T CELL-INDUCING VACCINE CONTAINING INTEREPITOPE SEQUENCE PROMOTING ANTIGEN PRESENTATION
|Posted date||Jul 13, 2015|
|International application number||2014JP076286|
|International publication number||WO 2015050158|
|Date of international filing||Oct 1, 2014|
|Date of international publication||Apr 9, 2015|
|Title||T CELL-INDUCING VACCINE CONTAINING INTEREPITOPE SEQUENCE PROMOTING ANTIGEN PRESENTATION|
|Abstract||The purpose of the present invention is to provide an interepitope sequence that effectively induces antigen presentation of each epitope in a long-chain peptide antigen having a plurality of epitopes. For this purpose, provided is a vaccine comprising a long-chain peptide antigen having a plurality of epitopes, said vaccine being characterized in that a sequence between the individual epitopes is one sequence selected from the group consisting of 2-10 consecutive tyrosine residues, 2-10 consecutive threonine residues, 2-10 consecutive alanine residues, 2-10 consecutive histidine residues, 2-10 consecutive glutamine residues and 2-10 consecutive asparagine residues. It is preferred that this vaccine is a vaccine selected from the group consisting of an anticancer vaccine, an antibacterial vaccine and an antiviral vaccine. It is also preferred that this vaccine is at least one vaccine selected from the group consisting of a peptide vaccine, a DNA vaccine, an mRNA vaccine and a dendritic cell vaccine.|
|Outline of related art and contending technology||
As a result of study for many years involved in the immune response against the cancer, cancer of the host immune cells in tumor rejection revealed the importance of. Impaired renal function with respect to a CD8 high degree of kidney CD8 failure, not a particularly effective drug therapy, the patient such that the renal failure, has been done and painful artificial dialysis CD4, CD8 artificial dialysis in the year @num@ the number of patients were reported to be @num@ million to break through ., such as CD80 or CD86 co-stimulatory molecules and cytokines to activate cells via T demonstrated, as described below, responsible for cell-mediated immune response against tumors or the positioning of the role of each cell (non-patent document 1) has been established.
Is a protein derived from the tumor cells, after the phagocytosis of the antigen presenting cell, and a protease proteasome in a cell, and a variety of peptidase cleaved into long peptide. The resulting peptides, 8-10 amino acid peptide major histocompatibility complex class I molecule (major histocompatibility complex, MHC) mounted as antigen epitope peptides, may be presented in the surface of antigen presenting cells. CD8+ Killer T cells, T cell receptor antigen MHC class I/(T cell receptor, TCR) may be utilized to specifically recognize peptide complex and activation. CD8 Activated+ killer T cells, tumor cells that are present on MHC class I/antigen peptide and detecting the complex, including perforin and granzymes using effector molecule to the destruction of tumor cells. CD8+ T is sufficient activation of killer cells, CD4+ important function of the helper T cells (non-patent document 2). Antigen presenting cell antigen incorporated into a protein within cells by peptidase protease cut into various lengths, of which 15-20 MHC class II antigenic peptide of amino acids forming a complex with the molecule on an antigen presenting cell may be presented in. CD4+ Helper T cells that specifically recognize and activation. CD4 Activated+ helper T cells, interferon (interferon, IFN) - γ or interleukin -2 (interleukin, IL) through the secretion of cytokines such as, CD8+ killer T cell differentiation and proliferation, enhances its ability. CD4 Also+ helper T cells, antigen presenting cells via path CD40 ligand/CD40 also serves to activate has, CD4+ helper T cells is activated by the antigen presenting cells with a CD8+ killer T cell stimulatory ability is enhanced (non-patent document 3). CD4+ B cells include helper T cells enhance antibody production of antigen-specific IgG also have an effect well known in the past.
Based on the understanding of one or more T-cell immune response, tumor-specific antigen administered repeat vaccine antigen, tumor-specific CD8+ killer T cells in a patient and to induce cancer growth and metastasis, a cancer vaccine therapy recurrence has been proposed. A synthetic peptide with an antigen of a cancer vaccine or recombinant protein, various ones such as processed cells known. The inventors have found that in the past, tumor antigen protein of the recombinant full length protein antigen is a cancer vaccine was produced. Is the full-length protein, CD8+ killer T cells and CD4+ recognition by helper T are included in the variety of antigenic peptides, both T cells and activated simultaneously expected. However, exogenous (extracellular) class II MHC of the antigen protein in CD4 via the second path+ helper T cell activation is likely to progress, CD8 via the second class I MHC+ killer T cell activation is hard to progress. This antigen-presenting cells and uptake of exogenous antigen protein in the antigen processing mechanism (non-patent document 4) due to the reason on. Therefore in abroad, short-chain peptide, CD8 primarily+ killer T epitope recognition by 8-10 residues chemically synthesizing, this vaccine antigen is an attempt has been made many clinical application. Short-chain peptides for incorporation within the antigen may be displayed on the cell surface of antigen processing and MHC molecule without passing through the direct coupling, presentation to T cells is likely to occur. In addition, short-chain peptides can be prepared by chemical synthesis, and genetically modified organism needs to be used as compared to the manufacture of the recombinant protein has the advantage that it may be convenient.
