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WO2025167977A1 - Utilisation combinée d'un conjugué anticorps-médicament et d'un inhibiteur de point de contrôle immunitaire - Google Patents

Utilisation combinée d'un conjugué anticorps-médicament et d'un inhibiteur de point de contrôle immunitaire

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Publication number
WO2025167977A1
WO2025167977A1 PCT/CN2025/075988 CN2025075988W WO2025167977A1 WO 2025167977 A1 WO2025167977 A1 WO 2025167977A1 CN 2025075988 W CN2025075988 W CN 2025075988W WO 2025167977 A1 WO2025167977 A1 WO 2025167977A1
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WO
WIPO (PCT)
Prior art keywords
cancer
drug
antibody
once
weeks
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/075988
Other languages
English (en)
Chinese (zh)
Inventor
刘军豪
孙丹妮
周远锋
邱鹏超
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changzhou Hansoh Pharmaceutical Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Original Assignee
Changzhou Hansoh Pharmaceutical Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changzhou Hansoh Pharmaceutical Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Changzhou Hansoh Pharmaceutical Co Ltd
Publication of WO2025167977A1 publication Critical patent/WO2025167977A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans

Definitions

  • This application belongs to the field of medicine and relates to the use of an antibody-drug conjugate, alone or in combination, in the preparation of a drug for the prevention and/or treatment of cancer.
  • the present invention provides the use of an antibody-drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, alone or in combination with an immune checkpoint inhibitor and an optional chemotherapeutic agent, in the preparation of a drug for the prevention and/or treatment of cancer.
  • Antibody-drug conjugates are a class of targeted biologics that link cytotoxic drugs to monoclonal antibodies via a linker. Using the monoclonal antibody as a carrier, small-molecule cytotoxic drugs are efficiently and effectively delivered to target tumor cells in a targeted manner. Tumor-specific antibodies enable ADCs to selectively deliver small-molecule cytotoxic drugs, minimizing off-target effects while retaining their anti-tumor properties, effectively improving the benefit-risk ratio of anti-tumor therapy.
  • B7 homolog 4 is a newly discovered member of the B7 family. It plays a crucial role in multiple cellular biological processes, such as cell differentiation, proliferation, and apoptosis, and may influence tumor cell invasion and metastasis.
  • B7 family is an important co-stimulatory molecule that influences processes such as T cell proliferation and B cell activation.
  • Studies have shown that B7 homolog 4 is highly expressed in various tumors, including cholangiocarcinoma, breast cancer, endometrial cancer, non-small cell lung cancer, ovarian cancer, gastric cancer, and pancreatic cancer, while its expression is limited in normal tissues. Therefore, B7 homolog 4 has potential as a target for ADCs.
  • Immune checkpoint inhibitors block the binding of immune checkpoints to their ligands, relieving the immune suppression caused by immune checkpoints and thereby reactivating immune cells to exert anti-tumor effects.
  • CTLA-4 cytotoxic T lymphocyte-associated antigen-4
  • PD-1 programmed death-1
  • PD-L1 programmed death-ligand 1
  • PD-1 monoclonal antibodies and three PD-L1 monoclonal antibodies have been approved for the clinical treatment of 11 cancer types, including non-small cell lung cancer, melanoma, head and neck cancer, colorectal cancer, and gastric cancer.
  • 11 cancer types including non-small cell lung cancer, melanoma, head and neck cancer, colorectal cancer, and gastric cancer.
  • ICIs have significant anti-tumor activity in many types of malignant tumors, their response rate is low in most tumors, and new regimens need to be developed to improve the response rate of ICIs treatment.
  • platinum-based drugs are non-specific cell cycle drugs that primarily form Pt-DNA adducts with DNA after entering tumor cells, thereby mediating tumor cell necrosis or apoptosis, thereby producing anti-cancer effects. Due to their unique anti-cancer mechanisms and broad anti-cancer spectrum, platinum-based drugs are currently one of the most widely used chemotherapy drugs in clinical practice. They are widely used as basic drugs in the treatment of common malignancies such as lung cancer, bladder cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, colorectal cancer, and head and neck tumors. Although platinum-based drugs have become the first-line chemotherapy drugs for the clinical treatment of tumors, their severe drug resistance has greatly limited their clinical application.
  • the present disclosure provides a use of an antibody-drug conjugate and an immune checkpoint inhibitor in combination for preparing a drug for treating cancer.
  • the structure of the antibody-drug conjugate is shown in formula (I):
  • Pc is an anti-B7H4 antibody or an antigen-binding fragment thereof.
  • the present disclosure also provides a use of an antibody-drug conjugate and a platinum drug in combination for preparing a drug for treating cancer.
