JP2019524106A - 有効性が増強された治療法のための疾患特異的標的としてのネオエピトープの選択 - Google Patents
有効性が増強された治療法のための疾患特異的標的としてのネオエピトープの選択 Download PDFInfo
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Abstract
Description
1)例えば、最初にRonaghiら、1998、A sequencing method based on real-time pyrophosphate、Science 281: 363〜365頁に記載されている、Roche関連会社454 Life Sciences社(コネチカット州Branford)のGS-FLX 454 Genome Sequencer(商標)で実装されるパイロシーケンシングとして知られる合成技術によるシーケンシング。この技術は、エマルジョンPCR増幅のために油に取り囲まれたPCR反応物質を含有する水性ミセル中で激しく渦撹拌することによって一本鎖DNA結合ビーズがカプセル封入される、エマルジョンPCRを使用する。パイロシーケンシング工程中、ポリメラーゼがDNA鎖を合成する際にヌクレオチドの取り込み中にリン酸分子から放出される光が記録される。
2)可逆的色素-ターミネーターに基づいており、例えばIllumina/Solexa Genome Analyzer(商標)及びIllumina HiSeq 2000 Genome Analyzer(商標)で実装されているSolexa社(現在はIllumina Inc.社の一部、カリフォルニア州San Diego)によって開発された、合成手法によるシーケンシング。この技術では、4つ全てのヌクレオチドを同時に、DNAポリメラーゼと共にフローセルチャネル中のオリゴ初回刺激したクラスター断片に加える。架橋増幅によりシーケンシングのために4つ全ての蛍光標識ヌクレオチドを有するクラスター鎖を伸長させる。
3)例えばApplied Biosystems社(現在はLife Technologies Corporation、カリフォルニア州Carlsbad)のSOLid(商標)プラットフォームで実装されている、ライゲーション手法によるシーケンシング。この技術では、固定長の全ての可能なオリゴヌクレオチドのプールを、シーケンシングした位置に従って標識する。オリゴヌクレオチドがアニーリング及びライゲーションされ、DNAリガーゼによる一致した配列の優先的なライゲーションは、その位置でのヌクレオチドの情報を与えるシグナルをもたらす。シーケンシングの前に、DNAをエマルジョンPCRによって増幅する。それぞれ同じDNA分子のコピーしか含有しない、生じるビーズをスライドガラス上に載せる。2つ目の例として、Dover Systems社(ニューハンプシャー州Salem)のPolonator(商標)G.007プラットフォームも、ランダムにアレイ配置したビーズに基づくエマルジョンPCRを使用して、並列シーケンシングのためにDNA断片を増幅することによって、ライゲーション手法によるシーケンシングを用いる。
4)例えば、Pacific Biosciences社(カリフォルニア州Menlo Park)のPacBio RSシステム又はHelicos Biosciences社(マサチューセッツ州Cambridge)のHeliScope(商標)プラットフォームで実装されている単一分子シーケンシング技術。この技術の明確な特徴は、単一分子リアルタイム(SMRT)DNAシーケンシングと定義される、単一のDNA又はRNA分子を増幅なしにシーケンシングするその能力である。例えば、HeliScopeは、それぞれのヌクレオチドが合成されていく最中にそれを直接検出するために、高感度の蛍光検出システムを使用する。蛍光共鳴エネルギー移動(FRET)に基づく同様の手法がVisigen Biotechnology社(テキサス州Houston)から開発されている。他の蛍光に基づく単一分子技法は、U.S.Genomics(GeneEngine(商標))及びGenovoxx(AnyGene(商標))からのものである。
