic BRCA mutations)

[0159] d) Somituximab, under the following conditions:

[0160] i. Somituximab is available in the region where enrollment took place, and

[0161] ii. The patient meets the criteria based on positive FRα expression according to an FDA-approved (or locally equivalent) test, and

[0162] iii. Undocumented medical exceptions for the patient, including chronic corneal conditions, history of corneal transplantation, or active ocular conditions requiring ongoing treatment / monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injection, active diabetic retinopathy with macular edema, macular degeneration, presence of optic disc edema, and / or monocular vision.

[0163] In one implementation, a patient who has received only one line of platinum-based therapy will have received at least four cycles of platinum-based therapy and must have had a response (complete response [CR] or partial response [PR]) or have unmeasurable disease at the start of platinum-based therapy, and then have progressed between >91 days and ≤183 days after the last platinum dosing date. In another implementation, a patient who has received two to four lines of platinum-based therapy will have progressed on or within 183 days of the last platinum dosing date.

[0164] In one implementation, the subject will not meet one or more of the following exclusion criteria (especially if the subject is being treated with PROC):

[0165] • Prior therapy using antibody-drug conjugates containing topoisomerase 1 inhibitors.

[0166] • Patients with primary platinum-refractory disease, defined as ovarian cancer that is unresponsive to first-line platinum-based regimens (CR or PR) or progresses ≤91 days after the last dose.

[0167] • A history of another malignancy within 3 years prior to the first dose of Rina-S, or any evidence of residual disease from a previously diagnosed malignancy. Malignancies with negligible risk of metastasis or death (e.g., 5-year OS ≥90%) are excluded, including but not limited to adequately treated cervical carcinoma in situ, non-melanoma skin cancer, ductal carcinoma in situ, or stage I uterine cancer.

[0168] • Known active central nervous system metastases or carcinomatous meningitis. Patients with previously treated brain metastases may participate if they are clinically stable for at least 4 weeks prior to study entry after treatment for the brain metastases, have no new or expanding brain metastases, and have discontinued prescribed corticosteroids and anticonvulsants for brain metastasis-related symptoms for at least 7 days prior to the first dose of the study drug. Patients with suspected brain metastases at screening may undergo a brain computed tomography (CT) / magnetic resonance imaging (MRI) scan prior to study entry.

[0169] • Hospitalization or clinical symptoms of gastrointestinal obstruction within the past 91 days, or imaging evidence of gastrointestinal obstruction at the time of screening. Enrollment of patients currently requiring parenteral nutrition must be discussed with the study medical monitor to determine eligibility.

[0170] • Ascites requiring frequent paracentesis (more than once every 4 weeks) for symptom management. Enrollment of patients with indwelling peritoneal catheters must be discussed with the medical monitor to determine eligibility.

[0171] In one implementation, the subject may have a specific level of FRα expression, such as as measured by the Ventana FOLR1-2.1 RxDx Assay. In one implementation, the subject does not have a tumor with high FRα expression according to the Ventana FOLR1-2.1 RxDx Assay (or a local equivalent test); for example, a patient may have <75% PS2+ FRα expression. In one implementation, the subject has <25% PS2+ FRα expression. In one implementation, the subject has a tumor with indeed high FRα expression according to the Ventana FOLR1-2.1 RxDx Assay, and specifically ≥75% PS2+ FRα expression levels. In one implementation, the subject has ≥75% PS2+ FRα expression levels according to the Ventana FOLR1-2.1 RxDx Assay and has not previously received somituximab.

[0172] In one implementation, the subject has a tumor expressing FRα, further defined by whether the subject has previously been treated with somituximab. In one implementation, the subject is somituximab-naïve and has non-high FRα expression [i.e., <75% PS2+]. In one implementation, the subject is somituximab-naïve and has high FRα expression [i.e., ≥75% PS2+]. In one implementation, the subject has previously been treated with somituximab.

[0173] In one implementation scheme, the subject will have received 1 to 4 lines of prior therapy, which must include platinum-based chemotherapy, bevacizumab, and / or somituximab.

[0174] Other implementation plans

[0175] The following sections describe several illustrative implementation schemes.

[0176] In one embodiment, the present invention provides a method for treating epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma, the method comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 40 mg / m². 2 Up to 200 mg / m 2 The dosage is administered, and the solid tumor is folate receptor 1 (FOLR1) positive. In one embodiment, the dosage is approximately 100 mg / m². 2 Approximately 140 mg / m 2 In one embodiment, the dose is approximately 110 mg / m². 2 Approximately 130 mg / m 2 In one implementation, the dose is approximately 120 mg / m². 2 .

[0177] In one embodiment, the present invention provides a method for treating a subject with high-grade serous or endometrioid EOC, primary peritoneal cancer, or fallopian tube cancer that is resistant to platinum-based chemotherapy, the method comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to the subject with a solid tumor, wherein the ADC is administered at a dose of 40 mg / m². 2 Up to 200 mg / m 2 The dosage is administered, and the solid tumor is folate receptor 1 (FOLR1) positive. In one embodiment, the dosage is approximately 100 mg / m². 2 Approximately 140 mg / m 2 In one embodiment, the dose is approximately 110 mg / m². 2 Approximately 130 mg / m 2 In one implementation, the dose is approximately 120 mg / m². 2 .

[0178] In one embodiment, the present invention employs a dosing regimen approximately every four weeks. In another embodiment, a dosing regimen of four weeks (Q4W) is employed. Therefore, further embodiments employing Q4W are described below.

[0179] In one embodiment, the present invention further provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m². 2 Up to 120 mg / m 2The dose is administered approximately every four weeks (Q4W), and the solid tumor is folate receptor 1 (FOLR1) positive.

[0180] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 Up to 120 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0181] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0182] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0183] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 Up to 100 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0184] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0185] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 Up to 120 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0186] In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0187] In one embodiment, the present invention provides a method of treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 Up to 120 mg / m 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0188] In one embodiment, the present invention provides a method of treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0189] In one embodiment, the present invention provides a method of treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0190] In one embodiment, the present invention employs a dosing regimen approximately every 5 weeks. In another embodiment, a dosing regimen of 5 weeks (Q5W) is employed. Therefore, further embodiments employing Q5W are described below.

[0191] In one embodiment, the present invention further provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m². 2 Up to 120 mg / m 2 The dose is administered approximately every five weeks (Q5W), and the solid tumor is folate receptor 1 (FOLR1) positive.

[0192] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 Up to 120 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0193] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0194] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0195] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 Up to 100 mg / m 2The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0196] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0197] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 Up to 120 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0198] In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0199] In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 Up to 120 mg / m 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0200] In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0201] In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0202] In one embodiment, the present invention employs a dosing regimen approximately every 6 weeks. In another embodiment, a dosing regimen of 6 weeks (Q6W) is employed. Therefore, further embodiments employing Q6W are described below.

[0203] In one embodiment, the present invention further provides a method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m². 2 Up to 120 mg / m 2 The dose is administered approximately every six weeks (Q6W), and the solid tumor is folate receptor 1 (FOLR1) positive.

[0204] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0205] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0206] In one embodiment, the present invention provides a method of treating ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every six weeks (Q6W). 2The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0207] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 Up to 100 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0208] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0209] In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0210] In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the ovarian cancer was folate receptor 1 (FOLR1) positive.

[0211] In one embodiment, the present invention provides a method of treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 Up to 120 mg / m 2The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0212] In one embodiment, the present invention provides a method of treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0213] In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the endometrial cancer was folate receptor 1 (FOLR1) positive.

[0214] This invention can also be used to treat breast cancer.

[0215] In one embodiment, the present invention uses a dosing regimen approximately every 4 weeks in the treatment of breast cancer. In another embodiment, a dosing regimen of 4 weeks (Q4W) is used in the treatment of breast cancer. Therefore, further embodiments of Q4W dosing related to breast cancer are described below.

[0216] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 Up to 120 mg / m 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0217] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0218] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0219] In one embodiment, the present invention uses a dosing regimen approximately every 5 weeks in the treatment of breast cancer. In another embodiment, a dosing regimen of 5 weeks (Q4W) is used in the treatment of breast cancer. Therefore, further embodiments of Q4W dosing related to breast cancer are described below.

