JP6942059B2 - クローディン−18.2−特異的免疫受容体およびt細胞エピトープ - Google Patents
クローディン−18.2−特異的免疫受容体およびt細胞エピトープ Download PDFInfo
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Description
本発明は、免疫療法に有用な、クローディン−18.2−特異的免疫受容体(T細胞受容体および人工T細胞受容体(キメラ抗原受容体;CAR))およびT細胞エピトープの提供に関する。
免疫系の進化は、脊椎動物に、自然免疫および適応免疫の2種類の防御に基づく極めて効果的なネットワークをもたらした。
病原体に関連する共通の分子パターンを認識する不変(インバリアント)受容体に依存する進化論的に古い自然免疫系とは対照的に、適応免疫は、B細胞(Bリンパ球)およびT細胞(Tリンパ球)上の高度に特異的な抗原受容体ならびにクローン選択に基づく。
T細胞は、ヒトおよび動物における細胞性免疫において中心的役割を果たす。特定の抗原の認識および結合には、T細胞表面上に発現されるT細胞受容体(TCR)が介在する。
抗原特異的免疫療法は、感染性疾患または悪性疾患を制御するために、患者における特異的免疫応答を増強または誘導することを目指している。病原体関連抗原および腫瘍関連抗原(TAA)が次々と同定されることで、免疫療法に適した標的が幅広く収集されることになった。これらの抗原に由来する免疫原性ペプチド(エピトープ)を提示する細胞は、能動免疫戦略または受動免疫戦略のいずれかによって特異的に標的化することができる。
腫瘍ワクチンは能動免疫によって内在性腫瘍特異的免疫応答を誘導することを目指している。癌細胞全体、タンパク質、ペプチドまたは免疫化ベクター、例えばRNA、DNAもしくはウイルスベクターなどを含む、異なる抗原フォーマットを、腫瘍ワクチン接種に用いることができ、それらはインビボで直接適用するか、または患者への移入に続いて、DCのパルス処理により、インビトロで適用することができる。
しかしながら、ほとんどの場合、検出される免疫応答を臨床転帰と体系的に関連付けることはできない(Curigliano, G. et al. (2006) Ann. Oncol. 17, 750−762; Rosenberg, S.A. et al. (2004) Nat. Med. 10, 909−915)。
それゆえに、腫瘍抗原由来のペプチドエピトープの厳密な定義は、ワクチン接種戦略の特異性および効率の改善だけでなく、さらに免疫モニタリングの方法にも貢献し得る。
ACTに基づく免疫療法は、非免疫レシピエントに移入されるか、または低い前駆体頻度から臨床的に妥当な細胞数までエクスビボで増加させた後に自己宿主に移入される、予め感作されたT細胞による受動免疫の一形態であると広く定義することができる。ACT実験に使用されている細胞タイプは、リンホカイン活性化キラー(LAK)細胞(Mule, J.J. et al. (1984) Science 225, 1487−1489; Rosenberg, S.A. et al. (1985) N. Engl. J. Med. 313, 1485−1492)、腫瘍浸潤リンパ球(TIL)(Rosenberg, S.A. et al. (1994) J. Natl. Cancer Inst. 86, 1159−1166)、造血幹細胞移植(HSCT)後のドナーリンパ球、ならびに腫瘍特異的T細胞株またはT細胞クローン(Dudley, M.E. et al. (2001) J. Immunother. 24, 363−373; Yee, C. et al. (2002) Proc. Natl. Acad. Sci. U. S. A 99, 16168−16173)である。
Riddellとその共同研究者らは、養子T細胞療法によるウイルス免疫の再構成を、HLA適合CMV血清陽性移植ドナー由来のCD8+ CMV特異的T細胞クローンを移入した後の免疫抑制患者において実証した(Riddell, S.R. (1992) Science 257, 238−241)。