However, short peptide antigens uptake into an antigen presenting cell antigen processing and not through, the cell surface directly into the molecule for binding to MHC, immunological problems pointed out (non-patent document 5). In exogenous antigen protein, co-stimulatory molecules (CD80, CD86 or the like) or dendritic cells with a professional antigen presenting cells such as macrophages and phagocytosed, processed within the cell, in a manner suitable strength T cell co-stimulation with antigen presented. On the other hand, short peptide antigens can couple directly into the molecule on the cell surface MHC, uptake of antigen does not have the ability to co-stimulatory molecules (phagocytosis ability) to be expressed in the somatic cells of being not large quantities and short-chain peptides lacking co-stimulatory antigen may be presented in an improper manner. In this case, a short chain peptide antigen T cells that recognize complexes of MHC from consumption tends to cause cell death, as a result a target antigen can lead to immune tolerance. Such short-chain peptide vaccine of the foregoing problems, the usefulness of the long-chain synthetic peptide antigen has attracted attention (non-patent document 5). Length of peptide antigens can, at least two T cell recognition of epitope peptides no less than several hundreds of residues of the polypeptide. Unlike the length of the short-chain peptides peptide antigens can, as it is directly into the molecule which can bind to MHC. Long-chain peptide antigen in the same manner as in the protein antigen, such as macrophages and dendritic cells to phagocytize a professional antigen presenting cells captured, processed in cells by performing a, long-chain peptide antigen for the first time T cell epitope peptides is included in the molecule forming a complex with the MHC, co-stimulatory T with appropriate to the cell concentration in a manner presented. Their ability to phagocytose antigens generally lacking a bodily cell of a long chain peptide antigens for does not function as a vaccine antigen, unlike the short-chain peptide vaccine antigen presenting an improper T cells does not occur. In addition, in the manufacture of the long chain peptide antigen can be used for chemical synthesis methods, short peptide antigens in the same manner as also has the advantage that it is relatively easy to manufacture.
Long-chain peptide antigens produced by chemical synthesis, be freely designed sequence may be a great advantage. 2 Long-chain peptide antigens of one or more T-cell epitopes so as to include a single designed peptide, their T-cell epitopes can be derived from a single cancer antigen protein, may be derived from a plurality of cancer antigen protein. Also, their T-cell epitope is constrained and may be a single MHC, may be restricted to a plurality of MHC. CD8+ CD4 Killer T cells recognize an epitope+ epitope recognition by helper T, long-chain peptide antigen at the same time can also be designed such that it contains. Length of peptide antigens can, in this way a variety of vaccine antigens can induce T cells capable of functioning as a high-performance. However, a series of long-chain peptide antigen epitope T cells included in the presented order efficiently, the basis of the mechanism of antigen-presenting reaction, antigen-presenting cells in the proteasome and a protease, peptidase by long-chain peptide sequence between each epitope determinant on the antigen appropriately cut, length and sequence of the MHC epitope peptides capable of binding to the molecule to be extracted as necessary. CD4+ MHC class II recognition by helper T for binding peptides, the class II MHC binding epitope on the molecule and either the end into the open state, for various lengths of epitope peptides capable of binding to MHC class II molecule is (non-patent document 6). Therefore, the class II MHC binding peptides with a length limitation is relatively gentle. On the other hand, CD8+ killer T recognition by class I MHC binding peptides is, class I MHC epitope on the molecule and the binding groove end to a closed state, and residues 8-10 of the length strictly limited epitope peptides capable of binding to MHC class I molecule only. Therefore, in particular MHC class I-binding peptides that is, an appropriate length of the peptide antigen-presenting cells produced in the formed film tends to be.
The length of the epitope binding to MHC and sequence, various proteases and the proteasome in a cell, a complex involved in the peptidase cleavage reaction determined. MHC class I-binding epitope peptides in the production of, a proteasome initially present in the cytoplasm of the antigen protein or a long chain peptide antigens in the rough. The resulting peptide fragment is the distal end of the other protease or peptidase, based on the sequence specificity constant substrate cut, until the appropriate length cutting (trimming reaction). N-terminus of the peptide fragments in the trim in the course of the enzyme group is present, the trim end C enzyme is not known, C MHC class I-binding epitope peptides of the first end of the determination of the proteasome are based only on the cleavage reaction (non-patent document 7). However, proteasome substrate sequence specificity is not clarified in detail, to the more-proteasome peptide sequence it is difficult to predict. One or more epitopes of ordinary skill in production mechanism, long-chain peptide antigen sequence between the epitope contained within the cells of the proteasome and a protease, is cleaved by peptidase is how, before and after the epitope peptides thereby largely influencing the production of, as a result, long-chain peptide vaccine antigens defining T cell derivation is considered to be a very important factors.
|Scope of claims||
(In Japanese)請求の範囲 [請求項1]
|IPC(International Patent Classification)||
National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
Contact Information for " T CELL-INDUCING VACCINE CONTAINING INTEREPITOPE SEQUENCE PROMOTING ANTIGEN PRESENTATION "
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