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WO2025130748A1 - Formulation d'anticorps anti-facteur xi/xia de coagulation - Google Patents

Formulation d'anticorps anti-facteur xi/xia de coagulation Download PDF

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Publication number
WO2025130748A1
WO2025130748A1 PCT/CN2024/138814 CN2024138814W WO2025130748A1 WO 2025130748 A1 WO2025130748 A1 WO 2025130748A1 CN 2024138814 W CN2024138814 W CN 2024138814W WO 2025130748 A1 WO2025130748 A1 WO 2025130748A1
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Prior art keywords
cdr
seq
antibody
histidine
sequence
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PCT/CN2024/138814
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English (en)
Chinese (zh)
Inventor
付菁源
罗良波
山伟
党雨蕾
全勇
葛均友
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors

Definitions

  • the present invention relates to the field of therapeutic antibodies, and more specifically, to a preparation of an anti-coagulation factor XI/XIa antibody or an antigen-binding fragment thereof and its medical use.
  • thrombosis or embolism involves all organs of the body, mainly the heart, brain and peripheral vascular diseases, with the characteristics of high incidence, high disability and lethality, and is the leading cause of death from cardiovascular diseases.
  • the prevention and treatment of thrombotic diseases mainly include three types of drugs: anticoagulants, antiplatelets and thrombolytics; among them, anticoagulants are mainly used clinically to prevent and treat venous thromboembolism caused by various reasons; in addition, they can also be used to prevent stroke in patients with atrial fibrillation and anticoagulant treatment in patients with acute coronary syndrome.
  • Coagulation factor XI participates in the intrinsic coagulation cascade, and its active form is coagulation factor XIa (FXIa).
  • the FXI protein is a dimer formed by two homologous monomers with a molecular weight of about 80 kDa through disulfide bonds.
  • the FXI monomer consists of four apple domains and a catalytic domain. After the formation of FXIa by coagulation factor XIIa (FXIIa), the binding site of FIX is exposed. After binding with FIX, it promotes the conversion of FIX to active FIXa, activating the downstream coagulation cascade.
  • the concentration of coagulation factor XI in mammalian plasma is about 25-30nM. It is a glycoprotein that exists in the form of zymogen. Almost all FXI forms a complex with high molecular weight kininogen (HK) and circulates in the blood. The effect of HK on the function of FXI is still unclear. HK may assist FXI in binding to platelets or endothelial cells, and studies have also observed that HK inhibits the activation of FXI.
  • the activation process of FXI is that each monomer is cleaved between Arg369-Ile370 under the action of different proteases to produce a protein composed of a heavy chain of about 50kDa containing an apple domain and a light chain of about 30kDa containing a catalytic domain.
  • the heavy chain and the light chain are connected by a disulfide bond formed by Cys362-Cys482.
  • Activated FXI, FXIa usually refers to each monomer of the dimer FXI cleaved at Arg369, but there are also cases where only one monomer is activated.
  • FXIa cleaves FIX in the presence of Ca 2+ , turning it into activated FIX (FIXa), which then converts coagulation factor X into its active form Xa.
  • FIXa activated FIX
  • Xa can then mediate the activation of coagulation factor II/thrombin.
  • Thrombin as the terminal protease in the coagulation cascade, can further promote the production of FXIa by directly activating FXI in a feedback mechanism.
  • Both coagulation factor XIIa and FXIa (autoactivation) in the coagulation cascade can convert FXI into FXIa.
  • FIX/FIXa activated FIX
  • FIX/FIXa can directly bind to platelets, promote the formation of platelet aggregates in the blood, and form distal microvascular occlusion. Therefore, FIX/FIXa promotes thrombosis through multiple pathways. And animal experiments and clinical observations have shown that the loss of FIX/FIXa has only a very small risk of bleeding. Therefore, FIX/FIXa is an ideal target for the prevention and treatment of diseases/disorders related to coagulation or thromboembolism. (Zilberman-Rudenko J. et. al. Coagulation factor XI promotes distal platelet activation and single platelet connfusion in the bloodstream under shear flow. Arterioscler Thromb Vasc Biol. 2016 March; 36 (3): 510-517.).
  • WO2020/211674 discloses new anti-coagulation factor XI/XIa antibodies, which can effectively block the activity of FXI and/or FXIa in thrombosis and show good therapeutic effects on coagulation or thromboembolism-related diseases.