ACTの限界を克服する一つのアプローチは、短期間のエクスビボ培養中に、所定の特異性を有する腫瘍反応性免疫受容体を発現するように再プログラムされた自己T細胞を、該患者に再注入する、自己T細胞の養子移入である(Kershaw M.H. et al. (2013) Nature Reviews Cancer 13 (8):525−41)。この戦略により、腫瘍反応性T細胞が患者に存在しない場合であっても、ACTを種々の一般的悪性病変に適用することが可能になる。T細胞の抗原特異性はもっぱらTCRα鎖およびβ鎖のヘテロ二量体型複合体に基づいているので、T細胞へのクローン化TCR遺伝子の移入により、それらを任意の目的抗原に対してリダイレクトすることを可能にする。それゆえに、TCR遺伝子治療は、処置選択肢として自己リンパ球による抗原特異的免疫療法を開発するための魅力的な戦略を提供する。TCR遺伝子移入の主な利点は、数日以内に治療量の抗原特異的T細胞が生成する点、および患者の内在性TCRレパートリーには存在しない特異性を導入することが可能になる点である。
キメラ抗原受容体(CAR)は、モノクローナル抗体の一本鎖可変フラグメント(scFv)とT細胞活性化のための1以上のシグナル伝達ドメインからなる細胞内部分を結合させて作製された受容体である。CARは、非MHC拘束性様式で天然抗原を認識し、それゆえに、そのHLAタイプが何であっても全ての個体に使用可能であり、それらはCD4+T細胞ならびにCD8+T細胞において機能する。
複数の腫瘍関連抗原(TAA)の発見が、抗原特異的免疫療法の概念の基礎になっている(Novellino, L. et al. (2005) Cancer Immunol. Immunother. 54, 187−207)。TAAは、その遺伝的不安定性のために腫瘍細胞上に発現される異常なタンパク質であり、正常細胞では発現されないか、または発現が限定されている。これらのTAAは、免疫系による悪性細胞の特異的認識につながり得る。
発明の概要
本発明は、特に、罹患細胞などの細胞の表面上に存在するか、または罹患細胞もしくは抗原提示細胞などの表面上に提示されるとき、腫瘍関連抗原CLDN18.2に特異的なT細胞受容体および人工T細胞受容体、ならびにこれらのT細胞受容体により認識されるエピトープ、すなわち、CLDN18.2−T細胞エピトープを含むペプチドに関する。
(i)配列番号8、10、12、14、16および18からなる群より選択されるT細胞受容体α鎖またはその変異体の少なくとも1つ、好ましくは2つ、より好ましくは3つ全てのCDR配列を含む、T細胞受容体α鎖、ならびに
(ii)配列番号8、10、12、14、16および18からなる群より選択されるT細胞受容体α鎖配列もしくはそのフラグメント、または該配列もしくはフラグメントの変異体を含むT細胞受容体α鎖
からなる群より選択される。
(i)配列番号9、11、13、15、17および19からなる群より選択されるT細胞受容体β鎖またはその変異体の少なくとも1つ、好ましくは2つ、より好ましくは3つ全てのCDR配列を含む、T細胞受容体β鎖、ならびに
(ii)配列番号9、11、13、15、17および19からなる群より選択されるT細胞受容体β鎖もしくはそのフラグメント、または該配列もしくはフラグメントの変異体を含むT細胞受容体β鎖
からなる群より選択される。
(I)(i)配列番号xのT細胞受容体α鎖またはその変異体の少なくとも1つ、好ましくは2つ、より好ましくは3つ全てのCDR配列を含むT細胞受容体α鎖、および
(ii)配列番号x+1のT細胞受容体β鎖またはその変異体の少なくとも1つ、好ましくは2つ、より好ましくは3つ全てのCDR配列を含むT細胞受容体β鎖(ここで、xは、8、10、12、14、16および18からなる群より選択される)
を含むT細胞受容体、および
(II)(i)配列番号xのT細胞受容体α鎖配列もしくはそのフラグメント、または該配列もしくはフラグメントの変異体を含むT細胞受容体α鎖、および
(ii)配列番号x+1のT細胞受容体β鎖配列もしくはそのフラグメント、または該配列もしくはフラグメントの変異体を含むT細胞受容体β鎖(ここで、xは、8、10、12、14、16および18からなる群より選択される)
を含むT細胞受容体
からなる群より選択されるT細胞受容体に関する。
NH2−シグナルペプチド−CLDN18.2の結合ドメイン−スペーサー領域−膜貫通ドメイン−T細胞シグナル伝達ドメイン−COOH。
(i)本発明のペプチド;
(ii)本発明の核酸;
(iii)本発明の細胞;
(iv)本発明の免疫反応性細胞;
(v)本発明の結合剤;
(vi)本発明のT細胞受容体;および
(vii)本発明の人工T細胞受容体。
(a)対象から単離されたT細胞を含むサンプルを、
(i)本発明のペプチド;
(ii)本発明のペプチドをコードするヌクレオチド配列を含む本発明の核酸;および
(iii)該核酸を含む本発明の細胞または本発明のペプチドもしくはそのプロセシング産物を提示する本発明の細胞
の1以上と共にインキュベートすること;および
(b)T細胞の特異的活性化を検出し、そこから該対象における免疫応答の有無を決定すること
