JP7229516B2 - 様々ながんに対する免疫療法で使用される新規ペプチドおよびペプチドの組み合わせ - Google Patents
様々ながんに対する免疫療法で使用される新規ペプチドおよびペプチドの組み合わせ Download PDFInfo
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Description
2012年には、1410万件の新規がん症例、3260万人のがん患者(診断の5年以内)、および820万件のがん死亡が世界的に推定された(Ferlay et al.,2013;Bray et al.,2013)。表1および表2は、それぞれ、世界および選択された地域における、現在の介入に関連のある様々ながん型における、推定された発症率、5年有病率、および死亡率の概要を提供する。
乳がん
乳がんは免疫原性がん実体であり、原発性腫瘍内の浸潤性免疫細胞の異なる型は、特徴的な予後および予測的有意性を示す。多数の初期免疫療法治験が、乳がん患者において実施されている。完了したワクチン接種研究のほとんどは、HER2と、MUC-1のような炭水化物抗原とを標的とし、かなり期待外れの結果が明らかにされた。乳がん患者における、イピリムマブおよびその他のT細胞活性化抗体による免疫チェックポイント調節の効果に関する臨床データが、浮上している(Emens,2012)。
CLLは現在治療可能ではないが、多くの患者は、遅い疾患進行または症状悪化のみを示す。患者が治療の早期開始の恩恵を受けることはないので、最初のアプローチは「経過観察」である(Richards et al.,1999)。症候性のまたは迅速に進行する疾患がある患者に対しては、いくつかの治療選択肢が利用できる。これらとしては、化学療法;標的療法;モノクローナル抗体、キメラ抗原受容体(CAR)、および能動的免疫療法のような免疫ベース治療法;および幹細胞移植が挙げられる。
結腸直腸がん(CRC)の病期次第で、異なる標準的治療法が、結腸および直腸がんに対して利用できる。標準手順としては、外科手術、放射線療法、化学療法、およびCRC標的療法が挙げられる(Berman et al.,2015a;Berman et al.,2015b)。
免疫療法は、進行した食道がんを治療するための有望な新規アプローチであってもよい。異なるMAGE遺伝子であるNY-ESO-1およびEpCAMをはじめとするいくつかのがん関連遺伝子およびがん精巣抗原は、食道がんにおいて過剰発現されることが示された(Kimura et al.,2007;Liang et al.,2005;Inoue et al.,1995;Bujas et al.,2011;Tanaka et al.,1997;Quillien et al.,1997)。これらの遺伝子は、免疫療法にとって非常に興味深い標的であり、それらの大多数についてその他の悪性病変の治療のために研究が行われている(ClinicalTrials.gov、015)。さらに、PD-L1およびPD-L2の上方制御が食道がんで報告され、より芳しくない予後と相関した。したがって、PD-L1陽性腫瘍を有する食道がん患者は、抗PD-L1免疫療法の恩恵を受けるかもしれない(Ohigashi et al.,2005)。
進行したGCに対する現行の薬剤投与計画は有効性に劣り、低い5年生存率をもたらす。免疫療法は、GC患者の生存率を改善する代替アプローチであるかもしれない。腫瘍関連リンパ球およびサイトカイン誘導キラー細胞の養子免疫伝達;HER2/neu、MAGE-3または血管内皮成長因子受容体1および2を標的とするペプチドベースのワクチン;およびHER2/neuを標的とする樹状細胞ベースのワクチンが、臨床GC治験において有望な結果を示した。免疫チェックポイント阻害および遺伝子操作T細胞は、追加的な治療選択肢に相当するかもしれず、それは現在前臨床および臨床試験で評価中である(Matsueda and Graham,2014)。
神経膠芽腫(WHOグレードIV)の治療選択肢は、非常に限られている。GBの治療のために、免疫チェックポイント阻害、ワクチン接種、および遺伝子操作T細胞の養子免疫伝達をはじめとする、異なる免疫療法のアプローチが調査されている。
進行した切除不能HCCにおける治療選択肢は、マルチチロシンキナーゼ阻害剤であるソラフェニブに限定される(Chang et al.,2007;Wilhelm et al.,2004)。ソラフェニブは、生存期間を約3ヶ月間増大させることが確認された唯一の全身薬物であり、目下このような患者に対する唯一の実験的治療選択肢に相当する(Chapiro et al.,2014;Llovet et al.,2008)。最近、HCCのための限定数の免疫療法治験が実施されている。免疫細胞のサブセットを活性化し、および/または腫瘍免疫原性を増大させるために、サイトカインが使用されている(Reinisch et al.,2002;Sangro et al.,2004)。その他の治験は、腫瘍浸潤性リンパ球または活性化末梢血リンパ球の輸液に焦点を合わせている(Shi et al.,2004;Takayama et al.,1991;Takayama et al.,2000)。
