JP7301391B2 - 熱ショックタンパク質のエピトープを含むワクチン及びこの用途 - Google Patents
熱ショックタンパク質のエピトープを含むワクチン及びこの用途 Download PDFInfo
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Description
熱ショックタンパク質90において、人間で最もよくあるMHC class II対立形質(allele)に結合親和性が良いと予想される15-merペプチドシーケンスを選定するために、SYFPEITHI(Institute for Cell Biology、Heidelberg、Germany)、ProPred(Institute of Microbial Technology、Chandigarh、India)、MHC-Thread(University of Aberdeen、AFPberdeen、United Kingdom)、Average Binding matrix method、Rankpep(Harvard、Boston、MA、USA)のコンピュータアルゴリズムを用いた(図1)。
マウスモデルにおいて、Hsp90多重ペプチドワクチンの免疫原性を確認するために、FVBマウス(6~8週齢)を、各群のあたり、5匹ずつ、生理食塩水(PBS)と免疫補助剤(CFA/IFA)群、又はHsp90ペプチドと免疫補助剤の群に分け、10日毎に3回ずつ、マウスなどに皮下注射で投与し、最後の投与から10日後、マウスの脾臓を摘出して脾細胞を分離し、インターフェロンガンマ(IFNγ)-固着化酵素抗体法(Eezyme Linked Immuno-SPOT assay、ELISPOT)を用いて、Hsp90多重ペプチド特異T細胞反応を観察した。
ウェルA1-A6(No Antigen)=100uL cells + 100uL Mouse T-cell Media
ウェルA7-A12(Nonspecific peptide)=100uL cells + 100uL 2X HIV p17
ウェルB1-B6(Positive Control)=100uL cells + 100uL 2X Conclavin A
ウェルB7-B12(Vaccine Peptide)=100uL cells + 100uL 2X Peptide
(Continuing for each mouse or pool of cells)
ペプチドの濃度を、mouse T cell mediaで2倍とした後、ウェルあたり、100ulずつ分周できるようにし、n+1個に作った(表4)。
抗腫瘍効果を確認するために、マウス乳房癌細胞株(mouse mamary cancer cell-FVB/N-Tg(MMTVneu)-202Mulマウス由来HER-2過発現乳房癌細胞株)を用いた。MMTVneu形質転換マウス雌6週齢を、各群あたり10匹ずつ、生理食塩水/免疫補助剤群と、HSP90ペプチド/免疫補助剤群とに分け、10日毎に3回ずつ皮下注射を投与し、最後の投与から10日後に、マウス乳房癌細胞株をマウスの脇に皮下注射して接種し、腫瘍の成長を3~4日間隔で観察し、腫瘍のサイズを測定して、HSP90多重ペプチドワクチンの抗腫瘍効果を確認した。実験方法は、実施例2と同様である。
4.1 腫瘍形成及び抗腫瘍測定
6週齢の雌MMTVneu形質転換マウスの脇へマウス由来の乳房癌細胞5×105個を皮下注射した。10日後、1つの対照群(PBS+免疫補助剤; Complete Freund’s Adjuvant、Incomplete Freund’s Adjuvant)、4つの実験群として、1群のHSP90多重ペプチドワクチン群(HSP90ワクチン+ 免疫補助剤)、2群(HSP90ワクチン+CTLA-4阻害剤; HSP90ワクチン+CTLA-4阻害剤+免疫補助剤)、3群(STINGアゴニスト+CTLA-4阻害剤; STINGアゴニスト+CTLA-4阻害剤+免疫補助剤)、4群(HSP90ワクチン+STINGアゴニスト+CTLA-4阻害剤)を、10日間隔で注射した。HSP90ワクチン及びSTINGアゴニスト(DMXAA、5,6-dimethylxanthenone-4-acetic acid、Invivogen製)は、3回、皮下注射及び腹腔注射し、anti-mouse CTLA-4(CD152, Bioxcell製)は、週2回ずつ、実験が終わるまで、腹腔注射を行った。実験期間中、腫瘍の成長を3~4日間隔で測定した。最後の投与の10日後、マウスの脾臓を摘出して、脾細胞を分離し、インターフェロンガンマ(IFNγ)-固着化酵素抗体法(EezymeLinked Immuno-SPOT assay、ELISPOT)を用いて、HSP90多重ペプチドの特異のT細胞反応を確認した。マウス脾細胞の準備及び凍結、ELISPOT実験方法は、実施例2と同様に行った。