  • the use of coagulation factor XI/XIa antibodies in clinical treatment requires solving the problems of physical and chemical properties suitable for administration and stability during storage.
  • a liquid preparation composed of an anti-coagulation factor XI/XIa antibody and a specific prescription has excellent stability and can obtain a high-concentration preparation with sufficiently low viscosity, thereby significantly reducing the difficulty of producing and administering high-concentration preparations, thereby improving patient compliance.
  • the present application provides a liquid formulation comprising:
  • the concentration of the antibody or antigen-binding fragment thereof that specifically binds to FXI and/or FXIa is 20-250 mg/ml (e.g., 20-200 mg/ml, 20-180 mg/ml, 20-160 mg/ml, 20-150 mg/ml, 50-250 mg/ml, 50-200 mg/ml, 50-180 mg/ml, 50-150 mg/ml, 100-250 mg/ml, 100-200 mg/ml, 100-180 mg/ml, 100-150 mg/ml, 120-250 mg/ml, 120-200 mg/ml, 120-180 mg/ml, 120-150 mg/ml).
  • 20-250 mg/ml e.g., 20-200 mg/ml, 20-180 mg/ml, 20-160 mg/ml, 20-150 mg/ml, 50-250 mg/ml, 50-200 mg/ml, 50-180 mg/ml, 50-150 mg/ml, 100-250 mg
  • the concentration of the antibody or antigen-binding fragment thereof that specifically binds to FXI and/or FXIa is 100-200 mg/ml (e.g., 100-180 mg/ml, 100-150 mg/ml, 120-200 mg/ml, 120-180 mg/ml, 120-150 mg/ml, 120 mg/ml, 150 mg/ml).
  • the arginine is at a concentration of 50-200 mM (e.g., 50-180 mM, 50-150 mM, 50-120 mM, 60-200 mM, 60-180 mM, 60-150 mM, 60-120 mM, 80-200 mM, 80-180 mM, 80-150 mM, 80-120 mM, 100-200 mM, 100-180 mM, 100-150 mM, 100-120 mM).
  • 50-200 mM e.g., 50-180 mM, 50-150 mM, 50-120 mM, 60-200 mM, 60-180 mM, 60-150 mM, 60-120 mM, 80-200 mM, 80-180 mM, 80-150 mM, 80-120 mM, 100-200 mM, 100-180 mM, 100-150 mM, 100-120 mM.
  • the arginine is at a concentration of 60-150 mM (e.g., 60-120 mM, 80-150 mM, 80-120 mM, 100-150 mM, 100-120 mM, 80 mM, 100 mM, 120 mM, 150 mM).
  • the surfactant is polysorbate 80 or polysorbate 20. In certain embodiments, the surfactant is polysorbate 20.
  • the concentration of the surfactant is 0.005%-0.04% w/v (eg, 0.011% w/v, 0.02% w/v).
  • the pH of the liquid formulation is 6.0-6.6.
  • the liquid formulation optionally comprises sodium chloride.
  • the concentration of sodium chloride is 0-130 mM (e.g., 0-120 mM, 0-60 mM, 0-40 mM, 0-20 mM, 10-130 mM, 10-120 mM, 10-60 mM, 10-40 mM, 10-20 mM, 20-130 mM, 20-120 mM, 20-60 mM, 20-40 mM).
  • the concentration of sodium chloride is 0-60 mM (e.g., 0-40 mM, 0-20 mM, 10-60 mM, 10-40 mM, 10-20 mM, 20-60 mM, 20-40 mM).
  • the liquid formulation does not contain sodium chloride.
  • the liquid formulation does not contain sucrose.
  • the antibody is selected from antibodies that specifically bind to FXI and/or FXIa disclosed in patent application WO 2020/211674 A1.
  • the antibody or antigen-binding fragment thereof comprises:
  • the CDRs are defined by the IMGT, AbM, Kabat, or Chothia numbering systems.
  • the antibody or antigen-binding fragment thereof comprises:
  • the CDRs are defined by the IMGT numbering system;
  • the CDRs are defined by the AbM numbering system;
  • the antibody or antigen-binding fragment thereof comprises:
  • CDR-H1 with a sequence of SEQ ID NO: 9 CDR-H2 with a sequence of SEQ ID NO: 39, CDR-H3 with a sequence of SEQ ID NO: 11; and, CDR-L1 with a sequence of SEQ ID NO: 12, CDR-L2 with a sequence of SEQ ID NO: 13, CDR-L3 with a sequence of SEQ ID NO: 14; in certain embodiments, the CDRs are defined by the AbM numbering system.
