Method for treating cancer with Anti-mesothelin antibody-drug conjugate

Abstract

The present invention relates to a method for treating and preventing cancer, and a composition and the use associated therewith. Specifically provided is a method for treating cancer by means of administering to an individual a certain dose of an anti-mesothelin antibody-drug conjugate. The method has significant effectiveness and safety.

Description

Method for treating cancer with anti-mesothelin antibody-drug conjugates Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a method for treating cancer using an anti-mesothelin (MSLN) antibody-drug conjugate. Background Art

[0002] Mesothelin (MSLN) is a cell surface glycoprotein with a molecular weight of 40 kDa. It is normally expressed in the mesothelial cells of the pleura, pericardium and peritoneum, and is expressed in trace amounts in the epithelial cells of the ovary, vaginal membrane, testicular rete and vascular surface. It is widely overexpressed in a variety of malignant tumor cells, such as extrahepatic bile duct cancer (95%), triple-negative cancer (66%), endometrial cancer (59%), colorectal cancer (30%), cervical cancer (25%), esophageal cancer (46%), and endometrial cancer (89%). Therefore, MSLN can serve as a potential target for antigen-specific therapy. Targeting the MSLN target, the main types of drugs currently being developed worldwide include antibody drugs (such as amatuximab) and vaccines (such as JNJ-64041757). According to research and development data, antibody drugs can effectively inhibit cancer progression and show acceptable toxicity in eliminating tumors, while vaccines have only shown moderate effects ((Lv J, Li P. Mesothelin as a biomarker for targeted therapy[J]. Biomarker Research, 2019, 7(1): 1-18.)). In recent years, the MSLN target has begun to be applied to antibody-drug conjugates (ADCs), and preliminary research data show that MSLN-ADC has certain potential in cancer treatment.

[0003] Antibody-Drug Conjugates (ADCs) are a new type of biological drug composed of a monoclonal antibody and a potent cytotoxic payload coupled through a bioactive linker. The mechanism of action of ADCs is that the ADC uses the monoclonal antibody to achieve specific binding with the target antigen and then internalizes into the target cancer cell. After the cytotoxic payload is internalized into the cancer cell, it exerts cytotoxicity and kills the cancer cell (Fu Z, Li S, Han S, et al. Antibody drug conjugate: the "biological missile" for targeted cancer therapy [J]. Signal Transduction and Targeted Therapy, (2022) 7: 93.). Since the launch of the world's first ADC (Mylotarg, ogamicin) in 2000, after decades of research and exploration, as of June 2023, only 15 ADC drugs have been approved for marketing worldwide. The corresponding target types and approved treatment indications are very limited, and do not involve MSLN targets. The therapeutic effects and drug resistance problems of ADC drugs still need to be improved and resolved. In order to fill the gap in MSLN antibody-drug conjugates in the treatment of cancer, it is necessary to further develop a method for treating cancer using MSLN antibody-drug conjugates.

[0004] The latest report from the International Agency for Research on Cancer, an agency of the World Health Organization, indicates that in 2022, there will be approximately 20 million new cancer cases and 9.7 million deaths worldwide. Lung cancer accounts for the largest proportion of these two figures, with 2.5 million new cases and 1.8 million deaths. Lung cancer is primarily divided into two subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), accounting for 15% and 85% of lung cancer cases, respectively. Currently, the main treatments for NSCLC include surgery, radiotherapy, and chemotherapy. Despite advances and improvements in these treatments, overall survival (OS) and progression-free survival (PFS) remain unsatisfactory, especially in the late stages of the disease. Therefore, the development of new and more advanced therapies is crucial. In recent years, immunotherapy, particularly ADCs, has become increasingly popular and has become one of the most promising treatments for NSCLC. They not only improve PFS and overall survival (OS), but also offer improved safety. However, as of February 4, 2024, only one ADC, ENHERTU, has been approved globally for the treatment of NSCLC, which is insufficient to meet the needs of the large patient population and overcome the problem of drug resistance in the later stages of treatment.

[0005] Ovarian cancer is the seventh most common cancer in women worldwide (the tenth in China). It is estimated that there are 239,000 new cases of ovarian cancer and 152,000 new deaths each year worldwide (Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: a review [J]. Cancer Biology & Medicine, 2017(01):9-32.). Although the incidence rate in China is relatively low, due to its large population base, there are still more than 55,000 new cases and 37,000 deaths each year. In the United States, it is estimated that there will be 19,710 new cases of ovarian cancer and 13,270 new deaths in 2023. Although there are many methods for treating ovarian cancer, such as surgery, chemotherapy, radiotherapy, and chemical drug therapy, the above treatments have significant side effects and low patient acceptance. Biological targeted drugs with relatively low side effects, especially ADC drugs, are widely used in cancer treatment. Many antibody-drug conjugate projects for the treatment of ovarian cancer have emerged worldwide. However, many projects have been terminated early due to poor clinical data. As of February 2, 2024, there is only one ADC drug approved for the treatment of ovarian cancer, Mirvetuximab soravtansine. Although this drug has clinically significant anti-tumor activity and safety, it cannot meet the needs of a large patient base and overcome the problem of drug resistance in the later stages of treatment.