[0220] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 Up to 120 mg / m 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0221] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0222] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0223] In one embodiment, the present invention uses a dosing regimen approximately every 6 weeks in the treatment of breast cancer. In another embodiment, a dosing regimen of 6 weeks (Q6W) is used in the treatment of breast cancer. Therefore, further embodiments of Q6W dosing in relation to breast cancer are described below.

[0224] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0225] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0226] In one embodiment, the present invention provides a method of treating breast cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the breast cancer was folate receptor 1 (FOLR1) positive.

[0227] This invention can also be used to treat NSCLC cancer.

[0228] In one embodiment, the present invention employs a dosing regimen approximately every 4 weeks in the treatment of NSCLC cancer. In another embodiment, a dosing regimen of 4 weeks (Q4W) is employed in the treatment of NSCLC cancer. Therefore, further embodiments of Q4W dosing in relation to NSCLC cancer are described below.

[0229] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 Up to 120 mg / m 2 The dosage was administered, and NSCLC cancer is folate receptor 1 (FOLR1) positive.

[0230] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0231] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0232] In one embodiment, the present invention employs a dosing regimen approximately every 5 weeks in the treatment of NSCLC cancer. In another embodiment, a dosing regimen of 5 weeks (Q4W) is employed in the treatment of NSCLC cancer. Therefore, further embodiments of Q4W dosing in relation to NSCLC cancer are described below.

[0233] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 Up to 120 mg / m 2 The dosage was administered, and NSCLC cancer is folate receptor 1 (FOLR1) positive.

[0234] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0235] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0236] In one embodiment, the present invention uses a dosing regimen approximately every 6 weeks in the treatment of NSCLC cancer. In another embodiment, a dosing regimen of 6 weeks (Q6W) is used in the treatment of NSCLC cancer. Therefore, further embodiments of Q6W dosing related to NSCLC cancer are described below.

[0237] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and NSCLC cancer is folate receptor 1 (FOLR1) positive.

[0238] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0239] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0240] This invention can also be used to treat mesothelioma.

[0241] In one embodiment, the present invention uses a dosing regimen approximately once every four weeks in the treatment of mesothelioma. In another embodiment, a dosing regimen of once every four weeks (Q4W) is used in the treatment of mesothelioma. Therefore, further embodiments of Q4W dosing in relation to mesothelioma are described below.

[0242] In one embodiment, the present invention provides a method of treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 Up to 120 mg / m 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0243] In one embodiment, the present invention provides a method of treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0244] In one embodiment, the present invention provides a method of treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every four weeks (Q4W). 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0245] In one embodiment, the present invention uses a dosing regimen approximately once every 5 weeks in the treatment of mesothelioma. In another embodiment, a dosing regimen of once every 5 weeks (Q5W) is used in the treatment of mesothelioma. Therefore, further embodiments of Q5W dosing in relation to mesothelioma are described below.

[0246] In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 Up to 120 mg / m 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0247] In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0248] In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every five weeks (Q5W). 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0249] In one embodiment, the present invention uses a dosing regimen approximately once every 6 weeks in the treatment of mesothelioma. In another embodiment, a dosing regimen of once every 6 weeks (Q6W) is used in the treatment of mesothelioma. Therefore, further embodiments of Q6W dosing in relation to mesothelioma are described below.

[0250] In one embodiment, the present invention provides a method of treating mesothelioma, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 Up to 120 mg / m 2 The dosage was administered, and the mesothelioma was folate receptor 1 (FOLR1) positive.

[0251] In one embodiment, the present invention provides a method of treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 100 mg / m² approximately every six weeks (Q6W). 2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0252] In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering an antibody-drug conjugate (ADC) rinatabartsesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 120 mg / m² approximately every six weeks (Q6W).2 The dosage was administered, and the NSCLC cancer was folate receptor 1 (FOLR1) positive.

[0253] Implementation plans for other numbers

[0254] The following describes the embodiments of the present invention:

[0255] 1. A method of treating solid tumors, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject suffering from a solid tumor, wherein the ADC is administered at a dose of 40 mg / m². 2 Up to 200 mg / m 2 The dosage was administered, and the solid tumor was folate receptor 1 (FOLR1) positive.

[0256] 2. According to the method of [1], wherein solid tumors are selected from the group consisting of: ovarian cancer, endometrial cancer, breast cancer, lung cancer and mesothelioma.

[0257] 3. According to the method of [1], the solid tumor is ovarian epithelial carcinoma, primary peritoneal carcinoma or fallopian tube carcinoma.

[0258] 4. According to the method of [1], the solid tumor is endometrial cancer.

[0259] 5. According to the method of [1], the solid tumor is non-small cell lung cancer (NSCLC).

[0260] 6. According to the method of [1], where the solid tumor is breast cancer, including HER2-negative breast cancer.

[0261] 7. According to the method of [1], wherein the solid tumor is pleural mesothelioma or peritoneal mesothelioma.

[0262] 8. According to the method of [1], wherein the solid tumor is a platinum-resistant tumor.

[0263] 9. According to the method of [8], wherein the solid tumor is a high-grade serous or endometrioid EOC, primary peritoneal carcinoma or fallopian tube carcinoma that is resistant to platinum-based chemotherapy.

[0264] 10. The method according to any one of [1]-[7], wherein the solid tumor is localized or metastatic.

[0265] 11. The method according to any one of [1]-

[10] , wherein at least one tumor is not removable by surgery.

[0266] 12. According to any one of [1]-

[11] , wherein the ADC is at 60 mg / m 2 Up to 180 mg / m2 Dosage administration.

[0267] 13. According to any one of [1]-

[11] , wherein the ADC is at 100 mg / m 2 Up to 140 mg / m 2 Dosage administration.

[0268] 14. According to any one of [1]-

[11] , wherein the ADC is at 100 mg / m 2 Up to 120 mg / m 2 Dosage administration.

[0269] 15. According to any one of [1]-

[11] , wherein the ADC is at approximately 120 mg / m 2 Dosage administration.

[0270] 16. The method according to any one of [1]-

[15] , wherein the ADC dose is administered to a human subject once or twice a week on a schedule selected from the following groups: (i) once a week; (ii) every other week; (iii) one week of treatment followed by a two-week, three-week, or four-week break; (iv) two weeks of treatment followed by a one-week, two-week, three-week, or four-week break; (v) three weeks of treatment followed by a one-week, two-week, three-week, four-week, or five-week break; (vi) four weeks of treatment followed by a one-week, two-week, three-week, four-week, or five-week break; (vii) five weeks of treatment followed by a one-week, two-week, three-week, four-week, or five-week break; and (viii) once a month.

[0271] 17. The method according to any one of [1]-

[15] , wherein the ADC dose is administered to the human subject once a week in a schedule selected from the following groups: (i) once a week; (ii) once every other week; (iii) one week of therapy followed by a two-week, three-week or four-week break.

[0272] 18. The method of any one of

[16] -

[17] , wherein the period is repeated 2, 4, 6, 8, 10, 12, 16 or 20 times.

[0273] 19. The method according to any one of [1]-

[18] , wherein the human subject has previously been treated with at least one anticancer therapy.

[0274] 20. According to the method of

[19] , at least one of the anticancer therapies includes treatment with a chemotherapy agent.

[0275] 21. The method according to any one of

[19] -

[20] , wherein the human subject failed to respond to at least one anticancer therapy prior to ADC treatment.

[0276] 22. The method according to any one of [1]-

[21] , wherein treatment with ADC results in a reduction of at least 15%, at least 20%, at least 30%, at least 40%, or at least 50% in the size of the solid tumor.

[0277] 23. The method according to any one of [1]-

[22] , wherein the ADC is administered in combination with one or more treatment modalities selected from the group consisting of: unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, local radiotherapy, surgery, and interfering RNA therapy.

[0278] 24. The method of any one of [1]-

[23] , wherein the ADC is administered in combination with platinum-based chemotherapy.

[0279] 25. The method according to

[24] , wherein the ADC is administered in combination with carboplatin.

[0280] 26. The method of any one of [1]-

[23] , wherein the ADC is administered in combination with a VEGF-based antagonist-based chemotherapy.

[0281] 27. The method according to

[26] , wherein the ADC is administered in combination with bevacizumab.

[0282] 28. The method of any one of [1]-

[23] , wherein the ADC is administered in combination with a PD-1 inhibitor.

[0283] 29. The method according to

[28] , wherein the ADC is administered in combination with pembrolizumab.