  • the antibody or antigen-binding fragment thereof comprises the following heavy chain variable region (VH) and light chain variable region (VL):
  • VH heavy chain variable region
  • VL light chain variable region
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDRs are defined by the IMGT numbering system.
  • the antibody or antigen-binding fragment thereof comprises the following heavy chain variable region (VH) and light chain variable region (VL):
  • VH heavy chain variable region
  • VL light chain variable region
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDRs are defined by the AbM numbering system.
  • the antibody or antigen-binding fragment thereof comprises the following heavy chain variable region (VH) and light chain variable region (VL):
  • VH heavy chain variable region
  • VL light chain variable region
  • VH heavy chain variable region
  • VL light chain variable region
  • the VH of the antibody or its antigen-binding fragment comprises: (a) a sequence as shown in any one of SEQ ID NOs: 15, 1, 16, and 17, or (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the sequence shown in any one of SEQ ID NOs: 15, 1, 16, and 17.
  • the VL of the antibody or its antigen-binding fragment comprises: (a) a sequence as shown in any one of SEQ ID NO: 18, 2, 19, 20, or (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in any one of SEQ ID NO: 18, 2, 19, 20.
  • the VH of the antibody or antigen-binding fragment thereof comprises: (a) a sequence as shown in SEQ ID NO:23 or 25, or (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in SEQ ID NO:23 or 25.
  • the VL of the antibody or its antigen-binding fragment comprises: (a) a sequence as shown in SEQ ID NO:24 or 26, or, (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in SEQ ID NO:24 or 26.
  • the VH of the antibody or its antigen-binding fragment comprises: (a) a sequence as shown in SEQ ID NO:15, or (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in SEQ ID NO:15; and/or the VL of the antibody or its antigen-binding fragment comprises: (a) a sequence as shown in SEQ ID NO:18, or (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in SEQ ID NO:18.
  • the antibody or antigen-binding fragment thereof comprises a VH as shown in any one of SEQ ID NOs: 15, 1, 16, 17, and a VL as shown in any one of SEQ ID NOs: 18, 2, 19, 20.
  • the antibody or antigen-binding fragment thereof comprises a VH as shown in SEQ ID NOs: 23 or 25, and a VL as shown in SEQ ID NOs: 24 or 26.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof further comprises:
  • the antibody or antigen-binding fragment thereof comprises a heavy chain constant region selected from:
  • the antibody or its antigen-binding fragment comprises a heavy chain constant region (CH) as shown in SEQ ID NO: 21 or a variant thereof, wherein the variant has a conservative substitution of up to 20 amino acids compared to SEQ ID NO: 21.
  • CH heavy chain constant region
  • the antibody or antigen-binding fragment thereof comprises a light chain constant region (CL) as shown in SEQ ID NO: 22 or a variant thereof, wherein the variant has a conservative substitution of up to 20 amino acids compared to SEQ ID NO: 22.
  • CL light chain constant region
  • the antibody or its antigen-binding fragment comprises a heavy chain constant region (CH) as shown in SEQ ID NO: 21 and a light chain constant region (CL) as shown in SEQ ID NO: 22.
  • CH heavy chain constant region
  • CL light chain constant region
  • the antibody or antigen-binding fragment thereof comprises:
  • a heavy chain comprising an amino acid sequence selected from the group consisting of:
  • a light chain comprising an amino acid sequence selected from the group consisting of:
  • the antibody or antigen-binding fragment thereof comprises:
  • a heavy chain comprising an amino acid sequence selected from the group consisting of:
  • a light chain comprising an amino acid sequence selected from the group consisting of:
  • (iii) comprises the sequence of the VL region shown in SEQ ID NO: 26 and the light chain constant region (CL) shown in SEQ ID NO: 22; or
  • the antibody or antibody fragment thereof is selected from any one of the following groups:
  • the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) and a light chain (LC); wherein the HC comprises: (a) a sequence as shown in SEQ ID NO:42, or (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in SEQ ID NO:42; and/or, the LC comprises: (a) a sequence as shown in SEQ ID NO:43, or (b) a sequence having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in SEQ ID NO:43.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) as shown in SEQ ID NO:42 and a light chain (LC) as shown in SEQ ID NO:43.
