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  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• • 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
  • A61K39/0005—Vertebrate antigens
  • A61K39/0011—Cancer antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/10—Cellular immunotherapy characterised by the cell type used
  • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
  • A61K40/32—T-cell receptors [TCR]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
  • A61K40/41—Vertebrate antigens
  • A61K40/42—Cancer antigens
  • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
  • A61K40/4203—Receptors for growth factors
  • A61K40/4205—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4
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  • 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
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
• • 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
  • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
  • C12N5/06—Animal cells or tissues; Human cells or tissues
  • C12N5/0602—Vertebrate cells
  • C12N5/0634—Cells from the blood or the immune system
  • C12N5/0636—T lymphocytes
• • 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
  • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
  • C12N5/06—Animal cells or tissues; Human cells or tissues
  • C12N5/0602—Vertebrate cells
  • C12N5/0634—Cells from the blood or the immune system
  • C12N5/0639—Dendritic cells, e.g. Langherhans cells in the epidermis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
  • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
  • C07K2317/622—Single chain antibody (scFv)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
  • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor

Definitions

• the luminal domain of TAPBPR retains its ability to function as a MHC class I peptide-exchange catalyst when presented to mammalian cells either as a soluble extracellular protein or as a membrane bound cell surface protein.
• Soluble or cell surface peptide exchange catalysts may be useful in a range of therapeutic applications in the modulation of immune responses, including for example loading immunogenic peptide onto tumours or other disease cells to induce their recognition by T cells.
• a first aspect of the invention provides a peptide-exchange protein comprising a fragment of TAP-binding protein-related (TAPBPR), said fragment consisting of the TAPBPR luminal domain.
• TAPBPR TAP-binding protein-related
• a seventh aspect provides an in vitro, ex vivo, or in vivo method of increasing the immunogenicity of mammalian cells comprising;
• the target cells may be disease cells, such as cancer cells or cells infected with a pathogen.
• a ninth aspect provides a method of stimulating or promoting an immune response in an individual comprising;
• ETVSK*QSNV or its nonbinding variant EGVSK*QSNG (in which the anchor residues are mutated) then analysed using flow cytometry.
• TAPBPR targeted to the plasma membrane (PM), but not the endoplasmic reticulum (ER), is detectable on the surface of cells and associates with MHC class I there
• CD172a+ dendritic cells include CD172a and BDCA1 (also known as CD1 c).
• Plasmacytoid DCs produce of type I interferon (IFN) during viral infections.
• Surface markers on plasmacytoid DCs include BDCA2 and BDCA4.
• Monocyte-derived DCs promote local T cell responses and enhance inflammation and chemokine production.
• Surface markers on monocyte-derived DCs include Fc RI and FcyRI expression is upregulated on activation. Macrophages eliminate pathogens and promote tissue homeostasis.
• Surface markers on macrophages include CD68. Expression of FcyRI is also upregulated on activation.
• Other suitable markers for dendritic cells include CD19, CD20, CD38, CD14 and/or Langerin/CD207.
• Peptide exchange proteins as described herein may be provided using synthetic or recombinant techniques which are standard in the art.
• the peptide exchange protein described herein may be produced with an affinity tag, which may, for example, be useful for purification.
• An affinity tag is a heterologous peptide sequence which forms one member of a specific binding pair. Polypeptides containing the tag may be purified by the binding of the other member of the specific binding pair to the polypeptide, for example in an affinity column.
• the tag sequence may form an epitope which is bound by an antibody molecule.
• an exogenous peptide as described herein may be immunogenic or non- immunogenic, depending on the application.
• the immunogenicity of the exogenous peptide may be the same as the immunogenicity of one or more endogenous peptides displayed in the MHO class I molecules.
