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WO2025140497A1 - Protéine de liaison à pvrig, anticorps bispécifique et utilisation - Google Patents

Protéine de liaison à pvrig, anticorps bispécifique et utilisation Download PDF

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Publication number
WO2025140497A1
WO2025140497A1 PCT/CN2024/143026 CN2024143026W WO2025140497A1 WO 2025140497 A1 WO2025140497 A1 WO 2025140497A1 CN 2024143026 W CN2024143026 W CN 2024143026W WO 2025140497 A1 WO2025140497 A1 WO 2025140497A1
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amino acid
seq
acid sequence
antigen
antibody
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Chinese (zh)
Inventor
梁世忠
吴杰雄
黎慧杰
俞金泉
李胜峰
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Bio Thera Solutions Ltd
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Bio Thera Solutions Ltd
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    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®

Definitions

  • the present invention belongs to the field of biomedicine, and in particular relates to PVRIG binding protein, bispecific antibody and application thereof.
  • T and NK cell co-inhibitory receptors are members of the immunoglobulin (Ig) superfamily. When they bind to the corresponding ligands expressed on antigen presenting cells or tumor cells, they weaken cell activation through protein tyrosine phosphatases (such as SHIP-1 and SHP-2), ultimately leading to reduced effector function and inhibiting gene expression.
  • Receptor blockers are able to specifically recognize and bind to certain receptors, preventing their corresponding ligands from binding to them. In tumor treatment, blocking the binding of co-inhibitory receptors to their ligands through receptor blockers helps activate the activity of immune cells and improve anti-tumor efficacy.
  • PVRIG is a co-inhibitory receptor belonging to the poliovirus receptor (PVR) family, also known as CD112R, which is usually expressed on natural killer cells (NK) and CD8+T cells.
  • PVRIG poliovirus receptor
  • Human PVRIG is a 36kD single-pass transmembrane protein that contains a transmembrane region, a long intracellular domain, and an extracellular immunoglobulin variable (IgV) domain. Since CD226 and PVRIG have the same binding site on CD112, CD226 competes with the inhibitory immune checkpoint PVRIG for binding to CD112 to promote T cell activation. Therefore, PVRIG can significantly inhibit the CD112/CD226 interaction in T cells.
  • the object of the present invention is to provide a PVRIG binding protein, a bispecific antibody or an antigen-binding fragment and applications thereof.
  • the present invention provides a bispecific antibody or antigen-binding fragment, comprising a first antigen-binding portion capable of binding to PVRIG; the first antigen-binding portion comprises one or more amino acid sequences of (a)-(c):
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:6, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:6;
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:7;
  • HCDR3 which comprises the amino acid sequence shown in any one of SEQ ID NOs: 8-12, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in any one of SEQ ID NOs: 8-12.
  • the first antigen binding portion comprises a heavy chain variable region (VH), wherein the VH comprises HCDR1, HCDR2 and HCDR3; wherein HCDR1 comprises the amino acid sequence shown in SEQ ID NO:6; HCDR2 comprises the amino acid sequence shown in SEQ ID NO:7; and HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO:8-12.
  • VH heavy chain variable region
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO: 19, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 19;
  • HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 20, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 20;
  • LCDR3 which comprises the amino acid sequence shown in SEQ ID NO:23, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:23.
  • the second antigen binding portion comprises a heavy chain variable region (VH), wherein the VH comprises HCDR1, HCDR2 and HCDR3; wherein HCDR1 comprises the amino acid sequence shown in SEQ ID NO:18; HCDR2 comprises the amino acid sequence shown in SEQ ID NO:19; and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:20.
  • VH heavy chain variable region
  • the second antigen binding portion comprises a light chain variable region (VL), wherein the VL comprises LCDR1, LCDR2 and LCDR3; wherein LCDR1 comprises the amino acid sequence shown in SEQ ID NO:21; LCDR2 comprises the amino acid sequence shown in SEQ ID NO:22; and LCDR3 comprises the amino acid sequence shown in SEQ ID NO:23.