[0006] Cervical cancer is a global public health problem and the fourth most common cancer in women. Globally, there were approximately 570,000 new cases and 311,000 deaths in 2018, and an estimated 604,127 new cases and 341,831 deaths in 2020, posing a serious threat to women's lives and health (Singh D, Vignat J, Lorenzoni V, et al. Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative[J]. The Lancet Global Health, 2023, 11(2): e197-e206., Arbyn M, Weiderpass E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis[J]. The Lancet Global Health, 2020, 8(2): e191-e203.). Currently, the treatments for cervical cancer include chemotherapy and radiotherapy, as well as surgery. Surgical treatment carries high risks and causes great trauma to the human body. While chemotherapy and radiotherapy kill tumor cells, they also kill a large number of normal cells, damaging the body's own immune system, inhibiting the function of bone marrow hematopoietic stem cells, and easily leading to drug resistance. Patients have a low acceptance of traditional treatments. Although ADC drugs can be used as an alternative to chemotherapy and radiotherapy, as of February 4, 2024, there is only one ADC drug approved worldwide for the treatment of cervical cancer, namely Tivdak, which cannot meet the needs of a large patient base and overcome the problem of drug resistance in the later stages of treatment.

[0007] It can be seen from the global incidence and treatment status of the above-mentioned exemplary cancers that there is still a great demand for ADC drug treatment among cancer patients worldwide. In order to fill the gap in anti-MSLN antibody-drug conjugates in the treatment of cancer, further improve the effectiveness of antibody-drug conjugates, and solve the problem of drug resistance that is easy to occur during patient medication, it is necessary to provide a method for treating cancer with an anti-MSLN antibody-drug conjugate.

[0008] All references cited herein, including patent applications, patent publications, and UniProtKB / Swish Prot accession numbers, are hereby incorporated by reference in their entirety as if each individual reference were specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0009] The present invention provides a method for treating cancer using an anti-MSLN antibody-drug conjugate, which has significant effectiveness and safety.

[0010] Specifically, the present invention provides a method for preventing and treating cancer, comprising administering an effective amount of an anti-mesothelin (MSLN) antibody-drug conjugate to an individual having the cancer, characterized in that the antibody-drug conjugate has a structural formula of Ab-(LU)n, wherein the Ab is an anti-MSLN antibody, the U is a conjugated cytotoxic molecule, the L is a linker between the cytotoxic molecule and the anti-MSLN antibody, and n is an integer between 1 and 8, representing the number of cytotoxic molecules connected to the antibody; the cancer is selected from ovarian cancer, cervical cancer, and lung cancer.

[0011] In some embodiments, the U comprises a microtubule inhibitor or a DNA damaging agent; in some preferred embodiments, the microtubule inhibitor comprises dolastatin or a derivative thereof, auristatin or a derivative thereof, or a maytansine alkaloid or a derivative thereof and the microtubule inhibitor comprises monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF) or monomethyl auristatin D (MMAD).

[0012] In some embodiments, the tubulin inhibitor comprises emtansine (DM1), maytansine (DM3), or ravtansine (DM4); and the DNA damaging agent comprises calicheamicin, duocarmycin, pyrrolobenzodiazepine (PBD), Dxd, or SN-38.

[0013] In some embodiments, the Ab comprises a heavy chain and a light chain; wherein the heavy chain comprises a heavy chain variable region (VH), and the light chain comprises a light chain variable region (VL); wherein the VH comprises CDR-H1, CDR-H2 and CDR-H3, the CDR-H1 comprising the following amino acid sequence: RYWMS (SEQ ID NO: 1), the CDR-H2 comprising the following amino acid sequence: EINPDSSTIVYTPSLKD (SEQ ID NO: 2) and the CDR-H3 comprising the following amino acid sequence: RGSHYYGYRTGYFDV (SEQ ID NO: 3); the VL comprises CDR-L1, CDR-L2 and CDR-L3, the CDR-L1 comprising the following amino acid sequence: SASSVSYMY (SEQ ID NO: 4), the CDR-L2 comprising the following amino acid sequence: DTSNLAS (SEQ ID NO: 5) and the CDR-L3 comprising the following amino acid sequence: QQWSSYPPT (SEQ ID NO: 6).

[0014] In some embodiments, the VH comprises the amino acid sequence shown in SEQ ID NO: 7 and / or the VL comprises the amino acid sequence shown in SEQ ID NO: 8, and the specific sequences are as follows:

[0015] In some embodiments, the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 9, and the specific sequence information is as follows:

[0016] In some embodiments, the light chain comprises the amino acid sequence shown in SEQ ID NO: 10, and the specific sequence information is as follows:

[0017] In some preferred embodiments, the anti-MSLN antibody comprises a heavy chain amino acid sequence as shown in SEQ ID NO:9 and the anti-MSLN antibody comprises a light chain amino acid sequence as shown in SEQ ID NO:10.

[0018] In some embodiments, the L is linked to the Ab through a sulfhydryl or amino moiety.

[0019] In some embodiments, L is selected from the following structures:

[0020] In some embodiments, the antibody drug conjugate is selected from the following structures: wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0021] In some embodiments, the antibody drug conjugate is administered intravenously to the individual.

[0022] In some embodiments, the anti-mesothelin antibody drug conjugate has a drug-antibody ratio (DAR) of 3-8; in some preferred embodiments, the anti-mesothelin antibody drug conjugate has a drug-antibody ratio (DAR) of 3-7; in some preferred embodiments, the anti-mesothelin antibody drug conjugate has a drug-antibody ratio (DAR) of 3-6; in some preferred embodiments, the anti-mesothelin antibody drug conjugate has a drug-antibody ratio (DAR) of 3.5-4.5; in some preferred embodiments, the anti-mesothelin antibody drug conjugate has a drug-antibody ratio (DAR) of about 4.

