WO2024002145A1 - Molécule d'anticorps se liant à il-17a et il-17f et son utilisation - Google Patents

Molécule d'anticorps se liant à il-17a et il-17f et son utilisation Download PDF

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WO2024002145A1
WO2024002145A1 PCT/CN2023/103119 CN2023103119W WO2024002145A1 WO 2024002145 A1 WO2024002145 A1 WO 2024002145A1 CN 2023103119 W CN2023103119 W CN 2023103119W WO 2024002145 A1 WO2024002145 A1 WO 2024002145A1
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antibody
antigen
antibodies
binding
chain variable
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PCT/CN2023/103119
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Chinese (zh)
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陈波
马慧敏
张伟
孟庆云
徐保鑫
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上海齐鲁制药研究中心有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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

Definitions

  • the present disclosure belongs to the field of immunology, and more specifically, the present disclosure relates to antibodies or antigen-binding fragments thereof that simultaneously bind interleukin 17A (IL-17A) and interleukin 17F (IL-17F), including the antibodies or antigens thereof Derivatives of binding fragments, pharmaceutical compositions and their use in the treatment of diseases associated with IL-17A and IL-17F, such as autoimmune or inflammatory diseases.
  • IL-17A interleukin 17A
  • IL-17F interleukin 17F
  • the interleukin 17 (IL-17) family has 6 members: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F. They can bind to their corresponding receptors and thereby mediate different physiological and pathological processes.
  • the human IL-17A gene encodes a polypeptide composed of 155 amino acids, including a signal peptide of 23 amino acids and a mature peptide chain of 132 amino acids. It forms a homodimer through disulfide bonds. The molecular weight is 35kD.
  • IL-17A is an important cytokine that is mainly secreted by Th17 cells and innate lymphocyte subsets.
  • IL-17A also has biological effects such as host defense and tissue repair (Nat. Immunol, 2019 Dec, 20(12): 1594-1602; Trends Immunol, 2017 May, 38(5): 310-322).
  • IL-17A has become an important target for the treatment of psoriasis, psoriatic arthritis and various other autoimmune diseases. Inhibiting IL-17A has been clinically proven to be an effective therapeutic strategy.
  • Two anti-IL-17A antibodies, secukinumab (Novartis) and ixekizumab (Eli Lily) have been approved for the treatment of patients with moderate to severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.
  • IL-17F is the member of the IL-17 family most closely related to IL-17A in terms of sequence and biological properties.
  • IL-17A and IL-17F are encoded in the same gene locus (6p12), their protein sequence homology is 55%, and they have the same receptors (IL-17RA and IL-17RC).
  • IL-17A and IL-17F can each be linked through a disulfide bond to form a homodimer, or they can form a heterodimer, IL-17A&F (Nat Rev Immunol, 2009 Aug, 9(8): 556- 567).
  • IL-17A and IL-17F are up-regulated in a variety of inflammatory tissues and can work synergistically with other pro-inflammatory cytokines to enhance the body's inflammatory response.
  • IL-17A and IL-17F are associated with a variety of autoimmune diseases and inflammatory diseases, such as moderate to severe plaque psoriasis, hidradenitis, psoriatic arthritis, rheumatoid arthritis, Ankylosing spondylitis, asthma, etc. (Immunity, 2019 Apr 16; 50(4): 892-906; Nat Rev Rheumatol, 2018 Aug, 14(8): 453-466; Front Immunol, 2018 Aug 2, 9: 1682;Ann Rheum Dis, 2011 May;70(5):727- 732). Given that IL-17A and IL-17F play similar roles in various pathological processes, it is suggested that neutralizing IL-17A and IL-17F simultaneously may be more effective than inhibiting IL-17A alone.
  • autoimmune diseases and inflammatory diseases such as moderate to severe plaque psoriasis, hidradenitis, psoriatic arthritis, rheumatoid arthritis, Ankylosing spondylitis, asthma, etc
  • Bimekizumab a monoclonal antibody drug targeting both IL-17A and IL-17F developed by UCB, has entered Phase III clinical trials in a variety of autoimmune diseases. Among them, in multiple phase III clinical head-to-head studies in the treatment of moderate to severe plaque psoriasis, bimekizumab has been proven to be more effective than a variety of marketed drugs, including adalimumab, ustekinumab, and secukinumab, showing higher levels of skin damage Clear.
  • the present disclosure provides an anti-IL-17A and IL-17F antibody or antigen-binding fragment thereof that specifically binds to IL-17A, IL-17F and/or IL-17A&F, and does not Significantly binds IL-17B, IL-17C, IL-17D and IL-17E.
  • the IL-17A is a peptide having GenBank Accession Number NP_002181.1 (mRNA: NM_002190) and the IL-17F is a peptide having GenBank Accession Number NP_443104.1 (mRNA: NM_052872).
  • the present disclosure provides an anti-IL-17A and IL-17F antibody or an antigen-binding fragment thereof, the antibody or an antigen-binding fragment thereof capable of specifically binding to IL-17A, IL-17F and/or IL-17A&F, comprising Heavy chain variable region and light chain variable region, the heavy chain variable region includes HCDR1, HCDR2 and HCDR3, the light chain variable region includes LCDR1, LCDR2 and LCDR3, the HCDR1, HCDR2, HCDR3, LCDR1, The amino acid sequences of LCDR2 and LCDR3 are:
  • the antibody or antigen-binding fragment thereof against IL-17A and IL-17F includes a heavy chain variable region and a light chain variable region, and the heavy chain variable region and the light chain variable region
  • the chain variable region has at least 80% to 100% sequence identity with a heavy chain variable region and a light chain variable region, respectively, from any one of the following groups:
  • the anti-IL-17A and IL-17F antibodies or antigen-binding fragments thereof of the present disclosure are murine antibodies, chimeric antibodies, or humanized antibodies.
