JP7026970B2 - 白血病およびその他のがんに対する免疫療法において使用するためのペプチドおよびペプチドの組み合わせ - Google Patents
白血病およびその他のがんに対する免疫療法において使用するための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)。
白血病のグループ内で、本発明は特に、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)および急性骨髄性白血病(AML)に重点を置く。
慢性リンパ球性白血病: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。
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され、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および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れ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/または進行に関連している。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、腫瘍で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から、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、子宮頸がんで発現される、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あらゆるギャップも塩基またはアミノ酸として数えられる。
1.悪性物質からのHLAリガンドは、質量分析法によって同定された
2.ゲノムワイドメッセンジャーリボ核酸(mRNA)発現解析を使用して、悪性組織(慢性リンパ球性白血病、慢性骨髄性白血病、および急性骨髄性白血病)において過剰発現される遺伝子が、一連の正常臓器および組織と比較して同定された
3.同定されたHLAリガンドは、遺伝子発現データと比較された。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、文献調査が実施された
5.mRNAレベルでの過剰発現の関連性は、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(または稀な)検出によって確認された。
6.選択されたペプチドによる生体内T細胞応答の誘導が実行可能かどうかを評価するために、健常ドナーならびに慢性リンパ球性白血病、慢性骨髄性白血病、および急性骨髄性白血病患者からのヒトT細胞を使用して、生体外で免疫原性アッセイが実施された。
細胞表面上に提示された腫瘍関連ペプチドの同定
組織サンプル
患者の腫瘍サンプルおよび正常組織は、University Hospital Tubingen(独国チュービンゲン)から入手された。採血前に、全ての患者の告知に基づく同意書が与えられていた。PBMCは、採血直後にフィコール・ハイパック密度勾配遠心分離を使用して、血液サンプルから単離した。PBMCペレットペレットは外科手術の直後に衝撃凍結し、TUMAPの単離まで-70℃未満で保存した。
衝撃凍結サンプルからの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、免疫沈殿によって得た。
得られたHLAペプチド貯留を逆相クロマトグラフィー(Ultimate 3000 RSLC Nano UHPLCシステム,Dionex)によってそれらの疎水性に従って分離し、溶出ペプチドをESI源を備えたLTQ-OrbitrapおよびFusion Lumosハイブリッド質量分析計(ThermoElectron)で分析した。ペプチドサンプルを4μl/分の流速で10分間かけて、2cm PepMap 100 C18 Nanotrapカラム(Dionex)上に、3%の溶媒B(20%H2O、80%アセトニトリル、および0.04%ギ酸)と共に装填した。分離は、50℃で動作するカラムオーブンに取り付けられた、粒度2μmの25cmまたは50cmのPepMap C18カラム(Dionex)上で実施した。適用した勾配は、流速300nl/分(25cmのカラムの場合)で90分以内、または流速175nl/分(50cmのカラムの場合)で140分以内で3から40%の溶媒Bに及んだ。(溶媒A:99%H2O、1%ACNおよび0.1%ギ酸;溶媒B:20%H2O、80%ACNおよび0.1%ギ酸)。
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であろう。
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(独国ダルムシュタットのAmbion)を使用して、これらのサンプルから全RNAを調製し、RNeasy(独国ヒルデンのQIAGEN)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(独国チュービンゲン)によって、次世代配列決定(RNAseq)によって実施した。簡単に述べると、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(米国カリフォルニア州サンディエゴのIllumina Inc.)のプロトコルに従って、配列決定ライブラリーを作成する。複数のサンプルに由来するライブラリーを等モル混合し、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し、50bpのシングルエンドリードを生成する。処理された読み取りをSTARソフトウェアを使用して、ヒトゲノム(GRCh38)にマッピングする。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(Reads Per Kilobase per Million mapped reads: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によって作成される)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によって作成される)提供される。エクソン読み取りを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し、RPKM値を得る。
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*02:01、HLA-A*24:02、HLA-A*01:01、HLA-A*03:01、HLA-B*07:02、およびHLA-B*44:02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10aおよび表10b)。
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、独国マンハイムのUniversity clinicsから告知に基づく同意の後に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ハのMiltenyi Biotec)を用いた正の選択を通じて、新鮮なHLA-A*02、HLA-A*24、HLA-A*01、HLA-A*03、HLA-B*07またはHLA-B*44白血球除去生成物からCD8+T細胞を単離した。
