JP2020535814A - 阻害性キメラ抗原受容体(iCAR)を調製するための普遍的プラットフォーム - Google Patents
阻害性キメラ抗原受容体(iCAR)を調製するための普遍的プラットフォーム Download PDFInfo
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Abstract
Description
本出願は、2017年9月28日出願の米国仮出願第62/564,454号、および2018年3月28日出願の米国仮出願第62/649,429号の優先権を主張し、それらの各々が参照により本明細書に組み込まれる。
本出願は、ASCII形式で電子提出され、参照によりその全体が本明細書に組み込まれる配列表を含む。2018年9月27日作成の当該ASCIIの写しは、120575−5003_ST25.txtという名称である。
本出願が優先権を主張している仮特許出願は、長い表セクションを含む。表の写しは、参照により本明細書に組み込まれ、本発明の実施に採用され得る、2018年3月28日出願の米国仮出願第62/649,429号の優先権とともにASCII形式のコンパクトディスクで米国特許商標庁に提出された。2018年3月28日作成の当該ASCII表は、次のとおりである:120575−5003−PR allCandExt1167Genes_5003_PR.txt、272,719,870バイト。
−厳密に腫瘍特異的な抗原。おそらく、すでに臨床的に検査されているこの群の唯一のメンバーは、神経膠芽腫で頻繁に過剰発現し、非小細胞肺癌腫、ならびに前立腺、乳房、頭頸部、および卵巣癌にも見られるが正常組織では見られない上皮成長因子受容体(EGFRvIII)の多様体IIIである。
−腫瘍および重要でない健康な組織上に発現する表面抗原。この群で可能性のあるCAR抗原は、主にB細胞系列に限定される分化関連分子である。これら(および数多くの臨床試験での標的抗原)のうちで卓越しているのは、B細胞分化の非常に早期に獲得され、B細胞受容体(BCR)によるシグナル伝達に関与する汎B細胞マーカーである、CD19である。膜前立腺抗原は、このカテゴリーの抗原の別のクラスを構成する。
−非悪性腫瘍促進細胞によって典型的に発現される抗原。かかる抗原の1つは、線維芽細胞活性化タンパク質(FAP)であり、これは様々な原発性および転移性癌の腫瘍関連線維芽細胞によってほぼ常に発現される細胞表面のセリンプロテアーゼである。別の抗原は、血管内皮増殖因子(VEGF)であり、これは腫瘍の血管新生中に高度に発現し、多くの重要な臓器の血管およびリンパ管内皮細胞上に通常発現する。
−重要な健康な組織と共有される腫瘍関連抗原(TAA)。
−コンビナトリアル(または「分割」)抗原認識。真の腫瘍特異的表面抗原はまれであるが、必ずしも所与の腫瘍によって共発現される腫瘍関連抗原として分類されない2つの異なる抗原の組み合わせによって、新しい腫瘍特異的シグネチャを定義することができる。CAR T細胞の活性をかかる抗原ペアに制限することによって、重要な安全規格を提供し、その結果、腫瘍特異的標的の範囲が拡張され、実質的な療法的価値があるものであり得る。第2および第3世代のCARは、CARエンドドメインで2つ以上のシグナル伝達部分をつなぐことを通じて単一抗原に係合すると、療法用T細胞に活性化および共刺激シグナルを提供するように設計されている。しかしながら、活性化および共刺激が、同じT細胞の、各々異なる抗原に特異的な2つのCAR間で分割される場合、完全な応答には、2つの抗原の存在下でのみ達成することができる2つの相補的なシグナルの協働を必要とするであろう。この原理は、いくつかの前臨床研究で実証されている(Kloss et al.,2013、Lanitis et al.,2013、Wilkie et al.,2012、WO2016/126608)。
(i)細胞外多型エピトープを含むタンパク質をコードする、少なくとも2つの発現対立遺伝子を有する遺伝子を同定することと、
(ii)発現対立遺伝子のうちの少なくとも1つが、細胞外多型エピトープ参照配列と比較して、細胞外多型エピトープ配列においてアミノ酸配列変化を呈することを決定することと、
(iii)遺伝子が、腫瘍型におけるヘテロ接合性の喪失(LOH)を受ける染色体領域に位置することを決定することと、
(iv)染色体領域がLOHを受けていることが見出された腫瘍型の原発組織で遺伝子が発現していることを決定することと、を含む方法によって同定される。
AG Knudsonによって1971年に提唱された腫瘍抑制遺伝子(TSG)の革新的な概念(Knudson Jr.,1971)に言及して、Devilee、Cleton−JansenおよびCornelisseは、「Ever since Knudson」(Devilee et al.,2001)と題した彼らのエッセイの冒頭の段落で、「多くの出版物は、多種多様な腫瘍における多くの異なる染色体上のLOHを記録しており、多数のTSGの存在を示唆している。Knudsonの2段階侵襲説は、これらのLOH事象がTSGの両方の対立遺伝子の不活性化における第2のステップであると予測している」と記載している。ヒトの癌における遺伝子的不安定性に関する彼らの独創的な考察(Lengauer et al.,1998)において、Lengauer、Kinzler、およびVogelsteinは、「大部分の癌は、染色体が喪失または獲得されていることを核型研究は示しており、核型データはかかる変化の真の程度を実に過小評価していることを、分子研究は示している。ヘテロ接合性の喪失、すなわち、腫瘍における母方または父方の対立遺伝子の喪失は広範囲におよび、多くの場合反対の対立遺伝子の獲得を伴う。例えば、腫瘍は、父方の第8染色体を複製しながら、母方の第8染色体を喪失し得、細胞には正常な第8染色体の核型を有するが、異常な第8染色体の「対立遺伝子型」が残っている。結腸、乳房、膵臓、または前立腺の「平均的な」癌は、その対立遺伝子のうちの25%を喪失している場合があり、腫瘍がその対立遺伝子の半分以上を喪失していることは珍しいことではない。」と記述した。その後、これらの観察は強化され、数多くの報告書において、事実上全ての癌腫を含むほぼ全てのヒトの癌に拡張された(考察については(McGranahan et al.,2012)を参照されたい)。ほぼ全ての個々の腫瘍が、完全な染色体、染色体腕全体、または異なるサイズのサブ染色体領域のうちの多数の喪失を呈することが、現在、明確に確立されている。エクソーム配列データに基づいて、任意の所与の細胞試料におけるLOHプロファイルを決定するための新しいアルゴリズム(例えば、Sathirapongsasuti et al.,2011など)が迅速に開発されている。現在、統計的バイアスが一部の解釈の有効性について疑問を投げかける場合があるが(Teo et al.,2012)、かかるアルゴリズムによって、NGS以前の時代にこの目的で採用されていた、LOHプロファイルを確立するための他のほとんどの方法論が改善され置き換えられる可能性が高い
本明細書で使用される「核酸分子」という用語は、DNAまたはRNA分子を指す。
本発明は、正常細胞を安全に保ちながら腫瘍細胞の特異的標的化を可能にする新しい手段を提供することを強調すべきである。本明細書に提示された概念は、iCAR(またはpCARまたは保護CAR)の新しい標的の同定を提供し、これらの標的は、それらがある染色体領域のLOHに起因して腫瘍細胞から喪失しているが、正常組織で発現したままの、多型細胞表面エピトープの単一対立遺伝子多様体を含むと定義される。多型多様性のため、2つの対立遺伝子を区別し、腫瘍細胞で欠落している対立遺伝子のみを標的とすることが可能である。さらに、標的抗原は、LOHによって喪失した領域にあるように選択され、したがってかかる遺伝子に単純に連結することができるので、それ自体が必ずしも腫瘍抑制遺伝子または癌に関与すると予測される遺伝子である必要はない。これは、腫瘍関連抗原または多型に関係なく腫瘍で下方制御された抗原を標的とする癌療法でこれまでに採用または提案された方法とは、概念的に異なる。本方法はまた、本明細書に記載のiCARおよび/またはpCARの共発現を通じて正常細胞の保護を与えることによって、腫瘍関連抗原を超えてaCARの選択を広げることを提供する。
本発明は、細胞外多型エピトープを有する候補遺伝子の同定に基づく、aCAR、iCARおよび/またはpCAR標的の同定のための方法を提供する。いくつかの実施形態では、aCARは、腫瘍組織上に発現する任意の細胞外タンパク質に向けることができる。いくつかの実施形態では、aCAR標的は、非腫瘍組織上にさらに発現し、iCAR標的はまた、非腫瘍組織上に発現するが、腫瘍組織上には発現しない。
本発明はまた、標的への特異的結合を提供するように設計された認識部分を提供する。認識部分は、aCAR、iCARおよび/またはpCARの特異的かつ標的化された結合の指示を可能にする。いくつかの実施形態では、標的への特異的結合を提供するように設計された認識部分は、細胞外多型エピトープへの特異的結合を提供する。いくつかの実施形態では、認識部分は、aCAR、iCARおよび/またはpCARの細胞外ドメインの一部である。いくつかの実施形態では、細胞外ドメインは、ヒト化抗体;ヒト抗体;抗体の機能的断片;ナノボディなどの単一ドメイン抗体;組み換え抗体;単一鎖可変断片(ScFv)などの抗体、それらの誘導体または断片を含む。いくつかの実施形態では、細胞外ドメインは、アフィボディ分子;アフィリン;アフィマー;アフィチン;アルファボディ;アンチカリン;アビマー;DARPin;ファイノマー(fynomer);Kunitzドメインペプチド;およびモノボディなどの抗体ミメティックを含む。いくつかの実施形態では、細胞外ドメインは、アプタマーを含む。
−集合的に、選択された認識部分は、22個のヒト常染色体全ての2つの腕の各々にある遺伝子アレイの細胞表面生成物を標的とする。隣接する遺伝子間の距離が短いほど、網羅範囲はより広く、したがって使用の普遍性がより大きい。
−選択した遺伝子の各々では、一組の対立遺伝子特異的認識部分が単離され、各々がヒト集団で一般的な異なる対立遺伝子多様体間の厳密な区別を可能にする。標的多様体の数が多いほど、患者に提供することができる療法用遺伝子ペアの数も多い。
本発明はまた、aCAR、iCARおよび/またはpCARの一部として細胞内ドメインを提供する。いくつかの実施形態では、細胞内ドメインは、少なくとも1つのシグナル伝達要素を含む。いくつかの実施形態では、細胞内ドメインは、エフェクター免疫細胞を阻害する少なくとも1つのシグナル伝達要素を含む。
いくつかの実施形態では、aCARは第1の核酸ベクターによってコードされ、iCARまたはpCARは第2の核酸ベクターによってコードされる。いくつかの実施形態では、aCARは第1の核酸ベクターによってコードされ、iCARまたはpCARは第2の核酸ベクターによってコードされる。いくつかの実施形態では、aCARは第1の核酸ベクターによってコードされ、iCARまたはpCARは第2の核酸ベクターによってコードされる。いくつかの実施形態では、iCARまたはpCARをコードするヌクレオチド配列は、第2のベクター上にある。
なお別の態様では、本発明は、安全なエフェクター免疫細胞を調製するための方法であって、(i)腫瘍関連抗原に向けられているTCR操作エフェクター免疫細胞を、本明細書で上に定義されるiCARもしくはpCARをコードするヌクレオチド配列を含む核酸分子でトランスフェクトするか、もしくはベクターで細胞を形質導入すること、または(ii)ナイーブエフェクター免疫細胞を、本明細書で上に定義されるiCARもしくはpCARをコードするヌクレオチド配列を含む核酸分子、および本明細書で上に定義されるaCARをコードするヌクレオチド配列を含む核酸分子でトランスフェクトするか、もしくはエフェクター免疫細胞を、本明細書で上に定義されるベクターで形質導入すること、を含む、方法を提供する。
いくつかの実施形態では、標的細胞は調製され、インビトロの系で試験される。いくつかの実施形態では、標的外細胞に対するaCARの活性を阻害する際のiCARおよび/またはpCAR構築物の機能性を試験するための、インビトロ組み換え系が確立されるであろう。いくつかの実施形態では、aCARエピトープ、iCARエピトープ、または両方を発現している標的細胞が生成されるであろう。いくつかの実施形態では、aCARエピトープ、pCARエピトープ、または両方を発現している標的細胞が生成されるであろう。いくつかの実施形態では、aCARエピトープを発現している組み換え細胞は、標的上の「腫瘍上の」細胞を表し、aCARおよびiCARエピトープの両方を発現している細胞は、標的上の「腫瘍外」の健康な細胞を表すであろう。
