Use of Anti-claudin 18.2 antibody-drug conjugate for treating gastric cancer and / or gastroesophageal junction adenocarcinoma

Abstract

Disclosed are a method for treating and preventing cancer, and compositions and uses related thereto. Specifically, provided is a method for treating cancer by means of administering a certain dose of a pharmaceutical composition comprising an anti-Claudin 18.2 antibody-drug conjugate to a subject. The method possesses remarkable efficacy and safety.

Description

Use of anti-claudin 18.2 antibody drug conjugate for treating gastric cancer and / or gastroesophageal junction adenocarcinoma TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, and particularly relates to a method for treating cancer by using an anti-Claudin 18.2 antibody drug conjugate. BACKGROUND

[0002] According to the latest survey data of the International Agency for Research on Cancer (IARC), the incidence of gastric cancer in the global population is 11.6 / 100,000, which is a globally high-incidence malignant tumor. More than 1 million new cases of gastric cancer are diagnosed worldwide each year, ranking fifth in malignant tumors, and the mortality rate ranks third. East Asia is the "epicenter" of gastric cancer worldwide, especially China, which has the highest incidence (12.3 / 100,000). According to the data released by the National Cancer Center in 2019, the incidence and mortality rates of gastric cancer are the second and third among all malignant tumors, respectively. Gastric cancer patients account for 44.1% of the total number of gastric cancer patients worldwide. Although the incidence and mortality rates of gastric cancer have decreased worldwide in recent years due to the popularization and promotion of various early screening technologies and early diagnosis and treatment concepts, gastric cancer is still the third leading cause of cancer-related deaths worldwide, and the prognosis of patients is poor. The prevention and treatment situation is still severe. Gastric cancer has high spatiotemporal heterogeneity, including tumor cell and tumor microenvironment heterogeneity, selection pressure during tumor evolution and treatment, making precise treatment of gastric cancer more difficult. Due to the limited number of patients who benefit from targeted or immunotherapy, and due to drug resistance, the duration of benefit from drug treatment is also limited. Therefore, the currently approved targeted or immunotherapeutic drugs cannot meet the needs of precise treatment of gastric cancer.

[0003] In recent years, the diagnosis and treatment of gastroesophageal junction adenocarcinoma (GEJA, EGJ) have attracted more and more clinical attention. Gastroesophageal junction adenocarcinoma refers to adenocarcinoma across the junction between the distal esophagus and the proximal stomach. In recent years, the incidence of gastroesophageal junction adenocarcinoma has shown an increasing trend worldwide, and effective treatment methods are urgently needed.

[0004] Claudins or CLDNs are widely distributed in various epithelial tissues and are important structural components of cell tight junctions. Studies have found that CLDNs protein is closely related to the maintenance of osmotic pressure, barrier function and cell polarity of epithelial cells. In addition, CLDNs have been shown to have changes in expression patterns during the development of many tumors. Targeted therapy research using CLDNs as specific marker proteins has received extensive attention. However, although most CLDNs are widely expressed, individual members such as CLDN 18 protein are often highly selectively expressed in specific tissues such as the gastrointestinal tract. CLDN 18 gene is located on human chromosome 3q22.3, and the first exon of the gene has two options, which form two different splicing mutants, and can express two protein subtypes with N-terminal 69 different amino acid sequences, namely Claudin 18.1 protein and CLDN 18.2 protein. Claudin 18.1 protein is a specific antigen selectively expressed by alveolar epithelial cells and is highly expressed only in normal alveolar tissue, but not in other normal tissues including pancreatic duct tissue. Claudin 18.2 protein is also a highly selective marker protein, but its distribution is completely different from that of Claudin 18.1 protein. Claudin 18.2 protein is highly restricted in normal healthy tissues, but is abnormally activated and overexpressed in many primary malignant tumors such as gastric cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer and non-small cell lung cancer. It is especially common in digestive system malignant tumors, including gastric cancer (70%), pancreatic cancer (50%), esophageal cancer (30%) and the like. Studies have shown that the expression of CLDN 18.2 protein is not limited to the primary lesion, but is also highly expressed in metastatic lesions, which may be involved in the process of malignant tumor cell proliferation and chemotactic metastasis. However, due to the high similarity between Claudin 18.2 and Claudin 18.1, and the fact that the first extracellular domain of Claudin 18.2 is identical to that of Claudin 18.1, the development of Claudin 18.2 therapeutic antibodies is very difficult, which is the main reason for the limitation of Claudin 18.2 targeted drug development, making it difficult to successfully develop Claudin 18.2 as a therapeutic drug for gastric cancer and other malignant tumors.