[0284] 30. The treatment outcome of the subject is improved according to any one of [1] to

[29] .

[0285] 31. According to the method of

[30] , wherein the improved treatment outcome is selected from objective responses of disease stability, partial response or complete response.

[0286] 32. According to the method of

[31] , the improved treatment outcome is a reduced tumor burden.

[0287] 33. According to the method of

[31] , the improved treatment outcome is progression-free survival or disease-free survival.

[0288] 34. The method of any one of [1] to

[15] , wherein the ADC dose is administered to a human subject once every three weeks.

[0289] 35. A method of treating solid tumors, comprising administering to a human subject with a solid tumor an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) and any of the following: (i) platinum-based chemotherapy, (ii) an anti-angiogenic agent, (iii) a PARP inhibitor, or (iv) an immune checkpoint inhibitor.

[0290] 36. The method according to

[35] includes administering Rina-S and platinum-based chemotherapy to a human subject.

[0291] 37. The method according to

[36] , wherein the platinum-based chemotherapy is selected from carboplatin, cisplatin and oxaliplatin.

[0292] 38. According to the method of

[37] , wherein the platinum-based chemotherapy is carboplatin.

[0293] 39. The method according to

[35] includes administering Rina-S and an anti-angiogenic agent to a human subject.

[0294] 40. According to the method of

[39] , wherein the anti-angiogenic agent is an anti-VEGF antibody.

[0295] 41. According to the method of

[40] , wherein the anti-VEGF antibody is bevacizumab.

[0296] 42. The method according to

[35] includes administering Rina-S and PARP inhibitors to human subjects.

[0297] 43. According to the method of

[42] , wherein the PARP inhibitor is olaparib.

[0298] 44. The method according to

[35] includes administering Rina-S and an immune checkpoint inhibitor to a human subject.

[0299] 45. According to the method of

[44] , wherein the immune checkpoint inhibitor is an inhibitor of the PD-1 or PD-L1 immune checkpoint protein.

[0300] 46. ​​According to the method of

[45] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0301] 47. According to the method of

[46] , wherein the anti-PD-1 antibody is selected from the group consisting of: pembrolizumab, nivolumab, cimipril, dotalimab, refulimab and durvalumab.

[0302] 48. According to the method of

[47] , wherein the anti-PD-1 antibody is pembrolizumab.

[0303] 49. According to the method of

[45] , wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[0304] 50. According to the method of

[49] , wherein the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, avelumab and durvalumab.

[0305] 51. According to the method of any one of

[35] -

[50] , wherein Rina-S is at 60 mg / m 2 Up to 180 mg / m 2 Dosage administration.

[0306] 52. According to the method of any one of

[35] -

[50] , wherein Rina-S is at approximately 100 mg / m 2 Approximately 140 mg / m 2 Dosage administration.

[0307] 53. According to any one of

[35] -

[50] , wherein Rina-S is at 100 mg / m 2 Dosage administration.

[0308] 54. According to any one of

[35] -

[50] , wherein Rina-S is at 120 mg / m 2 Dosage administration.

[0309] 55. The method of any one of [1]-

[54] , wherein Rina-S is administered to the subject via intravenous administration.

[0310] 56. The method of any one of

[35] -

[55] , wherein Rina-S is administered to the subject every three weeks (Q3W).

[0311] 57. The method according to any one of

[35] -

[43] or any one of

[51] -

[56] , wherein the human subject has ovarian cancer.

[0312] 58. The method according to any one of

[35] -

[56] , wherein the human subject has endometrial cancer.

[0313] 59. The method of any one of

[35] or

[44] -

[56] , wherein the subject has lung cancer.

[0314] 60. The method according to any one of

[35] or

[44] -

[56] , wherein the subject has colorectal cancer.

[0315] 61. A method for treating solid tumors, the method comprising administering an antibody-drug conjugate (ADC) to a human subject suffering from a solid tumor, wherein the ADC has a structure (Structure 1):

[0316]

[0317] The Ab is a folate receptor 1 (FOLR1) binding antibody containing a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region and VL region have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is administered at 40 mg / m 2 Up to 200 mg / m 2 Administer at the prescribed dosage.

[0318] 62. A method for treating cancers including solid tumors, the method comprising administering to a human subject with cancer an antibody-drug conjugate (ADC) having structure 1, wherein the Ab is a FOLR1-binding antibody comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region and the VL region have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is administered at a dose of 40 mg / m³. 2 Up to 200 mg / m 2 Administer at the prescribed dosage.

[0319] 63. An ADC having structure 1 for use in a method of treating solid tumors, wherein the Ab is a FOLR1-binding antibody comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH and VL regions have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, the method comprising administering the antibody at 40 mg / m 2 Up to 200 mg / m 2 The ADC was administered to subjects with solid tumors at a dose specified in the ADC administration.

[0320] 64. An ADC having structure 1 for use in a method of treating cancers including solid tumors, wherein the Ab is a FOLR1-binding antibody comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH and VL regions have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, the method comprising administering the antibody at 40 mg / m 2 Up to 200mg / m 2 The ADC was administered to subjects with cancer at a dose specified in the instructions.

[0321] 65. Use of the ADC having structure 1 in the preparation of a medicament for treating solid tumors, wherein the Ab is a FOLR1-binding antibody comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH and VL regions have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, wherein the medicament is for use at 40 mg / m 2 Up to 200 mg / m 2 The ADC dose was administered to subjects with solid tumors.

[0322] 66. Use of the ADC having structure 1 in the preparation of a medicament for treating cancers including solid tumors, wherein the Ab is a FOLR1-binding antibody comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH and VL regions have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, wherein the medicament is for use at 40 mg / m 2 Up to 200 mg / m 2 The ADC dose was administered to subjects with cancer.

[0323] 67. The method of any one of

[61] -

[66] , for use in the method of the ADC or for any purpose, wherein the solid tumor is folate receptor 1 (FOLR1) positive.

[0324] 68. The method of

[67] , the ADC used in the method, or the purpose thereof, wherein the solid tumor has been determined to be FOLR1 positive by a regulatory-approved test prior to administration of the ADC to a human subject.

[0325] 69. The method of any of

[61] -

[66] , the ADC used in the method, or the purpose thereof, wherein there is no step of determining the FOLR1 expression level prior to administration of the ADC to a human subject.

[0326] 70. The method of any one of

[61] -

[69] , for use in the method, or for any purpose, wherein the ADC is at 60 mg / m 2 Up to 140 mg / m 2 Administer at the prescribed dosage.

[0327] 71. The method according to any one of

[61] -

[70] , for use in the method, or for any purpose, wherein the ADC is at 100 mg / m 2 Administer at the prescribed dosage.

[0328] 72. The method of any one of

[61] -

[70] , for use in the method, or for any purpose, wherein the ADC is at 120 mg / m2 Administer at the prescribed dosage.

[0329] 73. The method of any one of

[61] -

[72] , the ADC used in the method, or the use thereof, wherein the human subject has cancer selected from the group consisting of: ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma.

[0330] 74. The method of any one of

[61] -

[73] , for use in the method of the ADC or for any purpose in which a human subject has ovarian cancer.

[0331] 75. The method of

[74] , the ADC used in the method, or the use thereof, in which the subject has platinum-resistant ovarian cancer (PROC).

[0332] 76. The method of

[74] , the ADC used in the method, or the use thereof, in which the subject has platinum-sensitive ovarian cancer (PSOC).

[0333] 77. The method of any one of

[61] -

[73] , the ADC used in the method, or the use thereof, wherein the human subject has endometrial cancer.

[0334] 78. The method of any of

[61] -

[77] , for use of an ADC in the method, or for any purpose in which the ADC is administered to the subject once every three weeks (Q3W).

[0335] 79. The method of any one of

[61] -

[78] , for use in the method, or for any purpose, wherein the Ab is an IgG1 antibody comprising an Fc domain having one or more amino acid substitutions that weaken the binding of the IgG Fc receptor (FcγR) compared to the IgG1 constant region having the amino acid sequence shown in SEQ ID NO: 3.

[0336] 80. The method of

[79] , for use in the ADC or purpose, wherein the antibody comprises substituted L234A and L235A (LALA) according to the EU number of Kabat.

[0337] 81. The method of any one of

[61] -

[80] , for use in the method, or for any purpose, wherein Ab comprises the heavy chain comprising SEQ ID NO: 6 and the light chain comprising SEQ ID NO: 5.