  • the antibodies against IL-17A and IL-17F are monoclonal antibodies.
  • the anti-IL-17A and IL-17F antibodies or antigen-binding fragments thereof further include a heavy chain constant region and/or a light chain constant region.
  • the heavy chain constant region Including natural Fc or modified variant Fc, Fc derived from mouse or human.
  • the antibodies against IL-17A and IL-17F are full-length antibodies.
  • the anti-IL-17A and IL-17F antibodies of the present disclosure are in the form of IgG1, IgG2, IgG3, or IgG4.
  • the antigen-binding fragments of the present disclosure are Fab, Fv, scFv, F(ab') 2 , linear antibodies, single domain antibodies.
  • the present disclosure provides a conjugate formed by conjugating the aforementioned antibody or antigen-binding fragment thereof with a capture label or detection label.
  • the detection markers include but are not limited to radionuclides, luminescent substances (such as fluorescein), colored substances or enzymes.
  • the present disclosure provides a fusion protein in which one of the fused portions comprises an anti-IL-17A and IL-17F antibody of the present disclosure or an antigen-binding fragment thereof.
  • the present disclosure provides a bispecific antibody or multispecific antibody in which one antigen-binding domain comprises an anti-IL-17A and an IL-17A of the present disclosure. 17F antibody or antigen-binding fragment thereof.
  • the present disclosure provides nucleic acids encoding any of the aforementioned antibodies or antigen-binding fragments thereof. And, the present disclosure also provides recombinant vectors comprising the nucleic acids.
  • the disclosure provides a host cell comprising an expression vector of the disclosure or containing a nucleic acid encoding the antibody or antigen-binding fragment thereof.
  • the host cell can be a prokaryotic cell, such as E. coli; or a eukaryotic cell, such as yeast or mammalian cells, such as CHO cells or HEK293 cells.
  • the present disclosure provides a method for preparing the antibody or antigen-binding fragment thereof, comprising: culturing a host cell of the present disclosure under suitable conditions, and purifying an expression product from the cell.
  • the present disclosure provides use of the antibodies, or antigen-binding fragments thereof, for the detection or diagnosis or treatment of diseases associated with expression of IL-17A and IL-17F.
  • the present disclosure provides a method of detecting IL-17A, IL-17F and/or IL-17A&F in a sample, comprising The method includes: contacting the sample with the aforementioned anti-IL-17A and IL-17F antibodies or antigen-binding fragments thereof; detecting the interaction between the anti-IL-17A and IL-17F antibodies or their antigen-binding fragments and IL-17A, IL-17F and/or Formation of complexes of IL-17A&F; optionally, antibodies against IL-17A and IL-17F or antigen-binding fragments thereof are detectably labeled.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of an antibody of the present disclosure or an antigen-binding fragment thereof, or an effective amount of a nucleic acid encoding the antibody or an antigen-binding fragment thereof, or comprising An effective amount of a recombinant vector containing an encoding nucleic acid, or an effective amount of a host cell containing an encoding nucleic acid, or an effective amount of a fusion protein of the disclosure, or an effective amount of a bispecific antibody or multispecific antibody of the disclosure.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further includes one or more additional other therapeutic agents.
  • the additional therapeutic agent is a pharmaceutical formulation that can be administered to a subject in combination with the pharmaceutical composition of the present disclosure.
  • the present disclosure provides methods of treating a disease associated with expression of IL-17A and IL-17F in a subject, comprising administering to a subject in need thereof a pharmaceutical composition of the present disclosure.
  • the disease is an autoimmune disease.
  • the disease is an inflammatory disease.
  • the methods further comprise administering to the subject additional other therapeutic agents.
  • Figure 1 shows the binding of humanized antibody Z1 to human IL-17A and IL-17F.
  • Figure 1A shows the binding activity of Z1 and human IL-17A
  • Figure 1B shows the binding activity of Z1 and human IL-17F.
  • Figure 2 shows the binding of humanized antibody Z1 to other members of the IL-17 family.
  • Figure 3 shows the functional detection results of humanized antibody Z1 at the cellular level.
  • Figure 3A shows the inhibition of IL-6 expression induced by IL-17A by Z1
  • Figure 3B shows the inhibition of IL-6 expression induced by IL-17F by Z1
  • Figure 3C shows the inhibition of IL-17A&F induced by Z1 Inhibition of IL-6 expression.
  • Figure 4 shows the results of the cell activity inhibition experiment of humanized antibody Z1.
  • Figure 4A shows the inhibition of SEAP release induced by IL-17A by Z1
  • Figure 4B shows the inhibition of SEAP release induced by IL-17F by Z1
  • Figure 4C shows the inhibition of SEAP release induced by IL-17A&F by Z1. Suppression situation.
  • Figure 5 shows the in vivo activity assay results of humanized antibody Z1.
  • the term "about” is meant to include ⁇ 20%, or in some cases ⁇ 10%, or in some cases ⁇ 5%, or in some cases ⁇ 20% of the specified value. A variation of ⁇ 1% in some cases, or ⁇ 0.1% in some cases.
  • IL-17A and IL-17F refer to molecules that are each covalently bonded as homodimers, and “IL-17A&F” refers to molecules that exist as heterodimers.
