JP2018519243A - 様々な腫瘍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
様々な腫瘍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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Abstract
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)。
乳がん
乳がん患者の標準的治療は、腫瘍病期、ホルモン受容体状態、およびHER2発現パターンの異なるパラメータに左右される。標準的治療としては、腫瘍の完全な外科的切除と、それに続く放射線療法が挙げられる。主にアントラサイクリンおよびタキサンによる化学療法が、切除前または後に開始されてもよい。HER2陽性腫瘍がある患者には、化学療法薬に加えて、抗HER2抗体トラスツズマブが投与される(S3−Leitlinie Mammakarzinom,2012)。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。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。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)。
食道がんの一次治療ストラテジーは、腫瘍病期と部位、組織型、および患者の医学的状態に左右される。化学療法薬措置としては、オキサリプラチンとフルオロウラシル、カルボプラチンとパクリタキセル、シスプラチンとフルオロウラシル、FOLFOX、およびシスプラチンとイリノテカンが挙げられる。食道がんにおける標的療法の無作為化データは非常に限られているので、HER2陽性腫瘍がある患者は、胃がんに関する指針に従って治療されるべきである(Stahl et al.,2013)。
胃がん(GC)は、粘膜層を覆う細胞中で始まり、増殖するにつれて外層を通して広がる。4種類の標準治療法が、使用される。胃がんの治療は、内視鏡的または外科的切除、化学療法、放射線療法または化学放射線治療を伴ってもよい(Leitlinie Magenkarzinom,2012)。
神経膠芽腫(WHO等級IV)に対する療の選択肢は、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研究されている。
疾病管理は、診断時の腫瘍段階、および肝臓の全体的な状態に左右される。HCCに対する化学療法としては、全身療法のためのドキソルビシン、5−フルオロウラシル、およびシスプラチンの組み合わせ、そして肝動脈輸液のためのドキソルビシン、フロクスウリジン、およびマイトマイシンCの組み合わせが挙げられる。しかし、ほとんどのHCCは、化学療法薬に対して高耐性を示す(Enguita−German and Fortes,2014)。
メラノーマの標準的治療は、周囲の健康な組織を含めた完全外科的切除である。治療の選択肢としては、単剤化学療法、多剤化学療法、および特異的阻害剤による標的療法が挙げられる(S3−Leitlinie Melanom,2013)。
治療選択肢は、がん型(小細胞または非小細胞)および病期によって決定され、外科手術、放射線療法、化学療法、およびベバシズマブやエルロチニブやゲフィチニブなどの標的生物学的療法が挙げられる(S3−Leitlinie Lungenkarzinom,2011)。
外科的切除は、早期ならびに進行期卵巣がんにおける一次治療である(S3−Leitlinie maligne Ovarialtumore,2013)。
膵臓がん患者のための治療の選択肢は、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。
前立腺がんのための治療ストラテジーは、主にがん病期に左右される。局所的に限定された非転移性前立腺がんでは、治療選択肢としては、積極的サーベイランス(待機および監視)、前立腺の完全外科的切除、および近接照射療法存在下または不在下における局所高用量放射線療法が挙げられる(S3−Leitlinie Prostatakarzinom,2014)。
初期治療は、最も一般的には、罹患した腎臓の部分的または完全除去のどちらかであり、依然として根治的治療の主流である(Rini et al.,2008)。予後スコアの悪い患者の第一選択治療として、いくつかのがん団体および協会によって作成された指針は、受容体チロシンキナーゼ阻害物質(TKI)であるスニチニブとパゾパニブ、インターフェロン−α(IFN−α)と組み合わされたモノクローナル抗体であるベバシズマブ、およびmTOR阻害剤であるテムシロリムスを推奨する。米国NCCNならびに欧州EAUおよびESMOによって作成された指針に基づいて、サイトカイン(IFN−α、IL−2)による先行治療法が失敗したRCC患者では、TKIであるソラフェニブ、パゾパニブまたは最近ではアキシチニブが、第二選択治療として推奨される。NCCN指針は、この状況(NCCNカテゴリーIによる高レベルの証拠)において、スニチニブもまた勧める。
SCLCの治療および予後は、診断されたがん病期に大きく左右される。臨床結果に基づくSCLCの進行度診断の方が、病的進行度診断よりも一般的である。臨床進行度診断は、理学的検査、様々な画像検査、および生検の結果を利用する。SCLCの標準的化学療法は、エトポシドまたはイリノテカンのどちらかと、シスプラチンまたはカルボプラチンのどちらかとの組み合わせを使用する(American Cancer Society,2015;S3−Leitlinie Lungenkarzinom,2011)。
AML治療は、導入療法と寛解後/「地固め療法」との2つの段階に分類される。導入療法は寛解を誘導するために投与され、併用化学療法からなる。地固め療法は、追加的な化学療法または造血細胞移植(HCT)からなる(Showel and Levis,2014)。
NHLは、60を超えるサブタイプを有する。最も一般的な3つのサブタイプは、びまん性大細胞リンパ腫(DLBCL、最も一般的なサブタイプ)、濾胞性リンパ腫(FL、2番目に一般的なサブタイプ)、および小リンパ球性リンパ腫/慢性リンパ球性リンパ腫(SLL/CLL、3番目に一般的なサブタイプ)である。DLBCL、FL、およびSLL/CLLは、NHLの約85%を占める(Li et al.,2015)。NHLの治療は、組織型および病期に左右される(National Cancer Institute,2015)。