いくつかの実施形態では、iCARおよび/またはpCARは、多様なアッセイを使用して、有効性および阻害する能力を含む、効果における活性について試験されるであろう。いくつかの実施形態では、iCARおよび/またはpCARの阻害効果は、インビトロおよび/またはインビボで試験されるであろう。いくつかの実施形態では、iCARおよび/またはpCARの阻害効果は、インビトロで試験されるであろう。いくつかの実施形態では、iCARおよび/またはpCARの阻害効果は、インビボで試験されるであろう。いくつかの実施形態では、インビトロアッセイは、サイトカイン分泌および/または細胞傷害性効果を測定する。いくつかの実施形態では、インビボアッセイは、iCARおよび/またはpCARの阻害、ならびに標的上腫瘍外の異種移植片の保護を評価するであろう。いくつかの実施形態では、インビボアッセイは、iCARおよび/またはpCARの阻害、ならびに標的上腫瘍外の組織および/または重要な臓器の保護を評価するであろう。
いくつかの実施形態では、iCARおよび/またはpCARは、ルシフェラーゼ細胞傷害性アッセイを使用して評価される。一般に、ルシフェラーゼ細胞傷害性アッセイでは、組み換え標的細胞(「T」と称され得る)は、ホタルルシフェラーゼを発現するように操作されている。いくつかの実施形態では、市販のHela−Luc細胞は、標的タンパク質をコードするDNAでトランスフェクトされ得る。インビトロルシフェラーゼアッセイは、Bright−Gloルシフェラーゼアッセイ(Promega、またはBPS Biosciences、または他の販売者から市販されている)に従って実施することができる。形質導入されたエフェクター(E)T細胞(iCARもしくはpCARとaCARとの両方、またはaCAR、またはモックCARで形質導入されている)は、HLA−A2、CD19、またはCD19とHLA−A2との両方、またはCD20、またはCD20とCD19との両方を発現している組み換え標的細胞と、24〜48時間培養して、異なるエフェクター対標的の比で試験することができる。いくつかの実施形態では、iCAR/aCAR、またはpCAR/aCARのペアは、上記の構成要素とともに、aCAR、pCARおよび/またはiCARのうちのいずれかを含む。いくつかの実施形態では、iCAR/aCARのペアは、HLA−A2標的化iCARおよびCD19標的化aCARを含む。いくつかの実施形態では、iCAR/aCARのペアは、CD20標的化iCARおよびCD19標的化aCARを含む。細胞殺傷は、Bright−Gloルシフェラーゼ系を用いて生細胞数を推定することによって、間接的に定量化されるであろう。
いくつかの実施形態では、カスパーゼ3検出アッセイを採用して、iCARおよび/またはpCARを検査して、「腫瘍上」細胞(例えば、腫瘍細胞)および「腫瘍外」細胞(例えば、非腫瘍細胞)のアポトーシスのレベルをインビトロで決定する。いくつかの実施形態では、活性化開裂カスパーゼ3に対する抗体による細胞傷害性リンパ球(CTL)誘導アポトーシスのカスパーゼ3検出を検査する。
経時的マイクロCTL−
標的結合を識別するために、iCARおよび/またはpCAR形質導入T細胞の経時的顕微鏡法を採用することができる。いくつかの実施形態では、標的細胞は、レポーター遺伝子(例えば、限定されないが、mCherryなどの蛍光タンパク質)で標識されるであろう。いくつかの実施形態では、形質導入T細胞は、「腫瘍上」または「腫瘍外」細胞のいずれかと最大5日間培養される。いくつかの実施形態では、経時的顕微鏡法を使用して、殺傷を視覚化することができる。いくつかの実施形態では、エンドポイント時点での標的細胞数を決定するために、生存細胞数染色およびCountBrightビーズ(Invitrogen)を使用するフローサイトメトリー分析が行われるであろう。
T細胞の活性化を決定するために、サイトカインの放出を検査してもよい。いくつかの実施形態では、iCAR/aCAR、および/またはpCAR/aCAR形質導入T細胞を組み換え標的細胞と培養し、例えば、BioLegendのELISA MAX(商標)デラックスセットキットに従って細胞培養上清中のサイトカイン分泌を測定することによって、またはサイトカインを生成するT細胞の割合のフローサイトメトリー分析によってのいずれかで、1つ以上のサイトカインのサイトカイン生成を定量化する。フローサイトメトリー分析では、一般に、サイトカインの分泌を防止するためにGolgi stopが採用されている。いくつかの実施形態では、6時間および18時間〜24時間の形質導入T細胞の標的細胞との培養に続き、T細胞を透過処理し、内部染色キット(Miltenyi)によって固定し、T細胞マーカー(CD3およびCD8)および1つ以上のサイトカインの抗体で染色するであろう。いくつかの実施形態では、サイトカインには、限定されないが、IL−2、INFγ、および/またはTNFαが含まれる。
形質導入T細胞の細胞溶解活性を決定するために、CD107aの染色も検査してもよい。一般に、T細胞の脱顆粒は、リソソーム関連膜タンパク質(LAMP−1)であるCD107aの表面発現によって同定することができ、LAMP−1の表面発現は、CD8 T細胞の細胞傷害性と相関することが示されている。さらに、この分子は、リソソームの管腔側に位置する。典型的には、CD107aは、活性化すると、活性化したリンパ球の細胞膜表面に移動する。さらに、CD107aは、細胞表面上に一過性に発現し、エンドサイトーシス経路を介して迅速に再内部化される。したがって、理論に縛られるわけではないが、CD107aの検出は、細胞刺激中の抗体染色によって、およびモネンシンの添加(例えば、エンドサイトーシスされたCD107a抗体複合体の酸性化およびその後の分解を防止するため)によって最大化される。
いくつかの実施形態では、iCARもしくはaCAR、またはaCARおよびiCARの両方を発現している形質導入T細胞(Jurkat、または一次T細胞)の改変標的細胞との共-培養に続き、iCARもしくはaCAR、またはaCARおよびiCARの両方の抗原をそれらの細胞表面上に発現している条件培地が収集され、サイトカインELISAによってサイトカインの濃度が測定されるであろう。いくつかの実施形態では、サイトカインは、IL−2、INFγ、および/またはTNFαからなる群から選択される。いくつかの実施形態では、サイトカインは、IL−2からなる群から選択される。いくつかの実施形態では、サイトカインは、INFγからなる群から選択される。いくつかの実施形態では、サイトカインは、TNFαからなる群から選択される。いくつかの実施形態では、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%、または約99%の減少が、二重CAR(aCAR/iCAR)形質導入細胞で実証される。
サイトメトリービーズアレイ(CBA)を使用して、サイトカイン、ケモカイン、および成長因子を含む多様な可溶性および細胞内タンパク質を測定する。いくつかの実施形態では、aCAR、またはaCARおよびiCARの両方の構築物で形質導入されたT細胞(一次T細胞またはJurkat細胞)(エフェクター細胞)は、細胞表面上にiCARおよびaCARの両方、またはaCARもしくはiCAR標的抗原を発現している改変標的細胞で刺激される。いくつかの実施形態では、エフェクター対標的比は、20:1〜最大1:1の範囲である。いくつかの実施形態では、エフェクター対標的比は、20:1、19:1、18:1、17:1、16:1、15:1、14:1、13:1、12:1、11:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、または1:1の範囲である。いくつかの実施形態では、数時間の共培養に続き、エフェクター細胞は、サイトカインを生成および分泌し、これはそれらのエフェクター状態を示す。いくつかの実施形態では、反応の上清を収集し、分泌されたIL−2を測定し、マルチプレックスCBAアッセイによって定量化した。
いくつかの実施形態では、T細胞の脱顆粒化は、リソソーム関連膜タンパク質(LAMP−1)であるCD107aの表面発現によって同定することができる。いくつかの実施形態では、LAMP−1の表面発現は、CD8 T細胞の細胞傷害性と相関することが示されている。いくつかの実施形態では、顆粒化(CD107a)は、殺傷能力のマーカーである。
いくつかの実施形態では、iCAR/aCAR、および/またはiCAR/pCARのペアは、インビボでの有効性について試験される。いくつかの実施形態では、NOD/SCID/γc−または同様のマウスに、腫瘍細胞を静脈内接種する。いくつかの実施形態では、腫瘍細胞は、ホタルルシフェラーゼを発現するように操作されたCD19陽性NALM6(ATCC、ヒトB−ALL細胞株)細胞である。いくつかの実施形態では、「標的上」細胞および「腫瘍外」細胞の確立および/または分化のために、iCARおよび/またはpCARエピトープを発現するようにNALM6を操作し、それにより健康な細胞を表すことができる。いくつかの実施形態では、iCARおよび/またはpCARエピトープは、少なくとも1つの細胞外多型エピトープを含む。いくつかの実施形態では、iCARおよび/またはpCARエピトープは、HLA−A2またはCD20に由来する。これらのアッセイで採用してもよい他の細胞には、限定されないが、Raji、または任意の他の組み換え細胞株が含まれる。いくつかの実施形態では、かかるアッセイは、PDX(患者由来異種移植片)モデルであってもよい。
いくつかの実施形態では、aCARおよびiCAR構築物の両方を発現しているT細胞が、同じ生物内で、標的細胞と「標的外」細胞とを区別するかどうか、ならびに「標的外」細胞を生かしながら標的細胞を効果的に殺傷するかどうかの試験するためには、インビボCTLアッセイによって評価されるであろう。
いくつかの実施形態では、腫瘍細胞は、iCAR標的、aCAR標的、または両方のいずれかを発現する。いくつかの実施形態では、aCAR腫瘍細胞株は、CD19陽性NALM6(ATCC、ヒトBALL細胞株)であり得る。いくつかの実施形態では、aCARおよびiCARの両方を発現する腫瘍細胞(すなわち、「腫瘍外」細胞)は、iCARエピトープ(例えば、HLA−A2)を発現するように操作され、それにより健康な細胞を表すNALM6である。いくつかの実施形態では、NALM6およびNALM6−HLA−A2はまた、容易な検出のために、レポーター遺伝子(例えば、ホタルルシフェラーゼ)を発現するように操作することができる。
いくつかの実施形態では、ヒトaCARおよびiCAR標的を発現するトランスジェニックマウスも使用して、形質導入T細胞の有効性が決定されるであろう。いくつかの実施形態では、系によって、有効性および毒性の問題のモニタリングが可能になるであろう。
さらに別の態様では、本発明は、LOHを特徴とする腫瘍を有する対象のための個別化されたバイオマーカーを選択する方法であって、方法が、(i)対象から腫瘍生検を得ることと、(ii)対象から正常組織の試料、例えばPBMCを得ることと、(iii)LOHに起因して腫瘍の細胞によっては発現されないが、正常組織の細胞によって発現される多型細胞表面エピトープの単一対立遺伝子多様体を同定し、それにより対象のための個別化されたバイオマーカーを同定することと、を含む、方法を提供する。
いくつかの実施形態では、本発明の方法は、次の例示的な実施形態を提供する。
1.エフェクター免疫細胞の望ましくない活性化を防止または減弱することが可能な阻害性キメラ抗原受容体(iCAR)または保護キメラ抗原受容体(pCAR)をコードするヌクレオチド配列を含む核酸分子であって、iCARまたはpCARが、ヘテロ接合性の喪失(LOH)に起因して哺乳類の腫瘍細胞上には存在しないが、少なくとも関連する哺乳類の正常組織の全ての細胞上に存在する多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合する細胞外ドメインと、エフェクター免疫細胞を阻害する少なくとも1つのシグナル伝達要素を含む細胞内ドメインと、を含む、核酸分子。
2.多型細胞表面エピトープが、HLA遺伝子、Gタンパク質共役受容体(GPCR)、イオンチャネル、もしくは受容体チロシンキナーゼ、好ましくはHLA−A、HLA−B、もしくはHLA−Cなどのハウスキーピング遺伝子生成物のもの、または表8から選択される遺伝子の多型細胞表面エピトープである、請求項1に記載の核酸分子。
3.当該細胞外ドメインが、(i)ヒト化抗体;ヒト抗体;抗体の機能的断片;ナノボディなどの単一ドメイン抗体;組み換え抗体;一本鎖可変断片(ScFv)などの抗体、その誘導体もしくは断片、(ii)アフィボディ分子;アフィリン;アフィマー;アフィチン;アルファボディ;アンチカリン;アビマー;DARPin;ファイノマー;Kunitzドメインペプチド;およびモノボディなどの抗体模倣物、または(iii)アプタマーを含む、請求項1に記載の核酸分子。
4.当該哺乳類組織がヒト組織であり、当該関連哺乳類正常組織が、腫瘍が発生した正常組織である、請求項1に記載の核酸分子。