[0338] 82. The method of any one of

[61] -

[80] , for use in the method, or for any purpose, wherein Ab comprises the heavy chain comprising SEQ ID NO: 4 and the light chain comprising SEQ ID NO: 5.

[0339] 83. The method, ADC, or use of any of

[61] -

[82] , wherein the method further comprises administering to a human subject any of: (i) platinum-based chemotherapy, (ii) an anti-angiogenic agent, (iii) a PARP inhibitor, or (iv) a checkpoint inhibitor, or wherein the use is for preparing a medicament for administering an ADC to a human subject and further administering to a human subject any of: (i) platinum-based chemotherapy, (ii) an anti-angiogenic agent, (iii) a PARP inhibitor, or (iv) an immune checkpoint inhibitor.

[0340] 84. The method of

[83] , the ADC used in the method, or the use thereof, wherein the method further comprises administering carboplatin to a human subject, or wherein the use thereof is for preparing a medicament for administering ADC and carboplatin to a human subject.

[0341] 85. The method of

[83] , the ADC used in the method, or the use thereof, wherein the method further comprises administering bevacizumab to a human subject, or wherein the use thereof is for preparing a medicament for administering an ADC and bevacizumab to a human subject.

[0342] 86. The method of

[83] , the ADC used in the method, or the use thereof, wherein the method further comprises administering olaparib to a human subject, or wherein the use thereof is for preparing a medicament for administering ADC and olaparib to a human subject.

[0343] 87. The method of

[83] , the ADC used in the method, or the use thereof, wherein the method further comprises administering an anti-PD-1 or anti-PD-L1 antibody to a human subject, or wherein the use thereof is for preparing a medicament for administering an ADC and an anti-PD-1 or anti-PD-L1 antibody to a human subject.

[0344] Example

[0345] abbreviation

[0346] CNS: Central Nervous System

[0347] HIV: Human Immunodeficiency Virus

[0348] IHC: Immunohistochemistry

[0349] EOC: Epithelial Ovarian Cancer

[0350] FRα: Folate receptor α (also known as "FOLR1")

[0351] HER2: Human Epidermal Growth Factor Receptor 2

[0352] HR: Hormone receptor

[0353] NSCLC: Non-small cell lung cancer

[0354] RECIST: Response Evaluation Criteria for Solid Tumors

[0355] TRAE: Treatment-related adverse events

[0356] ECOG: Eastern Cooperative Oncology Group

[0357] Example 1: Patient recruitment in Study 1

[0358] Table 1 shows the inclusion and exclusion criteria for the subjects. 23 patients had already been treated with Rina-S. Table 2 shows patient treatment and demographics.

[0359] Table 1: Inclusion and Exclusion Criteria (Part A Only)

[0360]

[0361] Table 2: Patient Management and Demographics (Patients Treated)

[0362]

[0363] The total number of participants was 23, ranging in age from 43 to 87 years. Of these, 21 were female, 18 were white, 3 were Asian, 1 was black or African American, and 1 was of another race. Table 3 shows the baseline characteristics of the patients.

[0364] Table 3: Baseline disease characteristics of patients (all patients treated)

[0365]

[0366] Example 2: Safety, tolerability, and maximum tolerated dose (MTD) testing of Rina-S

[0367] The objective of this study 1 was to determine the safety, tolerability, and maximum tolerated dose (MTD) of rinatabart sesutecan (Rina-S; PRO1184).

[0368] Figure 1 The study design shown is for the PRO1184-001 drug dosing schedule. Part A (dose escalation) included five tumor types. Part B (dose extension) included four tumor-specific cohorts and one basket cohort. Elevated doses of Rina-S, ranging from 60 mg / m², were administered to five different cancer patients over 21 days. 2 180 mg / m² at the end of the maximum therapeutic dose2 Study 1 included four tumor-specific cohorts and one basket cohort (ovarian cancer).

[0369] Safety assessments included physical examination, vital signs and anthropometric measurements, standard clinical laboratory assessments such as hematology and blood biochemistry, and monitoring for adverse and serious adverse events. Table 4 shows a summary of the safety data.

[0370] Table 4: Summary of Security Data

[0371]

[0372] Rina-S at least up to 120 mg / m² 2 (140 mg / m2 is under evaluation) The condition was well tolerated, with common adverse events including hematologic cytopenia, gastrointestinal adverse events, and fatigue. Most treatment-related adverse events (TRAEs) were mild or moderate. Grade ≥3 treatment-related adverse events occurred in 8 patients (34.8%). Treatment-related serious adverse events (SAEs) occurred in 3 patients, all of which were cytopenia. At 140 mg / m2... 2 and 180 mg / m 2 Dose-limiting toxicities were observed at dose levels, all of which were hematologic cytopenia. No interstitial lung disease / pneumonia, infusion-related reactions, or corneal lesions were observed.

[0373] The most common treatment-related adverse events (AEs) were nausea (n=5), decreased white blood cell count (n=3), and fatigue, decreased lymphocyte count, and decreased neutrophil count (n=2 each); most events were grade 1 or 2. Two patients experienced adverse events at 120 mg / m². 2 Patients treated reported treatment-related grade ≥3 hematological adverse events. No ocular toxicity or interstitial lung disease was observed. No diabetic thromboembolism (DLT) was observed.

[0374] Example 3: Determination of the antitumor activity of Rina-S in Study 1

[0375] Fifteen patients underwent at least one post-baseline tumor assessment. Ten patients were considered evaluable for efficacy (having undergone a baseline scan and at least one post-baseline tumor assessment). Treatment duration ranged from 0.6 weeks to 31.0 weeks. Seventeen of the 23 patients are still on treatment. Figure 2 The best changes in target lesion tumor burden relative to baseline were shown for ovarian cancer and endometrial cancer. Figure 3 The percentage change in tumor size over time is shown for ovarian cancer and endometrial cancer. Figure 4 It showed a decrease in CA-125 levels.

[0376] The overall response rate was 20.0% (95% CI: 2.5, 55.6), with 2 patients having a partial response (including 1 confirmed response) and 4 patients having stable disease. The antitumor response appeared to deepen over time.

[0377] In this large pre-treated patient population, Rina-S demonstrated encouraging antitumor activity across multiple FOLR1 expression levels, and most patients experienced a reduction in target lesions.

[0378] Antitumor activity was observed at two dose levels and in patients with high, intermediate and low FOLR1 expression, including an ongoing confirmed partial response in patients with endometrial cancer and reduced tumor measurements in additional patients.

[0379] Example 4: Recruiting patients from Study 2

[0380] Approximately 530 patients with platinum-resistant ovarian cancer (PROC) from about 90 sites worldwide were randomized. The inclusion and exclusion criteria for subjects are shown below.

[0381] Key inclusion criteria

[0382] • The patient must have high-grade serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer that is confirmed by histology or cytology.

[0383] • Patients must have received 1 to 4 lines of prior therapy.

[0384] • The patient must have received prior treatment with at least one of the following therapies:

[0385] o Platinum-based chemotherapy

[0386] o OBEVID, unless the patient has a documented contraindication.

[0387] Patients with known or suspected harmful germline or somatic BRCA mutations must have already been treated with a poly-ADP-ribose polymerase (PARP) inhibitor.

[0388] o Somituximab, condition:

[0389] ■ Somituximab is available in the regions where enrollment took place, and

[0390] ■ The patient meets the criteria based on positive FRα expression according to an FDA-approved (or locally equivalent) test, and

[0391] ■ Unrecorded medical exceptions for patients include chronic corneal conditions, a history of corneal transplantation, or active ocular conditions requiring continuous treatment / monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injection, active diabetic retinopathy with macular edema, macular degeneration, presence of optic disc edema, and / or monocular vision.

[0392] Note: Diagnostic tests (such as FRα and BRCA) should be performed in a Clinical Laboratory Improvement Amendments (CLIA; or local equivalent) certified laboratory using tests approved by the relevant regulatory agency (FDA or local equivalent).

[0393] • The patient must have platinum-resistant disease:

[0394] o Patients who have only received first-line platinum-based therapy must have received at least 4 cycles of platinum therapy and must have had a response (complete response [CR] or partial response [PR]) or have unmeasurable disease at the start of platinum-based therapy and then have progressed between >91 days and ≤183 days after the date of the last platinum administration.

