WO2019061962A1 - Anticorps anti-interleukine 17a, son procédé de préparation et son application - Google Patents

Anticorps anti-interleukine 17a, son procédé de préparation et son application Download PDF

Info

Publication number
WO2019061962A1
WO2019061962A1 PCT/CN2018/073457 CN2018073457W WO2019061962A1 WO 2019061962 A1 WO2019061962 A1 WO 2019061962A1 CN 2018073457 W CN2018073457 W CN 2018073457W WO 2019061962 A1 WO2019061962 A1 WO 2019061962A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
variable region
chain variable
heavy chain
light chain
Prior art date
Application number
PCT/CN2018/073457
Other languages
English (en)
Chinese (zh)
Inventor
朱向阳
于海佳
贾慧峰
俞玲
Original Assignee
华博生物医药技术（上海）有限公司
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 华博生物医药技术（上海）有限公司 filed Critical 华博生物医药技术（上海）有限公司
Publication of WO2019061962A1 publication Critical patent/WO2019061962A1/fr

Links

Classifications

    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • 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
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to the field of medicine, and in particular to an antibody targeted to interleukin 17A (also referred to as IL-17), a preparation method thereof and use thereof.
  • IL-17 interleukin 17A
  • IL-17A IL-17
  • IL-17B IL-17B
  • IL-17C IL-17D
  • IL-17E IL-25
  • IL-17F interleukin-17 cytokines
  • IL-17A was originally found to be secreted by activated CD4 + T cells. This type of characteristic T cell subset that secretes IL-17A is called Th17 cell.
  • Th17 cell cytotoxic CD8 + T cells (Tc17), ⁇ T cells, natural killer T cells (NKT-17), and B cells can also express IL-17A under specific conditions.
  • Innate immune cells, including monocytes, neutrophils, natural killer cells, and lymphoid tissue-like (Lti-like) cells can also produce IL-17A.
  • B cells can also produce IL-17A.
  • Some non-immune cells can also produce IL-17A under stress. Since Th17 cells are the most widely distributed in the body and have a wide range of effects in the inflammatory response, it is generally considered to be the main source of IL-17A.
  • the congenital cells that produce IL-17A mainly participate in the host's anti-infective immune response as the early defense cells of the body.
  • IL-17A is a homodimer that is linked by a disulfide bond from two chains of 155 amino acids with a molecular weight of 35 kDa.
  • the structure of IL-17 consists of a signal peptide (AA) consisting of 23 amino acids and a region of 123 amino acid chains.
  • the receptor for IL-17 binding to the type I cell surface is called IL-17R, and there are at least three of them: IL-17RA, IL-17RB and IL-17RC.
  • IL-17A and IL-17F bind to IL-17RA and IL-17RC receptor complexes in the form of homodimers or heterodimers to transduce signals and participate in autoimmune diseases, multiple inflammatory responses, and The host is resistant to an immune response.
  • IL-17C binds to IL-17RA and IL-17RE receptor complexes to activate downstream signaling and promotes anti-infective immunity, autoimmune diseases and inflammatory responses.
  • IL-17B was found to bind IL-17RB, but its downstream signal remains unclear.
  • IL-17RB also forms a receptor complex with IL-17RA to mediate IL-17E causing a type II immune response.
  • Il-17E has also been reported to promote apoptosis in tumor cells.
  • the receptor and downstream signals of IL-17D and the ligand and downstream signals of the orphan receptor IL-17RD are still unclear.
  • IL-17A primarily induces signal activation of non-hematopoietic-derived cells including epithelial cells and stromal cells. IL-17A induces the expression of a variety of inflammatory factors and chemokines to promote the recruitment of a variety of immune cells, thereby promoting autoimmune diseases. Studies have found that IL-17A and IL-17F, and their major secretory T cell subsets, Th17 cells also play important roles in a variety of autoimmune diseases, including autoimmune diseases such as rheumatoid arthritis (rheumatoid).
  • RA Arthritis, RA and multiple sclerosis (MS), as well as inflammatory boweldise (IBD), psoriasis, systemic lupus erythematosus (SLE), and type 1 diabetes ( Type1diabetes, T1D).
  • IBD inflammatory boweldise
  • SLE systemic lupus erythematosus
  • T1D Type1diabetes
  • IL-17A and IL-17F exert their functions of promoting inflammatory response mainly by inducing target cells to express various inflammatory factors and chemokines.
  • IL-17A binds to the cell surface receptor IL-17RA and recruits IL-17RC to form a heterodimer that mediates downstream signaling pathways.
  • IL-17 binds to its receptor and activates TRAF6 (TNF-receptor associated factor 6).
  • TRAF6 TRAF6 (TNF-receptor associated factor 6).
  • IL-17 shares the same transcriptional pathway as IL-1 and TNF, which activates NF-kB and three MAP (mitogen-activated protein) enzymes, including ERK1, ERK2, JNK, and p38. These pathways are found in both synovial and chondrocytes.
  • a heavy chain variable region of an antibody comprising the following three complementarity determining region CDRs:
  • the amino acid sequence of any one of the above amino acid sequences further comprises at least one of optionally adding, deleting, modifying and/or substituting (eg, 1-3, preferably 1-2, more preferably 1) amino acid and a derivative sequence capable of retaining IL-17A binding affinity.
  • the heavy chain variable region further comprises a FR region of a human source or a FR region of a murine source.
  • the heavy chain variable region has the amino acid sequence set forth in SEQ ID NO: 1.
  • the heavy chain variable region has the amino acid sequence set forth in SEQ ID NO: 5.
  • a heavy chain of an antibody having a heavy chain variable region according to the first aspect of the invention.
  • the heavy chain of the antibody further comprises a heavy chain constant region.
  • the heavy chain constant region is of human, murine or rabbit origin.
  • a light chain variable region of an antibody comprising the following three complementarity determining region CDRs:
  • amino acid sequence is CDR2' of GAT, and
  • the amino acid sequence of any one of the above amino acid sequences further comprises at least one of optionally adding, deleting, modifying and/or substituting (eg, 1-3, preferably 1-2, more preferably 1) amino acid and a derivative sequence capable of retaining IL-17A binding affinity.