  • VL light chain variable region
  • the second antigen binding portion comprises VH and VL; the VH comprises HCDR1, HCDR2 and HCDR3; the VL comprises LCDR1, LCDR2 and LCDR3; wherein HCDR1 comprises the amino acid sequence shown in SEQ ID NO:18; HCDR2 comprises the amino acid sequence shown in SEQ ID NO:19; HCDR3 comprises the amino acid sequence shown in SEQ ID NO:20; LCDR1 comprises the amino acid sequence shown in SEQ ID NO:21; LCDR2 comprises the amino acid sequence shown in SEQ ID NO:22; LCDR3 comprises the amino acid sequence shown in SEQ ID NO:23.
  • the heavy chain variable region of the second antigen binding portion comprises the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:24.
  • the light chain variable region of the second antigen binding portion comprises the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:25.
  • the heavy chain variable region of the second antigen binding portion comprises the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:24.
  • the second antigen binding portion further comprises a heavy chain constant region and a light chain constant region.
  • the heavy chain constant region of the second antigen binding portion comprises the amino acid sequence set forth in SEQ ID NO: 26 or 27, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence set forth in SEQ ID NO: 26 or 27, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence set forth in SEQ ID NO: 26 or 27.
  • the light chain of the antibody comprises the amino acid sequence shown in SEQ ID NO:31, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:31, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:31.
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:7;
  • HCDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 8-12, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence as shown in any one of SEQ ID NOs: 8-12;
  • the second antigen binding portion comprises one or more amino acid sequences of (d)-(i):
  • HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 18, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 18;
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO: 19, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 19;
  • HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 20, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 20;
  • LCDR1 which comprises the amino acid sequence shown in SEQ ID NO:21, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:21;
  • LCDR2 which comprises the amino acid sequence shown in SEQ ID NO:22, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:22;
  • LCDR3 which comprises the amino acid sequence shown in SEQ ID NO:23, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:23.
  • the first antigen-binding portion comprises a heavy chain variable region (VH), wherein the VH comprises HCDR1, HCDR2 and HCDR3; wherein HCDR1 comprises the amino acid sequence shown in SEQ ID NO:6; HCDR2 comprises the amino acid sequence shown in SEQ ID NO:7; HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO:8-12.
  • VH heavy chain variable region
  • the second antigen-binding portion comprises VH and VL; wherein the VH comprises HCDR1, HCDR2 and HCDR3; wherein the VL comprises LCDR1, LCDR2 and LCDR3; wherein HCDR1 comprises the amino acid sequence shown in SEQ ID NO:18; HCDR2 comprises the amino acid sequence shown in SEQ ID NO:19; HCDR3 comprises the amino acid sequence shown in SEQ ID NO:20; LCDR1 comprises the amino acid sequence shown in SEQ ID NO:21; LCDR2 comprises the amino acid sequence shown in SEQ ID NO:22; LCDR3 comprises the amino acid sequence shown in SEQ ID NO:23.
  • the first antigen binding portion comprises a heavy chain variable region (VH), the VH comprising HCDR1, HCDR2 and HCDR3; wherein HCDR1 comprises the amino acid sequence shown in SEQ ID NO:6; HCDR2 comprises the amino acid sequence shown in SEQ ID NO:7; HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO:8-12; the second antigen binding portion comprises VH and VL; the VH comprises HCDR1, HCDR2 and HCDR3; the VL comprises LCDR1, LCDR2 and LCDR3; wherein HCDR1 comprises the amino acid sequence shown in SEQ ID NO:18; HCDR2 comprises the amino acid sequence shown in SEQ ID NO:19; HCDR3 comprises the amino acid sequence shown in SEQ ID NO:20; LCDR1 comprises the amino acid sequence shown in SEQ ID NO:21; LCDR2 comprises the amino acid sequence shown in SEQ ID NO:22; LCDR3 comprises the amino acid sequence shown in SEQ ID NO:23.
  • VH heavy
  • the first antigen binding moiety is a single domain antibody.
  • the single domain antibody comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 13-17, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence as set forth in any one of SEQ ID NOs: 13-17, or an amino acid sequence having one or more conservative amino acid substitutions to an amino acid sequence as set forth in any one of SEQ ID NOs: 13-17.
  • the heavy chain variable region of the second antigen binding portion comprises the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:24.
  • the light chain variable region of the second antigen binding portion comprises the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:25.
