JP7219212B2 - Mhc結合ペプチドアレイおよびその使用方法 - Google Patents
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Description
(a)MHC組成物を4℃で一晩インキュベートする工程、
(b)MHC組成物から沈殿物を分離する工程、および
(c)沈殿物を含まないMHC組成物を、表面に接触させるために回収する工程
を含む方法によって作製される。
(a)可溶化α鎖をコードするアミノ酸配列を、コドン最適化デオキシリボ核酸(DNA)配列に逆翻訳する工程、
(b)コドン最適化デオキシリボ核酸(DNA)配列を二本鎖DNA分子として合成する工程、
(c)二本鎖DNA分子を封入体の形態で発現してα鎖を作製する工程、および
(d)α鎖を可溶化する工程
を含む方法によって作製される。
(a)少なくとも1つのT細胞と組成物とを接触させる工程、
(b)活性化に際し、少なくとも1つのT細胞から分泌される少なくとも1つの分子を検出する工程、および
(c)少なくとも1つのT細胞を画像化する工程
を含む組成物の少なくとも1つのペプチドによって刺激される少なくとも1つのT細胞の同定のために使用されてもよい。
[0100]本開示のペプチドまたは複数のペプチドの表面上のin situ合成は、パターニングプロセスを使用して、迅速かつ効率的に行われる。プロセスは、ペプチドの一または二次元アレイの作製が可能になるように自動化およびコンピュータ制御されてもよい。リソグラフィーマスクは必要でなく、したがってリソグラフィーマスクの作製に関連する多大なコストおよび時間的遅延がなくなり、ペプチドアレイの作製プロセスの間の時間のかかる操作および複数のマスクの整列が不要となる。
[0105]MHCのクラスIまたはクラスIIは、ヒトの全ての有核細胞の表面にわたって発現される。MHCクラスI(MHCI)複合体は、全ての有核細胞に存在するが、MHCクラスII(MHCII)複合体は、免疫系の細胞(つまり、マクロファージおよびリンパ球)にのみ存在する。MHC複合体は細胞内の中身のペプチド断片を提示して、免疫系が、非自己ペプチド配列の提示によって決定される外来の侵略者の存在についての本体の調査を行うことを可能にする。自己免疫状態の場合には、MHCが自己ペプチドを提示するとき、免疫系は、免疫系が非自己ペプチドに反応するのと同様の様式で刺激される。MHCの成分をコードする、ヒト白血球抗原(HLA)遺伝子を含む白血球抗原遺伝子は非常に多様で、MHCIおよびMHCII両方のMHCの多くの可能な順列をもたらす。
[0110]本開示で使用されるとき、単数形「a」、「and」および「the」は、文脈が明らかに他のことを指示しない限り、複数の参照物を含む。したがって、例えば、「方法」への参照は、複数のそのような方法を含み、「用量」への参照は、1つまたは複数の用量および当業者に既知の同等物を含むなどである。
ヒト白血球抗原(HLA)およびβ2ミクログロブリン(b2m)タンパク質の起源:
[0150]クローニングおよび大腸菌における発現
[0151]HLA-A*02:01およびb2mは、Roche Glycart AG(Schlieren、スイス)およびRoche Diagnostics GmbH(Penzberg、ドイツ)によって提供された。
MGSHSMRYFYTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYWDQETRNVKAQSQTDRVDLGTLRGYYNQSEDGSHTIQIMYGCDVGPDGRFLRGYRQDAYDGKDYIALNEDLRSWTAADMAAQITKRKWEAAHAAEQQRAYLEGRCVEWLRRYLENGKETLQRTDPPKTHMTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWE(配列番号1)
GSHSMRYFYTSVSRPGRGEPRFISVGYVDDTQFVRFDSDAASPREEPRAPWIEQEGPEYWDRNTQIYKAQAQTDRESLRNLRGYYNQSEAGSHTLQSMYGCDVGPDGRLLRGHDQYAYDGKDYIALNEDLRSWTAADTAAQITQRKWEAAREAEQRRAYLEGECVEWLRRYLENGKDKLERADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWE(配列番号2)
SHSMRYFDTAVSRPGRGEPRFISVGYVDDTQFVRFDSDAASPRGEPRAPWVEQEGPEYWDRETQKYKRQAQADRVSLRNLRGYYNQSEDGSHTLQRMSGCDLGPDGRLLRGYDQSAYDGKDYIALNEDLRSWTAADTAAQITQRKLEAARAAEQLRAYLEGTCVEWLRRYLENGKETLQRAEPPKTHVTHHPLSDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQRYTCHMQHEGLQEPLTLSWE(配列番号3)