を含み得る。
本発明を下記で詳細に説明するが、本発明は、本明細書に記載の特定の方法論、プロトコールおよび反応剤(reagent)に限定されるものではなく、変更も可能である。また、本明細書で用いる用語は、特定の態様を説明するためのみ用いられるものであって、本発明の範囲を限定しようとするものではなく、本発明の範囲は、添付の特許請求の範囲によってのみ規定される。他の定義がない限り、本明細書で用いる技術用語および科学用語は、当業者が一般的に理解している意味と同様の意味を有する。
第1のドメインは、CLDN18.2を認識し、結合する結合ドメインである。
第2のドメインは、共刺激ドメインである。共刺激ドメインは、標的部分へのCARの結合の際に細胞傷害性リンパ球の増殖および生存を増強するために働く。共刺激ドメインの同一性は、それがCARによる標的部分の結合の際に細胞増殖および生存を増強する能力を有する点でのみ制限される。好適な共刺激ドメインには、CD28、CD137(4−1BB)、腫瘍壊死因子(TNF)受容体ファミリーのメンバー、CD134(OX40)、TNFR−受容体のスーパーファミリーのメンバー、およびCD278(ICOS)、活性化T細胞上に発現されるCD28−スーパーファミリー共刺激分子が含まれる。当業者は、本発明に悪影響を及ぼすことなく、これらの特記された共刺激ドメインの配列変異体を用いることができ、ここで、該変異体は、それらがモデル化されるドメインと同じか、または同様の活性を有することを理解し得る。このような変異体は、それらが由来するドメインのアミノ酸配列と少なくとも約80%の配列同一性を有し得る。本発明のいくつかの態様において、CAR構築物は、2つの共刺激ドメインを含む。特定の組み合わせは、4つの記載されたドメインの全ての可能性のある変形を含むが、特定の例には、CD28+CD137(4−1BB)およびCD28+CD134(OX40)が含まれる。
(i)VHが、配列番号20のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号27のアミノ酸配列もしくはそのフラグメントを含む、
(ii)VHが、配列番号21のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号26のアミノ酸配列もしくはそのフラグメントを含む、
(iii)VHが、配列番号22のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号28のアミノ酸配列もしくはそのフラグメントを含む、
(iv)VHが、配列番号24のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号31のアミノ酸配列もしくはそのフラグメントを含む、
(v)VHが、配列番号23のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号30のアミノ酸配列もしくはそのフラグメントを含む、
(vi)VHが、配列番号25のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号29のアミノ酸配列もしくはそのフラグメントを含む、
(vii)VHが、配列番号25のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号32のアミノ酸配列もしくはそのフラグメントを含む、
(viii)VHが、配列番号25のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号33のアミノ酸配列もしくはそのフラグメントを含む、
(ix)VHが、配列番号25のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号34のアミノ酸配列もしくはそのフラグメントを含む。
VHが、配列番号23のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号30もしくはそのフラグメントを含む。
VHが配列番号21のアミノ酸配列もしくはそのフラグメントを含み、VLが、配列番号26のアミノ酸配列もしくはそのフラグメントを含む。
(i)以下の相補性決定領域CDR1、CDR2およびCDR3のセットを含むVH:
CDR1:GYTFTSYW、CDR2:IYPSDSYT、CDR3:TRSWRGNSFDY
および/または
(ii)以下の相補性決定領域CDR1、CDR2およびCDR3のセットを含むVL:
CDR1:QSLLNSGNQKNY、CDR2:WAS、CDR3:QNDYSYPFT