  • the first antigen binding portion is a single domain antibody comprising the amino acid sequence of any one of SEQ ID NOs: 13-17, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of SEQ ID NOs: 13-17, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence of any one of SEQ ID NOs: 13-17;
  • the heavy chain variable region of the second antigen binding portion comprises the amino acid sequence of SEQ ID NO: 24, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of
  • the light chain variable region of the second antigen binding portion comprises an amino acid sequence as shown in SEQ ID NO:25, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence as shown in SEQ ID NO:25, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence as shown in SEQ ID NO:25, or an amino acid sequence with one or more conservative amino acid substitutions compared to the amino acid sequence as shown in SEQ ID NO:25.
  • the second antigen binding portion further comprises a heavy chain constant region and a light chain constant region.
  • the heavy chain constant region of the second antigen binding portion comprises the amino acid sequence set forth in SEQ ID NO: 26 or 27, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence set forth in SEQ ID NO: 26 or 27, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence set forth in SEQ ID NO: 26 or 27.
  • the present invention provides a pharmaceutical composition, comprising the above-mentioned bispecific antibody or antigen-binding fragment, the above-mentioned PVRIG binding protein, the above-mentioned nucleic acid, the above-mentioned expression vector or the above-mentioned cell, and a pharmaceutically acceptable excipient.
  • the present invention provides use of the above-mentioned bispecific antibody or antigen-binding fragment, the above-mentioned PVRIG binding protein, the above-mentioned nucleic acid, the above-mentioned expression vector, the above-mentioned cell or the above-mentioned pharmaceutical composition in the preparation of a drug for treating or preventing a disease.
  • the present invention provides a method for treating or preventing a disease, comprising administering a therapeutically effective amount of the above-mentioned bispecific antibody or antigen-binding fragment, the above-mentioned PVRIG binding protein, the above-mentioned nucleic acid, the above-mentioned expression vector, the above-mentioned cell or the above-mentioned pharmaceutical composition to a patient in need thereof.
  • the disease is a proliferative disease or an infection.
  • the disease is a tumor.
  • the tumor is a benign tumor or a cancer.
  • the tumor is selected from prostate cancer, liver cancer, colorectal cancer, ovarian cancer, uterine cancer (such as endometrial cancer), breast cancer (such as triple negative breast cancer), pancreatic cancer, gastric cancer, cervical cancer, head and neck cancer, thyroid cancer, testicular cancer, bladder cancer, urothelial cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), melanoma, non-melanoma skin cancer (such as squamous and basal cell carcinoma), glioma, kidney cancer, lymphoma (such as non-Hodgkin lymphoma, e.g., diffuse large B-cell lymphoma; Hodgkin lymphoma), leukemia (such as acute myeloid leukemia, T-cell acute lymphoblastic leukemia
  • FIG1 illustrates two structures of the bispecific antibodies of the present invention
  • FIG1A is the structure of the bispecific antibody Bi-VH1
  • FIG1B is the structure of the bispecific antibody Bi-VH3.
  • FIG5 is a graph showing the binding curve of antibody or VHH-Fc fusion protein blocking the binding of ligand PVRL2 to cell surface PVRIG.
  • FIG6 shows that antibodies or VHH-Fc fusion proteins block the cellular activity of PVRL2-PVRIG interaction.
  • FIG. 7 shows that antibodies or VHH-Fc fusion proteins block the cellular activity of PVRL2-PVRIG interaction.
  • FIG8 shows cellular activity of antibodies blocking PVR-TIGIT interaction.
  • FIG. 9 shows the activity of antibodies or fusion proteins in activating NK cells.
  • a entity refers to one or more of that entity, e.g., "an antibody” should be understood as one or more antibodies, and thus, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein.
  • the terms “comprising” or “including” mean that the antibody, composition, method, etc. include the listed elements, such as components or steps, but do not exclude others. "Essentially consisting of” means that the antibody, composition, method, etc. exclude other elements that have a fundamental effect on the characteristics of the combination, but do not exclude elements that have no essential effect on the antibody, composition, method, etc. "Consisting of” means excluding elements not specifically listed.
  • Polypeptide is intended to encompass the singular “polypeptide” as well as the plural “polypeptides”, and refers to a molecule composed of amino acid monomers linearly linked by amide bonds (also known as peptide bonds).