  • the light chain variable region further comprises a human FR region or a murine FR region.
  • the light chain variable region has the amino acid sequence set forth in SEQ ID NO: 2.
  • the light chain variable region has the amino acid sequence set forth in SEQ ID NO: 6.
  • a light chain of an antibody having a light chain variable region according to the third aspect of the invention.
  • the light chain of the antibody further comprises a light chain constant region.
  • the light chain constant region is of human, murine or rabbit origin.
  • an antibody having:
  • the antibody has: a heavy chain according to the second aspect of the invention; and/or a light chain according to the fourth aspect of the invention.
  • the antibody for human IL-17A protein EC (preferably wild type) binding force 50 5-50ng / ml.
  • the antibody for human IL-17A protein EC (preferably wild type) binding force 50 12.6ng / ml.
  • the antibody is selected from the group consisting of an animal-derived antibody, a chimeric antibody, a humanized antibody, or a combination thereof.
  • the antibody is a diabody, or a single chain antibody.
  • the antibody is a monoclonal antibody.
  • the antibody is a partially or fully humanized monoclonal antibody.
  • the heavy chain variable region sequence of the antibody is as set forth in SEQ ID NO.: 1 or 5; and/or
  • the light chain variable region sequence of the antibody is set forth in SEQ ID NO.: 2 or 6.
  • the heavy chain variable region sequence of the antibody is set forth in SEQ ID NO.: 1; and the light chain variable region sequence of the antibody is set forth in SEQ ID NO.: 2.
  • the heavy chain variable region sequence of the antibody is set forth in SEQ ID NO.: 5; and the light chain variable region sequence of the antibody is set forth in SEQ ID NO.: 6.
  • the antibody is in the form of a drug conjugate.
  • a recombinant protein having:
  • the tag sequence comprises a 6His tag.
  • the recombinant protein comprises a fusion protein.
  • the recombinant protein is a monomer, a dimer, or a multimer.
  • a CAR construct wherein the scFV segment of the monoclonal antibody antigen-binding region of the CAR construct is a binding region that specifically binds to IL-17A, and the scFv has a The heavy chain variable region of the first aspect of the invention and the light chain variable region of the third aspect of the invention.
  • a recombinant immune cell is provided, the immune cell expressing an exogenous CAR construct according to the seventh aspect of the invention.
  • the immune cells are selected from the group consisting of NK cells, T cells.
  • the immune cells are from a human or non-human mammal (e.g., a mouse).
  • an antibody drug conjugate comprising:
  • a coupling moiety coupled to the antibody moiety being selected from the group consisting of a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, or a combination thereof.
  • the antibody moiety is coupled to the coupling moiety via a chemical bond or linker.
  • an active ingredient selected from the group consisting of the heavy chain variable region according to the first aspect of the invention, the weight according to the second aspect of the invention a light chain variable region according to the third aspect of the invention, a light chain according to the fourth aspect of the invention, or an antibody according to the fifth aspect of the invention, the recombinant according to the sixth aspect of the invention a protein, an immune cell according to the eighth aspect of the invention, the antibody drug conjugate according to the ninth aspect of the invention, or a combination thereof, wherein the active ingredient is used for (a) preparing a detection reagent or kit; / or (b) preparation of a medicament for preventing and/or treating an IL-17A-related disease.
  • the active ingredient is used to prevent and/or treat an IL-17A related disease.
  • the IL-17A-associated disease is selected from the group consisting of inflammation, autoimmune disease, or a combination thereof; preferably an autoimmune disease.
  • the disease is selected from the group consisting of psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory arthritis, or a combination thereof, preferably inflammatory arthritis.
  • the inflammatory arthritis is selected from the group consisting of osteoarthritis, rheumatoid arthritis, rheumatoid arthritis, or a combination thereof, preferably rheumatoid arthritis.
  • the antibody is in the form of a drug conjugate (ADC).
  • ADC drug conjugate
  • the detection reagent or kit is for diagnosing an IL-17A related disease.
  • the detection reagent or kit is for detecting IL-17A protein in a sample.
  • the detection reagent is a test piece.
  • a pharmaceutical composition comprising:
  • an active ingredient the active ingredient being selected from the group consisting of a heavy chain variable region according to the first aspect of the invention, a heavy chain according to the second aspect of the invention, according to the third aspect of the invention a light chain variable region, a light chain according to the fourth aspect of the invention, or an antibody according to the fifth aspect of the invention, the recombinant protein according to the sixth aspect of the invention, according to the eighth aspect of the invention Immunocyte, an antibody drug conjugate according to the ninth aspect of the invention, or a combination thereof;
  • the pharmaceutical composition is a liquid formulation.
  • the pharmaceutical composition is an injection.
  • a polynucleotide is provided, the polynucleotide encoding a polypeptide selected from the group consisting of:
  • the invention provides a vector comprising the polynucleotide of the twelfth aspect of the invention.
  • the vector comprises: a bacterial plasmid, a bacteriophage, a yeast plasmid, a plant cell virus, a mammalian cell virus such as an adenovirus, a retrovirus, or other vector.
  • a genetically engineered host cell comprising the vector or genome according to the thirteenth aspect of the present invention, which is integrated with the twelfth aspect of the present invention, is provided Polynucleotide.