  • the term "antibody against IL-17A and IL-17F” or "antibody that binds to IL-17A and IL-17F” refers to an antibody that is capable of binding with sufficient affinity to IL-17A, IL-17A and IL-17F. 17F and/or IL-17A&F, that is, the antibody can recognize and bind to IL-17A, IL-17F, and IL-17A&F.
  • Human-derived IL-17A, IL-17F, and IL-17A&F are respectively represented as: hIL-17A, hIL-17F, hIL-17A&F. Therefore, "antibody against human IL-17A” and “antibody against human IL-17F “, “antibody against hIL-17A”, “antibody against hIL-17F”, “antibody against human IL-17A&F”, “antibody against hIL-17A&F”, “antibody against hIL-17A”, “antibody against Expressions such as “antibodies against hIL-17F” and “antibodies against hIL-17A&F” specifically refer to the ability to bind hIL-17A, hIL-17F and/or hIL-17A&F with sufficient affinity so that the antibodies can be used to target hIL-17A&F. Diagnostic and/or therapeutic agents for 17A, hIL-17F and/or hIL-17A&F.
  • Cynomolgus monkey-derived IL-17A is designated cyno IL-17A.
  • cynomolgus monkey-derived IL-17F is designated cyno IL-17F.
  • the term "antibody” typically refers to a Y-shaped tetramer containing two heavy (H) polypeptide chains and two light (L) polypeptide chains held together by covalent disulfide bonds and non-covalent interactions. protein. Natural IgG antibodies have such a structure. Each light chain consists of It consists of a light chain variable domain (VL) and a light chain constant domain (CL). Each heavy chain contains a heavy chain variable domain (VH) and a heavy chain constant domain (CH), also known as the heavy chain constant region (CH).
  • VL light chain variable domain
  • CL light chain constant domain
  • VH heavy chain variable domain
  • CH heavy chain constant domain
  • IgA Five major classes of antibodies are known in the art: IgA, IgD, IgE, IgG and IgM.
  • the corresponding heavy chain constant domains are called ⁇ , ⁇ , ⁇ , ⁇ and ⁇ respectively.
  • IgG and IgA can be further divided into different Subclasses, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4, IgA can be divided into IgA1 and IgA2.
  • the light chains of antibodies from any vertebrate species can be recognized as one of two distinct types, termed kappa and lambda, based on the amino acid sequence of their constant domains.
  • the heavy chain constant region contains three domains called CH1, CH2 and CH3 (IgM and IgE have a fourth domain, CH4).
  • CH1 and CH2 domains are separated by a flexible hinge region, which is a proline- and cysteine-rich segment of variable length.
  • Each type of antibody further contains inter- and intra-chain disulfide bonds formed by paired cysteine residues.
  • variable region or “variable domain” shows significant variation in the amino acid composition from one antibody to another and is primarily responsible for antigen recognition and binding.
  • the variable regions of each light/heavy chain pair form the antigen-binding site, such that a complete IgG antibody has two binding sites (i.e. it is bivalent).
  • the variable region (VH) of the heavy chain and the variable region (VL) of the light chain each contain three regions of extreme variability known as the hypervariable region (HVR), or more commonly, as Complementarity determining region (CDR), VH and VL each have 4 framework regions FR, represented by FR1, FR2, FR3, and FR4 respectively.
  • CDR and FR sequences typically occur in the following sequence of the heavy chain variable domain (VH) (or light chain variable domain (VL)): FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3 -HCDR3(LCDR3)-FR4.
  • VH heavy chain variable domain
  • VL light chain variable domain
  • Fc is used herein to define the C-terminal region of an immunoglobulin heavy chain, which region contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions. Unless otherwise stated, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, which is also known as the EU index, as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
  • antibodies in a broad sense may include, for example, polyclonal antibodies (polyclonal antibodies), monoclonal antibodies, chimeric antibodies, humanized antibodies and primatized antibodies, CDR-grafted antibodies (CDR- grafted antibodv), human antibodies (including recombinantly produced human antibodies), recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies ( Including mutant proteins and their variants), etc.
  • polyclonal antibodies polyclonal antibodies
  • monoclonal antibodies monoclonal antibodies
  • chimeric antibodies humanized antibodies and primatized antibodies
  • CDR-grafted antibodies CDR-grafted antibodv
  • human antibodies including recombinantly produced human antibodies
  • recombinantly produced antibodies intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies ( Including mutant proteins and their variants), etc.
  • full-length antibody intact antibody
  • intact antibody intact antibody
  • intact antibody may be used interchangeably herein to refer to an antibody whose structure is substantially similar to that of a native antibody or which has an Fc region.
  • monoclonal antibody refers to a substantially homogeneous antibody produced by a single cell clone and directed only against a specific antigenic epitope.
  • Monoclonal antibodies can be prepared using a variety of techniques known in the art, including hybridoma technology, recombinant technology, phage display technology, transgenic animals, synthetic technology, or a combination of the above technologies.
  • chimeric antibody is a construct in which a portion of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody from a specific species or belonging to a specific antibody class or subclass, and this or these The remainder of the chain is identical or homologous to the corresponding sequence in an antibody from another species or belonging to another antibody class or subclass, as well as in fragments of such antibodies.
  • a chimeric antibody contains all or most of a selected murine heavy chain and light chain variable region operably linked to a human light chain and heavy chain constant region. Constant region sequences, or variants or derivatives thereof, can be operably associated with the disclosed heavy and light chain variable regions using standard molecular biology techniques to provide anti-IL- Full-length antibodies to 17A and IL-17F.
