WO2013125738A1 - Polypeptides dérivés de l'antigène des leucocytes du porc et utilisation correspondante - Google Patents

Polypeptides dérivés de l'antigène des leucocytes du porc et utilisation correspondante Download PDF

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WO2013125738A1
WO2013125738A1 PCT/KR2012/001323 KR2012001323W WO2013125738A1 WO 2013125738 A1 WO2013125738 A1 WO 2013125738A1 KR 2012001323 W KR2012001323 W KR 2012001323W WO 2013125738 A1 WO2013125738 A1 WO 2013125738A1
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polypeptide
cells
seq
hla
present
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PCT/KR2012/001323
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Korean (ko)
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이종길
박찬수
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충북대학교 산학협력단
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    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity

Definitions

  • the present invention relates to a pig major histocompatibility antigen (SLA) -derived polypeptide that is indirectly recognized by T cells via human HLA, a nucleic acid encoding the polypeptide, and a method of using the same.
  • SLA major histocompatibility antigen
  • Organ transplantation is the only ultimate treatment for end-stage organ failure, but there is a risk of rejection after xenotransplantation.
  • Transplant rejection occurs in the order of hyperacute rejection, acute vascular rejection, acute cellular xenograft rejection, and chronic rejection.
  • the paths by which T cells recognize heterologous antigens during xenotransplantation include direct recognition and indirect recognition.
  • Direct recognition is that human T cells recognize and activate swine leukocyte antigen (SLA) directly.
  • Indirect recognition is that human antigen presenting cells (APCs) detect pig SLA.
  • the human T cell recognizes that the SLA-derived heterologous antigen peptide (peptide) is presented through its main histocompatibility antigen (HLA) through intracellular treatment (FIG. 1).
  • Indirect recognition is much more important than direct recognition in the rejection of human T cells when transplanting porcine cells or organs to humans, because not only is the porcine SLA molecule different from the human HLA molecule, The interaction between pig co-stimulatory molecules and human co-stimulatory factors is much weaker than in the allogenic response. Therefore, it is necessary to identify what porcine SLA antigen-derived peptides (ie, peptides involved in the indirect recognition process) presented by human HLA antigens, and to develop a technique for inducing this peptide specific immunotolerance. It is very important in terms of control of xenotransplant rejection by T cells.
  • HLA class I molecules HLA-A, B, C
  • class II molecules DP, DQ, DR
  • HLA class I and class II molecules are so diverse (polymorphic)
  • the peptides derived from SLA presented through HLA molecules can be different depending on the human HLA haplotype, so any peptide derived from SLA has a T cell response. Whether the main peptide (immunodominant peptide) of induction is inevitably different from person to person.
  • T cells For the regulation of cell mediated rejection, it is essential to regulate the immune response of T cells, which play a major role in the natural immune response.
  • human T cells For the regulation of human T cells, it is basically the identification of a pig SLA-derived epitope, which is present on the surface of pig cells and is known as a major antigen for organ transplant rejection, to determine which is the main epitope of the immune rejection reaction. Required.
  • antigenic peptides Once antigenic peptides have been identified, studies related to the induction of identified peptide-specific regulatory T cells (Tregs) should be supported. Induction of antigen-specific Tregs may be a major means of overcoming chronic immune rejection as well as acute cell mediated immunorejection.
  • the present inventors are most commonly present in Koreans using transgenic mice (HLA-DRA / H2-Ea, HLA-DRB1 * 0401 / H2-Eb) expressing human HLA-DRB1 * 0401 molecules.
  • the present invention was completed by finding an SLA-derived peptide presented through HLA-DRB1 (35.0%), which is an HLA-DR allele.
  • SLA major histocompatibility antigen
  • another object of the present invention is to provide a protein, a polynucleotide, a vector comprising the same, and a host cell capable of regulating or controlling an immune rejection response following xenotransplantation.
  • the present invention (a) SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 17, SEQ ID NO: 20 and SEQ ID NO: 32, and (b) one or a plurality of in the sequence of (a)
  • An isolated or recombinant polypeptide comprising any one or more polypeptide sequences selected from the group consisting of sequences whose amino acids have been modified by substitution, deletion or addition.
  • the polypeptide is derived from swine leukocyte antigen (SLA) and can be recognized in T cells through human major histocompatibility antigen (HLA).
  • a sequence in which one or a plurality of amino acids in the sequence of (a) is modified by substitution, deletion or addition maintains the same function as the original polypeptide sequence, but is not limited thereto. However, it has at least 50%, preferably at least 70%, more preferably at least 80%, more preferably at least 90% sequence homology with the original polypeptide sequence.
  • the polypeptide may be used to activate T cells or to inhibit the proliferation of T cells.
  • the polypeptide may be used to suppress an immune response.
  • the present invention also provides an isolated or recombinant protein comprising the polypeptide according to the present invention and an Ig Fc polypeptide.