子宮内膜がんの80%以上は、類内膜腺がん(I型)として発生し、これはエストロゲン曝露と関連する高度から中等度に分化した形態である。子宮内膜がんおよび子宮頸がんの治療は、病期依存性である(World Cancer Report,2014)。
胆管細胞がん(CCC)は、治療が困難であり、通常は致死性である。唯一の根治的治療選択肢は、完全切除術(R0)である。胆管がんにおける生物学的療法の有効性は、相反している。ソラフェニブ、ベバシズマブ、パゾパニブ、およびレゴラフェニブなどの血管増殖を標的とする薬物が、現在CCC治療のために試験されている。さらに、セツキシマブおよびパニツマブなどのEGFRを標的とする薬物が、化学療法と組み合わせて臨床試験で使用される(American Cancer Society,2015)。これまでに試験されたほとんどの薬物では、疾患制御および全生存期間は、有意に改善されなかったが、さらなる臨床試験が進行中である。
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(National Cancer Institute,2015)。
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、メラノーマおよび正常メラノサイトに見られる。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、メラノーマ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で検出され、ならびに多数の正常組織で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得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、腫瘍細胞内におけるそれらの過剰発現は、先に確立された免疫寛容の破壊による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)イソ型があるタンパク質では、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、特異的でなく腫瘍で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、腫瘍で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で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、ヒト乳頭腫16型ウイルスタンパク質E6およびE7であり、これらは子宮頸がんで発現される。
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。
(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.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、重要な正常(非がん性)組織では、非常に低いレベルで発現される遺伝子が同定された。これらの遺伝子が、一連の正常な臓器および組織と比較して悪性組織(HCC、CRC、GB、GC、NSCLC、PC、RCC、BPH/PCA、SCLC、NHL、AML、GBC、CCC、UBC、UEC)で過剰発現されるかどうかが評価された。
2.悪性材料(HCC、CRC、GB、GC、食道がん、NSCLC、PC、RCC、BPH/PCA、OC、MCC、メラノーマ、乳がん、SCLC、NHL、AML、GBC、CCC、UBC、UEC、CLL)からのHLAリガンドが、質量分析によって同定された。
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で検出される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HCC、CRC、GB、GC、食道がん、NSCLC、PC、RCC、BPH/PCA、OC、MCC、メラノーマ、乳がん、SCLC、NHL、AML、GBC、CCC、UBC、UEC、または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
患者の腫瘍組織は、Asterand(Detroit,USAおよびRoyston,Herts,UK);Val d’Hebron University Hospital(Barcelona);BioServe(Beltsville,MD,USA);Center for cancer immune therapy(CCIT),Herlev Hospital(Herlev);Geneticist Inc.(Glendale,CA,USA);University Hospital of Geneva;University Hospital of Heidelberg;University Hospital of Munich;京都府立医科大学(KPUM);大阪市立大学(OCU);ProteoGenex Inc.,(Culver City,CA,USA);University Hospital of Tubingenから得られた。正常組織は、Bio−Options Inc.,CA,USA;BioServe,Beltsville,MD,USA;Capital BioScience Inc.,Rockville,MD,USA;Geneticist Inc.,Glendale,CA,USA;University Hospital of Geneva;University Hospital of Heidelberg;University Hospital Munich;ProteoGenex Inc.,Culver City,CA,USA;University Hospital of Tubingenから得られた。全ての患者の告知に基づく同意書が、外科手術または検死解剖前に得られた。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、以前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された。
ペプチドが、正常組織と比較して、この実体のがんサンプル上で過剰提示されれば、それは実体中で興味深いと見なされた。MEL=メラノーマ、BRCA=乳がん、OSCAR=食道がん。BPHは、良性前立腺過形成ならびに膵臓がんを含む。