  • humanized antibody is a hybrid immunoglobulin, immunoglobulin chain or fragment thereof containing minimal sequence derived from a non-human immunoglobulin.
  • a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's CDRs are replaced by those from a non-human species with the desired specificity, affinity, and properties (donor antibody ), such as mouse, rat, rabbit or primate.
  • donor antibody such as mouse, rat, rabbit or primate.
  • framework region residues of human immunoglobulins are replaced by corresponding non-human residues.
  • backmutations can be introduced into humanized antibodies, where residues in one or more FRs of the variable region of the recipient human antibody are replaced by the corresponding residues from the donor antibody from a non-human species. replace. Such back mutations may help maintain the proper three-dimensional configuration of the grafted CDR(s) and thus improve affinity and antibody stability.
  • Antibodies from a variety of donor species may be used, including, but not limited to, mice, rats, rabbits, or non-human primates. Additionally, humanized antibodies may contain novel residues not found in the recipient antibody or in the donor antibody to further improve antibody performance.
  • sequence identity or “sequence similarity” or “sequence homology” means that the sequences are aligned (and gaps introduced where necessary) to obtain the maximum percent sequence identity without any The percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence after conservative substitutions are considered part of the sequence identity.
  • Sequence alignment to determine percent amino acid sequence identity can be performed using various methods in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN (DNASTAR) software.
  • One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to obtain maximal alignment over the full length of the sequences being compared.
  • antibody fragment includes at least a portion of an intact antibody.
  • a “fragment” of an antibody molecule includes an "antigen-binding fragment” of an antibody, and the term “antigen-binding fragment” refers to an immunoglobulin or antibody that specifically binds to or reacts with a selected antigen or antigenic epitope thereof Polypeptide fragments, or fusion protein products further derived from this fragment, such as single-chain antibodies, extracellular binding regions in chimeric antigen receptors, etc.
  • Exemplary antibody fragments or antigen-binding fragments thereof include, but are not limited to: variable light chain fragments (VL), variable heavy chain fragments (VH), Fab fragments, F(ab') 2 fragments, Fd fragments, Fv fragments, Single domain antibodies, linear antibodies, single chain antibodies (scFv) And bispecific antibodies or multispecific antibodies formed from antibody fragments, etc.
  • Fab fragment includes the heavy chain variable region and the light chain variable region, and also includes the constant region of the light chain and the first constant region CH1 of the heavy chain, which are monovalent antibody fragments.
  • F(ab') 2 fragment includes 2 Fab fragments and the hinge region, which are bivalent antibody fragments.
  • Fd fragment generally includes the heavy chain variable region and the constant region CH1; the term “Fv fragment” contains the antibody heavy chain variable region and the light chain variable region, but no constant region, and has the minimum of all antigen-binding sites. Antibody fragments.
  • scFv refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguous (for example via a synthetic linker such as a short flexible polypeptide linker), and can be expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived.
  • a scFv may have the VL and VH variable regions described in any order (eg, relative to the N-terminus and C-terminus of the polypeptide), the scFv may include VL-linker-VH or may include VH-linker-VL.
  • fusion protein refers to the connection of different polypeptides/proteins through genetic recombination or chemical methods to form a larger molecule, which may or may not be connected using a linker.
  • multispecific antibody refers to an antibody that is functionally linked (e.g., chemical coupling, genetic fusion, non-covalent binding, or other methods) to one or more other binding molecules to form two or more different binding molecules.
  • Novel antibody constructs that bind sites and/or target sites.
  • bispecific antibodies which specifically refer to antibody constructs that are specific for two different antigens.
  • bispecific antibodies or multispecific antibodies include at least 2 antigen-binding domains.
  • an antigen refers to a substance that is recognized and specifically bound by an antibody or its antigen-binding fragment.
  • an antigen can include any immunogenic fragment or determinant of the selected target, including single epitopes, multiple epitopes, and single epitopes. Domain, multi-domain, or complete extracellular domain (ECD) or protein. Peptides, proteins, glycoproteins, polysaccharides and lipids, their parts and their combinations can all constitute antigens.
  • Non-limiting exemplary antigens include tumor antigens or pathogen antigens, among others.
  • Antigen may also refer to a molecule that triggers an immune response.
  • antigen or cells or preparations containing the antigen can be used to generate antibodies specific for an antigenic determinant.
  • the antigen may be an isolated full-length protein, a cell surface protein (e.g., for immunization with cells expressing at least a portion of the antigen on their surface), or a soluble protein (e.g., for immunization with only the ECD portion of the protein) or protein Construct (e.g., Fc antigen).
  • the antigen can be produced in genetically modified cells. Any of the foregoing antigens may be used alone or in combination with one or more immunogenicity enhancing adjuvants known in the art.
  • the DNA encoding the antigen may be genomic or non-genomic (eg, cDNA) and may encode at least a portion of the ECD sufficient to elicit an immunogenic response.
  • Any vector may be used to transform cells in which the antigen is expressed, including, but not limited to, adenoviral vectors, lentiviral vectors, plasmids, and non-viral vectors such as cationic lipids.
  • epitope also known as “antigenic determinant” refers to the site on an antigen that specifically binds to an immunoglobulin or antibody.
  • Epitopes can be formed from adjacent amino acids, or non-adjacent amino acids that are juxtaposed by the tertiary folding of the protein. formed from adjacent amino acids
  • Epitopes are generally maintained after exposure to denaturing solvents, whereas epitopes formed by tertiary folding are usually lost after treatment with denaturing solvents.
  • Epitopes usually consist of 3-15 amino acid residues.