  • Polypeptide refers to any single chain or multiple chains of two or more amino acids, and does not refer to the specific length of the product. Therefore, the definition of “polypeptide” includes peptides, dipeptides, tripeptides, oligopeptides, "proteins", “amino acid chains” or any other terms used to refer to two or more amino acid chains, and “polypeptide” can be used to replace any of the above terms, or used interchangeably with any of the above terms.
  • Polypeptide is also intended to refer to products modified after the expression of the polypeptide, including but not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage or non-natural amino acid modifications.
  • the polypeptide can be derived from a natural biological source or produced by recombinant technology, but it is not necessarily translated from a specified nucleic acid sequence, and it may be produced in any manner including chemical synthesis.
  • the CDR region of an antibody is responsible for the binding specificity of the antibody to an antigen.
  • known antibody heavy chain and light chain variable region sequences there are currently several methods for determining the CDR region of an antibody, including Kabat, IMGT, Chothia and AbM numbering systems.
  • the application of the definition of the CDR of an antibody or its variant will be within the scope of the term defined and used herein. If the variable region amino acid sequence of the given antibody is given, then those skilled in the art can determine which residues are included in a specific CDR usually, without relying on any experimental data outside the sequence itself.
  • Antibody refers to a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen.
  • An antibody can be a complete antibody and any antigen-binding fragment thereof or a single chain thereof. Therefore, “antibody” includes any protein or peptide that contains at least a portion of an immunoglobulin molecule that has biological activity of binding to an antigen.
  • Antibodies and antigen-binding fragments include but are not limited to the complementarity determining region (CDR) of a heavy chain or light chain or its ligand-binding portion, a heavy chain variable region (VH), a light chain variable region (VL), a heavy chain constant region (CH), a light chain constant region (CL), a framework region (FR) or any portion thereof, or at least a portion of a binding protein.
  • the CDR region includes the CDR region (LCDR1-3) of the light chain and the CDR region (HCDR1-3) of the heavy chain.
  • the heavy chain constant region includes the CH1 domain, the hinge (e.g., the upper, middle and/or lower hinge region) domain, the CH2 domain, and the CH3 domain; the crystallizable segment (Fc fragment) is equivalent to the CH2 and CH3 domains.
  • Antibodies and antigen-binding fragments can specifically recognize and bind to polypeptides or polypeptide complexes of one or more (such as two) antigens.
  • Antibodies or antigen-binding fragments that specifically recognize and bind to multiple (such as two) antigens can be referred to as multispecific (such as bispecific) antibodies or antigen-binding fragments.
  • a complete antibody includes a heavy chain and/or a light chain.
  • the categories of heavy chains include gamma, mu, alpha, delta or epsilon ( ⁇ , ⁇ , ⁇ , ⁇ ), among which there are some subclasses (e.g., ⁇ 1- ⁇ 4).
  • the nature of the chain determines the "type" of the antibody, which is IgG, IgM, IgA, IgD or IgE, respectively.
  • Antibody subclasses such as IgG1, IgG2, IgG3, IgG4, etc., have been fully characterized and the functional specificity conferred is also known. All antibody types are within the scope of protection of the present invention.
  • the antibody includes two heavy chains or and two light chains, and these four chains are connected in a "Y" configuration by disulfide bonds, wherein the light chain starts from the "Y" mouth and continues through the variable region to surround the heavy chain.
  • Antibody fragment or “antigen-binding fragment” refers to a portion of an antibody, such as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc. Regardless of its structure, an antibody fragment binds to the same antigen recognized by the intact antibody.
  • Antibody fragments include aptamers, spiegelmers, and bivalent antibodies.
  • Antigen-binding fragment also includes any synthetic or genetically engineered protein that acts as an antibody by binding to a specific antigen to form a complex.
  • Fab generally refers to the part of a conventional antibody (such as IgG) that binds to an antigen, including the heavy chain variable region VH, light chain variable region VL, heavy chain constant region domain CH1, and light chain constant region CL of the antibody.
  • the C-terminus of VH is linked to the N-terminus of CH1 to form a heavy chain Fd fragment
  • the C-terminus of VL is linked to the N-terminus of CL to form a light chain
  • the C-terminus of CH1 is further linked to the hinge region and other constant region domains of the heavy chain to form a heavy chain.
  • Fab also refers to a variant structure of Fab.
  • non-essential amino acid residues of immunoglobulin polypeptides are preferably replaced by other amino acid residues from the same side chain family.