  • a method of detecting IL-17A protein in a sample (including a diagnostic or non-diagnostic) in vitro comprising the steps of:
  • a test panel comprising: a substrate (support plate) and a test strip, the test strip comprising the antibody according to the fifth aspect of the invention or The immunoconjugate of the ninth aspect of the invention.
  • a kit comprising:
  • a first container comprising the antibody of the fifth aspect of the invention.
  • the kit contains the test plate according to the sixteenth aspect of the invention.
  • a method for preparing a recombinant polypeptide comprising:
  • a nineteenth aspect of the invention provides a method of an IL-17A-associated disease, the method comprising: administering to a subject in need thereof an antibody according to the fifth aspect of the invention, antibody-drug coupling of the antibody Or a CAR-T cell expressing the antibody, or a combination thereof.
  • the present inventors have unexpectedly obtained an anti-IL-17A monoclonal antibody having extremely excellent affinity and specificity, and a humanized antibody obtained based on the antibody, through extensive and intensive research.
  • Antibodies of the invention bind with high specificity can be IL-17A antigen, which has high affinity (ELISA assay which EC 50 of about 15.4ng / ml), and significantly inhibit the binding of IL-17A and IL-17 receptor, and There are no visible side effects to the mammal itself.
  • the present invention has been completed on this basis.
  • conjugate refers to a soluble receptor or fragment thereof or analog thereof, or an antibody or fragment thereof, or an analog thereof, that is capable of binding to a target.
  • IL-17A conjugate refers to an antibody or a fragment thereof or an analog thereof which specifically recognizes IL-17A and binds to IL-17A.
  • administering and “treating” mean that the exogenous drug, therapeutic, diagnostic, or composition is applied to an animal, human, subject, cell, tissue, organ, or biological fluid.
  • administering and “treatment” can refer to treatment, pharmacokinetics, diagnostics, research, and experimental methods.
  • the treatment of the cells includes contact of the reagents with the cells, contact of the reagents with the fluid, and contact of the fluid with the cells.
  • administering also mean in vitro and ex vivo treatment by reagents, diagnostics, binding compositions or by another cell.
  • Treatment when applied to a human, animal or research subject, refers to therapeutic treatment, prophylactic or preventive measures, research and diagnosis; includes IL-17A conjugates with humans or animals, subjects, cells, tissues, Contact with physiological compartments or physiological fluids.
  • treating refers to the administration of a therapeutic agent for internal or external use to a patient, comprising any of the IL-17A conjugates of the invention, and compositions thereof, which have one or more symptoms of the disease, and are known Therapeutic agents have a therapeutic effect on these symptoms.
  • the patient is administered in an amount (a therapeutically effective amount) of a therapeutic agent effective to alleviate the symptoms of one or more diseases.
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may occur but does not necessarily have to occur.
  • “optionally comprising 1-3 antibody heavy chain variable regions” means that the antibody heavy chain variable region of a particular sequence may have, but is not required to be, one, two or three.
  • the term "antibody” refers to an immunoglobulin that is a tetrapeptide chain structure formed by the joining of two identical heavy chains and two identical light chains by interchain disulfide bonds.
  • the amino acid composition and sequence of the immunoglobulin heavy chain constant region are different, so the antigenicity is also different. Accordingly, immunoglobulins can be classified into five classes, or different types of immunoglobulins, namely, IgM, IgD, IgG, IgA, and IgE, and the heavy chain constant regions corresponding to different classes of immunoglobulins are respectively referred to as ⁇ . , ⁇ , ⁇ , ⁇ , and ⁇ .
  • IgG stands for the most important class of immunoglobulins and can be divided into four subclasses due to differences in chemical structure and biological function: IgG1, IgG2, IgG3 and IgG4.
  • Light chains are divided into kappa or lambda chains by the constant region.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known to those skilled in the art.
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly, being the variable region (V region); the remaining amino acid sequence near the C-terminus is relatively stable and is a constant region (C region).
  • the variable region includes three hypervariable regions (HVR) and four relatively conserved FR regions (FR). The amino acid sequences of the four FRs are relatively conservative and are not directly involved in the binding reaction.
  • the three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining region (CDR).
  • Each of the light chain variable region (LCVR) and the heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, and the order from the amino terminus to the carboxy terminus is FR1, CDR1, FR2, CDR2. FR3, CDR3, FR4.
  • the three CDR regions of the light chain i.e., the light chain hypervariable region (LCDR), refer to LCDR1, LCDR2, and LCDR3;
  • the three CDR regions of the heavy chain, the heavy chain hypervariable region (HCDR) refer to HCDR1, HCDR2, and HCDR3.
  • the CDR amino acid residues of the LCVR and HCVR regions of the antibodies or antigen-binding fragments of the invention conform to known Kabat numbering rules (LCDR1-3, HCDR2-3) in number and position, or in accordance with the kabat and chothia numbering rules (HCDR1) ).
  • the four FR regions in the native heavy and light chain variable regions are generally in a beta-sheet configuration, joined by three CDRs forming a linker, and in some cases may form a partial beta sheet structure.
  • the CDRs in each chain are closely joined together by the FR region and together with the CDRs of the other chain form the antigen binding site of the antibody.
  • the amino acid sequence of the same type of antibody can be compared to determine which amino acids constitute the FR or CDR regions.