GB=神経膠芽腫、BRCA=乳がん、CRC=結腸直腸がん、RCC=腎細胞がん、CLL=慢性リンパ球性白血病、HCC=肝細胞がん、NSCLC=非小細胞肺がん、SCLC=小細胞肺がん、NHL=非ホジキンリンパ腫、AML=急性骨髄性白血病、OC=卵巣がん、PC=膵臓がん、BPH=前立腺がんおよび良性前立腺過形成、OSCAR=胃食道接合部のがんを含むめた食道がん、GBC_CCC=胆嚢腺がんおよび胆管細胞がん、MEL=メラノーマ、GC=胃がん、UBC=膀胱がん、UTC=子宮がん
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などの高い安全性リスクがある治療の選択肢では、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られないタンパク質に由来する。本発明では、全ての起源遺伝子の正常組織発現は、約3000個の正常組織サンプルをカバーする、上記のRNA発現データのデータベースに基づいて、最小であることが示された。さらに、いくつかのがん実体(HCC、CRC、GB、GC、NSCLC、PC、RCC、BPH/PCA)の場合は、正常および腫瘍組織のRNA分析が付加されて、それぞれのがんを有する患者集団中の標的カバー度が推定された。
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)。腫瘍組織標本は、手術直後にスナップ凍結され、その後、液体窒素下で乳鉢と乳棒を用いて均質化された。全RNAは、TRI試薬(Ambion,Darmstadt,Germany)を使用してこれらのサンプルから調製され、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された。
カバー度は、30個のGB、16個のCRC、56個のRCC、12個のHCC、38個のNSCLC、11個のPC、34個のGC、および20個の前立腺がんサンプルの発現プロファイル(Affymetrixマイクロアレイ)の解析によって、推定された。
過剰発現は、遺伝子の最大発現を示した関連正常組織と比較した、腫瘍上における1.5倍を超えるより高い発現と定義された。<19%過剰発現=I、20〜49%=II、50〜69%=III、>70%=IV。ペプチドが、いくつかの起源遺伝子に由来し得る場合、最小のカバー度がある遺伝子が決定要因となった。
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成される。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た。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あたりキロベースあたり読み取り、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。
過剰発現は、遺伝子の最大発現を示した関連正常組織と比較した、腫瘍上における1.5倍を超えるより高い発現と定義された。<19%過剰発現=I、20〜49%=II、50〜69%=III、>70%=IV。ペプチドが、いくつかの起源遺伝子に由来し得る場合、最小のカバー度がある遺伝子が決定要因となった。ベースラインは、以下の関連正常組織を含んだ:脂肪組織、副腎、動脈、骨髄、脳、軟骨、結腸、食道、胆嚢、心臓、腎臓、肝臓、肺、リンパ節、膵臓、下垂体、直腸、骨格筋、皮膚、小腸、脾臓、胃、胸腺、甲状腺、気管、膀胱、および静脈。同一組織型のいくつかのサンプル発現データが利用できる場合、全ての各サンプルの算術平均が、計算のために使用された。AML=急性骨髄性白血病、NHL=非ホジキンリンパ腫、BRCA=乳がん、CLL=慢性リンパ球性白血病、GBC_CCC=胆嚢腺がんおよび胆管細胞がん、MEL=メラノーマ、OC=卵巣がん、OSCAR=食道がん、胃食道接合部がんを含む、SCLC=小細胞肺がん、UBC=膀胱がん、UTC=子宮がん
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、これまでに本発明の47個の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6AおよびB)。
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。PBMCおよび単離CD8+リンパ球またはPBMCは、10%熱不活性化ヒトAB血清(PAN−Biotech,Aidenbach,Germany)、100U/mlペニシリン/100μg/mlストレプトマイシン(Cambrex,Cologne,Germany)、1mMピルビン酸ナトリウム(CC Pro,Oberdorla,Germany)、20μg/mlゲンタマイシン(Cambrex)を添加した、RPMI−Glutamax(Invitrogen,Karlsruhe,Germany)からなるT細胞培地(TCM)中で、使用時まで培養された。2.5ng/mlのIL−7(PromoCell,Heidelberg,Germany)および10U/mlのIL−2(Novartis Pharma,Nurnberg,Germany)もまた、この段階でTCMに添加された。pMHC/抗CD28被覆ビーズの生成、T細胞刺激、および読み取りは、高度に定義された生体外システム内で、刺激条件あたり4種の異なるpMHC分子と、読み取り条件あたり8種の異なるpMHC分子を使用して実施された。
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細胞系の生成によって生体外免疫原性が実証され得る。本発明の15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3および図6に示される。本発明からの2つのペプチドの結果が、表6AおよびBに要約される。
出願人によって実施された本発明のペプチドの生体外免疫原性実験の例示的結果。<20%=+;21%-49%=++;50%-69%=+++;>=70%=++++
出願人によって実施された、本発明のHLA-A*02拘束性ペプチドについての生体外免疫原性実験の代表的結果である。生体外免疫原性実験の結果が示される。陽性ウェルおよびドナーの百分率(評価可能内)は、示されるように要約される<20%=+;20%-49%=++;50%-69%=+++;>=70%=++++
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。
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、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が実施された。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された。