5.当該エフェクター免疫細胞が、T細胞、ナチュラルキラー細胞、またはサイトカイン誘導キラー細胞である、請求項1に記載の核酸分子。
6.エフェクター免疫細胞を阻害することが可能な当該少なくとも1つのシグナル伝達要素が、免疫チェックポイントタンパク質のシグナル伝達要素と相同である、請求項1に記載の核酸分子。
7.当該免疫チェックポイントタンパク質が、PD1;CTLA4;BTLA;2B4;CD160;CEACAM1などのCEACAM;KIR2DL1、KIR2DL2、KIR2DL3、KIR2DL4、KIR2DL5A、KIR2DL5B、KIR3DL1、KIR3DL2、KIR3DL3、LIR1、LIR2、LIR3、LIR5、LIR8、およびCD94−NKG2AなどのKIR;LAG3;TIM3;T細胞活性化のVドメインIg抑制因子(VISTA);インターフェロン遺伝子の刺激因子(STING);免疫受容阻害チロシンモチーフ(ITIM)含有タンパク質、T細胞免疫グロブリンおよびITIMドメイン(TIGIT)、ならびにアデノシン受容体(例えばA2aR)からなる群から選択される、請求項6に記載の核酸分子。
8.当該細胞外ドメインが、柔軟なヒンジおよび膜貫通型の標準的なモチーフを通じて、当該細胞内ドメインに融合されている、請求項1に記載の核酸分子。
9.請求項1〜8のいずれか一項に記載の核酸分子と、核酸分子に作動可能に連結されたプロモーターなどの少なくとも1つの制御要素とを含む、ベクター。
10.抗原の非多型細胞表面エピトープまたは多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合する細胞外ドメインであって、当該エピトープが、腫瘍関連抗原であるか、または少なくとも関連する腫瘍の細胞と正常組織の細胞とによって共有される、細胞外ドメインと、エフェクター免疫細胞を活性化および/または共刺激する少なくとも1つのシグナル伝達要素を含む細胞内ドメインと、を含むaCARをコードする、ヌクレオチド配列を含む核酸分子をさらに含む、請求項9に記載のベクター。
11.aCARの細胞外ドメインが、抗原の非多型細胞表面エピトープに特異的に結合し、iCARの細胞外ドメインが、当該aCARの細胞外ドメインに結合するものとは異なる抗原の多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合する、請求項10に記載のベクター。
12.aCARの細胞外ドメインが、CD19などの表1に列挙されている抗原から選択される非多型細胞表面エピトープに特異的に結合する、請求項10または11に記載のベクター。
13.エフェクター免疫細胞を活性化または共刺激する当該少なくとも1つのシグナル伝達要素が、例えばCD3ζもしくはFcRγ鎖の免疫受容活性化チロシンモチーフ(ITAM);KIR2DSおよびKIR3DSなどの活性化キラー細胞免疫グロブリン様受容体(KIR)、もしくはDAP12などのアダプター分子;または、例えばCD27、CD28、ICOS、CD137(4−1BB)、もしくはCD134(OX40)の共刺激シグナル伝達要素と相同である、請求項10に記載のベクター。
14.ヌクレオチド配列が、aCARをコードするヌクレオチド配列とiCARをコードするヌクレオチド配列との間に、内部リボソーム進入部位(IRES)を含む、請求項10に記載のベクター。
15.aCARをコードするヌクレオチド配列が、iCARをコードするヌクレオチド配列の下流にある、請求項14に記載のベクター。
16.ヌクレオチド配列が、aCARをコードするヌクレオチド配列とiCARをコードするヌクレオチド配列との間に、ウイルス自己開裂型2Aペプチドを含む、請求項10に記載のベクター。
17.ウイルス自己開裂型2Aペプチドが、ゾセアアシグナウイルス(TaV)由来のT2A、口蹄疫ウイルス(FMDV)由来のF2A、ウマ鼻炎Aウイルス(ERAV)由来のE2A、およびブタテッショウウイルス1(PTV1)由来のP2Aからなる群から選択される、請求項16に記載のベクター。
18.柔軟なリンカーを介して当該iCARに連結された当該構成的aCARをコードするヌクレオチド配列を含む、請求項10に記載のベクター。
19.請求項1〜8に定義されるエフェクター免疫細胞の望ましくない活性化を防止または減弱することが可能な阻害性キメラ抗原受容体(iCAR)を調製する方法であって、
(i)既知の多様体の少なくとも1つのデータベースから、タンパク質をコードする遺伝子のヒトゲノム多様体のリストを取得することと、
(ii)
(a)多様体を選択し、その対応する参照対立遺伝子と比較して、それぞれの遺伝子によってコードされるタンパク質にアミノ酸配列の多様性を生じること、
(b)アミノ酸配列の多様性が、コードされるタンパク質の細胞外ドメインにある、遺伝子の多様体を選択すること、
(c)少なくとも1つの腫瘍においてヘテロ接合性の喪失(LOH)を受ける遺伝子の多様体を選択すること、ならびに
(d)(c)に従ってLOHを受ける少なくとも1つの腫瘍の少なくとも原発組織で発現する遺伝子の多様体を選択し、それにより、LOHに起因して少なくとも1つの腫瘍において喪失した遺伝子、および少なくとも1つの腫瘍の少なくとも原発組織で発現する遺伝子のそれぞれによってコードされるタンパク質の細胞外ドメインに、アミノ酸配列の多様性を有する多様体のリストを得ること、によって、(i)によって取得した多様体のリストをフィルタリングすることと、
(iii)(ii)で得たリストから少なくとも1つの単一多様体を含む配列領域を定義し、少なくとも1つの単一多様体を含む配列領域および対応する参照対立遺伝子を含む配列領域をサブクローニングおよび発現し、それによりそれぞれのエピトープペプチドを得ることと、
(iv)クローニングされた配列領域によってコードされるエピトープペプチド、または(iii)で得た対応する参照対立遺伝子によってコードされるエピトープペプチドのいずれかに特異的に結合するiCAR結合ドメインを選択することと、
(vii)各々が(iv)で定義されるiCAR結合ドメインを含む、請求項1〜8のいずれか一項で定義されたiCARを調製することと、を含む、方法。
20.各多様体のマイナー対立遺伝子頻度が1、2、3、4、または5%以上である、請求項19に記載の方法。
21.安全なエフェクター免疫細胞を調製するための方法であって、(i)腫瘍関連抗原に向けられているTCR操作エフェクター免疫細胞を、請求項1〜8のいずれか一項に記載のiCARをコードするヌクレオチド配列を含む核酸分子でトランスフェクトするか、もしくは請求項9に記載のベクターで細胞を形質導入すること、または(ii)ナイーブエフェクター免疫細胞を、請求項1〜8のいずれか一項に記載のiCARをコードするヌクレオチド配列を含む核酸分子、および請求項10〜13のいずれか一項に定義されているaCARをコードするヌクレオチド配列を含む核酸分子でトランスフェクトするか、もしくはエフェクター免疫細胞を、請求項10〜18のいずれか一項に記載のベクターで形質導入すること、を含む、方法。
22.請求項21に記載の方法によって得られる、安全なエフェクター免疫細胞。
23.その表面上に、抗原の非多型細胞表面エピトープに特異的に結合する細胞外ドメインを含むaCARと、当該aCARの細胞外ドメインに結合する異なる抗原の多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合する細胞外ドメインを含むiCARとを発現している、請求項22に記載の安全なエフェクター免疫細胞。
24.aCARの細胞外ドメインが、CD19などの表1に列挙されている抗原から選択される非多型細胞表面エピトープに特異的に結合する、請求項22または23に記載の安全なエフェクター免疫細胞。
25.aCARおよびiCARが、別個のタンパク質として細胞表面上に存在する、請求項22に記載の安全なエフェクター免疫細胞。
26.iCARをコードする当該ヌクレオチド配列の発現レベルが、aCARをコードするヌクレオチド配列の発現レベル以上である、請求項22に記載の安全なエフェクター免疫細胞。
27.LOHを特徴とする腫瘍を有する対象のための個別化されたバイオマーカーを選択する方法であって、
(i)対象から腫瘍生検を得ることと、
(ii)対象から正常組織の試料、例えばPBMCを得ることと、
(iii)LOHに起因して腫瘍の細胞によっては発現されないが、正常組織の細胞によって発現される多型細胞表面エピトープの単一対立遺伝子多様体を同定し、
それにより対象ための個別化されたバイオマーカーを同定することと、を含む、方法。
28.LOHを特徴とする腫瘍を有する患者の癌を治療するための方法であって、請求項22に記載のエフェクター免疫細胞を患者に投与することを含み、iCARが、ヘテロ接合性の喪失(LOH)に起因して腫瘍の細胞には存在しないが、少なくとも患者の関連する哺乳類の正常組織の全ての細胞上に存在する多型細胞表面エピトープをコードする、単一対立遺伝子多様体に向けられている、方法。
29.iCARが、ヘテロ接合性の喪失(LOH)に起因して腫瘍の細胞には存在しないが、少なくとも患者の関連する哺乳類の正常組織の全ての細胞上に存在する多型細胞表面エピトープをコードする、単一対立遺伝子多様体に向けられている、LOHを特徴とする腫瘍を有する患者の治療で使用するための、請求項22に記載の安全なエフェクター免疫細胞。
30.(iii)のaCARを発現しているが、(iii)のiCARが欠如している免疫エフェクター細胞の少なくとも1つの集団を癌患者に投与することを含む治療と比較して、治療が、低減された標的上腫瘍外反応性を生じる、請求項29に記載の使用のための安全なエフェクター免疫細胞。
31.それらの表面上に、腫瘍関連抗原または抗原の非多型細胞表面エピトープに特異的に結合する細胞外ドメインを含むaCARと、当該aCARの細胞外ドメインに結合するものとは異なる抗原である、腫瘍の少なくとも原発組織で発現する抗原の、またはHLA−Aなどのハウスキーピングタンパク質の、多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合する細胞外ドメインを含むiCARと、を発現している、請求項29に記載の使用のための安全なエフェクター免疫細胞。
32.自家または普遍的(同種)エフェクター細胞である、請求項28に記載の使用のための安全なエフェクター免疫細胞。
33.T細胞、ナチュラルキラー細胞、またはサイトカイン誘導キラー細胞から選択される、請求項28〜32のいずれか一項に記載の使用のための安全なエフェクター免疫細胞。
34.各1つが、当該核酸分子が単一の連続核酸分子を形成する、制御されたエフェクター免疫細胞活性化系の異なるメンバーをコードするヌクレオチド配列を含むか、または2つ以上の別個の核酸分子を含み、制御されたエフェクター免疫活性化系がエフェクター免疫細胞に向けられて、ヘテロ接合性の喪失(LOH)に起因して1つ以上の染色体またはそれらの断片を喪失した腫瘍細胞を殺傷し、関連正常組織の細胞を生かす、2つ以上の核酸分子の組み合わせであって、
(a)第1のメンバーが、抗原の非多型細胞表面エピトープまたは異なる多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合する第1の細胞外ドメインを含む活性化キメラ抗原受容体(aCAR)ポリペプチドを含み、当該非多型または多型細胞表面エピトープが、腫瘍関連抗原であるか、または関連する異常な哺乳類組織の細胞と正常な哺乳類組織の細胞とによって共有され、
(b)第2のメンバーが、LOHに起因して異常な哺乳類組織によって発現されないが、関連する哺乳類の正常組織の全ての細胞上に存在する多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合する第2の細胞外ドメインを含む調節ポリペプチドを含む、2つ以上の核酸分子の組み合わせ。
35.第1のメンバーが、
(a)エフェクター免疫細胞を活性化および/または共刺激する少なくとも1つのシグナル伝達要素を含む細胞内ドメインをさらに含む構成的aCAR、ならびに
(b)ヘテロ二量体化小分子の結合部位の第1のメンバーを含む細胞内ドメイン、および任意選択的に少なくとも1つの共刺激シグナル伝達要素をさらに含むが、活性化シグナル伝達要素が欠如した条件付きaCARから選択され、第2のメンバーが、
(c)エフェクター免疫細胞を阻害する少なくとも1つのシグナル伝達要素を含む細胞内ドメインをさらに含む阻害性キメラ抗原受容体(iCAR)、または
(d)シェダーゼの基質を含む細胞外調節領域;膜内開裂プロテアーゼの基質を含む膜貫通型の標準的なモチーフ;ならびに細胞内ドメインであって、当該細胞内ドメインが、エフェクター免疫細胞を活性化および/もしくは共刺激する少なくとも1つのシグナル伝達要素およびヘテロ二量体化小分子の結合部位の第2のメンバーを含む細胞内ドメインをさらに含む、保護キメラ抗原受容体(pCAR)である、請求項34に記載の組み合わせ。
36.