[0158]100mgの封入体を、2.0mlのエッペンドルフチューブに移し、1mlのpH7.8の50mM Tris-HCl、5mMのEDTA、1%のTween20、2mMのDTT中に再懸濁し、2,000×gで2分間遠心分離した。上清を除去し、ペレットをボルテックスによってほぐした。
[0162]HLA/b2m複合体の調製
[0163]典型的には、630μlのpH8.5の10mM Tris-HClを、20μlのpH7.8の20mM Tris-HCl中10% BSA、300μgの30mg/ml可溶化b2mおよび600μgの15~40mg/ml可溶化α鎖と室温(RT)で示された順序で混合した。対照試料は、b2mタンパク質を含めなかった。混合試料を4℃で一晩インキュベートし、12,000×gで4分間遠心分離して沈殿物を除去した。上清を、およそ400μlの2回の試料ロードを使用してAmiconUltra 10Kフィルター(Millipore)で濃縮し、それぞれ12,000×gで2分間遠心分離した。試料バッファーを、350μlのpH8.8の10mM Tris-HClをフィルター保持体積に加えることによってpH8.5の10mM Trisに置き換え、12,000×gで4分間の遠心分離によって濃縮した。バッファー交換手順をさらに2回、各回で350μlのpH8.5の10mM Tris-HClを使用して、繰り返した。最終の遠心分離工程後、保持体積(およそ100μl)を1,000×gで2分間の遠心分離によって新鮮なチューブに回収し、5.0μmのUltrafreeフィルター(Millipore)を通して濾過し、4℃で保存した。
[0165]合成および脱保護後のペプチドアレイスライドを、密封された容器に-20℃で保存するかまたは直ぐに使用した。試料を適用する前に、スライドを、アレイブロッキングおよび基準マークの染色のために、0.7μg/mlのCy-5標識ストレプトアビジン(Amersham)1×結合バッファー(1%カゼイン、10mM Tris pH7.4、0.25% Tween20)中で1時間、室温でインキュベートし、水で濯ぎ、スライドホルダーを備えた卓上遠心分離機を使用して30秒間の遠心分離によって乾燥させた。
[0167]ペプチド/HLA/b2m会合が成功するための影響力のあるパラメータ:
[0168]本実施例に関して、BSAの最適濃度は、HLA/b2m混合物に対して2~3%の添加であることが分かった。BSAなしでは、複合体形成は観察されなかった。
[0176]いくつかの試薬が、効率的なペプチド/HLA/b2m複合体会合のために重要であるとして文献で報告された。それらの中には、0.4MのL-アルギニン、0.25%のグルコピラノシド、5mMの還元型L-グルタチオン(glutathatione)/0.5mMの酸化型L-グルタチオン(glutathatione)、L-GLジペプチドなどの補助ペプチドおよび低親和性ペプチドがある。これらの試薬は、ペプチドアレイ上のHLA/b2m複合体会合に対して最小限の効果または阻害性効果を有することが分かった。
セット1
[0179]12プレックスのレイアウト:
[0180]バッチ処理9マー・ペプチド(123,675ペプチド):5つの対照タンパク質;NY-ES01、WT1、MAGE3、MAGE4、FOXP3;3つの異なるリンカーのタイプ(PEG8、6-アミノヘキサン酸、Gly:SER 4:1ミックス)および5つの異なるリンカーの長さを表す、1アミノ酸工程サイズのタイル状の9マー・ペプチド。
[0183]12プレックスのレイアウト:Wilms腫瘍からの2つのペプチドおよび1つの他のペプチド。Wilms腫瘍は、腎芽腫としても知られる稀な腎臓がんである。
[0188]本開示の組成物および方法は、MHCによってin vivoで提示されるとき免疫優性であろうこれらのペプチドを同定するために使用することができる。本開示の組成物は、少なくとも106個の特有のペプチドを、表面に同時に含むことができるので、目的の任意の抗原を、例えば、表面上のMHCI複合体に結合した9アミノ酸配列の全ての順列で提示することができる。単一の高度多重化実験では、完全かつ適切に会合したペプチド-MHCI複合体を特異的に認識する任意の抗体を使用して、in vivoで提示され得るペプチドが容易に同定される。同じ実験で、1つまたは複数のT細胞を表面に導入して、適切に会合したペプチド-MHCI複合体に含まれるペプチドのどれが1つまたは複数のT細胞を刺激するかを決定することができる。いずれも少なくとも106個の特有のペプチドについて単一の実験で決定することができる、これらの2つの基準(ペプチドが適切なペプチド-MHC複合体を形成するかおよびT細胞を刺激するかの基準)のみに基づいて、本開示の組成物および方法は、MHCによってin vivoで提示される場合に免疫優性であろうこれらのペプチドをin vitroで同定するための優れた手段を提供する。