  • the ingredients of the liquid formulation are selected from the group consisting of:
  • the liquid formulations of the present invention can be stable at 5°C ⁇ 3°C and can be stored for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.
  • the liquid formulations of the present invention are stable at 25°C ⁇ 2°C and can be stored for at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, or at least about 1 year.
  • the liquid formulations of the present invention are stable at about 40°C (e.g., 40°C ⁇ 2°C) and can be stored for at least about 7 days, at least about 14 days, at least about 21 days, or at least about 28 days.
  • the liquid preparation of the present invention can be prepared by combining various components at predetermined concentrations using methods known in the art. For example, an antibody or antigen-binding fragment thereof that specifically binds to FXI and/or FXIa can be dialyzed into a solution containing other components in the liquid preparation and adjusted to a desired concentration. The preparation is filtered and sterilized using a filter with a pore size of 0.22 ⁇ m. The prepared preparation is packaged for easy use.
  • the packaging material can be a glass bottle (e.g., a vial), a metal alloy container, a prefilled syringe, or a pen-type syringe.
  • the liquid preparation of the present invention may be included in any container suitable for storing medicine and other pharmaceutical compositions.
  • the liquid preparation of the present invention may be included in a sealed and sterilized plastic container, metal alloy container or glass container with a certain volume, such as an ampoule, a vial or a syringe. Therefore, in certain preferred embodiments, the liquid preparation of the present invention is included in a glass bottle (such as an ampoule or a vial), a syringe or a microinfusion device. In certain exemplary embodiments, the liquid preparation of the present invention is included in a glass bottle (such as an ampoule or a vial).
  • the present application provides an article of manufacture comprising a container containing the liquid formulation as described above.
  • the container is a glass vial, a metal alloy container, or a prefilled syringe.
  • the article of manufacture may further include a package insert with instructions for use.
  • the preparation comprises a therapeutically effective amount of the antibody or antigen-binding fragment thereof that specifically binds FXI and/or FXIa.
  • the preparation comprises 100-800 mg (e.g., 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 200-300 mg, 200-400 mg, 200-500 mg, 200-800 mg) of the antibody or antigen-binding fragment thereof that specifically binds FXI and/or FXIa.
  • 100-800 mg e.g., 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 200-300 mg, 200-400 mg, 200-500 mg, 200-800 mg
  • the antibody or antigen-binding fragment thereof that specifically binds FXI and/or FXIa.
  • the specification of the preparation is 100 mg (2 ml)/bottle to 500 mg (2 ml)/bottle.
  • the specification of the preparation is 100 mg (3 ml)/bottle to 800 mg (3 ml)/bottle.
  • the specifications of the liquid preparation are selected from the following group: 100 mg (2 ml)/bottle, 150 mg (2 ml)/bottle, 200 mg (2 ml)/bottle, 240 mg (2 ml)/bottle, 300 mg (2 ml)/bottle, 360 mg (2 ml)/bottle, 400 mg (2 ml)/bottle, 500 mg (2 ml)/bottle, 100 mg (3 ml)/bottle, 200 mg (3 ml)/bottle, 300 mg (3 ml)/bottle, 400 mg (3 ml)/bottle, 500 mg (3 ml)/bottle, 600 mg (3 ml)/bottle, 700 mg (3 ml)/bottle, 800 mg (3 ml)/bottle.
  • Liquid preparations of the present invention can be applied to a subject by parenteral route, such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.), or transdermal, mucosal, nasal, respiratory and/or oral administration.
  • parenteral route such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.), or transdermal, mucosal, nasal, respiratory and/or oral administration.
  • the liquid preparation is applied to a subject (e.g., people) by intravenous injection or subcutaneous injection.
  • the present application provides the use of the liquid preparation or product as described above in the preparation of a drug, wherein the drug is used for:
  • the disease or condition associated with coagulation or thromboembolism is selected from the group consisting of thrombosis, thrombotic stroke, atrial fibrillation, atrial fibrillation associated stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, acute coronary syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, myocardial infarction (MI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary artery intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, migraine, Disseminated intravascular coagulation, thromboembolic disorders induced by medical devices (e.g., catheters), severe systemic inflammatory response syndrome, metastatic cancer, infectious diseases, organ failure (e.g.,
  • the present application provides a method for preventing and/or treating a disease or condition associated with coagulation or thromboembolism in a subject, and/or delaying the occurrence of a disease or condition associated with coagulation or thromboembolism, and/or reducing or inhibiting the recurrence of a disease or condition associated with coagulation or thromboembolism, the method comprising administering an effective amount of the liquid preparation or product as described above to a subject in need thereof.
