JP2021502110A - がん特異的抗原に対するtリンパ球のスクリーニング - Google Patents
がん特異的抗原に対するtリンパ球のスクリーニング Download PDFInfo
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Abstract
Description
本発明は、2017年10月6日出願の米国仮特許出願62/569,215の優先権利益を主張するものであり、その全体は参照により組み込まれる。
本明細書で使用する専門用語は特定の実施形態を説明するためだけのものであり、本明細書に記載する実施形態の範囲を限定することを意図するものではない。特に定義しない限り、本明細書で使用する全ての技術用語及び科学用語は、本発明が属する技術分野の当業者が一般に理解する意味と同一の意味を有する。しかしながら、矛盾が生じた場合には、本明細書(定義を含む)が優先される。それゆえ、本明細書に記載の実施形態に関しては以下の定義を適用する。
ペプチド
標準的な固相合成法を使用することにより9マー及び10マーのペプチドを合成してから、逆相高速液体クロマトグラフィー(HPLC)を用いて精製を行った(表1a〜eを参照のこと)。ペプチドの純度(>90%)及び同一性を、それぞれ分析HPLCと質量分析法を用いて測定した。ペプチドを20mg/mlでジメチルスルホキシド中に溶解し、−80℃で保存した。
TISI(HLA−A*24:02、Bリンパ芽球様細胞株)については、International Histocompatibility Working Groupから購入した。T2(HLA−A*02:01、Bリンパ芽球様細胞株)、EB−3(HLA−A3/Aw32、Bリンパ芽球様細胞株)、Jiyoye(HLA−A32、Bリンパ芽球様細胞株)、SW480(HLA−A*24:02、結腸腺癌)、HCC1143(HLA−A*31:01、乳癌)、BT549(HLA−A*02:01、乳癌)、及び、C1R(HLA−AとHLA−Bを欠く、Bリンパ芽球)については、American Type Culture Collection(Rockville,MD)から購入した。全ての細胞は、それらの対応する寄託者の推奨に基づいて培養された。
TISI及びT2に加えて、ヒト白血球抗原(HLA)をトランスフェクションしたC1R細胞を刺激細胞として使用した。HLAクラスI(A*24:02、A*02:01、A*11:01、A*33:03、または、A*03:01)のオープンリーディングフレームをコードするcDNAをPCRを用いて増幅してから、発現ベクターに挿入した。HLAクラスI発現ベクターをC1R細胞にトランスフェクションしてから、G418(Invitrogen,Carlsbad,CA)の存在下で14日間培養した。G418を補足した培地を含有する96ウェル細胞培養プレート(Corning,Inc.,Corning,NY)にG418耐性単一細胞及びフィーダー細胞を播種してから、更に30日間培養した。トランスフェクションしたHLAクラスIのC1R細胞上における発現をフローサイトメトリー解析により確認した。
単球由来樹状細胞(DC)を抗原提示細胞として使用して、HLAクラスI上に提示されるペプチドに反応を示す細胞傷害性Tリンパ球(CTL)を誘導した。DCをインビトロで作製した(参照文献37(その全体は参照により組み込まれる))。Ficoll−Paque PLUS(GE Healthcare)を用いて健康なボランティアの血液から末梢血単核球(PBMC)を単離した。2%加熱不活化ヒト血清を含有するAIM−V培地(Invitrogen)(AIM−V/2%HS培地)中の1000IU/mlの顆粒球−マクロファージコロニー刺激因子(R&D Systems,Minneapolis,MN)と1000IU/mlのインターロイキン(IL)−4(R&D System)の存在下で、単球(PBMC中の接着細胞)を培養して、DCを生じさせた。