[0395] o Patients who have received 2 to 4 lines of platinum-based therapy must have progressed on or within 183 days of the date of their last platinum dose.

[0396] Key inclusion criteria

[0397] • Prior therapy using antibody-drug conjugates containing topoisomerase 1 inhibitors.

[0398] • Patients with primary platinum-refractory disease, defined as ovarian cancer that is unresponsive to first-line platinum-based regimens (CR or PR) or progresses ≤91 days after the last dose.

[0399] • A history of another malignant tumor within 3 years prior to the first administration of the study drug, or any evidence of residual disease from a previously diagnosed malignant tumor. Malignant tumors with negligible risk of metastasis or death (e.g., 5-year OS ≥90%) are excluded, including but not limited to adequately treated cervical carcinoma in situ, non-melanoma skin cancer, ductal carcinoma in situ, or stage I uterine cancer.

[0400] • Known active central nervous system metastases or carcinomatous meningitis. Patients with previously treated brain metastases may participate if they are clinically stable for at least 4 weeks prior to study entry after treatment for the brain metastases, have no new or expanding brain metastases, and have discontinued prescribed corticosteroids and anticonvulsants for symptoms related to brain metastases for at least 7 days prior to the first dose of the study drug. Patients with suspected brain metastases at screening should undergo a brain computed tomography (CT) / magnetic resonance imaging (MRI) scan prior to study entry.

[0401] • Hospitalization or clinical symptoms of gastrointestinal obstruction within the past 91 days, or imaging evidence of gastrointestinal obstruction at the time of screening. Enrollment of patients currently requiring parenteral nutrition must be discussed with the study medical monitor to determine eligibility.

[0402] • Ascites requiring frequent paracentesis (more than once every 4 weeks) for symptom management. Enrollment of patients with indwelling peritoneal catheters must be discussed with the medical monitor to determine eligibility.

[0403] The 530 PROC patients comprised the following: approximately 420 patients, including those whose tumors did not show high FRα expression according to the Ventana FOLR1-2.1 RxDx Assay (or local equivalent test) (i.e., FRα expression <75% PS2+), patients previously treated with somituximab, and patients who were not candidates for somituximab due to their medical condition; and approximately 110 patients with high FRα expression (i.e., FRα expression ≥75% PS2+), who had not previously received somituximab, but were enrolled in regions where somituximab was not an available therapy.

[0404] Example 5: Test samples, dosage, and administration method of Study 2

[0405] Rinatabart Sesutecan (Rina-S): Rina-S will be administered on day 1 of a 21-day treatment cycle. Rina-S will be administered as a 30-minute intravenous (IV) infusion.

[0406] Investigator-selective (IC) therapy: The patient will receive one of the following chemotherapy regimens for a 4-week period, at the investigator's discretion: Paclitaxel 80 mg / m² administered via 1-hour IV infusion every 4 weeks (Q4W) on days 1, 8, and 15. 2 Topotecan 1.25 mg / m² was administered via 30-minute IV infusion on days 1, 8, and 15. 2 Alternatively, topotecan 4 mg / m² can be administered via 30-minute IV infusion on days 1–5. 2 Q4W: Pegylated liposomal doxorubicin (PLD) 40 mg / m² administered via IV infusion at 1 mg / min on day 1. 2 After the first cycle, the drug can be delivered as follows: as a 1-hour infusion; and as a 30-minute IV infusion of gemcitabine 1000 mg / m² on days 1, 8, and 15 (Q4W). 2 or 800 mg / m 2 The researcher shall decide at their discretion.

[0407] The treatment period is estimated to be 4 to 6 months (the expected duration of treatment varies from patient to patient). Patients will continue to receive the investigational drug until the first occurrence of disease progression, unacceptable toxicity, investigator's decision, withdrawal of consent, pregnancy, death, or early termination of the study by the sponsor. Patients with undetermined progression may continue to receive the investigational drug with the approval of the medical monitor and if the patient is clinically stable in the investigator's opinion. If progression is clearly confirmed in the next response assessment, the investigational drug will be discontinued.

[0408] Example 6: Determination of the antitumor activity of Rina-S in Study 2

[0409] Efficacy Analysis

[0410] Primary endpoint: PFS as assessed by the investigator

[0411] This study aims to evaluate progression-free survival (PFS) in PROC patients receiving either Rina-S or IC, with the assumption that Rina-S is superior to IC in PFS. The study is considered to have achieved its objective if Rina-S is superior to IC in PFS when PFS is finally analyzed using PAS.

[0412] PFS is defined as the time from randomization to first recording to disease progression (PD) as assessed by the investigator according to RECIST v1.1, or to death from any cause (whichever comes first).

[0413] The nonparametric Kaplan-Meier method will be used to estimate the PFS curve for each treatment arm. The median PFS and its two-sided 95% confidence interval (CI) will be calculated using the complementary log-log transformation method (Collett, London: Chapman and Hall, pp. 237-251 (1994)). Treatment differences in PFS will be assessed using the stratified log-rank test. A stratified Cox proportional hazards model with Efron's tie treatment approach will be used to assess the magnitude of treatment differences (i.e., hazard ratios) between treatment arms. The hazard ratios and their 95% CIs for the tie treatment approach with Efron and the stratified Cox model with a single treatment covariate will be reported. The same stratification factor used for randomization will be applied to both the stratified log-rank test and the stratified Cox model.

[0414] Because progression is assessed periodically, PD can occur at any time within the time interval between the last assessment where PD was not recorded and the assessment where PD was recorded. For the primary analysis, for patients with PD, the true date of disease progression will be approximated to the date of the first assessment of PD objectively recorded using RECIST v1.1, regardless of whether the study drug was discontinued.

[0415] PFS will be calculated as follows:

[0416] PFS (days) = (Date of first recorded PD or death - Date of randomization) + 1

[0417] Patients without recorded disease progression (PD) or death will be censored on the last disease assessment date. In patients who received antitumor therapy different from the study drug or were removed from the study before tumor progression was recorded, progression-free survival (PFS) will also be censored on the last disease assessment date on which no PD or death was recorded. If a patient did not have any tumor assessment in the study, PFS will be censored on day 1.

[0418] The PFS based on BICR will be analyzed using the same methodology as the sensitivity analysis. Furthermore, the consistency between investigator assessments and BICR assessments of PD will be evaluated. Inconsistencies between investigator assessments and BICR assessments regarding censoring status, time to PD, and time to censoring will be tabulated, listing the inconsistencies.

[0419] Key secondary endpoints:

[0420] Overall Survival

[0421] OS is defined as the time from randomization to death for any reason. OS is calculated as follows:

[0422] OS (days) = (Death date - Randomization date + 1).

[0423] Patients who survive (without OS events) will have their last known survival date erased.

[0424] A nonparametric Kaplan-Meier method will be used to estimate the OS curve for each treatment arm. The median OS and its two-sided 95% CI will be calculated using a complementary log-log transformation method (Collett, London: Chapman and Hall, pp. 237-251 (1994)). Treatment variability in OS will be assessed using a stratified log-rank test. A stratified Cox proportional hazards model with Efron's knot treatment approach will be used to assess the magnitude of treatment variability (i.e., hazard ratio) between treatment arms. The hazard ratios and their 95% CIs for the knot treatment approach with Efron and the stratified Cox model with a single treatment covariate will be reported. The same stratification factor used for randomization will be applied to both the stratified log-rank test and the stratified Cox model. Kaplan-Meier estimates of OS rates at 12 months will be compared between the Rina-S arm and the IC arm, and the proportionality of the hazard ratios over time will be explored.

[0425] Objective response rate

[0426] ORR is defined as the percentage of patients with the best response who have achieved CR or PR using RECIST v1.1. Investigator-based response will be used as the primary analysis for ORR, and response based on BICR (incorporating CA-125 normalized status for CR) will be used as the sensitivity analysis.

[0427] If the investigator-assessed PFS is declared positive at the time of the primary analysis, and the OS is also declared positive, then the final analysis will be performed on the investigator-assessed ORR. The following hypothesis will be tested at a one-sided α level of 0.025:

[0428] H0: ORR Rina-S = ORR IC vs H a ORR Rina-S ORR IC

[0429] ORR Rina-S It is the ORR in the Rina-S arm, and the ORR IC It is the ORR in the IC arm.

