JPWO2015002134A1 - 細胞性免疫誘導ワクチン - Google Patents
細胞性免疫誘導ワクチン Download PDFInfo
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- JPWO2015002134A1 JPWO2015002134A1 JP2015525203A JP2015525203A JPWO2015002134A1 JP WO2015002134 A1 JPWO2015002134 A1 JP WO2015002134A1 JP 2015525203 A JP2015525203 A JP 2015525203A JP 2015525203 A JP2015525203 A JP 2015525203A JP WO2015002134 A1 JPWO2015002134 A1 JP WO2015002134A1
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Abstract
Description
(1) 前記MHCクラスIエピトープ領域と、前記抗原タンパク質と同一又は異なる抗原タンパク質に由来するMHCクラスIIエピトープ領域と、少なくとも1つの高次構造安定化領域とが、単一の塩基配列の異なる読み枠でコードされるように塩基配列を設計した時に、該塩基配列が必然的にコードするアミノ酸配列として生じる配列。
(2) (1)のアミノ酸配列のうち数個のアミノ酸が置換した配列。
(1) 前記抗原タンパク質と同一又は異なる抗原タンパク質に由来するMHCクラスIIエピトープと、高次構造安定化領域とが、単一の塩基配列の異なる読み枠でコードされ、かつ、残りの読み枠で終止コドンが生じないように塩基配列を設計した時に、当該残りの読み枠で該塩基配列が必然的にコードするアミノ酸配列として生じる配列。
(2) (1)のアミノ酸配列のうち数個のアミノ酸が置換した配列。
天然抗原OVA(配列番号24)から、OVA-I:●(OVA MHCクラスIエピトープ, OVA258-265, SIINFEKL)とOVA-II:■(OVA MHCクラスIIエピトープ, OVA324-340, ISQAVHAAHAEINEAGR) を選択した(図1a)。
芝清隆らが開発したMolCraft法(K. Shiba, Journal of Molecular Catalysis B: Enzymatic 28 (2004) 145-153)を用い、OVAのMHCクラスI、クラスIIエピトープ、αヘリックスなどのタンパク質安定化配列、CyberGeneにより自動的に定められた配列などのペプチドモチーフ配列(表2)が組み合わせ的に結合した人工タンパク質遺伝子を合成した。#2101のMPR法(芝清隆ら、PNAS vol.94, pp.3805-3810, 1997)による人工タンパク質遺伝子の合成工程の概略を図2の6)〜9)に示す。
これらの人工タンパク質ライブラリーの中から、始めに8種類の人工タンパク質(図1c中に示したF138A, G142A, G142C, F182A, F58B, F58C, F112A, F112C)を選択し、in vitro抗原提示能アッセイを行った。人工タンパク質のアミノ酸配列を図3、4及び配列番号26〜43に示した。
4−1.F37A人工タンパク質は天然OVAよりも100倍強力に抗原提示する
次に、ライブラリーの中から、F182Aと似た構造を持つ人工タンパク質を含め、さらに8種類の人工タンパク質を選択し、in vitroで抗原提示能を評価した。10μg/mlの抗原濃度で、F182Aに加えて、F37A(配列番号44)とF36C(配列番号31)が抗原提示能を示した。抗原提示能を示したF182A、F37A、F36Cはいずれも共通の配列パターンを持っていた。即ち、●▽●▽●▽(▽は一部又は全部が(▽/▼)でもよい)の配列である。これは、LESIINFEKLTDFSGSSCSSCRDQRGWP(●▽、配列番号22)又はLESIINFEKLTDLRQFTCRDQRGWP(●(▽/▼)、配列番号53)の配列が3回タンデムに結合している構造である。以下、▽の一部又は全部が(▽/▼)であるものも含めて「●▽●▽●▽」と表現する。
