JP2017525336A - 数種の血液腫瘍、特に慢性リンパ性白血病(cll)に対する新規免疫療法 - Google Patents
数種の血液腫瘍、特に慢性リンパ性白血病(cll)に対する新規免疫療法 Download PDFInfo
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Abstract
Description
表5:本発明によるより好ましいペプチドおよび治療される疾患
a)がん精巣抗原:T細胞によって認識され得る、これまでに同定された最初の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で発現し、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またはNY−ESO−1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。
(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;および
(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リガンドは、質量分析法によって同定された
2.マイクロアレイによる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(CLL)中の遺伝子過剰発現が同定された
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。ステップ2で検出された、選択的発現または過剰発現された遺伝子によってコードされたペプチドは、多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(またはまれな検出)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細胞応答の誘導が可能かどうかを評価するために、健常ドナーならびにCLL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が実施された。
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
患者の腫瘍サンプルは、University of Tubingen,Tubingen,Germanyによって提供された。全ての患者の告知に基づく同意書が与えられた。リガンドーム解析では、CLL患者(>80%CLL細胞出現頻度)に由来するPBMC、ならびに健常ボランティア(HV)に由来するPBMCが、密度勾配遠心分離によって単離された。告知に基づく同意は、ヘルシンキプロトコルに従って得られた。この試験は、地域倫理委員会の指針に準拠して実施された。HLAタイピングは、Department of Hematology and Oncology,Tubingenによって実施された。サンプルは、さらなる使用まで−80℃で保存された。
健康な自己由来Bリンパ球との比較のために、少なくとも0.5%のCD5−CD19+正常B細胞を含有する患者サンプル中で、HLA表面発現の定量化が実施された。HLA表面発現は、QIFIKIT(登録商標)定量的フローサイトメトリーアッセイ(Dako)を使用して、製造会社の使用説明書に準拠して分析された。手短に述べると、各三つ組み試験サンプルが、汎HLAクラスI特異的モノクローナル抗体(mAb)W6/32、HLA−DR特異的mAbL243(どちらも社内で作成)またはIgGアイソタイプ対照(BioLegend)で、それぞれ染色された。表面マーカー染色は、直接標識CD3(BD)、CD5(BD)、およびCD19(BD)抗体を用いて実施された。FACSCanto Analyzer(BD)上のフローサイトメトリー分析の直前に、7−AAD(BioLegend)が生存マーカーとして添加された。
HLAクラスIおよびII分子は、以前記載されたような標準イムノアフィニティー精製を用いて単離された。手短に述べると、スナップ凍結細胞ペレットが、1×プロテアーゼ阻害剤を含有する(Complete、Roche,Basel,Switzerland)、10mMのCHAPS/PBS(AppliChem,St.Louis,MO,USA/Gibco,Carlsbad,CA,USA)中で溶解された。HLA分子は、それぞれCNBr活性化セファロース(GE Healthcare,Chalfont St Giles,UK)に共有結合する、汎HLAクラスI特異的mAb W6/32および汎HLAクラスII特異的mAb Tu39を使用して、シングルステップで精製された。HLA:ペプチド複合体は、0.2%トリフルオロ酢酸(TFA、Merck,Whitehouse Station,NJ,USA)の反復添加によって溶出された。溶出画分E1〜E8は貯留されて遠心分離濾過ユニット(Amicon、Millipore,Billerica,MA,USA)を使用して、限外濾過によって遊離HLAリガンドが単離された。HLAリガンドは、ZipTip C18ピペット(Millipore)先端を使用して、濾液から抽出され脱塩された。抽出されたペプチドは、35μlの80%アセトニトリル(ACN、Merck)/0.2%TFA中で溶出され、完全に乾燥するまで遠心分離され、25μlの1%ACN/0.05%TFAに再懸濁された。サンプルは、LC−MS/MSによる分析まで、−20℃で保存された。