7日間の培養の後、3マイクロg/mlのβ2−ミクログロブリンの存在下、AIM−V培地中、37℃で3時間、単球由来DCに20マイクロg/mlの合成ペプチドを負荷した。X線照射(20Gy)でこれらのペプチド負荷DCを不活化してから、CD8 Positive Isolation Kit(Thermo Fisher Scientific,Carlsbad,CA)を使用してPBMCから得た自家CD8+T細胞と1:20の比率で混合した。これらの培養液を48ウェル細胞培養プレート(Corning)内に入れた。それぞれのウェルは、0.5mlのAIM−V/2%HS培地中の、1.5×104のペプチド負荷DC、3×105のCD8+T細胞、及び、10ng/mlのIL−7(R&D System)、を含有していた。翌々日(2日目)、20IU/mlの終濃度となるように培養液にIL−2(Novartis)を加えた。7日目と14日目に、自家ペプチド負荷DCでCD8+T細胞を更に刺激した。DCは上記の同じ方法で毎回調製した。21日目にELISPOTアッセイでCD8+T細胞のペプチド特異的IFN−γ産生を試験した(参照文献38〜39(それら全体は参照により組み込まれる))。
限界希釈後、Rapid Expansion Method(参照文献40(その全体は参照により組み込まれる))を使用してCD8+T細胞を増殖させた。EB−3及びJiyoyeをマイトマイシンCで処理してフィーダー細胞として使用した。25mlのAIM−V/5%HS培地中のフィーダー細胞(それぞれ5×106の細胞)と40ng/mlの抗CD3抗体と共に、CD8+T細胞を培養した。翌日(1日目)、3000IUのIL−2を培養液に加えた。5日目、8日目、及び、11日目に、半分の容積の培地を、60IU/mlのIL−2を含有する新鮮なAIM−V/5%HS培地に交換した。14日目から16日目の間にELISAでCD8+T細胞のペプチド特異的IFN−γ産生を試験した(参照文献38〜39(それら全体は参照により組み込まれる))。
CD8+T細胞のペプチド特異的IFN−γ産生を試験するために、ELISPOTアッセイまたはELISAを実施した。ペプチドを負荷した、T2、TISI、または、HLAクラスIを発現するC1R細胞(1×104の細胞)を刺激細胞として調製した。CD8+T細胞をキラー細胞として使用した。製造業者の手順(BD Biosciences,San Jose,CA)に従いIFN−γELISPOTアッセイ及びIFN−γELISAを実施した。
CTL及びTCR改変T細胞をIL−2(100U/mL)で16時間前処理した。実験の前に、標的細胞をIFN−γ(100U/mL)で48時間前処理した。1ug/mLのCalcein AM(Dojindo,Kumamoto,Japan)と共に細胞を30分間インキュベートした。PBSによる3回の洗浄後、2×104の標的細胞を、2×105のFOXM1/UBE2T特異的CTLまたは4×105のTCR改変T細胞と混合して、Lab−Tek Chamber Slide Cover Glass Slide Sterile 16 Well(Thermo Scientific)に入れた。倒立顕微鏡Axio Vert.A1 TL(Zeiss,Oberkochen,Germany)を用いて低速度撮影記録を実施した。ImageJプログラム(National Institutes of Health,Bethesda,MD)を使用して生細胞及び死細胞を定量した。