を含む。
VH:CDR1:GYTFTSYW、CDR2:IYPSDSYT、CDR3:TRSWRGNSFDY、VL:CDR1:QSLLNSGNQKNY、CDR2:WAS、CDR3:QNDYSYPFT。
本明細書で用いる技術および方法は本明細書に記載されているか、またはそれ自体公知の方法で実施され、例えば、Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Yに記載のような方法で実施される。キットおよび反応剤の使用を含むすべての方法は、特に指示がない限り、製造者の情報に従って行われる。
細胞株および反応剤
HLA−A*0201(Britten, C.M. et al. (2002), J. Immunol. Methods 259, 95−110)を安定にトランスフェクトされたヒト慢性骨髄性白血病細胞株K562(Lozzio, C.B. & Lozzio, B.B (1975), Blood 45, 321−334)(例えば、K562−A2と呼ばれる)を、TCR検証アッセイのために、標準条件下で培養した。初代ヒト新生児包皮線維芽細胞株CCD−1079Sk(ATCC受託番号CRL−2097)を、製造者の指示に従って培養した。
PBMCを、バフィーコートからFicoll−Hypaque(Amersham Biosciences, Uppsala, Sweden)密度勾配遠心分離により単離した。HLAアレル型をPCR標準法により決定した。単球を、抗CD14マイクロビーズ(Miltenyi Biotech, Bergisch−Gladbach, Germany)を用いて濃縮した。未成熟DC(iDC)を、Kreiter et al. (2007), Cancer Immunol. Immunother., CII, 56, 1577−87に記載の通り、サイトカイン添加培養培地中で5日間、単球を分化させることにより得た。
クローディン−18.2またはHIV−gagの配列に対応する11個のアミノ酸重複を有するN末端およびC末端の遊離15マーのペプチドのプール(抗原ペプチドプールと呼ばれる)を、標準固相化学(JPT GmbH, Berlin, Germany)により合成し、最終濃度0.5mg/mlとなるようにDMSOで希釈した。9マーのペプチドを、PBS中10%DMSO中で再構成した。パルス刺激のために、刺激細胞を、異なるペプチド濃度を用いて培養培地中で37℃にて1時間インキュベートした。
全ての構築物は、既述のpST1−sec−insert−2βgUTR−A(120)−Sap1プラスミド(Holtkamp, S. et al. (2006), Blood 108, 4009−4017)の変異体である。マウスTCR鎖をコードするプラスミドの作製のために、マウスTCR−α、−β1および−β2定常領域をコードするcDNAを、商業的プロバイダから注文し、類似性に基づいてクローニングした(それぞれ、GenBank受託番号M14506、M64239およびX67127)。特定のV(D)J PCR産物を、かかるカセットに導入して、完全長TCR鎖を産生した(pST1−マウスTCRαβ−2βgUTR−A(120)と称する)。
完全長CLDN18.2、CLDN18.2 aa1−80およびCLDN6抗原を、既報の通り、pST1プラスミド中のMHCクラスI輸送シグナル(MITD)に連結させてクローニングした(Kreiter, S. et al. (2008), J. Immunol. 180, 309−318)。
IVT RNAの作製を既報の通り実施し(Holtkamp, S. et al. (2006), Blood 108, 4009−4017)、予冷した4−mm gap滅菌エレクトロポレーションキュベット(Bio−Rad Laboratories GmbH, Munich, Germany)中、X−VIVO15培地(Lonza, Basel, Switzerland)中に懸濁した細胞に添加した。エレクトロポレーションを、Gene−Pulser−II装置(Bio−Rad Laboratories GmbH, Munich, Germany)を用いて実施した(T細胞:450V/250μF;K562−A2:200V/300μF)。