HLAクラスI拘束性ペプチドとHLA-A*02:01との結合は、ペプチド交換収率によって評価された:>10%=+;>20%=++;>50=+++;>75%=++++
表8:本発明による好ましいペプチド
抗体および/またはTCRなどのバインダーの生成は、骨の折れる方法であり、いくつかの選択された標的のみに実施されてもよい。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。本明細書に記載されるような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、記載されるように、細胞あたりの絶対ペプチドコピー数を分析した。固形腫瘍サンプル中の細胞あたりの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が作成された。内標準は、各ペプチドの二重同位体標識変異体であり、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のみが異なるが、他の物理化学的性質に差異を示さない(Anderson et al.,2012)。内標準が各MSサンプルに添加され、全てのMSシグナルは内標準のMSシグナルに対して正規化されて、MS実験間の可能な技術的変動が平準化された。
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、組織サンプルは均質溶解産物に処理され、それから小さな溶解産物アリコートが取り出される。アリコートは3つに分割され、それからDNAが単離される(QiaAmp DNA Mini Kit,Qiagen,Hilden,Germany)。各DNA単離からの全DNA含有量は、蛍光ベースのDNA定量化アッセイ(Qubit dsDNA HS Assay Kit,Life Technologies,Darmstadt,Germany)を使用して、少なくとも2つの反復試験で定量化される。
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、細胞あたりの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9に示される。
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Claims (39)
- 配列番号1〜配列番号288、および配列番号1〜配列番号288と少なくとも88%相同的なその変異配列の群から選択されるアミノ酸配列を含んでなるペプチドであって、前記変異体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細胞を前記変異体ペプチドおよびその薬学的に許容可能な塩と交差反応させ;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に結合すると、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288の1つのいずれか一項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体。
- 前記ペプチドまたはその変異体が、8〜100、好ましくは8〜30、より好ましくは8〜100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288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体。
- 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体。
- 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体。
- 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体をエン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と結合する、核酸。
- 請求項7に記載の核酸を発現する、発現ベクター。
- 請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の核酸または請求項8に記載の発現ベクターを含んでなり、好ましくは樹状細胞などの抗原提示細胞である、組換え宿主細胞。
- 医療で使用される、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、または請求項9に記載の宿主細胞。
- 請求項1〜6のいずれか一項に記載のペプチドを提示する、または請求項7に記載の核酸を発現する、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その変異体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1〜6のいずれか一項に記載のペプチドまたはその変異体を製造する方法。
- 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1〜4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。
- MHC分子と結合すると、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体である、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体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。
- がんの診断および/または治療で使用される、またはがんに対する薬剤の製造で使用される、請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の細胞、請求項13に記載の活性化Tリンパ球または請求項15に記載の抗体。
- がんが、ペプチド配列番号1〜配列番号288がそれに由来するタンパク質の過剰発現を示す、肝細胞がん(HCC)、結腸直腸がん(CRC)、神経膠芽腫(GB)、胃がん(GC)、食道がん、非小細胞肺がん(NSCLC)、膵臓がん(PC)、腎細胞がん(RCC)、良性前立腺過形成(BPH)、前立腺がん(PCA)、卵巣がん(OC)、メラノーマ、乳がん、慢性リンパ球性白血病(CLL)、メルケル細胞がん(MCC)、小細胞肺がん(SCLC)、非ホジキンリンパ腫(NHL)、急性骨髄性白血病(AML)、胆嚢がんおよび胆管細胞がん(GBC、CCC)、膀胱がん(UBC)、子宮がん(UEC)、およびその他の腫瘍の群から選択される、請求項16に従って使用される、請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の細胞、請求項13に記載の活性化Tリンパ球または請求項15に記載の抗体。