ペプチドサンプルは、逆相液体クロマトグラフィー(nanoUHPLC、UltiMate 3000 RSLCnano、ThermoFisher,Waltham,MA,USA)によって分離され、引き続いてオンライン接続されたLTQ Orbitrap XLハイブリッド質量分光計(ThermoFiher)中で分析された。サンプルは、5回の技術的複製中で分析された。5μl(サンプルの20%に相当する)のサンプル容積が、75μm×2cm捕捉カラム(Acclaim PepMap RSLC、ThermoFisher)に、4μl/分で5.75分間にわたり注入された。引き続いてペプチド分離が、50μm×50cm分離カラム(Acclaim PepMap RSLC、ThermoFisher)上で、2.4から32.0%に及ぶACN勾配を適用して、50℃および175nl/分の流速で140分間にわたり実施された。溶出ペプチドは、ナノスプレーイオン化によってイオン化され、調査スキャンで最も豊富な5つの前駆イオンのフラグメントスペクトルを生じる、トップ5CID(衝突誘起解離)法を実装する、質量分光計内で分析された。分解能は、60,000に設定された。HLAクラスIリガンドでは、質量範囲は400〜650m/zに限定され、電荷状態2および3が断片化を許された。HLAクラスIIでは、300〜1,500m/zの質量範囲が分析されて、電荷状態≧2が断片化を許された。
データ処理のために、ソフトウェアProteome Discoverer(v1.3、ThermoFisher)を使用して、Swiss−Protデータベース(www.uniprot.org、リリース:2013年9月27日;20,279個の概説されるタンパク質配列が含まれる)に含まれるヒトプロテオームに対する、Mascot検索エンジン(Mascot 2.2.04、Matrix Science)の検索結果が組み込まれた。検索は、技術的複製のデータを統合し、酵素特異性によって制限されなかった。前駆体質量許容差は5ppmに、フラグメント質量許容差は0.5Daに設定された。酸化メチオニンは、動的修飾として許容された。偽発見率(FDR)は、シャッフルされた標的データベースからなるデコイデータベースに対するプロセッシングに基づいて、Percolatorアルゴリズムによって判定された。FDRは、q≦0.05(5%FDR)の目標値に設定された。q≦0.05があるペプチドスペクトラムマッチ(PSM)は、相加的直交パラメータに従ってフィルターされ、スペクトル品質および妥当性が保証された。Mascotスコアは、≧20にフィルターされた。HLAクラスIでは、ペプチド長は、8〜12アミノ酸(aa)長に限定された。HLAクラスIIでは、ペプチドは、12〜25aa長に限定された。タンパク質分類は無効にされて、ペプチド(例えば、複数のタンパク質中への保存配列マッピング)の複数の注釈が許された。品質管理のために、サンプル当たり、≧300のユニークなHLAクラスIリガンドおよび≧100のユニークなHLAクラスIIリガンドの収率閾値が適用された。HLA注釈は、SYFPEITHI(www.syfpeithi.de)または拡張社内データベースを使用して実施された。
治療過程にわたる相対HLAリガンド存在量の無標識定量化(LFQ)のために、注射された対合サンプルペプチド量が正規化されて、各サンプル毎に5つの技術的複製で、LC−MS/MS分析が実施された。
自動ペプチド合成装置EPS221(Abimed)を使用して、記載されるような9−フルオレニルメチル−オキシカルボニル/tert−ブチル(Fmoc/tBu)ストラテジーを使用して、ペプチドが合成された。合成ペプチドが、LC−MS/MS同定の検証のため、ならび機能的実験のために使用された。