A2/DR1マウス(Pajot A. et al. (2004), Eur. J. Immunol. 34, 3060−69)のT細胞を、抗原をコードするIVT RNAを用いた反復的節内免疫化により、目的の抗原に対してインビボでプライミングした(Kreiter S. et al. (2010), Cancer Research 70, 9031−40)。節内免疫化のために、マウスをキシラジン/ケタミンで麻酔した。鼠径部リンパ節を外科的に露出させ、極細針(31G、BD Biosciences)を付けた使い捨て0.3 ml注射器を用いて、リンゲル液およびRnaseフリー水に希釈した10μL RNA(20μg)をゆっくり注射し、創部を閉じた。6回の免疫化サイクル後にマウスを屠殺し、脾臓細胞を単離した。
脾臓を滅菌条件下で切離した後、それらをPBS含有ファルコンチューブに移した。脾臓を鉗子で機械的に破壊し、セルストレーナー(40μm)で細胞懸濁液を得た。脾細胞をPBSで洗浄し、遠心分離し、赤血球溶解用の低張緩衝液に再懸濁した。室温(RT)で5分間インキュベートした後、20〜30mlの培地またはPBSを添加することによって反応を停止させた。脾臓細胞を遠心分離し、PBSで2回洗浄した。
抗原特異的再刺激のために、免疫化A2/DR1マウスからの脾臓細胞2.5x106個/ウェルを24ウェルプレートに播種し、目的の抗原または対照抗原をコードする重複ペプチドのプールをパルス処理した。24時間のインキュベーション後に、細胞を収穫し、FITCコンジュゲート抗CD3抗体、PEコンジュゲート抗CD4抗体、PerCP−Cy5.5コンジュゲート抗CD8抗体およびDylight−649コンジュゲート抗CD137抗体で染色した。選別はBD FACS Ariaフローサイトメーター(BD Biosciences)で行った。CD137、CD3およびCD8に関して陽性な細胞を選別し、フィーダー細胞としてヒトCCD−1079Sk細胞を含む96ウェルV底プレート(Greiner Bio−One)に、1ウェル当たり1細胞を取得し、4℃で遠心分離し、直ちに−80℃で保存した。
選別されたT細胞から、RNeasy Micro Kit(Qiagen, Hilden, Germany)を用いて、供給者の指示に従って、RNAを抽出した。cDNA合成のために鋳型スイッチプロトコールを用いた:ミント逆転写酵素(Evrogen JSC)を、第1鎖合成反応のプライミングのためのオリゴ(dT)−T−primer longおよびオリゴ(riboG)配列を導入するTS−short(Eurofins Genomic)と組み合わせて、逆転写酵素のターミナルトランスフェラーゼ活性および鋳型スイッチによる伸長型鋳型の作製を可能にした(Matz, M. et al. (1999)Nucleic Acids Res. 27, 1558−1560)。製造者の指示に従って合成された第1鎖cDNAを、200μM dNTPの存在下での、5U PfuUltra Hotstart High−Fidelity DNAポリメラーゼ(Agilent Technologies)および0.48μMプライマーTS−PCRプライマーによる21サイクルの増幅に供した(サイクル条件:95℃で2分、94℃で30秒、65℃で30秒、72℃で1分、72℃で6分間の最終伸長)。TCR遺伝子の増幅の成功を、マウスTCR−β定常領域特異的プライマーでコントロールし、強いバンドが検出された場合にのみ、引き続きクローン型特異的マウスVα−/Vβ−PCRを行った。
マウスTCRコンセンサスプライマーを設計するために、ImMunoGeneTics(IMGT)データベース(http://www.imgt.org)に列挙されている全てのマウスTCR−Vβおよび−Vα遺伝子を、それぞれの対応するリーダー配列と共に、BioEdit Sequence Alignment Editor(例えば、http://www.bio−soft.net)でアラインメントした。最大3つの縮重塩基、40−60%のGC含量、および3’末端にGまたはCを有する24〜27bp長のフォワードプライマーを、可能な限り多くのリーダー配列にアニールするように設計し、稀な制限酵素部位およびコザック配列を特徴とする15bpの5’伸長部を設けた。リバースプライマーは、定常領域遺伝子の第1エクソンにアニールするように設計され、プライマーmTRACex1_asはCαのアミノ酸24〜31に対応する配列に結合し、mTRBCex1_asはCβ1およびCβ2中のアミノ酸(aa)8〜15に結合する。どちらのオリゴヌクレオチドも5’リン酸基を有するように合成した。プライマーを、同一のアニーリング温度を有する2〜6個のフォワードオリゴのプールにまとめた。
