JP2020506690A - 卵巣がん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新規ペプチドおよびペプチド組み合わせ - Google Patents
卵巣がん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新規ペプチドおよびペプチド組み合わせ Download PDFInfo
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Abstract
Description
2012年に23万9千件の新規症例が推定されている卵巣がんは、女性では7番目に最も頻度が高いがんであり、女性の全てのがんの4%に相当する。卵巣がんの致死率は、女性生殖器のその他のがんと比較してかなり高い傾向があり、症例致死率は資源により乏しい環境でより高い。そのため、卵巣がんは、女性の間で8番目に頻度の高いがん死亡原因であり、15万2千人が死亡している。2012年には、全ての新規症例のほぼ55%が、高いまたは非常に高い人間開発水準国で発生し;新規症例の37%および死亡例の39%が、欧州および北米で生じた。発生率は、北欧および東欧、北米、およびオセアニアで最大であり、アフリカおよびアジアの大半で比較的低い傾向にある。特に欧州および北米などの人間開発水準が非常に高い特定の国々では、発生率は漸減している。
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。
(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.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(卵巣がん)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細胞応答の誘導が可能かどうかを評価するために、健常ドナーならびに卵巣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
患者の腫瘍組織および正常組織は、University Hospital Tubingen(独国チュービンゲン)から入手された。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られた。組織は切除の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、HLA−DR特異的抗体L243および汎HLAクラスII特異的抗体Tu39、CNBr活性化セファロース、酸処理、および限外濾過を用いて、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32%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*0201、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11)。
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118個のペプチドに関する結果は、表11aおよび表11b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複合体の安定性
HLA−B*08:01ペプチドについて、ペプチド−MHC安定性アッセイを実施した。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)。次に、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。
HLAクラスIIアロタイプに対する選択されたペプチドの結合スコア
主要組織適合性複合体クラスII(MHC‐II)分子は、主にプロフェショナル抗原提示細胞の表面上に発現され、そこでそれらは、多くの宿主免疫応答の開始および結果を編成するTヘルパー細胞にペプチドを提示する。したがって、どのペプチドがMHC‐II分子によって提示されるかを理解することは、Tヘルパー細胞の活性化を理解するために重要であり、T細胞エピトープを同定するために使用され得る。MHCクラスII分子によって提示されるペプチドは、MHCα鎖およびβ鎖の残基によって形成される結合溝に結合する。ペプチド−MHC結合親和性は、主にペプチド結合コアのアミノ酸配列によって決定される。HLAクラスII結合予測アルゴリズムは、最も重要なクラスII対立遺伝子に対してのみ利用可能であり、SYFPEITHIアルゴリズムを用いて試験されている(Rammensee et al.,1999)。アルゴリズムは、例えば、ヒト腫瘍関連抗原TRP2(クラスI)(Sun et al.,2000)およびSSX2(クラスII)(Neumann et al.,2004)などの広範囲の抗原から、クラスIおよびクラスIIエピトープを同定するために既に成功裏に使用されている。表20は、選択されたペプチドに結合する可能性が高いHLAクラスIIアロタイプを示す。SYFPEITHIスコアが18以上であれば、ペプチドはHLA分子に結合すると見なされた。
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Claims (32)
- 配列番号1〜配列番号772、および配列番号1〜配列番号772と少なくとも88%相同的なその変異配列からなる群から選択されるアミノ酸配列を含んでなるペプチド、およびその薬学的に許容可能な塩であって;前記変異型が、主要組織適合性複合体(MHC)分子と結合し、および/またはT細胞を前記変異型ペプチドと交差反応させ;前記ペプチドが完全長ポリペプチドでない、ペプチド。