CLL患者および健常ボランティアからのPBMCが、10%貯留ヒト型血清(PHS、社内製造)、100mMのβ−メルカプトエタノール(Roth,Karlsruhe,Germany)、および1%ペニシリン/ストレプトマイシン(GE)が添加されたRPMI1640培地(Gibco)中で、培養された。CD8+T細胞刺激では、PBMCが解凍されて、1μg/mlペプチドでパルス処理された。ペプチドパルス処理PBMC(5〜6×106細胞/ml)は、37℃および5%CO2で、12日間培養された。0日目および1.5日目に、5ng/mlのIL−4(R&D systems,Minneapolis,MN,USA)および5ng/mlのIL−7(Promokine,Heidelberg,Germany)が、培養液に添加された。3、5、7、および9日目に、2ng/mlのIL−2(R&D systems)が培養液に添加された。ペプチド刺激PBMCは、12日目にELISPOTアッセイによって、13日目に細胞内サイトカイン染色によって、それぞれ機能解析された。CD4+T細胞刺激では、培養は、次の2つの修正を加えて、CD8+T細胞について記載されたようにして実施された:パルス処理は10μg/mlのHLAクラスIIペプチドを用いて実施され、IL−4およびIL−7は添加されなかった。
IFN−γELISPOTアッセイは、以前記載されたようにして実施された(33)。手短に述べると、96ウェルニトロセルロースプレート(Millipore)が、1mg/mlのIFN−γmAb(Mabtech,Cincinnati,OH,USA)で被覆され、4℃で一晩培養された。プレートは、10%PHSによって37℃で2時間ブロックされた。5×105個の細胞/ウェルの予備刺激PBMCが、1μg/ml(HLAクラスI)または2.5μg/ml(HLAクラスII)ペプチドでパルス処理されて、24〜26時間培養された。読み取りは、製造会社の使用説明書に従って実施された。スポットは、ImmunoSpot S5分析器(CTL,ShakerHeights,OH,USA)を使用して計数された。>15スポット/ウェルカウントされ、ウェルあたりの平均スポットカウントが、陰性対照ウェルの平均スポット数よりも少なくとも3倍高ければ、T細胞応答は陽性と見なされた(がんイムノガイディングプログラム(CIP)ガイドラインに準拠する)。
ペプチド特異的CD8+T細胞の発生頻度および機能性は、細胞内IFN−γおよびTNF−α染色によって分析された。PBMCは、1μg/mlの個々のペプチドでパルス処理されて、10μg/mlのBrefeldin A(Sigma,St.Louis,MO,USA)および10μg/mlのGolgiStop(BD)の存在下で6〜8時間培養された。細胞は、Cytofix/Cytoperm(BD)、CD8−PECy7(Beckman Coulter,Fullerton,CA,USA)、CD4−APC(BD Bioscience)、TNF−α−PE(Beckman Coulter)、およびIFN−γ−FITC(BD)を使用して標識された。サンプルは、FACS Canto II上で分析された。
原発性CLL細胞は自己由来正常B細胞と比較してHLA発現の損失または下方制御を示さない
悪性腫瘍中のHLA損失または下方制御は、T細胞ベースの免疫療法の主要な限界を提起してもよい。したがって、最初のステップとして、本発明者らは、自己由来CD19+CD5−Bリンパ球と比較して、CD19+CD5+CLL細胞上で、HLA発現レベルを評価した。HLA表面レベルは、7人のCLL患者のパネルにおいて、フローサイトメトリーによって定量化された。HLA表面発現レベルは、患者個人不均一性を明らかにし、全HLAクラスI分子カウントは、CLL細胞上の約42,500〜288,500個の分子/細胞、および正常B細胞上の約32,000〜256,500個の分子/細胞に及ぶ。3連でのHLA表面発現の患者個人分析は、4/7の患者において、小さいが、有意な発現レベルの差を明らかにした(P<0.01)(図1a)。HLA−DR発現は、CLL細胞上で約29,000〜100,500、B細胞上で約19,500〜79,500に及んだ。HLA−DRレベル(P<0.01)の軽微な差異が、5/7の患者で検出された。正常B細胞と比較したCLL細胞上の平均HLA表面発現の統計解析は、HLAクラスIおよびII発現に有意な差異がないことを示した(図1c、d)。総合すると、これらのデータは、正常B細胞との比較してHLA損失または下方制御の形跡なしに、CLL細胞上における高レベルのHLAクラスIおよびII発現を示す。
30人のCLL患者のHLAクラスIリガンドームをマッピングすることで、本発明者らは、7,377個の起源タンパク質に相当する全部で18,844個の異なるペプチドを同定し得て、最大達成可能カバー度の>95%を達成した(図7)。患者当たりで同定された異なるペプチド数は、345〜2,497に及んだ(平均値1,131)。全体として、30を超える異なるHLA−Aおよび−B対立遺伝子によって拘束されるペプチド(白人母集団_ENREF_27の>99%をカバーする)が、この試験で同定された。30人のPBMCドナーのHVコホートでは、7,180個の異なる起源タンパク質に相当する、合計17,322個のユニークなペプチドが同定された(>90%カバー度)。HVコホート中のHLA対立遺伝子分布は、CLL患者コホート中のHLA−Aの100%およびHLA−B対立遺伝子の>80%をカバーした。