単離されたT細胞に由来する予め増幅したcDNA6μlを、0.6μM mVα−/mVβ−特異的オリゴプール、0.6μM mCα−またはmCβ−オリゴ、200μM dNTPおよび5U PfuUltra II Fusion HS DNAポリメラーゼの存在下で、40サイクルのPCRに供した(Agilent;サイクル条件:95℃で1分、94℃で30秒、アニーリング温度で30秒、72℃で30秒、72℃で3分間の最終伸長)。Qiagenのキャピラリー電気泳動システムを用いてPCR産物を分析した。470−550bpにバンドを有するサンプルを、アガロースゲルでサイズ分画し、バンドを切り出し、Gel Extractionキット(Qiagen, Hilden, Germany)を用いて精製した。mTRBCex1_asおよびmTRBCex1_asプレイマーがそれぞれ、マウスにおけるTCR定常領域遺伝子Cβ1およびCβ2の両方に合致するので、配列解析を行い、V(D)Jドメインおよびβ定常領域の両方の配列を明らかにした。DNAを消化し、完全なマウスTCR−α/β鎖のための適当なバックボーンを含むIVTベクター中にクローニングした。
トランスフェクトされたTCR遺伝子の細胞表面発現を、TCR β鎖の適当な可変領域ファミリーまたは定常領域に対する蛍光色素−コンジュゲート抗TCR抗体(Beckman Coulter Inc., Fullerton, USA)をCD3、CD8またはCD4に対する抗体(BD Biosciences)と組み合わせて用いて、フローサイトメトリーで分析した。トランスフェクションされたCARの細胞表面発現を、それぞれのCAR構築物に含まれるscFvフラグメントを認識する蛍光色素−結合イディオタイプ特異的抗体(Ganymed Pharmaceuticals)を用いて分析した。フローサイトメトリー分析を、FACS CANTO IIフローサイトメーターでFACS Divaソフトウェア(BD Biosciences)を用いて行った。
細胞介在性細胞傷害を評価するために、51Cr放出法の代替法および最適化法として、バイオルミネセンスに基づくアッセイを用いた。標準的なクロム放出アッセイとは対照的に、このアッセイでは、共インキュベーション後の生存可能なルシフェラーゼ発現標的細胞の数を計算することによって、エフェクター細胞の溶解活性を測定する。標的細胞に、ホタルPhotinus pyralisのホタル・ルシフェラーゼ(EC 1.13.12.7)をコードするルシフェラーゼ遺伝子を安定にまたは一過性にトランスフェクトした。ルシフェラーゼは、ルシフェリンの酸化を触媒する酵素である。この反応はATP依存的であり、2段階で起こる:
ルシフェリン+ATP→ルシフェリルアデニレート+PP i
ルシフェリルアデニレート+O 2 →オキシルシフェリン+AMP+光。
(1−(CPSexp−CPSmin)/(CPSmax−CPSmin)))*100。
マイクロタイタープレート(Millipore, Bedford, MA, USA)に、抗ヒトIFNγ抗体1−D1k(Mabtech, Stockholm, Sweden)を室温で一晩、または抗マウスIFNy抗体AN18(Mabtech)を4℃で一晩、コーティングし、2%ヒトアルブミン(CSL Behring, Marburg, Germany)またはマウス培養培地でブロッキングした。エレクトロポレーションの24時間後に、マウス設定では1ウェル当たり5x105の脾細胞、ヒト設定においては2〜5×104/ウェルの抗原提示刺激細胞を、0.3−3x105/ウェルのTCR−トランスフェクトCD4+またはCD8+エフェクター細胞と共に、トリプリケートで播種した。プレートを、一晩(37℃、5%CO2)インキュベートし、PBS中0.05% Tween 20で洗浄し、最終濃度1μg/mlの抗ヒトIFNγビオチン化mAB 7−B6−1(Mabtech)または抗マウスIFNγビオチニル化mAb R4−6A2(Mabtech)と共に、37℃で2時間インキュベートした。アビジン結合西洋ワサビペルオキシダーゼH(Vectastain Elite Kit;Vector Laboratories、Burlingame、USA)をウェルに添加し、室温で1時間インキュベートし、3−アミノ−9−エチルカルバゾール(Sigma, Deisenhofen, Germany)で発色させた。
CD8+T細胞をCAR RNAでトランスフェクトし、約20時間後に、0.8μMのCFSEで標識した。標識したT細胞を洗浄し、RNA−トランスフェクトした自己由来iDC(E:T比=10:1)と共に培養した。共培養の4日後、細胞を収集し、細胞分裂後の娘細胞内のCFSE蛍光の漸進的な半減に基づいてフローサイトメトリーにより増殖を分析した。
BALB/cマウスをJavier Labから購入した。月齢(8週齢)および性別(メス)適合動物を、実験を通して使用した。コンジェニック系統BALB/c−Thy1.1マウスを、BioNTech AG(Germany)の動物施設で飼育した。