抗腫瘍免疫応答を増強することは、進行性黒色腫の治療のための有望なストラテジーのようである。米国では、免疫チェックポイント阻害剤であるイピリムマブ、ならびにBRAFキナーゼ阻害剤であるベムラフェニブおよびダブラフェニブ、およびMEK阻害剤であるトラメチニブは、進行性黒色腫の治療のために既に承認されている。イピリムマブは直接的にT細胞阻害を減少させることによって、キナーゼ阻害剤は間接的にメラノサイト分化抗原の発現を増強することによって、どちらのアプローチも患者の抗腫瘍免疫を増加させる。追加的なチェックポイント阻害剤(ニボルマブおよびランブロリズマブ)インヒビターが、最初の有望な結果をもって臨床研究で現在調査されている。さらに(Additionaly)、イピリムマブとニボリュマブ、イピリムマブとgp100由来ペプチドワクチン、イピリムマブとダカルバジン、イピリムマブとIL-2、およびイプリムマブとGM-CSFをはじめとする、抗腫瘍免疫応答を標的とする異なる併用療法が、臨床試験において試験されている(Srivastava and McDermott,2014)。
疾患は、通常は、発見時までに広がっているので、放射線療法および化学療法が頻繁に使用され、時に手術と組み合せて使用される。(S3-Leitlinie Lungenkarzinom,2011)。NSCLCに対する治療選択肢を拡大するために、異なる免疫療法アプローチが試験されており、あるいはなおも調査中である。L-BLP25またはMAGEA3を用いたワクチン接種は、NSCLC患者においてワクチン媒介延命効果を実証できなかった一方で、同種異系細胞株由来ワクチンは、有望な臨床試験結果を示した。さらに、上皮成長因子受容体であるガングリオシドと、いくつかのその他の抗原とを標的とするさらなるワクチン接種治験が現在進行中である。患者の抗腫瘍T細胞応答を高める代案のストラテジーは、特異的抗体によって阻害T細胞受容体またはそれらのリガンドをブロックすることからなる。NSCLCにおける、イピリムマブ、ニボルマブ、ペンブロリズマブ、MPDL3280A、およびMEDI-4736をはじめとする、これらの抗体のいくつかの治療的可能性が、現在臨床試験で評価されている(Reinmuth et al.,2015)。
炎症促進性腫瘍浸潤性リンパ球、特にCD8陽性T細胞の存在は、予後良好と相関し、腫瘍関連抗原に対して特異的なT細胞が、がん組織から単離され得ることから、免疫療法は、卵巣がん患者の治療を改善する有望なストラテジーのようである。
膵臓がん患者のための治療選択肢は、非常に限られている。効果的治療のための1つの大きな問題は、診断時における典型的に進行した腫瘍病期である。ワクチン接種ストラテジーは、膵臓がんの治療のためのさらに革新的で有望な代案として調査されている。KRAS変異体、反応性テロメラーゼ、ガストリン、サバイビン、CEA、およびMUC1を標的とするペプチドベースのワクチンが臨床試験で既に評価されており、ある程度有望な結果が得られている。さらに、膵臓がん患者における、樹状細胞ベースのワクチン、同種異系GM-CSF分泌ワクチン、およびアルゲンパンツセルLの臨床試験もまた、免疫療法の有益な効果を明らかにした。異なるワクチン接種プロトコルの効率をさらに調べるための追加的な臨床試験が、現在進行中である(Salman et al.,2013)。
樹状細胞ベースのワクチンであるシプロイセルTは、FDAによって承認された最初の抗がんワクチンであった。CRPCがある患者の生存期間に対するその好ましい効果のために、さらなる免疫療法の開発に向けた多大な努力がなされている。ワクチン接種ストラテジーについては、ペプチドワクチンである前立腺特異的抗原(PSA)-TRICOM、個別化ペプチドワクチンであるPPV、DNAワクチンであるpTVG-HP、およびGM-CSF発現全細胞ワクチンであるGVAXが、異なる臨床試験で有望な結果を示した。さらに、シプロイセルT以外の樹状細胞ベースのワクチン、すなわちBPX-101およびDCVAC/Paは、前立腺がん患者において臨床的奏効を引き起こすことが示された。イピリムマブおよびニボルマブのような免疫チェックポイント阻害物質が、単剤療法として、ならびにアンドロゲン奪取療法、局所放射線療法、PSA-TRICOM、およびGVAXをはじめとするその他の治療法との併用で、現在臨床試験で評価されている。第II相試験で進行を有意に遅延させ、無憎悪生存期間を延長させた免疫調節物質タスキニモドは、現在第III相試験でさらに調査されている。もう一つの免疫修飾物質であるレナリドミドは、初期臨床試験で有望な効果をもたらしたが、第III相試験では生存率を改善できなかった。これらの期待外れな結果にもかかわらず、さらなるレナリドミド治験が継続されている(Quinn et al.,2015)。
RCCの既知の免疫原性(immunogenity)は、進行したRCCにおける免疫療法およびがんワクチンの使用を支持する基礎に相当する。リンパ球PD-1発現と、RCCの進行期、グレード、および予後との間の興味深い相関、ならびにRCC腫瘍細胞による選択的PD-L1発現と、より芳しくない臨床転帰との潜在的関連性は、単独での、または抗血管新生薬またはその他の免疫療法アプローチと併用される、RCC治療のための新規抗PD-1/PD-L1薬の開発をもたらした(Massari et al.,2015)。進行したRCCでは、TRIST試験と称される第III相がんワクチン治験が、第一選択標準的治療に追加された、TroVax(ポックスウイルスベクターと共に腫瘍関連抗原5T4を使用したワクチン)が、局所的進行またはmRCCがある患者の生存期間を延長するかどうかを評価する。いずれの群でも生存期間中央値に達しておらず、399人の患者(54%)が試験に残っているが、データの解析は、TroVaxが免疫学的に活性であり、5T4特異的抗体応答の強度と改善された生存期間との間に相関があることの双方を実証する、以前の臨床結果を裏付けている。さらにRCCにおいて過剰発現されるエピトープを使用してペプチドワクチンを検索する、いくつかの研究がある。