  • the protein may perform a function of regulating or controlling an immune response.
  • the present invention also provides an isolated or recombinant protein comprising the polypeptide according to the present invention and a peptide that facilitates secretion of the polypeptide.
  • the peptide that facilitates secretion may be a signal peptide.
  • the present invention also provides a polynucleotide encoding the polypeptide or protein according to the present invention.
  • the present invention also provides a vector comprising the polynucleotide sequence according to the present invention.
  • the present invention also provides a host cell comprising the vector according to the present invention.
  • the present invention also provides a pharmaceutical composition comprising the polypeptide according to the present invention.
  • the pharmaceutical composition according to the present invention can be used for the prevention or treatment of immune rejection reaction following xenotransplantation.
  • the pig major histocompatibility antigen (SLA) -derived polypeptide of the present invention exhibited the activity of inhibiting the binding of human influenza virus-derived peptide HA 306-318 to human HLA-DR4. It can be evaluated with this powerful peptide. Accordingly, the peptides of the present invention can be used to induce a peptide specific CD4 T cell response or to inhibit heteroimmune rejection by inducing the production of peptide specific regulatory T cells.
  • 1 is a diagram showing a path for T cells to recognize heterologous antigen during xenotransplantation.
  • Figure 2 is a graph showing the binding of influenza virus derived peptide (HA 306-318 ) to human HLA-DR4 (DRB1 * 0401).
  • FIG. 3 is a graph showing the ability of the polypeptide of SEQ ID NO: 10 to inhibit binding of human influenza virus derived peptide (HA 306-318 ) to human HLA-DR4 (DRB1 * 0401) at a concentration of 1 ⁇ M.
  • Figure 4 is a graph showing an ability to inhibit binding to the human HLA-DR4 (DRB1 * 0401) of the polypeptide of SEQ ID NO: 11 1 ⁇ M concentrations of influenza virus-derived peptide (HA 306-318).
  • FIG. 5 is a graph showing the ability of the polypeptide of SEQ ID NO: 17 to inhibit the binding of human influenza virus derived peptide (HA 306-318 ) to human HLA-DR4 (DRB1 * 0401) at a concentration of 1 ⁇ M.
  • FIG. 6 is a graph showing the ability of the polypeptide of SEQ ID NO: 20 to inhibit binding of human influenza virus derived peptide (HA 306-318 ) to human HLA-DR4 (DRB1 * 0401) at a concentration of 1 ⁇ M.
  • FIG. 7 is a graph showing the ability of the polypeptide of SEQ ID NO: 32 to inhibit the binding of influenza virus derived peptide (HA 306-318 ) to human HLA-DR4 (DRB1 * 0401) at a concentration of 1 ⁇ M.
  • the present invention relates to a polypeptide derived from porcine major histocompatibility antigen (SLA), which may be recognized by T cells via human HLA.
  • SLA major histocompatibility antigen
  • the inventors were able to identify human CD4 T cell activating epitopes among swine SLA-derived polypeptides while developing a technique to induce heterologous antigen specific immunotolerance.
  • Human CD4 T cells recognize only antigens presented through HLA class II molecules, which are human antigen presenting cells.
  • porcine SLA molecules are phagocytosed by human antigen presenting cells and then presented to human T cells through human HLA class II molecules through intracellular processing and CD4 T cells are activated, resulting in heteroimmune rejection.
  • the inventors have found, through computer modeling and in vitro experiments, peptides derived from porcine SLA that are highly antigenic peptides presented through human HLA-DR4 molecules (Table 1). Since the polypeptide of the present invention exhibited the activity of inhibiting the binding of human influenza virus-derived peptide HA 306-318 to human HLA-DR4, the antigenicity presented through the HLA-DR4 molecule can be evaluated as a strong peptide.
  • the present invention can provide an isolated or recombinant polypeptide comprising a peptide derived from porcine major histocompatibility.
  • Isolated means when the nucleic acid, protein or other component is partially or completely separated from the component to which it is normally associated (other protein, nucleic acid, cell, synthetic reagent, etc.).
  • recombinant refers to when the nucleic acid or polypeptide is derived from a nucleic acid or protein that is artificial or process, or artificial or process.
  • the polypeptides, peptides and proteins are used interchangeably to refer to polymers of amino acid residues and are used in both naturally occurring and non-naturally occurring amino acid polymers.
  • the term includes amino acid chains of any length, including full length proteins (ie, antigens), wherein the amino acid residues are linked by covalent peptide bonds.
  • Polypeptides of the invention include polypeptides having the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 17, SEQ ID NO: 20, or SEQ ID NO: 32, as well as variants that perform the same function.
  • Such "variant" polypeptides include polypeptide sequences that differ by at least one amino acid residue from the sequence of the original polypeptide.