新規CLL関連抗原を同定するために、本発明者らは、CLLおよびHVコホートのHLAリガンド起源プロテオームを比較した。HLA起源タンパク質重複分析は、CLLのHLAリガンドーム中で、2,148個のタンパク質(マッピングされたCLL起源プロテオームの29.1%)が、排他的に表示されることを明らかにした(図2a)。幅広く適用できる既製ペプチドワクチンを設計する目的で、本発明者らは、引き続いて、以下の基準に従って、可能な標的の選択に優先順位をつけた:
CLL排他性は、最重要基準と定義され、CLLリガンドーム中の表示の出現頻度に従った抗原格付けがそれに続く(図2b)。本発明者らのプラットフォームは、CLL患者の≧20%でCLL限定的表示を示す、225個の異なるHLAリガンドによって表示される、49個の起源タンパク質(CLL起源プロテオームの0.7%)を強調した。同一抗原格付けストラテジーをHV PBMC限定的抗原に適用することで、71個のリガンドーム由来良性組織結合抗原(LiBAA)と298個の対応するリガンド(LiBAP)の組が同定され、免疫学的アッセイで内部対照として使用された。
新規CLL関連抗原の同定と並んで、二次的アプローチは、天然に提示されるHLAリガンドの本データセット内の小数の確立されたCLL抗原の格付けに焦点を合わせた。本発明者らは、8個の記載されるCLL関連抗原に相当する、28個の異なるHLAリガンドを同定できた。注目すべきことに、フィブロモジュリン(FMOD−324−333、RINEFSISSF、HLA−A*23(配列番号526)のみが、CLL患者コホートにおける低い表示出現頻度のために、本データセット中のCLL抗原の#437に格付けされるCLL限定的表示を示した。残りの7個の抗原は、CLL上およびHV PBMC双方の上で表示を示し、したがってCLL排他性という最重要基準を満たせなかった。しかし、CD19、CD20、RHAMM、およびPRAMEでは、様々な程度のCLL関連過剰出現が検出された(図2c)。
異なる病期にわたる新規標的の適用性を評価するために、本発明者らは、ビネーA(n=9)、B(n=7)、およびC(n=14)の病期にある患者を比較する、部分集合特異的リガンドームプロファイリングを実施した。2,148個のCLL排他的起源タンパク質の重複分析からは、それらの内550個(25.6%)が、少なくとも2つの病期で共有され、137個のタンパク質(6.1%)のコアグループが、全ての3つの病期にある患者で表示されることが分かった(図2d)。注目すべきことに、共通起源タンパク質のコアグループに属するLiTAAの45/49(91.8%)は、3つの部分集合の全てで表示された。ビネー病期A、B、およびCにわたる、全ての49個のLiTAAの表示頻度の色分け地図解析は、図2eに示される。
本発明者らのHLAクラスI LiTAPの免疫原性および特異性を評価するために、本発明者らは、次に、12日間免疫復活IFNγ ELISPOTアッセイを実施した。15個のLiTAP(6A*02、4A*03、および5B*07 LiTAPs)のパネルが、CLL患者および健常ボランティアから得られたHLAマッチPBMCの刺激のために実装された(図3a)。本発明者らは、CLL患者(3/4A*03(図3c)、6/6A*02および5/5B*07 LiTAP(図8c、f))では、試験されたLiTAPの14/15(93.3%)についてIFNγ分泌を観察したが、健常対照では見られなかった(0/10、図3b、図8b、e)。これらの知見は、PA * 03 3 (DMXL11271−1279SSSGLHPPK)について、CD8+T細胞の四量体染色、およびIFNγとTNFαの細胞内サイトカイン染色によって、例示的に確認された(図9a、b)。HLAマッチ良性組織由来LiBAPを使用したELISPOTアッセイが実施されて、CLL患者において観察されたLiTAP指向免疫認識のCLL特異性が調節された。本発明者らは、9個のLiBAP(3個のA*02、3個のA*03、3個の*B*07)のパネルを試験して、試験されたCLL患者のいずれにおいても、有意なIFNγ分泌がないことを観察した(0/7A*03(図3d)、0/10A*02+、および0/5B*07(図8a、d))。
CD4+T細胞が抗がん免疫応答において果たす重要な間接的および直接的役割の理由から、最適ワクチン設計は、追加的なHLAクラスIIエピトープの組み入れを必要とする。本発明者らは、CLLおよびHV PBMCリガンドームの重複分析を実施して、CLL患者のリガンドーム中で、937個のタンパク質(同定されたCLL起源タンパク質の63.0%)が排他的に表示されることを同定した(図4a)。HLAクラスIについて記載される同一抗原格付けストラテジーを適用することで、本発明者らは、460個の対応するLiTAPによって表示される、73個のHLAクラスII LiTAAを同定した(図4b)。IFNγ ELISPOTアッセイにおける7個のHLAクラスII LiTAPのパネルの機能特性解析(図4c)は、CLL患者(図4e)では、6/7(85.7%)LiTAPについて有意なIFNγ分泌を明らかにしたが、健常対照(0/10、図4d)では見られなかった。