5)例えば複製中に単一鎖上のポリメラーゼ分子の動きを監視するためにチップ上に配置されている様々なナノ構造を使用する、単一分子シーケンシングのためのナノ技術。ナノ技術に基づく手法の非限定的な例は、Oxford Nanopore Technologies社(英国Oxford)のGridON(商標)プラットフォーム、Nabsys社(ロードアイランド州Providence)によって開発されたハイブリダイゼーション支援のナノポアシーケンシング(HANS(商標))プラットフォーム、及びコンビナトリアルプローブアンカーライゲーション(cPAL(商標))と呼ばれるDNAナノボール(DNB)技術を用いた商標を有するリガーゼに基づくDNAシーケンシングプラットフォームである。
6)単一分子シーケンシングのための電子顕微鏡観察に基づく技術、例えばLightSpeed Genomics社(カリフォルニア州Sunnyvale)及びHalcyon Molecular社(カリフォルニア州Redwood City)によって開発されたもの。
7)DNAの重合中に放出される水素イオンの検出に基づくイオン半導体シーケンシング。例えば、Ion Torrent Systems社(カリフォルニア州San Francisco)は、この生化学的プロセスを超並列の様式で行うために微小測定ウェルの高密度アレイを使用する。それぞれのウェルは異なるDNA鋳型を有する。ウェルの下にイオン感受性層があり、その下に商標を有するイオンセンサーがある。
CクラスIに提示されたエピトープである及び/又はMHCに提示されたエピトープが由来する抗原を発現する細胞に対するCD8+T細胞応答を誘発することができるエピトープを提供する。一実施形態では、癌特異的体細胞突然変異を含有しないエピトープは腫瘍抗原に由来する。一実施形態では、癌特異的体細胞突然変異を含有しないネオエピトープ及びエピトープは癌の処置において相乗効果を有する。好ましくは、本発明に従って提供されるワクチンは細胞毒性及び/又はヘルパーT細胞応答のポリエピトープ刺激に有用である。
高コピー数を有し、遺伝子の少なくとも1コピーが疾患特異的突然変異を含有した遺伝子を探索することにより、神経膠芽腫試料に関するゲノム情報(Chinら、2008、Comprehensive genomic characterization defines human glioblastoma genes and core pathways、Nature 455:1061〜1068頁)を解析した。品質解析は、解析した11,574種の個々の遺伝子のコピー数割り当ての高忠実度が存在することを示し、試料のゲノムの倍数性を1.95であると決定した。図1aは、公知ドライバー遺伝子であり、処置のための標的であった、第7染色体上の上皮成長因子受容体(EGFR)周囲の局所的遺伝子のグラフ表示を示す。このゲノムにおけるEGFRが、76の誤差補正された絶対的コピー数を有し、そのうち13コピーが、疾患特異的一塩基多様性を含有したことが示された。図1bは、最高の絶対的コピー数を有する、このゲノム試料における遺伝子のリストを提供する。2を超える絶対的コピー数を有する4種の追加的な遺伝子が存在する。実際に、EGFR増幅は、原発性神経膠芽腫の公知遺伝的特徴であり(Benitoら、2009、Neuropathology 30 (4):392〜400頁)、この遺伝子は、処置のための標的として考慮されてきた(Taylor、2012、Curr Cancer Drug Targets. Mar; 12(3):197〜209頁)。
遺伝子の少なくとも1コピーが疾患特異的突然変異を有する遺伝子を探索し、疾患特異的突然変異を有する遺伝子のコピーの数及び遺伝子のコピーの総数、遺伝子が突然変異を有するか否かに着目することにより、ヒトにおける腫瘍由来のメラノーマ細胞の試料から得られるエクソームを解析した。図2は、疾患特異的突然変異が遺伝子の複数のコピーに見出される接合状態によって選別された遺伝子のリストを提供する。例えば、OXGR1遺伝子における疾患特異的突然変異は、最高の接合状態(4)を有し、特に、総計5コピーのOXGR1遺伝子が存在し、そのうち4コピーが疾患特異的突然変異を含有するため、4/5又は0.8の最高の接合率も有する。リストは、総計4コピーのうち3コピーの遺伝子が突然変異を有する10種の追加的な遺伝子を提供し、これらの遺伝子における疾患特異的突然変異が、3/4又は0.75の接合率を有することを示す。残っている収載された遺伝子は、総計3コピーのうち2コピーが突然変異を有するため、2/3又は0.66の接合率を有する突然変異を有する。