  • the variant polypeptide may comprise about 1%, 2%, 3%, 4%, 5%, 6%, of the original polypeptide sequence and the total number of polypeptide sequence residues, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 30% 40%, 50% or more different polypeptide sequences.
  • the variant polypeptide comprises at least about 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91% relative to the original polypeptide sequence. , 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% polypeptide sequence having sequence identity.
  • Variant polypeptides are polypeptide sequences of the original polypeptide by deletion, addition or substitution of one or more amino acid residues of the original polypeptide, or any combination of such deletion (s), addition (s) and / or substitution (s). And polypeptide sequences different from.
  • polypeptides of the present invention provide novel polypeptides, collectively referred to as polypeptides of the present invention, which are intended to include variants and / or derivatives of the polypeptide sequences disclosed herein.
  • Polypeptides of the invention include recombinant or variant polypeptides that bind to human HLA.
  • Polypeptides of the invention include recombinant fusion proteins comprising the variant polypeptides of the invention and include monomeric and dimeric forms of such fusion proteins.
  • Polypeptides of the invention include multimers comprising one or more variant polypeptides of the invention.
  • the invention also includes conjugates comprising one or more variant polypeptides of the invention.
  • Some polypeptides of the invention are soluble polypeptides.
  • the present invention includes soluble fusion proteins comprising variant polypeptides linked to different polypeptides (eg, immunoglobulin polypeptides such as Ig Fc polypeptides) that enhance the solubility of the variant polypeptides.
  • the present invention can be used to treat diseases, disorders and abnormalities of the immune system, including the regulation of T cell dependent immune responses.
  • Polypeptides, proteins, or nucleic acids encoding such polypeptides or proteins of the invention include, for example, autoimmune diseases, disorders and disorders, immunoproliferative diseases, graft-related disorders, treatment of immune system diseases, disorders and disorders in which immunosuppression is desired, donor tissue
  • autoimmune diseases, disorders and disorders immunoproliferative diseases, graft-related disorders
  • treatment of immune system diseases, disorders and disorders in which immunosuppression is desired donor tissue
  • donor tissue can be useful for treatment methods involving transplantation of tissues, cells, organs or grafts from a donor to a recipient in which the suppression of an immune response in a cell, organ or graft resistant recipient is desirable. It can be used for the prevention or treatment of the immune rejection reaction.
  • the polypeptide of the present invention comprises a variety of mutagenesis, screening methods, etc. in order to suppress the immune response by T cells, including the function or binding activity abnormalities of human HLA-DR4 molecules Can be used to make novel variant molecules.
  • the molecule may inhibit or block signaling pathways important for T cell activation, such that T cells may not be selectively activated but have reduced proliferative capacity.
  • variant molecules using the polypeptides of the invention can function as immunosuppressive agents by inhibiting or blocking T cell-dependent immune responses as antagonists of signaling pathways for T cells to function.
  • Polypeptides of the invention can provide isolated or recombinant proteins comprising peptides that facilitate their secretion.
  • the peptide that facilitates the secretion may be a signal peptide.
  • the signal peptide is generally a peptide (or amino acid) sequence preceding the subject polypeptide, which is bound to and translated with the subject polypeptide, and serves to direct the polypeptide to the secretory system or to facilitate it.
  • Signal peptides are generally covalently attached or fused to the amino terminus of the subject polypeptide and facilitate the secretion of the subject polypeptide from the host cell.
  • Signal peptides are generally cleaved from the polypeptide of interest after translation.
  • the present invention also provides a polynucleotide encoding an polypeptide or protein of the invention.
  • the amino acid sequence may be encoded in any one of six different reading frames provided by the polynucleotide sequence and its complement.
  • Nucleic acids and polynucleotides are used interchangeably to refer to polymers of nucleic acid residues in single- or double-stranded form (eg, deoxyribonucleotides or ribonucleotides). Unless specifically limited, the term includes nucleic acids comprising known analogues of natural nucleotides that have similar binding properties as the original nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
  • nucleic acid sequences also implicitly include obviously indicated sequences as well as their conservatively modified variants (eg, degenerate codon substitutions) and complementary nucleic acid sequences.
  • degenerate codon substitutions can be achieved by generating a sequence in which the third position of one or more selected (or all) codons is replaced with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19 : 5081 (1991); Ohtsuka et al., J. Biol. Chem. 260: 2605 2608 (1985); and Cassol et al. (1992); Rossolini et al., Mol. Cell.
  • the variant nucleic acid comprises a nucleotide sequence that differs from the nucleotide sequence of the original nucleic acid (such as a WT nucleic acid) by one or more nucleic acid residues.
  • the variant nucleic acid is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11 of the total number of nucleotide sequences of the original nucleic acid. %, 12%, 13%, 14%, 15%, 20%, 30% 40%, 50% or more different nucleotide sequences.
  • the variant nucleic acid is at least about 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, relative to the nucleotide sequence of the original nucleic acid. Nucleotide sequences having 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity.