SCLCの検出、診断、および治療に関する革新が起こった。早期のがん検出のために、X線でなくCTスキャンを使用することで、肺がんによる死亡リスクが低下することが示された。現今では、SCLCの診断は、蛍光または仮想気管支鏡検査によって支援され得て、リアルタイムの腫瘍イメージング(imagining)は、放射線治療によって実施され得る。ベバシズマブ(Avastin)、スニチニブ(スーテント)、およびニンテダニブ(BIBF1120)のような新規抗血管新生薬は、SCLCの治療において治療効果を有することが示された。(American Cancer Society,2015)。免疫療法は、過度に調査されたがん療法の分野に相当する。SCLCの治療には、様々なアプローチが点在する。アプローチの1つは、天然ヒト免疫抑制剤であるCTLA-4のブロックを標的とする。CTLA-4の阻害は、がんと戦うために免疫系を増強することを意図する。近年、SCLCの治療のための有望な免疫チェックポイント阻害剤の開発が始まっている。もう一つのアプローチは抗がんワクチンに基づき、それは現在臨床試験においてSCLC治療のために利用できる(American Cancer Society,2015;National Cancer Institute(NCI),2011)。
1つの治療選択肢は、CD33を抗体薬物コンジュゲート(抗CD33+カレキアマイシン、SGN-CD33a、抗CD33+アクチニウム-225)、二重特異性抗体(CD33+CD3(AMG330)またはCD33+CD16の認識)およびキメラ抗原受容体(CAR)で標的化することである(Estey,2014)。
NHLの治療は、組織型および病期に左右される(National Cancer Institute,2015)。リンパ腫患者では、自然腫瘍退縮が観察され得る。したがって、能動免疫療法が治療選択肢である(Palomba,2012)。重要なワクチン接種選択肢としては、Idワクチンが挙げられる。Bリンパ球は、それらの重鎖および軽鎖の可変領域内に、各細胞クローンに特有の(=イディオタイプ、Id)特異的アミノ酸配列がある、表面免疫グロブリンを発現する。イディオタイプは、腫瘍関連抗原として機能する。受動免疫化は、組換えマウス抗Idモノクローナル抗体を単独で、またはIFNα、IL2またはクロランブシルとの組み合わせで、注射することを含む。
いくつかの免疫療法アプローチもまた、現在試験されている。第I/II相臨床試験では、子宮がんに罹患している患者が、ウィルムス腫瘍遺伝子1(WT1)mRNAによって電気穿孔された自己由来樹状細胞(DC)で、ワクチン接種された。アジュバントに対する局所アレルギー反応の1症例を除いて、有害な副作用は観察されず、6人の患者のうち3人が免疫学的応答を示した(Coosemans et al.,2013)。
胆管がん(CCC)は診断が困難なため、大部分が進行期において同定されている。胆嚢がん(GBC)は、世界的に最も頻度が高く悪性度が高い、胆管の病変である。GBCでは、腫瘍の10%のみが切除可能であり、外科手術を実施した場合でも,大部分は転移性疾患に進行し、予後は、5年生存率が5%未満のCCCよりも芳しくない。大部分の腫瘍は切除不能であるが、有効なアジュバント療法は未だにない(Rakic et al.,2014)。いくつかの研究では、化学療法薬または化学療法と標的療法(抗VEGFR/EGFR)との併用が全生存期間の延長をもたらし、将来の有望な治療選択肢かもしれない(Kanthan et al.,2015)。一般に胆管のがん腫はまれであることから、GBCまたはCCCに特有の少数の研究のみがある一方で、それらのほとんどは全ての胆管がんを含む。これが、過去数十年にわたり治療法が改善されていない理由であり、R0切除術が依然として唯一の根治的治療選択肢である。
膀胱がんの標準的治療法としては、外科手術、放射線療法、化学療法、および免疫療法が挙げられる。
頭頸部扁平上皮がん(HNSCC)は、疫学、病因、および治療において差異を有する異種性の腫瘍である(Economopoulou et al.,2016)。早期HNSCCの治療は、外科手術または放射線のどちらかを用いた単独療法を伴う(World Health Organization,2014)。進行がんは、化学療法と手術および/または放射線療法との併用によって治療される。
a)がん精巣抗原:T細胞によって認識され得る初めて同定されたTAAはこのクラスに属し、元々はがん精巣(CT)抗原と称されたが、それは、そのメンバーが組織学的に異なるヒト腫瘍において発現し、正常組織では精巣の精母細胞/精原細胞のみに存在し、時として胎盤に存在するためであった。精巣の細胞は、クラスIおよびII HLA分子を発現しないので、これらの抗原は正常組織のT細胞によって認識され得ず、したがって免疫学的に腫瘍特異的と見なされる。CT抗原の周知の例は、MAGEファミリーメンバーおよびNY-ESO-1である。