[0023] In some embodiments, the dose range of the antibody drug conjugate administered to the individual is 1 mg / kg-5 mg / kg (including but not limited to: 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg); in some preferred embodiments, the dose range of the antibody drug conjugate administered to the individual is selected from 1.0 mg / kg-3.0 mg / kg, 1.0 mg / kg, / kg-2.5 mg / kg, 1.0 mg / kg-2.0 mg / kg, 1.5 mg / kg-3.0 mg / kg, 1.5 mg / kg-2.5 mg / kg, 1.5 mg / kg-2.0 mg / kg, 2.0 mg / kg-3.0 mg / kg or 2.0 mg / kg-2.5 mg / kg; in some more preferred embodiments, the dose range of a single administration of antibody drug conjugate to the individual is 2.0 mg / kg-3.0 mg / kg or 1.0 mg / kg-2.0 mg / kg.

[0024] In some embodiments, the dose of the antibody drug conjugate administered to the individual is 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, or 2.5 mg / kg; in some specific embodiments, the dose of the antibody drug conjugate administered to the individual is 2.0 mg / kg; in some specific embodiments, the dose of the antibody drug conjugate administered to the individual is 2.5 mg / kg;

[0025] The protein content of the active ingredient in the antibody drug conjugate of the present invention is determined by UV / visible light photometry.

[0026] In some embodiments, the antibody-drug conjugate is administered to the individual once or more (e.g., 2 times, 3 times, 4 times) every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; in some preferred technical solutions, the antibody-drug conjugate is administered to the individual once every 3 weeks.

[0027] In some embodiments, the individual patient's cancer cells express MSLN on their surface at a level of IHC ≥ 1+, as determined by immunohistochemistry (IHC).

[0028] In some embodiments, the individual patient: (a) received one or more standard therapies prior to administration of the antibody drug conjugate; or / and (b) had disease progression or was not relieved by treatment; or / and (c) was unable to receive standard treatment; or / and (d) had no standard treatment options.

[0029] In some embodiments, the lung cancer is non-small cell lung cancer; in some preferred embodiments, the lung cancer is non-squamous non-small cell lung cancer.

[0030] In some embodiments, the individual with non-squamous non-small cell lung cancer has received platinum-containing doublet chemotherapy and / or a PD-L1 inhibitor and / or has been treated prior to administration of the anti-MSLN antibody drug conjugate.

[0031] In some embodiments, the individual with non-squamous non-small cell lung cancer has received two or more lines of therapy prior to administration of the anti-MSLN antibody drug conjugate.

[0032] In some embodiments, the ovarian cancer is high-grade serous carcinoma.

[0033] In some embodiments, the cancer is ovarian cancer, and the individual patient's cancer cells express MSLN at the level of IHC2+ or IHC3+ on the surface of their cancer cells, as determined by immunohistochemistry (IHC).

[0034] In some embodiments, the FIGO stage of the ovarian cancer is IV or the individual has received bevacizumab (trade name: Avastin) monoclonal antibody treatment or PARPi inhibitor (poly ADP-ribose polymerase inhibitor) treatment before administration of the anti-MSLN antibody drug conjugate.

[0035] In some embodiments, the individual with ovarian cancer has received 1-4 lines of anti-tumor therapy and / or is platinum-sensitive or resistant prior to administration of the anti-MSLN antibody drug conjugate.

[0036] In some embodiments, the cervical cancer is selected from recurrent or metastatic cervical cancer.

[0037] In some embodiments, the individual has received 1-2 lines of systemic anti-tumor therapy prior to administration of the anti-MSLN antibody drug conjugate; in some embodiments, the 1-2 lines of systemic anti-tumor therapy are platinum-containing chemotherapy and / or PD-L1 inhibitors and / or PD-1 inhibitors.

[0038] In some embodiments, the individual with cervical cancer has received two or more lines of therapy prior to administration of the anti-MSLN antibody drug conjugate.

[0039]

definition

[0040] As used herein, the term "mesothelin," also known as Mesothelin or MSLN, refers to any naturally occurring, mature mesothelin derived from the processing of a mesothelin precursor protein in cells. The term includes mesothelin from any vertebrate source, including mammals such as primates (e.g., humans and monkeys) and rodents (e.g., mice and rats), and unless otherwise indicated, the term also includes naturally occurring variants of mesothelin, such as splice variants or allelic variants.

[0041] As used herein, "CDR region" or "CDR" refers to the hypervariable regions of the heavy and light chains of immunoglobulins as defined by Kabat et al. (Kabat et al., Sequences of proteins of immunological interest, 5 th Ed., US Department of Health and Human Services, NIH, 1991, and later editions). There are three heavy chain CDRs and three light chain CDRs. As used herein, the term CDR or CDRs is intended to refer to one, several, or even all of these regions, as appropriate, that contain the majority of amino acid residues responsible for binding through the antibody's affinity for an antigen or its recognized epitope. The CDR regions herein are described using the Kabat system (Kabat, EA, et al. (1991). Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication NO: 91-3242).

[0042] As used herein, "antibody" is used in the broadest sense and encompasses various antibody structures, including but not limited to monospecific antibodies, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments. In particular, as used herein, "antibody" refers to a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated as VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated as VL) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL regions can be further subdivided into multiple regions with high variability, referred to as complementarity determining regions (CDRs), interspersed with multiple regions that are more conserved, referred to as framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. These variable regions of heavy and light chains comprise a binding domain that interacts with an antigen. The constant region of an antibody can mediate the binding of an immunoglobulin to a tissue or factor of the host, including various cells of the immune system (such as effector cells) and the first component (Clq) of the classical complement system. Chimeric or humanized antibodies are also encompassed in the antibodies according to the present invention.

[0043] The term "dolastatin" as used herein refers to a polypeptide isolated from a marine organism, Dollapple auricularia, including but not limited to dolastatin 10 and dolastatin 15. Dolastatin peptides are mitotic inhibitors that exhibit strong anticancer activity and are therefore candidates for anticancer drugs. Researchers have further discovered and synthesized many derivatives of dolastatin peptides, such as MMAE, MMAD, and MMAF.