[0198]先に、いくつかのリンカーを、会合体の表面上の最適化されたペプチド-MHC会合体に対するアレイ表面へのペプチドの結合について評価した。その試験から、3~5個のHEX部分(各部分が6アミノヘキサン酸を含む)からなるリンカーが、HLA特異的抗体でのpMHC複合体検出後の最も高いシグナルおよび低バックグラウンドの基準に基づいて好ましいリンカーとして選択された。
1.表面-5HEX-ペプチド
2.表面-HEX-E-3HEX-ペプチド
3.表面-HEX-D-3HEX-ペプチド
4.表面-HEX-K-3HEX-ペプチド
5.表面-2HEX-E-HEX-ペプチド
6.表面-3HEX-GluB-ペプチド(GluB=側鎖を介して連結されたt-ブチル保護グルタミン酸)
Claims (14)
- 複数のペプチドを含むペプチドマイクロアレイであって、前記ペプチドが、ペプチド-主要組織適合遺伝子複合体(ペプチド-MHC)会合体を形成し、それぞれの会合体がマイクロアレイペプチドおよび主要組織適合遺伝子複合体(MHC)を含み、ここで、
前記ペプチドがMHCの必須構成要素であり、リンカーを介してそのC末端で前記ペプチドマイクロアレイの表面に結合され、
前記MHCは、α鎖およびβ鎖を含むクラスI MHCであり、 ここで、前記MHCのα鎖がヒト白血球抗原(HLA)遺伝子から誘導される配列によってコードされ、および前記MHCのα鎖は切断され、C末端のヒンジ領域、膜貫通領域または細胞質領域が除去されており、
前記複数のペプチドが前記表面上で合成され、
前記複数のペプチドが空間的に順序付けられており、それらの配列が事前に決定されている、前記ペプチドマイクロアレイ。 - MHCが、好ましくはウシ血清アルブミン(BSA)である担体分子を含む、請求項1に記載のペプチドマイクロアレイ。
- α鎖が、膜貫通領域または細胞質領域を含まない、請求項1または2に記載のペプチドマイクロアレイ。
- α鎖が、ヒンジ領域を含まない、請求項1~3のいずれか1項に記載のペプチドマイクロアレイ。
- 前記ペプチドマイクロアレイが、少なくとも106個の特有のペプチドを有する、請求項1~4のいずれか1項に記載のペプチドマイクロアレイ。
- α鎖が、α1ドメイン、α2ドメインおよびα3ドメインを含む、請求項1~5のいずれか1項に記載のペプチドマイクロアレイ。
- 前記MHCが、野生型クラスI MHCである、請求項1~6のいずれか1項に記載のペプチドマイクロアレイ。
- 請求項1~7のいずれか一項に記載のペプチドマイクロアレイを作製する方法であって、複数のペプチドを含むマイクロアレイの表面と、MHC組成物とを、複数のペプチド-MHC会合体を生成するために適切な条件下で接触させる工程を含み、
ここで前記ペプチドがMHCの必須構成要素であり、リンカーを介してそのC末端で前記ペプチドマイクロアレイの表面に結合され、
前記MHCは、α鎖およびβ鎖を含むクラスI MHCであり、 ここで、前記MHCのα鎖がヒト白血球抗原(HLA)遺伝子から誘導される配列によってコードされ、および前記MHCのα鎖は切断され、C末端のヒンジ領域、膜貫通領域または細胞質領域が除去されており、
前記複数のペプチドが前記表面上で合成され、
前記複数のペプチドが空間的に順序付けられており、それらの配列が事前に決定されている、前記方法。 - 表面に接触させる前に、MHC組成物が、
(a)MHC組成物を4℃で一晩インキュベートする工程、
(b)MHC組成物から沈殿物を分離する工程、および
(c)沈殿物を含まないMHC組成物を、表面に接触させるために回収する工程、
を含む方法によって作製される、請求項8に記載の方法。 - MHCによってin vivoで提示されるときに免疫優性である1つまたは複数のペプチド抗原の同定のための、請求項1~7のいずれか一項に記載のペプチドマイクロアレイの使用。
- ペプチド抗原が、がん抗原である、請求項10に記載の使用。
- がん抗原を含むワクチンを調製するための、請求項11に記載の使用。
- 免疫応答を増強または誘導する医薬の製造のための、請求項11に記載の使用。
- ペプチドマイクロアレイの少なくとも1つのペプチドによって刺激される少なくとも1つのT細胞の同定のための請求項1~7のいずれか一項に記載のペプチドマイクロアレイの使用であって、
(a)少なくとも1つのT細胞とペプチドマイクロアレイとを接触させる工程、
(b)活性化に際し、少なくとも1つのT細胞から分泌される少なくとも1つの分子を検出する工程、および、
(c)少なくとも1つのT細胞を画像化する工程、
を含む、前記使用。
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