  • Variant nucleic acids may be those of the original nucleic acid, for example, by deletion, addition or substitution of one or more nucleotide residues of the original nucleic acid, or any combination of such deletion (s), addition (s) and / or substitution (s). It may comprise different nucleotide sequences. Variations in nucleic acids may arise from alternative splicing or truncation of nucleotides, or errors in processing or cleavage of nucleotides.
  • the reference or parent nucleic acid may itself be a variant nucleic acid.
  • the present invention also provides a vector comprising the polynucleotide sequence of the present invention.
  • the vector can be any agent capable of delivering or maintaining nucleic acid in a host cell, for example, a nucleic acid complexed with a plasmid (eg, a DNA plasmid), a naked nucleic acid, a viral vector, a virus, one or more polypeptides or other molecules.
  • a plasmid eg, a DNA plasmid
  • Vectors may be used to transduce, transfect, transform, or replicate a nucleic acid and / or protein other than those inherent in the cell or in a manner that is not inherent to the cell.
  • Vectors may include substances that help introduce nucleic acids into cells, such as viral particles, liposomes, protein coatings, and the like. Any method of delivering nucleic acid into a cell can be used. Unless otherwise indicated, a vector means any particular method of delivering nucleic acid into a cell or does not mean that any particular cell type is the subject of transduction. In one embodiment of the invention, the vector may be an expression vector.
  • An expression vector generally refers to a nucleic acid construct or sequence that is produced recombinantly or synthetically, with a series of specific nucleic acid components that allow transcription of a particular nucleic acid in a host cell.
  • Expression vectors generally comprise a nucleic acid to be transcribed that is operably linked to a promoter.
  • the expression includes any step involved in the production of a polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification, and / or secretion.
  • an expression vector compatible with a prokaryotic host cell may be used as the expression vector of the present invention.
  • prokaryotic expression vectors include a BLUESCRIPT vector (Stratagene), a T7 expression vector (Invitrogen), a pET vector (Novagen), and the like. This includes.
  • Expression vectors that are compatible with eukaryotic host cells include, for example, pCMV vector (Invitrogen), pIRES vector (Clontech), pSG5 vector (Stratagene), pCDNA3.1 (Invitrogen Life Technologies), pCDNA3 (Invitrogen Life Technologies), Ubiquitous Chromatin Opening Element (UCOE TM) expression vector (Millipore).
  • the vector of the present invention may include a suitable promoter or regulatory sequence.
  • Expression control sequences are generally linked to and / or operably linked to the nucleic acid sequences of the present invention.
  • Expression control sequences are nucleotide sequences that promote, enhance, or control the expression of other nucleotide sequences.
  • Suitable expression control sequences include promoters including constitutive promoters, inducible promoters and / or inhibitory promoters, enhancers that amplify expression, initiation sequences, termination translation sequences, splicing control sequences, and the like.
  • promoters including constitutive promoters, inducible promoters and / or inhibitory promoters, enhancers that amplify expression, initiation sequences, termination translation sequences, splicing control sequences, and the like.
  • the nucleic acids are generally functionally linked to appropriate transcriptional regulatory sequences (promoters) to induce mRNA synthesis.
  • Promoters have a particularly important effect on the level of recombinant polypeptide expression.
  • Any suitable promoter can be used.
  • suitable promoters include cytomegalovirus (CMV) promoters with or without the first intron A, HIV long terminal repeat promoters, phosphoglycerate kinase (PGK) Promoter, Ross Granulomatous Virus
  • RSV Rous sarcoma virus, RSV
  • RSV promoters such as the RSV long terminal repeat (LTR) promoter, SV40 promoter, mouse mammary tumor virus (MMTV) promoter, HSV promoter such as Lap2 promoter or herpes thymidine kinase (herpes) thymidine kinase promoters (such as described in Wagner et al. (1981) Proc. Natl. Acad. Sci.
  • promoters derived from SV40 or the Epstein Barr virus include adeno- Associated virus (adeno-associated viral, AAV) promoters, such as the p5 promoter, metallothionein promoters (eg, both metallothionein promoters or mouse metallothionein promoters (Palmiter et al. (1983) Science 222) : 809-814)), human ubiquitin C promoter, E.
  • coli promoters such as the lac and trp promoters, phage lambda PL promoters, and prokaryotic or eukaryotes
  • Other promoters known to control the expression of a gene in a cell comprises (from virus infected cells directly, or in a cell).
  • nucleic acid of the invention or a corresponding polypeptide of the invention
  • Northern Blot analysis e.g., McMaster et al., Proc. Natl. Acad. Sci. USA 74 (11): 4835-38 (1977) and Sambrook
  • reverse transcriptase- polymerase chain e.g., reverse transcriptase- polymerase chain
  • RT-PCR reaction, RT-PCR
  • in situ hybridization techniques eg US Pat. No. 5,750,340
  • quantification of proteins can be found in Lowry assays and other protein quantitative assays (see, eg, Bradford, Anal. Biochem. 72: 248-254 (1976); Lowry et al., J. Biol. Chem. 193: 265 (1951)). Can be achieved.