  • Methods for determining the epitope to which a given antibody binds are well known in the art and include immunoblotting and immunoprecipitation assays. Methods for determining the spatial conformation of an epitope include techniques in the art and techniques described herein, such as X-ray crystallography and two-dimensional nuclear magnetic resonance.
  • polypeptide peptide
  • protein protein
  • the terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acids of any length.
  • the polymer may be linear, cyclic or branched, it may contain modified amino acids, especially conservatively modified amino acids, and it may be interrupted by non-amino acids.
  • the term also includes amino acid polymers that have been modified, for example, by glycosylation, lipidation, acetylation, phosphorylation, methylation, etc., or any other manipulation, such as conjugation with a labeling component.
  • amino acid refers to natural and/or non-natural or synthetic amino acids, including glycine and the D or L optical isomers, as well as amino acid analogs and peptide mimetics.
  • a polypeptide or amino acid sequence "derived from” a specified protein refers to the source of the polypeptide. The term also includes polypeptides expressed from the specified nucleic acid sequence.
  • amino acid modification includes amino acid substitutions, insertions and/or deletions in a polypeptide sequence.
  • amino acid substitution or “substitution” means the replacement of an amino acid at a specific position in the parent polypeptide sequence with another amino acid.
  • substitution S32A means that serine at position 32 is replaced by alanine.
  • sequence identity or homology of a humanized antibody variable region to a human receptor variable region can be determined as discussed herein, and when so measured, will preferably share at least 60% or 65% of the sequence. Identity, more preferably at least 70%, 75%, 80%, 85% or 90% sequence identity, even more preferably at least 93%, 95%, 98% or 99% sequence identity.
  • residue positions that are not identical differ by conservative amino acid substitutions.
  • a "conservative substitution” is an amino acid substitution in which one amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (eg, charge or hydrophobicity). Generally speaking, conservative amino acid substitutions do not materially alter the functional properties of the protein.
  • Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine amino acids, proline, phenylalanine, methionine), ⁇ -branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, Phenylalanine, tryptophan, histidine).
  • basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g.
  • one or more amino acid residues in the CDR regions or in the framework regions of the antibodies of the present disclosure may be replaced with other amino acid residues of similar side chains.
  • the percent sequence identity or degree of similarity can be adjusted upward to correct for the conservative nature of the substitution.
  • PTM post-translational modification
  • these PTMs may cause changes in the physical and chemical properties of the antibody, change the interaction with the antibody Fc receptor, and affect the binding activity to the target antigen; the occurrence of some PTMs may even reduce the stability of the antibody and cause immunogenicity (JARASCH et al., JOURNAL OF PHARMACEUTICAL SCIENCES, 2015).
  • JARASCH et al., JOURNAL OF PHARMACEUTICAL SCIENCES, 2015 The negative effects can be eliminated through amino acid modification of the PTM site, such as conservative substitutions. Amino acid substitutions of antibody CDRs based on the purpose of modifying the PTM are also clearly within the scope of the present disclosure.
  • Antibodies of the present disclosure may also include substitutions or modifications of the constant region (e.g., Fc), including but not limited to amino acid residue substitutions, mutations, and/or modifications, which result in compounds having the following preferred characteristics, including, but not limited to Limited to: altered pharmacokinetics, increased serum half-life, increased binding affinity, decreased immunogenicity, increased yield, altered binding to Fc receptor (FcR), enhanced or reduced ADCC or CDC, altered glycosylation and/or disulfide bonds and modified binding specificity.
  • the constant region e.g., Fc
  • Fc constant region
  • affinity refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen).
  • KD refers to the dissociation constant of a specific antibody-antigen interaction. Binding affinity can be determined using various techniques known in the art, such as surface plasmon resonance, biolayer interferometry, dual polarization interferometry, static light scattering, dynamic light scattering, isothermal titration calorimetry, ELISA, analytical ultraspeed Centrifugation and flow cytometry, etc.
  • composition refers to a preparation or a combination of preparations containing one, two or more active ingredients, which allows the active ingredients contained therein to be present in a biologically active form and which does not contain any chemicals necessary for administration. Additional components of the formulation have unacceptable toxicity to subjects.
  • a “pharmaceutical composition” exists in the form of a combination of separate preparations containing two or more active ingredients, it can be administered simultaneously, sequentially, separately or at intervals. The purpose is to exert the biological activity of the multiple active ingredients and use them together. For treating diseases.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic agent is administered.
  • the term "effective amount" refers to the dose of a pharmaceutical formulation of an antibody or antigen-binding fragment thereof of the present disclosure that produces the desired effect in a treated patient when administered to the patient in single or multiple doses.
  • the effective amount can be readily determined by the attending physician, who is one of skill in the art, by considering factors such as: ethnic differences; weight, age and health status; the specific disease involved; the severity of the disease; the response of the individual patient; The specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosing regimen selected; and the use of any concomitant therapy.
  • host cell refers to cells into which exogenous nucleic acid is introduced, including the progeny of such cells.
  • Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom, regardless of the number of passages.
  • the progeny may not be identical in nucleic acid content to the parent cells but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected in the originally transformed cells are included herein.
  • transfection refers to the introduction of exogenous nucleic acid into a eukaryotic cell. Transfection can be achieved by various means known in the art, including calcium phosphate-DNA co-precipitation, DEAE-dextran-mediated transfection, polybrene-mediated transfection, electroporation, microinjection, Liposome fusion, lipofection, protoplast fusion, retroviral infection and biolistics.