  • the subject is a mammal; in certain embodiments, the subject is a human.
  • the disease or condition associated with coagulation or thromboembolism is selected from the group consisting of thrombosis, thrombotic stroke, atrial fibrillation, atrial fibrillation associated stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, acute coronary syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, myocardial infarction (MI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary artery intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, migraine, Disseminated intravascular coagulation, thromboembolic disorders induced by medical devices (e.g., catheters), severe systemic inflammatory response syndrome, metastatic cancer, infectious diseases, organ failure (e.g.,
  • FXI factor XI
  • factor XI factors XI proteins of various species.
  • FXIa factor XIa
  • FXI and FXIa include mutants and variants of native FXI and FXIa proteins, respectively, having an amino acid sequence substantially the same as the native primary structure (amino acid sequence) described herein.
  • antibody refers to an immunoglobulin molecule that is usually composed of two pairs of polypeptide chains, each pair having a light chain (LC) and a heavy chain (HC).
  • Antibody light chains can be classified as ⁇ (kappa) and ⁇ (lambda) light chains.
  • Heavy chains can be classified as ⁇ , ⁇ , ⁇ , ⁇ or ⁇ , and the isotype of the antibody is defined as IgM, IgD, IgG, IgA and IgE, respectively.
  • the variable region and the constant region are connected by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 3 or more amino acids.
  • Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH).
  • the heavy chain constant region consists of three domains (CH1, CH2 and CH3).
  • Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL).
  • the light chain constant region consists of one domain CL.
  • the constant domain is not directly involved in the binding of antibodies to antigens, but exhibits a variety of effector functions, such as mediating the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.
  • VH and VL regions can also be subdivided into regions with high variability (called complementary determining regions (CDRs)), interspersed with more conservative regions called framework regions (FRs).
  • CDRs complementary determining regions
  • FRs framework regions
  • Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions (VH and VL) of each heavy chain/light chain pair form antigen binding sites, respectively.
  • the allocation of amino acids in each region or domain can be defined by numbering systems such as IMGT, Kabat, Chothia or AbM.
  • antibody includes not only intact antibodies but also antigen-binding fragments of antibodies.
  • CDR complementarity determining region
  • Kabat numbering system Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991
  • Chothia numbering system Chothia & Lesk (1987) J. Mol. Biol. 196:901-917
  • the term "antigen-binding fragment" of an antibody refers to a polypeptide of a full-length or partial fragment of an antibody, such as a polypeptide of a fragment of a full-length antibody, which retains the ability to specifically bind to the same antigen bound by the full-length antibody and/or competes with the full-length antibody for specific binding to the antigen, which is also referred to as an "antigen-binding portion".
  • an antigen-binding portion See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd edition, Raven Press, NY (1989), which is incorporated herein by reference in its entirety for all purposes.
  • Antigen-binding fragments of antibodies can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies.
  • Non-limiting examples of antigen-binding fragments include Fab, Fab', F(ab') 2 , Fd, Fv, dAb and complementarity determining region (CDR) fragments, single-chain antibodies (e.g., scFv), chimeric antibodies, diabodies, linear antibodies, nanobodies (technology from Domantis), domain antibodies (technology from Ablynx), and polypeptides that are small enough to have the specific antigen-binding ability of a full-length antibody.
  • Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23: 1126-1136.
  • buffer refers to a buffer solution that resists the change of pH by the action of its acid-base conjugate components.
  • buffers include acetate, succinate, gluconate, histidine, citrate, glycylglycine and other organic acid buffers.
  • the buffer suitable for use in the liquid formulation disclosed herein is selected from citric acid-citrate buffer, histidine buffer and acetic acid-acetate buffer.
  • buffer concentration has a meaning commonly understood by those skilled in the art, and generally refers to the content of the buffer substance in the buffer solution.
  • the buffer concentration refers to the total concentration of histidine and its salts in the buffer solution.