  • Vectors of the invention may comprise ribosomal-binding sites for translation initiation and transcription-termination regions.
  • suitable transcription-termination regions are polyadenylation sequences that facilitate cleavage and polyadenylation of RNA transcripts produced from DNA sequences.
  • Synthetic optimization sequences as well as the polyadenylation sequence of BGH (Bovine Growth Hormone), human growth hormone gene, polyoma virus, TK (Thymidine Kinase), EBV (Epstein) Any, including Papstein Barr Virus, rabbit beta globin, and papillomaviruses, including human papillomaviruses and BPV (Bovine Papilloma Virus) Suitable polyadenylation sequences can be used
  • the vectors or polynucleotides of the invention further comprise site-specific recombination sites, which can be used to modulate the transcription of the nucleotide sequence of interest.
  • the vector or polynucleotide of the present invention can target polypeptide expression to a desired cell compartment, membrane, or organelle.
  • a nucleic acid encoding a secretion / position shift sequence may be included.
  • an amino acid sequence corresponding to the relocation sequence (s) In addition, dihydrofolate reductase resistance, neomycin resistance, or tetracycline in E. coli
  • the vectors or polynucleotides of the invention may comprise one or more selection marker nucleotide sequences or genes. Nucleotides may contain an origin of replication useful for propagation in microorganisms. There.
  • the present invention also provides engineered host cells transduced, transfected, or transformed with the vector of the present invention or the nucleic acid of the present invention.
  • Host cell herein refers to any cell that is easy to transform with the nucleic acid.
  • the engineered host cell can be cultured in a conventional nutrient medium modified to be suitable for activating a promoter, selecting a transformant, or amplifying a nucleic acid of interest.
  • Polypeptides of the invention can be used in various expression hosts, including but not limited to animal cells, such as mammalian cells (eg, CHO cells), including human and non-human primate cells, and in plants, yeast, fungi, bacteria, And can be produced in non-animal cells such as the like.
  • animal cells such as mammalian cells (eg, CHO cells), including human and non-human primate cells, and in plants, yeast, fungi, bacteria, And can be produced in non-animal cells such as the like.
  • suitable expression hosts include bacterial cells such as E.
  • coli coli, Streptomyces, and Salmonella typhimurium
  • Fungal cells such as Saccharomyces cerevisiae, Pichia pastoris, and Neurospora crassa
  • Insect cells such as Drosophila and Spodoptera frugiperda
  • Mammalian cells such as CHO (eg CHO-K1), COS (eg COS-1, COS-7), BHK, and HEK (eg HEK 293) cells, Bowes melanoma cells, And plant cells.
  • the present invention provides a cell comprising any one or more of the nucleic acids, vectors, or other constructs of the invention or any combination thereof. Also included are cells comprising one or more of the polypeptides, fusion proteins, or other constructs described herein, or any combination of one or more thereof.
  • Cells of the invention are generally isolated or recombinant cells and may include host cells. Such cells, such as recombinant cells, can be modified by transformation, transfection, and / or infection by at least one nucleic acid, vector, or other construct of the invention.
  • Such cells may be eukaryotic cells (eg mammalian, yeast or plant cells) or prokaryotic cells (eg bacterial cells), such as calcium phosphate transfection (see eg calcium phosphate co-precipitation method), DEAE- Including dextran-mediated transfection, electroporation (Irving et al., Cell 64: 891-901 (1991)), gene or vaccine guns, injections, lipid infections and biolistics or other conventional techniques well-known above.
  • Various known methods can be used to transform into any such construct of the invention.
  • Host cell strains are optionally selected according to their ability to regulate the expression of the inserted sequence or to process the expressed protein in a desired manner.
  • Such modifications of proteins include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation.
  • Different host cells such as E. coli, Bacillus sp., Yeast, or mammalian cells such as CHO, HeLa, BHK, MDCK, HEK 293, WI38, etc., have specific cellular machinery and characteristic mechanisms for such post-translational activity. It can be chosen to ensure accurate modification and processing of the introduced foreign protein.
  • Nucleic acids of the invention can be inserted into appropriate host cells (in culture or in host organisms) to allow the host to express the protein of interest. Any suitable host cell is transformed and / or transduced with the nucleic acid of the invention. Examples of suitable expression hosts include: bacterial cells such as E.
  • coli coli, Streptomyces, Bacillus sp., And Salmonella typhimurium
  • Fungal cells such as Saccharomyces cerevisiae, Pichia pastoris, and Neurospora crassa
  • Insect cells such as Drosophila and Spodoptera frugiperda
  • Vero cells HeLa cells, CHO cells (eg CHO-K1), COS cells, WI38 cells, NIH-3T3 cells (and other fibroblasts such as MRC-5 cells), MDCK cells, KB cells, SW-13 cells , Mammalian cells such as MCF7 cells, BHK cells, HEK-293 cells, Bowes melanoma cells and plant cells.