[0044] As used herein, the term "administer" or "administer" refers to the physical introduction of a therapeutic agent into a subject using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. The therapeutic agent can be administered by non-parenteral routes or orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical administration. Administration can also be performed, such as once, multiple times and / or for one or more extended periods.

[0045] As used herein, the term "cancer" refers to a broad class of diseases characterized by uncontrolled growth of abnormal cells in the body, and "cancer" may include solid tumors or non-solid tumors.

[0046] As used herein, the term "anti-MSLN antibody drug conjugate" refers to a compound in which an optional anti-MSLN antibody is conjugated to a cytotoxic molecule via an optional linker.

[0047] The term "anti-MSLN antibody" as used herein refers to antibodies that bind to the MSLN protein, including all types of antibodies defined herein. Anti-MSLN antibodies inhibit MSLN activation or downstream signaling through various mechanisms. As non-limiting examples, anti-MSLN antibodies can prevent ligand binding, receptor activation, or receptor signal propagation, resulting in reduced MSLN expression or localization on the cell surface, inhibition of MSLN cleavage, or induction of antibody-mediated cytotoxicity.

[0048] The drug-to-antibody ratio (DAR) used in the present invention refers to the average number of drug molecules linked to each antibody molecule in the prepared pharmaceutical composition.

[0049] The term "about" in the DAR value used in the present invention refers to a range of 0.5 above or below the DAR value. For example, a DAR value of about 4 means that the DAR value range between 3.5 and 4.5 is also within the DAR value range of about 4.

[0050] The term "treatment" as used herein refers to any type of intervention or procedure performed on an individual subject, or the administration of an active agent, such as an antibody drug conjugate herein, to a subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of symptoms, complications, conditions, or biochemical markers associated with a disease; the term "treatment" as used herein is not intended to be an absolute term, for example, "treatment" used in a clinical setting is intended to include obtaining beneficial or desired clinical results, and may include improving the condition of an individual subject with cancer, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of tumors or cancer cells.

[0051] As used herein, the term "prevention" refers to any type of intervention or procedure performed on a patient with the goal of preventing a disease or condition from developing or at least incompletely developing (e.g., reducing the symptoms or severity of the disease or condition), such as the development of side effects (e.g., diarrhea).

[0052] As used herein, the term "effective amount" refers to any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes regression of a disease, such as by reducing the severity of disease symptoms, increasing the frequency and duration of disease-free periods, or preventing impairment or disability resulting from afflictions of the disease. The ability of a therapeutic agent to promote regression of a disease can be assessed using various methods known to those skilled in the art, for example, in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the therapeutic agent in in vitro assays.

[0053] The term "metastasis" as used herein refers to the spread of cancer cells from the place where they were first formed (primary site) to one or more other sites (one or more secondary sites) in a subject. During the metastatic process, cancer cells break away from the original (primary) tumor, travel through the blood or lymphatic system, and form new tumors (metastases) in other organs or tissues of the body. The new metastatic tumors include cancer cells that are identical or similar to the primary tumor. At the secondary site, tumor cells can proliferate and begin to grow or colonize at the distant site, generating secondary tumors.

[0054] As used herein, the term "individual" includes any human or non-human animal; the term "non-human animal" includes, but is not limited to, vertebrates, such as non-human primates, sheep, dogs, and rodents, such as mice, rats, and guinea pigs; in some embodiments, the individual is a human; the terms "subject," "patient," "individual," and "individual patient" are used interchangeably herein.

[0055] As used herein, the term “and / or” refers to the specific disclosure of each of two specific features or components, regardless of whether the other is included. The term “and / or” used in phrases such as “A and / or B” is intended to include “A and B,” “A or B,” and “A” and “B” (alone). Similarly, the term “and / or” used in phrases such as “A, B, and / or C” is intended to cover the following: A, B, C; A, B or C; A or B; A or C; B or C; A and B; A and C; B and C; A (alone); B (alone); and C (alone).

[0056] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those commonly understood by one skilled in the art. DETAILED DESCRIPTION

[0057] Example 1 A multicenter, open-label, multi-cohort extended clinical study to evaluate the safety, efficacy, and pharmacokinetic characteristics of anti-MSLN-ADC-1 for injection in patients with advanced malignant solid tumors

[0058] The preparation of the antibody drug conjugate contained in the anti-MSLN-ADC-1 drug refers to the preparation method of RC88-PY-MAA-Val-Cit-PAB-MMAE in Example 2b of the published patent application WO2019 / 223579, the entire text of which is incorporated into the present invention by reference. The heavy chain of the anti-MSLN antibody in the anti-MSLN-ADC-1 is the amino acid sequence shown in SEQ ID NO: 9 and the light chain is the amino acid sequence shown in SEQ ID NO: 10. The specific structure of the antibody drug conjugate is as follows: wherein n is 1, 2, 3, 4, 5, 6, 7 or 8. The anti-MSLN-ADC-1 drug has a drug-to-antibody ratio (DAR) of approximately 4.

[0059] 1. Clinical Study Design

[0060] (1) Overview

[0061] This clinical study is a multicenter, open-label, multi-cohort expansion study consisting of two phases: Phase I and Phase II. This study aims to evaluate the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of anti-MSLN-ADC-1 for injection in patients with advanced malignant solid tumors expressing MSLN, and to provide a reference for the confirmation of dose and efficacy in subsequent studies.