(i)iCARもしくはpCARの細胞外ドメインが、aCARの細胞外ドメインに結合するものとは異なる抗原である、抗原の多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合するか、
(ii)当該pCARもしくはiCARの細胞外ドメインが、当該aCARの細胞外ドメインに結合する同じ抗原の異なる多型細胞表面エピトープの単一対立遺伝子多様体に特異的に結合するか、または
(iii)当該pCARもしくはiCARの細胞外ドメインが、当該aCARの細胞外ドメインに結合する同じ多型細胞表面エピトープの異なる単一対立遺伝子多様体に特異的に結合する、請求項34または35に記載の組み合わせ。
37.シェダーゼの当該基質が、ディスインテグリン、およびメタロプロテイナーゼ(ADAM)、またはベータ−セクレターゼ1(BACE1)の基質である、請求項34に記載の組み合わせ。
38.当該基質が、細胞外ドメインの一部を形成し、Lin12/NotchリピートおよびADAMプロテアーゼ開裂部位を含む、請求項37に記載の組み合わせ。
39.膜内開裂プロテアーゼの当該基質が、SP2、y−セクレターゼ、シグナルペプチドペプチダーゼ(spp)、spp様プロテアーゼ、またはロンボイドプロテアーゼの基質である、請求項34に記載の組み合わせ。
40.当該基質が、膜貫通型の標準的なモチーフの一部を形成し、Notch、ErbB4、E−カドヘリン、N−カドヘリン、エフリン−B2、アミロイド前駆体タンパク質、またはCD44の膜貫通ドメインに相同である/これらに由来する、請求項39に記載の組み合わせ。
41.別個のタンパク質として、当該条件付きaCARの細胞外ドメインおよび細胞内ドメインをコードするヌクレオチド配列を含み、各ドメインが、膜貫通型の標準的なモチーフに独立して融合され、ヘテロ二量体化小分子の結合部位の異なるメンバーを含む、請求項34に記載の組み合わせ。
42.ヘテロ二量体化小分子のための当該結合部位の当該第1および第2のメンバーのうちの各々1つが、
(i)タクロリムス(FK506)結合タンパク質(FKBP)およびFKBP、
(ii)FKBPおよびカルシニューリン触媒サブユニットA(CnA)、
(iii)FKBPおよびシクロフィリン、
(iv)FKBPおよびFKBP−ラパマイシン関連タンパク質(FRB)、
(v)ジャイレースB(GyrB)およびGyrB、
(vi)ジヒドロ葉酸還元酵素(DHFR)およびDHFR、
(vii)DmrBホモ二量体化ドメイン(DmrB)およびDmrB、
(viii)PYLタンパク質(別名アブシジン酸受容体およびRCAR)およびABI、
(ix)GAIシロイヌナズナタンパク質(別名ジベレリン酸非感受性およびDELLAタンパク質GAI;GAI)およびGID1シロイヌナズナタンパク質(ジベレリン受容体GID1としても知られている、GID1)、から選択されるタンパク質に由来する、請求項34に記載の組み合わせ。
特許出願は、長い表セクションを含む。表のコピーは、CD−ROMで本明細書とともに提出される。
緒論:
癌細胞のゲノム喪失によって引き起こされる脆弱性に対処するための療法的戦略を提案する。提案される戦略は、活性化CAR T細胞(aCAR)と阻害性CAR T細胞(iCAR)との組み合わせを使用して、母方および父方の対立遺伝子でヘテロ接合性の(すなわち、多型タンパク質のコード変化を伴う)細胞膜タンパク質をコードするゲノムセグメントを喪失した腫瘍をより安全に標的とする。
ABSOLUTEアルゴリズムによって処理したTCGAからのコピー数プロファイルを使用して、HLA−Aの対立遺伝子喪失比率の実際のデータに基づいた推定値を評価した。一般的に利用可能なABSOLUTEセグメント化コピー数データは、(https://www.synapse.org/#!Synapse:syn1710464.2)1からダウンロードした。ABSOLUTEアルゴリズムは、単一癌ゲノム内の各対立遺伝子セグメントの整数コピーレベルを出力する。染色体6(HLA遺伝子座に存在する)の単一コピーが喪失している場合、対立遺伝子のコピー数は、保持されたセグメントでは1、喪失したセグメントでは0であろう。コピー数に変化のないヘテロ接合性の喪失の場合、保持されたセグメントはコピー数2を有し、喪失したセグメントはコピー数0を有するであろう。ABSOLUTEによって処理した一般的に入手可能なコピー数データは、12の腫瘍型で利用可能であった(表4)。肺扁平上皮癌腫(LUSC)は、他の腫瘍型と比較して、最も高いHLA−A LOHの頻度を有した(図6)。子宮/子宮内膜癌(UCEC)は、評価可能な全ての腫瘍のうち、最も低いHLA−A LOHの頻度を有した(ABSOLUTEデータが入手不可能であることに起因して、AML試料は含まなかった)。HLA−A遺伝子の588個の欠失のうち、遺伝子内ブレークポイントは1つもなかった(図7)。HLA−A遺伝子のほとんどの欠失は、染色体の大部分を包含した(図8)。ABSOLUTEコピー数データはAML試料では入手不可能であったが、これらの試料の相対コピー数データを手動で検査したところ、欠失はないことが明らかになった(図11)。
一般的に入手可能な、できる限り多くの腫瘍型のLOHの頻度を得ようと努めた。しかしながら、これらのデータは、ABSOLUTEによって処理されておらず、ABSOLUTEによって処理する生データは一般的に入手不可能である。代わりに、TCGAからの32の腫瘍型の相対コピー数データを使用した(図13)。これらのデータは、cbioportal(cbioportal.org/data_sets.jsp)からダウンロードした。相対コピー数データは、腫瘍試料のAffymetrix SNP 6.0アレイから得た。
TCGAから入手可能な32の腫瘍全てに対する、HLA−AのLOHを有した患者の一部分を算出した(図10A、COADおよびREADは一緒に分析した)。HLA−A LOHの最も高い比率を有する腫瘍は、腎臓嫌色素性癌であった。HLA−A LOHの最も低い比率を有する腫瘍は、ブドウ膜黒色腫であった(表6)。これらの分析で導出したLOHの比率がゲノム位置の小さな摂動に対して強固であることを確実にするために、HLA−Aの上流および下流遺伝子のLOHの比率を分析して、HLA−LOHの比率がHLA−Aと同様であるかどうかを調べた。予想通り、上流および下流遺伝子、HLA−GおよびZNRD1のLOHの比率は、それぞれHLA−Aと全く同じであった。(図3A〜C)。これらのデータは、HLA−A LOH呼び出しが、ゲノム位置の小さな偏差に対して強固であることを実証している。次に、他のHLA遺伝子(A、B、C)が,HLA−Aと比較して同様のLOHの比率を有するかどうかを決定しようと努めた。これらの遺伝子は全て、染色体6pの1.3Mb領域内に含まれる。ゲノム距離では、これは小さな領域である。HLA−BおよびHLA−CでHLA−A分析を繰り返した。LOHのパターンは、分析した32の腫瘍全体で3つのHLA遺伝子全てでほぼ同一であった(図10A〜C)。
腫瘍内のゲノムの不均一性は、これまでに分析されたほぼ全てのヒトの癌で、最近高く評価されている特色である2、3。腫瘍細胞の一部分にのみ存在する遺伝子的変更を標的とする療法は、当該変化がある腫瘍細胞にのみ影響を与え得る。腫瘍細胞上に存在しない抗原を標的とするiCAR戦略は、抗原がクローン的に欠失していない場合、一部の腫瘍細胞をaCAR攻撃から保護する場合がある。したがって、HLA遺伝子がクローンLOHを受ける可能性が高い腫瘍を同定しようと努めた。進化の初期に発生するLOHは、腫瘍の開始および/または維持における選択力によって推進される可能性が高い。したがって、3つの方式で第6染色体(HLA遺伝子座に存在する)の腫瘍抑制因子を探した。第1に、評価された各腫瘍型の、第6染色体上で有意に変異している遺伝子を探した4。スプレッドシートでは、「chr6_mutsig_sig_genes」列の下に第6染色体上に有意な変異を有する遺伝子が報告されている。
実施例1の参考文献:
1.Zack TI,Schumacher SE,Carter SL,Cherniack AD,Saksena G,Tabak B,Lawrence MS,Zhsng CZ,Wala J,Mermel CH,Sougnez C,Gabriel SB,Hernandez B,Shen H,Laird PW,Getz G,Meyerson M,Beroukhim R.Pan−cancer patterns of somatic copy number alteration.Nature genetics.2013;45:1134−1140
2.Gibson WJ,Hoivik EA,Halle MK,Taylor−Weiner A,Cherniack AD,Berg A,Holst F,Zack TI,Werner HM,Staby KM,Rosenberg M,Stefansson IM,Kusonmano K,Chevalier A,Mauland KK,Trovik J,Krakstad C,Giannakis M,Hodis E,Woie K,Bjorge L,Vintermyr OK,Wala JA,Lawrence MS,Getz G,Carter SL,Beroukhim R,Salvesen HB.The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis.Nature genetics.2016;48:848−855
3.Gerlinger M,Rowan AJ,Horswell S,Math M,Larkin J,Endesfelder D,Gronroos E,Martinez P,Matthews N,Stewart A,Tarpey P,Varela I,Phillimore B,Begum S,McDonald NQ,Butler A,Jones D,Raine K,Latimer C,Santos CR,Nohadani M,Eklund AC,Spencer−Dene B,Clark G,Pickering L,Stamp G,Gore M,Szallasi Z,Downward J,Futreal PA,Swanton C.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.The New England journal of medicine.2012;366:883−892
4.Lawrence MS,Stojanov P,Mermel CH,Robinson JT,Garraway LA,Golub TR,Meyerson M,Gabriel SB,Lander ES,Getz G.Discovery and saturation analysis of cancer genes across 21 tumour types.Nature.2014;505:495−501
5.Vogelstein B,Papadopoulos N,Velculescu VE,Zhou S,Diaz LA,Jr.,Kinzler KW.Cancer genome landscapes.Science.2013;339:1546−1558
6.Zheng S,Cherniack AD,Dewal N,Moffitt RA,Danilova L,Murray BA,Lerario AM,Else T,Knijnenburg TA,Ciriello G,Kim S,Assie G,Morozova O,Akbani R,Shih J,Hoadley KA,Choueiri TK,Waldmann J,Mete O,Robertson AG,Wu HT,Raphael BJ,Shao L,Meyerson M,Demeure MJ,Beuschlein F,Gill AJ,Sidhu SB,Almeida MQ,Fragoso M,Cope LM,Kebebew E,Habra MA,Whitsett TG,Bussey KJ,Rainey WE,Asa SL,Bertherat J,Fassnacht M,Wheeler DA,Cancer Genome Atlas Research N,Hammer GD,Giordano TJ,Verhaak RGW.Comprehensive pan−genomic characterization of adrenocortical carcinoma.Cancer cell.2016;29:723−736
7.Compagno M,Lim WK,Grunn A,Nandula SV,Brahmachary M,Shen Q,Bertoni F,Ponzoni M,Scandurra M,Califano A,Bhagat G,Chadburn A,Dalla−Favera R,Pasqualucci L.Mutations of multiple genes cause deregulation of nf−kappab in diffuse large b−cell lymphoma.Nature.2009;459:717−721
緒論:
iCARの標的が非腫瘍組織によってのみ発現される場合、阻害性CAR T細胞は、抗腫瘍有効性を減少させることなく、CAR−T療法の腫瘍外毒性を減少させることができる。iCAR標的が非腫瘍細胞によってのみ発現されるであろう、1つのかかるシナリオは、腫瘍細胞で欠失したゲノムの一部分によってiCAR抗原がコードされている場合である。ワークフローのこのセクションの目的は、かかる対立遺伝子を同定することである。
Exome Aggregation Consortium(ExAC)データベースを分析の入力値として使用した(exac.broadinstitute.org)。ExACデータベースは、合計60,706のエクソームの様々な集団レベルのシーケンシング研究からのエクソームをまとめたものである1。ExACは、代替対立遺伝子と比較した参照対立遺伝子の数(対立遺伝子頻度)を含む、各多様体に関する情報を含む。対立遺伝子頻度情報は、表7で詳述されるように、データベース内のサブ集団に拡張される。
表7.ExACデータベース内のサブ集団。注:ゲノムの全ての位置がエクソームで十分に網羅されていないので、この表に全ての個体を表している。出典:http://exac.broadinstitute.org/faq.