  • the constant regions are not directly involved in the binding of the antibody to the antigen, but they exhibit different effector functions, such as antibody-dependent cytotoxicity of the participating antibodies.
  • the term "antigen-binding fragment” refers to a Fab fragment having an antigen-binding activity, a Fab' fragment, a F(ab')2 fragment, or a single Fv fragment.
  • the Fv antibody contains the antibody heavy chain variable region, the light chain variable region, but no constant region, and has the smallest antibody fragment of the entire antigen binding site.
  • Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the desired structure for antigen binding.
  • antigenic determinant refers to a three-dimensional spatial site that is discrete on an antigen and that is recognized by an antibody or antigen-binding fragment of the invention.
  • the present invention encompasses not only intact antibodies, but also fragments of immunologically active antibodies or fusion proteins formed by antibodies with other sequences. Accordingly, the invention also includes fragments, derivatives and analogs of the antibodies.
  • antibodies include murine, chimeric, humanized or fully human antibodies prepared by techniques well known to those skilled in the art.
  • Recombinant antibodies such as chimeric and humanized monoclonal antibodies, including human and non-human portions, can be prepared using recombinant DNA techniques well known in the art.
  • the term "monoclonal antibody” refers to an antibody that is secreted from a clone of a single cell source. Monoclonal antibodies are highly specific and target a single epitope.
  • the cell may be a eukaryotic, prokaryotic or phage clonal cell line.
  • chimeric antibody is obtained by splicing a V region gene of a murine antibody with a C region gene of a human antibody into a chimeric gene, and then inserting the vector into an antibody molecule expressed by the host cell. It not only retains the high specificity and affinity of the parental mouse antibody, but also enables its human Fc segment to effectively mediate biological effects.
  • humanized antibody is a variable region engineered form of a murine antibody of the invention having a CDR region derived from (or substantially derived from) a non-human antibody, preferably a mouse monoclonal antibody. And FR regions and constant regions derived substantially from human antibody sequences; the CDR region sequences of the murine antibodies are grafted onto different types of human germline antibody framework sequences. Because CDR sequences are responsible for most of the antibody-antigen interactions, recombinant antibodies that mimic the properties of a particular naturally occurring antibody can be expressed by constructing an expression vector.
  • the antibody may be monospecific, bispecific, trispecific, or more multiple specificity.
  • the antibody of the present invention further includes a conservative variant thereof, which means that there are up to 10, preferably up to 8, more preferably up to 5, optimally compared to the amino acid sequence of the antibody of the present invention. Up to 3 amino acids are replaced by amino acids of similar or similar nature to form a polypeptide. These conservative variant polypeptides are preferably produced by amino acid substitution according to Table A.
  • IL-17A generally refers to native or recombinant human IL-17A, as well as non-human homologs of human IL-17A. Unless otherwise indicated, the molar concentration of IL-17A was calculated using the molecular weight of the homodimer of IL-17A (eg, 30 KDa for human IL-17A).
  • human IL-17A (huIL-17A) refers to the mature form of human IL-17A protein accession numbers NP-002180 and AAT22064 (ie residues 24-155), as well as its natural variants and polymorphisms. Sex.
  • the present invention provides a highly specific and high affinity antibody against IL-17A comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) amino acid sequence, the light chain comprising a light chain Variable region (VL) amino acid sequence.
  • VH heavy chain variable region
  • VL light chain Variable region
  • the respective CDRs of the heavy chain variable region (VH) amino acid sequence and the light chain variable region (VL) amino acid sequence are selected from the group consisting of:
  • the sequence formed by adding, deleting, modifying and/or substituting at least one amino acid sequence preferably has a homology of at least 80%, preferably at least 85%, more preferably at least 90. %, optimally at least 95% of the amino acid sequence.
  • the antibody of the present invention may be a double-stranded or single-chain antibody, and may be selected from an animal-derived antibody, a chimeric antibody, a humanized antibody, more preferably a humanized antibody, a human-animal chimeric antibody, and more preferably a whole human. Sourced antibodies.
  • the antibody derivative of the present invention may be a single chain antibody, and/or an antibody fragment such as Fab, Fab', (Fab') 2 or other known antibody derivatives in the field, and IgA, IgD, IgE. Any one or more of IgG and IgM antibodies or antibodies of other subtypes.
  • the animal is preferably a mammal, such as a mouse.
  • the antibody of the invention may be a murine antibody, chimeric antibody, humanized antibody, CDR grafted and/or modified antibody that targets human IL-17A.
  • any one or more of the above SEQ ID No.: 7, 8 and 9 or which have been added, deleted, modified and/or substituted for at least one amino acid have IL-
  • the 17A binding affinity sequence is located in the CDR region of the heavy chain variable region (VH).
  • VL light chain variable region
  • VH CDR1, CDR2, CDR3 are each independently selected from any one or more of SEQ ID No.: 7, 8, and 9, or they are added, deleted, modified And/or a sequence having at least one amino acid having IL-17A binding affinity;
  • VL CDR1, CDR2, CDR3 are each independently selected from any one of SEQ ID No.: 10, amino acid sequence: GAT and SEQ ID No.: Or a sequence of several sequences, or a sequence having IL-17A binding affinity for addition, deletion, modification and/or substitution of at least one amino acid.