  • the structure of the antibody-drug conjugate is shown in formula (I):
  • n is a non-zero integer or decimal from 1 to 10, preferably a decimal or integer from 1 to 8, preferably a decimal or integer from 2 to 8, more preferably from 3 to 8, and can be an integer or a decimal, more preferably 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.
  • Pc is an anti-B7H4 antibody or an antigen-binding fragment thereof.
  • the above-mentioned anti-B7H4 antibody or its antigen-binding fragment comprises: heavy chain HCDR1, HCDR2, HCDR3 as shown in SEQ ID NO: 01, 02 and 03 amino acid sequences, respectively, and light chain LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 04, 05 and 06 amino acid sequences, respectively.
  • the anti-B7H4 antibody or antigen-binding fragment thereof is selected from a humanized antibody or a fragment thereof.
  • the anti-B7H4 antibody or antigen-binding fragment thereof described herein is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') 2 fragments.
  • the anti-B7H4 antibody or antigen-binding fragment thereof described herein comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably a heavy chain constant region of IgG1 or IgG4 isotype.
  • the anti-B7H4 antibody or antigen-binding fragment thereof comprises a light chain constant region of ⁇ or ⁇ .
  • the heavy chain variable region sequence of the anti-B7H4 antibody or its antigen-binding fragment is the sequence shown in SEQ ID NO: 07 or a variant thereof
  • the light chain variable region sequence is the sequence shown in SEQ ID NO: 08 or a variant thereof.
  • the order is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • the italics in the sequence are FR sequences, and the underlines are CDR sequences.
  • the CDR sequences are derived from the Kabat definition rules.
  • the heavy chain sequence of the anti-B7H4 antibody or its antigen-binding fragment is the sequence shown in SEQ ID NO: 09 or a variant thereof
  • the light chain sequence is the sequence shown in SEQ ID NO: 10 or a variant thereof.
  • Heavy chain (IgG1) amino acid sequence (SEQ ID NO: 09)
  • the immune checkpoint inhibitor is selected from antibodies or antigen-binding fragments thereof targeting PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, A2aR, B7-H3, B7-H4, preferably antibodies or antigen-binding fragments thereof targeting PD-1 or PD-L1.
  • the immune checkpoint inhibitor is selected from Adebrelimab, Camrelizumab, Dostarlimab, Toripalimab, Sintilimab, Tislelizumab, Zimberelimab, Penpulimab, Serplulimab, Pucotenlimab, Pembrolizumab , Nivolumab, Sugemalimab, Envafolimab, Atezolizumab, Durvalumab, Ipilimumab, Candonilimab, preferably Adebrelimab, Camrelizumab, Dostarlimab, Pembrolizumab, Durvalumab.
  • Adebelimumab The sequences of the heavy and light chains of the aforementioned Adebelimumab are shown below:
  • Dotalizumab is a PD-1 blocking IgG4 humanized monoclonal antibody with the trade name JEMPERLI.
  • the main structure and function of dotalizumab have been described in WO2014/179664, WO 2018/085468 and WO2018/129559.
  • the heavy and light chain sequences of dotalizumab are as follows:
  • dotarizumab or a biosimilar thereof is administered to a patient in need thereof at a dose of 500 mg once every three weeks (Q3W).
  • patients in need thereof are administered 500 mg of dotarizumab or a biosimilar thereof once every three weeks (Q3W) for 4-6 cycles, followed by 1000 mg of dotarizumab or a biosimilar thereof once every 6 weeks (Q6W).
  • Pembrolizumab is a PD-1 blocking IgG4 humanized monoclonal antibody, sold under the trade name KEYTRUDA.
  • the heavy and light chain sequences of pembrolizumab are as follows:
  • pembrolizumab or a biosimilar thereof is administered to a patient in need thereof at a dose of 200 mg once every three weeks (Q3W); or, at a dose of 400 mg once every six weeks (Q6W).
  • Imfinzi is a PD-L1 blocking IgG1 monoclonal antibody marketed under the trade name IMFINZI.
  • the heavy and light chain sequences of durvalumab are as follows:
  • durvalumab or a biosimilar thereof is administered to patients in need thereof who are ⁇ 30 kg at a dose of 1500 mg once every three weeks (Q3W).
  • durvalumab or a biosimilar thereof is administered to patients in need thereof who are ⁇ 30 kg at a dose of 20 mg/kg once every three weeks (Q3W).
  • durvalumab or a biosimilar thereof is administered to patients in need thereof ⁇ 30 kg at a dose of 1120 mg once every three weeks (Q3W).