- MHCクラスIまたはII分子に結合する能力を有し、前記MHCに結合した際に、CD4および/または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。
- そのアミノ酸配列が、配列番号1〜配列番号722のいずれか1つに記載の一続きのアミノ酸を含んでなる、請求項1または2に記載のペプチドまたはその変異型。
- 前記ペプチドまたはその変異型が、8〜100、好ましくは8〜30、より好ましくは8〜16のアミノ酸の全長を有し、最も好ましくは前記ペプチドが、配列番号1〜配列番号772のいずれかに記載のアミノ酸配列からなり、またはそれから本質的になる、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変異型。
- 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1〜4のいずれか一項に記載のペプチドまたはその変異型。
- 前記ペプチドが、特にHLA−DR抗原関連不変鎖(Ii)のN末端アミノ酸を含んでなる融合タンパク質の一部である、請求項1〜5のいずれか一項に記載のペプチドまたはその変異型。
- MHC分子と結合した際に、好ましくは請求項1〜5のいずれか一項に記載のペプチドまたはその変異型である、請求項1〜5のいずれか一項に記載のペプチドまたはその変異型を特異的に認識する、特に可溶性または膜結合抗体である、抗体、好ましくはモノクローナル抗体またはその断片。
- MHC分子と結合した際に、請求項1〜5のいずれか一項に記載のペプチドまたはその変異型であり、好ましくは請求項1〜5のいずれか一項に記載のペプチドまたはその変異型である、HLAリガンドと反応する、T細胞受容体、好ましくは可溶性または膜結合性、またはその断片。
- 前記リガンドアミノ酸配列が、配列番号1〜配列番号772のいずれか1つと少なくとも88%同一であり、または前記リガンドアミノ酸配列が配列番号1〜配列番号722のいずれか1つからなる、請求項8に記載の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、任意選択的に、免疫刺激ドメインまたは毒素などのさらなるエフェクター機能を保有する、請求項8または9に記載のT細胞受容体。
- 請求項1〜5のいずれか一項に記載のペプチドまたはその変異型、好ましくはMHC分子と結合している請求項1〜5のいずれか一項に記載のペプチドまたはその変異型を特異的に認識する、アプタマー。
- 請求項1〜5のいずれか一項に記載のペプチドまたはその変異型、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片をコードする核酸であって、任意選択的に異種プロモーター配列または前記核酸を発現する発現ベクターに連結している、核酸。
- 請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、または請求項12に記載の核酸または発現ベクターを含んでなり、好ましくは樹状細胞、T細胞またはNK細胞などの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1〜4のいずれか一項に記載のペプチドである、活性化Tリンパ球を製造するインビトロ法。
- 請求項1〜4のいずれか一項に記載のアミノ酸配列を含んでなるポリペプチドを提示する細胞を選択的に認識する、請求項14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1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球、またはコンジュゲートされまたは標識された活性成分からなる群から選択される、少なくとも1つの活性成分と、薬学的に許容可能な担体、および任意選択的に、薬学的に許容可能な賦形剤および/または安定剤を含んでなる医薬組成物。
- 請求項13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、ペプチドまたはその変異型、抗体またはその断片、またはT細胞受容体またはその断片を単離するステップとを含んでなる、請求項1〜6のいずれか一項に記載のペプチドまたはその変異型、請求7項に記載の抗体またはその断片、または請求項8または9に記載のT細胞受容体またはその断片を製造する方法。
- 医薬品で使用するための請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球。
- 請求項15で定義される活性T細胞の有効数を患者に投与するステップを含んでなる、その標的細胞が、請求項1〜4のいずれか一項に記載のアミノ酸配列を含んでなるポリペプチドを提示する患者において、標的細胞を死滅させる方法。
- がんの診断および/または治療で使用するための、またはがんに対する薬剤の製造で使用するための、請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球。
- 前記がんが、ペプチド配列番号1〜配列番号772がそれに由来するタンパク質の過剰発現を示す、卵巣がん、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、慢性リンパ球性白血病、非ホジキンリンパ腫、急性骨髄性白血病、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、およびその他の腫瘍の群から選択される、請求項20に記載の使用。