[0005] Currently, there are very limited treatment options for treating gastric cancer and / or gastroesophageal junction adenocarcinoma, and there is a need to develop treatment options with better efficacy and no serious safety risks. The present application solves this need. SUMMARY

[0006] The present application relates to a method for treating cancer, administering to an individual a pharmaceutical composition comprising an effective amount of an anti-Claudin18.2 antibody drug conjugate, the structure of the antibody drug conjugate is Ab-(L-D)n, wherein Ab is an anti-Claudin18.2 antibody or an antigen binding fragment thereof, D is a conjugated cytotoxic molecule, L is a linker between the cytotoxic molecule and the anti-Claudin18.2 antibody, n is an integer between 1 and 8, n represents the number of cytotoxic molecules linked to the antibody, and the Ab comprises the following HCDR1-3 and LCDR1-3 combinations:

[0007] HCDR1: comprising the following amino acid sequence NYLIE (SEQ ID NO: 1), HCDR2: comprising the following amino acid sequence LINPGSGGTNYNEKFKG (SEQ ID NO: 2), HCDR3: comprising the following amino acid sequence GGYYGNSFAY (SEQ ID NO: 3); and LCDR1: comprising the following amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 4), LCDR2: comprising the following amino acid sequence WASTRES (SEQ ID NO: 5), LCDR3: comprising the following amino acid sequence QNAYYYPYT (SEQ ID NO: 6);

[0008] The drug-to-antibody ratio (DAR) of the antibody drug conjugate in the pharmaceutical composition is in the range of 2-8.

[0009] The cancer is selected from gastric cancer (GC) and / or gastroesophageal junction adenocarcinoma (GEJA).

[0010] In the present application, the complementarity determining regions CDR1-3 of the heavy and light chain variable regions adopt the Kabat numbering system. Table 1 Amino acid sequences of CDR1-3 of heavy and light chain variable regions

[0011] In certain embodiments, the anti-Claudin 18.2 antibody drug conjugate of the present application, D comprises a tubulin inhibitor, a DNA inhibitor or other toxin molecule; in some preferred embodiments, the tubulin inhibitor comprises, but is not limited to, Auristatins, Maytansinoid Derivatives, tubulysin, halichondrin, Cryptophycins, EG5 inhibitors and derivatives thereof; the DNA inhibitor further comprises a DNA damaging agent or a topoisomerase I inhibitor; in some more preferred embodiments, the tubulin inhibitor comprises, but is not limited to, Auristatin F (AF), monomethyl auristatin D (MMAD), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF) and derivatives thereof; the Maytansinoid Derivatives further comprise, but are not limited to, DM1, DM2, DM4 and derivatives thereof; the halichondrin further comprises, but is not limited to, eribulin and derivatives thereof; the DNA inhibitor comprises, but is not limited to, calicheamicin, pyrrolobenzodiazepine (PBD), indolinobenzodiazepine (IBD), duocarmycin and derivatives thereof; the topoisomerase I inhibitor further comprises, but is not limited to, camptothecin derivatives; in some more preferred embodiments, the camptothecin derivatives further comprise, but are not limited to, Exatecan, SN38, DXD and derivatives thereof; the other toxin molecule comprises, but is not limited to, amanitin, Maaa-1181a, taxol, daunomycin, vinblastine, Doxorubicin, methotrexate or derivatives.

[0012] In certain embodiments, the anti-Claudin 18.2 antibody drug conjugate of the present application, L is covalently linked to an amino residue or a thiol residue on Ab; in some preferred embodiments, L is covalently linked to a thiol residue on Ab; in some more preferred embodiments, L is covalently linked to a thiol residue formed after the interchain disulfide bond on Ab is opened.

[0013] In certain embodiments, the anti-Claudin 18.2 antibody drug conjugate of the present application, L is selected from the following structures:

[0014] In certain embodiments, the present application relates to an anti-Claudin 18.2 antibody drug conjugate, Ab, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the heavy chain variable region (VH) comprises an amino acid sequence as set forth in SEQ ID NO: 7; and / or the light chain variable region (VL) comprises an amino acid sequence as set forth in SEQ ID NO: 8.

[0015] SEQ ID NO: 7:

[0016] SEQ ID NO: 8:

[0017] In certain embodiments, the present application relates to an anti-Claudin 18.2 antibody drug conjugate, Ab, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 9; and / or the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 10.