9,362,319個の多様体で分析を開始し、29,904個の多様体はこれらの2つのフィルターを満たした。これらの多様体は、10,302個の遺伝子に含まれた。これらの2つのフィルターに一致する全ての対立遺伝子を分析に含めた。
様々な組織の種類で発現する遺伝子の同定に、Genotype−Tissue Expression(GTEX)データベースv6p(dbGaP 受託番号phs000424.v6.p1)(https://gtexportal.org/home/)2を使用した。GTEXデータベースは、多様な健康な組織の種類からの8,555個のヒト試料のRNAシーケンシングからなる。このデータベースから、いくつかのアノテーションを得た。まず、全ての組織全体の各遺伝子の平均発現を決定した。各遺伝子の平均発現は、組織ごとの中央値の発現データを取得し、組織全体のこれらの値の平均を算出することによって計算した。これらのデータは、https://gtexportal.org/home/datasetsから入手可能なGTEx_Analysis_v6p_RNA−seq_RNA−SeQCv1.1.8_gene_median_rpkm.gctファイルから得た。
タンパク質機能への対立遺伝子の影響:
iCARが膜タンパク質の1つの対立遺伝子を喪失した癌細胞のみを効果的に認識するために、タンパク質の構造は、どの対立遺伝子がコードされているかに基づいて十分に異なる。得られたタンパク質への各SNPの効果を定量化するために、いくつかの測定を行った。まず、報告されたSNP多様体クラス(例えば、ミスセンス、ナンセンス)を、「結果」の列に報告した。コンセンサスタンパク質翻訳への影響は、「protein_consequence」(例、p.Arg482Gln)の列に含んだ。SIFTアルゴリズムによって、タンパク質多様体がタンパク質の構造、およびしたがって機能への影響を有するかどうかを予測しようと試みる6。スコアは、0(有害)〜1(良性)の範囲であり得る。SIFTスコア(バージョンsift5.2.2)は、スコアが利用可能な全てのSNPに含まれた。例えば、フレームシフト変異のスコアは利用不可能である。PolyPhen(v2.2.2)もまた、多様体がタンパク質の構造および機能に影響を与え得る可能性を予測するために使用した。Polyphenアルゴリズムは、スコア0は良性に対応し、スコア1は有害に対応する、SIFTとは反対の様式でスコアを報告する。
iCARが対立遺伝子を認識するためには、対立遺伝子がタンパク質の細胞外部分に含まれなければならない。各SNPについて、コンセンサス翻訳で影響を受けるアミノ酸の位置を抽出し、これをUniprotデータベースから細胞外としてアノテーションしたドメインと比較した。Uniprotデータベースは、www.uniprot.org/downloadsからダウンロードした。全てのタンパク質のドメインの特徴付けの欠如に起因して、多くの偽陰性が発生する可能性がある。1167個の遺伝子で、合計3288個のSNPが細胞外としてアノテーションされた(表8)。
分析された対立遺伝子のペプチドの状況は、これらの配列を認識する抗体を生成しようとするときにおそらく問題になるであろう。参考までに、SNPによってコードされるアミノ酸の前後にある10アミノ酸(合計21アミノ酸配列)を含める。コンセンサスアミノ酸配列には、uniprotデータベースを使用した。uniprotデータベース配列が、予測された位置でいずれかのSNPによってコードされるアミノ酸と一致しなかった場合の矛盾にアノテーションして、誤った配列を含めない。これらの21個のアミノ酸配列は、BepipredなどのB細胞エピトープ予測プログラムへの入力として有用であり得る。
LOHを受けている腫瘍の割合
提案された療法が有益であり得る腫瘍を有する患者を見つけるには、腫瘍の大部分でヘテロ接合性の喪失(LOH)を受けるSNPであろう、iCARの標的が必要であろう。セグメントのコピー数ファイルは、cbio癌ゲノミクスポータルhttp://www.cbioportal.org/からダウンロードした8。一例として、全てのSNPについてLOHを受けているブドウ膜黒色腫腫瘍の割合を、図12に示す。
抵抗性ゲノム標的化療法の可能なメカニズムの1つは、意図したゲノム変更のうちの1つが、癌細胞の一部分にのみ存在する場合である。腫瘍発生の最も初期の段階に存在する可能性が高い標的を同定しようと試みる1つのメカニズムは、各腫瘍のドライバー事象を同定することである。腫瘍抑制遺伝子の不活性化の最も頻繁なメカニズムは、変異およびその後の非変異染色体のLOHである。ドライバー遺伝子、特に各腫瘍型におけるこのプロセスを受ける可能性の高い腫瘍抑制遺伝子(TSG)を見出そうと試みた。この分析では、全ての腫瘍に対してMUTSIG 2.0を実行した結果を使用して、各腫瘍型で有意に変異した遺伝子を同定した。有意に変異した遺伝子のうちの1つが、TP53、PTEN、APC、MLL3、MLL2、VHL、CDKN2A、RB1を含む「ホールマーク」腫瘍抑制遺伝子のリストに含まれているかどうかで、アノテーションした。最後に、SNPと同じ染色体上に含まれる場合、ドライバー遺伝子、TSG、および「ホールマーク」TSGのリストでは、SNPにアノテーションした。
候補のSNPに継続的な「スコア」を提供するために、より良好なSNP候補に関連するはずのいくつかの異なる測定基準を組み合わせた。スコアは、次のうちの各々のパーセンタイルランクの成果からなる。
1.そのSNPにLOHを有する腫瘍の割合(高いほど良好である)、2.対立遺伝子の有病率(高いほど良好である)、3.組織全体の発現値の標準偏差対中央値の比(低いほど良好であり、より一貫性がある)、4.染色体上に腫瘍抑制遺伝子があるかどうか(有さないものよりも有するものがより良好である)
表8.例示的なiCAR標的
1.Lek M,Karczewski KJ,Minikel EV,Samocha KE,Banks E,Fennell T,O’Donnell−Luria AH,Ware JS,Hill AJ,Cummings BB,Tukiainen T,Birnbaum DP,Kosmicki JA,Duncan LE,Estrada K,Zhao F,Zou J,Pierce−Hoffman E,Berghout J,Cooper DN,Deflaux N,DePristo M,Do R,Flannick J,Fromer M,Gauthier L,Goldstein J,Gupta N,Howrigan D,Kiezun A,Kurki MI,Moonshine AL,Natarajan P,Orozco L,Peloso GM,Poplin R,Rivas MA,Ruano−Rubio V,Rose SA,Ruderfer DM,Shakir K,Stenson PD,Stevens C,Thomas BP,Tiao G,Tusie−Luna MT,Weisburd B,Won HH,Yu D,Altshuler DM,Ardissino D,Boehnke M,Danesh J,Donnelly S,Elosua R,Florez JC,Gabriel SB,Getz G,Glatt SJ,Hultman CM,Kathiresan S,Laakso M,McCarroll S,McCarthy MI,McGovern D,McPherson R,Neale BM,Palotie A,Purcell SM,Saleheen D,Scharf JM,Sklar P,Sullivan PF,Tuomilehto J,Tsuang MT,Watkins HC,Wilson JG,Daly MJ,MacArthur DG,Exome Aggregation C.Analysis of protein−coding genetic variation in 60,706 humans.Nature.2016;536:285−291
2.Consortium GT.Human genomics.The genotype−tissue expression(gtex)pilot analysis:Multitissue gene regulation in humans.Science.2015;348:648−660
3.
6.Ng PC,Henikoff S.Sift:Predicting amino acid changes that affect protein function.Nucleic acids research.2003;31:3812−3814
7.
8.Cerami E,Gao J,Dogrusoz U,Gross BE,Sumer SO,Aksoy BA,Jacobsen A,Byrne CJ,Heuer ML,Larsson E,Antipin Y,Reva B,Goldberg AP,Sander C,Schultz N.The cbio cancer genomics portal:An open platform for exploring multidimensional cancer genomics data.Cancer discovery.2012;2:401−404
実施例3.KICH試料におけるHLA LOHの検証のためのDNAシーケンシング分析
ライブラリーの準備およびシーケンシング
目的−インシリコ分析に基づいて、HLA LOH予測の湿式検証のための最初の腫瘍型として、KICH癌を選択した。目的は、正常組織に由来するDNAに基づいて、各患者のHLA遺伝子型を同定し、次いでHLA対立遺伝子のうちの1つの喪失の同定を試みて、癌組織のHLAアロタイプを分析することであった。
Illuminaアダプター配列:
5’−AATGATACGGCGACCACCGAGATCTACAC[i5]TCGTCGGCAGCGTC
5’−CAAGCAGAAGACGGCATACGAGAT[i7]GTCTCGTGGGCTCGG
[i5,i7]−試料特有のシーケンシングデータを同定するための独特なデュアルインデックス配列
HLAシーケンシングに加えて、HLA−LOHを確認し、ゲノム全体の追加のLOH事象を同定するために、エクソームシーケンシングも実施した
Illuminaのペアエンド生リード(150X2、HiSeq)は、FastQCを使用して品質チェックした。Illuminaの生リードは、最小リード長50bpおよび最小ベース品質30のパラメーターを使用して、アダプタークリッピングおよび低品質ベーストリミング用にTrim Galoreソフトウェアによって処理した。処理したリードは、Bowtie2を使用して参照ヒトゲノム(hg19)にアラインメントした。次いで、試料の各々の整列させた.bamファイルを処理して、.bamファイルを除去した最終PCR複製を得、Qualimapを使用してアラインメントの品質をチェックした。
略号:ADP、アデノシン二リン酸;ALL、急性リンパ芽球性白血病;AML、急性骨髄性白血病;APRIL、増殖誘導リガンド;BAFF、TNFファミリーのB細胞活性化因子;BCMA、B細胞成熟抗原;BCR、B細胞受容体;BM、骨髄;CAIX、炭酸脱水酵素IX;CAR、キメラ抗原受容体;CEA、癌胎児性抗原;CLL、慢性リンパ性白血病;CNS、中枢神経系;CSPG4、コンドロイチン硫酸プロテオグリカン4;DC、樹状細胞;ECM、細胞外マトリックス;EGFR、上皮成長因子受容体;EGFRvIII、EGFRの多様体III;EphA2、エリスロポエチン生成肝細胞癌腫A2;FAP、線維芽細胞活性化タンパク質;FR−α、葉酸受容体−アルファ;GBM、多形膠芽腫;GPI、グリコホスファチジルイノシトール;H&N、頭頸部;HL、ホジキンリンパ腫;Ig、免疫グロブリン;L1−CAM、L1細胞接着分子;MM、多発性骨髄腫;NB、神経芽細胞腫;NF−KB、核因子−KB;NHL、非ホジキンリンパ腫;NK、ナチュラルキラー;NKG2D−L、NKG2Dリガンド;PBMC、末梢血単核細胞;PC、形質細胞;PLL、前リンパ性白血病;PSCA、前立腺幹細胞抗原;PSMA、前立腺特異的膜抗原;RCC、腎細胞癌腫;ROR1、受容体チロシンキナーゼ様オーファン受容体1;TCL、T細胞白血病/リンパ腫;Th2、Tヘルパー2;TNBC、トリプルネガティブ乳癌;TNFR、腫瘍壊死因子受容体;VEGFR−2、血管内皮増殖因子−2。
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LOHは、対立遺伝子特異的抗体を使用して、腫瘍細胞試料に対して正常細胞試料を区別して染色することによって、タンパク質レベルで検出することができる。例えば、癌試料におけるHLA−LOHの検証は、患者のHLAアロタイプに特異的な市販のHLA抗体を使用して行うことができる。以下の表11は、使用することができる、利用可能な対立遺伝子特異的抗体の例を詳細に示す。
凍結組織試料−
多くの場合、凍結組織は、ホルマリン系溶液で固定され、OCT(最適切断温度化合物)に包埋されて、試料の凍結切断が可能である。OCT中組織は、−80℃で凍結保存される。凍結ブロックを切断前に、−80℃のクライオスタットチャンバーから取り出し、平衡化し、薄い切片(多くの場合5〜15μm厚)に切断する。切片は、組織学的スライドに載せる。スライドは、−20℃〜−80℃で保存することができる。
IHC染色の前に、スライドを室温(RT)で10〜20分間解凍する。
組織を、ホルムアルデヒド固定液に包埋する。パラフィンワックスを添加する前に、RTで特定の時間および期間の間、エタノールの濃度を徐々に上げながら(70%、90%、100%)キシレンとともに徐々に組織を浸漬することによって脱水する。次いで、組織をパラフィンワックスに包埋する。
プロトコル:
1.スライドを洗浄緩衝液で10分間再水和する(PBSX1)。洗浄緩衝液を排水する。
2.抗原取得を実施する−)必要な場合(熱誘導抗原取得または酵素による取得)。
3.細胞内抗原では、透過処理を実施する−PBSX1中0.1%のトリトンX−100で、スライドをRTで10分間培養する。
4.ブロッキング−ブロッキング緩衝液で、組織をRTで30分間ブロックする。ブロッキング緩衝液は検出方法に依存する(通常PBSX1中5%の動物血清、またはPBSX1中1%のBSA)。
5.一次抗体−抗体製造者の指示書に従って、一次抗体を培養緩衝液で希釈する(例えば、PBS中1%BSA、1%のロバ血清、他の培養緩衝液も使用してもよい)。希釈した一次抗体中で、組織を4℃で一晩培養する。一次抗体は、上で詳述したモノクローナル抗HLA−A、抗HLA−B、または抗HLA−C対立遺伝子特異的抗体であり得る。
共役一次抗体を使用する場合、光から保護し、ステップ8に進む。
陰性対照として、一次抗体を含まない、培養緩衝液のみで組織を培養する。
また、実験で使用したモノクローナル抗体のアイソタイプに一致する対照にも実施する。
6.6.洗浄−スライドを洗浄緩衝液で洗浄する(−3X5〜15分)。
7.7.二次抗体−抗体製造者の指示書に従って、二次抗体を培養緩衝液で希釈する。希釈した二次抗体中の組織を、RTで30〜60分間培養する。光から保護する。
8.8.洗浄−スライドを洗浄緩衝液で洗浄する(−3X5〜15分)。
9.9.DAPI染色−DAPI培養緩衝液を希釈する(〜300nM〜3μM)。300μlのDAPI溶液を各切片に添加する。RTで5〜10分間培養する。
10.10.洗浄−スライドをX1PBSで1回洗浄する。
11.11.退色防止用封入剤とともに載せる。
12.12.スライドを光から保護し続ける。