[0430] ORR will be analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by randomization stratification factors (Cochran, Biometrics 10, 417-451 (1954); Mantel and Haenszel, J Natl CancerInst 22, 719-748 (1959)) to examine differences between the Rina-S arm and the IC arm. P-values, odds ratios, and their 95% CIs will be reported. The 95% CI for ORR of the treatment arm based on the Clopper-Pearson method (Clopper and Pearson, Biometrika 26, 404-413 (1934)) will also be provided. The PAS population will be used as the primary population for ORR, and supportive analyses of ORR will be performed using patients from the ITT and EE analysis sets.

[0431] The ORR of the BICR will be analyzed using the same PAS-based methodology as the sensitivity analysis. Furthermore, the consistency of the best overall response (BOR) between the investigator's assessment and the BICR assessment will be evaluated. Inconsistencies between the investigator's assessment and the BICR assessment at the time of BOR and to BOR will be tabulated, and the data on the inconsistencies will be listed.

[0432] Determining the sample size

[0433] The primary endpoint of this study was investigator-assessed progression-free survival (PFS), with investigator-assessed overall survival (OS) and objective response rate (ORR) being key secondary endpoints.

[0434] The primary analysis will be performed on the primary analysis set (PAS). This set excludes patients with high FRα expression who would have been candidates for somituximab but did not receive prior therapy due to enrollment in regions where it was unavailable. Approximately 80% of the study population is expected to be included in the PAS.

[0435] The final PFS analysis (the primary PFS analysis) focused on demonstrating superior PFS in the Rina-S arm compared to the IC arm, and it was based on the following assumptions:

[0436] • In the IC arm, PFS follows an exponential distribution, with a median of 4 months.

[0437] • The hazard ratio between the Rina-S arm and the IC arm is 0.67 (corresponding to a 6-month median PFS in the Rina-S arm).

[0438] • For a total of approximately 530 patients, the enrollment period was 21 months, reaching approximately 420 patients in the main population.

[0439] The annual censoring rate for PFS was 10%. In this study, a proposed PFS hazard ratio of 0.67 for hypothesis testing was suggested, equivalent to approximately a 2-month improvement in median PFS under a hypothetical exponential distribution, which may be considered clinically significant. In patients with PROC, improvements in PFS were associated with reduced tumor-related symptoms, improved patient-reported outcomes, and improved overall survival.

[0440] Of the 262 PFS events, the study had 90% power to demonstrate the superiority of the Rina-S arm over the IC arm at a true hazard ratio of 0.67 and a one-sided α = 0.025. To ensure adequate follow-up of treated patients, the primary PFS analysis will be performed when at least 262 PFS events occur and patients in the PAS have the opportunity to be followed for at least 3 months after randomization (or when PD, death, or withdrawal from the study has been recorded within 3 months after randomization).

[0441] If the primary endpoint of PFS is statistically significant at a one-sided alpha level of 0.025, then a stratified test procedure will be used to test the two key secondary endpoints in the following order at a one-sided alpha level of 0.025 to control for the Type I error rate across the study.

[0442] • OS

[0443] • ORR assessed by researchers according to RECIST v1.1.

[0444] The key secondary endpoint of OS will only be tested after PFS is declared positive. At this time point, an interim analysis of OS will be performed (approximately 131 OS events are expected [53%]), and a final analysis of OS will be performed when at least 248 OS events have occurred, or at the end of the study when all treated patients have had the opportunity to be followed for at least 3 years after randomization, or have died or withdrawn from the study (whichever occurs first). The O'Brien-Fleming consumption function will be applied to both OS analysis time points at a one-sided alpha level of 0.025. The exact alpha allocation for the interim OS analysis depends on the cumulative number of OS events up to that time. With 248 OS events, the study has 80% power to demonstrate that the Rina-S arm is superior to the IC arm when the true hazard ratio is 0.70 and the one-sided alpha is 0.025. In addition, the sample size calculation for the OS analysis assumed a median OS of 13 months for the IC arm, a censoring rate of 2% per year, and that the enrollment schedule was the same as that specified in the sample size calculation for the PFS analysis.

[0445] Once the efficacy limit of overall survival (OS) has been exceeded, the investigator-defined objective response rate (ORR) will be tested. Since all patients will be enrolled at that point, the following hypothesis will be tested at the 2.5% level on one side, without applying a group sequential consumption function:

[0446] H0: ORR Rina-S = ORR IC vs H a ORR Rina-S ORR IC

[0447] ORR Rina-S It is the ORR in the Rina-S arm, and the ORR IC It is the ORR in the IC arm.

[0448] Assuming true ORR Rina-S It is 30%, and the actual ORR is 30%. IC The difference in ORR was 16%, and the method of Farrington and Manning (Farrington and Manning, Stat Med 9, 1447-1454 (1990)) was used in a study to test the difference between two binomial event rates. The sample size of approximately 420 patients (210 patients / group) reached approximately 93% power to detect the difference in ORR in 14% (30% vs. 16%).

[0449] Sample size calculations for PFS, OS, and ORR were performed using the R package gsDesign.

[0450] Example 7: Dose escalation and dose expansion in Study 1

[0451] As a continuation of Study 1, 53 patients (regardless of FRα expression) were treated in Part A (dose escalation), including 32 patients with previously treated ovarian cancer (OC), 11 patients with previously treated endometrial cancer (EC), and 10 patients with other tumor types (NSCLC, breast cancer, and mesothelioma). The median number of prior therapies for ovarian and endometrial cancer patients was 5 (1–14) and 3 (1–14), respectively. 75% of ovarian cancer patients had received bevacizumab, and 91% were platinum-resistant. All endometrial cancer patients received PD-1 inhibitors. 60–180 mg / m² was evaluated in Part A. 2 The Rina-S dose. The MTD is 140 mg / m². 2 In Part B (Dose Extension), select 100 and 120 mg / m². 2 The dosage was evaluated.

[0452] In Part B, 35 patients with ovarian cancer and 13 patients with endometrial cancer were previously treated. The median number of prior therapies for ovarian cancer and endometrial cancer patients were 3 (1–4) and 3 (1–7), respectively.

[0453] The planned tumor-specific dose expansion included OC, EC, and EGFR-mutant NSCLC, regardless of FRα expression (FRα levels were retrospectively assessed). Ovarian cancer patients in Part B (cohort B1, ovarian cancer dose expansion) were randomized 1:1 to Rina-S 100 mg / m². 2 Or Rina-S 120 mg / m 2 The inclusion criteria for queue B1 are shown below.

[0454] 1) Occult cancer (OC) confirmed by histology or cytology (must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer).

[0455] 2) Previous treatment (for PROC, 1st-3rd line or 4th line, regardless of platinum sensitivity status)

[0456] 3) ECOG PS 0-1

[0457] 4) Measurable diseases according to RECIST v1.1

[0458] 5) Adequate hematological, liver, kidney, and heart function.

[0459] Table 5 shows the patient demographics and disease characteristics in cohort B1.

[0460] Table 5: Ovarian Cancer Dosage Extension – Patient Demographics and Disease Characteristics

[0461]

[0462] Example 8: Overall Safety of Rina-S

[0463] As a continuation of Study 1, for those at 100 or 120 mg / m 2 In the treated Part A patients (n=35), the most common (>20%) treatment-related adverse events (TRAEs) were nausea (n=20.57%), neutropenia (n=18.51%), leukopenia (n=16.46%), anemia (n=15.43%), thrombocytopenia (n=11.31%), and vomiting (n=9.26%); most events were grade 1 / 2. The most common (>10%) grade >3 TRAEs were neutropenia (n=12.34%), anemia (n=9.26%), leukopenia (n=8.23%), and thrombocytopenia (n=5.14%). Table 6 shows the overall safety profile of cohort B1. OC dose extensions of 100 and 120 mg / m2: TEAEs of any grade and grade 3-4 were reported in 100% and 60%-63.6% of patients, respectively; TEAEs leading to dose reduction occurred in 11.1%-16.2% of patients; safety profiles were similar across cohorts. Figure 5 The overall security is shown in detail.

[0464] Table 6: Overall safety of cohort B1: OC dose expansion

[0465]

[0466] As a result, no ocular toxicity, neuropathy, or interstitial lung disease was observed. The safety profile of the new Rina-S in Part B is consistent with that in Part A.

[0467] Example 9: Determination of the antitumor activity of Rina-S in Study 1

[0468] As a continuation of Study 1, the antitumor activity of Rina-S was evaluated in dose escalation and dose expansion.