  • stable transfection or “stable transfection” refers to the introduction and integration of exogenous nucleic acid, DNA or RNA into the genome of a transfected cell.
  • stable transfectant refers to cells that stably integrate foreign DNA into their genomic DNA.
  • isolated polynucleotide or “isolated nucleic acid” refers to a nucleic acid molecule, DNA or RNA, that has been removed from its natural environment.
  • isolated polynucleotide encoding a polypeptide contained in a vector is considered isolated for the purposes of this disclosure.
  • isolated polynucleotides include recombinant polynucleotides maintained in heterologous host cells or purified (partially or substantially) polynucleotides in solution.
  • Isolated polynucleotides include polynucleotide molecules that are contained in cells that normally contain the polynucleotide molecule, but that are present extrachromosomally or in a chromosomal location that is different from its native chromosomal location.
  • Isolated RNA molecules include in vivo or in vitro RNA transcripts of the present disclosure, as well as plus- and minus-stranded and double-stranded forms.
  • nucleic acid molecule encoding refers to the sequence of deoxyribonucleotides along a deoxyribonucleic acid chain. The order of these deoxyribonucleotides determines the order of the amino acids along the polypeptide (protein) chain. Thus, a nucleic acid sequence encodes an amino acid sequence.
  • the antibody or antigen-binding fragment thereof according to the invention uses genetic engineering methods to add one or more human FR regions to the non-human CDR region.
  • the human FR germline sequence can be obtained from the website of ImMunoGeneTics (IMGT) at http://imgt.cines.fr, or from the Journal of Immunoglobulin, (2001) ISBN: 012441351.
  • Engineered antibodies of the present disclosure, or antigen-binding fragments thereof, may be prepared and purified using conventional methods.
  • cDNA sequences encoding heavy and light chains can be cloned and recombined into expression vectors.
  • the recombinant immunoglobulin expression vector can stably transfect CHO cells.
  • mammalian expression systems result in glycosylation of the antibody, particularly at the highly conserved N-terminus of the Fc region.
  • Stable clones are obtained by expressing antibodies that specifically bind to human antigens. Positive clones were expanded in serum-free medium in bioreactors to produce antibodies.
  • the culture medium secreting antibodies can be purified and collected using conventional techniques.
  • Antibodies can be filtered and concentrated using conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange.
  • the term "individual” or “subject” refers to any animal, such as a mammal or marsupial.
  • Subjects of the present disclosure include, but are not limited to, humans, non-human primates (such as cynomolgus or rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, sheep, rats and any species of poultry.
  • the terms “disease” or “disorder” or “disorder” or the like refer to any change or disorder that impairs or interferes with the normal function of a cell, tissue or organ.
  • the “disease” includes but is not limited to: tumors, pathogenic infections, autoimmune diseases, T cell dysfunction diseases, or immune tolerance defects (such as transplant rejection).
  • autoimmune disease refers to a disease in which the body's immune system malfunctions, causing the body to attack its own tissues. The causes are complex and symptoms vary depending on the type of disease and the organs involved.
  • Inflammatory and autoimmune diseases described in this disclosure may include, but are not limited to, psoriasis, psoriatic arthritis, atopic dermatitis, hidradenitis suppurativa, systemic sclerosis, rheumatoid arthritis, systemic juvenile atopic dermatitis, Inflammatory arthritis (JIA), inflammatory bowel disease, systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease (COPD), ankylosing spondylitis and other spinal diseases Column arthrosis, etc.
  • treatment refers to clinical intervention in an attempt to modify an individual or to treat a cell-induced disease process, either prophylactically or in the clinical pathological process.
  • Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing the direct or indirect pathological consequences of any disease, preventing metastasis, slowing down the progression of the disease, improving or alleviating the condition, alleviating or improving the prognosis, etc.
  • the term “combination” refers to a treatment regimen that provides at least two or more different therapies to achieve a specified therapeutic effect, and the therapies may be either physical, such as radiation therapy, or chemical, such as administration of Subject drugs, the drugs also include combination drugs.
  • “Combination drug” refers to a combination of two or more pharmaceutical preparations each having active ingredients, which need to be used together when administered to a subject. The active ingredients can be mixed together to form a single dosing unit, or they can be formed into separate dosing units and used separately; during administration, different pharmaceutical preparations can be administered substantially simultaneously, simultaneously or sequentially.
  • SD rats aged 6-8 weeks (Vitong Lever, Animal Production License Number: SCXK (Beijing) 2019-0002) were selected for animal immunization.
  • Each rat was injected with 30 ⁇ g of recombinant human IL-17A (hIL-17A) protein and 30 ⁇ g of recombinant human IL-17F (hIL-17F) protein respectively.
  • the dose of hIL-17A and hIL-17F protein injected for the first time was 60 ⁇ g/ Rats, injected every other week.
  • the titer of immune serum was tested by ELISA to determine the immune response of the animals.
  • rats with higher serum titers were selected for euthanasia, and spleens and lymph nodes were collected for preparation of hybridoma cells.
  • Lymph node and spleen cells from immunized rats were collected and mixed with Sp2/0 myeloma cells in the electrofusion solution at a ratio of 1:1 respectively.
  • HAT medium DMEM+20% FBS+1 ⁇ HAT
  • ELISA method was used to initially screen hybridoma cells, and positive clones that combined with both human IL-17A (hIL-17A) and human IL-17A&F (hIL-17A&F) antigens were screened out, and then transferred to 24-well plates for culture. Three days later, the hybridoma supernatant was tested again by ELISA to select positive clones that combined with hIL-17A, hIL-17F, hIL-17A&F and cyno IL-17A (cyno IL-17A).