  • the number of amino acids added, deleted, modified and/or substituted is preferably not more than 40%, more preferably not more than 35%, more preferably 1-33% of the total amino acid number of the initial amino acid sequence. More preferably, it is 5-30%, more preferably 10-25%, and still more preferably 15-20%.
  • the number of amino acids added, deleted, modified and/or substituted is usually 1, 2, 3, 4 or 5, preferably 1-3, more preferably 1-2. The best is 1.
  • any method suitable for the production of monoclonal antibodies can be used to produce the anti-IL-17A antibodies of the invention.
  • an animal can be immunized with a linked or naturally occurring IL-17A homodimer or a fragment thereof. Suitable immunization methods can be used, including adjuvants, immunostimulants, repeated booster immunizations, and one or more routes can be used.
  • IL-17 can be used as an immunogen (antigen) for the production of a non-human antibody specific for IL-17A, and the biological activity of the antibody is screened.
  • the stimulating immunogen can be a full length mature human IL-17A, including a native homodimer, or a peptide containing a single/multiple epitope.
  • the immunogen can be used alone or in combination with one or more immunogenic enhancers known in the art.
  • the immunogen can be purified from natural sources or produced in genetically modified cells.
  • the DNA encoding the immunogen can be genomic or non-genomic (e.g., cDNA) in its source.
  • the DNA encoding the immunogen can be expressed using a suitable genetic vector including, but not limited to, an adenoviral vector, an adeno-associated viral vector, a baculovirus vector, a material, and a non-viral vector.
  • a suitable genetic vector including, but not limited to, an adenoviral vector, an adeno-associated viral vector, a baculovirus vector, a material, and a non-viral vector.
  • Example 1 An exemplary method of producing an anti-human IL-17A antibody of the invention is described in Example 1.
  • the humanized antibody can be selected from any class of immunoglobulins, including IgM, IgD, IgG, IgA, and IgE.
  • the antibody is an IgG antibody, and an IgG1 subtype is used. Optimization of the necessary constant domain sequences is readily achieved by screening antibodies using the biological assays described in the Examples below to produce the desired biological activity.
  • any type of light chain can be used in the compounds and methods herein.
  • kappa, lambda chains or variants thereof are useful in the compounds and methods of the invention.
  • Example 5 An exemplary method of humanizing an anti-human IL-17A antibody of the invention is described in Example 5.
  • sequence of the DNA molecule of the antibody or fragment thereof of the present invention can be obtained by a conventional technique such as PCR amplification or genomic library screening.
  • the coding sequences of the light and heavy chains can also be fused together to form a single chain antibody.
  • the recombinant sequence can be used to obtain the relevant sequences in large quantities. This is usually done by cloning it into a vector, transferring it to a cell, and then isolating the relevant sequence from the proliferated host cell by conventional methods.
  • synthetic sequences can be used to synthesize related sequences, especially when the fragment length is short.
  • a long sequence of fragments can be obtained by first synthesizing a plurality of small fragments and then connecting them.
  • the DNA sequence can then be introduced into various existing DNA molecules (or vectors) and cells known in the art.
  • the invention also relates to vectors comprising the appropriate DNA sequences described above, as well as appropriate promoters or control sequences. These vectors can be used to transform appropriate host cells to enable them to express proteins.
  • the host cell can be a prokaryotic cell, such as a bacterial cell; or a lower eukaryotic cell, such as a yeast cell; or a higher eukaryotic cell, such as a mammalian cell.
  • Preferred animal cells include, but are not limited to, CHO-S, CHO-K1, HEK-293 cells.
  • the step of transforming a host cell with recombinant DNA as described in the present invention can be carried out by techniques well known in the art.
  • the obtained transformant can be cultured by a conventional method, and the transformant expresses the polypeptide encoded by the gene of the present invention. Depending on the host cell used, it is cultured under appropriate conditions using a conventional medium.
  • the resulting host cells are cultured under conditions suitable for expression of the antibody of the invention.
  • immunoglobulin purification steps such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, ion exchange chromatography, hydrophobic chromatography, molecular sieve chromatography or affinity chromatography, etc.
  • the antibodies of the present invention are purified by conventional separation and purification means well known to those skilled in the art.
  • the resulting monoclonal antibodies can be identified by conventional means.
  • the binding specificity of a monoclonal antibody can be determined by immunoprecipitation or in vitro binding assays such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).
  • RIA radioimmunoassay
  • ELISA enzyme-linked immunosorbent assay
  • the invention provides the use of an antibody of the invention, for example, for the preparation of a diagnostic preparation, or for the preparation of a medicament for the prevention and/or treatment of a disease associated with IL-17A.
  • the IL-17A-related diseases include inflammatory diseases, autoimmune diseases, and the like, including but not limited to psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel disease (such as Crohn Disease, ulcerative colitis, etc.), osteoarthritis, rheumatoid arthritis (RA), rheumatoid arthritis or osteoporosis, inflammatory fibrosis (eg scleroderma, pulmonary fibrosis and sclerosis), Asthma (including allergic asthma), allergies, and cancer.
  • the composition is a pharmaceutical composition comprising the above antibody or active fragment thereof or a fusion protein thereof or an ADC thereof or a corresponding CAR-T cell, and a pharmaceutically acceptable carrier.