[0469] In Part A (dose escalation), Rina-S demonstrated encouraging antitumor activity in patients with OC and EC who had undergone extensive pretreatment. Table 7 shows the antitumor activity results for Part A. Figure 6 This demonstrates the optimal changes in target lesions with escalating OC and EC doses.

[0470] Table 7: Part A: Dosage escalation for OC and EC

[0471]

[0472] a Response evaluable population. The response evaluable population includes all treated patients who have a baseline and at least one evaluable post-baseline tumor assessment, or who have a documented disease progression at any time after the first dose of Rina-S. Response evaluation is performed according to RECIST v1.1.

[0473] b Based on researcher assessment.

[0474] In Part B, Rina-S was at 120 mg / m². 2 Encouraging antitumor activity, including complete response, was demonstrated in OC patients who had undergone extensive pretreatment. Table 8 shows the results of antitumor activity in cohort B1 of Part B. Treatment duration ranged from 3.0 to 42.0+ weeks. The median follow-up time in the study was 24 weeks. Figure 7 This demonstrates the optimal changes in target lesions with OC dose extension.

[0475] Table 8: Cohort B1: OC Dose Expansion a

[0476]

[0477] a Based on researcher assessment.

[0478] b The response can be assessed in the population.

[0479] c 120 mg / m 2 One patient in the cohort who had prior somituximab was not evaluable for response.

[0480] like Figure 8 As shown, in patients with OC who had undergone extensive pretreatment, most were observed to be using Rina-S 120 mg / m² in the early stages (week 6). 2 The response, and at the data cutoff, using 120 mg / m 2 All confirmed responses are still in progress. Figure 9 As shown, responses were observed in OC patients across all FRα expression levels.

[0481] Example 9: In vitro activity of a combination of Rina-S and standard care medications

[0482] Cells were seeded at an appropriate density depending on the cell line (typically 1,000–3,000 cells per well in 100 μL of suitable medium) in 96-well plates (flat-bottomed wells). After overnight incubation, cells were treated with increasing concentrations of Rina-S, carboplatin, or olaparib alone, or in combination with Rina-S and carboplatin (12.5 μM) or olaparib (30 μM) (concentration selected based on IC50 value). Cell viability was assessed after 4 days. Cell-Titer Glo (Promega, CAT# G7572) was added to the wells, and luciferase readings were collected after 5 minutes and analyzed using a microplate reader. All readings were normalized to the percentage of viable cells in the untreated control wells, and the IC50 was calculated using GraphPad Prism® software. 50 value.

[0483] like Figure 10A and 10B As shown, the combination of Rina-S and carboplatin did not enhance the cytotoxicity of Rina-S against OVCAR-8, while the combination of Rina-S and olaparib enhanced the cytotoxic effect of Rina-S against HEC-1-A.

[0484] Example 10: Markers of Icitecan and Rina-S-induced immunogenic cell death (ICD)

[0485] Markers of ICD induced by Rina-S and eczematidine were evaluated in FOLRα-positive cells. KB and 3LL-FRα were used at 5... 10 3 10 cells / well seeded in a 96-well plate (for ATP and HMGB1 assays) or 4 cells / well. 10 4Cells / well were seeded in 24-well plates (for calreticulin assay) and incubated overnight at 37°C. The wells of the plates used were flat-bottomed. For extracellular ATP (adenosine triphosphate) and HMGB1 (high-mobility group box 1 protein) assays, the cell supernatant was removed and 200 μL of serially diluted Rina-S (10-fold dilution; 1000 to 0.1 nM) or eczemab (10-fold dilution; 800 to 0.8 nM) was added to the wells, followed by incubation for 24–72 h. ATP and HMGB1 released in the supernatant were detected using the CTG kit (Promega; Cat No: G7572) and the Lumit HMGB1 Immunoassay kit (Promega; Cat No: W6112), respectively. For the detection of calreticulin on the cell surface, the cell supernatant was removed, and 500 μL of serially diluted Rina-S (10-fold dilution; 100 to 1 nM) or eczema (10-fold dilution; 80 to 0.8 nM) was added to the wells and incubated for 48 hours. Calreticulin on the cell surface was detected by flow cytometry using an anti-calreticulin monoclonal antibody (Enzolifesciences; Cat No: ADI-SPA-601PE-D).

[0486] like Figure 11A-11F As indicated, Rina-S and eczema upregulated ICD biomarkers in FOLRα-positive cells in a concentration-dependent manner.

[0487] Example 11: In vivo antitumor activity of the combination of Rina-S and SoC agent in a mouse model

[0488] Rina-S, in combination with carboplatin, bevacizumab, olaparib (PARPi), or immunotherapy, showed a strong enhancement of antitumor activity. In vivo evaluation of Rina-S in combination with standard of care (SOC) agents was conducted in preclinical mouse models of ovarian and endometrial cancer. Tumors with tumor size ranging from 100.16 to 180.86 mm were observed approximately 15 and 17 days post-inoculation. 3 Mice with average tumor size were randomized to 4 groups (n = 5-6 per group). On day 0 or day 1 after randomization (defined as day 0), mice received a specified concentration of the test sample or PBS. Specifically: Female NDG (hyperimmune deficiency phenotype) mice (n = 6 mice / group) carrying established OVCAR-8 ovarian cancer xenografts were administered Rina-S (3 mg / kg, single dose) or bevacizumab (5 mg / kg, single dose). Figure 12A Rina-S (3 mg / kg single dose) or carboplatin (60 mg / kg, QW) 4) Figure 12B ), IV or IP, alone or in combination. Female BALB / c nude mice (n = 5 mice / group) carrying established HEC-1-A endometrial cancer xenografts were treated with Rina-S (5 mg / kg, single dose) or olaparib (50 mg / kg, once daily for 5 days x 4 weeks), IV or by oral gavage, alone or in combination. Figure 12C ).

[0489] Rina-S was evaluated in combination with immuno-oncology agents in preclinical models of lung and colorectal cancer. Approximately 6 days post-inoculation, tumors with diameters ranging from 65 to 142 mm were observed. 3 Mice with average tumor size were randomized to 4 or 6 groups (n = 6 per group). On day 0 or day 1 after randomization (defined as day 0), mice received the specified concentration of the test product or PBS. Specifically: Female C57BL / 6 mice (n = 6 mice / group) carrying established lung cancer (3LL-FRα) xenografts were administered Rina-S (2.5 mg / kg, single dose) or CS1003 (nofazinlimab; anti-PD-1) (10 mg / kg, Q3D). 4), IV, alone or in combination ( Figure 12D Female C57BL / 6 mice (n=6 mice / group) carrying established MC38-FRα colorectal cancer xenografts were administered Rina-S (1.5 or 2.5 mg / kg, single dose) or CS1003 (0.5 mg / kg, Q3D). 4), IV, alone or in combination ( Figure 12E ).

[0490] Measure the tumor size in two dimensions twice a week using calipers, and use the following formula in mm. 3 Calculate tumor volume: V = 0.5axb 2 Where a and b are the long and short diameters of the tumor, respectively. The tumor volume exceeds 2000 mm. 3 The experiment was defined as ending when the animal reached its end. Animal weight was measured twice weekly. Monitoring animal weight served as an indirect measure of tolerance.

[0491] Rina-S in combination with carboplatin, bevacizumab, or olaparib resulted in enhanced antiproliferative effects in in vivo OVCAR-8 and HEC-1-A models, suggesting that these combinations may be clinically beneficial for relevant tumor types such as ovarian and endometrial cancer. No significant weight loss was observed in any treatment group, and no morbidity or mortality was reported during the treatment period.

[0492] The combination of Rina-S and CS1003 (anti-PD-1) resulted in enhanced anti-tumor effects in in vivo 3LL-FRα and MC38-FRα models, suggesting that combination therapy with Rina-S and immune checkpoint inhibitors (ICIs) is beneficial in clinical practice.

[0493] Having described the basic concept thus, it will be quite apparent to those skilled in the art, upon reading this detailed disclosure, that the foregoing detailed disclosure is intended to be presented by way of example only and is not restrictive. Various changes, modifications, and alterations may be made, and such changes, modifications, and alterations are intended to be directed to those skilled in the art, although not expressly stated herein. These changes, modifications, and alterations are intended to be made by this disclosure and are within the spirit and scope of the exemplary embodiments of this disclosure.