遺伝子の全コピーが同じ疾患特異的突然変異を有する遺伝子を探索し、これらの遺伝子のいずれが必須遺伝子であるか決定することにより、ヒトにおける腫瘍由来のメラノーマ細胞の試料から得られるエクソームを解析した。これらの遺伝子は、マウスにおいて必須であるという知識から、ヒトにおけるその必須の度合を推量することにより、必須であると決定された(Georgiら、2013、From mouse to human: evolutionary genomics analysis of human orthologs of essential genes、PLoS Genetics 9 (5):e1003484頁;Liaoら、2007、Mouse duplicate genes are as essential as singletons、Trends Genet. 23:378〜381頁)。図3は、遺伝子の全コピーが同じ疾患特異的突然変異を有する多数の遺伝子を収載する。更に、3種の強調された遺伝子は、マウスデータからその必須の度合を推量することにより、必須であると決定された。
Claims (59)
- 遺伝子におけるアレル(突然変異したアレル)における疾患特異的突然変異に起因するネオエピトープの、疾患特異的標的としての適合性を決定するための方法であって、罹患細胞又は罹患細胞集団における、ネオエピトープをコードする突然変異したアレルのコピー数を決定する工程を含む方法。
- 突然変異したアレルの高コピー数が、ネオエピトープの疾患特異的標的としての適合性を示す、請求項1に記載の方法。
- 突然変異したアレルのコピー数が高いほど、ネオエピトープの疾患特異的標的としての適合性が高くなる、請求項2に記載の方法。
- 突然変異したアレルのコピー数が、2を超える場合が、ネオエピトープの疾患特異的標的としての適合性を示す、請求項1に記載の方法。
- 突然変異したアレルのコピー数が、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90を超える又は100を超える場合が、ネオエピトープの疾患特異的標的としての適合性を示す、請求項4に記載の方法。
- 突然変異したアレルが、その少なくとも1コピーが突然変異したアレルを有する(接合率)遺伝子のコピーで高割合で見出され、前記接合率が、突然変異がマッピングされるヌクレオチド部位のコピーの総数に対する、突然変異したアレルのコピー数の比である、請求項1から5のいずれか一項に記載の方法。
- 接合率が高いほど、ネオエピトープの疾患特異的標的としての適合性が高くなる、請求項6に記載の方法。
- 接合率が0.5を超え、好ましくは、接合率が1である、請求項6又は7に記載の方法。
- 突然変異したアレルのコピー数及び/又は接合率及び/又は突然変異したアレルがマッピングされるヌクレオチド部位のコピーの総数が、罹患細胞で高割合で見出される、請求項1から8のいずれか一項に記載の方法。
- 突然変異したアレルのコピー数及び/又は接合率及び/又は突然変異したアレルがマッピングされるヌクレオチド部位のコピーの総数を有する罹患細胞の割合が高いほど、ネオエピトープの疾患特異的標的としての適合性が高くなる、請求項9に記載の方法。
- 罹患細胞の割合が1である、請求項9又は10に記載の方法。
- 遺伝子が、その発現が、癌性表現型への細胞の形質転換をもたらす、又はその発現欠如が、その癌性表現型を失う癌性細胞をもたらすドライバー遺伝子である、請求項1から11のいずれか一項に記載の方法。
- 遺伝子が、必須遺伝子である、請求項1から11のいずれか一項に記載の方法。
- 必須遺伝子が、サイレンシングされる又はその発現が低下されると、必須遺伝子が発現される細胞、好ましくは、罹患細胞において成長不全又は適応度の低下を少なくとももたらす遺伝子である、請求項13に記載の方法。