  • the invention also provides host cells that are transduced, transformed or transfected with at least one nucleic acid or vector of the invention.
  • the vectors of the present invention generally comprise the nucleic acids of the present invention.
  • Host cells are engineered (eg, transduced, transformed, infected or transfected) using a vector of the invention, which can be, for example, a cloning vector or an expression vector.
  • the vector may be in the form of a plasmid, viral particles, phage, attenuated bacteria, or any other suitable type of vector.
  • Suitable host cells for the production of recombinant polypeptides of the invention and / or for transduction and / or infection with the viral vectors of the invention for replication of the viral vectors of the invention include the above-described cells. Examples of cells proven to be suitable for packaging viral vector particles are described, for example, in Polo et al., Proc. Natl. Acad. Sci. 96 (8): 4598-603 (1999), Farson et al., J. Gene Med. 1 (3): 195-209 (1999), Sheridan et al., Mol. Ther. 2 (3): 262-75 (2000), Chen et al., Gene Ther. 8 (9): 697-703 (2001), and Pizzaro et al., Gene Ther. 8 (10): 737-745 (2001).
  • replication-deficient viral vectors such as AAV vectors, complementary cell lines, helper virus transformed cell lines, or cell lines transformed with plasmids encoding essential genes are required for replication of the viral vector.
  • Engineered host cells can be cultured in conventional nutrient media modified to be suitable for activating a promoter, selecting a transformant, or amplifying a nucleic acid of interest.
  • Host cells can be cultured in serum-containing medium or serum-free medium.
  • the present invention includes immortalized cells or cell lines comprising one or more polypeptides of the invention (eg, including dimeric or monomeric fusion proteins and multimeric polypeptides), conjugates, nucleic acids or vectors.
  • polypeptides of the invention eg, including dimeric or monomeric fusion proteins and multimeric polypeptides
  • the present invention also provides a pharmaceutical composition comprising the polypeptide of the present invention.
  • the pharmaceutical composition may be used for the prevention or treatment of an immune rejection reaction following xenotransplantation.
  • the pharmaceutical composition refers to a composition suitable for pharmaceutical use in a subject, including an animal or a human.
  • Pharmaceutical compositions generally comprise an effective amount of an activator and a carrier, excipient or diluent.
  • the carrier, excipient or diluent is generally a pharmaceutically acceptable carrier, excipient or diluent, respectively.
  • the prophylaxis is intended to prevent or reduce the risk of a subject developing a pathology, disease or disorder when the agent is administered to a subject that does not exhibit signs or symptoms of the pathology, disease or disorder or exhibits only its initial signs or symptoms.
  • Prophylactically useful agents refer to agents that are useful for preventing the development of a disease, pathology or disorder, or which inhibit or inhibit further development or enhancement of a disease, pathology or disorder.
  • the treatment is performed on a subject who exhibits the symptoms or signs of a pathology, disease or disorder, which treatment is performed on the subject for the purpose of reducing or eliminating such signs or symptoms.
  • a therapeutic activity is the activity of an agent that, when administered to a subject suffering from such signs or symptoms, eliminates or reduces the signs or symptoms of a pathology, disease or disorder.
  • Molecules or components of the invention can be administered to a subject as a composition.
  • the composition generally comprises at least one such molecule or component and an excipient, carrier, or diluent.
  • the composition may comprise a pharmaceutical composition comprising at least one such molecule or component and a pharmaceutically acceptable excipient, carrier, or diluent (eg, PBS).
  • the pH of the compositions of the present invention generally ranges from about pH 6.0 to about pH 9.0, including, for example, about pH 6.5 to about pH 8.5, and usually ranges from about pH 7.0 to about pH 8.0.
  • compositions of the invention include one or more salts (e.g., sodium chloride, sodium phosphate, calcium chloride, etc.), one or more buffers (e.g., HEPES, sodium citrate, sodium phosphate (e.g., Na2HPO4 / Na3PO4), succinate, tartrate, fumarate , Gluconate, oxalate, lactate, acetate, tris (hydroxymethyl) aminomethane (Tris), etc., one or more sugars or sugars (e.g.
  • One or more monosaccharides, disaccharides and / or polysaccharides may be included in the composition.
  • the composition of the present invention may comprise any concentration of said molecule or component effective to inhibit an immune response when administered to a subject.
  • an effective amount or dose of a molecule of the invention administered to a particular subject can be, for example, the disease, disorder, or condition being treated, the efficacy (ie, efficacy) of the particular variant of the invention to be administered, the mode of administration of the subject, and the particular It may vary depending on the individual's ability of the subject to withstand a specific amount of molecule.