HSP90多重ペプチドワクチン効果の生物学的標識者として、血中HER2 ECD(Human Epidermal growth factor Receptor type2 ExtraCellular Domain)における変化を、酵素免疫測定法(EezymeLinked Immunosorbent assay、ELISA)により分析した。具体的な分析方法は、以下の通りである。
a. 炭酸塩緩衝液 : 1リットルのビーカーに、0.8gのNa2CO3と1.47gのNAHCO3を入れ、1次蒸溜水の400mlを入れて溶解させた後、pH9.6に調整し、1次蒸溜水を500mlまで満たす。フィルタリング後、4℃で保管した。
下記のステップを経て、ELISA実験を行った。ステップ1及びステップ2は、氷条件で行った。
実験の結果、マウスモデルにおいて、対照群、1群(HSP90多重ペプチドワクチン群)、2群(HPS90多重ペプチドワクチン+CTLA-4阻害剤)、及び3群(STINGアゴニスト+CTLA-4阻害剤)と比較して、4群(HSP90多重ペプチドワクチン+STINGアゴニスト+CTLA-4阻害剤)は、併合治療する場合、腫瘍のサイズが顕著に減少することを確認した(図4a)。また、対照群に比べて、全ての実験群において、HER2-ECD反応性が減少することを確認した(図4b)。HSP90ペプチド反応は、4群(HSP90多重ペプチドワクチン+STINGアゴニスト+CTLA-4阻害剤)において、インターフェロンガンマ(IFN-γ)の分泌により、更なる特異反応性を現わしている(図4c)。これにより、本発明のHSP90ペプチドワクチンを、STINGアゴニスト/CTLA-4阻害剤と併合治療することで、HSP90ペプチドワクチンの効果が増加又は減少するので、HSP90ペプチドをワクチンとして使用可能であることが分かる。
Claims (8)
- 配列番号1のアミノ酸配列で表示されるエピトープ及び配列番号2のアミノ酸配列で表示されるエピトープを含むことを特徴とする多重ペプチドワクチン。
- 配列番号1のアミノ酸配列で表示されるエピトープをエンコードする核酸及び配列番号2のアミノ酸配列で表示されるエピトープをエンコードする核酸を含む多重ペプチドワクチン遺伝子から製造された組み換え多重エピトープタンパク質を含むことを特徴とする請求項1に記載の多重ペプチドワクチン。
- 配列番号1のアミノ酸配列で表示されるエピトープをエンコードする核酸及び配列番号2のアミノ酸配列で表示されるエピトープをエンコードする核酸を含むことを特徴とする多重ペプチドワクチン遺伝子。
- 配列番号1のアミノ酸配列で表示されるエピトープをエンコードする核酸は、配列番号3の塩基配列で表示され、及び、配列番号2のアミノ酸配列で表示されるエピトープをエンコードする核酸は、配列番号4の塩基配列で表示されることを特徴とする請求項3に記載の多重ペプチドワクチン遺伝子。
- (1) 配列番号1のアミノ酸配列で表示されるエピトープ及び配列番号2のアミノ酸配列で表示されるエピトープを含む多重ペプチドワクチン、又は、
(2) 配列番号1のアミノ酸配列で表示されるエピトープをエンコードする核酸及び配列番号2のアミノ酸配列で表示されるエピトープをエンコードする核酸を含む多重ペプチドワクチン遺伝子と、
免疫補助剤とを含むことを特徴とするワクチン組成物。 - (1) 配列番号1のアミノ酸配列で表示されるエピトープ及び配列番号2のアミノ酸配列で表示されるエピトープを含む多重ペプチドワクチン、又は、
(2) 配列番号1のアミノ酸配列で表示されるエピトープをエンコードする核酸及び配列番号2のアミノ酸配列で表示されるエピトープをエンコードする核酸を含む多重ペプチドワクチン遺伝子を含むことを特徴とする癌予防又は治療用組成物。 - CTLA-4(cytotoxic T-lymphocyte-associated protein 4)、PD-1(Programmed cell death protein 1)、LAG-3(Lymphocyte Activation Gene-3)、TIM-3(T-cell Immunoglobulin and Mucin-domain containing-3)、TIGIT(T-cell Immunoreptor with IG and ITIM domain)、及びVISTA(V-domain Ig Suppressor of T cell Activation)からなる群より選ばれた免疫チェックポイント阻害剤を含むことを特徴とする請求項6に記載の癌予防又は治療用組成物。
- 更に、STINGアゴニストを含むことを特徴とする請求項6に記載の癌予防又は治療用組成物。
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