- a)請求項1〜6のいずれか一項に記載のペプチド変異体、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10に記載の細胞、請求項13に記載の活性化Tリンパ球、または請求項15に記載の抗体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;
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288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18に記載のキット。
- 前記ペプチドが、配列番号1〜配列番号288からなる群から選択される、請求項18または19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内の免疫原性および/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)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、少なくとも1つのペプチドを選択するステップと;
d)ステップc)に基づいて、個別化ワクチンを)調合するステップと
を含んでなる、個別化抗がんワクチンを製造する方法。 - 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相当する正常組織サンプルからの発現データと比較して、前記腫瘍サンプル中で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分子と結合する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21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21または22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21〜23のいずれか一項に記載の方法。
- 前記貯蔵庫に包含されるペプチドが、
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細胞を使用する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と;または
ba.質量分析を使用して、前記腫瘍サンプルからHLAリガンドを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、健常組織上の検出欠如またはまれな検出が、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;
bf.健常ドナーまたは前記患者からのヒトT細胞を使用する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と
に基づいて同定される、請求項21〜24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21〜25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288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21〜26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、前記変異と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21〜27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28に記載の方法。
- HLAリガンドと反応性である、好ましくは組換え可溶性または膜結合T細胞受容体であるT細胞受容体であって、前記リガンドが、配列番号1〜配列番号288からなる群から選択されるアミノ酸配列と少なくとも75%の同一性を有する、T細胞受容体。
- 前記アミノ酸配列が、配列番号1〜配列番号288と少なくとも88%同一である、請求項30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288のいずれかからなる、請求項30または31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30〜32のいずれか一項に記載のT細胞受容体。
- 請求項30〜33のいずれか一項に記載のTCRをエン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と結合する、核酸。
- 請求項34に記載の核酸を発現する、発現ベクター。
- 請求項34に記載の核酸、または請求項15に記載の抗体をコードする核酸、または請求項35に記載の発現ベクターを含んでなる、好ましくはT細胞またはNK細胞である、組換え宿主細胞。
- 請求項36に記載の宿主細胞を培養するステップと、前記T細胞受容体を前記宿主細胞および/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30〜33のいずれか一項に記載のT細胞受容体を製造する方法。
- 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体、好ましくはMHC分子と結合する請求項1〜5のいずれか一項に記載のペプチドまたはその変異体を特異的に認識する、アプタマー。
- 請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の細胞、請求項13に記載の活性化Tリンパ球または請求項15に記載の抗体または請求項30〜32のいずれか一項に記載のT細胞受容体または請求項38に記載のアプタマー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、薬学的に許容できる担体と、任意選択的に、追加的な薬学的に許容可能な賦形剤および/または安定剤とを含んでなる医薬組成物。
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