  • durvalumab or a biosimilar thereof is administered to patients in need thereof weighing ⁇ 30 kg at a dose of 15 mg/kg once every three weeks (Q3W).
  • the present invention discloses the use of the antibody-drug conjugate and the immune checkpoint inhibitor, further combined with a platinum drug, in the preparation of a drug for treating cancer.
  • the present invention discloses use of the antibody-drug conjugate in combination with the platinum drug in the preparation of a drug for treating cancer.
  • the platinum drug is selected from: carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, miboplatin, enloplatin, iproplatin, dicycloplatin, preferably carboplatin and/or cisplatin.
  • the antibody drug conjugate and the immune checkpoint inhibitor are contained in different preparations as active ingredients and are administered simultaneously or at different times.
  • the antibody-drug conjugate, the immune checkpoint inhibitor, and the platinum drug are contained in different preparations as active ingredients, and are administered simultaneously or at different times.
  • the antibody-drug conjugate and the platinum drug are contained in different preparations as active ingredients, and are administered simultaneously or at different times.
  • the antibody drug conjugate and the immune checkpoint inhibitor are contained in a single formulation as active ingredients and administered.
  • the antibody drug conjugate, the immune checkpoint inhibitor, and the platinum drug are contained in a single preparation as active ingredients and administered.
  • the antibody drug conjugate and the platinum drug are contained in a single formulation as active ingredients and administered.
  • the dosage of the antibody drug conjugate is 0.1 mg/kg to 12.0 mg/kg, preferably 1.0 mg/kg to 12.0 mg/kg, more preferably 1.0 mg/kg to 10.0 mg/kg, and further preferably 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3.6 mg/kg, 3.8 mg/kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4 .6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0m
  • the antibody drug conjugate is administered at a starting dose of 2.8 mg/kg, 3.8 mg/kg, or 4.8 mg/kg, and the dosing frequency is once every three weeks.
  • the dose of the immune checkpoint inhibitor is 1.0 mg/kg to 100 mg/kg, preferably 1.0 mg/kg to 40 mg/kg, more preferably 1.0 mg/kg to 30 mg/kg, and further preferably 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3.6 mg/kg, 3.8 mg/kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4.6 mg/kg, 4.8 mg/kg kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2
  • the dose of the immune checkpoint inhibitor is 10 mg to 2000 mg, preferably 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 0mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 310mg, 320mg, 325mg, 330mg, 340mg, 350mg, 360mg, 370mg, 375mg,
  • the immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.
  • the dose of the immune checkpoint inhibitor is 20 mg/kg, and the administration frequency is once every three weeks.
  • the dosage of the platinum drug is calculated as the area under the curve (AUC) and is 1 to 20 mg/ml/min, preferably 1 to 10 mg/ml/min, more preferably 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, and the frequency of administration is once a week, once every two weeks, once every three weeks or once every four weeks.
  • AUC area under the curve
  • the dosage of the platinum drug is 10 mg/m 2 to 500 mg/m 2 , preferably 10 mg/m 2 to 200 mg/m 2 , more preferably 25 mg/m 2 , 50 mg/m 2 , 75 mg/m 2 , 100 mg/m 2 , 125 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 or 200 mg/m 2 , and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.
  • the platinum drug is administered for up to 6 cycles.
  • the dosage of the platinum drug is: cisplatin 75 mg/m 2 or carboplatin AUC 5 mg/ml/min intravenous drip, and the administration frequency is once every three weeks.
  • the cancer is selected from at least one of the following: uterine cancer, breast cancer, biliary tract cancer, lung cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, esophageal cancer, nasopharyngeal cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, leukemia, malignant lymphoma, plasma cell neoplasm, myeloma, neuroepithelial tissue tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma.
  • the uterine cancer is selected from endometrial cancer
  • the breast cancer is selected from triple-negative breast cancer
  • the biliary tract cancer is selected from gallbladder cancer and bile duct cancer.
  • the cancer is an advanced solid tumor for which adequate standard treatment has failed or is intolerant, or for which there is no effective standard treatment.
  • the cancer is a recurrent, metastatic and/or drug-resistant cancer.
  • the cancer is an advanced solid tumor such as advanced endometrial cancer, triple-negative breast cancer or biliary tract cancer.
  • the cancer is advanced endometrial cancer for which adequate standard treatment has failed or there is no effective standard treatment; untreated advanced endometrial cancer; advanced triple-negative breast cancer for which adequate standard treatment has failed or there is no effective standard treatment; untreated advanced triple-negative breast cancer; advanced biliary tract cancer for which adequate standard treatment has failed or there is no effective standard treatment; untreated advanced biliary tract cancer.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate and immune checkpoint inhibitor, and one or more pharmaceutically acceptable carriers, excipients, and diluents.