  • these materials can be formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium wherein the pH is usually from about 5 to about 8, preferably from about 6 to about 8, although the pH may be The nature of the formulation and the condition to be treated vary.
  • the formulated pharmaceutical compositions can be administered by conventional routes including, but not limited to, intratumoral, intraperitoneal, intravenous, or topical administration.
  • the antibody of the present invention may also be a cell therapy for expression of a nucleotide sequence in a cell, for example, the antibody is used for chimeric antigen receptor T cell immunotherapy (CAR-T) and the like.
  • CAR-T chimeric antigen receptor T cell immunotherapy
  • the pharmaceutical composition of the present invention can be directly used for binding to an IL-17A protein molecule, and thus can be used for the prevention and treatment of diseases associated with IL-17A.
  • other therapeutic agents can be used simultaneously.
  • the pharmaceutical composition of the present invention contains a safe and effective amount (e.g., 0.001 to 99% by weight, preferably 0.01 to 90% by weight, more preferably 0.1 to 80% by weight) of the above-mentioned monoclonal antibody (or a conjugate thereof) of the present invention and pharmacy An acceptable carrier or excipient.
  • Such carriers include, but are not limited to, saline, buffer, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical preparation should be matched to the mode of administration.
  • the pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • compositions such as injections and solutions are preferably prepared under sterile conditions.
  • the amount of active ingredient administered is a therapeutically effective amount, for example from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day.
  • the polypeptides of the invention may also be used with other therapeutic agents.
  • a safe and effective amount of the pharmaceutical composition is administered to the mammal, wherein the safe and effective amount is usually at least about 10 micrograms per kilogram of body weight, and in most cases no more than about 50 milligrams per kilogram of body weight.
  • the dose is from about 10 micrograms per kilogram of body weight to about 20 milligrams per kilogram of body weight.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the antibodies of the invention can be used in detection applications, for example for detecting samples, to provide diagnostic information.
  • the sample (sample) used includes cells, tissue samples, and biopsy specimens.
  • biopsy shall include all types of biopsies known to those skilled in the art.
  • the biopsy used in the present invention may include a tissue sample prepared, for example, by an endoscopic method or a puncture or needle biopsy of an organ.
  • Samples used in the present invention include fixed or preserved cell or tissue samples.
  • the invention also provides a kit comprising an antibody (or a fragment thereof) of the invention, and in a preferred embodiment of the invention, the kit further comprises a container, instructions for use, a buffer, and the like.
  • the antibody of the invention may be immobilized on a test plate.
  • the antibody of the present invention has excellent biological activity and specificity, and has high binding ability (EC 50 can be as high as about 10-15 ng/ml by ELISA).
  • IL-17A has a good binding affinity and can be used as an antibody targeting IL-17A.
  • the humanized antibody of the present invention not only has better affinity with IL-17A but also has lower immunogenicity than the murine antibody.
  • the antibody of the present invention can significantly inhibit the binding of IL-17A to the IL-17 receptor without any visible side effects to the mammal itself.
  • human IL-17A protein was used as an antigen.
  • BALB/c mice were subjected to multi-subcutaneous immunization, and the serum titer of the immunized mice was monitored. After the requirement, the mouse spleen cells and myeloma were taken (Sp2/ 0) Hybridomas polyclonal cells obtained by fusion of cells and screening by HAT.
  • High specific binding polyclonal was screened by ELISA, monoclonal culture was performed, and highly specific monoclonal cells were screened by ELISA; IL-6 release assay was performed by HT1080 cells, and cell function was screened. The effect of the monoclonal cell line, and then the affinity and half-life were analyzed by the Biacore method, and finally the monoclonal cells expressing IL-17A were obtained.
  • Human IL-17A was prepared into 1 ⁇ g/ml coating solution with CBS, 50 ⁇ L/well was added to the enzyme standard plate, and coated at 2 ⁇ 8°C for more than 12 hours. The residual liquid of the plate was discarded, and 3% milk was added, 200 ⁇ L per well, room temperature. Closed for 1 hour. One well of not less than 200 ⁇ L of PBST was added to each well, and the hybridoma supernatant was diluted to 100 ⁇ g/ml, and 10 gradients were further diluted 10 times, and 100 ⁇ L/well was added to the plate.
  • the murine antibody produced by the hybridoma 14F10/9F6 has a higher binding activity to human IL-17a.
  • the DNA sequence encoding the variable region of the mouse antibody expressed by hybridoma 14F10/9F6 was determined based on the 5' RACE technique. Briefly, gene-specific cDNAs for heavy and light chains were prepared using the SMART 5' RACE Synthesis Kit (TAKARA, No. 634859) according to the manufacturer's instructions. The PCR product was analyzed by agarose gel electrophoresis. The variable region size of both the heavy and light chains is approximately 500 base pairs. The amplified amplified PCR product obtained by the reaction was cloned into the vector pEASY-Blunt Simple plasmid (Beijing Full Gold, No. CB111-02) and transformed into Stellar E.
  • CDR1' amino acid sequence: GAT and SEQ ID NO.: 11).
  • Chimeric heavy and light chains were constructed by ligating PCR cloned mouse 14F10/9F6 VH and VL region cDNAs to human IgGl and k constant regions, respectively.
  • the 5' and 3' ends of the mouse cDNA sequence were modified with PCR primers designed to add appropriate leader sequences to each strand and to increase restriction sites that enable cloning into the existing recombinant antibody expression vector pHB-Fc. .