TCR配列を同定した(参照文献41(その全体は参照により組み込まれる))。増殖T細胞またはデキストラマー陽性T細胞からトータルRNAを抽出した。SMARTライブラリ構築キット(Clontech,Mountain View,CA)を使用して、一般的な5’−RACEアダプターを有するcDNAを合成した。SMARTアダプター配列に対応するフォワードプライマー、及び、TCRAまたはTCRBのそれぞれの定常領域に対応するリバースプライマーを使用して、フュージョンPCRを実施し、TCRA cDNAまたはTCRB cDNAを増幅した。Nextera Indexキット(Illumina,San Diego,CA)を使用してバーコードを含むIlluminaインデックス配列を付加した後、MiSeq(Illumina)上で300bpペアエンドリードを用いて調製ライブラリをシークエンスした。Tcripソフトウェアを使用して、得られたシークエンスリードを解析した(参照文献41(その全体は参照により組み込まれる))。フュージョンPCR産物を雛形として使用したサンガーシークエンス(Thermo Scientific)により、配列も確認した。
TCRA配列とTCRB配列の両方をコドン最適化してから、pMP71−PREにクローニングした(参照文献18、42(それら全体は参照により組み込まれる))。TCR発現を最大化するために、改変マウスTCRA定常ドメイン及び改変マウスTCRB定常ドメインを使用した。一過性レトロウイルス上清を作製してから、ドナー由来のPBMCの形質導入を行った(参照文献18(その全体は参照により組み込まれる))。抗ヒトTCRβV抗体を用いてTCRの発現を評価した。FOXM1に対するTCR改変T細胞及びUBE2Tに対するTCR改変T細胞用の適切な条件で、APCコンジュゲート抗マウスTCRβモノクローナル抗体(H57−597,eBioscience,San Diego,CA)による染色を使用して、形質導入TCR改変T細胞のみを形質導入し、それに続いて、製造業者の取扱説明書に従い抗APCマイクロビーズ(Miltenyi Biotec,Bergisch Gladbach,Germany)と共に培養した。抗体が占有していない所望のTCRを形質導入したT細胞の数を増加させるために、条件は、5つの異なる抗体希釈条件を比較することによるピーク蛍光強度及びソート細胞の数を基準とした。FOXM1に対するTCR改変T細胞とUBE2Tに対するTCR改変T細胞をソートするには、それぞれ1:2000(0.1ug/mL)の比率と1:4000(0.05ug/mL)の比率の抗体染色が適切であるということが明らかとなった。
ペプチド特異的CTL
表1a〜eのHLA−A*24:02、HLA−A*02:01、HLA−A*11:01、HLA−A*33:03、または、HLA−A*03:01拘束性ペプチドに特異的なCTLクローンを誘導した。それぞれのペプチドを含むHLAデキストラマーを用いてCTLを捕捉し、これらの細胞のTCR配列を同定した(ペプチド特異的CTL内のTCRにおけるCDR3アミノ酸配列については表2a〜eを参照のこと)。ペプチドを含むまたは含まないHLA発現細胞を使用して、44種のCTLクローンの全てにおけるペプチド特異的IFN−γ産生についてELISAアッセイによる評価を行った。
FOXM1に由来するペプチドに特異的なCTLクローン及びUBE2Tに由来するペプチドに特異的なCTLクローンを誘導した(参照文献19〜20(それら全体は参照により組み込まれる))。インターフェロン(IFN)−γEnzyme−Linked ImmunoSpot(ELISPOT)アッセイにより健康ドナーのPBMCからHLA−A*24:02拘束性CTLを誘導することができる、高免疫原性FOXM1由来ショートペプチド及び高免疫原性UBE2T由来ショートペプチドを同定した(例えば、それぞれIYTWIEDHF(配列番号:3)及びRYPFEPPQI(配列番号:13))。限界希釈によりCTLクローンを得た後、特定のペプチド負荷で刺激されたHLA−A*24:02を発現する抗原提示C1R細胞(C1R−A24細胞)に曝露される際にこれらFOXM1特異的CTL及びUBE2T特異的CTLがIFN−γを産生する一方で、C1R−A24細胞に対するペプチド刺激がない場合にIFN−γ産生が検出されないまたは低いIFN−γ産生が検出されることが確認されたが(図1A)、このことは、作製したFOXM1特異的CTL及びUBE2T特異的CTLがHLA−A*24:02拘束性ペプチドを特異的に認識していることを示している。