  • a string of amino acids may be replaced by a structurally similar string of amino acids that differ in sequence and/or in the composition of the side chain family.
  • the PVRIG binding proteins or bispecific antibodies provided by the present invention include modified derivatives, i.e., modified by covalent attachment of any type of molecule to the PVRIG binding protein or bispecific antibody, wherein the covalent attachment does not prevent the PVRIG binding protein or bispecific antibody from binding to the epitope.
  • the PVRIG binding protein or bispecific antibody can be glycosylated, acetylated, pegylated, phosphorylated, amidated, derivatized by known protecting/blocking groups, proteolytically cleaved, linked to cellular ligands or other proteins, etc. Any of the numerous chemical modifications can be performed by existing techniques, including but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc.
  • the PVRIG binding protein or bispecific antibody described herein may be neutral, i.e., substantially free of net charge, such as when the pH of the composition containing the PVRIG binding protein or bispecific antibody is the isoelectric point of the protein, the protein is electrically neutral.
  • the protein described herein may exist in the form of a positive ion, such as when the pH is below the isoelectric point, the protein molecule as a whole exhibits a positive charge.
  • the protein described herein may exist in the form of a negative ion, such as when the pH is above the isoelectric point, the protein molecule as a whole exhibits a negative charge.
  • the effective dose and treatment regimen for treating a particular patient will depend on various factors, including the specific PVRIG binding protein or bispecific antibody or derivative used, the patient's age and weight, general health, sex and diet, as well as the time of administration, frequency of excretion, drug combination, and the severity of the specific disease being treated. These factors are determined by medical care personnel, including those of ordinary skill in the art.
  • the dosage used can be determined by pharmacological and pharmacokinetic principles well known in the art.
  • the PVRIG binding protein or bispecific antibody of the present invention is administered to the patient at a dose of 0.01 mg/kg to 100 mg/kg of the patient's body weight each time. In some embodiments, the administration is once a week, every two weeks, every three weeks, or every four weeks.
  • the antibodies provided by the present invention can be derived from any animal, such as mammals.
  • the antibodies are human, mouse, donkey, rabbit, goat, camel, llama, horse or chicken antibodies.
  • the variable region can be of condricthoid origin (e.g., from sharks).
  • Treatment refers to therapeutic treatment and preventive or prophylactic measures, the purpose of which is to prevent, slow down, improve or stop undesirable physiological changes or disorders, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in the extent of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement, alleviation, reduction or disappearance of the disease state (whether partial or complete), extension of the expected survival period compared to not receiving treatment, etc.
  • Patients in need of treatment include patients who already have a disease or disorder, patients who are susceptible to a disease or disorder, or patients who need to prevent the disease or disorder, and patients who can or are expected to benefit from the administration of the antibodies or pharmaceutical compositions provided by the present invention for detection, diagnostic procedures and/or treatment.
  • Patient refers to any mammal in need of diagnosis, prevention, prognosis or treatment, including humans, dogs, cats, rabbits, mice, horses, cows, etc.
  • Antibodies or fusion proteins can be prepared using conventional recombinant DNA techniques. Vectors and cell lines that produce antibodies or fusion proteins can be selected, constructed and cultured using techniques known to those skilled in the art. These techniques are described in various laboratory manuals and major publications, such as Recombinant DNA Technology for Production of Protein Therapeutics in Cultured Mammalian Cells, D.L. hacker, F.M. Wurm, in Reference Module in Life Sciences, 2017, the entire contents of which, including supplementary content, are incorporated herein by reference.
  • the DNA encoding the antibody or fusion protein can be designed and synthesized according to the amino acid sequence of the antibody or fusion protein described herein in a conventional manner, placed in an expression vector, and then transfected into a host cell, and the transfected host cell is cultured in a culture medium to produce a monoclonal antibody or fusion protein.
  • the expression vector includes at least one promoter element, a protein coding sequence, a transcription termination signal, and a polyA tail. Other elements include enhancers, Kozak sequences, and donor and acceptor sites for RNA splicing on both sides of the insertion sequence.
  • Efficient transcription can be obtained by the early and late promoters of SV40, the long terminal repeats from retroviruses such as RSV, HTLV1, HIVI, and the early promoters of cytomegalovirus, and promoters of other cells such as the actin promoter can also be used.