13.13.蛍光顕微鏡を使用して、スライドを視覚化する。
プロトコル:
1.1.スライドを洗浄緩衝液で10分間再水和する(PBSX1)。洗浄緩衝液を排水する。
2.2.抗原取得を実施する−必要な場合、上を参照する。
3.3.HRP試薬では、メタノール中3.0%の過酸化水素を用いて、内因性ペルオキシダーゼ活性を少なくとも15分間ブロックする。
4.4.切片をdH2O中に5分間浸漬することによって、洗浄する。
5.5.細胞内抗原では、透過処理を実施する−PBSX1中0.1%のトリトンX−100で、スライドをRTで10分間培養する。
6.6.ブロッキング−ブロッキング緩衝液で、組織をRTで30分間ブロックする。ブロッキング緩衝液は検出方法に依存する(通常PBSX1中5%の動物血清、またはPBSX1中1%のBSA)。
7.7.一次抗体−抗体製造者の指示書に従って、一次抗体を培養緩衝液で希釈する(例えば、PBS中1%BSA、1%のロバ血清、他の培養緩衝液も使用してもよい)。希釈した一次抗体中で、組織を4℃で一晩培養する
8.8.洗浄−スライドを洗浄緩衝液で洗浄する(−3X5〜15分)。
9.9.RTで30〜60分間、組織を二次抗体−HRP共役二次抗体と培養する。
10.10.洗浄−スライドを洗浄緩衝液で洗浄する(3X5〜15分)。
11.11.製造者のガイドラインに従って、ABC−HRP試薬を添加する。RTで60分間培養する。
12.12.製造者のガイドラインに従って、DAB溶液(または他の色素原)を調製し、組織切片に適用する。色素原反応により、エピトープ部位が茶色に変わる(通常、数秒〜10分)。シグナルの強度が画像化に適切であるときには、次のステップに進む
13.13.洗浄−スライドを洗浄緩衝液で洗浄する(−3X5〜15分)。
14.14.スライドをdH2Oで洗浄する(−2X5〜15分)
15.15.核染色−ヘマトキシリン溶液を添加する。RTで5分間培養する。
16.16.組織切片を脱水する(95%エタノール−2X2分。100%エタノール−2X2分。キシレン−2X2分)。
17.17.退色防止用封入剤とともに載せる
18.18.明視野照明を使用して、スライドを視覚化する
研究の目的は、CAR−T療法の標的上の「腫瘍外」効果を阻害するであろう合成受容体を作製することである。その程度まで、活性化および阻害性CARで構成されるCAR構築物のライブラリーを確立した。
CD19 CAR活性化の調節に対するiCAR構築物の効果を研究するために、以下の表12に詳述されるように、組み換えJurkatエフェクター細胞を構築した。Jurkat(ATCC TIB152)、CD4+T細胞株、およびJurkat−NFAT(NFAT応答要素の制御下でホタルルシフェラーゼタンパク質を発現するように操作されたBPS Biosciencesから購入したJurkat細胞株)を、レトロネクチンでコーティングした(Takara)レンチウイルスベクター結合プレートを使用して、またはポリブレンの存在下で形質導入した。形質導入された細胞に、さらに抗生物質選択を施して、表12に記載の細胞株を得た。選択に続き、細胞にフローサイトメトリー分析を施して、各構築物にコードされたレポータータンパク質の発現を検証した。
標的外細胞に対するaCARの活性を阻害する際のiCAR構築物の機能性を試験するための、インビトロ組み換え系を確立した。この目的のために、aCARエピトープ、iCARエピトープ、または両方を発現している標的細胞を生成した。aCARエピトープを発現している組み換え細胞は、「標的上」の「腫瘍上の」細胞を表し、aCARおよびiCARエピトープの両方を発現している細胞は、「標的上」の「腫瘍外」の健康な細胞を表す。
iCARの阻害効果は、インビトロおよびインビボの両方で試験されるであろう。
ルシフェラーゼ細胞傷害性Tリンパ球(CTL)アッセイ
ホタルルシフェラーゼおよび1つまたは2つのCAR標的抗原を発現するように操作された、上記のHela−Luc組み換え標的細胞を使用して、アッセイは実施されるであろう。インビトロルシフェラーゼアッセイは、Bright−Gloルシフェラーゼアッセイの製造者のプロトコル(Promega)に従って、生物発光を読み取り値として実施されるであろう。
細胞傷害性T細胞が標的細胞を殺傷する経路のうちの1つは、Fasリガンドを通じてアポトーシスを誘導することによる。カスパーゼの順次活性化は、細胞アポトーシスの実行段階で重要な役割を果たす。pro−カスパーゼ3からカスパーゼ3への開裂によって、立体構造的変化、および触媒活性の発現を生じる。開裂した活性化形態のカスパーゼ3は、モノクローナル抗体によって特異的に認識されることができる。
形質導入T細胞は、「腫瘍上」または「腫瘍外」細胞のいずれかと最大5日間培養されるであろう。経時的顕微鏡を使用して、殺傷が視覚化されるであろう。あるいは、エンドポイント時点での標的細胞数を決定するために、生存細胞数染色およびCountBrightビーズ(Invitrogen)を使用するフローサイトメトリー分析が行われるであろう。
T細胞が活性化されると、細胞は、定量化してT細胞の活性化および阻害を評価するために使用することができるサイトカインを分泌する。サイトカインは、フローサイトメトリーによって、またはELISAもしくはサイトメトリービーズアレイ(CBA)による培地中の分泌タンパク質の測定によって、細胞内で検出することができる。
iCARもしくはaCAR、またはaCARおよびiCARの両方を発現している形質導入T細胞(Jurkat、または一次T細胞)の改変標的細胞との共-培養に続き、iCARもしくはaCAR、またはaCARおよびiCARの両方の抗原をそれらの細胞表面上に発現している条件培地は収集され、製造指示書に従って(例えばBioLegenedまたは同様の)サイトカインELISA(IL−2、INFγおよびまたはTNFα)によって、および(Miltenyiまたは同様の)サイトメトリービーズアレイによってサイトカインの濃度を測定されるであろう。
図16Aに図示されるように、Jurkat CD19 aCARおよびJurkat CD19 aCAR/HLA−A2 iCARエフェクター細胞を、Raji、Raji−HLA−A2、およびThp1標的細胞と共培養し、ELISAによるIL−2測定用に対応する上清を収集した。Jurkat CD19−aCAR/HLA−A2−iCARと、CD19を発現しているRaji標的細胞(「腫瘍」)との培養はIL−2分泌を示したが、しかしながらこれらのエフェクター細胞と、CD19およびHLA−A2の両方を発現しているRaji−HLA−A2標的細胞(「腫瘍外」)との培養は、IL−2分泌の80%超の阻害を生じた。逆に、CD19 aCAR Jurkat細胞をRajiまたはRaji−HLA−A2標的細胞と培養すると、IL−2分泌は影響を受けなかった(図16B)。この結果は、以下で説明するNFAT活性化アッセイと一緒に、腫瘍細胞では発現されない抗原を発現している正常細胞を特異的に保護するiCAR構築物の効力を示唆している。
細胞表面上にiCARもしくはaCAR、またはaCARおよびiCARの両方の標的抗原を発現している組み換え標的細胞と、6〜24時間共培養したiCARもしくはaCAR、またはaCARおよびiCARの両方を発現している形質導入T細胞(Jurkat、または一次T細胞)は、ゴルジ輸送ブロッカー(例えばブレフェルジンA、モネンシン)を受けて、サイトカインの細胞内蓄積を可能にするであろう。次いで、T細胞は浸透され、内部染色キット(例えばMiltenyi)によって固定され、抗CD3およびCD8、ならびにまたはIL−2およびまたはINFγおよびまたはTNFαで染色されるであろう。
サイトメトリービーズアレイ(CBA)を使用して、サイトカイン、ケモカイン、および成長因子を含む多様な可溶性および細胞内タンパク質を測定する。
NFAT活性化によって測定されるT細胞活性化の決定のために、表12に詳述されるように、Jurkat−NFAT細胞に、異なる組み合わせのaCARおよびiCARを形質導入した。表13に記載されているように、CD19 aCAR、HLA−A2 iCAR、または両方を発現しているエフェクターJurkat−NFAT細胞株を、CD19(Raji細胞−「標的上」)、CD19およびHLA−A2(Raji−HLA−A2「腫瘍外」)またはHLA−A2(Thp1「腫瘍外」)の両方、のいずれかを発現している標的細胞と共培養した。陽性対照として、エフェクター細胞をPMAおよびイオノマイシンの存在下で刺激し、これによりNFATシグナル伝達に必要なカルシウム放出を誘発した。37oCで16時間の培養に続き、製造者の指示書に従ってBPS Biosciencesキット「ワンステップルシフェラーゼアッセイ系」を使用して、ルシフェラーゼを定量化した。予想通り、CD19−CAR構築物を発現しているJurkat NFAT細胞株は、CD19を発現しているRaji細胞株の存在下で特異的に活性化されたが、これらの細胞がCD19を発現しないThp1細胞株と共培養されると、活性化は示されなかった(図18)。
T細胞の脱顆粒は、リソソーム関連膜タンパク質(LAMP−1)であるCD107aの表面発現によって同定することができる。LAMP−1の表面発現は、CD8 T細胞の細胞傷害性と相関することが示されている。この分子は、リソソームの管腔側に位置する。CD107aは、活性化すると、活性化したリンパ球の細胞膜表面に移動する。CD107aは、細胞表面上に一過性に発現し、エンドサイトーシス経路を介して迅速に再内部化される。したがって、CD107aの検出は、細胞刺激中の抗体染色によって、およびモネンシンの添加(エンドサイトーシスされたCD107a抗体複合体の酸性化およびその後の分解を防止するため)によって最大化される。
iCAR+aCAR/aCAR構築物(エフェクター細胞)で形質導入されたPBMCは、PMA+イオノマイシン(陽性対照)または細胞表面上にiCAR+aCAR/aCAR/iCAR抗原を発現する改変標的細胞のいずれかで刺激する。共培養の数時間の間に、エフェクター細胞が脱顆粒化され、CD107aが細胞表面上に検出されることができる。この発現は一過性であり、CD107aはエンドサイトーシス経路を介して迅速に再内部化される。したがって、CD107aの検出は、細胞刺激中の抗体染色によって、およびモネンシンの添加(エンドサイトーシスされたCD107a抗体複合体の酸性化およびその後の分解を防止するため)によって最大化される。BFAは最適なサイトカイン発現に必要である。
ヒト異種移植片マウスモデルにおけるインビボCTLアッセイ
aCARおよびiCAR構築物の両方を発現しているT細胞が、同じ生物内で、標的細胞と「標的外」細胞とを区別することができるかどうか、ならびに「標的外」細胞を生かしながら標的細胞を効果的に殺傷するかどうかの試験は、インビボCTLアッセイによって評価されるであろう。
NOD/SCID/γc−または同様のマウスは、腫瘍細胞を接種されるであろう。接種は、ip/ivまたはscであってもよい。腫瘍細胞は、iCAR標的、aCAR標的、または両方のいずれかを発現するであろう。1つの例示的な可能性のあるaCAR腫瘍細胞株は、CD19陽性NALM6(ATCC、ヒトBALL細胞株)であり得る。例示的なaCARおよびiCARの両方を発現する腫瘍細胞(すなわち、「腫瘍外」細胞)は、iCARエピトープ(例えば、HLA−A2)を発現するように操作され、それにより健康な細胞を表すNALM6である。NALM6およびNAlM6−HLA−A2はまた、容易な検出のために、レポーター遺伝子(例えば、ホタルルシフェラーゼ)を発現するように操作することができる。マウスは、標的細胞の可能な全ての組み合わせを接種したいくつかの研究群に分けられるであろう。一例として、1つの群にはNALM6細胞が注射され、他方にはiCARエピトープを発現しているNALM−6が注射されるであろう。数日後、腫瘍がすでに確立されている間、マウスは、aCAR、またはaCAR/iCAR、またはiCARで形質導入されたT細胞を静脈内注入されるであろう。加えて、非形質導入T細胞の対照群、T細胞なし、またはシグナル伝達ドメインを含まない形質導入T細胞も含まれるであろう。腫瘍が実験の終点、すなわち最大許容腫瘍体積に達するまで、マウスはモニタリングされるであろう。モニタリングは、機械的手段(キャリパー)によって腫瘍体積を測定することによって、およびインビボ画像化システム(IVIS)を使用することによっても行われるであろう。終点日に、マウスを犠牲にし、腫瘍負荷を定量化し、浸潤T細胞集団がFACSによって分析されるであろう。iCAR構築物を発現しているT細胞が同じ生物内の標的細胞と「標的外」細胞とを区別することができるかどうかを試験するために、いくつかの比の「腫瘍上」/「腫瘍外NALM−6細胞のいくつかの可能な混合物の後、続いてaCAR単独、またはaCARおよびiCARの両方のいずれかを発現している形質導入T細胞がマウスに注入されるであろう。マウスを犠牲にし、フローサイトメトリーによって、2つのマーカー、CD19およびiCARエピトープでの脾臓および骨髄の「腫瘍上」および「腫瘍外細胞の存在が分析されるであろう。
ヒトaCARおよびiCAR標的を発現するトランスジェニックマウスも使用して、形質導入T細胞の有効性が決定されるであろう。これらの環境下では、マウスは完全に機能する免疫系を有し、iCAR/aCAR形質導入T細胞の潜在的な毒性を評価することができる。CAR構築物はヒト抗原と一致するscFvを含含有するが、シグナル伝達ドメインはマウスT細胞を活性化または阻害するように改変されるであろう。かかるモデルの1つの例は、ヒトHLA−A2分子のみを発現するHHD−HLA−A2マウスであるが、他の全てのタンパク質はマウスのみのものである。この場合、CD19 aCARのscFvは、マウスCD19ホモログに向けられるであろう。HLA分子が欠如したヒト標的細胞(例えば、LCL 721.221細胞、またはC1R−neoATCC(登録商標)CRL−2369(商標)、または同様のもの)が使用されるであろう。マウスCD19を発現するように標的は改変されるであろう。この系によって、有効性および毒性の問題のモニタリングが可能になるであろう。
異なる腫瘍で同定された保存および喪失対立遺伝子多様体のいくつかのペアが選択され、mAb生成技法を使用するそれらのポリペプチド生成物は、多様体特異的mAbの生成に役立つであろう。候補mAbの区別力は、選択された対立遺伝子を発現している組み換え細胞株への結合によって決定されるように、二重染色、およびフローサイトメトリー実験または免疫組織化学によってアッセイされるであろう。
Claims (66)
- エフェクター免疫細胞の望ましくない活性化を防止または減弱させることが可能な阻害性キメラ抗原受容体(iCAR)または保護キメラ抗原受容体(pCAR)を調製するための標的を同定する方法であって、前記標的が、
(i)細胞外多型エピトープを含むタンパク質をコードする、少なくとも2つの発現対立遺伝子を有する遺伝子を同定することと、
(ii)前記発現対立遺伝子のうちの少なくとも1つが、細胞外多型エピトープ参照配列と比較して、前記細胞外多型エピトープ配列においてアミノ酸配列変化を呈することを決定することと、
(iii)前記遺伝子が、腫瘍型におけるヘテロ接合性の喪失(LOH)を受ける染色体領域に位置することを決定することと、
(iv)前記染色体領域がLOHを受けたことが見出された前記腫瘍型の原発組織で前記遺伝子が発現していることを決定することと、を含む方法によって同定される、方法。 - 前記LOH位置が、置換、欠失、および挿入からなる群から選択される、請求項1に記載の方法。