[0062] (2) Phase 1

[0063] The study plans to enroll patients with confirmed MSLN-expressing advanced malignant solid tumors. After screening, eligible patients will receive an injectable anti-MSLN-ADC-1. Six dose cohorts are planned: 0.1, 0.5, 1.0, 1.5, 2.0, and 2.5 mg / kg, administered by intravenous infusion. One subject will be enrolled in the 0.1 mg / kg dose cohort; subjects will be enrolled in a "3+3" dose-escalation approach at 0.5, 1.0, 1.5, 2.0, and 2.5 mg / kg. If the maximum tolerated dose (MTD) is not reached after escalation to 2.5 mg / kg, the investigator and the sponsor will jointly analyze the known PK, safety, and efficacy characteristics to determine whether to proceed to a higher dose and the most appropriate dose increment. The dose escalation trial will proceed until the MTD is reached, or the investigator and the sponsor determine the appropriate dose to terminate the escalation based on the known PK, safety, and efficacy characteristics of the escalation phase.

[0064] After completing the 21-day dose-limiting toxicity (DLT) evaluation, subjects will continue to receive the drug once every 3 weeks (Q3W) until intolerable toxicity occurs, the investigator assesses that the subject will not benefit, or the sponsor terminates the study. Subjects will not benefit in the following two situations:

[0065] Disease progression occurs after receiving treatment at a higher dose that does not reach the MTD. After the DLT evaluation period of the higher-dose group, subjects who have disease progression in the lower-dose group are allowed to continue receiving higher-dose treatment until the investigator determines that the subject no longer benefits from the higher-dose group (i.e., the subject is still evaluated as having disease progression in the higher-dose group);

[0066] Subjects in the MTD group or those who cannot use a higher dose (the next dose is escalating) need to stop taking the drug if the disease progresses once.

[0067] RECIST v1.1 was used for baseline screening and tumor imaging during treatment. Tumor assessments were performed every 6 weeks (±7 days) until disease progression or death. Tumor assessment time points were not affected by dose adjustments or interruptions.

[0068] All subjects will undergo IRC assessment.

[0069] During the study, the dose and dosing interval will be adjusted as necessary based on the pharmacokinetic results obtained. Additional subjects may be enrolled to obtain sufficient PK data.

[0070] The MTD was defined as the highest dose level at which no more than 1 subject experienced a DLT among at least 6 subjects evaluable for DLT.

[0071] (3) Second stage

[0072] This phase is the multi-cohort indication expansion phase. Based on the data gradually obtained in the first phase, the sponsor and the investigator will discuss and select an appropriate dose for multi-cohort indication exploration. Patients with confirmed advanced malignant solid tumors with confirmed MSLN expression [≥1+ determined by immunohistochemistry (IHC) in the central laboratory] will be included, including but not limited to ovarian cancer, cervical cancer and other cancers that may benefit. Multiple cohorts will be expanded according to different cancer types.

[0073] Qualified screening subjects received anti-MSLN-ADC-1 drug treatment Q3W, administered by intravenous drip, until disease progression (PD), death, intolerable toxic reactions, withdrawal of informed consent, loss to follow-up, end of study, or initiation of other anti-tumor treatments, with the maximum duration of administration not exceeding 2 years.

[0074] The evaluation criteria used RECIST v1.1 for baseline screening and tumor imaging evaluation during treatment. Subjects were required to undergo clinical tumor imaging evaluation every 6 weeks (±7 days) until disease progression, receipt of new anti-tumor treatment, or death (whichever occurred first).

[0075] The imaging results of this phase will be evaluated by the IRC and researchers.

[0076] During the study, the subjects' blood was collected for pharmacokinetic and immunogenicity analysis, the subjects' tumor specimens were collected for analysis, and the subjects' blood was collected for biomarker analysis to explore its relationship with drug efficacy.

[0077] After completing the end-of-treatment visit, all subjects will be followed up for survival every 90 days (±14 days).

[0078] 2. Research Objectives

[0079] (1) Objectives of the Phase I study: Primary objective: To determine the safety and tolerability of the anti-MSLN-ADC-1 drug for injection; Secondary objective: To preliminarily evaluate the pharmacokinetic characteristics (PK) of the anti-MSLN-ADC-1 drug for injection; To preliminarily evaluate the immunogenicity of the anti-MSLN-ADC-1 drug for injection; To preliminarily evaluate the efficacy of the anti-MSLN-ADC-1 drug for injection; Exploratory objective: Biomarker evaluation.

[0080] (2) Objectives of Phase 2 study The primary objective is to evaluate the efficacy of anti-MSLN-ADC-1 for injection in the treatment of patients with MSLN-expressing advanced malignant solid tumors (including but not limited to ovarian cancer, cervical cancer and other cancers that may benefit patients); The secondary objective is to further evaluate other efficacy indicators of anti-MSLN-ADC-1 for injection in the treatment of patients with MSLN-expressing advanced malignant solid tumors (including but not limited to ovarian cancer, cervical cancer and other cancers that may benefit patients); Evaluate the PK characteristics of anti-MSLN-ADC-1 for injection; Evaluate the immunogenicity of anti-MSLN-ADC-1 for injection; Exploratory objective: Biomarker evaluation.

[0081] 3. Study endpoints

[0082] (1) Phase I study endpoints: Primary endpoint: Adverse events (AEs) and maximum tolerated dose (MTD); Secondary endpoints: PK parameters and immunogenicity parameters; Objective response rate (ORR) assessed by an independent imaging review committee (IRC); ORR and progression-free survival (PFS) assessed by investigators; Exploratory endpoints: Exploratory analysis of the relationship between the proportion of mesothelin (MSLN)-positive cells in tumor tissue, shed MSLN in peripheral blood serum, and potential biomarkers such as CA19-9 and CA125 and efficacy.