試験されたHLAクラスIペプチドでは、ペプチド特異的T細胞株の生成によって、生体外免疫原性を実証し得た。本発明の14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2~図9に示される。本発明からの63個のペプチドに関する結果は、表10aおよび表10b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(lyophilizes)(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。
ペプチドMHCクラスI安定性
HLA-B*08:01ペプチドのペプチドMHC安定性は、ImmunAware(デンマーク国コペンハーゲン)によって実施した。近接度に基づく均一なリアルタイムアッセイを用いてデータを得て、HLAクラスI分子からのペプチドの解離を測定した。最初に、ヒト組換えHLA-B*08:01およびb2mを大腸菌において発現させ、一連の液体クロマトグラフィーベースの工程で精製した(Ferre et al.,2003;Ostergaard et al.,2001)。その後、MHC重鎖と会合したb2mの量を37℃で経時的に測定することによって、ペプチド‐MHC複合体(pMHC)の安定性を判定し得た。(Harndahl et al.,2012)。データを一相解離方程式に当てはめることによって、各重鎖に会合するb2mの半減期として表される各pMHCの安定性を計算した。
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Claims (15)
- 配列番号134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。
- MHCに結合した際に、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、請求項1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が、修飾されおよび/または非ペプチド結合を含む、修飾および/または非ペプチド結合ペプチド、またはその薬学的許容可能な塩。
- HLA-DR抗原関連不変鎖(Ii)の80個のN末端アミノ酸及び、請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩を含んでなる融合タンパク質、またはその薬学的許容可能な塩。
- MHC分子と結合する請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩を特異的に認識する、または請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩を特異的に認識する、抗体。
- MHC分子と結合した際に、請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩であるHLAリガントと反応する、または請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩であるHLAリガンドと反応する、T細胞受容体。
- 前記T細胞受容体が可溶性分子として提供され、免疫刺激ドメインまたは毒素から選択される、さらなるエフェクター機能を保有する、請求項6に記載のT細胞受容体。
- 請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩、請求項4に記載の融合タンパク質もしくはその薬学的許容可能な塩、請求項5に記載の抗体、または請求項6もしくは7に記載のT細胞受容体を含んでなる組換え宿主細胞であって、前記宿主細胞が、樹状細胞、T細胞またはNK細胞である抗原提示細胞から選択される、組換え宿主細胞。
- T細胞を、適切な抗原提示細胞の表面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1~3のいずれか一項に記載のペプチドまたはその薬学的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1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩、請求項4に記載の融合タンパク質もしくはその薬学的許容可能な塩、請求項5に記載の抗体、請求項6もしくは7に記載のT細胞受容体、または請求項8に記載の宿主細胞からなる群から選択される、少なくとも1つの活性成分、またはコンジュゲートされもしくは標識されたこれらの活性成分と、薬学的に許容可能な担体を含んでなる医薬組成物。
- 請求項8に記載の宿主細胞を培養するステップと、前記宿主細胞および/またはその培養液から、ペプチド、抗体、またはT細胞受容体を単離するステップとを含んでなる、請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩、請求項4に記載の融合タンパク質もしくはその薬学的許容可能な塩、請求項5に記載の抗体、または請求項6もしくは7に記載のT細胞受容体を製造する方法。
- がん治療用薬剤の製造のための、請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩、請求項4に記載の融合タンパク質もしくはその薬学的許容可能な塩、請求項5に記載の抗体、請求項6もしくは7に記載のT細胞受容体、または請求項8に記載の宿主細胞の使用。
- 前記がんが、配列番号134に示されるアミノ酸配列からなる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)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML);および非ホジキンリンパ腫、移植後リンパ球増殖性疾患(PTLD)によって代表されるその他のリンパ系新生物;ならびに原発性骨髄線維症、本態性血小板減少症、真性赤血球増加症から選択されるその他の骨髄性新生物;ならびに肝細胞がん、結腸直腸がん、神経膠芽腫、胃がん、食道がん、非小細胞肺がん、小細胞肺がん、膵臓がん、腎細胞がん、前立腺がん、黒色腫、乳がん、胆嚢がんおよび胆管がん、膀胱がん、子宮がん、頭頸部扁上皮がん、中皮腫から選択されるその他の新生物、およびその他の腫瘍の群から選択される、請求項12に記載の使用。
- (a)溶液または凍結乾燥形態にある、請求項1~3のいずれか一項に記載のペプチドもしくはその薬学的許容可能な塩、請求項4に記載の融合タンパク質もしくはその薬学的許容可能な塩、請求項5に記載の抗体、請求項6もしくは7に記載のT細胞受容体、または請求項8に記載の宿主細胞を含有する医薬組成物を含んでなる容器;または、前記(a)及び(b)配列番号1~配列番号133及び配列番号135~配列番号279に示されるアミノ酸配列からなる群から選択される少なくとももう1つのペプチド、を含んでなるキット。
- (iii)緩衝液、(iv)希釈剤、(v)フィルター、(vi)針及び(v)シリンジの群から選択される1つまたは複数をさらに含んでなる、請求項14に記載のキット。
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