  • the pHB-Fc plasmid vector was prepared as follows: the pcDNA/HA-FLAG (Accession#: FJ524378) vector was used as the starting plasmid, and the restriction region EcoRI was followed by the constant region sequence of human IgG1 or k, endonuclease HindIII.
  • the human cytomegalovirus (HCMV) promoter sequence (Accession#: X17403) was added to the front of the ampicillin tolerance gene, and the Chinese hamster glutamine synthetase gene was added in front of the HCMV promoter (Accession#: X03495). .
  • the host cell used for protein expression was CHO-K1 cells (Cat# CCL-61) purchased from ATCC. The cells were acclimated into CHO-K1 cells that were cultured in suspension in serum-free medium (EX-CELLTM 302) after a series of domestication steps. Using the cells, the constructed light and heavy chain recombinant expression plasmids were transferred into cells by electroporation. Put in the incubator for 3-5 days. The antibody concentration from the CHO-K1 transfection supernatant was measured by indirect ELISA. This shows that transfected CHO-K1 cells secrete approximately 30 mg/L of chimeric antibody.
  • Novartis humanized anti-IL-17 antibody (Novartis mAb) as a positive control was cloned according to the humanized sequence provided in US 7,807,155 B2 (AIN 457) and transiently transfected for expression.
  • the method was the same as in Example 1.
  • the chimeric antibody was used in place of the hybridoma supernatant, and the HRP-conjugated rabbit anti-human IgG Fc antibody (Luoyang Qiongtong Experimental Material Center) was used instead of HRP-conjugated goat anti-mouse IgG Fc. Human IL-17A binding activity.
  • the antigen-antibody binding ability of the anti-IL-17A antibody to IL-17A of different species was determined by the ELSIA method.
  • the method was the same as in Example 1.
  • the chimeric antibody was used in place of the hybridoma supernatant, and the HRP-conjugated rabbit anti-human IgG Fc antibody (Luoyang Qiongtong Experimental Material Center) was used instead of HRP-conjugated goat anti-mouse IgG Fc.
  • Human IL-17A, mouse IL-17A and simian IL-17A binding activity Human IL-17A, mouse IL-17A and simian IL-17A binding activity.
  • the chimeric antibody of the present invention binds to simian IL-17A in addition to human IL-17A, but does not bind to mouse IL-17A, and the chimeric antibody and The affinity of human and simian IL-17A was better than that of the positive control.
  • variable chain sequences of antibodies are compared to the available sequences in the NCBI protein database, and by identification and analysis, the human framework on which the CDR-grafted heavy and light chains are suitably constructed is finally determined.
  • one preferred FR region is the humanized FR region derived from hu-VH (SEQ ID NO: 3) and the light chain is hu-VL (SEQ ID NO: 4):
  • the point mutation antibody expression plasmid was derived.
  • the humanized point mutant antibody expression plasmid was separately expressed by CHO-K1 (ATC C, NO. CCL-61) cells, and purified to obtain a humanized antibody protein.
  • a humanized antibody with excellent performance was obtained by ELISA, receptor binding inhibition assay, Biacore and cell activity assay.
  • VH and VL sequences of the humanized antibody are shown in SEQ ID NO.: 5 and 6, respectively:
  • the method was the same as in Example 1.
  • the hybridoma supernatant was replaced with a humanized antibody, and the HRP-conjugated rabbit anti-human IgG Fc antibody (Luoyang Qiongtong Experimental Material Center) was used instead of HRP-conjugated goat anti-mouse IgG Fc. Human IL-17A binding activity.
  • Murine antibody EC 50 values of the humanized antibody is about 3 times. It was also found that the antibody of the present invention has a lower EC 50 value and a stronger binding activity to human IL-17A than the positive control antibody Novartis mAb.
  • the antigen-antibody binding kinetics and affinity were determined using the BIACORE method.
  • a human antibody capture antibody Human Antibody Capture Antiboy
  • an anti-human capture-CM5 chip Anti-Human Capture-CM5 chip
  • the mixture was equilibrated at room temperature for 20 to 30 minutes, and the chip was loaded into the instrument. Dilute the antigen with equilibration buffer, dilute the antigen with a 10 ml initial dilution of 5 concentration gradients, and set 2 zero concentrations (ie equilibration buffer) and one replicate concentration (typically the lowest concentration repeat).
  • the antibody sample was diluted to the experimental working concentration with an equilibration buffer and sealed at 2 to 8 °C. After the sample analysis is completed, the corresponding analysis program is used to analyze the data, confirming that there is no obvious reference binding, selecting the kinetics, 1:1 binding model (Kinetics, 1:1 binding modle), fitting analysis, and obtaining the power of the sample. Learning parameters.
  • the affinity constant (KD(M)) of human IL-17A showed that the affinity of the humanized antibody of the present invention was comparable to that of the chimeric antibody, and both were nearly an order of magnitude higher than the positive control antibody, and had a stronger affinity.
  • the present inventors also measured the biological activity, antigen binding specificity, and in vivo efficacy test of humanized antibody cells, and found that the humanized antibody of the present invention has good biological activity and specificity, and can be significantly improved. Symptoms of IL-17A related diseases.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Cell Biology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un anticorps anti-interleukine 17A, son procédé de préparation et son application. L'invention concerne plus particulièrement un anticorps monoclonal anti-IL 17A. Ledit anticorps peut être combiné de manière hautement spécifique à un antigène IL-17A, présente une forte affinité et une faible immunogénicité, et sert à préparer des médicaments pour la prévention ou le traitement de maladies associées à l'IL-17A, telles que les inflammations quelles qu'elles soient ou les maladies auto-immunes.
PCT/CN2018/073457 2017-09-30 2018-01-19 Anticorps anti-interleukine 17a, son procédé de préparation et son application WO2019061962A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710916535.7A CN107522783B (zh) 2017-09-30 2017-09-30 一种抗白介素17a的抗体、其制备方法和应用
CN201710916535.7 2017-09-30