b)分化抗原:これらのTAAは、腫瘍と、それから腫瘍が生じる正常組織との間で共有される。既知の分化抗原のほとんどは、黒色腫および正常メラノサイトに見いだされる。これらのメラノサイト系関連タンパク質の多くは、メラニン生合成に関与し、したがって腫瘍特異的でないが、それでもなおがん免疫療法のために広く利用されている。例としては、黒色腫に対するチロシナーゼとMelan-A/MART-1、または前立腺がんに対するPSAが挙げられるが、これに限定されるものではない。
c)過剰発現TAA:広範に発現されるTAAをエンコードする遺伝子は、組織学的に異なる型の腫瘍において検出され、多数の正常組織においても概してより低い発現レベルで検出されている。正常組織によってプロセスされて潜在的に提示さるエピトープの多くは、T細胞認識の閾値レベル未満であり得る一方で、腫瘍細胞におけるそれらの過剰発現は、以前確立された免疫寛容を破壊することにより、抗がん応答を始動し得る。このクラスのTAAの顕著な例は、Her-2/neu、サバイビン、テロメラーゼまたはWT1である。
d)腫瘍特異的抗原:これらのユニークなTAAは、正常な遺伝子(β-カテニン、CDK4など)の変異から生じる。これらの分子変化のいくつかは、腫瘍性形質転換および/または進行に関連する。腫瘍特異的抗原は、通常、正常組織に対する自己免疫反応のリスクなしに、強力な免疫応答を誘導できる。他方、これらのTAAは、ほとんどの場合、その上でそれらが同定されたまさにその腫瘍のみと関係があり、通常は、多くの個々の腫瘍間で共有されない。腫瘍特異的(関連)イソ型を有するタンパク質では、ペプチドの腫瘍特異性(または関連性)はまた、ペプチドが腫瘍(関連)エクソンに由来する場合に生じてもよい。
e)異常な翻訳後修飾から生じるTAA:このようなTAAは、特異的でなく腫瘍において過剰発現もされないタンパク質から生じてもよいが、それでもなお、腫瘍において主に活性である翻訳後プロセスによって腫瘍関連になる。このクラスの例は、腫瘍にMUC1のような新規エピトープをもたらす改変グリコシル化パターン、または腫瘍特異的であってもなくてもよい分解中のタンパク質スプライシングのような事象から生じる。
f)オンコウイルスタンパク質:これらのTAAはウイルスタンパク質であり、それらは発がん過程において重要な役割を果たしてもよく、外来性である(ヒト由来でない)ため、それらはT細胞応答を誘起し得る。このようなタンパク質の例は、子宮頸がんにおいて発現されるヒト乳頭腫16型ウイルスタンパク質E6およびE7である。
同一性百分率=100[1-(C/R)]
式中、Cは、参照配列と比較される配列との間のアライメント長にわたる、参照配列と比較配列の間の差異の数であり、
(i)比較配列中に対応する整列塩基またはアミノ酸を有しない、参照配列中の各塩基またはアミノ酸、および
(ii)参照配列中の各ギャップ、および
(iii)比較配列中の整列塩基またはアミノ酸と異なる、参照配列中の各整列塩基またはアミノ酸が差異を構成して、
(iiii)アライメントは、整合配列の1位から開始しなくてはならず;
Rは、比較配列とのアライメント長にわたる参照配列中の塩基またはアミノ酸の数であり、参照配列中に生じる任意のギャップもまた、塩基またはアミノ酸として数えられる。
このRNA発現および質量分析データの複合解析は、本発明の289個のペプチドをもたらした。
(a)溶液中のまたは凍結乾燥形態の上述の医薬組成物を含有する容器;
(b)任意選択的に、凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;
(c)任意選択的に、(i)溶液の使用、または(ii)凍結乾燥製剤の再構成および/または使用のための取扱説明書
を含んでなるキットをさらに目的とする。
1.悪性物質からのHLAリガンドを質量分析法によって同定した
2.ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を使用して、一連の正常器官および組織と比較して悪性組織中の遺伝子過剰発現を同定した
3.同定されたHLAリガンドを遺伝子発現データと比較した。好ましくは、ステップ2で検出されたような選択的に発現されまたは過剰発現される遺伝子によってコードされる、腫瘍組織上で過剰提示されまたは選択的に提示されるペプチドが、多重ペプチドワクチンのための適切なTUMAP候補と見なされた。
4.同定されたペプチドのTUMAPとしての妥当性を支持する追加的な証拠を同定するために、文献調査を実施した
5.mRNAレベルでの過剰発現の関連性をステップ3からの選択されたTUMAPの腫瘍組織上における再検出と、健常組織における検出の欠如(またはまれな)検出によって確認した。
6.選択されたペプチドによる生体内T細胞応答の誘導が可能かどうかを評価するために、健常ドナーならびにがん患者からのヒトT細胞を使用して、生体外免疫原性アッセイを実施した。
図1E-Rは正常組織と比較した、種々のがん組織中の様々なペプチドの過剰提示である。分析は、490個を超えるA*02陽性正常組織サンプルおよび70個のA*24陽性正常組織サンプル、543個のA*02陽性がんサンプルおよび200個のA*24陽性がんサンプルからのデータを含んだ。示されているのは、ペプチドが提示されたと認められたサンプルのみである。