[0018] The heavy chain amino acid sequence of the anti-Claudin 18.2 antibody is set forth in SEQ ID NO: 9:

[0019] The light chain amino acid sequence of the anti-Claudin 18.2 antibody is set forth in SEQ ID NO: 10:

[0020] In certain embodiments, the drug antibody ratio of the antibody drug conjugate in the pharmaceutical composition is between 3-8; in certain preferred embodiments, the drug antibody ratio of the antibody drug conjugate in the pharmaceutical composition is between 3-7; in certain preferred embodiments, the drug antibody ratio of the antibody drug conjugate in the pharmaceutical composition is between 3-6; in certain preferred embodiments, the drug antibody ratio of the antibody drug conjugate in the pharmaceutical composition is between 3-5, and in certain preferred embodiments, the drug antibody ratio of the antibody drug conjugate in the pharmaceutical composition is between 3.5-4.5.

[0021] In some embodiments, the dose of the antibody drug conjugate in the pharmaceutical composition administered to the individual in a single administration is in the range of 1 mg / kg to 5 mg / kg; preferably the dose is selected from the group consisting of 1 mg / kg to 3 mg / kg, 1 mg / kg to 2.5 mg / kg, 1 mg / kg to 2.0 mg / kg, 1.5 mg / kg to 3.0 mg / kg, 1.5 mg / kg to 2.5 mg / kg, 1.5 mg / kg to 2.0 mg / kg, 2.0 mg / kg to 3.0 mg / kg, or 2.0 mg / kg to 2.5 mg / kg; more preferably the dose is in the range of 1.5 mg / kg to 2.5 mg / kg or 1.5 mg / kg to 2.0 mg / kg or 2.0 mg / kg to 2.5 mg / kg.

[0022] In some embodiments, the dose of the antibody drug conjugate in the pharmaceutical composition administered to the individual in a single administration is selected from the group consisting of 1.5 mg / kg, 1.6 mg / kg, 2.0 mg / kg, 2.3 mg / kg or 2.5 mg / kg; preferably the dose is 2.0 mg / kg.

[0023] In some embodiments, the pharmaceutical composition is administered to the individual once or more than once every 1 week or every 2 weeks or every 3 weeks or every 4 weeks; preferably the pharmaceutical composition is administered to the individual once every 2 weeks.

[0024] In some embodiments, the pharmaceutical composition is administered to the individual by subcutaneous injection, abdominal injection, intramuscular injection or intravenous injection; preferably the pharmaceutical composition is administered to the individual by intravenous injection.

[0025] In some embodiments, the anti-Claudin 18.2 antibody drug conjugate of the present application is administered to the individual for 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks or 72 weeks or more than 72 weeks.

[0026] In some embodiments, the anti-Claudin 18.2 antibody drug conjugate of the present application is ADC-1, which has the following structure (Ab-Mc-Val-Cit-PAB-MMAE, Ab is an anti-Claudin 18.2 antibody, the heavy chain amino acid sequence is SEQ ID NO: 9, and the light chain amino acid sequence is SEQ ID NO: 10):

[0027] wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8.

[0028] In certain embodiments, the anti-Claudin 18.2 antibody drug conjugate ADC-2 of the present application is as follows (Ab-D07-Val-Cit-PAB-MMAE, Ab is an anti-Claudin 18.2 antibody, the heavy chain amino acid sequence of which is SEQ ID NO: 9, and the light chain amino acid sequence of which is SEQ ID NO: 10):

[0029] wherein n is an integer selected from 1, 2, 3, 4.

[0030] In certain embodiments, the anti-Claudin 18.2 antibody drug conjugate ADC-3 of the present application is as follows (Ab-PY-Val-Cit-MMAE, Ab is an anti-Claudin 18.2 antibody, the heavy chain amino acid sequence of which is SEQ ID NO: 9, and the light chain amino acid sequence of which is SEQ ID NO: 10):

[0031] wherein n is an integer selected from 1, 2, 3, 4.

[0032] In certain embodiments, the cancer of the present application is a Claudin 18.2 positive expressing cancer; preferably, the cancer is a Claudin 18.2 moderately or highly expressing cancer; more preferably, the cancer is a locally advanced unresectable or metastatic malignant cancer positive for Claudin 18.2 expression.

[0033] In certain embodiments, the individual has received ≥2 lines of prior treatment.

[0034] In certain embodiments, the treatment is a treatment with statistically significant effect on gastric cancer (GC) and / or gastroesophageal junction adenocarcinoma (GEJA).

