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VACCINE PREPARATION FOR CANCER TREATMENT meetings

Foreign code F130007224
File No. S2011-1174-N0
Posted date Mar 22, 2013
Country WIPO
International application number 2012JP071979
International publication number WO 2013031882
Date of international filing Aug 30, 2012
Date of international publication Mar 7, 2013
Priority data
  • P2011-189234 (Aug 31, 2011) JP
Title VACCINE PREPARATION FOR CANCER TREATMENT meetings
Abstract [Problem] To provide a method of clearly deriving killer T cells and helper T cells in a cancer treatment vaccine in which the vaccine antibody is a synthetic long peptide which is derived from a tumor-specific antigen protein and/or pathogen-derived protein and which simultaneously contains a CD8-positive, cytotoxic T-cell recognizing epitope and a CD4-positive, helper T-cell recognizing epitope peptide.
[Solution] By simultaneously dosing an immunopotentiating agent with a conjugate of a hydrophobized polysaccharide (the antigen delivery system) to the synthetic long peptide, it is possible to achieve clear derivation of antigen-specific killer T-cells and helper T-cells from the cancer treatment vaccine in which the synthetic long peptide is the antigen.
Outline of related art and contending technology BACKGROUND ART
As a result of study for many years involved in the immune response against the cancer, cancer of the host tumor rejection in the importance of cell-mediated immunity was found. In particular, CD8 positive cells (hereinafter referred to as killer T cells) cytotoxic T cells directly destroy the tumor can have the effect of effector cells, CD4 - positive helper T cells (helper T cells or less) is a killer T cells and antigen presenting cells to enhance the function of cells and are key regulators, centered on the dendritic cells as well as antigen presenting cells presenting the antigen to stimulate T cells with, various 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.
A protein derived from tumor cells as an antigen or vaccine is the administered protein, such as dendritic cells after antigen presentation was incorporated into the cells, and a variety of proteases within the cell long peptide cleaved into. The resulting peptides, 8-10 amino acid peptide major histocompatibility complex class I antigen molecules (major histocompatibility complex, MHC) mounted as epitope peptides, may be presented at the cell surface. Killer T cells, T-cell receptor (T cell receptor, TCR) antigen using MHC class I/peptide complexes in specifically recognize activated. 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.
Killer T cells so as to be sufficiently activated, helper T cells is very important in the function of the (non-patent document 2). Antigen presenting cells such as dendritic cells protein is an intracellular antigen incorporated into a variety of proteases of the cut into a length, of which 15-20 MHC class II antigenic peptide of amino acids forming a complex with the molecule presented on antigen presenting cells. Helper T cells that specifically recognize and activation. Activated helper T cells, interferon (interferon, IFN) - γ or interleukin -2 (interleukin, IL) through the secretion of cytokines such as, killer T cell proliferation and survival, enhances its ability. The helper T cells, ligand CD40 via the path/CD40 also serves to have activated dendritic cells, helper T cells activated by dendritic cells is a killer T cell stimulatory ability is enhanced (non-patent document 3). Helper T cells of antigen-specific IgG B cells also have an effect that enhance antibody production is well known in the past.
In this way killer T cell is a dendritic cell by antigen presenting cells such as antigen-specific activated, helper T cells and killer T cells of dendritic cells important to further enhance the function of both behave as an enhancer. This 3 type of immune cells, effective operation of the cell-mediated immunity against tumors on both the absence of an essential. The inventors have found that, only those cells that stimulate killer T helper T cell vaccine is not activated, killer T cells induced only poor, do not exhibit the effect reported treatment (non-patent document 4) and, in the development of therapeutic cancer vaccines these 3 type of immune cell activation and how effectively function so as to provide a, is an important issue.
The inventors have found that in the past, the simultaneous activation of killer T cells and helper T cells in inter-, recombinant antigenic protein of a tumor antigen is a full-length protein valency therapeutic cancer vaccines was produced. Is full-length protein, killer T cells and helper T cells recognized by each of the various antigen peptide is included, the simultaneous activation of both T cells is expected. However, exogenous (extracellular) class II MHC antigenic protein is via the second path tends to be helper T cell activation is, via the second class I MHC killer T cell activation is hard to progress. This antigen-presenting cells in the processing of exogenous antigen on the uptake of proteins due to the reason and mechanism (non-patent document 5).
Therefore in abroad, short-chain peptides, mainly killer T epitope recognition by 8-10 residues chemically synthesizing, many clinical application as a vaccine attempts have been made. Short-chain peptides uptake into antigen-presenting cells without passing through and processing, the direct coupling MHC molecules on the cell surface, is likely to occur in the presentation to T cells. In addition, recombinant full length protein is produced using E. coli or mammalian cells such as necessary to purify and, manufacturing and quality control system in a large amount of time and labor intensive. On the other hand, short-chain peptides can be prepared by chemical synthesis, as compared to the manufacture of the recombinant protein has the advantage that it may be convenient.
However, a short chain peptide therapeutic cancer vaccines has several important problems have been noted. Short-chain peptide vaccines for many of the killer T cell recognition of epitope peptides from include only, without activation of helper T cells and vaccine unit price, induced cell-mediated immunity is insufficient therapeutic effect and the quality (non-patent document 4). Killer T cells and helper T cells recognized epitopes each short chain as a synthetic peptide, a vaccine comprised of a mixture of thereof, killer T cells and helper T cells by the simultaneous activation of the cells in the induction of good quality killer T is a possibility that the therapeutic effect is obtained. However, in this case, killer T cells and helper T cell recognition of epitope peptides is administered as a separate component, each of the separate dendritic cells presenting the peptide and the, killer T cells and helper T cells does not lead to a high possibility that the interaction of (non-patent document 3).