図2A-Iは、正常組織(白色バー)および種々のがんサンプル(黒色バー)のパネルにおいて、がんで高度に過剰発現されまたは排他的に発現される、本発明の起源遺伝子の例示的発現プロファイルを示す。
細胞表面に提示される腫瘍関連ペプチドの同定および定量化
組織サンプル
患者の腫瘍組織は、Asterand(米国ミシガン州デトロイト;英国ハートフォードシャー州ロイストン)Bio-Options Inc.(米国カリフォルニア州ブレア);BioServe(米国メリーランド州ベルツビル);Center for cancer immune therapy(CCIT),Herlev Hospital(デンマーク国ヘアレウ);Geneticist Inc.(米国カリフォルニア州グレンデール);Indivumed GmbH(独国ハンブルク);Istituto Nazionale Tumori"Pascale"(イタリア国ナポリ);京都府立医科大学(KPUM)(日本国京都);Leiden University Medical Center(LUMC)(オランダ国ライデン);ProteoGenex Inc.(米国カリフォルニア州カルバーシティ);Saint Savas Hospital(ギリシャ国アテネ);Stanford Cancer Center(米国カリフォルニア州スタンフォード);Tissue Solutions Ltd(英国グラスゴー);University Hospital Bonn(独国ボン);University Hospital Geneva(スイス国ジュネーブ);University Hospital Heidelberg(独国ハイデルベルク);University Hospital Munich(独国ミュンヘン);大阪市立大学(OCU)(日本国大阪);University Hospital Tubingen(独国チュービンゲン);Val d’Hebron University Hospital(スペイン国バルセロナ)から入手された。
衝撃凍結組織サンプルからのHLAペプチド貯留は、わずかに修正されたプロトコル(Falk et al.,1991;Seeger et al.,1999)に従って、HLA-A*02-特異的抗体BB7.2、HLA-A、-B、-C特異的抗体W6/32、CNBr活性化セファロース、酸処理、および限外濾過を使用して、免疫沈殿によって固形組織から得られた。
得られたHLAペプチド貯留は、逆相クロマトグラフィー(nanoAcquity UPL C system,Waters)によってそれらの疎水性に従って分離し、ESI源を装着したLTQ-velosおよびfusion hybrid質量分光計(ThermoElectron)内で溶出ペプチドを分析した。ペプチド貯留は、毎分400nLの流速を適用して、1.7μm C18逆相材料(Waters)で充填された分析用融合シリカマイクロキャピラリーカラム(75μm内径×250mm)上に直接挿入した。引き続いて、毎分300nLの流速で10%から33%へのBの二段階180分間二成分勾配を用いて、ペプチドを分離した。勾配は、溶媒A(水中の0.1%ギ酸)および溶媒B(アセトニトリル中の0.1%ギ酸)から構成された。nanoESI源への導入には、金被覆ガラス毛管(PicoTip,New Objective)を使用した。LTQ-Orbitrap質量分光計は、TOP5ストラテジーを使用してデータ依存モードで操作した。手短に述べると、Orbitrap(R=30000)内の高質量精度の完全スキャンでスキャンサイクルを開始し、これもまたOrbitrap(R=7500)内の5種の最も豊富な前駆イオンのMS/MSスキャンがそれに続き、以前選択されたイオンは動的に排除された。タンデム質量スペクトルは、SEQUESTおよび追加的な手動調節によって解釈した。同定されたペプチド配列は、生成された天然ペプチド断片化パターンと、配列が同一の合成参照ペプチドの断片化パターンとの比較によって確認した。
びその他の結合分子の標的になり得る。
本発明のペプチドをコードする遺伝子発現プロファイリング
正常細胞と比較した腫瘍細胞上のペプチドの過剰提示または特異的提示は、免疫療法におけるその有用性にとって十分であり、いくつかのペプチドは、それらの起源タンパク質が正常組織にもまた存在するにもかかわらず、腫瘍特異的である。それでもなお、mRNA発現プロファイリングは、免疫療法のためのペプチド標的の選択において、安全性のレベルを高めることができる。特に、アフィニティ成熟TCRなどの安全性リスクが高い治療選択肢では、理想的な標的ペプチドは、腫瘍に特有で正常組織上には見いだされないタンパク質に由来する。
外科的に除去された組織標本は、告知に基づく同意書が各患者から入手された後に、上述の通り提供された(実施例1を参照されたい)。腫瘍組織標本を手術直後にスナップ凍結し、その後、液体窒素下で乳鉢と乳棒を用いて均質化した。TRI試薬(Ambion,Darmstadt,Germany)を使用して、これらのサンプルから全RNAを調製し、RNeasy(QIAGEN,Hilden,Germany)による精製がそれに続き;どちらの方法も製造業者のプロトコルに従って実施した。