Publications (1)

Publication Number Publication Date
WO2019061962A1 true WO2019061962A1 (fr) 2019-04-04

Family

ID=60684174

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/073457 WO2019061962A1 (fr) 2017-09-30 2018-01-19 Anticorps anti-interleukine 17a, son procédé de préparation et son application

Country Status (2)

Country Link
CN (1) CN107522783B (fr)
WO (1) WO2019061962A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107522783B (zh) * 2017-09-30 2020-07-07 华博生物医药技术（上海）有限公司 一种抗白介素17a的抗体、其制备方法和应用
CN110606892B (zh) * 2018-06-14 2023-09-26 华博生物医药技术（上海）有限公司 一种高亲和力高生物活性的lag-3抗体及其应用
WO2020024931A1 (fr) * 2018-07-31 2020-02-06 Shen Weiqun Anticorps anti-il-17 a et leur utilisation
CN111303283A (zh) * 2018-12-12 2020-06-19 上海君实生物医药科技股份有限公司 抗il-17a抗体及其应用
CN110585430B (zh) * 2019-09-29 2023-09-08 华博生物医药技术（上海）有限公司 一种人源化抗人il-17a单克隆抗体的药物组合物
CN111040035B (zh) * 2019-12-31 2022-05-24 南京融捷康生物科技有限公司 针对il-17ra蛋白的抗体及其制备方法和应用
EP4289863A1 (fr) * 2020-12-17 2023-12-13 Shanghai Huaota Biopharmaceutical Co., Ltd. Anticorps bispécifique ciblant il-17a et il-36r et son application
TW202241505A (zh) * 2021-01-04 2022-11-01 大陸商江蘇恆瑞醫藥股份有限公司 抗il-17抗體治療自體免疫性疾病和炎症的方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101646690A (zh) * 2006-08-11 2010-02-10 先灵公司 抗il-17a抗体
CN104231080A (zh) * 2013-03-15 2014-12-24 中国医学科学院药物研究所 全人源抗人白介素17a单链抗体
WO2015070697A1 (fr) * 2013-11-18 2015-05-21 上海恒瑞医药有限公司 Conjugué de il-17a et utilisations associées
CN104684571A (zh) * 2012-09-21 2015-06-03 科瓦根股份公司 新的il-17a结合分子及其医学应用
WO2015137843A1 (fr) * 2014-03-14 2015-09-17 Закрытое Акционерное Общество "Биокад" Anticorps anti-il-17, procédé de production et procédé d'utilisation
CN105073775A (zh) * 2013-02-08 2015-11-18 诺华股份有限公司 抗-il-17a抗体及其在治疗自身免疫性和炎性病症中的用途
WO2016113557A1 (fr) * 2015-01-12 2016-07-21 Crescendo Biologics Limited Protéines de liaison à il-17a
CN107522783A (zh) * 2017-09-30 2017-12-29 华博生物医药技术（上海）有限公司 一种抗白介素17a 的抗体、其制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8669345B2 (en) * 2006-01-27 2014-03-11 Biogen Idec Ma Inc. Nogo receptor antagonists
US8282964B2 (en) * 2007-10-27 2012-10-09 Medical Diagnostic Laboratories, Llc Ex-vivo treatment of peripheral plasmacytoid dendritic cells with IFN-lambda

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101646690A (zh) * 2006-08-11 2010-02-10 先灵公司 抗il-17a抗体
CN104684571A (zh) * 2012-09-21 2015-06-03 科瓦根股份公司 新的il-17a结合分子及其医学应用
CN105073775A (zh) * 2013-02-08 2015-11-18 诺华股份有限公司 抗-il-17a抗体及其在治疗自身免疫性和炎性病症中的用途
CN104231080A (zh) * 2013-03-15 2014-12-24 中国医学科学院药物研究所 全人源抗人白介素17a单链抗体
WO2015070697A1 (fr) * 2013-11-18 2015-05-21 上海恒瑞医药有限公司 Conjugué de il-17a et utilisations associées
WO2015137843A1 (fr) * 2014-03-14 2015-09-17 Закрытое Акционерное Общество "Биокад" Anticorps anti-il-17, procédé de production et procédé d'utilisation
WO2016113557A1 (fr) * 2015-01-12 2016-07-21 Crescendo Biologics Limited Protéines de liaison à il-17a
CN107522783A (zh) * 2017-09-30 2017-12-29 华博生物医药技术（上海）有限公司 一种抗白介素17a 的抗体、其制备方法和应用

Also Published As

Publication number Publication date
CN107522783A (zh) 2017-12-29
CN107522783B (zh) 2020-07-07

Similar Documents

Publication Publication Date Title
KR102662387B1 (ko) B7-h3 항체, 이의 항원-결합 단편 및 이의 의학적 용도
US10981983B2 (en) Antibody targeting interleukin 17A and preparation method and application thereof
CN107522783B (zh) 一种抗白介素17a的抗体、其制备方法和应用
WO2017215524A1 (fr) Anticorps humains monoclonal interleukine-17a , son procédé de préparation et son utilisation
WO2019091436A1 (fr) Anticorps 4-1bb, procédé de préparation et utilisation de celui-ci
US11525005B2 (en) Anti-CD40 antibody, antigen binding fragment thereof and medical use thereof
WO2022095926A1 (fr) Anticorps ciblant l'interleukine 36r, son procédé de préparation et son utilisation
CN114286827B (zh) 人源化抗il17a抗体及其应用
MX2011001909A (es) Anticuerpos anti-interleucina-13 modificados, composiciones, metodos y usos.
WO2018153366A1 (fr) Anticorps anti-tim-3, fragment de liaison à l'antigène de celui-ci, et utilisations médicales de celui-ci
CN115746132B (zh) 抗il-17a抗体及其用途
KR20230116857A (ko) 항 tslp 항체의 약학 조성물 및 이의 용도
WO2022228183A1 (fr) Anticorps anti-siglec 15, son procédé de préparation et son utilisation
CN114437212A (zh) 抗人胸腺基质淋巴细胞生成素抗体及其制备方法和应用
WO2019238074A1 (fr) Anticorps lag-3 ayant une affinité élevée et une haute activité biologique, et utilisation associée
WO2022127842A1 (fr) Anticorps bispécifique ciblant il-17a et il-36r et son application
WO2023029089A1 (fr) Anticorps humanisé anti-cd3
CN111018984B (zh) 抗ck8单克隆抗体及其应用
CN114980926A (zh) 一种抗il-4r抗体药物组合物及其用途
CN111018988B (zh) 一种抗cd19的抗体、制备方法及其应用
CN111040033A (zh) 靶向肿瘤细胞的抗人角蛋白18的单克隆抗体及其应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18861850

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18861850

Country of ref document: EP

Kind code of ref document: A1