[0035] In certain embodiments, the present application provides use of an anti-Claudin 18.2 antibody drug conjugate in the manufacture of a medicament for the treatment of gastric cancer (GC) and / or gastroesophageal junction adenocarcinoma (GEJA).

[0036] In certain embodiments, the drug to antibody ratio of the anti-Claudin 18.2 antibody drug conjugate in the pharmaceutical composition is between 2-8; in certain preferred embodiments, the drug to antibody ratio of the anti-Claudin 18.2 antibody drug conjugate in the pharmaceutical composition is between 3-8; in certain more preferred embodiments, the drug to antibody ratio of the anti-Claudin 18.2 antibody drug conjugate in the pharmaceutical composition is between 3-7; in certain more preferred embodiments, the drug to antibody ratio of the anti-Claudin 18.2 antibody drug conjugate in the pharmaceutical composition is between 3-6; in certain more preferred embodiments, the drug to antibody ratio of the anti-Claudin 18.2 antibody drug conjugate in the pharmaceutical composition is between 3-5; in certain more preferred embodiments, the drug to antibody ratio of the anti-Claudin 18.2 antibody drug conjugate in the pharmaceutical composition is between 3.5-4.5.

[0037] The detection method of the above antibody drug conjugate content is ultraviolet-visible spectrophotometry. According to Lambert-Beer law, the strength of light absorption of a substance at a certain wavelength is related to the concentration of the absorbing substance and the thickness of the liquid layer. Since the antibody drug conjugate contains small molecule drugs, the small molecule drugs have certain light absorption in the ultraviolet / visible region. The protein concentration of the antibody drug conjugate should be the concentration of the monoclonal antibody plus the concentration of the small molecule drug. After confirming the wavelength accuracy of the equipment, the absorbance of the antibody drug conjugate at 248 nm and 280 nm is measured according to the absorbance value of the antibody drug and the extinction coefficient of the antibody and the drug. The concentration of the antibody and the drug can be determined by the following equation, i.e. mAb and C drug . The total absorbance value of the antibody drug conjugate at 280 nm is the sum of the absorbance of the drug and the antibody A 280 , and the total absorbance value of the antibody drug conjugate at 248 nm is the sum of the absorbance of the drug and the antibody A 248 , which can be calculated by the following equations 1 and 2, respectively:

[0038] is the extinction coefficient value of the drug at 280 nm (unit: (mg / ml) -1 · cm -1 ), is the extinction coefficient value of the antibody at 280 nm (unit: (mg / ml) -1 · cm -1 ), and L is the thickness of the liquid layer through which the light passes (unit: cm).

[0039] is the extinction coefficient value of the drug at 248 nm (unit: (mg / ml)-1 • cm -1 ), is the extinction coefficient value of the antibody at 248 nm (unit: (mg / ml) -1 • cm -1 ), L is the thickness of the liquid layer through which light passes (unit: cm).

[0040] The concentrations (mg / ml) of the antibody and the drug are obtained by the above two equations, respectively: C mAb and C drug

[0041] N is the dilution factor, then the concentration C ADC of the antibody-drug conjugate is: C ADC = C mAb + C drug Definition

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same or similar meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present application, the definitions and terms used in the art are specifically incorporated by reference from Current Protocols in Molecular Biology (Ausubel). Abbreviations for amino acid residues are those commonly used in the art to designate one of the 20 commonly occurring L-amino acids by standard three letter and / or one letter codes.

[0043] Complementarity determining region (CDR) determination or numbering methods for antibody variable domains include IMGT, Kabat, Chothia, AbM, and Contact methods, which are well known in the art.

[0044] The term "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, 5th Ed., U.S. Department of Health and Human Services, NIH, 1991, and subsequent editions). There are three heavy chain CDRs and three light chain CDRs. The term CDR or CDRs as used herein is intended to indicate one, several or even all of these regions which contain the majority of the amino acid residues responsible for binding by virtue of the affinity of the antibody for the antigen or its recognized epitope. The CDR regions in the present application are identified using the Rabat system (Kabat, E. A., et al. (1991). Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication NO: 91-3242).

[0045] The term "antibody" is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, particularly "antibodies" as used herein refer 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 regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. These variable regions of the heavy and light chains contain the binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. Chimeric or humanized antibodies are also encompassed within the antibodies according to the application.