[0494] Furthermore, certain terms have been used to describe embodiments of this disclosure. For example, the terms "an embodiment," "an embodiment," and "some embodiments" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of this disclosure. Therefore, it is emphasized and should be understood that two or more references to "an embodiment," "an embodiment," or "an alternative embodiment" in various parts of this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments of this disclosure, particular features, structures, or characteristics may be appropriately combined.

[0495] Furthermore, those skilled in the art will understand that aspects of this disclosure may be illustrated and described herein in any of a plurality of patentable classes or contexts, including any new and useful process, machine, manufacture or composition of substance, or any new and useful improvement thereof.

[0496] Furthermore, the order of the processing elements or sequence, or the use of numbers, letters, or other names, is not intended to limit the claimed process and method to any order other than that which may be specified in the claims. Although the foregoing disclosure has discussed by way of various examples what is currently considered a useful embodiment of this disclosure, it should be understood that such details are for this purpose only, and the appended claims are not limited to the disclosed embodiments, but are intended to cover modifications and equivalent arrangements within the spirit and scope of the disclosed embodiments.

[0497] Similarly, it should be understood that in the foregoing description of embodiments of this disclosure, various features are sometimes combined in a single embodiment, drawing, or description thereof to simplify the disclosure, which aids in understanding one or more of the various embodiments. However, this approach of the disclosure should not be construed as reflecting an intention to require more features than expressly recited in each claim. Rather, the subject matter of the claims lies in fewer than all features of a single foregoing disclosed embodiment.

Claims

1. A method for treating solid tumors that are positive for folate receptor 1 (FOLR1), said method comprising administering 40 mg / m² 2 Up to 200mg / m 2 The dose of rinatabart sesutecan (Rina-S) was administered to human subjects with the aforementioned solid tumor.

2. The method according to claim 1, wherein the solid tumor is selected from the group consisting of ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma.

3. The method according to claim 1 or 2, wherein the solid tumor is ovarian epithelial carcinoma, primary peritoneal carcinoma, or fallopian tube carcinoma.

4. The method according to claim 1 or 2, wherein the solid tumor is endometrial cancer.

5. The method according to claim 1 or 2, wherein the solid tumor is ovarian cancer.

6. The method according to claim 1, wherein the solid tumor is: a) Non-small cell lung cancer (NSCLC); b) Breast cancer, including HER2-negative breast cancer; c) Pleural mesothelioma; or d) Peritoneal mesothelioma.

7. The method according to any one of the preceding claims, wherein the solid tumor is a platinum-resistant tumor, optionally a high-grade serous or endometrioid EOC, primary peritoneal carcinoma, or fallopian tube carcinoma resistant to platinum-based chemotherapy.

8. The method according to any one of the preceding claims, wherein the solid tumor is platinum-resistant ovarian cancer.

9. The method according to any one of claims 1-3 or 5, wherein the solid tumor is platinum-sensitive ovarian cancer.

10. The method according to any one of the preceding claims, wherein the solid tumor is localized or metastatic; and / or wherein at least one tumor is not surgically removable.

11. The method according to any one of the preceding claims, wherein Rina-S is at 60 mg / m² 2 Up to 180 mg / m 2 Dosage administration.

12. The method according to any one of the preceding claims, wherein Rina-S is at 100 mg / m² 2 Up to 140 mg / m 2 Dosage administration.

13. The method according to any one of the preceding claims, wherein Rina-S is at 100 mg / m² 2 Up to 120 mg / m 2 Dosage administration.

14. The method according to any one of the preceding claims, wherein Rina-S is at about 100 mg / m³ 2 Dosage administration.

15. The method according to any one of the preceding claims, wherein Rina-S is at about 120 mg / m³ 2 Dosage administration.

16. The method according to any one of the preceding claims, wherein the Rina-S dose is administered to the human subject once or twice a week on a schedule selected from the group consisting of: (i) once a week; (ii) every other week; (iii) one week of treatment followed by a two-week, three-week, or four-week break; (iv) two weeks of treatment followed by a one-week, two-week, three-week, or four-week break; (v) three weeks of treatment followed by a one-week, two-week, three-week, four-week, or five-week break; (vi) four weeks of treatment followed by a one-week, two-week, three-week, four-week, or five-week break; (vii) five weeks of treatment followed by a one-week, two-week, three-week, four-week, or five-week break; and (viii) once a month.

17. The method according to any one of claims 1-15, wherein the Rina-S dose is administered to the human subject at a cycle of once every three weeks (Q3W).

18. The method according to any one of claims 16-17, wherein the cycle is repeated 2, 4, 6, 8, 10, 12, 16 or 20 times.

19. The method according to any one of claims 1-18, wherein the human subject has previously been treated with at least one anticancer therapy, optionally wherein (a) The at least one anticancer therapy includes treatment with chemotherapy agents, and / or (b) wherein the subject had failed to respond to at least one of the anticancer therapies prior to treatment with Rina-S.

20. The method according to any one of the preceding claims, wherein Rina-S is administered in combination with one or more treatment modalities selected from the group consisting of: unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, local radiotherapy, surgery, and interfering RNA therapy.

21. The method according to any one of the preceding claims, wherein Rina-S is applied as follows: (a) In combination with platinum-based chemotherapy, optionally with decarboplatin; (b) In combination with VEGF-based antagonist chemotherapy, optionally debevacizumab; or (c) Combined with a PD-1 inhibitor, optionally depembrolizumab.

22. The method according to any one of the preceding claims, wherein the treatment outcome of the subject is improved, optionally wherein... (a) The improved treatment outcome is selected from objective responses of disease stability, partial response, or complete response; (b) The improved treatment outcome described therein is a reduced tumor burden, and / or (c) The improved treatment outcome mentioned above is progression-free survival or disease-free survival.

23. A method of treating solid tumors, comprising administering rinatabart sesutecan (Rina-S) to a human subject with a solid tumor and any of the following: (i) platinum-based chemotherapy, such as carboplatin; (ii) an anti-angiogenic agent, such as an anti-VEGF antibody, such as bevacizumab; (iii) a PARP inhibitor, such as olaparib; or (iv) an immune checkpoint inhibitor, such as an inhibitor of the PD-1 or PD-L1 immune checkpoint protein, such as an anti-PD-1 antibody, such as pembrolizumab.

24. The method according to any one of the preceding claims, wherein Rina-S has the following structure (Structure 1): Ab is a folate receptor 1 (FOLR1) binding antibody containing a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region and the VL region have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8.

25. The method of claim 24, wherein Ab is a FOLR1 binding antibody comprising a heavy chain containing the amino acid sequence shown in SEQ ID NO: 6 or optionally SEQ ID NO: 4, and a light chain containing the amino acid sequence shown in SEQ ID NO:

5.

26. The method according to any one of the preceding claims, wherein the Rina-S is administered to the human subject via intravenous administration.

27. The method according to any one of the preceding claims, wherein the FOLR1 expression level of the tumor has not been determined prior to the administration of Rina-S.

28. The method according to any one of claims 1-26, wherein, according to a regulatory-approved FOLR1 expression assay, optionally the Ventana FOLR1-2.1 RxDx Assay, the subject's tumor sample has high FOLR1 expression.

29. The method according to any one of claims 1-26, wherein, according to a regulatory-approved FOLR1 expression assay, optionally the Ventana FOLR1-2.1 RxDx Assay, the subject's tumor sample has intermediate or low FOLR1 expression.

30. The method according to any one of claims 1-26 and 28, wherein the human subject does not meet the criteria for treatment with somituximab.

31. Rinatabart sesutecan (Rina-S), which is used in a method of treating solid tumors, said method comprising administering 40 mg / m² 2 Up to 200 mg / m 2 For example, 60 mg / m 2 Up to 140 mg / m 2 For example, 100 mg / m 2 Or 120 mg / m 2 The Rina-S was administered to subjects with solid tumors at a dose specified in the text.

32. Use of Rinatabart sesutecan (Rina-S) in the preparation of a medicament for the treatment of solid tumors, wherein the medicament is used at a dose of 40 mg / m². 2 Up to 200 mg / m 2 For example, 60 mg / m 2 Up to 140 mg / m 2 For example, 100 mg / m 2 Or 120mg / m 2 The Rina-S dose was administered to a human subject suffering from the solid tumor.

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