- 必須遺伝子が、多種多様な異なる組織において発現され、0を超える最小RPKM閾値で発現される、請求項13に記載の方法。
- 遺伝子における疾患特異的突然変異に起因するネオエピトープの、疾患特異的標的としての適合性を決定するための方法であって、罹患細胞又は罹患細胞集団における、その少なくとも1コピーが疾患特異的突然変異を有する遺伝子のコピー数を決定する工程を含む方法。
- 遺伝子の高コピー数が、ネオエピトープの疾患特異的標的としての適合性を示す、請求項16に記載の方法。
- 遺伝子のコピー数が高いほど、ネオエピトープの疾患特異的標的としての適合性が高くなる、請求項16又は17に記載の方法。
- 遺伝子が、その発現が、癌性表現型への細胞の形質転換をもたらす、又はその発現欠如が、その癌性表現型を失う癌性細胞をもたらすドライバー遺伝子である、請求項16から18のいずれか一項に記載の方法。
- 遺伝子のコピー数が、罹患細胞において高割合で見出される、請求項16から19のいずれか一項に記載の方法。
- コピー数を有する罹患細胞の割合が高いほど、ネオエピトープの疾患特異的標的としての適合性が高くなる、請求項20に記載の方法。
- 罹患細胞の割合が1である、請求項20又は21に記載の方法。
- コピー数が、絶対的コピー数である、請求項1から22のいずれか一項に記載の方法。
- 絶対的コピー数が、誤差補正された絶対的コピー数である、請求項23に記載の方法。
- 絶対的コピー数又は誤差補正された絶対的コピー数が、倍数性、好ましくは、罹患細胞のゲノムの倍数性、又は染色体、又は罹患細胞において突然変異若しくは突然変異した遺伝子が位置する染色体の部分の倍数性に対して正規化される、請求項23又は24に記載の方法。
- 遺伝子における疾患特異的突然変異に起因するネオエピトープの、疾患特異的標的としての適合性を決定するための方法であって、罹患細胞又は罹患細胞集団において、疾患特異的突然変異を有する遺伝子が必須遺伝子であるか決定する工程を含む方法。
- 必須遺伝子が、サイレンシングされる又はその発現が低下されると、必須遺伝子が発現される細胞、好ましくは、罹患細胞の成長不全又は適応度の低下を少なくとももたらす遺伝子である、請求項26に記載の方法。
- 必須遺伝子が、多種多様な異なる組織において発現され、0を超える最小RPKM閾値で発現される、請求項26に記載の方法。
- 遺伝子が必須遺伝子であり、必須遺伝子の全コピーが疾患特異的突然変異を有することが、ネオエピトープの疾患特異的標的としての適合性を示す、請求項26から28のいずれか一項に記載の方法。
- 罹患細胞が高割合で、必須遺伝子の全コピーが疾患特異的突然変異を有する必須遺伝子のコピーを含有する、請求項26又は29のいずれか一項に記載の方法。
- 必須遺伝子の全コピーが疾患特異的突然変異を有する必須遺伝子のコピーを含有する罹患細胞の割合が高いほど、ネオエピトープの疾患特異的標的としての適合性が高くなる、請求項30に記載の方法。
- 罹患細胞の割合が1である、請求項30又は31に記載の方法。
- 少なくとも2種の遺伝子における疾患特異的突然変異に起因する少なくとも2種のネオエピトープの組合せの、疾患特異的標的の組合せとしての適合性を決定するための方法であって、疾患特異的突然変異をそれぞれ有する少なくとも2種の遺伝子の組合せが、合成致死的又は合成病的遺伝子であるか決定する工程を含む方法。
- 少なくとも2種の遺伝子の組合せが、合成致死的又は合成病的である場合が、疾患特異的標的の組合せとしてのネオエピトープの組合せの適合性を示す、請求項33に記載の方法。
- 少なくとも2種の遺伝子の全コピーが、疾患特異的突然変異を有する、請求項33又は34に記載の方法。
- 罹患細胞が高割合で疾患特異的突然変異を有する少なくとも2種の遺伝子を含有する、請求項35に記載の方法。
- 罹患細胞の割合が1である、請求項36に記載の方法。
- 疾患特異的突然変異が、一塩基多様性である、請求項1から37のいずれか一項に記載の方法。
- 疾患が癌である、請求項1から38のいずれか一項に記載の方法。
- ネオエピトープが、罹患細胞のゲノム又はその部分をシーケンシングする工程を含む方法によって同定される、請求項1から39のいずれか一項に記載の方法。