  • molecules or components of the invention eg, polypeptides, nucleic acids, vectors, compositions, and / or cells of the invention
  • the molecules or components of the present invention may be administered in a therapeutically effective amount once, twice, three or four times a month, twice a week, once every two weeks, or once every two months.
  • any of the methods described herein may further comprise administering to the subject an effective amount of at least one additional therapeutic or immunosuppressive agent or compound.
  • the invention relates to (1) an effective amount of at least one first immunosuppressive agent, wherein each such first immunosuppressive agent is directed to a subject in need of suppressing an immune response.
  • a nucleic acid, a vector, a composition, and / or a cell and (2) administering an effective amount of at least one second immunosuppressive agent, wherein the method comprises: The reaction is suppressed.
  • DMARDs disease-modifying anti-rheumatic drugs
  • MTX methotrexate
  • cytokine antagonists e.g. IL-2 or IL-6 Antagonists
  • steroidal compounds e.g., corticosteroids, glucosteroids, e.g.
  • prednisone or methylprednisone nonsteroidal compounds
  • sodium salicylate magnesium salicylate
  • ibuprofen acetylsalicylic acid
  • acetaminophen antibodies
  • anti-inflammatory cytokines Biological agents that block synthesis or production
  • Raptiva efalizumab anti-inflammatory agents or compounds
  • non-steroidal anti-inflammatory drugs NSAIDs
  • Red or immunosuppressive agents can be administered to a subject in a pharmaceutical composition, including additional agents and pharmaceutically acceptable excipients or carriers.
  • the effective amount and dose of the agent to be administered will vary depending on the specific agent Some such agents are currently used for the treatment of immunosuppression and the appropriate dosages are determined by the subject's ability to withstand the specific amount or dose and the disease, disorder or condition to be treated, And the immunosuppressive efficacy of the agent.
  • HLA molecule-specific monoclonal antibody Since a large amount of HLA molecule-specific monoclonal antibody is required for the measurement of the binding force between the HLA molecule and the peptide, 500 ⁇ l pristane (Sigma Aldrich), which is about 1 week ago, was used for L243 (ATCC), a hybridoma producing HLA molecule-specific monoclonal antibody. ) in which the the Balb / c (Orient bio) treated by 10 7 (cells) in the mouse peritoneal cavity by intraperitoneal injection causes inflammation following, peritoneal fluid samples were collected in a month using a 18G needle.
  • HLA-specific monoclonal antibody present in the intraperitoneal solution was added to the column filled with a bead containing protein A-bound beads in agarose and bound only to the HLA-specific monoclonal antibody.
  • HLA-specific monoclonal antibody was eluted using elution buffer (pH3), and then buffer exchange was performed with PBS.
  • the total protein content of each elution fraction was measured using a BCA assay kit (Thermo science), and the final purified antibody was identified as a single band through SDS-PAGE.
  • Lysis buffer (1% NP-40 detergent) immediately added with a protease inhibitor (2 mM phenylmethylsulfonyl fluoride, 10 ⁇ g / ml aprotinin, 25 mM indoacetamide) to PRIESS cells expressing HLA molecules on the cell surface.
  • a protease inhibitor (2 mM phenylmethylsulfonyl fluoride, 10 ⁇ g / ml aprotinin, 25 mM indoacetamide)
  • 0.15 M NaCl, 0.02% sodium azide in 0.05 M Sodium phosphate buffer, pH7 was added to 1 ml per 1 ⁇ 10 8 cells to destroy the cells at 4 ° C. for 1 hour, centrifuged at 4000 g for 10 minutes, and then cell debris. Supernatant was removed.
  • HLA-DR4 specific monoclonal antibody PRIESS cell lysate, a cell line expressing human HLA-DR4 (DRB1 * 0401) molecules
  • PRIESS cell lysate a cell line expressing human HLA-DR4 (DRB1 * 0401) molecules
  • a cell line expressing human HLA-DR4 (DRB1 * 0401) molecules was added, incubated for 2 hours, washed with physiological saline, and bound.
  • biotin-coupled influenza virus-derived peptide HA 306-318 (PKYVKQNTLKLAT, SEQ ID NO: 33) (synthesized by peptron) was added to each concentration and incubated overnight, followed by streptavidin.
  • influenza virus-derived peptide HA 306-318 binds to HLA-DR4 in a concentration-dependent manner, and the binding is almost saturated at a concentration of about 1000 nM (FIG. 2).
  • a peptide derived from the extracellular domain present in the cell membranes of swine leukocyte antigen (SLA) class I (SLA-1,2,3) and class II (SLA-DR, DQ) molecules is derived from the extracellular domain present in the cell membranes of swine leukocyte antigen (SLA) class I (SLA-1,2,3) and class II (SLA-DR, DQ) molecules.