• the exogenous peptide may have the same amino acid sequence as one or more endogenous peptides. Loading of MHO class I molecules with the exogenous peptide as described here may increase the total amount of peptide with the amino acid sequence that is displayed on the cells and may thereby increase or reduce the immunogenicity of the cells.
• the immunogenic peptide may comprise an antigen or an epitope that is characteristic of a disease cell.
• the immunogenic peptide may comprise an antigen or an epitope that is characteristic of a cancer cell or a pathogen-infected cell.
• the expressed polypeptide comprising or consisting of the peptide exchange protein may be isolated and/or purified, after production. This may be achieved using any convenient method known in the art. Techniques for the purification of recombinant polypeptides are well known in the art and include, for example HPLC, FPLC or affinity chromatography. In some embodiments, purification may be performed using an affinity tag on the polypeptide as described above.
• the mammalian cells may be antigen presenting cells (APCs), such as dendritic cells.
• APCs antigen presenting cells
• the loading of the surface MHC class I molecules with immunogenic exogenous peptides may increase the ability of the APCs to induce immune responses, for example immune responses against the antigenic epitopes contained in the immunogenic peptide.
• APCs loaded with immunogenic peptide as described above may be used to stimulate T cells in vitro or ex vivo or administered to an individual to stimulate T cells in vivo.
• a method of producing antigen presenting cells for generating or increasing an immune response in an individual may comprise;
• an immunogenic peptide to the individual, such that the peptide exchange protein loads the immunogenic peptide onto surface MHC class I molecules of the cancer cells of the individual, thereby eliciting or increasing an immune response in the individual against the cancer cells.
• the target cells are pathogen-infected cells.
• this may be useful in treating pathogen infections in which a peptide vaccine is currently used to induce CD8+ T cells responses, such as infections of HIV, EBV, CMV, hepatitis viruses, influenza, polio, human papilloma virus, measles, mumps, rubella, chicken pox, ebola, or zika; or cancer, for example by boosting the number of T cells capable of recognising a particular antigen.
• pathogen infections such as infections of HIV, EBV, CMV, hepatitis viruses, influenza, polio, human papilloma virus, measles, mumps, rubella, chicken pox, ebola, or zika
• cancer for example by boosting the number of T cells capable of recognising a particular antigen.
• MHC class I associated diseases may include the spondyloarthropathies (associated with HLA-B27), Behcet’s disease (associated with HLA-B51 ), Birdshot Chorioretinopathy (associated with HLA-A29) psoriasis and psoriatic arthritis (associated with HLA-Cw6).
• MHC class I molecules may be immobilised on the solid support by any convenient technique.
• the MHC class I molecules may be biotinylated and may be bound to the support through a biotin/streptavidin interaction.
• the MHC class I molecules displaying the target peptide may be contacted with a population of T cells, for example a population of T cells previously obtained from an individual.
• the binding of the MHC class I molecules to T cells in the population may be determined. Binding may be determined by any convenient technique, such as flow cytometry.
• the frequency or number of T cells within the population that bind to the MHC class I molecules displaying the target molecule may be determined. This may be useful in research or for diagnostic or prognostic applications.
• TAPBPRTM endoplasmic reticulum 12
• TAPBPR ER endoplasmic reticulum 12
• TAPBPR ER tapasin 13
• Figure 2a Immunoprecipitation of the surface pool of TAPBPR indicated that MHC class I was associated with surface expressed TAPBPR on TAPBPR WT and TAPBPRTM transduced cells but not from those transduced with TAPBPRTM 5 , a mutated TAPBPR variant which does not bind to MHC class I 15 ( Figure 2b).
• Figure 2b As the amount of surface TAPBPR isolated ( Figure 2b) closely correlated with surface TAPBPR expression observed using flow cytometry ( Figure 2a) with barely detectable quantities isolated from cells expressing TAPBPR ER , and
• SEQ ID NO: 16 sTAPBPR-LONG-PD-L1-NB4 (mature TAPBPR domain underlined) atgggcacacaggagggctggtgcctgctgctgcctggctctatctggagcagcagaaaccaagccccacccagc agaggggcagtggcgggcagtggacgtggtcctagactgtttcctggtgaaggacggtgcgcaccgtggagctctcg ccagcagtgaggacagggcctcccttgtgctgaagcaggtgccagtgctggacgatggctccctggaggac ttcaccgatttccaagggggcacactggcccaagatgacccacctattatctttgaggcctcagtggacctggtggtggtgg

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