  • the cells were subcloned using the semi-solid medium method to obtain stable single hybridoma cells; the obtained single clones were re-screened through experiments such as binding activity detection and cell-level biological function assay, and a total of 30 pairs of hIL were selected.
  • -17A ⁇ Both hIL-17F and hIL-17A&F are hybridoma cell lines with good binding activity.
  • the selected hybridoma cell lines are expanded into culture bottles containing complete culture medium for antibody production. When the cell viability rate is about 30%, the cell supernatant is collected for purification. The cell culture supernatant was purified by Protein A chromatography column (GE Healthcare). Use the absorbance value at 280nm to determine the concentration of the purified antibody, and use SDS-PAGE (Invitrogen) and SEC-HPLC (Agilent 1260) to determine the purity of the antibody. Through a combination of experiments such as activity measurement and cell-level biological function testing, four hybridoma cell lines were finally selected for sequencing.
  • Humanize the selected lead monoclonal antibody 1.103.12 use the human constant domain to replace the parent (mouse antibody)
  • the constant domain of the antibody is used to prepare chimeric antibodies, and then the human antibody sequence is selected based on the homology between the parent and human antibodies for humanization.
  • mouse antibody 1.103.12 was compared with the human IgG germline sequence (germline) in the IMGT database, and IGHV3-23*04 IGHJ1 and IGKV7-3*01 IGKJ2 were selected as the heavy chain and light chain CDRs respectively. migration template.
  • the heavy chain CDR region of 1.103.12 namely HCDR1 (SEQ ID NO: 9), HCDR2 (SEQ ID NO: 10) and HCDR3 (SEQ ID NO: 11), was transplanted into the framework region of IGHV3-23*04 IGHJ1;
  • the light chain CDR region of 1.103.12 namely LCDR1 (SEQ ID NO: 12), LCDR2 (SEQ ID NO: 13) and LCDR3 (SEQ ID NO: 14), was transplanted into the backbone region of IGKV7-3*01 IGKJ2; based on experience Back mutations and combined back mutations are performed on specific sites in the backbone region to form various humanized variants.
  • the correctly sequenced heavy chain expression plasmid and light chain expression plasmid were co-transfected into 293F cells for expression and purification.
  • the concentration of the purified antibody was determined by absorbance at 280 nm, and the purity of the antibody was detected by SDS-PAGE and SEC-HPLC.
  • Z1 The amino acid sequence of its heavy chain variable region is shown in SEQ ID NO: 33, and the light chain The amino acid sequence of the variable region is shown in SEQ ID NO: 34.
  • the ELISA method was selected to determine the relationship between the humanized antibody Z1 obtained in Example 3 and human IL-17A, IL-17F and other IL-17 family members (IL-17B, IL-17C, IL-17D, IL-17E ) binding activity.
  • the experimental process is roughly as follows: coat 100 ⁇ L/well of antigen (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E: 0.5 ⁇ g/mL; IL-17F: 2 ⁇ g/mL), overnight at 4°C . Block with 200 ⁇ L of blocking solution (2% BSA in PBS) for 1 hour at room temperature. Wash three times with PBST, and all washes were performed on a BioTek automatic plate washer. Add 100 ⁇ L of diluted antibody to each well. The starting concentration of the antibody is 10 ⁇ g/mL or 80 nM, and the antibody is diluted according to a 1:4 ratio. Incubate at room temperature for 2 hours. Wash 3 times with PBST.
  • the half binding concentration (EC 50 ) was calculated using GraphPad prism 8.0 software.
  • the EC 50 of Z1 with IL-17A and IL-17F were 0.057nM and 0.087nM respectively.
  • This result shows that humanized antibody Z1 has strong binding activity to both IL-17A and IL-17F, but not to other members of the IL-17 family (IL-17B, IL-17C, IL-17D, IL-17E). There is no obvious binding activity, indicating that the antibody obtained by the present disclosure has good selectivity.
  • Affinity test process Capture: Use 1 ⁇ HBS-EP+running buffer to dilute antibody Z1, inject 1 ⁇ g/mL antibody Z1 into the detection channel, and the flow rate is 30 ⁇ L/min.
  • Use 1 ⁇ HBS-EP+running buffer to carry out gradient dilution of the antigen, respectively: hIL-17A: 10nM-0.3125nM; hIL-17F: 20nM-0.625nM; hIL-17A&F: 5nM-0.3125nM; cyno IL-17A: 10nM-0.3125nM; cyno IL-17F: 20nM-0.625nM; test sample: flow each antigen through the reference channel and experimental channel in order from low to high concentration.
  • Binding takes 180s and dissociating takes 1200s. After each binding and dissociation process, 50mM HCl is used for surface regeneration.
  • Use Biacore Insight Evaluation analysis software to fit according to the 1:1 binding model, and calculate the binding rate constant ka, dissociation rate constant kd and equilibrium dissociation constant KD value of the antibody. The results are shown in Table 3 below. Data show that antibody Z1 has good affinity with hIL-17A, hIL-17F, hIL-17A&F, cyno IL-17A and cyno IL-17F.
  • Anti-IL-17A and IL-17F antibodies were used to inhibit the level of IL-6 secreted by HFF-1 cells stimulated by IL-17A, IL-17F and IL-17A&F to detect the biological activity of antibody Z1.