抗原提示を示した人工タンパク質に共通の配列●▽●▽●▽が、抗原提示に重要であることを明らかにするために、F37Aの配列のOVA-I配列(●)をWT1(Wilms tumor 1)のMHCクラスIエピトープ配列(RMFPNAPYL、配列番号23の194番〜202番残基)に、ひとつひとつ置換した変異体を作製した(図5c)。W▽の配列を配列番号25に示す。人工タンパク質のアミノ酸配列を図6及び配列番号44〜52に示した。
天然OVAやαヘリックス構造を多く含む人工タンパク質(F182C,F37C,F36B)は典型的なαヘリックス構造を示すグラフパターンを示した。一方、F36AやF182Bはランダムコイルを特徴とするグラフパターンを示した。
人工タンパク質が、抗原提示細胞に取り込まれ、クロスプレゼンテーションを介して、エピトープを抗原提示していることを確認するために、クロスプレゼンテーションに関与するプロテアソームの阻害剤、PiroximicinとMG132で処理して、細胞性免疫誘導能を評価した。その結果、F182AとF37Aの細胞性免疫誘導能が抑制された(図5d)。さらに、クロスプレゼンテーションを促進する効果のあるリソソーム阻害剤(Chloroquin)で処理したところ、F182AとF37Aの細胞性免疫誘導能が増強した。
抗原提示細胞が免疫を誘導するためには、MHC分子への抗原提示に加えて、補助刺激分子(CD80やCD86)の発現、即ち、抗原提示細胞の成熟化が必要であることが知られている。そこで、マウス骨髄単球細胞からGM-CSFを用いて誘導したBMDC骨髄由来樹状細胞にF37Aを添加し、成熟マーカーであるCD80とCD86の発現を調べた。
次に、抗原をC57Bl/6マウスの皮内に100μg/匹、2週間間隔で3回投与し、免疫した。検討群として、OVA-Iペプチド群 (OVA MHCクラスIエピトープ, OVA257-264, SIINFEKLを投与)、天然OVAタンパク質群、F37A人工タンパク質群を設定した。また、アジュバントとして、MPL(monophosphoryl lipid A)とフロイントアジュバントCFA(コンプリートアジュバント(結核菌死菌添加)1回、インコンプリートアジュバント2回)を用いて免疫を行った。
次に、OVA発現腫瘍に対する腫瘍抑制効果を検証した。マウスを上記と同じように免疫し、腫瘍細胞EG7-OVA(2x106個)をマウスの背中に皮下投与した。その後、1週間ごとに腫瘍径を測定した。その結果、アジュバントを用いない群で、腫瘍細胞接種後3週の腫瘍径に群間で差は認められなかった。しかし、MPLをアジュバントとして用いると、OVA免疫群とF37A免疫群で有意な腫瘍の増殖抑制効果が認められた(図11b)。F37Aは、フロイントのオイルアジュバントを用いないでも、細胞性免疫を誘導し、その細胞性免疫が機能できることが確認された。
免疫マウスから血清を採取し、抗OVA抗体ができているか否かを、OVAを抗原としたELISA法により調べた(図11c)。
F37AのOVA特異的CTL誘導にMHCクラスIIエピトープ配列OVA-IIが関与しているかどうか調べるために、MHCクラスIIエピトープを持たないF36C人工タンパク質でマウスを免疫した。また、F37Aに存在するMHCクラスIエピトープ配列OVA-Iが細胞性免疫誘導に機能していることを明らかにするために、3つのOVA-IをすべてWT1 MHCクラスIエピトープに置換したMT825人工タンパク質を用いてマウスを免疫した。免疫は、抗原100μgを用い、アジュバントMPL(20μg/匹)と同時に2週間隔で3回腹腔内に投与した(図12a)。
免疫したマウスのCTLアッセイの結果、F37Aの免疫群は、MT825免疫群およびOVA免疫群に比べて有意にCTLを誘導した(図12b)。また、F37Aと同じ特徴的な配列パターン(●▽●▽●▽)を持ち、MHCクラスIIエピトープ配列を持たないF36CにもCTLを誘導する傾向が見られた。OVA-Iを一つも持たないMT825は全くCTLを誘導することはなかった。これらの結果から、OVA特異的CTLの誘導には、必ずしもMHCクラスIIエピトープ配列は必要ではないことが示唆された。
MT825にCTL誘導能が見られないことから、OVA特異的CTL誘導には、F37AのOVA-I (OVA MHCクラスIエピトープ, SIINFEKL)配列が必須であることが明らかになった。
免疫したマウスに、OVA-Iペプチド(SIINFEKL)特異的なCD8陽性T細胞が存在することを、OVA-I配列特異的なテトラマー試薬を用いて測定した。テトラマー試薬は、MHCクラスI分子にエピトープペプチドOVA-Iが結合した4量体であり、T細胞のOVA-I特異的なT細胞レセプター(TCR)を発現する細胞を定量することが可能である。