次に、本発明者らは、共通の相乗的標的を同定するために、HLAクラスIおよびIIリガンドームの複合解析を実施した。CLL限定的起源タンパク質の重複分析は、132個のタンパク質が、HLAクラスIおよびIIリガンドームの双方で表示されることを明らかにした(図4f)。色分け地図解析は、リガンドーム(B4GALT1(26.7%クラスI/30.0%クラスII)、HLA−DMA(20.0%クラスI/20%クラスII)、図4g)の双方で≧20%の表示頻度を提示する2個のタンパク質を同定した。際だったことに、クラスI LiTAP(HLA−DMA206−214、HEIDRYTAI、B*18)の1つは、対応するHLAクラスII LiTAP(VTHEIDRYTAIAY(配列番号924))に完全に包埋されていることが明らかにされた。総合して、本発明者らは、T細胞エピトープとして確認し得たクラスII LiTAPのパネル、並びにクラスI LiTAAをカバーする一連の可能な相乗的HLAクラスIIリガンドを同定した。
ペプチドベースの免疫療法の範囲は、MRDの維持療法および根除である。結果として、CLLにおけるペプチドワクチン接種は、標準化学/免疫療法後に行われる。したがって、本発明者らは、異なる薬剤投与計画が実施されたCLL患者の異なる時点にわたり、HLA発現を解析して、リガンドームプロファイリングを実施した。
最終段階として、本発明者らは、>1のLiTAP特異的(n=10)T細胞応答と対比して、0〜1のLiTAP特異的(n=23)T細胞応答がある症例を比較するELISPOTアッセイによって分析された(図6b)、33人のCLL患者の後向き生存分析を実施した(図6a)。低応答コホートでは6/23(26.1%)の患者、高応答コホートでは0/11の患者が死亡した。全生存期間は、>1免疫反応を示すコホートで長期化するようである。
ペプチドの合成
全てのペプチドは、Fmocストラテジーを使用する、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合成された。分取RP−HPLCによる精製後、イオン交換法を実施して、生理学的適合性カウンターイオン(例えばトリフルオロ酢酸、酢酸、アンモニウムまたは塩化物)が組み込まれた。
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は、それらのMHC結合能力(親和性)についてさらに試験された。個々のペプチドMHC複合体は、切断感受性ペプチドが切断されて、分析される関心のあるペプチドで交換される、ペプチドリガンド交換によって製造された。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、概して、Rodenko et al.(Rodenko et al.,Nat Protoc.1(2006):1120−1132)に記載されるようにして実施された。
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調査を実施した。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。
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、University clinics Mannheim,Germanyから得られた健常ドナーのCD8ミクロビーズ(Miltenyi Biotec,Bergisch−Gladbach,Germany)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。
試験されたHLAクラスIペプチドでは、ペプチド特異的T細胞系の生成によって、生体外免疫原性が実証され得た。代表的結果として、ペプチドKFAEEFYSF(配列番号20)は、試験されたドナー5人の内2人で、生体外T細胞応答をもたらした。
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
本発明のHLA−A*02結合ペプチドの分析/確認のために、ペプチド同定で使用されるサンプルの他に、正常および腫瘍(CLL)組織の双方を含んでなる非依存性サンプルセットが使用された。全ての患者の告知に基づく同意書は、外科手術または検死解剖前に得た。組織は切除直後に衝撃凍結されて、TUMAPの単離まで−70℃未満で保存された。
衝撃凍結組織サンプルからのHLAペプチド貯留は、わずかに改変されたプロトコル(Falk et al.,Nature 351(1991):290−296;Seeger et al.,Immunogenetics 49(1999):571−576)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、固形組織からの免疫沈殿によって得られた。