  • the pharmaceutical composition further comprises the platinum drug, and one or more pharmaceutically acceptable carriers, excipients, and diluents.
  • the present disclosure also provides a method for treating cancer, comprising administering the above-mentioned antibody-drug conjugate and an immune checkpoint inhibitor in combination to a subject in need thereof, wherein the combined administration can be simultaneous or at different time points.
  • the present disclosure also provides a method for treating cancer, comprising administering the above-mentioned antibody-drug conjugate, an immune checkpoint inhibitor, and a platinum drug in combination to a subject in need thereof, wherein the combined administration can be simultaneous or at different time points.
  • the present disclosure also provides a method for treating cancer, comprising administering the above-mentioned antibody-drug conjugate and a platinum drug in combination to a subject in need thereof, wherein the combined administration can be simultaneous or at different time points.
  • the cancer is selected from at least one of the following: uterine cancer, breast cancer, biliary tract cancer, lung cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, esophageal cancer, nasopharyngeal cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, leukemia, malignant lymphoma, plasma cell neoplasm, myeloma, neuroepithelial tissue tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma.
  • the breast cancer is selected from triple-negative breast cancer
  • the biliary tract cancer is selected from gallbladder cancer and bile duct cancer.
  • the cancer is a recurrent, metastatic and/or drug-resistant cancer.
  • the cancer is an advanced solid tumor such as advanced endometrial cancer, triple-negative breast cancer or biliary tract cancer.
  • the cancer is advanced endometrial cancer for which adequate standard treatment has failed or there is no effective standard treatment; untreated advanced endometrial cancer; advanced triple-negative breast cancer for which adequate standard treatment has failed or there is no effective standard treatment; untreated advanced triple-negative breast cancer; advanced biliary tract cancer for which adequate standard treatment has failed or there is no effective standard treatment; untreated advanced biliary tract cancer.
  • Another aspect of the present disclosure provides the aforementioned anti-B7H4 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H4 antibody-drug conjugate is used in combination with the aforementioned anti-PD-1 antibody or an antigen-binding fragment thereof.
  • Another aspect of the present disclosure provides the aforementioned anti-B7H4 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H4 antibody-drug conjugate is used in combination with the aforementioned anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • Another aspect of the present disclosure provides the aforementioned anti-B7H4 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H4 antibody-drug conjugate is used in combination with the aforementioned anti-PD-1 antibody or antigen-binding fragment thereof and the aforementioned platinum drug.
  • Another aspect of the present disclosure provides the aforementioned anti-B7H4 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H4 antibody-drug conjugate is used in combination with the aforementioned anti-PD-L1 antibody or antigen-binding fragment thereof and the aforementioned platinum drug.
  • Another aspect of the present disclosure provides the aforementioned anti-B7H4 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H4 antibody-drug conjugate is used in combination with the aforementioned platinum drug.
  • the so-called “combination” is a mode of administration, which includes various situations in which two or more drugs are administered sequentially or simultaneously.
  • the time period may be within one dosing cycle, optionally within 4 weeks, 3 weeks, 2 weeks, or 1 week.
  • This period includes treatments in which the anti-PD-1 or PD-L1 antibody or antigen-binding fragment thereof, and the anti-B7H4 antibody-drug conjugate are administered by the same route of administration or by different routes of administration.
  • antibody drug conjugate refers to an antibody linked to a biologically active drug via a stable linker.
  • antibody drug conjugate refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug via a stable linker.
  • antibody refers to immunoglobulins, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and order of the constant region of immunoglobulins' heavy chains vary, resulting in different antigenicity. Consequently, immunoglobulins can be divided into five classes, or isotypes, namely IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • Igs are further divided into subclasses based on the amino acid composition of their hinge regions and the number and location of heavy chain disulfide bonds.
  • variable region The approximately 110 amino acids near the N-terminus of an antibody's heavy and light chains vary greatly in sequence, forming the variable region (Fv region); the remaining amino acid sequences near the C-terminus are relatively stable, forming the constant region.
  • the variable region comprises three hypervariable regions (HVRs) and four framework regions (FRs), whose sequences are relatively conserved. These three hypervariable regions determine the antibody's specificity and are also known as complementarity-determining regions (CDRs).
  • Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, arranged in the following order from amino to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDR regions of the light chain are LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain are HCDR1, HCDR2, and HCDR3.
  • the amino acid sequences of the above CDRs are shown in accordance with the Kabat definition rules.
  • the CDRs of antibodies can be defined in the art by a variety of methods, such as Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loop (Chothia et al.