In addition, short-chain peptides uptake into antigen presenting and processing without passing through, the cell surface directly into the molecule for binding to MHC is also a problem pointed out (non-patent document 6). That is, the exogenous antigenic protein is, as macrophages or dendritic cells with a co-stimulatory molecules phagocytosed and professional antigen presenting cells, processed within the cell, in a manner suitable strength T cell co-stimulation with antigen are presented, such short-chain peptides include MHC molecules on the cell surface without passing through the course for directly coupling to, antigen uptake capacity (phagocytosis ability) also leads to antigen processing capabilities and does not express co-stimulatory molecules of the peptide of interest is generally large quantities and body cells that may be presented in an improper manner and, there is a possibility that immune tolerance.
A vaccine comprising the such short-chain peptides of the foregoing problems, in recent years, the simultaneous activation of killer T cells and helper T cells and full-length protein can be, manufacturing is easy and inexpensive short-chain peptides having the merits of each of the long chain of the usefulness of the synthetic peptides (long peptide) has been proposed (non-patent document 6). Is long peptide, and helper T cells generally killer T cell recognition epitope such as several tens of residues including at least one each of the polypeptide. Antigen-presenting cells that have incorporated the long peptide and helper T cells by the simultaneous activation of killer T cells is expected. In addition, a vaccine antigen is long peptide can be used for chemical synthesis methods, as well as short-chain peptides has an advantage that is relatively easy to manufacture.
Unlike further long peptide is a short chain peptide, as it is directly into the molecule which can bind to MHC. Incorporated in the long peptide is a dendritic cell or the like obtained by performing the processing of cells, and helper T cells included in the long peptide killer T cell recognition of epitope peptides MHC molecule form a complex, in a manner appropriate to the cell concentration T presented. In addition, the ability of the uptake of antigen processing in somatic cells lack the ability to generally does not function as a vaccine antigen for long peptide, antigen-presentation to inappropriate T cells does not occur.
From the above, synthetic long peptide vaccines for cancer treatment is a vaccine antigen, killer T cells and helper T cells are capable of the simultaneous activation of the other hand, the relatively inexpensive excellent cancer therapeutic agents can be produced which can be expected. However, the synthetic long peptide vaccine antigen in vaccines for cancer treatment, in and of itself be sufficient when administered at T cell activation is not obtained, for maximizing the effectiveness of the vaccine is a dendritic cell antigen presenting cells such as required for efficient activation.
In order to further increase the immunogenicity of the vaccines, immune enhancing agent (adjuvant) conventionally used. A variety of substances derived from bacteria and virus, such as a nucleic acid (DNA or RNA), protein, lipopolysaccharide and the like have been used as immune enhancing agent, recent studies have, these materials are required for the activation of dendritic cells within the cell and the cell surface Toll-like receptors, and co-stimulatory molecules (CD80 or CD86) elevated expression of MHC molecules, such as interferon and cytokine production via T cells is possible to significantly enhance the stimulatory activity has been elucidated. Toll-like receptor agonist for the other than, the chemotherapeutic agent is a taxane family compounds such as the effect of activating dendritic cells (non-patent document 7) or that is, to obtain dendritic cells from the immunosuppressive activity of the function of preventing signal transduction inhibitors that are also used to enhance vaccine efficacy has been reported to be effective (non-patent document 8), such materials also can be used as a possibility that the immune enhancing agent.
In addition, the inventors have found that, in antigen presenting cells such as dendritic cells exogenous antigen class I MHC protein killer T cell activation via the second path (referred to as cross priming or cross-presentation) of the delivery system to facilitate the research for a vaccine antigen, the function of the hydrophobic polysaccharide found (patent document 1). For example, a full-length protein tumor antigen protein HER2 is one type of hydrophobic polysaccharide (cholesteryl pullulan, abbreviated as CHP) or cholesteryl mannan (cholesteryl mannan, abbreviated as CHM) and complexed to vaccine formulations can be accomplished, in human dendritic cells in vitro when administered to a helper T cells as well as killer T cells efficiently activated, when administered to further mice model mouse is unsuccessful, the full-length protein was administered at HER2 compared with the case where a single, superior anti-tumor effect (non-patent document 9). Another similar results NY-ESO-1 tumor antigen protein in cases where a full-length protein has been reproduced (non-patent document 10). However, the low molecular weight highly useful in the long peptide was unknown. In addition, the size of the vaccine antigen delivery system is directly connected to the performance of the vaccine and the surface charge become apparent that is important. The current, widely used in the vaccine antigen in a liposome delivery system, that the larger the size, or the more positively charged, with vaccines that induce T cell activation and antibody production has been a report that is improved (non-patent document 14-16). However vaccine antigen delivery systems include the hydrophobic polysaccharide, such conditions was unknown.
Scope of claims (In Japanese)請求の範囲 [請求項1]
腫瘍特異的抗原タンパク質及び/又は病原体由来抗原タンパク質に由来しCD8陽性細胞傷害性T細胞認識エピトープ及びCD4陽性ヘルパーT細胞認識エピトープを同時に含む1種類以上の合成ロングペプチドと疎水化多糖類との複合体を含む薬剤と、1種類以上の免疫増強剤によって構成されるがん治療用ワクチン製剤。