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され、ESI源を装着したLTQ−velosおよびfusionハイブリッド質量分光計(ThermoElectron)内で溶出ペプチドが分析された。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、挿入された。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、ペプチドが分離された。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)が使用された。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された。手短に述べると、スキャンサイクルは、Orbitrap(R=30000)内の高質量精度の完全スキャンで開始され、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、あらかじめ選択されたイオンは動的に除外された。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された。同定されたペプチド配列は、生じ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定された。
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Claims (48)
- 配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016から選択される配列と少なくとも80%同一であるアミノ酸配列を含んでなる、9〜100アミノ酸長のペプチド、またはその薬学的に許容可能な塩。
- 前記ペプチドが、ヒト主要組織適合性複合体(MHC)クラスI分子および/またはヒト主要組織適合性複合体(MHC)クラスII分子に結合する能力を有する、請求項1に記載のペプチド。
- 前記ペプチドが、9〜30アミノ酸長である、請求項1に記載のペプチド。
- 10アミノ酸長以下のN末端および/またはC末端アミノ酸伸長を含んでなる、請求項1に記載のペプチド。
- (a)配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016と少なくとも80%同一であるアミノ酸配列からなるペプチド;
(b)10アミノ酸長以下のコア配列のN末端伸長を有する(a)のペプチド;および
(c)10アミノ酸長以下のC末端伸長を有する(a)または(b)のペプチド
からなる群から選択される、請求項1〜3のいずれか一項に記載のペプチド。 - 前記アミノ酸配列が、配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016と少なくとも90%同一である、請求項1〜5のいずれか一項に記載のペプチド。
- 前記アミノ酸配列が、配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016と少なくとも95%同一である、請求項1〜6のいずれか一項に記載のペプチド。
- 前記アミノ酸配列が、配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016のいずれかを含んでなる、請求項1〜6のいずれか一項に記載のペプチド。
- 前記アミノ酸配列が、配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016のいずれかからなる、請求項1または2に記載のペプチド。
- 前記ペプチドが、修飾されおよび/または非ペプチド結合を含む、請求項1〜9のいずれか一項に記載のペプチド。
- 配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016からなる群から選択されるアミノ酸配列と少なくとも80%の同一性を有するHLAリガンドと、反応性のT細胞受容体。
- 前記アミノ酸配列が、配列番号1〜配列番号225または配列番号543〜配列番号1016と少なくとも(to least)90%、または少なくとも95%同一である、請求項11に記載のT細胞受容体。
- 前記アミノ酸配列が、配列番号1〜配列番号225または配列番号543〜配列番号1016のいずれかを含んでなる、請求項11または12に記載のT細胞受容体。
- 前記アミノ酸配列が、配列番号1〜配列番号225、配列番号226〜配列番号542または配列番号543〜配列番号1016のいずれかからなる、請求項11〜13のいずれか一項に記載のT細胞受容体。
- (a)配列番号1〜配列番号225または配列番号543〜配列番号1016と少なくとも80%同一であるアミノ酸;および