  • histidine buffer refers to a buffer comprising histidine, in which the histidine may exist alone or in the form of: for example, histidine hydrochloride, histidine acetate, histidine phosphate or histidine sulfate.
  • an amino acid buffer e.g., histidine hydrochloride buffer
  • L-histidine free alkali, solid
  • a corresponding acid e.g., hydrochloric acid
  • a pH regulator may be added to obtain a liquid preparation of a suitable pH range according to actual conditions in subsequent preparation steps.
  • the histidine in the histidine buffer suitable for the liquid preparation disclosed herein exists alone or in the form of histidine hydrochloride or histidine acetate.
  • citric acid-citrate buffer is a mixture comprising citric acid and citrate.
  • the citric acid-citrate buffer is a citric acid-sodium citrate buffer, that is, a mixture comprising citric acid and sodium citrate.
  • Citric acid-citrate buffer e.g., citric acid-sodium citrate buffer
  • a base e.g., sodium hydroxide
  • acetic acid-acetate buffer is a mixture comprising acetic acid and acetate.
  • the acetic acid-acetate buffer is an acetic acid-sodium acetate buffer, that is, a mixture comprising acetic acid and sodium acetate.
  • the acetic acid-acetate buffer e.g., acetic acid-sodium acetate buffer
  • mass volume ratio means the percentage weight (in grams) of a single component relative to the total volume (in milliliters) of a mixture containing the component. For example, 20 mg of a component in a total volume of 100 ml is 0.02% w/v.
  • the term "effective amount" refers to an amount sufficient to obtain or at least partially obtain the desired effect.
  • a disease prevention effective amount refers to an amount sufficient to prevent, prevent, or delay the occurrence of a disease
  • a disease treatment effective amount refers to an amount sufficient to cure or at least partially prevent the disease and its complications in a patient who already has the disease. Determining such an effective amount is well within the capabilities of those skilled in the art. For example, an effective amount for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously, etc.
  • the liquid preparation provided in the present application which comprises an anti-coagulation factor XI/XIa antibody and a specific prescription composition, has excellent stability and can obtain a high-concentration preparation with sufficiently low viscosity, thereby significantly reducing the difficulty of production and administration of the high-concentration preparation, thereby improving patient compliance, and has significant clinical value.
  • Figure 1 Viscosity-protein concentration variation trend.
  • the anti-coagulation factor XI/XIa antibody (hereinafter referred to as "protein") injection of the present application is a sterile, transparent, preservative-free injection obtained by aseptic filtration and filling of the anti-coagulation factor XI/XIa antibody stock solution. According to the device used for clinical administration, the injection thrust is 6.41N (75mm/min) and 12.68N (150mm/min).
  • the monoclonal antibody of anti-coagulation factor XI/XIa is the humanized antibody 36G9.10hz73 in patent application WO 2020/211674 A1, which has a heavy chain as shown in SEQ ID NO:42 and a light chain as shown in SEQ ID NO:43.
  • the antibody preparation was prepared according to the table below, the pH was adjusted to 6.0, and the viscosity was tested.
  • the viscosity of antibody preparation F1 is 8.7 cp
  • the viscosities of antibody preparations F2 to F4 are 2.7 cp, 10.6 cp, and 3.3 cp, respectively. It can be seen that the combination of sodium chloride, arginine, and glutamic acid can reduce the viscosity of the preparation, while sucrose can increase the viscosity of the preparation.
  • the antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.
  • the viscosity of antibody preparation F1 is 30.8 cp, and the viscosities of antibody preparations F2 to F4 are 10.1 cp, 10.1 cp, and 6.3 cp, respectively, indicating that sodium chloride can effectively reduce the viscosity of the preparation, PS80 (polysorbate 80) has little effect on the viscosity, and arginine can effectively reduce the viscosity of the preparation.
  • the antibody preparations F2 to F4 prepared above have clear appearance and no visible protein particles. After shaking at 1000 rpm for 4 hours, trace protein floccules were visible in antibody preparation F2, while preparations F3 and F4 remained clear and had no visible protein particles, indicating that adding PS80 to the preparation can improve the appearance of the preparation after shaking.
  • the polymer contents of the antibody preparations F2 to F4 prepared above were 1.6%, 1.7% and 1.6%, respectively. After shaking at 1000 rpm for 4 hours, the polymer contents of preparations F2 to F4 remained unchanged. After being placed at 40°C for 14 days, the polymer contents of preparations F2 to F4 increased to 3.4%, 4.0% and 4.5%, respectively, indicating that the polymer content of the preparations added with PS80 increased faster under high temperature conditions.