腫瘍および正常組織RNAサンプルの遺伝子発現解析は、CeGaT(Tubingen,Germany)によって、次世代配列決定(RNAseq)によって実施された。簡単に述べると、配列決定ライブラリーは、RNA断片化、cDNA転換、および配列決定アダプターの付加を含む、Illumina HiSeq v4試薬キットを使用して、販売業者(Illumina Inc.,San Diego,CA,USA)のプロトコルに従って作製される。複数のサンプルに由来するライブラリーは等モル混合され、Illumina HiSeq 2500配列決定装置上で、製造会社の使用説明書に従って配列決定され、50bpのシングルエンドリードが生成される。処理された読み取りは、STARソフトウェアを使用して、ヒトゲノム(GRCh38)にマッピングされる。発現データは、ensembl配列データベース(Ensembl77)の注釈に基づいて、RPKM(100万個のマッピングされた読み取り当たりキロベース当たり読み取り、ソフトウェアCufflinksによって生成される)として転写物レベルで、そしてエクソンレベルで(全読み取り、ソフトウェアBedtoolsによって生成される)提供される。エクソン読み取りは、エクソン長さおよびアライメントサイズについて正規化されて、RPKM値が得られる。
MHCクラスI提示ペプチドの生体外免疫原性
本発明のTUMAPの免疫原性に関する情報を得るために、本発明者らは、ペプチド/MHC複合体および抗CD28抗体を負荷した人工抗原提示細胞(aAPC)によるCD8+T細胞の反復刺激に基づく、生体外T細胞プライミングアッセイを用いて研究を実施した。このようにして、本発明者らは、本発明のHLA-A*0201拘束性TUMAPの免疫原性を示し得て、これらのペプチドが、それに対するCD8+前駆T細胞がヒトに存在する、T細胞エピトープであることを実証した(表19)。
ペプチドMHC複合体(pMHC)および抗CD28抗体を負荷した、人工抗原提示細胞による生体外刺激を実施するために、本発明者らは、最初に、告知に基づく同意後に、独国のUniversity clinics Mannheimから得られた健常ドナーのCD8ミクロビーズ(独国ベルギッシュ・グラートバッハのMiltenyi Biotec)を使用した正の選択を通じて、新鮮HLA-A*02白血球除去生成物からCD8+T細胞を単離した。
HLAクラスIペプチドを試験するために、ペプチド特異的T細胞株の生成によって生体外免疫原性が実証され得た。本発明の2種のペプチドの、TUMAP特異的多量体染色後の例示的フローサイトメトリー結果は、対応する陰性対照と共に図3に示される。本発明からの10種のペプチドの結果は、表19Aに要約される。本発明の7種のペプチドに関する、TUMAP特異的多量体染色後における例示的フローサイトメトリー結果は、対応する陰性対照と共に図4および図5に示される。本発明からの60種のペプチドの結果は、表19Bに要約される。
ペプチドの合成
Fmocストラテジーを使用した標準的な十分に確立された固相ペプチド合成を使用して、全てのペプチドを合成した。個々のペプチドのアイデンティティーおよび純度は、質量分析および分析用RP-HPLCによって判定された。ペプチドは、純度>50%の白色から灰白色の凍結乾燥物(トリフルオロ酢酸塩)として得られた。全てのTUMAPは、好ましくはトリフルオロ酢酸塩または酢酸塩として投与され、その他の塩形態もまた可能である。
MHC結合アッセイ
本発明によるT細胞ベースの治療法のための候補ペプチドを、それらのMHC結合能力(親和性)についてさらに試験した。個々のペプチド-MHC複合体は、UVリガンド交換によって生成され、UV感受性ペプチドはUV照射に際して切断されて、分析される目的ペプチドで交換された。ペプチド受容性MHC分子と効果的に結合して安定化し得るペプチド候補のみが、MHC複合体の分離を防止する。交換反応の収率を判定するために、安定化MHC複合体の軽鎖(β2m)の検出に基づくELISAを実施した。アッセイは、Rodenko et al.(Rodenko et al.,2006)に一般的に記載されるようにして実施した。
細胞表面に提示される腫瘍関連ペプチドの絶対定量化
抗体および/またはTCRなどのバインダーの生成は、骨の折れる工程であり、いくつかの選択された標的に対してのみ実施されてもよい。腫瘍関連および特異的ペプチドの場合、選択基準としては、提示の排他性および細胞表面に提示されるペプチドの密度が挙げられるが、これに限定されない。実施例1に記載されるペプチドの単離および相対定量化に加えて、本発明者らは、記載される細胞当たりの絶対的ペプチドコピー数も分析された。固形腫瘍サンプル中の細胞当たりのTUMAPコピーの定量化は、単離されたTUMAPの絶対定量化、TUMAP単離の効率、および分析される組織サンプルの細胞計数を必要とする。
質量分析によるペプチドの正確な定量化のために、内標準法を使用して各ペプチドの検量線を作成した。内標準は各ペプチドの二重同位体標識変異型であり、すなわち、2つの同位体標識アミノ酸がTUMAP合成に含まれた。それは、腫瘍関連ペプチドとはその質量異なるのみであるが、他の物理化学的性質に差異を示さない(Anderson et al.,2012)。内標準を各MSサンプルに添加して、全てのMSシグナルを内標準のMSシグナルに対して正規化し、MS実験間の可能な技術的変動を平準化した。少なくとも3つの異なるマトリックス中、すなわち、ルーチンのMSサンプルと同様の天然サンプルからのHLAペプチド溶出液中で検量線を作成し、各調製物を二連のMS試験で測定した。評価のために、MSシグナルを内標準のシグナルに対して正規化し、検量線をロジスティック回帰によって算出した。組織サンプルからの腫瘍関連ペプチドの定量化のためには、それぞれのサンプルにも内標準が添加され、MSシグナルが、内標準に対して正規化され、ペプチド検量線を使用して定量化された。