(b)HLA−DR抗原関連不変鎖(Ii)のN末端アミノ酸1〜80
を含んでなる、融合タンパク質。 - 前記(a)のアミノ酸配列が、配列番号1〜配列番号225または配列番号543〜配列番号1016と少なくとも90%若しくは少なくとも95%同一である、請求項15に記載の融合タンパク質。
- 前記(a)のアミノ酸配列が、配列番号1〜配列番号225または配列番号543〜配列番号1016を含んでなる、請求項16に記載の融合タンパク質。
- (a)請求項1〜10のいずれか一項に記載のペプチド;
(b)請求項11〜14のいずれか一項に記載のT細胞受容体;または
(c)請求項15〜17のいずれか一項に記載の融合タンパク質をエンコードする核酸。 - DNA、cDNA、PNA、RNAまたはそれらの組み合わせである、請求項に18記載の核酸。
- 請求項18または19に記載の核酸を含んでなる、発現ベクター。
- 請求項18または19に記載の核酸、または請求項20に記載の発現ベクターを含んでなる、宿主細胞。
- 例えば、樹状細胞などの抗原提示細胞である、請求項21に記載の宿主細胞。
- 請求項1〜10のいずれか一項に記載のペプチド、請求項12〜14のいずれか一項に記載のT細胞受容体、または請求項15〜17のいずれか一項に記載の融合タンパク質を製造する方法であって、請求項21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前記ペプチド、前記T細胞受容体、または前記融合タンパク質を単離するステップとを含んでなる、方法。
- CTLを適切な抗原提示細胞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CTLが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1〜10のいずれか一項に記載のペプチドである、活性化細胞傷害性Tリンパ球(CTL)を製造するためのインビトロ法。
- 前記抗原が、十分な量の前記抗原を抗原提示細胞に接触させることで、適切な抗原提示細胞の表面に発現されるクラスIまたはII MHC分子上に負荷される、請求項24に記載の方法。
- 前記抗原提示細胞が、請求項1〜9のいずれか一項に記載の前記ペプチドを発現する能力がある発現ベクターを含んでなる、請求項25に記載の方法。
- 請求項24〜26のいずれか一項に記載の方法によって製造される、活性化細胞毒性Tリンパ球(CTL)。
- 前記患者に請求項27に記載の細胞傷害性Tリンパ球(CTL)の有効数を投与するステップを含んでなる、患者において標的がん細胞を死滅させる方法。
- 薬剤としての、または薬剤の製造における、請求項1〜10のいずれか一項に記載のペプチド、請求項12〜14のいずれか一項に記載のT細胞受容体、請求項15〜17のいずれか一項に記載の融合タンパク質、請求項18または19に記載の核酸、請求項20に記載の発現ベクター、請求項22または23に記載の宿主細胞、または請求項27に記載の活性化細胞傷害性Tリンパ球の使用。
- 前記薬剤がワクチンである、請求項29に記載の使用。
- 前記薬剤ががんに対して有効である、請求項29または30に記載の使用。
- 前記がんが、慢性リンパ管白血病(CLL)および/または急性骨髄性白血病(AML)である、請求項29〜31のいずれか一項に記載の使用。
- 請求項1〜10のいずれか一項に記載のペプチドからなる群から選択される少なくとも1つの活性成分、請求項12〜14のいずれか一項に記載のT細胞受容体、請求項15〜17のいずれか一項に記載の融合タンパク質、請求項18または19に記載の核酸、請求項20に記載の発現ベクター、請求項22または23に記載の宿主細胞、および請求項27に記載の活性化細胞毒性Tリンパ球、および薬学的に許容可能な担体を含んでなる、医薬組成物。
- a)APOBEC0D、CDK14、RASGRF1、CDCA4L、CELSR3、AKAP0、CTDP0、DNMBP、TAGAP、ABCA3、DMXL0、PARP2、TP53I11、B2GALT0、IRF6、KDM1B、TBC0D22A、ZNF296、BACH1、PRR12、ZFAND3、ATP4G0、DMD、ARID4B、ZNF638、DDX46、RRM1B、BLNK、HSH1D、ERP44、METTL5A、ELP2、NLRP1、ZC2H12D、NELFE、ATP5V0C0、HLA−DMA、TUFM、EIF5、CKAP3、COBLL0、TMED3、TNFRSF13C、UBL6、CXorf21、ASUN、SL24D0、およびTRAF7IP3からなる群から選択されるタンパク質に由来して、ヒト主要組織適合性複合体(MHC)クラスI分子および/またはヒト主要組織適合性複合体(MHC)クラスII分子に結合する能力を有するペプチド;
b)(a)に記載のペプチドと反応性のT細胞受容体;
c)(a)に記載のペプチドと、HLA−DR抗原関連不変鎖(Ii)のN末端アミノ酸1〜80とを含んでなる融合タンパク質;