BALB/c−Thy1.1マウスの脾細胞を単離し、5ng/mLのrh IL−7および10ng/mLのrh IL−15(both Miltenyi)の存在下で、2μg/mLの可溶性抗CD3(eBioscience)および1μg/mLの可溶性抗CD28(Novus Biosciences)によって予め活性化させた。予活性化の24時間後および48時間後に、T細胞を、RetroNectin法(Takara)を用いてCLDN18.2−CAR−effLuc−GFPをコードするトリシストロン性ベクターでレトロウイルス的(MLV−E)に形質導入した。その後、形質導入したT細胞を、5ng/mL rh IL−7および10ng/mL rh IL−15の存在下で3日間増殖させ、次いで、マウスに養子移植する前に、Ficoll−Paque PREMIUM(1.084)を用いてフィコール分離した。
5x106 CLDN18.2 CAR形質導入BALB/c−Thy1.1+ T細胞を、BALB/cマウスに静脈内注射(i.v.)した。次いで、マウスを、養子T細胞移植(ACT)の24時間後に、F12:RNA比が1.3:2のRNA(Lip)でワクチン接種した。全身生物発光撮像を行った。
CLDN18.2−CAR−effLuc−GFPで形質導入されたT細胞の増殖を、IVIS発光イメージングシステム(Caliper Life Sciences)を用いるインビボ生物発光イメージングによって評価した。簡潔には、D−ルシフェリン(80mg/kg体重; Perkin Elmer)の水溶液の注射の5分後に、放出された光子を定量した(1分間の積分時間)。動物内のルシフェラーゼ発現細胞にからの透過光の強度を、グレースケール画像として表し、黒は最も弱い強度であり、白色から暗灰色が最も強い生物発光シグナルである。マウスのグレースケール対照画像を、LED低照度照明下で得た。Living Image 4.0ソフトウェアを用いて画像を重ね合わせた。
本発明者らは、CLDN18.2のaa 1−80をコードするIVT−RNAを用いる反復結節内免疫化によるA2/DR1マウスにおけるCLDN18.2の免疫原性の可能性を確認した。ヒトCLDN18遺伝子は、N末端の69アミノ酸が異なる2つのタンパク質アイソフォーム(CLDN18.1およびCLDN18.2)を生じる、2つの代替第1エクソンを有する(図4A)。CLDN18.1は正常組織でも、とりわけ肺で発現されるため、本発明者らは、CLDN18.2特異的T細胞反応性を排他的に誘導するために、CLDN18.2のN末端部分のみを用いた。本発明者らは、これらのマウスの脾細胞を、CLDN18.2特異的T細胞の単離およびその後の対応するTCR遺伝子のクローニングに使用した。免疫化したマウスからの脾細胞を、CLDN18.2特異的T細胞の誘導の成功について分析し、IFNγ−ELISPOTアッセイによりエキソビボでの予測されたHLA−A*02結合CLDN18.2ペプチドに対するそれらの反応性を分析した(図5)。
CLDN18.2特異的T細胞の単離のために、免疫化したマウスの脾細胞をインビトロで再刺激し、CD137の活性化誘導上昇制御に基づいてフローサイトメトリーにより単一細胞を単離した(図6)。
TCRを免疫学的検証アッセイに供したところ、6つ全てのCLDN18.2−TCRが、以前にエキソビボでのELISPOT分析により同定された、2つのHLA−A*0201−拘束性エピトープ CLDN18.2 aa7−15(CLDN18.2−A2−5)およびCLDN18.2 aa8−16(CLDN18.2−A2−6)の一方または両方を認識したことが明らかとなった(図7)。
本発明者らは、CD3ζおよびCD28のそれぞれのシグナル伝達および共刺激部分を含むCLDN18.2を標的とする第2世代のCARを作製した。CD28細胞内ドメインにおけるlck結合部分の欠失は、CAR連結に際してIL2分泌を抑制し、調節性T細胞の誘導を防止する(Kofler D.M. et al., (2011) Molecular Therapy 19 (4), 760−767)。CARの細胞外部分におけるIgG1 Fc‘スペーサー’ドメインの改変は、 ‘オフターゲット’の活性化および自然免疫応答の意図しない開始を回避する(Hombach A. et al., (2010) Gene Therapy 17, 1206−1213)。