あらゆるタンパク質精製処理と同様に、組織サンプルからのタンパク質の単離には、目的タンパク質のいくらかの損失が伴う。TUMAP単離の効率を判定するために、絶対定量化のために選択された全てのTUMAPについて、ペプチド/MHC複合体が生成された。添加されたものを天然ペプチド/MHC複合体から識別できるように、TUMAPの単一同位体標識バージョンが使用され、すなわち、1つの同位体標識アミノ酸がTUMAP合成に含まれた。これらの複合体は、新鮮に調製された組織溶解産物に、すなわち、TUMAP単離手順の可能な限り早い時点で添加され、次に、以下の親和性精製において、天然ペプチド/MHC複合体のように捕捉された。したがって単一標識TUMAPの回収率を測定することで、個々の天然TUMAPの単離効率に関する結論が可能になる。
絶対ペプチド定量化に供した組織サンプルの細胞数を測定するために、本発明者らは、DNA含量分析を適用した。この方法は、異なる起点の幅広いサンプルに、最も重要なことには、冷凍サンプルに適用できる(Alcoser et al.,2011;Forsey and Chaudhuri,2009;Silva et al.,2013)。ペプチド単離プロトコル中に、組織サンプルを均質溶解産物に処理して、それから小さな溶解産物アリコートを取り出す。アリコートを3つに分割し、それからDNAを単離する(QiaAmp DNA Mini Kit、独国ヒルデンのQiagen)。蛍光ベースのDNA定量化アッセイ(Qubit dsDNA HS Assay Kit、独国ダルムシュタットのLife Technologies)を使用して、少なくとも2つの反復試験において、各DNA単離からの全DNA含有量を定量化する。
前述の実験のデータを用いて、本発明者らは、サンプルの全ペプチド量を総細胞数で除算して、それに続いて単離効率により除算することで、細胞当たりのTUMAPコピー数を算出した。選択されたペプチドの細胞コピー数は、表22に示される。
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Claims (19)
- 配列番号32に示されるアミノ酸配列からなるペプチドまたはその薬学的に許容可能な塩であって、前記ペプチドが、主要組織適合性複合体(MHC)クラスIもしくはII分子に結合する能力を有し、前記MHCに結合すると、CD4および/もしくはCD8T細胞によって認識されることができるようになるペプチド、またはその薬学的に許容可能な塩。
- 請求項1に記載のペプチドが、修飾され、および/もしくは非ペプチド結合を含むペプチド、またはその薬学的に許容可能な塩。
- HLA-DR抗原関連不変鎖(Ii)のN末端アミノ酸と、請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩を含んでなる、融合タンパク質。
- MHC分子と結合すると、請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩を特異的に認識する、または、請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩を特異的に認識する、可溶性抗体もしくは膜結合抗体もしくは該抗体フラグメント。
- 前記抗体または該抗体フラグメントが、
(i)モノクローナル抗体及び/またはヒト化抗体、または該抗体フラグメント、または
(ii)MHC分子と結合すると請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩を認識し、二重特異性抗体及び/またはキメラ抗体、または該抗体フラグメント
である、請求項4に記載抗体または該抗体フラグメント。 - MHC分子と結合すると、HLAリガンドと反応する可溶性または膜結合性であるT細胞受容体(TCR)であって、前記リガンドが請求項1に記載のペプチドもしくはその薬学的に許容可能な塩である、T細胞受容体、または
MHC分子と結合すると、HLAリガンドと反応する可溶性または膜結合性であるT細胞受容体(TCR)であって、前記リガンドが請求項1に記載のペプチドもしくはその薬学的に許容可能な塩である、T細胞受容体であって、該T細胞受容体が可溶性分子として提供され、さらに免疫刺激ドメインまたは毒素を含むエフェクター機能を保有する、T細胞受容体。 - 請求項1もしくは2に記載のペプチドまたは請求項6に記載のTCRをエンコードする核酸、または
請求項1もしくは2に記載のペプチドまたは請求項6に記載のTCRをエンコードする核酸であって、該核酸が異種プロモーター配列と結合する核酸。 - 請求項7に記載の核酸を発現する能力がある、発現ベクター。
- 請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩、請求項7に記載の核酸または請求項8に記載の発現ベクターを含んでなる組換え宿主細胞、または