[請求項2]
前記の合成ロングペプチドがT細胞認識エピトープを少なくとも2つ以上含む23~120アミノ酸から成るポリペプチドであることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項3]
前記合成のロングペプチドは、全アミノ酸配列のうち22個以下の連続するアミノ酸配列を用いた場合には、CD8陽性細胞傷害性T細胞に免疫寛容、消耗、機能不全を生じ得ることを特徴とする請求項2に記載のがん治療用ワクチン製剤。

[請求項4]
前記の合成ロングペプチドがT細胞認識エピトープを少なくとも2つ以上含む23~80アミノ酸から成るポリペプチドであることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項5]
前記の合成ロングペプチドがT細胞認識エピトープを少なくとも2つ以上含む23~40アミノ酸から成るポリペプチドであることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項6]
前記のCD8陽性細胞傷害性T細胞認識エピトープが、腫瘍特異的抗原タンパク質のアミノ酸配列の一部であることを特徴とする請求項1記載のがん治療用ワクチン製剤。

[請求項7]
前記のCD4陽性ヘルパーT細胞認識エピトープが、腫瘍特異的抗原タンパク質のアミノ酸配列の一部であることを特徴とする請求項1記載のがん治療用ワクチン製剤。

[請求項8]
前記の腫瘍特異的抗原タンパク質が、MAGEファミリー、NY-ESO-1、SPANXファミリー、HER2、WT1、hTERT、RHAMMまたはサバイビンから選ばれることを特徴とする請求項17記載のがん治療用ワクチン製剤。

[請求項9]
前記のCD8陽性ヘルパーT細胞認識エピトープが、病原体由来タンパク質のアミノ酸配列の一部であることを特徴とする請求項1記載のがん治療用ワクチン製剤。

[請求項10]
前記のCD4陽性ヘルパーT細胞認識エピトープが、病原体由来タンパク質のアミノ酸配列の一部であることを特徴とする請求項1記載のがん治療用ワクチン製剤。

[請求項11]
前記の病原体由来抗原タンパク質が、B型肝炎ウイルス、C型肝炎ウイルス、EBウイルス、ヒトパピローマウイルス、ヒトTリンパ向性ウイルス、ヒトヘルペスウイルス8型、ヒト免疫不全ウイルスから選ばれることを特徴とする請求項1記載のがん治療用ワクチン製剤。

[請求項12]
前記の疎水化多糖類の構成多糖類がプルランまたはマンナンであることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項13]
前記の疎水化多糖類の疎水基がコレステロールであることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項14]
前記の疎水化多糖類が非イオン性であることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項15]
前記の疎水化多糖類と合成ロングペプチドとの複合体化後の粒子径が180nm以下であることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項16]
前記の疎水化多糖類と合成ロングペプチドとの複合体化後の粒子径が100nm以下であることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項17]
前記の免疫増強剤が、Toll様受容体のアゴニストであることを特徴とする請求項16に記載のがん治療用ワクチン製剤。

[請求項18]
前記のToll様受容体のアゴニストが、ポリIC RNAまたはCpGオリゴDNAであることを特徴とする請求項17に記載のがん治療用ワクチン製剤。

[請求項19]
前記の免疫増強剤が、抗原提示細胞を活性化する化学療法剤であることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項20]
前記の抗原提示細胞を活性化する化学療法剤が、タキサン系化合物またはアントラサイクリン系化合物であることを特徴とする請求項19に記載のがん治療用ワクチン製剤。

[請求項21]
前記の免疫増強剤が、抗原提示細胞の免疫抑制活性獲得を防ぐ作用を有する薬剤であることを特徴とする請求項1に記載のがん治療用ワクチン製剤。

[請求項22]
前記の抗原提示細胞の免疫抑制活性獲得を防ぐ作用を有する薬剤がJAK/STATの阻害物質またはIDOの阻害物質である請求項21に記載のがん治療用ワクチン製剤。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • MIE UNIVERSITY
  • National University Corporation Tokyo Medical and Dental University
  • Inventor
  • SHIKU, Hiroshi
  • HARADA, Naozumi
  • MURAOKA, Daisuke
  • AKIYOSHI, Kazunari
IPC(International Patent Classification)
Specified countries 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 IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT QA RO RS RU RW 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 ML MR NE SN TD TG
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