  • the experimental process is roughly as follows: HFF-1 cells in good growth status are seeded into a 96-well cell culture plate at a density of 1 ⁇ 10 4 cells/well, and placed in an incubator to incubate overnight. On the second day of the experiment, take another 96-well plate and add 50 ⁇ L of IL-17A (final concentration: 50ng/mL), IL-17F (final concentration: 200ng/mL) or IL-17A&F (final concentration: 100ng/mL) to each well. )Recombinant protein.
  • GraphPad prism 8.0 software to fit different antibody concentrations and corresponding IL-6 level data to a 4-parameter nonlinear logic formula to calculate the half inhibitory concentration (IC 50 ) value.
  • Z1 interacts with IL-17A, IL-17F and The IC 50 of IL-17A&F are 0.62nM, 1.41nM and 1.76nM respectively.
  • Anti-IL-17A and IL-17 antibodies were used to inhibit the release of secreted embryonic alkaline phosphatase (SEAP) from HEK-Blie TM IL-17 cells (InvivoGen) stimulated by IL-17A, IL-17F and IL-17A&F. Biological activity of antibody Z1.
  • SEAP embryonic alkaline phosphatase
  • HEK-Blue TM IL-17 cells that are growing well are seeded in a 96-well plate at a density of 5 ⁇ 10 4 cells/well, and incubated overnight in a cell culture incubator.
  • IL-17A final concentration: 50ng/mL
  • IL-17F final concentration: 200ng/mL
  • IL-17A&F final concentration: 100ng/mL
  • Recombinant protein Add 50 ⁇ L of diluted antibody to the wells that already contain 50 ⁇ L of IL-17A, IL-17F, or IL-17A&F to prepare a protein-antibody mixture.
  • the antibody was diluted at a ratio of 1:3, with an initial concentration of 10 ⁇ g/mL, and a total of 9 dilution concentrations. Incubate in a 37°C cell culture incubator for 1 hour.
  • IC 50 half inhibitory concentration
  • Human IL-17A can bind to mouse IL-17 receptor, thereby stimulating mice to express and secrete a variety of inflammatory factors and chemokines such as CXCL1/KC.
  • chemokines such as CXCL1/KC.
  • in vivo activity experiments in mice were performed. The specific experimental process is as follows: C57BL/6 female mice (Shanghai Nanmo, Animal License: SYXK (Shanghai) 2018-0002) were randomly divided into 8 groups and weighed, with 6 mice in each group.
  • mice One group of mice was injected intraperitoneally with sterile PBS buffer, one group was injected with isotype control antibody IgG (3000 ⁇ g/kg), and the remaining groups of mice were injected with antibody drug solutions of different concentrations, including: antibody Z1 of the present disclosure, reference For the antibody secukinumab, the respective concentration gradients are 3000 ⁇ g/kg, 300 ⁇ g/kg, and 30 ⁇ g/kg. 16 hours later, except the PBS group, all other groups were subcutaneously injected with 150 ⁇ g/kg human IL-17A. After 2 hours, blood samples were collected, and the whole blood was allowed to stand at room temperature for 2 hours, centrifuged at 3000 rpm and 4°C for 10 min, and the upper serum was aspirated. The samples were placed in multiple portions at -80°C to avoid repeated freezing and thawing.
  • Use Mouse CXCL1/KC Quantikine ELISA Kit R&D
  • the data in Figure 5 further shows that the inhibition rate of CXCL1/KC is at a dose of 300 ⁇ g/kg, Z1 vs secukinumab: 32% vs 15%; at a dose of 3000 ⁇ g/kg, Z1 vs secukinumab: 51% vs 39%. It can be seen that the in vivo efficacy of Z1 is slightly better than the reference antibody secukinumab that is currently on the market.
  • test antibody Z1 and the reference antibody ixekizumab are diluted with sodium chloride injection, and administered by a single intravenous bolus injection.
  • the dosage is 3 mg/kg, and the dosage volume is 2 mL/kg.
  • One day is the first day of the experiment (D1).

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Abstract

La présente divulgation concerne un anticorps anti-IL-17A et IL-17F ou un fragment de liaison à l'antigène de celui-ci, et un dérivé et une composition pharmaceutique comprenant l'anticorps ou le fragment de liaison à l'antigène de celui-ci. De plus, la présente divulgation concerne en outre l'utilisation de l'anticorps ou du fragment de liaison à l'antigène de celui-ci dans le diagnostic et le traitement de maladies associées à IL-17A et IL-17F.
PCT/CN2023/103119 2022-06-29 2023-06-28 Molécule d'anticorps se liant à il-17a et il-17f et son utilisation WO2024002145A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101316861A (zh) * 2005-09-28 2008-12-03 津莫吉尼蒂克斯公司 Il-17a和il-17f拮抗剂以及使用所述拮抗剂的方法
US20200031919A1 (en) * 2017-03-10 2020-01-30 Suzhou Kanova Biopharmaceutical Co., Ltd. Monoclonal antibody against both il-17a and il-17f and use of the same
EP3689907A1 (fr) * 2019-01-31 2020-08-05 Numab Therapeutics AG Anticorps dirigés contre il-17a et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101316861A (zh) * 2005-09-28 2008-12-03 津莫吉尼蒂克斯公司 Il-17a和il-17f拮抗剂以及使用所述拮抗剂的方法
US20200031919A1 (en) * 2017-03-10 2020-01-30 Suzhou Kanova Biopharmaceutical Co., Ltd. Monoclonal antibody against both il-17a and il-17f and use of the same
EP3689907A1 (fr) * 2019-01-31 2020-08-05 Numab Therapeutics AG Anticorps dirigés contre il-17a et leurs procédés d'utilisation

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