  • Suitable expression vectors may include pIRES1neo, pRetro-Off, pRetro-On, pLXSN, pLNCX, pcDNA3.1 (+/-), pcDNA/Zeo (+/-), pcDNA3.1/Hygro (+/-), pSVL, pMSG, pRSVcat, pSV2dhfr, pBC12MI, pCS2, and pCHO1.0, etc.
  • Commonly used mammalian host cells include HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells, and CHO cells, etc.
  • the gene sequence of antibody or fusion protein can be inserted into expression vector by standard methods (for example, complementary restriction sites on connection gene sequence and carrier, or if restriction sites are not present, then flat end connection).
  • expression vector can already carry antibody constant region sequence.
  • a method for converting antibody-related VH and VL sequences into full-length antibody gene is to insert them into expression vectors encoding heavy chain constant region and light chain constant region respectively, so that VH sequence is operably connected to CH sequence in carrier, and VL sequence is operably connected to CL sequence in carrier.
  • recombinant expression vector can encode signal peptide that promotes host cell secretion of antibody or fusion protein.
  • gene sequence can be cloned into the carrier of signal peptide that promotes host cell secretion of antibody or fusion protein, so that 3' end of gene sequence encoding signal peptide is connected in frame with 5' end of gene sequence encoding antibody (heavy chain and/or light chain) or fusion protein.
  • the expression vector needs to contain a screening marker, and common screening markers include dihydrofolate reductase, glutamine synthetase, neomycin resistance, hygromycin resistance and other screening genes, so as to facilitate the screening and separation of successfully transfected cells.
  • the constructed plasmid is transfected into host cells without the above genes, and after culturing in a selective medium, the successfully transfected cells grow in large quantities and produce the desired target protein.
  • the obtained antibody or fusion protein can be separated or purified by conventional technical means, such as protein A-agarose gel, ion exchange chromatography, hydroxyapatite chromatography, gel electrophoresis or affinity chromatography.
  • Example 1 Preparation of PVRIG recombinant protein and anti-PVRIG antibodies SF35 and H4
  • the DNA sequence of the PVRIG recombinant protein PVRIG-his (shown in SEQ ID NO: 1) was inserted into the expression plasmid to obtain a recombinant plasmid.
  • the above plasmid was then transiently transfected into HEK293 cells through polyetherimide (PEI), and the supernatant was collected after culture and purified to obtain a PVRIG-his protein sample.
  • PEI polyetherimide
  • amino acid sequence of PVRIG-his is as follows:
  • the amino acid sequences of the heavy and light chains of antibody SF35 and antibody H4 are shown in Table 3.
  • the nucleic acid sequences of the heavy and light chains of the antibodies were cloned into expression plasmids, respectively, and then transferred into CHO-K1 cells. After culture, the supernatant was collected and purified to obtain the antibodies.
  • Example 2 Preparation of anti-PVRIG/TIGIT bispecific antibodies and VHH-Fc fusion proteins
  • bispecific antibody Bi-VH1 whose schematic diagram is shown in FIG1A
  • bispecific antibody Bi-VH3 whose schematic diagram is shown in FIG1B
  • the structural feature of the bispecific antibody Bi-VH1 is that the anti-PVRIG VHH fragment is connected to the N-terminus of the heavy chain of the anti-TIGIT antibody, such as the bispecific antibodies Bi-VH1-94Y and Bi-VH1-94W
  • the structural feature of the bispecific antibody Bi-VH3 is that the anti-PVRIG VHH fragment is connected to the C-terminus of the heavy chain of the anti-TIGIT antibody, such as the bispecific antibodies Bi-VH3-94Y and Bi-VH3-94W.
  • the VHH-Fc fusion protein comprises the following structures from the N-terminus to the C-terminus: the anti-PVRIG VHH fragment, the peptide linker and the Fc fragment.