- 前記LOH位置が、SNPである、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA遺伝子である、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−A、HLA−B、HLA−C、HLA−G、HLA−E、HLA−F、HLA−K、HLA−L、HLA−DM、HLA−DO、HLA−DP、HLA_DQ、またはHLA−DR遺伝子である、請求項4に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−A遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−B遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−C遺伝子である、請求項5に記載の方法。
- 細胞外多型エピトープを含む遺伝子がHLA−G遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−E遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−F遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−K遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−L遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−DM遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−DO遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−DP遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA_DQ遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、HLA−DR遺伝子である、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ABCA4、ADAM30、AQP10、ASTN1、C1orf101、CACNA1S、CATSPER4、CD101、CD164L2、CD1A、CD1C、CD244、CD34、CD46、CELSR2、CHRNB2、CLCA2、CLDN19、CLSTN1、CR1、CR2、CRB1、CSF3R、CSMD2、ECE1、ELTD1、EMC1、EPHA10、EPHA2、EPHA8、ERMAP、FCAMR、FCER1A、FCGR1B、FCGR2A、FCGR2B、FCGR3A、FCRL1、FCRL3、FCRL4、FCRL5、FCRL6、GJB4、GPA33、GPR157、GPR37L1、GPR88、HCRTR1、IGSF3、IGSF9、IL22RA1、IL23R、ITGA10、KIAA1324、KIAA2013、LDLRAD2、LEPR、LGR6、LRIG2、LRP8、LRRC52、LRRC8B、LRRN2、LY9、MIA3、MR1、MUC1、MXRA8、NCSTN、NFASC、NOTCH2、NPR1、NTRK1、OPN3、OR10J1、OR10J4、OR10K1、OR10R2、OR10T2、OR10X1、OR11L1、OR14A16、OR14I1、OR14K1、OR2AK2、OR2C3、OR2G2、OR2G3、OR2L2、OR2M7、OR2T12、OR2T27、OR2T1、OR2T3、OR2T29、OR2T33、OR2T34、OR2T35、OR2T3、OR2T4、OR2T5、OR2T6、OR2T7、OR2T8、OR2W3、OR6F1、OR6K2、OR6K3、OR6K6、OR6N1、OR6P1、OR6Y1、PDPN、PEAR1、PIGR、PLXNA2、PTCH2、PTCHD2、PTGFRN、PTPRC、PTPRF、PVRL4、RHBG、RXFP4、S1PR1、SCNN1D、SDC3、SELE、SELL、SELP、SEMA4A、SEMA6C、SLAMF7、SLAMF9、SLC2A7、SLC5A9、TACSTD2、TAS1R2、TIE1、TLR5、TMEM81、TNFRSF14、TNFRSF1B、TRABD2B、USH2A、VCAM1、およびZP4からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ABCG5、ALK、ASPRV1、ATRAID、CD207、CD8B、CHRNG、CLEC4F、CNTNAP5、CRIM1、CXCR1、DNER、DPP10、EDAR、EPCAM、GPR113、GPR148、GPR35、GPR39、GYPC、IL1RL1、ITGA4、ITGA6、ITGAV、LCT、LHCGR、LRP1B、LRP2、LY75、MARCO、MERTK、NRP2、OR6B2、PLA2R1、PLB1、PROKR1、PROM2、SCN7A、SDC1、SLC23A3、SLC5A6、TGOLN2、THSD7B、TM4SF20、TMEFF2、TMEM178A、TPO、およびTRABD2Aからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ACKR2、ALCAM、ANO10、ATP13A4、BTLA、CACNA1D、CACNA2D2、CACNA2D3、CASR、CCRL2、CD200、CD200R1、CD86、CD96、CDCP1、CDHR4、CELSR3、CHL1、CLDN11、CLDN18、CLSTN2、CSPG5、CX3CR1、CXCR6、CYP8B1、DCBLD2、DRD3、EPHA6、EPHB3、GABRR3、GP5、GPR128、GPR15、GPR27、GRM2、GRM7、HEG1、HTR3C、HTR3D、HTR3E、IGSF11、IL17RC、IL17RD、IL17RE、IL5RA、IMPG2、ITGA9、ITGB5、KCNMB3、LRIG1、LRRC15、LRRN1、MST1R、NAALADL2、NRROS、OR5AC1、OR5H1、OR5H14、OR5H15、OR5H6、OR5K2、OR5K3、OR5K4、PIGX、PLXNB1、PLXND1、PRRT3、PTPRG、ROBO2、RYK、SEMA5B、SIDT1、SLC22A14、SLC33A1、SLC4A7、SLITRK3、STAB1、SUSD5、TFRC、TLR9、TMEM108、TMEM44、TMPRSS7、TNFSF10、UPK1B、VIPR1、およびZPLD1からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ANTXR2、BTC、CNGA1、CORIN、EGF、EMCN、ENPEP、EPHA5、ERVMER34−1、EVC2、FAT1、FAT4、FGFRL1、FRAS1、GPR125、GRID2、GYPA、GYPB、KDR、KIAA0922、KLB、MFSD8、PARM1、PDGFRA、RNF150、TENM3、TLR10、TLR1、TLR6、TMEM156、TMPRSS11A、TMPRSS11B、TMPRSS11E、TMPRSS11F、UGT2A1、およびUNC5Cからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ADAM19、ADRB2、BTNL3、BTNL8、BTNL9、C5orf15、CATSPER3、CD180、CDH12、CDHR2、COL23A1、CSF1R、F2RL2、FAM174A、FAT2、FGFR4、FLT4、GABRA6、GABRG2、GPR151、GPR98、GRM6、HAVCR1、HAVCR2、IL31RA、IL6ST、IL7R、IQGAP2、ITGA1、ITGA2、KCNMB1、LIFR、LNPEP、MEGF10、NIPAL4、NPR3、NRG2、OR2V1、OR2Y1、OSMR、PCDH12、PCDH1、PCDHA1、PCDHA2、PCDHA4、PCDHA8、PCDHA9、PCDHB10、PCDHB11、PCDHB13、PCDHB14、PCDHB15、PCDHB16、PCDHB2、PCDHB3、PCDHB4、PCDHB5、PCDHB6、PCDHGA1、PCDHGA4、PDGFRB、PRLR、SEMA5A、SEMA6A、SGCD、SLC1A3、SLC22A4、SLC22A5、SLC23A1、SLC36A3、SLC45A2、SLC6A18、SLC6A19、SLCO6A1、SV2C、TENM2、TIMD4、およびUGT3A1からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、BAI3、BTN1A1、BTN2A1、BTN2A2、BTN3A1、BTN3A2、BTNL2、CD83、DCBLD1、DLL1、DPCR1、ENPP1、ENPP3、ENPP4、EPHA7、GABBR1、GABRR1、GCNT6、GFRAL、GJB7、GLP1R、GPR110、GPR111、GPR116、GPR126、GPR63、GPRC6A、HFE、HLA−A、HLA−B、HLA−C、HLA−DOA、HLA−DPA1、HLA−DPB1、HLA−DQA1、HLA−DQA2、HLA−DQB1、HLA−DQB2、HLA−DRB1、HLA−DRB5、HLA−E、HLA−F、HLA−G、IL20RA、ITPR3、KIAA0319、LMBRD1、LRFN2、LRP11、MAS1L、MEP1A、MICA、MICB、MOG、MUC21、MUC22、NCR2、NOTCH4、OPRM1、OR10C1、OR12D2、OR12D3、OR14J1、OR2B2、OR2B6、OR2J1、OR2W1、OR5V1、PDE10A、PI16、PKHD1、PTCRA、PTK7、RAET1E、RAET1G、ROS1、SDIM1、SLC16A10、SLC22A1、SLC44A4、TAAR2、TREM1、TREML1、およびTREML2からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、AQP1、C7orf50、CD36、CDHR3、CNTNAP2、DPP6、EGFR、EPHA1、EPHB6、ERVW−1、GHRHR、GJC3、GPNMB、GRM8、HUS1、HYAL4、KIAA1324L、LRRN3、MET、MUC12、MUC17、NPC1L1、NPSR1、OR2A12、OR2A14、OR2A25、OR2A42、OR2A7、OR2A2、OR2AE1、OR2F2、OR6V1、PILRA、PILRB、PKD1L1、PLXNA4、PODXL、PTPRN2、PTPRZ1、RAMP3、SLC29A4、SMO、TAS2R16、TAS2R40、TAS2R4、TFR2、THSD7A、TMEM213、TTYH3、ZAN、およびZP3からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ADAM18、ADAM28、ADAM32、ADAM7、ADAM9、ADRA1A、CDH17、CHRNA2、CSMD1、CSMD3、DCSTAMP、FZD6、GPR124、NRG1、OR4F21、PKHD1L1、PRSS55、SCARA3、SCARA5、SDC2、SLC10A5、SLC39A14、SLC39A4、SLCO5A1、TNFRSF10A、およびTNFRSF10Bからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ABCA1、AQP7、ASTN2、C9orf135、CA9、CD72、CNTNAP3B、CNTNAP3、CRB2、ENTPD8、GPR144、GRIN3A、IZUMO3、KIAA1161、MAMDC4、MEGF9、MUSK、NOTCH1、OR13C2、OR13C3、OR13C5、OR13C8、OR13C9、OR13D1、OR13F1、OR1B1、OR1J2、OR1K1、OR1L1、OR1L3、OR1L6、OR1L8、OR1N1、OR1N2、OR1Q1、OR2S2、PCSK5、PDCD1LG2、PLGRKT、PTPRD、ROR2、SEMA4D、SLC31A1、TEK、TLR4、TMEM2、およびVLDLRからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ABCC2、ADAM8、ADRB1、ANTXRL、ATRNL1、C10orf54、CDH23、CDHR1、CNNM2、COL13A1、COL17A1、ENTPD1、FZD8、FGFR2、GPR158、GRID1、IL15RA、IL2RA、ITGA8、ITGB1、MRC1、NRG3、NPFFR1、NRP1、OPN4、PCDH15、PKD2L1、PLXDC2、PRLHR、RET、RGR、SLC16A9、SLC29A3、SLC39A12、TACR2、TCTN3、TSPAN15、UNC5B、およびVSTM4からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、AMICA1、ANO1、ANO3、APLP2、C11orf24、CCKBR、CD248、CD44、CD5、CD6、CD82、CDON、CLMP、CRTAM、DCHS1、DSCAML1、FAT3、FOLH1、GDPD4、GDPD5、GRIK4、HEPHL1、HTR3B、IFITM10、IL10RA、KIRREL3、LGR4、LRP4、LRP5、LRRC32、MCAM、MFRP、MMP26、MPEG1、MRGPRE、MRGPRF、MRGPRX2、MRGPRX3、MRGPRX4、MS4A4A、MS4A6A、MTNR1B、MUC15、NAALAD2、NAALADL1、NCAM1、NRXN2、OR10A2、OR10A5、OR10A6、OR10D3、OR10G4、OR10G7、OR10G8、OR10G9、OR10Q1、OR10S1、OR1S1、OR2AG1、OR2AG2、OR2D2、OR4A47、OR4A15、OR4A5、OR4C11、OR4C13、OR4C15、OR4C16、OR4C3、OR4C46、OR4C5、OR4D6、OR4A8P、OR4D9、OR4S2、OR4X1、OR51E1、OR51L1、OR52A1、OR52E1、OR52E2、OR52E4、OR52E6、OR52I1、OR52I2、OR52J3、OR52L1、OR52N1、OR52N2、OR52N4、OR52W1、OR56B1、OR56B4、OR5A1、OR5A2、OR5AK2、OR5AR1、OR5B17、OR5B3、OR5D14、OR5D16、OR5D18、OR5F1、OR5I1、OR5L2、OR5M11、OR5M3、OR5P2、OR5R1、OR5T2、OR5T3、OR5W2、OR6A2、OR6T1、OR6X1、OR8A1、OR8B12、OR8B2、OR8B3、OR8B4、OR8D1、OR8D2、OR8H1、OR8H2、OR8H3、OR8I2、OR8J1、OR8J2、OR8J3、OR8K1、OR8K3、OR8K5、OR8U1、OR9G1、OR9G4、OR9Q2、P2RX3、PTPRJ、ROBO3、SIGIRR、SLC22A10、SLC3A2、SLC5A12、SLCO2B1、SORL1、ST14、SYT8、TENM4、TMEM123、TMEM225、TMPRSS4、TMPRSS5、TRIM5、TRPM5、TSPAN18、およびZP1からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