[0046] The term "dolastatin" refers to polypeptides isolated from a marine organism, Dolabella auricularia, including but not limited to dolastatin 10 and dolastatin 15. Dolastatins are mitotic inhibitors that exhibit strong anticancer activity and thus are candidates for anticancer drugs. Researchers have further discovered and synthesized many derivatives of dolastatins, such as MMAE, MMAD and MMAF.

[0047] The term "Drug-to-Antibody Ratio" or "DAR" refers to the average number of drug molecules attached to each antibody molecule in a prepared pharmaceutical composition.

[0048] The terms "administration" or "administering" refer to the act of physically introducing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to one of skill in the art. Exemplary routes of administration include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, intraspinal, or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinally, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. A therapeutic agent can be administered by a non-parenteral route, as well as orally. Other non-parenteral routes include topical, epidermal, or mucosal routes of administration, e.g., intranasal, vaginal, rectal, sublingual, or topical administration. Administration can also be performed, e.g., once, multiple times, and / or over one or more extended periods.

[0049] The term "cancer" refers to a large family of diseases characterized by uncontrolled abnormal cell growth in the body, "cancer" can include solid tumors or non-solid tumors.

[0050] The term "anti-Claudin 18.2 antibody drug conjugate" refers to a compound obtained by conjugating an optional anti-Claudin 18.2 antibody with a cytotoxic molecule via an optional linker.

[0051] The term "treatment" refers to any type of intervention or process performed on an individual subject, or administration of an active agent, such as an antibody drug conjugate in the present application, to the subject, with the objective of reversing, alleviating, improving, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of a symptom, complication, condition, or biochemical indicia associated with a disease; the term "treatment" as used herein does not refer to an absolute term, for example, "treatment" as used in a clinical setting is intended to include obtaining beneficial or desired clinical results, and can include improving the condition of a subject individual suffering from cancer, beneficial or desired clinical results include, but are not limited to, one or more of the following: reduction (or destruction) of tumor or cancer cell proliferation. Preferably, "treatment" is a statistically significant treatment. The statistically significant effect can be relative to a placebo treatment, or relative to another anti-tumor or anti-cancer treatment. By "statistically significant" is meant that the results are not due to chance, statistical significance can be determined by any method known in the art.

[0052] The term "effective amount" refers to any amount of a drug, when used alone or in conjunction with another therapeutic agent, that protects an individual subject from the onset of a disease or promotes the regression of a disease, such as a reduction in the severity of symptoms of the disease, an increase in the frequency and duration of periods without symptoms of the disease, or a prevention of damage or disability due to the disease affliction. The ability of a therapeutic agent to promote the regression of a disease can be assessed using various methods known to those skilled in the art, for example, in human subject individuals during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the therapeutic agent in in vitro assays.

[0053] The term "metastasis" refers to the spread of cancer cells from where they first formed (the primary site) to one or more other sites in the subject (one or more secondary sites). During metastasis, 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 comprise cancer cells that are the same as or similar to the primary tumor. At the secondary site, the tumor cells can proliferate and begin to grow or colonize at that distant site, generating a secondary tumor.

[0054] 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 in the present application.

[0055] The term "and / or", used in the phrases "A and / or B" and the like, as used in the present application, is intended to mean either "A and B" or "A or B" or (alone) "A" and (alone) "B". Likewise, the term "and / or" used in the phrases "A, B, and / or C" and the like, is intended to encompass the following aspects: A, B, C; A, B, or C; A or B, C; A or C, B; 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] The term "treatment-emergent adverse events (TEAEs)" are adverse events that are new onset or worsening after the start of treatment.

[0057] The term "treatment-related adverse events (TRAEs)" are TEAEs that are judged as related, very likely related, and likely related to the study drug. For the sake of conservatism, TEAEs with a judgment of "unable to determine" or missing relatedness to the study drug are also considered as TRAEs. DETAILED DESCRIPTION

[0058] Embodiments of the present application will be described in detail below with reference to the examples, but those skilled in the art will understand that the examples below are only for the purpose of illustrating the present application and should not be considered as limiting the scope of the present application.