  • CDR complementarity determining region
  • antigen-binding fragment refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody.
  • binding fragments included in "antigen-binding fragments” include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge on the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a single domain or dAb fragment (Ward et al., (1989) Nature 341: 544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs, optionally connected by a synthetic linker.
  • CDR complementarity determining region
  • drug loading refers to the average number of cytotoxic drugs loaded per ligand in a molecule of Formula (I), and can also be expressed as the ratio of the amount of drug to the amount of antibody.
  • the drug loading can range from 0 to 12, preferably 1 to 10, cytotoxic drugs (D) attached per antibody (Pc).
  • the drug loading is expressed as n, also known as the DAR value, and exemplary values are 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • the average number of drug products per ADC molecule after the conjugation reaction can be determined by conventional methods such as UV/visible spectroscopy, mass spectrometry, ELISA assays, and HPLC characterization.
  • anti-PD-L1 antibody or antigen-binding fragment thereof refers to an antibody that specifically binds to PD-L1 (programmed cell death ligand 1; CD274; B7-H1) and has the activity of reducing, inhibiting, and/or interfering with signal transduction caused by the interaction between PD-L1 and PD-1 or B7.1 (CD80) as a binding partner.
  • PD-L1 programmed cell death ligand 1
  • B7-H1 programmed cell death ligand 1
  • the anti-PD-L1 antibody used in the present disclosure is not particularly limited as long as its clinical efficacy and safety have been demonstrated.
  • pharmaceutical composition is a product comprising one or more active ingredients (e.g., antibodies, ADCs) in optionally specified amounts, as well as any product produced directly or indirectly by combining one or more active ingredients in optionally specified amounts.
  • active ingredients e.g., antibodies, ADCs
  • the different active ingredients in the pharmaceutical composition can be administered independently in separate formulations, including administration simultaneously or at different time points for combined synergistic effect.
  • pharmaceutical composition and “formulation” are not mutually exclusive.
  • treating means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect.
  • the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or inhibit the development of such symptoms to any clinically measurable degree.
  • the amount of a therapeutic agent effective to alleviate any specific disease symptom can vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient.
  • Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms.
  • the embodiments of the present disclosure e.g., treatment methods or products
  • may not be effective in alleviating every symptom of the target disease they should alleviate the symptoms of the target disease in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.
  • Figure 4 Effects of Drug A, Drug D, and Drug E alone or in combination on tumor volume in the mouse MC38-hB7H4 homograft tumor model
  • Figure 5 Effects of Drug A, Drug D, and Drug E alone or in combination on body weight changes in the mouse MC38-hB7H4 homograft tumor model
  • Figure 6 Effects of Drug A, Drug D, and Drug E alone or in combination on tumor volume in the mouse CT26-hB7H4 homograft tumor model
  • Figure 7 Effects of Drug A, Drug D, and Drug E alone or in combination on body weight changes in the CT26-hB7H4 homograft tumor model in mice
  • Figure 8 Effects of drug A, drug E, and drug B alone or in combination on tumor volume in the mouse MC38-hB7H4 homograft tumor model
  • Figure 9 Effects of Drug A, Drug E, and Drug B alone or in combination on body weight changes in the mouse MC38-hB7H4 homograft tumor model
  • hu2F7 an anti-B7H4 antibody
  • an isotecan analog were used to prepare the anti-B7H4 antibody-drug conjugate shown in the following structure.
  • the hu2F7 heavy chain sequence is shown in SEQ ID NO: 09, and the light chain sequence is shown in SEQ ID NO: 10.
  • Drug A an anti-B7H4 antibody-drug conjugate prepared by the method of Example 1, using physiological saline for drug preparation.
  • Drug B Cisplatin API, purchased from MCE, product number HY-17394, prepared with double-distilled water.
  • Drug C Carboplatin API, purchased from MCE, product number HY-17393, prepared with double-distilled water.
  • Biosafety cabinet (BSC-1300IIA 2 , Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); CO 2 incubator (Thermo311); centrifuge (Eppendorf 5810R); microplate reader (BioTek Synergy H1 or PerkinElmer Envision); pipette (Eppendorf or Rainin)
  • OVCAR-3 cells were purchased from ATCC; RL95-2 cells were purchased from Nanjing Kebai; Cell Titer-Glo was purchased from Promega Company with the catalog number G7573; RPMI 1640 was purchased from Gibco with the catalog number 22400-089; DMEM was purchased from Gibco with the catalog number 11995-065; FBS was purchased from Gibco with the catalog number 10091148; PBS was purchased from Gibco with the catalog number 10010023; trypsin was purchased from Gibco with the catalog number 25200056; Insulin-Transferrin-Se was purchased from Gibco with the catalog number 51500-056; and cell culture plates were purchased from thermo company with the catalog number 165306.