請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩、請求項7に記載の核酸、または請求項8に記載の発現ベクターを含んでなる組換え宿主細胞であって、該宿主細胞が樹状細胞を含む抗原提示細胞である、組換え宿主細胞。 - 医療において使用するための、請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩、請求項3に記載の融合タンパク質、請求項7に記載の核酸、請求項8に記載の発現ベクター、または請求項9に記載の宿主細胞を含んでなる、医薬。
- 請求項1に記載のペプチドを提示する、請求項9に記載の宿主細胞を培養するステップと、前記ペプチドを前記宿主細胞またはその培養液から単離するステップとを含んでなる、または
請求項7に記載の核酸を発現する、請求項9に記載の宿主細胞を培養するステップと、前記ペプチドまたは前記TCRを前記宿主細胞またはその培養液から単離するステップとを含んでなる、または
請求項8に記載の発現ベクターを含んでなる、請求項9に記載の宿主細胞を培養するステップと、前記ペプチドまたは前記TCRを前記宿主細胞またはその培養液から単離するステップとを含んでなる、
請求項1に記載のペプチド、または請求項6に記載のT細胞受容体を製造する方法。 - T細胞を、適切な抗原提示細胞の表面に、または抗原提示細胞を模倣する人工コンストラクトの表面に発現される抗原負荷ヒトクラスIまたはII MHC分子に、前記T細胞を抗原特異的様式で活性化するのに十分な時間にわたり、生体外で接触させるステップを含んでなり、前記抗原が、請求項1に記載のペプチドもしくはその薬学的に許容可能な塩である、活性化Tリンパ球を製造するインビトロ法。
- 請求項1に記載のペプチドを提示する細胞を選択的に認識する、請求項12に記載の方法によって製造される活性化Tリンパ球。
- 請求項13に記載の活性化Tリンパ球を含んでなる標的細胞死滅剤であって、その標的細胞が、請求項1に記載のペプチドを提示する患者のものである標的細胞死滅剤。
- 請求項1もしくは2に記載のペプチドもしくはその薬学的に許容可能な塩、請求項3に記載の融合タンパク質、請求項4もしくは5に記載の抗体もしくは該抗体のフラグメント、請求項6に記載のT細胞受容体、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、または請求項13に記載の活性化Tリンパ球からなる群から選択される、少なくとも1つの活性成分及び薬学的に許容可能な担体を含んでなる、医薬組成物。
- がんに対する薬剤の製造のための、請求項1もしくは2に記載のペプチドまたはその薬学的に許容可能な塩、請求項3に記載の融合タンパク質、請求項4もしくは5に記載の抗体もしくは該抗体のフラグメント、請求項6に記載のT細胞受容体、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、または請求項13に記載の活性化Tリンパ球の使用。
- 請求項1もしくは2に記載のペプチドもしくはその薬学的に許容可能な塩、請求項3に記載の融合タンパク質、請求項4もしくは5に記載の抗体もしくは該抗体のフラグメント、請求項6に記載のT細胞受容体、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、請求項13に記載の活性化Tリンパ球、または請求項15に記載の医薬組成物を含んでなる、がんの診断及び/または治療のための医薬。
- がんが、請求項1に記載のペプチドが由来するタンパク質の過剰発現を示す、慢性リンパ球性白血病(CLL)、非小細胞および小細胞肺がん(NSCLC、SCLC)、卵巣がん(OC)、黒色腫(MEL)、および子宮がん(UEC)の群から選択される、請求項16に記載の使用、または請求項17に記載の医薬。
- (a)請求項1もしくは2に記載のペプチドもしくはその薬学的に許容可能な塩、請求項3に記載の融合タンパク質、請求項4もしくは5に記載の抗体もしくは該抗体のフラグメント、請求項6に記載のT細胞受容体、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、または請求項13に記載の活性化Tリンパ球を含有する医薬組成物を溶液または凍結乾燥形態で含んでなる容器;及び
(b)前記凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器
を含んでなる、または
(a)請求項1もしくは2に記載のペプチドもしくはその薬学的に許容可能な塩、請求項3に記載の融合タンパク質、請求項4もしくは5に記載の抗体もしくは該抗体のフラグメント、請求項6に記載のT細胞受容体、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、または請求項13に記載の活性化Tリンパ球を含有する医薬組成物を溶液または凍結乾燥形態で含んでなる容器;及び
(b)前記凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器を含んでなるキットであって、(iii)緩衝液、(iv)希釈剤、(v)フィルター、(vi)針もしくは(vii)シリンジから選択される1つもしくは複数をさらに含んでなる、
キット。
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