  • SLA swine leukocyte antigen
  • SLA-DR class II
  • DQ class II
  • Computer modeling of a peptide consisting of 15 amino acids that is expected to have good binding to the antigen-binding crefts of a human leukocyte antigen (HLA) class II molecule, HLA-DR4 (or more precisely, DRB1 * 0401) molecule program name: SYFPEITHI program
  • 32 peptides having excellent binding strength to HLA-DR4 and high covalentity with various SLA alleles among the predicted peptides were synthesized by using
  • the binding ability of the synthesized peptides to HLA-DR4 is a method of relatively comparing the extent to which the influenza virus-derived peptide HA 306-318 described in Example 1 inhibits HLA-DR4 binding (FIG. 2). Measured. That is, PRIESS cell lysate, a cell line expressing human HLA-DR4 molecules, was added to an ELISA plate coated with L243, an HLA-DR4-specific monoclonal antibody, incubated for 2 hours, and then washed with physiological saline to remove all unbound proteins.
  • HA 306-318 1000 nM, a biotin-bound influenza virus-derived peptide, and synthesized SLA-derived peptide were added at different concentrations, followed by incubation overnight, and then streptavidin-attached alkaline phosphatase and substrate 4 After adding -MUP (4-methylumbelliferyl phosphate), the fluorescence value was measured at an excitation wavelength of 440 nm and an emission wavelength of 365 nm.
  • Peptide Name Peptide sequence IC 50 SLA-1,2,3 Epitope (a1 & 2) pep1 PHSLSYFYTAVSRPD (SEQ ID NO: 1) 500 pep2 EPRVPWIQQEGQDYW (SEQ ID NO: 2) 500 pep3 GQDYWDEETRKVKDN (SEQ ID NO: 3) 600 pep4 QDYWDEETRKVKDNA (SEQ ID NO: 4) 1000 ⁇ pep5 PEYWDRETQISKETA (SEQ ID NO: 5) 1000 ⁇ pep6 QEYWDRETQISKDNA (SEQ ID NO: 6) 1000 ⁇ pep7 RNAMGSAQTFRVNLN (SEQ ID NO: 7) 500 Pep8 QNAMGSAQTFRVNLK (SEQ ID NO: 8) 650 pep9 YIALNEDLRSWTAAD (SEQ ID NO: 9) 800 pep10 LRSWTAADTAAQITK (SEQ ID NO: 10) 300 pep11
  • the strong affinity with HLA-DR4 was shown to be pep11 (SEQ ID NO: 11) derived from SLA class I (IC 50 : 50 nM) and pep32 (SEQ ID NO: 32) derived from SLA class II (IC 50 : 50). nM), as well as pep10 (SEQ ID NO: 10) (IC 50 : 300 nM), pep17 (SEQ ID NO: 17) (IC 50 : 400 nM), pep20 (SEQ ID NO: 20) (IC 50 : 250 nM) 3-7.

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Abstract

La présente invention concerne des polypeptides dérivés de l'antigène des leucocytes du porc (SLA) que les lymphocytes T reconnaissent indirectement via l'antigène leucocytaire humain (HLA). La présente invention porte également sur des acides nucléiques codant pour les polypeptides et sur un procédé d'utilisation des polypeptides et des acides nucléiques. Les polypeptides dérivés de l'antigène des leucocytes du porc (SLA) peuvent présenter une activité d'inhibition de la liaison de HA306 -318, qui sont des peptides dérivés du virus de la grippe, au HLA-DR4, et donc, être évalués comme des peptides ayant une antigénicité puissante présentée par l'intermédiaire des molécules HLA-DR4. En conséquence, les peptides de la présente invention peuvent induire une réaction des lymphocytes T CD4 peptido-spécifiques ou induire une production de lymphocytes T régulateurs peptido-spécifiques et, de ce fait, peuvent être utilisés dans l'inhibition d'une réponse de rejet immunitaire hétérogène.
PCT/KR2012/001323 2012-02-21 2012-02-21 Polypeptides dérivés de l'antigène des leucocytes du porc et utilisation correspondante WO2013125738A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019006330A1 (fr) * 2017-06-30 2019-01-03 Indiana University Research And Technology Corporation Compositions et procédés de détection de la réactivité à des sla

Citations (1)

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Publication number Priority date Publication date Assignee Title
US6521448B1 (en) * 1997-08-19 2003-02-18 Diacrin, Inc. Porcine MHC class I genes and uses thereof

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US6521448B1 (en) * 1997-08-19 2003-02-18 Diacrin, Inc. Porcine MHC class I genes and uses thereof

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CASARES ET AL.: "Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc chimera leading to T helper cell type 2 differentiation", THE JOURNAL OF EXPERIMENTAL MEDICINE, vol. 190, no. 4, 16 August 1999 (1999-08-16), pages 543 - 553, XP008040180 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019006330A1 (fr) * 2017-06-30 2019-01-03 Indiana University Research And Technology Corporation Compositions et procédés de détection de la réactivité à des sla

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