  • OVCAR-3 and RL95-2 cells were cultured to the appropriate cell density using RPMI1640 medium containing 20% FBS and MEM medium containing 10% FBSD, respectively, the cells were collected and adjusted to the appropriate cell concentration using complete medium.
  • the cell suspension was plated in a 96-well plate with 180 ⁇ L per well and placed in a 37°C, 5% CO2 incubator to adhere overnight.
  • a solvent control double-distilled water or a fixed concentration of drug B or drug C solution was added to a 96-well plate. Then, different concentrations of drug A solution were prepared using culture medium. Drug A was added to the 96-well plate at 10 ⁇ L per well of each compound. The plate was cultured in a 37°C, 5% CO2 incubator for 6 days. CellTiter-Glo solution was then added, the plates were shaken to mix evenly, and incubated in the dark for 10 minutes. The plates were read using a Synergy H1 microplate reader.
  • drug B was administered at three fixed concentrations: 500 nM, 167 nM, and 56 nM; drug C was administered at three fixed concentrations: 2000 nM, 667 nM, and 222 nM; in RL95-2 cells, drug B was administered at three fixed concentrations: 2000 nM, 667 nM, and 222 nM.
  • drug A was administered at a starting concentration of 1000 nM, diluted 1:3, and administered across a total of nine concentration gradients.
  • the specific drug application schedule is shown in Table 1. Six days after combined drug application, the in vitro proliferation inhibitory effects of drug A combined with drug B, or drug A combined with drug C, on human ovarian and endometrial cancer cells were assessed using the CTG assay.
  • the cell inhibition rate was calculated according to the following formula:
  • Inhibition rate (%) (1 - (sample well signal value - average blank control well signal value) / (average control well signal value - average blank control well signal value)) ⁇ 100%.
  • Sample wells are cell culture wells that receive the test drug combination.
  • Control wells are cell culture wells that receive only vehicle control or fixed concentrations of Drug B and Drug C.
  • Blank control wells are wells that receive only culture medium.
  • Drug A anti-B7H4 antibody-drug conjugate, prepared using the method described in Example 1, with normal saline used for drug preparation.
  • Drug D Anti-Mouse PD-1 Antibody (mPD-1) monoclonal antibody, purchased from MCE, product number HY-P99144, the drug was prepared with normal saline.
  • MC38-hB7H4 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 5 ⁇ g/mL Puromycin at 37°C in a 5% CO2 incubator. MC38-hB7H4 cells in the logarithmic growth phase were harvested and counted. Resuspend the cells in PBS to 5 ⁇ 106 cells/mL before plating.
  • C57BL/6J female mice weighing 17–24 g, were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.
  • MC38-hB7H4 cell suspension containing 5 ⁇ 10 5 cells was subcutaneously inoculated into the right dorsal region of C57BL/6J mice. Tumor growth was observed and animals were randomly grouped based on tumor volume and body weight. The average tumor volume at the time of grouping was 98 mm 3 . The day of grouping was defined as day 0, or PG-D0. All animals were dosed starting from PG-D0 based on their body weight at grouping. The remaining animals were euthanized at the end of the experiment. Specific dosages and dosing schedules are shown in Table 7. Tumor volume was measured, mice were weighed, and the data were recorded.
  • Dosage regimen and grouping a Dosing volume: 10 ⁇ l/g of mouse body weight. Stop dosing when the body weight drops by more than 15% and return to normal. Resume dosing when the dose is less than 10%.
  • T/C (%) average tumor volume of a treatment group at the end of drug administration / average tumor volume of the vehicle control group at the end of treatment ⁇ 100%.
  • Table 8 Evaluation of the antitumor efficacy of drug A alone or in combination therapy in the MC38-hB7H4 homograft tumor model a. Mean ⁇ SEM; b. Comparison with the Vehicle group - Statistical analysis was performed using Dunnett's multiple comparisons test in a two-way ANOVA.
  • the average tumor volume of tumor-bearing mice in the Vehicle group reached 2661 mm 3 on day 14 after administration. Throughout the experiment, no animals discontinued the drug due to weight loss, and no animals became ill or died.
  • the tumor inhibition effects of each treatment group were compared based on the tumor volume on the 14th day after administration. Statistics showed that tumor-bearing mice were tolerant to drug A monotherapy or combined treatment with drug D and drug E.