[0083] (2) Phase II study endpoints Primary endpoint: ORR assessed by IRC; Secondary endpoints: Duration of response (DOR), PFS, disease control rate (DCR) assessed by IRC; DOR, PFS, DCR, ORR and overall survival (OS) assessed by investigators; AEs; PK characteristics and immunogenicity; Exploratory endpoints: Exploratory analysis of the relationship between the proportion of MSLN-positive cells in tumor tissue, shed MSLN in peripheral blood serum, and potential biomarkers such as CA19-9 and CA125 and efficacy.

[0084] 4. Study Population

[0085] Phase I: patients with advanced malignant solid tumors;

[0086] Stage II: Advanced malignant solid tumors expressing MSLN, including but not limited to ovarian cancer, cervical cancer, etc.

[0087] 5. Selection Criteria

[0088] Patients who meet all of the following criteria can be included in this study:

[0089] (1) Voluntarily agree to participate in the study and sign the informed consent form in general; Age requirements: 18-70 years old (including 18 and 70 years old) in the first stage; ≥18 years old in the second stage; Expected survival period ≥12 weeks; ECOG physical status 0 or 1 point; Female subjects included must have a negative pregnancy test within 7 days before the study administration and must be non-breastfeeding; At the same time, female subjects included should be surgically sterilized, postmenopausal patients, or agree to use a medically approved contraceptive method (such as intrauterine devices, birth control pills or condoms) during the study treatment period and within 6 months after the end of the treatment period; Male subjects included: should be surgically sterilized, or agree to use a medically approved contraceptive method during the study treatment period and within 6 months after the end of the study treatment period; Be able to understand the requirements of the trial, and be willing and able to comply with the trial and follow-up procedures.

[0090] (2) Adequate organ function requires bone marrow function (no use of G-CSF, GM-CSF, Meg-CSF, TPO, EPO, red blood cell transfusion, or platelet transfusion within 14 days before the examination): Hemoglobin ≥ 9 g / dL; absolute neutrophil count ≥ 1.5 × 10 9 / L; Platelet ≥100×10 9 / L; Coagulation function: Prothrombin time (PT) ≤ 1.5 times the upper limit of normal (ULN); Partial thromboplastin time (APTT) ≤ 1.5 x ULN; Liver function (based on the normal values ​​of the clinical trial center): Serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN in the absence of liver metastasis; ALT and AST ≤ 5 x ULN in the presence of liver metastasis; Renal function (based on the normal values ​​of the clinical trial center): Serum creatinine ≤ 1.5 x ULN, or creatinine clearance (CrCl) calculated by the Cockcroft-Gault formula ≥ 60 mL / min, or 24-hour urine CrCl ≥ 60 mL / min; Cardiac function and myocardial injury markers: New York Heart Association (NYHA) grade < 3; Left ventricular ejection fraction ≥ 50%; Troponin T or I ≤ ULN Creatine kinase (CK) or creatine kinase isoenzyme (CK-MB) ≤ 2.5 × ULN.

[0091] (3) Tumor-related requirements: Phase I subjects must be patients with locally advanced or metastatic malignant solid tumors confirmed by histology or cytology, who are refractory to standard treatment (disease progression after treatment or no relief from treatment) or cannot tolerate standard treatment, and who cannot accept or do not have standard treatment; The inclusion requirements of the Phase II expansion cohort are as follows: Tumor tissue specimens must be confirmed to be MSLN positive (≥1+ by IHC test in the central laboratory); Ovarian cancer (OC) cohort: (1) Pathological type is high-grade serous carcinoma; (2) Platinum-sensitive or platinum-resistant patients who have failed 1-4 lines of anti-tumor treatment; Cervical cancer (CC) cohort: (1) Cervical cancer confirmed by histology or cytology and recurrent or metastatic cervical cancer without other pathological components; (2) Patients who have received 1-2 lines of systemic anti-tumor treatment in the past, and must have received platinum-containing chemotherapy and / or PD-L1 inhibitors or PD-1 treatment (except those who are intolerant to PD-1 / PD-L1); Non-squamous non-small cell lung cancer (NSCLC) cohort: (1) previously received systemic therapy and had progressed; (2) previously received ≥2 lines of treatment; (3) had no driver gene mutations; (4) previously received double-platinum chemotherapy and / or anti-PD-1 or PD-L1 inhibitors. Subjects were required to provide primary or metastatic tumor specimens that could be used for MSLN testing. Evaluation criteria (tumor evaluation was performed using RECIST v1.1 criteria, and all patients were required to have at least one measurable lesion.

[0092] 7. Statistical Analysis

[0093] For the Phase 1 study, the number of dose levels investigated and any emerging toxicities of the investigational drug will determine the sample size. The initial estimate is approximately 31 subjects. For the Phase 2 study, patients with advanced solid tumors expressing MSLN, including but not limited to ovarian cancer, cervical cancer, and non-squamous non-small cell lung cancer, are expected to enroll a minimum of 51 subjects.

[0094] 8. Research Methods

[0095] This study enrolled patients with advanced malignant solid tumors expressing MSLN. The dose-escalation phase explored anti-MSLN-ADC-1 at doses of 0.1-3.0 mg / kg, with 2.0 mg / kg and 2.5 mg / kg Q3W (every 3 weeks) selected for the dose-expansion phase. The primary endpoint was the objective response rate (ORR) assessed by the investigator according to RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), safety, and tolerability.

[0096] 9. Statistical Analysis 1

[0097] As of December 20, 2023, a total of 164 patients with advanced solid tumors were enrolled, of whom 92.1% were stage III-IV patients and 69.5% were ECOG 1 patients.