  • VHH-Fc fusion protein N1-94Y-Fc contains two identical sequences (as shown in SEQ ID NO:36), and its nucleic acid sequence is shown in SEQ ID NO:46
  • VHH-Fc fusion protein N1-94W-Fc contains two identical sequences (as shown in SEQ ID NO:37), and its nucleic acid sequence is shown in SEQ ID NO:47
  • VHH-Fc fusion protein 32 contains two identical sequences (as shown in SEQ ID NO:38), and its nucleic acid sequence is shown in SEQ ID NO:48
  • VHH-Fc fusion protein 34 contains two identical sequences (as shown in SEQ ID NO:39), and its nucleic acid sequence is shown in SEQ ID NO:49
  • VHH-Fc fusion protein 37 contains two identical sequences (as shown in SEQ ID NO:40), and its nucleic acid sequence is shown in SEQ ID NO:
  • the bispecific antibody Bi-VH1-94Y contains two first polypeptides with identical sequences (as shown in SEQ ID NO:41) and two second polypeptides with identical sequences (as shown in SEQ ID NO:31), the first polypeptide is composed of an anti-PVRIG VHH fragment (as shown in SEQ ID NO:13), a peptide linker L1 (GGGGSGGGGS, as shown in SEQ ID NO:32) and an anti-TIGIT heavy chain sequence (as shown in SEQ ID NO:29), and the second polypeptide is composed of an anti-TIGIT light chain sequence (as shown in SEQ ID NO:31), the nucleic acid sequence of the first polypeptide is as shown in SEQ ID NO:51, and the nucleic acid sequence of the second polypeptide is as shown in SEQ ID NO:45;
  • the heterologous antibody Bi-VH1-94W contains two first polypeptides with identical sequences (as shown in SEQ ID NO:42) and two second poly
  • the nucleic acid sequences of the first polypeptide and the second polypeptide of the bispecific antibody are cloned into expression plasmids respectively, and then transiently transfected into HEK293F cells. After culture, the supernatant is collected and purified to obtain the bispecific antibody.
  • the nucleic acid sequence of the VHH-Fc fusion protein is cloned into an expression plasmid, and then transiently transfected into HEK293F cells. After culture, the supernatant is collected and purified to obtain the VHH-Fc fusion protein.
  • Biacore T200 was used to detect the affinity of antibodies and VHH-Fc fusion proteins to PVRIG-his and TIGIT-his proteins.
  • Antibodies or VHH-Fc fusion proteins were coupled to the surface of the CM5 chip, and then the chip was used to capture PVRIG-his or TIGIT-his, respectively.
  • Different concentrations of PVRIG-his or TIGIT-his proteins were injected into the CM5 chip.
  • VHH-Fc fusion proteins 32, 34, and 37 showed strong affinity to PVRIG-his protein, with KD values of 0.65nM, 0.89nM, and 0.96nM, respectively.
  • bispecific antibodies Bi-VH1-94Y, Bi-VH1-94W, Bi-VH3-94Y and Bi-VH3-94W, and parent anti-TIGIT antibody h10D8OF dilute them to 200 nM with 1 ⁇ PBS as the starting concentration in a 96-well V-shaped plate, and perform 3-fold gradient dilution with 1 ⁇ PBS to obtain a total of 9 serial dilution concentrations.
  • the cells were collected by flow cytometry, and the fluorescent antibodies bound to the cell surface were detected to obtain the mean fluorescence intensity (MFI) value of the original data.
  • MFI mean fluorescence intensity
  • the full-length human TIGIT gene sequence is as follows:
  • Bi-VH1-94Y, Bi-VH1-94W, Bi-VH3-94Y and Bi-VH3-94W VHH-Fc fusion proteins N1-94W-Fc, N1-94Y-Fc, 32, 34 and 37, and antibodies SF35 and hIgG1 (Beijing Sino Biological Technology Co., Ltd., Cat. No. MA14OC2903).
  • the cDNA of PVRIG (purchased from Beijing Sino Biological Shenzhou Technology Co., Ltd., catalog number HG28312-UT) was transferred into Jurkat-NFAT cells (Construction of Jurkat-NFAT cells: Plasmid containing NFAT luciferase reporter gene was electroporated into Jurkat cells) to obtain Jurkat-NFAT cells overexpressing PVRIG, named Jurkat-NFAT-PVRIG.
  • Jurkat-NFAT-PVRIG cells with good growth were taken, centrifuged and the supernatant was discarded, and the cells were resuspended in 1 ⁇ PBS to a density of 1 ⁇ 10 7 cells/mL, and added to a 96-well V-shaped plate (Corning, catalog number: 3897) at a rate of 50 ⁇ L/well. At this time, the number of cells was 5 ⁇ 10 5 cells/well. 50 ⁇ L of the corresponding concentration of antibody or VHH-Fc fusion protein sample was added to each well and mixed. At this time, the maximum final concentration of the antibody or VHH-Fc fusion protein was 100 nM.