  • the anti-tumor efficacy of the drug A_5mg/kg and drug D_10mg/kg combination treatment group was significantly better than that of each single-drug treatment group.
  • the anti-tumor efficacy of the drug A_5mg/kg and drug E_30mg/kg combination treatment group was significantly better than that of the drug A_5mg/kg monotherapy group and better than that of the drug E_30mg/kg monotherapy group.
  • Drug A anti-B7H4 antibody-drug conjugate, prepared using the method described in Example 1, with normal saline used for drug preparation.
  • Drug D Anti-Mouse PD-1 Antibody (mPD-1) monoclonal antibody, purchased from MCE, product number HY-P99144, the drug was prepared with normal saline.
  • CT26-hB7H4 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 5 ⁇ g/mL Puromycin at 37°C in a 5% CO2 incubator.
  • CT26-hB7H4 cells in the logarithmic growth phase were harvested and counted. Resuspend the cells in PBS to 7.5 ⁇ 106 cells/mL before plating.
  • mice were subcutaneously inoculated with 0.1 mL of CT26-hB7H4 cell suspension (containing 7.5 ⁇ 10 5 cells) on the right back. Tumor growth was observed and animals were randomly grouped based on tumor volume and body weight. The average tumor volume at the time of grouping was 115 mm 3 . The day of grouping was defined as day 0, or PG-D0. All animals were dosed starting from PG-D0 according to their body weight at grouping. The remaining animals were euthanized at the end of the experiment. Specific dosage and dosing schedule are shown in Table 11. Tumor volume was measured, mice were weighed, and the data were recorded.
  • Dosage and grouping b Dosing volume: 10 ⁇ l/g of mouse body weight. Stop dosing when the body weight drops by more than 15% and return to normal. Resume dosing when the dose is less than 10%.
  • T/C (%) average tumor volume of a treatment group at the end of drug administration / average tumor volume of the vehicle control group at the end of treatment ⁇ 100%.
  • the average tumor volume of tumor-bearing mice in the vehicle group reached 2021 mm 3 on day 14 after administration. Compared with the vehicle group, the average tumor volume of each treatment group decreased to varying degrees. Throughout the experiment, no animals discontinued the drug due to weight loss, and no animals became ill or died.
  • tumor-bearing mice tolerated drug A alone or in combination with drugs D and E.
  • the mean tumor volume decreased to varying degrees in each treatment group, with a statistically significant difference observed in the drug A 5 mg/kg combined with drug D 10 mg/kg group.
  • the antitumor efficacy of the drug A 5 mg/kg plus drug D 10 mg/kg combination group was superior to that of the monotherapy groups, while the antitumor efficacy of the drug A 5 mg/kg plus drug E 30 mg/kg combination group was superior to that of the monotherapy groups.
  • Example 5 Efficacy of anti-B7H4 antibody-drug conjugates combined with immune checkpoint inhibitors and platinum drugs in the mouse MC38-hB7H4 homograft model
  • Drug A anti-B7H4 antibody-drug conjugate, prepared using the method described in Example 1, with normal saline used for drug preparation.
  • Drug E Anti-Mouse PD-L1 Antibody (mPD-L1) monoclonal antibody, purchased from MCE, product number HY-P99145, the drug was prepared with normal saline.
  • Cisplatin API purchased from MCE, product number HY-17394, ultrapure water was used for drug preparation.
  • mice C57BL/6J female mice, weighing 20-21 g, were purchased from SPIEF (Suzhou) Biotechnology Co., Ltd.
  • MC38-hB7H4 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin (P-streptomycin), and 5 ⁇ g/mL puromycin at 37°C in a 5% CO2 incubator. MC38-hB7H4 cells in the logarithmic growth phase were harvested and counted. Resuspend the cells in PBS to 5 ⁇ 106 cells/mL before plating.
  • MC38-hB7H4 cell suspension containing 5 ⁇ 10 5 cells
  • mice were subcutaneously inoculated into the right dorsal region of C57BL/6J mice. Tumor growth was observed and the mice were randomly grouped based on tumor volume and body weight. The average tumor volume at the time of grouping was 106 mm 3 . The day of grouping was defined as day 0 (PG-D0).
  • Dosage regimen and grouping a. Dosing volume: 10 ⁇ l/g of mouse body weight. Stop dosing when body weight drops by more than 15% and return to 10%. Resume dosing within 24 hours.
  • T/C (%) average tumor volume of a treatment group at the end of drug administration / average tumor volume of the vehicle control group at the end of treatment ⁇ 100%.