[0098] (1) Effectiveness analysis

[0099] 1) Enrollment of the Ovarian Cancer (OC) Cohort: A total of 60 patients were screened for this cohort, all of whom had IHC2+ or IHC3+ MSLN expression. Of these, 70% (42 / 60) had FIGO stage IV; 55% (33 / 60) had previously received bevacizumab; 48.3% (29 / 60) had previously received a PARPi inhibitor; and 90% (54 / 60) had platinum resistance. The median number of prior systemic therapies for the enrolled patients ranged from 4 to 7, with a median of 4. Results: a. Among 43 patients with at least one post-baseline tumor assessment, the overall ORR was 39.5% (17 / 43); b. Among patients who had previously received 2-4 lines of treatment, the corresponding ORR at the 2.0 mg / kg dose was 47.6% (10 / 21), and the corresponding ORR at the 2.5 mg / kg dose was 33.3% (2 / 6).

[0100] 2) Patient enrollment in the non-squamous non-small cell lung cancer (NSCLC) cohort: This cohort included 26 patients who had progressed on previous systemic treatment. Twenty-three of these patients underwent a post-baseline tumor assessment, and 86.9% (20 / 23) of these 23 patients had previously received ≥2 lines of treatment; 15 patients did not have driver gene mutations, and 73% (11 / 15) of these 15 patients had previously received double-platinum chemotherapy and anti-PD-1 inhibitors or anti-PD-L1 inhibitors. Results: a. Among the 23 patients who underwent a post-baseline tumor assessment, the ORR was 21.7% (5 / 23); b. Among the 15 patients without driver gene mutations, the ORR was 33.3% (5 / 15), including 1 complete response (CR).

[0101] 3) Patient Enrollment in the Cervical Cancer (CC) Cohort: This cohort enrolled 18 patients who had progressed on prior systemic therapy. Among the 17 patients who underwent a post-baseline tumor assessment, 64.7% (11 / 17) had received ≥2 lines of therapy, and 70.5% (12 / 17) had received prior treatment with platinum-doublet chemotherapy and an anti-PD-1 or anti-PD-L1 inhibitor. Results: Among the 17 patients who underwent a post-baseline tumor assessment, the ORR was 35.3% (6 / 17).

[0102] From the above data, it can be seen that the anti-MSLN-ADC-1 drug has significant effectiveness in treating ovarian cancer, non-squamous non-small cell lung cancer and cervical cancer.

[0103] (2) Safety analysis: Both the 2.0 mg / kg and 2.5 mg / kg dose groups in this trial showed good safety effects.

[0104] 10. Statistical Analysis 2

[0105] As of February 21, 2024, a total of 170 patients with advanced solid tumors were enrolled.

[0106] (1) Effectiveness analysis

[0107] 1) Ovarian cancer (OC) cohort

[0108] In the 2.0 mg / kg group of the OC cohort, 31 evaluable patients who had received two to four prior lines of therapy were enrolled. Among these patients, the ORR and confirmed objective response rate (cORR) were 45.2% and 41.9%, respectively. The median duration of response (DoR) was 8.02 months. Median overall survival (OS) is not yet mature.

[0109] 2) Non-squamous non-small cell lung cancer (NSCLC) cohort

[0110] In the NSCLC cohort, among 16 efficacy-evaluable EGFR / ALK wild-type patients, the ORR and cORR were 31.3% (5 / 16) and 25% (4 / 16), respectively. In patients with high MSLN expression (PS2#≥50), the ORR, cORR, median PFS, and median DoR were 41.7% (5 / 12), 33.3% (4 / 12), 6.87 months, and 9.13 months, respectively.

[0111] 3) Cervical cancer (CC) cohort

[0112] In the CC cohort, among 18 CC patients with evaluable efficacy, the ORR and cORR were 33.3% (6 / 18) and 27.8% (5 / 18), respectively; among 12 patients who had previously received ≥2 lines of treatment, the ORR and cORR were 41.7% (5 / 12) and 33.3% (4 / 12), respectively.

[0113] From the above data, it can be seen that the anti-MSLN-ADC-1 drug has significant effectiveness in treating ovarian cancer, non-squamous non-small cell lung cancer and cervical cancer.

[0114] In summary, the anti-MSLN-ADC-1 drug of the present invention showed acceptable safety and encouraging preliminary efficacy in the treatment of ovarian cancer, non-squamous non-small cell lung cancer, and cervical cancer, providing important research basis for the application of anti-MSLN antibody-drug conjugates in the treatment of cancer.

[0115] The present invention has been described by way of specific preferred embodiments, but it should be understood that the invention as claimed should not be unduly limited to these specific embodiments. Indeed, various variations of the described modes for implementing the invention that are obvious to those skilled in the relevant art should also be included within the scope of the appended claims.

Claims

1. A method for preventing and treating cancer, comprising administering to an individual having the cancer an effective amount of an anti-mesothelin (MSLN) antibody drug conjugate, characterized in that The structural formula of the antibody-drug conjugate is Ab-(LU)n, wherein the Ab is an anti-MSLN antibody, the U is a conjugated cytotoxic molecule, the L is a linker between the cytotoxic molecule and the anti-MSLN antibody, and n is an integer between 1 and 8, representing the number of cytotoxic molecules connected to the antibody; and the cancer is selected from ovarian cancer, cervical cancer, and lung cancer.

2. The method according to claim 1, characterized in that The U comprises a tubulin inhibitor or a DNA damaging agent; Preferably, the microtubule inhibitor comprises dolastatin or its derivatives, auristatin or its derivatives, or maytansine alkaloids or its derivatives; Preferably, the microtubule inhibitor includes monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF) or monomethyl auristatin D (MMAD); preferably, the microtubule inhibitor includes emtansine (DM1), maytansine (DM3) or ravtansine (DM4); preferably, the DNA damaging agent includes calicheamicin, duocarmycin, pyrrolobenzodiazepine (PBD), Dxd or SN-38.