[0059] Example 1: Open-label, multicenter, phase I / IIa clinical study of anti-Claudin 18.2 antibody drug conjugate (ADC-1, drug antibody ratio (DAR): 3.5-4.5) for injection in patients with Claudin 18.2 expression-positive locally advanced unresectable or metastatic malignant solid tumors

[0060] This is an open-label, multicenter, phase I / II clinical trial to evaluate the safety and efficacy of anti-Claudin 18.2 antibody drug conjugate for injection in the treatment of patients with advanced or metastatic solid tumors. The study design includes a dose escalation phase followed by a cohort expansion phase at doses of 1.5, 2.0, and 2.5 mg / kg, respectively. Anti-Claudin 18.2 antibody drug conjugate (ADC-1) is administered intravenously once every two weeks. The primary endpoint is objective response rate (ORR) and safety. A pooled analysis is performed for GC / GEJA patients with CLDN18.2 medium / high expression (≥2+ membrane staining intensity ≥2+). I. Experimental purposes:

[0061] To preliminarily evaluate the tolerability and safety of anti-Claudin 18.2 antibody drug conjugate (ADC-1) in patients with Claudin 18.2 positive locally advanced unresectable or metastatic malignant solid tumors, and determine the maximum tolerated dose (MTD) and recommended dose for phase II clinical trial (RP2D). 1. Phase I

[0062] Primary objective: To explore the tolerability, safety of ADC-1 in patients with locally advanced unresectable or metastatic malignant solid tumors, determine the maximum tolerated dose (MTD) and recommended dose for phase II clinical trial (RP2D).

[0063] Secondary objective: To evaluate the pharmacokinetic characteristics and immunogenicity of ADC-1 in patients with locally advanced unresectable or metastatic malignant solid tumors; To preliminarily explore the effectiveness of ADC-1 in patients with locally advanced unresectable or metastatic malignant solid tumors. To explore the correlation between Claudin 18.2 expression and the efficacy of ADC-1, and support the development of subsequent companion diagnostic reagents. 2. Phase IIa

[0064] Primary objective: To explore the clinical effectiveness and safety of long-term use of ADC-1 in patients with different tumor types at the RP2D dose, and provide more trial basis for subsequent research. To optimize the effectiveness and safety of different administration methods of ADC-1.

[0065] Secondary objective: To evaluate the pharmacokinetic characteristics and immunogenicity of ADC-1 in patients with locally advanced unresectable or metastatic malignant solid tumors; To preliminarily explore the effectiveness of ADC-1 in patients with locally advanced unresectable or metastatic malignant solid tumors. To explore the correlation between Claudin 18.2 expression and the efficacy of ADC-1, and support the development of subsequent companion diagnostic reagents. 2. Phase IIa

[0066] 1. Voluntarily participate in this study, and sign the informed consent form in writing;

[0067] 2. 18 years old ≤ age ≤ 75 years old, gender unrestricted in the phase I dose escalation phase; 18 years old or older, gender unrestricted in the phase IIa cohort expansion / dose optimization phase;

[0068] 3. ECOG performance status score of 0 or 1;

[0069] 4. Expected survival of more than 12 weeks;

[0070] 5. Patients with locally advanced unresectable or metastatic malignant solid tumors who have progressed after adequate standard treatment, or who cannot tolerate adequate standard treatment, or for whom there is no standard treatment;

[0071] 6. The subject agrees to provide tumor tissue specimen for CLDN 18.2 detection at screening, and needs to meet the following criteria: Patients with gastric cancer / gastroesophageal junction adenocarcinoma with positive Claudin 18.2 expression (membrane staining positive observed in any tumor cell) for Phase I dose escalation stage; Patients with gastric cancer / gastroesophageal junction adenocarcinoma with positive Claudin 18.2 expression (membrane staining positive observed in any tumor cell) for Phase IIa dose expansion stage; Patients with gastric cancer / gastroesophageal junction adenocarcinoma with positive Claudin 18.2 expression (membrane staining positive observed in any tumor cell) for Phase IIa dose optimization stage.

[0072] 7. At least one measurable target lesion based on imaging examination (CT / MRI) according to RECIST v1.1 criteria;

[0073] 8. Adequate bone marrow, liver, and renal function (according to the normal value of the clinical trial center): absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L, platelet ≥ 100 x 10 9 / L, hemoglobin ≥ 90 g / L, serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN), ALT, AST or ALP ≤ 3 times ULN when there is no liver metastasis; ALT, AST or ALP ≤ 5 times ULN when there is liver metastasis, serum creatinine ≤ 1.5 times ULN, International Normalized Ratio (INR) ≤ 1.5 times ULN, APTT ≤ 1.5 times ULN;

[0074] 9. Male or female subjects of childbearing potential must agree to take effective contraceptive measures during the study period and for 6 months after the end of the last dose, such as double-barrier contraceptive methods, condoms, oral or injected contraceptive drugs, intrauterine devices, etc.