  • the antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.
  • the viscosity of antibody preparations F1 and F2 was in the range of 6.0 to 8.0 cp, and their appearance met the requirements after being stored at 40°C for 14 days.
  • the polymer contents of the antibody preparations F1 and F2 prepared above were 1.6% and 1.6%, respectively. After being placed at 40°C for 14 days, the polymer contents of preparations F1 and F2 were 4.5% and 2.5%, respectively, indicating that the addition of glutamic acid and the reduction of arginine in the preparation significantly reduced the growth rate of polymers in the preparation under high temperature conditions.
  • the antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.
  • the viscosity of antibody preparations F1 to F4 was in the range of 8.0 to 11.0 cp, and their appearance met the requirements after being placed at 40°C for 14 days.
  • the aggregate contents of the antibody preparations F1 to F4 prepared above were 1.5%, 1.4%, 1.4% and 1.4%, respectively. After being placed at 40°C for 14 days, the aggregate contents of the preparations F1 to F4 were 4.2%, 3.9%, 3.6% and 2.6%, respectively, indicating that reducing the sodium chloride concentration in the formula and increasing the arginine-glutamic acid concentration reduced aggregate formation.
  • the antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.
  • the antibody preparation was prepared according to the table below, the pH was adjusted to 6.0, and the protein particles were detected by Flowcam.
  • the Flowcam test results after storage at 40°C are shown in the following table.
  • the protein particles all meet the requirements, and the effect of surfactant on the formation of protein particles is that PS20 is better than PS80.
  • the antibody preparations were prepared according to the table below, and the viscosity and appearance were tested.
  • the aggregate content was tested by SEC-HPLC, and the protein particles were tested by Flowcam.
  • the viscosity of antibody preparations F1 and F2 was in the range of 8.0 to 10.0 cp, and the appearance, aggregate content, and protein particles all met the quality requirements.

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Abstract

La présente invention concerne le domaine des anticorps thérapeutiques. Plus particulièrement, la présente invention concerne une formulation d'anticorps anti-facteur Ⅺ/Ⅺa de coagulation, qui comprend un anticorps anti-facteur Ⅺ/Ⅺa de coagulation, un tampon, de l'acide glutamique et de l'arginine. La formulation d'anticorps anti-facteur Ⅺ/Ⅺa de coagulation de la présente invention peut maintenir une stabilité d'anticorps après un stockage à long terme tout en obtenant une viscosité suffisamment faible à des concentrations élevées. De plus, la présente invention concerne en outre l'utilisation de la formulation d'anticorps anti-facteur Ⅺ/Ⅺa de coagulation dans la préparation d'un médicament pour la prévention et/ou le traitement de maladies ou de troubles liés à la coagulation sanguine ou à la thromboembolie.
PCT/CN2024/138814 2023-12-22 2024-12-12 Formulation d'anticorps anti-facteur xi/xia de coagulation Pending WO2025130748A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108409863A (zh) * 2017-02-10 2018-08-17 上海仁会生物制药股份有限公司 抗凝血因子xi抗体
EA201892716A1 (ru) * 2016-06-14 2019-05-31 Мерк Шарп И Доум Корп. Антитела к фактору свертывания xi
CN113474374A (zh) * 2019-04-16 2021-10-01 四川科伦博泰生物医药股份有限公司 抗FXI/FXIa抗体及其用途
CN114478781A (zh) * 2018-08-09 2022-05-13 上海仁会生物制药股份有限公司 抗凝血因子xi抗体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA201892716A1 (ru) * 2016-06-14 2019-05-31 Мерк Шарп И Доум Корп. Антитела к фактору свертывания xi
CN108409863A (zh) * 2017-02-10 2018-08-17 上海仁会生物制药股份有限公司 抗凝血因子xi抗体
CN114478781A (zh) * 2018-08-09 2022-05-13 上海仁会生物制药股份有限公司 抗凝血因子xi抗体
CN113474374A (zh) * 2019-04-16 2021-10-01 四川科伦博泰生物医药股份有限公司 抗FXI/FXIa抗体及其用途
US20220162338A1 (en) * 2019-04-16 2022-05-26 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Anti-fxi/fxia antibody and use thereof

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