  • the 96-well V-shaped plate was placed in a 4°C refrigerator for incubation for 60 minutes. After the incubation was completed, the 96-well V-shaped plate was centrifuged to remove the supernatant, and then washed with 1 ⁇ PBS and the supernatant was removed for the next incubation.
  • Anti-FC PE purchased from BioLegend, catalog number 366903
  • VHH-Fc fusion proteins 32, 34 and 37 can bind to human PVRIG highly expressed on the surface of Jurkat-NFAT-PVRIG cells with high affinity.
  • the EC50 of VHH-Fc fusion protein 32 is 0.67nM
  • the EC50 of VHH-Fc fusion protein 34 is 0.95nM
  • the EC50 of VHH-Fc fusion protein 37 is 0.87nM.
  • the bispecific antibodies Bi-VH1-94Y, Bi-VH1-94W, Bi-VH3-94Y and Bi-VH3-94W can all bind to Jurkat-NFAT-PVRIG cells significantly, with EC 50 values of 0.26 nM, 0.32 nM, 1.72 nM and 2.33 nM, respectively.

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Abstract

L'invention concerne une protéine de liaison à PVRIG, un anticorps bispécifique et une utilisation. L'anticorps bispécifique ou le fragment de liaison à l'antigène comprend une première fraction de liaison à l'antigène capable de se lier à PVRIG et/ou une seconde fraction de liaison à l'antigène capable de se lier à TIGIT. La protéine de liaison à PVRIG ou l'anticorps bispécifique peut être utilisé pour traiter ou prévenir des maladies.
PCT/CN2024/143026 2023-12-29 2024-12-27 Protéine de liaison à pvrig, anticorps bispécifique et utilisation Pending WO2025140497A1 (fr)

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EP4245374A2 (fr) * 2022-03-18 2023-09-20 Compugen Ltd. Pvrl2 et/ou pvrig en tant que biomarqueurs de traitement
CN116925233A (zh) * 2022-04-02 2023-10-24 普米斯生物技术(珠海)有限公司 抗tigit-抗pvrig双特异性抗体、其药物组合物及用途
WO2023236980A1 (fr) * 2022-06-08 2023-12-14 山东先声生物制药有限公司 Composition pharmaceutique d'anticorps bispécifique pvrig/tigit et son utilisation

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Publication number Priority date Publication date Assignee Title
US20170240613A1 (en) * 2015-09-02 2017-08-24 The Regents Of The University Of Colorado Compositions and methods for modulating t-cell mediated immune response
CN113039202A (zh) * 2018-06-01 2021-06-25 康姆普根有限公司 抗pvrig/抗tigit双特异性抗体和使用方法
CN115003333A (zh) * 2020-03-13 2022-09-02 江苏恒瑞医药股份有限公司 Pvrig结合蛋白及其医药用途
WO2022007807A1 (fr) * 2020-07-07 2022-01-13 百奥泰生物制药股份有限公司 Anticorps bispécifique et son utilisation
CN114907479A (zh) * 2021-02-09 2022-08-16 上海君实生物医药科技股份有限公司 抗cd112r抗体及其用途
WO2023040940A1 (fr) * 2021-09-15 2023-03-23 江苏恒瑞医药股份有限公司 Utilisation d'une protéine de liaison pvrig/tigit en combinaison avec un inhibiteur de point de contrôle immunitaire dans le traitement de cancers
WO2023125561A1 (fr) * 2021-12-27 2023-07-06 上海健信生物医药科技有限公司 Anticorps anti-tigit, anticorps bispécifique et utilisation associée
EP4245374A2 (fr) * 2022-03-18 2023-09-20 Compugen Ltd. Pvrl2 et/ou pvrig en tant que biomarqueurs de traitement
CN116925233A (zh) * 2022-04-02 2023-10-24 普米斯生物技术(珠海)有限公司 抗tigit-抗pvrig双特异性抗体、其药物组合物及用途
WO2023236980A1 (fr) * 2022-06-08 2023-12-14 山东先声生物制药有限公司 Composition pharmaceutique d'anticorps bispécifique pvrig/tigit et son utilisation

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