- a)溶液または凍結乾燥形態にある、請求項1〜6のいずれか一項に記載のペプチドまたは変異型、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球を含有する医薬組成物を含んでなる容器;
b)任意選択的に、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;
c)任意選択的に、配列番号1〜配列番号774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、および
d)任意選択的に、(i)前記溶液の使用、または(ii)前記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。 - (iii)緩衝液、(iv)希釈剤、(v)フィルター、(vi)針、または(v)シリンジの1つまたは複数をさらに含んでなる、請求項22に記載のキット。
- a)前記個々の患者からの腫瘍サンプルによって提示される腫瘍関連ペプチド(TUMAP)を同定するステップと;
b)a)で同定された前記ペプチドを、正常組織との比較で腫瘍における免疫原性および/または過剰提示について予備選別されたペプチド貯蔵庫と比較するステップと;
c)少なくとも1つのペプチドを、前記患者において同定されたTUMAPと一致する前記貯蔵庫から選択するステップと;
d)ステップc)に基づいて、個別化ワクチンまたは化合物ベースのまたは細胞療法を作成および/または処方するステップと
を含んでなる、個々の患者のための化合物ベースのおよび/または細胞療法のための個別化抗がんワクチンを生産する方法。 - 前記TUMAPが、
a1)前記腫瘍サンプルからの発現データを前記腫瘍サンプルの組織型に対応する正常組織サンプルからの発現データと比較して、前記腫瘍サンプルにおいて過剰発現されまたは異常に発現されるタンパク質を同定するステップと;
a2)前記発現データを、前記腫瘍サンプル中のMHCクラスI/またはクラスII分子と結合しているMHCリガンドの配列と相関させて、前記腫瘍によって過剰発現されまたは異常に発現されるタンパク質に由来するMHCリガンドを同定するステップと
によって同定される、請求項24に記載の方法。 - 結合ペプチドを前記腫瘍サンプルから単離されたMHC分子から溶出させて、前記溶出したリガンドを配列決定することで、MHCリガンドの配列が同定される、請求項24または25に記載の方法。
- 前記腫瘍サンプルの組織型に対応する前記正常組織が、前記同一患者から得られる、請求項24〜26のいずれか一項に記載の方法。
- 前記貯蔵庫に包含される前記ペプチドが、
aa.正常組織または組織群と比較して悪性組織で過剰発現される遺伝子を同定するステップを含んでなる、マイクロアレイまたは配列決定ベース発現プロファイリングなどの高度並列法によって、ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を実施するステップと;
ab.ステップaaで検出された、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、ペプチドを選択するステップと;
ac.健常ドナーまたは前記患者からのヒトT細胞を使用した生体外免疫原性アッセイを含んでなる、前記選択されたペプチドによる生体内T細胞応答の誘導を判定するステップ;または
ba.HLAリガンドを前記腫瘍サンプルから質量分析を使用して同定するステップと;
bb.正常組織または組織群と比較して悪性組織で過剰発現される遺伝子を同定するステップを含んでなる、マイクロアレイまたは配列決定ベース発現プロファイリングなどの高度並列法によって、ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を実施するステップと;
bc.前記同定されたHLAリガンドを前記遺伝子発現データと比較するステップと;
bd.ステップbcで検出された、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、ペプチドを選択するステップと;
be.ステップbdから選択されたTUMAPを腫瘍組織上で再検出し、健常組織上の検出の欠如または希な検出が、mRNAレベルにおける過剰発現の関連性を裏付けるステップと;
bf.健常ドナーまたは前記患者からのヒトT細胞を使用した生体外免疫原性アッセイを含んでなる、前記選択されたペプチドによる生体内T細胞応答の誘導を判定るステップ
に基づいて同定される、請求項24〜27のいずれか一項に記載の方法。 - 前記貯蔵庫に包含さ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結合についての患者免疫モニタリング、MHC多量体染色、ELISPOTアッセイおよび/または細胞内サイトカイン染色を含んでなる方法によって判定される、請求項24〜28のいずれか一項に記載の方法。
- 前記貯蔵庫が、配列番号1〜配列番号774からなる群から選択される複数のペプチドを含んでなる、請求項24〜29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特有の少なくとも1つの変異を同定するステップと、前記ワクチンに包含するために、または細胞療法を作成するために、前記変異に関連があるペプチドを選択するステップとをさらに含んでなる、請求項24〜30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31に記載の方法。
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