3. The method according to claim 1 or 2, characterized in that The Ab comprises a heavy chain and a light chain; Wherein, the heavy chain includes a heavy chain variable region (VH), and the light chain includes a light chain variable region (VL); Wherein, the VH comprises CDR-H1, CDR-H2 and CDR-H3, the CDR-H1 comprises the following amino acid sequence: RYWMS (SEQ ID NO: 1), the CDR-H2 comprises the following amino acid sequence: EINPDSSTIVYTPSLKD (SEQ ID NO: 2) and the CDR-H3 comprises the following amino acid sequence: RGSHYYGYRTGYFDV (SEQ ID NO: 3); the VL comprises CDR-L1, CDR-L2 and CDR-L3, the CDR-L1 comprises the following amino acid sequence: SASSVSYMY (SEQ ID NO: 4), the CDR-L2 comprises the following amino acid sequence: DTSNLAS (SEQ ID NO: 5) and the CDR-L3 comprises the following amino acid sequence: QQWSSYPPT (SEQ ID NO: 6); preferably, the VH comprises the amino acid sequence as shown in SEQ ID NO: 7 and / or the VL comprises the amino acid sequence as shown in SEQ ID NO: 8; preferably, the heavy chain comprises the amino acid sequence as shown in SEQ ID NO:

9. NO:9; preferably, the light chain comprises the amino acid sequence shown in SEQ ID NO:

10.

4. The method according to claim 3, characterized in that The L is connected to the Ab via a sulfhydryl or amino group; Preferably, L is selected from the following structures:

5. The method according to any one of claims 1 to 4, characterized in that The antibody drug conjugate is selected from the following structures: wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.

6. The method according to any one of claims 1 to 5, characterized in that The antibody drug conjugate is administered intravenously to the individual.

7. The method according to any one of claims 1 to 6, characterized in that The drug-antibody ratio (DAR) of the anti-mesothelin antibody drug conjugate is between 3-8, more preferably between 3-7, more preferably between 3-6, more preferably between 3.5-4.5, and more preferably about 4.

8. The method according to any one of claims 1 to 7, characterized in that The dosage range of the antibody drug conjugate for a single administration to a subject is 1 mg / kg-5 mg / kg; preferably, the dosage range is selected from 1 mg / kg-3 mg / kg, 1 mg / kg-2.5 mg / kg, 1 mg / kg-2.0 mg / kg, 1.5 mg / kg-3.0 mg / kg, 1.5 mg / kg-2.5 mg / kg, 1.5 mg / kg-2.0 mg / kg, 2.0 mg / kg-3.0 mg / kg or 2.0 mg / kg-2.5 mg / kg; more preferably, the dosage range is 2.0 mg / kg-3.0 mg / kg or 1.0 mg / kg-2.0 mg / kg; preferably, the dosage range of the antibody drug conjugate for a single administration to a subject is selected from 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg or 2.5 mg / kg; more preferably, the dosage range is 2.0 mg / kg; Further preferably, the anti-MSLN antibody drug conjugate is administered to the individual once or more every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-MSLN antibody drug conjugate is administered to the individual once every 3 weeks.

9. The method according to any one of claims 1 to 8, characterized in that The cancer cells of the individual patient express MSLN on the surface at a level of IHC ≥ 1+, as determined by immunohistochemistry (IHC).

10. The method according to any one of claims 1 to 9, characterized in that The individual patient: (a) received one or more standard treatments before administration of the antibody drug conjugate; or / and (b) disease progression or inability to respond to treatment; or / and (c) unable to receive standard treatment; or / and (d) No standard treatment options exist.

11. The method according to any one of claims 1 to 10, characterized in that The lung cancer is non-small cell lung cancer; preferably non-squamous non-small cell lung cancer.

12. The method according to claim 11, characterized in that The individual with non-squamous non-small cell lung cancer has received platinum-containing doublet chemotherapy and / or PD-L1 inhibitor and / or PD-1 inhibitor treatment before the administration of the anti-MSLN antibody-drug conjugate; preferably, the individual with non-squamous non-small cell lung cancer has received more than two lines of treatment before the administration of the anti-MSLN antibody-drug conjugate.

13. The method according to any one of claims 1 to 10, characterized in that The ovarian cancer was a high-grade serous carcinoma.

14. The method according to claim 13, characterized in that The cancer is ovarian cancer, and the cancer cells of the individual patient express MSLN on the surface at the level of IHC2+ or IHC3+, as determined by immunohistochemistry (IHC).

15. The method according to claim 13 or 14, characterized in that The FIGO stage of the ovarian cancer is stage IV, or the individual has received bevacizumab monoclonal antibody treatment or PARPi inhibitor treatment before the administration of the anti-MSLN antibody-drug conjugate, or the ovarian cancer individual has received 1-4 lines of anti-tumor treatment and / or is sensitive or resistant to platinum before the administration of the anti-MSLN antibody-drug conjugate.

16. The method according to any one of claims 1 to 10, characterized in that The cervical cancer is selected from recurrent or metastatic cervical cancer; preferably, the individual has received 1-2 lines of systemic anti-tumor treatment before the administration of the anti-MSLN antibody-drug conjugate; preferably, it is platinum-containing chemotherapy and / or PD-L1 inhibitors and / or PD-1 treatment; preferably, the cervical cancer individual has received more than 2 lines of treatment before the administration of the anti-MSLN antibody-drug conjugate.

Images