上記の通り免疫したマウスに、EG7-OVA(2x106個)接種し、腫瘍の腫瘍径を測定した。腫瘍接種後3週では、F37AとF36C免疫群で有意に腫瘍増殖の抑制が認められた(図12d)。個々のマウスの腫瘍増殖は図12eに示した。OVA免疫群でも腫瘍増殖の抑制傾向が見られた。
外来抗原が抗原提示細胞に取りこまれ、MHC class I分子に抗原エピトープを提示するクロスプレゼンテーションの細胞内経路は、未だ不明な点が多い。クロスプレゼンテーションを介して強力に細胞性免疫を誘導できるF37Aがどのようなメカニズムで抗原提示するかを調べた。
Claims (11)
- 抗原タンパク質に由来するMHCクラスIエピトープ領域と、下記(1)及び(2)のいずれかであるスペーサー配列とが少なくとも3回交互に繰り返し連結したタンデムリピート構造を含むポリペプチド、又は該ポリペプチドをコードするポリヌクレオチドを含み、生体内で該ポリペプチドを発現可能な組換えベクターを有効成分として含有するワクチン。
(1) 前記MHCクラスIエピトープ領域と、前記抗原タンパク質と同一又は異なる抗原タンパク質に由来するMHCクラスIIエピトープ領域と、少なくとも1つの高次構造安定化領域とが、単一の塩基配列の異なる読み枠でコードされるように塩基配列を設計した時に、該塩基配列が必然的にコードするアミノ酸配列として生じる配列。
(2) (1)のアミノ酸配列のうち数個のアミノ酸が置換した配列。 - 抗原タンパク質に由来するMHCクラスIエピトープ領域と、下記(1)及び(2)のいずれかであるスペーサー配列とが少なくとも3回交互に繰り返し連結したタンデムリピート構造を含むポリペプチド、又は該ポリペプチドをコードするポリヌクレオチドを含み、生体内で該ポリペプチドを発現可能な組換えベクターを有効成分として含有するワクチン。
(1) 前記抗原タンパク質と同一又は異なる抗原タンパク質に由来するMHCクラスIIエピトープと、高次構造安定化領域とが、単一の塩基配列の異なる読み枠でコードされ、かつ、残りの読み枠で終止コドンが生じないように塩基配列を設計した時に、当該残りの読み枠で該塩基配列が必然的にコードするアミノ酸配列として生じる配列。
(2) (1)のアミノ酸配列のうち数個のアミノ酸が置換した配列。 - 前記MHCクラスIエピトープ領域と前記MHCクラスIIエピトープ領域が同一の抗原タンパク質に由来する、請求項1又は2記載のワクチン。
- 前記(2)の配列は、(1)のアミノ酸配列のうちの数個の残基からなる領域が、MHCクラスIIエピトープ領域又は高次構造安定化領域の一部に由来するアミノ酸配列に置換した配列である、請求項1ないし3のいずれか1項に記載のワクチン。
- 前記高次構造安定化領域が、αへリックス形成性領域及びβシート形成性領域から選択される少なくとも1つである、請求項1ないし4のいずれか1項に記載のワクチン。
- 前記(1)の配列は、1つの読み枠に前記MHCクラスIエピトープ領域がコードされ、他の1つの読み枠に前記MHCクラスIIエピトープ領域がコードされ、さらに他の1つの読み枠に少なくとも1つのαへリックス形成性領域がコードされるように前記塩基配列を設計した時に、MHCクラスIエピトープ領域をコードする読み枠内でMHCクラスIエピトープ領域に隣接して生じるアミノ酸配列である、請求項1ないし5のいずれか1項に記載のワクチン。
- 前記ポリペプチドは、N末端側領域及びC末端側領域の少なくともいずれか一方に前記MHCクラスIIエピトープ領域を含む、請求項1ないし6のいずれか1項に記載のワクチン。
- 前記抗原タンパク質が、腫瘍抗原、がん幹細胞抗原、ウイルス抗原、又は寄生虫抗原である請求項1ないし7のいずれか1項に記載のワクチン。
- 前記抗原タンパク質が、WT1、サバイビン、サバイビン-B2、MAGE-A3、MEGE-A4、チロシナーゼ、gp100、Melan-A、TRP-2、SNRPD1、CDK4、NY-ESO-1、HER2、MUC-1、CD20、又はp53である請求項1ないし7のいずれか1項に記載のワクチン。
- 前記ポリペプチドの等電点が6.0〜8.6である請求項1ないし9のいずれか1項に記載のワクチン。
- トール様受容体経路を活性化するアジュバントと組み合わせて用いられる請求項1ないし10のいずれか1項に記載のワクチン。
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