  • Table 16 Evaluation of the antitumor efficacy of drug A alone or in combination therapy in the MC38-hB7H4 homograft tumor model a. Mean ⁇ SEM; b. Based on the tumor volume on day 14 after administration, compared with the Vehicle group, Dunnett's Statistical analysis was performed using multiple comparisons test. In addition, statistical analysis was performed using t-test based on the tumor volume on day 14 after administration.
  • the average tumor volume of tumor-bearing mice in the Vehicle group reached 3297 mm 3 on day 14 after administration. Throughout the experiment, no animals discontinued the drug due to weight loss, and no animals became ill or died.
  • tumor-bearing mice tolerated drug A alone or in combination with drug E or drug B.
  • the combination of drug A 5 mg/kg and drug E 30 mg/kg had significantly better tumor inhibition than either the single-drug groups, as did the combination of drug A 5 mg/kg and drug B 5 mg/kg.
  • the triple-drug combination of drug A, drug E, and drug B exhibited significantly better antitumor efficacy than either the single-drug treatment groups, as did the combination of drug A, drug E, or drug A and drug B.
  • Dosage form Sterile powder for injection, Specification: 50 mg/bottle, Manufacturer: Shanghai Hansoh Biopharmaceutical Technology Co., Ltd.
  • Adebelimumab properties: colorless to light yellow clear liquid, specifications: 600mg (12ml)/bottle, manufacturer: Suzhou Shengdia Biopharmaceutical Co., Ltd.
  • Cisplatin Appearance: Light yellow-green to light yellow to slightly viscous clear liquid
  • Manufacturer Jiangsu Hausen Pharmaceutical Co., Ltd.
  • the study is designed to have two combination therapy cohorts, each consisting of a dose-finding phase and a dose-expansion phase:
  • the starting dose of the anti-B7H4 antibody-drug conjugate for the dual therapy cohort was 4.8 mg/kg, with two pre-defined dose groups (3.8 mg/kg and 4.8 mg/kg). If the starting dose was not tolerated, the dose was reduced to 3.8 mg/kg.
  • the starting dose of the anti-B7H4 antibody-drug conjugate for the triple therapy cohort was 3.8 mg/kg, with three pre-defined dose groups (2.8 mg/kg, 3.8 mg/kg, and 4.8 mg/kg). If the starting dose was not tolerated, the dose was reduced to 2.8 mg/kg.
  • Cohort 1A Anti-B7H4 antibody-drug conjugate administered every 3 weeks at the entry dose level until disease progression or other discontinuation criteria are met.
  • Cohort 2A Anti-B7H4 antibody-drug conjugate every 3 weeks, continuing at the entry dose level until disease progression or other discontinuation criteria are met.
  • Cisplatin 75 mg/m2 or carboplatin AUC 5 mg/ml/min every 3 weeks is recommended for up to 6 cycles.
  • Cohort 1B Anti-B7H4 antibody-drug conjugate every 3 weeks, expanded dose/recommended dose, continued until disease progression or other discontinuation criteria are met.
  • Cohort 2B Anti-B7H4 antibody-drug conjugate every 3 weeks, expanded dose/recommended dose, continued until disease progression or other discontinuation criteria are met.
  • Cisplatin or carboplatin select the corresponding recommended dose and number of cycles according to the indication (see Table 17)
  • the maximum tolerated dose (MTD) or maximum applicable dose (MAD) of anti-B7H4 antibody-drug conjugate combination therapy is the maximum tolerated dose (MTD) or maximum applicable dose (MAD) of anti-B7H4 antibody-drug conjugate combination therapy.
  • Safety of anti-B7H4 antibody-drug conjugate combination therapy incidence of adverse events (AEs); incidence of serious adverse events (SAEs); proportion of subjects with dose adjustments and treatment discontinuations due to AEs; changes in physical examination, ophthalmological examination, vital signs, body weight, laboratory tests (blood count, urine count, blood biochemistry, coagulation function), ECG, echocardiogram, and ECOGPs;

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Abstract

La présente invention concerne l'utilisation d'un conjugué anticorps-médicament seul ou en combinaison dans la préparation d'un médicament pour la prévention et/ou le traitement de cancers. Plus particulièrement, la présente invention propose l'utilisation d'un conjugué anticorps-médicament ou d'un sel pharmaceutiquement acceptable de celui-ci, d'un métabolite de celui-ci, ou d'un solvate de celui-ci seul ou en combinaison avec un inhibiteur de point de contrôle immunitaire dans la préparation d'un médicament pour la prévention et/ou le traitement de cancers.
PCT/CN2025/075988 2024-02-08 2025-02-06 Utilisation combinée d'un conjugué anticorps-médicament et d'un inhibiteur de point de contrôle immunitaire Pending WO2025167977A1 (fr)

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