d)a)〜c)のいずれかをコードする核酸、または前記核酸を含んでなる発現ベクター;
e)d)の発現ベクターを含んでなる宿主細胞;および
f)CTLを適切な抗原提示細胞の表面に発現されるa)に記載のペプチドと、前記CTL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、前記生体外で接触させるステップを含んでなる方法によって得られる、活性化細胞毒性Tリンパ球(CTL);および
薬学的に許容可能な担体
からなる群から選択される、少なくとも1つの活性成分を含んでなる医薬組成物。 - 請求項34に記載の医薬組成物の有効量を患者に投与するステップを含んでなる、患者において標的細胞を死滅させる方法。
- (a)少なくとも1つの原発性腫瘍サンプルから、および少なくとも1つの対応する正常な組織サンプルから、天然に提示されるHLAリガンドを溶出させて同定するステップと、
(b)同定された前記HLAリガンドに基づいて、前記少なくとも腫瘍サンプルおよび前記少なくとも正常な組織サンプルのリガンドームを作成するステップと;および
(c)a)前記少なくとも1つの腫瘍サンプルの細胞によって排他的に提示される抗原に由来し、b)前記少なくとも1つの腫瘍サンプルの前記リガンドーム中で高頻度の提示を示す、包含に適する少なくとも1つのHLAリガンドを選択するステップとを含んでなる、ペプチドベースのワクチンへの封入に適する腫瘍関連ペプチドを同定する方法。 - 前記提示頻度が、少なくとも5%、少なくとも10%、および少なくとも20%から選択される、請求項36に記載の方法。
- 複数のサンプルが使用されて、複数のリガンドームが作成される、請求項36または37に記載の方法。
- 個々の患者に由来する腫瘍サンプルがステップ(a)で使用される、請求項36〜38のいずれか一項に記載の方法。
- ステップ(c)の前記選択するステップが、対応する非腫瘍組織と比較して腫瘍中の免疫原性および過剰提示について予備選別されたペプチドのデータベースと、前記リガンドームを比較するステップを含んでなる、請求項36〜39のいずれか一項に記載の方法。
- 前記同定するステップが、前記腫瘍サンプルに由来するMHC分子から結合ペプチドを溶出させるステップと、前記溶出ペプチドを配列決定するステップとを含んでなる、請求項36〜40のいずれか一項に記載の方法。
- 前記少なくとも正常な組織サンプルの組織型が、前記患者に由来する腫瘍サンプルに対応する、請求項36〜41のいずれか一項に記載の方法。
- 前記データベースに含まれる前記ペプチドが、
1)前記腫瘍材料からのHLAリガンドを質量分析法によって同定するステップと;
2)マイクロアレイを使用する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、一連の正常組織と比較することで、腫瘍材料中で過剰発現される遺伝子を同定するステップと;
3)同定されたHLAリガンドを遺伝子発現データと比較するステップと;
4)ステップb)で検出された、特異的に発現または過剰発現される遺伝子によってコードされるペプチドを選択するテップと;
5)正常組織に対比して、ステップc)からの選択されたHLAリガンドを腫瘍組織上で再検出することで、mRNAレベルにおける過剰発現の関連性を確認するステップと;および
6)選択されたペプチドによって、生体内T細胞応答誘導が達成され得るかどうかを評価するために、患者または健常ドナーに由来するヒトT細胞を使用して、生体外免疫原性アッセイを実施するステップと
を含んでなる方法によって同定される、請求項40〜42のいずれか一項に記載の方法。 - 前記データベースに含まれる前記ペプチドの免疫原性が、生体外免疫原性アッセイ、個々のHLA結合に対する患者免疫モニタリング、MHC多量体染色、ELISPOTアッセイ、および細胞内サイトカイン染色の群から選択される方法によって判定される、請求項40〜43のいずれか一項に記載の方法。
- 前記データベースが、配列番号1〜配列番号1016のペプチドを含んでなる、請求項40〜44のいずれか一項に記載の方法。
- 前記個々の患者からの正常な対応する組織と比較して、前記腫瘍サンプルに固有の少なくとも1つの変異を有する、少なくとも1つのペプチドを同定するステップと、任意選択的に、前記ペプチドをワクチンへの包含のために選択するステップとをさらに含んでなる、請求項40〜45のいずれか一項に記載の方法。
- 前記少なくとも1つの変異が、全ゲノム配列決定によって同定される、請求項46に記載の方法。
- (c)に従って選択された少なくとも1つの腫瘍関連ペプチドを含んでなるペプチドベースのワクチンを製造するステップをさらに含んでなる、請求項36〜47のいずれか一項に記載の方法であって、前記ペプチドベースのワクチンが個別化される、方法。
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