CLDN18.2を発現する標的細胞のCLDN18.2−CAR−介在溶解は、CLDN18.2−CARのその標的抗原への結合を阻止することにより、30:1の高E:T比でさえも効率的に阻害することができた。CLDN6−CAR介在溶解の阻害は観察されず、抗体のCLDN18.2−CARへの選択的結合を確認することはできなかった。この実験は、一方では、CLDN18.2−CARにより介在される溶解が専らCARのCLDN18.2特異性に依存し、他方では、CLDN18.2−CAR検出に用いられるイディオタイプ特異的抗体が、原則として、重篤な有害事象の場合にはインビボでCLDN18.2−CAR T細胞の阻害に適用可能であることを確認した。
Claims (17)
- (I)(i)配列番号xのT細胞受容体α鎖の3つ全てのCDR配列を含むT細胞受容体α鎖、および
(ii)配列番号x+1のT細胞受容体β鎖の3つ全てのCDR配列を含むT細胞受容体β鎖(ここで、xは、8、10、12、14、16および18からなる群より選択される)
を含む、T細胞受容体、および
(II)(i)配列番号xのT細胞受容体α鎖配列を含むT細胞受容体α鎖、および
(ii)配列番号x+1のT細胞受容体β鎖配列を含むT細胞受容体β鎖(ここで、xは、8、10、12、14、16および18からなる群より選択される)
を含む、T細胞受容体、
からなる群より選択される、T細胞受容体であって、クローディン−18.2(CLDN18.2)のエピトープに結合するT細胞受容体。 - クローディン−18.2(CLDN18.2)に結合し、CLDN18.2の結合ドメイン、膜貫通ドメイン、およびT細胞シグナル伝達ドメインを含む人工T細胞受容体であって、CLDN18.2の結合ドメインが、配列番号23のアミノ酸配列を含むVH(CLDN18.2)、および配列番号30のアミノ酸配列を含むVL(CLDN18.2)を含む、人工T細胞受容体。
- CLDN18.2の結合ドメインが、配列番号35のアミノ酸配列を含む、請求項2に記載の人工T細胞受容体。
- T細胞シグナル伝達ドメインが、CD28と結合してよい、CD3−zeta、好ましくはCD3−zetaの細胞内ドメインを含む、請求項2または3の人工T細胞受容体。
- 新生タンパク質の小胞体への輸送を指示するシグナルペプチドを含む、請求項2から4のいずれか一項に記載の人工T細胞受容体。
- 膜貫通ドメインにCLDN18.2の結合ドメインを連結させるスペーサー領域を含む、請求項2から5のいずれか一項に記載の人工T細胞受容体。
- 配列番号41のアミノ酸配列を含む、請求項2から6のいずれか一項に記載の人工T細胞受容体。
- 請求項1に記載のT細胞受容体のT細胞受容体α鎖およびβ鎖をコードするか、または請求項2から7のいずれか一項に記載の人工T細胞受容体をコードするヌクレオチド配列を含む核酸。
- 請求項1に記載のT細胞受容体のT細胞受容体α鎖およびβ鎖または請求項2から7のいずれか一項に記載の人工T細胞受容体をコードするヌクレオチド配列を含む核酸、を含む組成物。
- 請求項1に記載のT細胞受容体のT細胞受容体α鎖およびβ鎖、または請求項2から7のいずれか一項に記載の人工T細胞受容体を含む、および/または該T細胞受容体の該T細胞受容体α鎖およびβ鎖をコードするか、または該人工T細胞受容体をコードする核酸配列を含む、細胞。
- 請求項8に記載の核酸または請求項10に記載の組成物を用いてT細胞を形質転換する工程を含む、免疫反応性細胞の製造方法。
- (i)請求項8に記載の核酸;
(ii)請求項10に記載の細胞;
(iii)請求項1に記載のT細胞受容体;
(iv)請求項2から7のいずれか一項に記載の人工T細胞受容体;および
(v)請求項9に記載の組成物、
のいずれか1つを含む、医薬組成物。 - 薬学的に許容される担体をさらに含む、請求項12に記載の医薬組成物。
- 癌の処置または予防のための、請求項12または13に記載の医薬組成物。
- 癌がCLDN18.2陽性癌である、請求項14に記載の医薬組成物。
- 対象におけるCLDN18.2陽性癌細胞を死滅させる方法に使用するための、請求項8に記載の核酸、請求項10に記載の細胞、請求項1に記載のT細胞受容体、請求項2から7のいずれか一項に記載の人工T細胞受容体、または請求項9に記載の組成物を含む医薬組成物であって、方法が、治療的有効量の医薬組成物を対象に提供する工程を含むものである、医薬組成物。
- 対象におけるCLDN18.2陽性癌細胞を死滅させるための医薬の製造における、請求項8に記載の核酸、請求項10に記載の細胞、請求項1に記載のT細胞受容体、請求項2から7のいずれか一項に記載の人工T細胞受容体、または請求項9に記載の組成物の使用。
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