[0019] Test drug: anti-Claudin 18.2 antibody drug conjugate (ADC-1) for injection

[0021] Table 3 Secondary efficacy indicators

[0075] Five. Statistical analysis of effectiveness

[0076] In the dose optimization phase, 28 subjects with gastric cancer or gastroesophageal junction cancer were enrolled to receive ADC-1 Q3W treatment. The median age of all enrolled subjects was 55.5 years (range: 33-71), most of the subjects were gastric cancer (25 cases, 89.3%), and most of the subjects (27 cases, 96.4%) were in stage IV at enrollment, and most of the subjects had ECOG score ≥1 (92.9%) at baseline. Among the 27 subjects with evaluable efficacy, 1 (3.7%) subject achieved complete remission (CR), 7 (25.9%) subjects achieved PR, 13 (48.1%) subjects achieved SD, 6 (22.2%) subjects achieved PD, the ORR was 29.6%, and the disease control rate was 77.8%. The ORR of the 1.6 mg / kg, 2.0 mg / kg and 2.3 mg / kg dose groups was 22.2% (2 / 9), 30.0% (3 / 10) and 37.5% (3 / 8), respectively.

[0077] The 95% CI of ORR and DCR was calculated using the Clopper-Pearson method. Table 4 Dose optimization phase effectiveness results The 95% CI of ORR and DCR was calculated using the Clopper-Pearson method.[1] The percentage is based on the number of subjects with CR / PR response; the rest of the percentages are calculated based on N.

[0078] The best overall response (BOR) was defined as the best response at all time points before the first disease progression or the start of new anti-tumor treatment (whichever occurred first) (data cutoff date: March 10, 2025).

[0079] The treatment of GC / GEJA using the method in the present application can produce beneficial efficacy and safety, especially the clinical data of the 2.0 mg / kg treatment group of anti-claudin 18.2 antibody drug conjugate showed that all patients were well tolerated, further indicating that it has good efficacy and controllable safety.

Claims

1. A method for treating cancer, characterized in that, A pharmaceutical composition comprising an effective amount of an anti-Claudin 18.2 antibody drug conjugate, the structure of the antibody drug conjugate is Ab-(L-D)n, wherein the Ab is an anti-Claudin 18.2 antibody or an antigen binding fragment thereof, the D is a conjugated cytotoxic molecule, the L is a linker between the cytotoxic molecule and the anti-Claudin 18.2 antibody, n is an integer between 1 and 8, n represents the number of cytotoxic molecules linked on the antibody, the Ab comprises the following HCDR1-3 and LCDR1-3 combinations: HCDR1: comprising the following amino acid sequence NYLIE (SEQ ID NO: 1), HCDR2: comprising the following amino acid sequence LINPGSGGTNYNEKFKG (SEQ ID NO: 2), HCDR3: comprising the following amino acid sequence GGYYGNSFAY (SEQ ID NO: 3); and LCDR1: comprising the following amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 4), LCDR2: comprising the following amino acid sequence WASTRES (SEQ ID NO: 5), LCDR3: comprising the following amino acid sequence QNAYYYPYT (SEQ ID NO: 6); the Drug-to-Antibody Ration (DAR) of the antibody drug conjugate in the pharmaceutical composition ranges between 2-8; the cancer is selected from gastric cancer (GC) and / or gastroesophageal junction adenocarcinoma (GEJA).

2. The method of claim 1, wherein, The D comprises a tubulin inhibitor, a DNA inhibitor or other toxin molecule; further preferably, the tubulin inhibitor comprises, but is not limited to, Auristatins, Maytansinoid Derivatives, tubulysin, halichondrin, Cryptophycins, EG5 inhibitors and derivatives thereof; the DNA inhibitor further comprises a DNA damaging agent or a topoisomerase I inhibitor; more preferably, the tubulin inhibitor comprises, but is not limited to, Auristatin F (AF), Monomethyl Auristatin D (MMAD), Monomethyl Auristatin E (MMAE), Monomethyl Auristatin F (MMAF) and derivatives thereof; the Maytansinoid Derivatives further comprise, but are not limited to, DM1, DM2, DM4 and derivatives thereof; the halichondrin further comprises, but is not limited to, eribulin and derivatives thereof; the DNA inhibitor comprises, but is not limited to, calicheamicin, pyrrolobenzodiazepine (PBD), indolinobenzodiazepine (IBD), duocarmycin and derivatives thereof; the topoisomerase I inhibitor further comprises, but is not limited to, camptothecin derivatives; further preferably, the camptothecin derivatives further comprise, but are not limited to, Exatecan, SN38, DXD and derivatives thereof; the other toxin molecule comprises, but is not limited to, amanitin, Maaa-1181a, taxol, daunomycin, vinblastine, Doxorubicin, methotrexate or derivatives.