- 医薬の製造における使用のための、請求項1から40のいずれか一項に記載の方法。
- ワクチンの製造における使用のための、請求項1から40のいずれか一項に記載の方法。
- ワクチンが、1種若しくは複数の適したネオエピトープ又は適したネオエピトープの組合せに由来する、請求項42に記載の方法。
- ワクチンが、1種若しくは複数の適したネオエピトープ又は適したネオエピトープの組合せを含むペプチド又はポリペプチド、又は前記ペプチド若しくはポリペプチドをコードする核酸を含む、請求項42又は43に記載の方法。
- ワクチンを提供するための方法であって、請求項1から40のいずれか一項に記載の方法に従って適したネオエピトープ又は適したネオエピトープの組合せを同定する工程を含む方法。
- ワクチンが、1種若しくは複数の適したネオエピトープ又は適したネオエピトープの組合せを含むペプチド又はポリペプチド、又は前記ペプチド若しくはポリペプチドをコードする核酸を含む、請求項45に記載の方法。
- 請求項42から46のいずれか一項に記載の方法によって産生されるワクチン。
- 適したネオエピトープ、又は適したネオエピトープの組合せにおける1種のネオエピトープに標的化された抗原受容体を発現する組換え免疫細胞の製造における使用のための、請求項1から40のいずれか一項に記載の方法。
- 免疫細胞がT細胞であり、抗原受容体がT細胞受容体である、請求項48に記載の方法。
- 適したネオエピトープ、又は適したネオエピトープの組合せにおける1種のエピトープに標的化された組換え免疫細胞を提供するための方法であって、請求項1から40のいずれか一項に記載の方法によって同定される適したネオエピトープ、又は適したエピトープの組合せにおける1種のエピトープに標的化された組換え抗原受容体を免疫細胞にトランスフェクトする工程を含む方法。
- 免疫細胞がT細胞であり、抗原受容体がT細胞受容体である、請求項50に記載の方法。
- 請求項48から51のいずれか一項に記載の方法によって産生された組換え免疫細胞。
- 哺乳類における1種又は複数のネオエピトープを発現する標的細胞集団又は標的組織に対する免疫応答をもたらすための方法であって、
(a)請求項1から40のいずれか一項に記載の方法に従って同定される1種若しくは複数のネオエピトープに標的化された1種若しくは複数の抗原受容体を発現する1個若しくは複数の免疫細胞を哺乳類に投与する工程、
(b)請求項1から40のいずれか一項に記載の方法に従って同定されるネオエピトープのうち1種若しくは複数をコードする核酸を投与する工程、又は
(c)請求項1から40のいずれか一項に記載の方法に従って同定されるネオエピトープのうち1種若しくは複数を含むペプチド若しくはポリペプチドを投与する工程
を含む方法。 - 免疫細胞がT細胞であり、抗原受容体がT細胞受容体である、請求項53に記載の方法。
- 免疫応答が、T細胞媒介性免疫応答である、請求項53又は54に記載の方法。
- 免疫応答が抗腫瘍免疫応答であり、1種又は複数の適したネオエピトープを発現する標的細胞集団又は標的組織が、腫瘍細胞又は腫瘍組織である、請求項53から55のいずれか一項に記載の方法。
- ネオエピトープの発現に関連する疾患、障害又は状態を有する哺乳類を処置するための方法であって、
(a)請求項1から40のいずれか一項に記載の方法に従って同定される1種若しくは複数のネオエピトープに標的化された1種若しくは複数の抗原受容体を発現する1個若しくは複数の免疫細胞を哺乳類に投与する工程、
(b)請求項1から40のいずれか一項に記載の方法に従って同定されるネオエピトープのうち1種若しくは複数をコードする核酸を投与する工程、又は
(c)請求項1から40のいずれか一項に記載の方法に従って同定されるネオエピトープのうち1種若しくは複数を含むペプチド若しくはポリペプチドを投与する工程
を含む方法。 - 免疫細胞がT細胞であり、抗原受容体がT細胞受容体である、請求項57に記載の方法。
- 疾患、障害又は状態が、癌である、請求項57又は58に記載の方法。
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