ANO4、AVPR1A、BCL2L14、CACNA2D4、CD163、CD163L1、CD27、CD4、CLEC12A、CLEC1B、CLEC2A、CLEC4C、CLEC7A、CLECL1、CLSTN3、GPR133、GPRC5D、ITGA7、ITGB7、KLRB1、KLRC2、KLRC3、KLRC4、KLRF1、KLRF2、LRP1、LRP6、MANSC1、MANSC4、OLR1、OR10AD1、OR10P1、OR2AP1、OR6C1、OR6C2、OR6C3、OR6C4、OR6C6、OR6C74、OR6C76、OR8S1、OR9K2、ORAI1、P2RX4、P2RX7、PRR4、PTPRB、PTPRQ、PTPRR、SCNN1A、SELPLG、SLC2A14、SLC38A4、SLC5A8、SLC6A15、SLC8B1、SLCO1A2、SLCO1B1、SLCO1B7、SLCO1C1、SSPN、STAB2、TAS2R10、TAS2R13、TAS2R14、TAS2R20、TAS2R30、TAS2R31、TAS2R42、TAS2R43、TAS2R46、TAS2R7、TMEM119、TMEM132B、TMEM132C、TMEM132D、TMPRSS12、TNFRSF1A、TSPAN8、およびVSIG10からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ATP4B、ATP7B、FLT3、FREM2、HTR2A、KL、PCDH8、RXFP2、SGCG、SHISA2、SLC15A1、SLITRK6、およびTNFRSF19からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ADAM21、BDKRB2、C14orf37、CLEC14A、DLK1、FLRT2、GPR135、GPR137C、JAG2、LTB4R2、MMP14、OR11G2、OR11H12、OR11H6、OR4K1、OR4K15、OR4K5、OR4L1、OR4N2、OR4N5、SLC24A4、およびSYNDIG1Lからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ANPEP、CD276、CHRNA7、CHRNB4、CSPG4、DUOX1、DUOX2、FAM174B、GLDN、IGDCC4、ITGA11、LCTL、LTK、LYSMD4、MEGF11、NOX5、NRG4、OCA2、OR4F4、OR4M2、OR4N4、PRTG、RHCG、SCAMP5、SEMA4B、SEMA6D、SLC24A1、SLC24A5、SLC28A1、SPG11、STRA6、TRPM1、およびTYRO3からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ATP2C2、CACNA1H、CD19、CDH11、CDH15、CDH16、CDH3、CDH5、CNGB1、CNTNAP4、GDPD3、GPR56、GPR97、IFT140、IL4R、ITFG3、ITGAL、ITGAM、ITGAX、KCNG4、MMP15、MSLNL、NOMO1、NOMO3、OR2C1、PIEZO1、PKD1、PKD1L2、QPRT、SCNN1B、SEZ6L2、SLC22A31、SLC5A11、SLC7A6、SPN、TMC5、TMC7、TMEM204、TMEM219、およびTMEM8Aからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ABCC3、ACE、AOC3、ARL17B、ASGR2、C17orf80、CD300A、CD300C、CD300E、CD300LF、CD300LG、CHRNB1、CLEC10A、CNTNAP1、CPD、CXCL16、ERBB2、FAM171A2、GCGR、GLP2R、GP1BA、GPR142、GUCY2D、ITGA2B、ITGA3、ITGAE、ITGB3、KCNJ12、LRRC37A2、LRRC37A3、LRRC37A、LRRC37B、MRC2、NGFR、OR1A2、OR1D2、OR1G1、OR3A1、OR3A2、OR4D1、OR4D2、RNF43、SCARF1、SCN4A、SDK2、SECTM1、SEZ6、SHPK、SLC26A11、SLC5A10、SPACA3、TMEM102、TMEM132E、TNFSF12、TRPV3、TTYH2、およびTUSC5からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、APCDD1、CDH19、CDH20、CDH7、COLEC12、DCC、DSC1、DSG1、DSG3、DYNAP、MEP1B、PTPRM、SIGLEC15、およびTNFRSF11Aからなる群から選択される、請求項5に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ABCA7、ACPT、BCAM、C19orf38、C19orf59、C5AR1、CATSPERD、CATSPERG、CD22、CD320、CD33、CD97、CEACAM19、CEACAM1、CEACAM21、CEACAM3、CEACAM4、CLEC4M、DLL3、EMR1、EMR2、EMR3、ERVV−1、ERVV−2、FAM187B、FCAR、FFAR3、FPR1、FXYD5、GFY、GP6、GPR42、GRIN3B、ICAM3、IGFLR1、IL12RB1、IL27RA、KIR2DL1、KIR2DL3、KIR2DL4、KIR3DL1、KIR3DL2、KIR3DL3、KIRREL2、KISS1R、LAIR1、LDLR、LILRA1、LILRA2、LILRA4、LILRA6、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、LINGO3、LPHN1、LRP3、MADCAM1、MAG、MEGF8、MUC16、NCR1、NOTCH3、NPHS1、OR10H1、OR10H2、OR10H3、OR10H4、OR1I1、OR2Z1、OR7A10、OR7C1、OR7D4、OR7E24、OR7G1、OR7G2、OR7G3、PLVAP、PTGIR、PTPRH、PTPRS、PVR、SCN1B、SHISA7、SIGLEC10、SIGLEC11、SIGLEC12、SIGLEC5、SIGLEC6、SIGLEC8、SIGLEC9、SLC44A2、SLC5A5、SLC7A9、SPINT2、TARM1、TGFBR3L、TMC4、TMEM91、TMEM161A、TMPRSS9、TNFSF14、TNFSF9、TRPM4、VN1R2、VSIG10L、VSTM2B、およびZNRF4からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ABHD12、ADAM33、ADRA1D、APMAP、ATRN、CD40、CD93、CDH22、CDH26、CDH4、FLRT3、GCNT7、GGT7、JAG1、LRRN4、NPBWR2、OCSTAMP、PTPRA、PTPRT、SEL1L2、SIGLEC1、SIRPA、SIRPB1、SIRPG、SLC24A3、SLC2A10、SLC4A11、SSTR4、およびTHBDからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、CLDN8、DSCAM、ICOSLG、IFNAR1、IFNGR2、IGSF5、ITGB2、KCNJ15、NCAM2、SLC19A1、TMPRSS15、TMPRSS2、TMPRSS3、TRPM2、およびUMODL1からなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、CACNA1I、CELSR1、COMT、CSF2RB、GGT1、GGT5、IL2RB、KREMEN1、MCHR1、OR11H1、P2RX6、PKDREJ、PLXNB2、SCARF2、SEZ6L、SSTR3、SUSD2、TMPRSS6、およびTNFRSF13Cからなる群から選択される、請求項1に記載の方法。
- 前記細胞外多型エピトープを含む前記遺伝子が、ATP6AP2、ATP7A、CNGA2、EDA2R、FMR1NB、GLRA4、GPR112、GUCY2F、HEPH、P2RY10、P2RY4、PLXNA3、PLXNB3、TLR8、VSIG4、およびXGからなる群から選択される、請求項1に記載の方法。
- 前記腫瘍が、乳房腫瘍、前立腺腫瘍、卵巣腫瘍、子宮頸部腫瘍、皮膚腫瘍、膵臓腫瘍、結腸直腸腫瘍、腎腫瘍、肝臓腫瘍、脳腫瘍、リンパ腫、白血病、肺腫瘍、神経膠腫からなる群から選択される、請求項1〜41のいずれかに記載の方法。
- 前記腫瘍が、副腎腫瘍、腎臓腫瘍、黒色腫、DLBC、乳房腫瘍、肉腫、卵巣腫瘍、肺腫瘍、膀胱腫瘍、および肝臓腫瘍からなる群から選択される、請求項1〜41のいずれかに記載の方法。
- 前記副腎腫瘍が、副腎皮質癌腫である、請求項43に記載の方法。
- 前記腎臓腫瘍が、嫌色素性腎細胞癌腫である、請求項43に記載の方法。
- 前記黒色腫が、ブドウ膜黒色腫である、請求項43に記載の方法。
- (i)請求項1〜46のいずれかに記載のiCARまたはpCARと、(ii)活性化キメラ抗原受容体(aCAR)と、を発現している、安全なエフェクター免疫細胞。
- 前記aCARが、腫瘍関連抗原または非多型細胞表面エピトープに、向けられているかまたは特異的に結合する、請求項47に記載の安全なエフェクター免疫細胞。
- 前記aCARが、腫瘍関連タンパク質、表1に列挙されているCAR標的、iCARも発現している腫瘍組織で発現する任意の細胞表面タンパク質に、向けられているかまたは特異的に結合する、請求項47に記載の安全なエフェクター免疫細胞。
- 前記非多型細胞表面エピトープが、CD19、CD20、CD22、CD10、CD7、CD49f、CD56、CD74、CAIX Igκ、ROR1、ROR2、CD30、LewisY、CD33、CD34、CD38、CD123、CD28、CD44v6、CD44、CD41、CD133、CD138、NKG2D−L、CD139、BCMA、GD2,GD3、hTERT、FBP、EGP−2、EGP−40、FR−α、L1−CAM、ErbB2,3,4、EGFRvIII、VEGFR−2、IL−13Rα2、FAP、メソテリン、c−MET、PSMA、CEA、kRas、MAGE−A1、MUC1MUC16、PDL1、PSCA、EpCAM、FSHR、AFP、AXL、CD80、CD89、CDH17、CLD18、GPC3、TEM8、TGFB1、NY−ESO−1、WT−1、およびEGFRからなる群から選択される、請求項49に記載の安全なエフェクター免疫細胞。
- 前記安全なエフェクター免疫細胞が、自家または普遍的(同種)エフェクター細胞である、請求項47〜50のいずれかに記載の安全なエフェクター免疫細胞。
- 前記安全なエフェクター免疫細胞が、T細胞、ナチュラルキラー細胞、およびサイトカイン誘導キラー細胞からなる群から選択される、請求項47〜51のいずれかに記載の安全なエフェクター免疫細胞。
- 前記iCARまたはpCARの発現レベルが、前記aCARの発現レベル以上である、請求項47〜52のいずれかに記載の安全なエフェクター免疫細胞。
- 前記iCARまたはpCARが、第1のベクターによって発現され、前記aCARが、第2のベクターによって発現される、請求項47〜53のいずれかに記載の安全なエフェクター免疫細胞。
- 前記iCARまたはpCAR、および前記aCARの両方が、同じベクターによって発現される、請求項47〜53のいずれかに記載の安全なエフェクター免疫細胞。
- 前記aCARをコードするヌクレオチド配列が、前記iCARまたはpCARをコードするヌクレオチド配列の下流にある、請求項55に記載の安全なエフェクター免疫細胞。
- 前記ヌクレオチド配列が、前記aCARをコードする前記ヌクレオチド配列と前記iCARまたはpCARをコードする前記ヌクレオチド配列との間に、ウイルス自己開裂型2Aペプチドを含む、請求項55に記載の安全なエフェクター免疫細胞。
- 前記ウイルス自己開裂型2Aペプチドが、ゾセアアシグナ(Thosea asigna)ウイルス(TaV)由来のT2A、口蹄疫ウイルス(FMDV)由来のF2A、ウマ鼻炎Aウイルス(ERAV)由来のE2A、およびブタテッショウウイルス1(PTV1)由来のP2Aからなる群から選択される、請求項57に記載の安全なエフェクター免疫細胞。
- 前記aCARをコードする前記ヌクレオチド配列が、柔軟なリンカーを介して前記iCARまたはpCARに連結されている、請求項55に記載の安全なエフェクター免疫細胞。
- 前記aCARが、エフェクター免疫細胞を活性化または共刺激する少なくとも1つのシグナル伝達要素を含む、請求項47〜59のいずれかに記載の安全なエフェクター免疫細胞。
- エフェクター免疫細胞を活性化または共刺激する前記少なくとも1つのシグナル伝達要素が、例えばCD3ζまたはFcRγ鎖の免疫受容活性化チロシンモチーフ(ITAM)と相同である、請求項60に記載の安全なエフェクター免疫細胞。
- エフェクター免疫細胞を活性化または共刺激する前記少なくとも1つのシグナル伝達要素が、KIR2DSおよびKIR3DSなどの活性化キラー細胞免疫グロブリン様受容体(KIR)と相同である、請求項60に記載の安全なエフェクター免疫細胞。
- エフェクター免疫細胞を活性化または共刺激する前記少なくとも1つのシグナル伝達要素が、DAP12などのアダプター分子と相同であるか、またはアダプター分子である、請求項60のいずれかに記載の安全なエフェクター免疫細胞。
- エフェクター免疫細胞を活性化または共刺激する前記少なくとも1つのシグナル伝達要素が、CD27、CD28、ICOS、CD137(4−1BB)、CD134(OX40)、もしくはGITRの共刺激シグナル伝達要素と相同であるか、またはそれらの共刺激シグナル伝達要素である、請求項60に記載の安全なエフェクター免疫細胞。
- LOHを特徴とする腫瘍を有する患者の癌を治療するための方法であって、請求項1〜64のいずれかに記載のiCARを発現している安全なエフェクター免疫細胞を前記患者に投与することを含む、方法。
- LOHを特徴とする腫瘍を有する患者の癌を治療するための方法であって、請求項47〜64のいずれかに記載の安全なエフェクター免疫細胞を前記患者に投与することを含む、方法。
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DK3688155T3 (da) | 2023-04-03 |
HUE061502T2 (hu) | 2023-07-28 |
IL273598A (en) | 2020-05-31 |
BR112020006106A2 (pt) | 2020-11-17 |
EP3688155B1 (en) | 2023-01-04 |
WO2019068007A1 (en) | 2019-04-04 |
ES2941966T3 (es) | 2023-05-29 |
PT3688155T (pt) | 2023-04-11 |
JP2023104959A (ja) | 2023-07-28 |
CA3077174A1 (en) | 2019-04-04 |
US11660315B2 (en) | 2023-05-30 |
US20240139238A1 (en) | 2024-05-02 |
MX2020003526A (es) | 2020-09-14 |
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