3. The method according to claim 1 or 2, characterized in that, The L is covalently linked to an amino residue or a thiol residue on the Ab; preferably, the L is covalently linked to a thiol residue on the Ab; more preferably, the L is covalently linked to a thiol residue formed after opening of an interchain disulfide bond on the Ab.

4. The method according to any one of claims 1-3, characterized in that, L is selected from the following structures:

5. The method according to any one of claims 1-4, characterized in that, The Ab comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: The heavy chain variable region (VH) comprises an amino acid sequence as set forth in SEQ ID NO: 7; and / or The light chain variable region (VL) comprises an amino acid sequence as set forth in SEQ ID NO:

8.

6. The method of claim 5, wherein, The Ab comprises a heavy chain and a light chain, wherein: The heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 9; and / or The light chain comprises an amino acid sequence as set forth in SEQ ID NO:

10.

7. The method according to any one of claims 1 to 6, characterized in that, The drug antibody ratio of the antibody drug conjugate in the pharmaceutical composition is between 3-8, further preferably between 3-7, further preferably between 3-6, further preferably between 3-5, further preferably between 3.5-4.

5.

8. The method according to any one of claims 1 to 7, characterized in that, The dose of the antibody drug conjugate in the pharmaceutical composition administered to the individual at a single time is in the range of 1 mg / kg to 5 mg / kg; preferably the dose is selected from the group consisting of 1 mg / kg to 3 mg / kg, 1 mg / kg to 2.5 mg / kg, 1 mg / kg to 2.0 mg / kg, 1.5 mg / kg to 3.0 mg / kg, 1.5 mg / kg to 2.5 mg / kg, 1.5 mg / kg to 2.0 mg / kg, 2.0 mg / kg to 3.0 mg / kg or 2.0 mg / kg to 2.5 mg / kg; more preferably the dose is in the range of 1.5 mg / kg to 2.5 mg / kg or 1.5 mg / kg to 2.0 mg / kg or 2.0 mg / kg to 2.5 mg / kg.

9. The method of claim 8, wherein, The dose of the antibody drug conjugate in the pharmaceutical composition administered to the individual at a single time is selected from the group consisting of 1.5 mg / kg, 1.6 mg / kg, 2.0 mg / kg, 2.3 mg / kg or 2.5 mg / kg; preferably the dose is 1.6 mg / kg, 2.0 mg / kg, 2.3 mg / kg; more preferably the dose is 2.3 mg / kg; more preferably the dose is 2.0 mg / kg.

10. The method according to claim 8 or 9, characterized in that, The pharmaceutical composition is administered to the individual once or more than once every 1 week or every 2 weeks or every 3 weeks or every 4 weeks; preferably the pharmaceutical composition is administered to the individual once every 2 weeks.

11. The method according to any one of claims 1-10, characterized in that, The administration to the individual is by subcutaneous injection, abdominal injection, intramuscular injection or intravenous injection; preferably the administration is by intravenous injection.

12. The method according to any one of claims 1-11, characterized in that, The administration to the individual is for 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks or 72 weeks or more than 72 weeks.

13. The method according to any one of claims 1-12, characterized in that, The antibody drug conjugate has the following structure: wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8; or wherein n is an integer selected from 1, 2, 3, 4; or wherein n is an integer selected from 1, 2, 3, 4.

14. The method of any one of claims 1-13, wherein, The cancer is a Claudin 18.2 positive expressing cancer; preferably the cancer is a Claudin 18.2 moderately or highly expressing cancer; more preferably the cancer is a locally advanced unresectable or metastatic malignancy that is positive for Claudin 18.2 expression.

15. The method of claim 14, wherein, The individual has received prior treatment with ≥2 lines of therapy.

16. Use of an anti-Claudin 18.2 antibody drug conjugate for the manufacture of a pharmaceutical composition for the treatment of gastric cancer (GC) and / or gastroesophageal junction adenocarcinoma (GEJA) according to any one of claims 1 to 15.

17. Use according to claim 16, characterized in that, The drug antibody ratio of the anti-Claudin 18.2 antibody drug conjugate in the pharmaceutical composition is between 2 and 8; further preferably between 3 and 8; preferably between 3 and 7; further preferably between 3 and 6; further preferably between 3 and 5; further preferably between 3.5 and 4.5.

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