続いて、次世代シークエンシングを用いたTCRレパートリー解析により、これらFOXM1特異的CTL及びUBE2T特異的CTLのTCRA鎖及びTCRB鎖をシークエンスした(図2A)。これらCTLクローンの両方は、単クローン性のTCRレパートリーを示した(図2A)。DNAシークエンシングにより、FOXM1−CTL(CACPIMWGSNYKLTF(配列番号:49)及びCASSLRVHEQYF(配列番号:50))ならびにUBE2T−CTL(CAMREGRNFNKFYF(配列番号:69)及びCASSLSGGPNEQFF(配列番号:70))における、支配的なTCRA CDR3クロノタイプ及びTCRB CDR3クロノタイプを同定した。cDNA情報を使用してTCR発現ベクターを構築してからレンチウイルスベクターにクローニングし、FOXM1を認識するTCR改変T細胞及びUBE2Tを認識するTCR改変T細胞を作製した。TCRvβ特異的抗体を用いて形質導入効率を測定した(代表的な染色データについては図2Bに示した)。アッセイ用に、TCR形質導入細胞のみを形質導入した。
次に、TCR改変T細胞が、図1B及び図1Cに示すとおりオリジナルのCTLクローンと同様にがん細胞を殺傷するかどうかを評価した。FOXM1に対するTCR改変T細胞とUBE2Tに対するTCR改変T細胞は、最初の5時間の間にそれぞれ47.5%と39.3%の細胞生存率を低下させて、HLA−A24陽性SW480細胞に対する有意な殺傷効果を発揮したが、HLA−A24陰性HCC1143細胞に対してはそうではなかった(図3A〜図3D)。TCR改変T細胞は、ELISPOTアッセイでそれぞれのペプチドを負荷したC1R−A24細胞と共培養した際に、ペプチド特異的IFN−γ産生を示した(図3E及び図3F)。
以下の参照文献について、それらの一部は上記において数字で引用しているが、それらの全体は参照により組み込まれる。
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Claims (36)
- (a)候補抗原配列を含む刺激ペプチドで標的リンパ球を刺激することと、
(b)前記候補ペプチドに結合するT細胞受容体(TCR)で免疫活性化リンパ球を捕捉することであって、前記捕捉することは、前記免疫活性化リンパ球を、前記候補抗原配列を含む捕捉用ペプチドに結合した主要組織適合遺伝子複合体(MHC)を提示する捕捉用試薬と接触させることを含む、前記捕捉することと、
(c)前記捕捉した免疫活性化リンパ球の前記TCRの全てまたは一部をシークエンスすることと、
を含む、方法。 - 前記標的リンパ球は健康ドナーから得られる、請求項1に記載の方法。
- 前記標的リンパ球はCD8+細胞傷害性リンパ球である、請求項1に記載の方法。
- 前記刺激することはインビトロで実施される、請求項1に記載の方法。
- 前記捕捉用試薬はMHC多量体である、請求項1に記載の方法。
- 前記MHC多量体はMHCデキストラマーである、請求項5に記載の方法。
- 前記シークエンスすることは次世代シークエンシング技術を含む、請求項1に記載の方法。
- シークエンスした前記TCRの前記一部はTCR−α鎖及び/またはTCR−β鎖を含む、請求項1に記載の方法。
- シークエンスした前記TCRの前記一部は、前記TCR−α鎖及び/またはTCR−β鎖の1つまたは複数の相補性決定領域(CDR)を含む、請求項8に記載の方法。
- シークエンスした前記TCRの前記一部は、前記TCR−α鎖及び/またはTCR−β鎖のCDR3を含む、請求項9に記載の方法。
- 前記標的リンパ球は標的リンパ球の集団であり、前記刺激ペプチドは、異なる候補抗原配列を含む刺激ペプチドの集団のうちの1つであり、
前記捕捉することは、免疫活性化リンパ球の前記集団を、前記候補抗原配列を含む捕捉用ペプチドの集団に結合した主要組織適合遺伝子複合体(MHC)を提示する捕捉用試薬と接触させることを含む、
請求項1に記載の方法。 - 請求項1から請求項11のうちの1項に記載の方法により同定されるTCR認識がん特異的抗原。
- 請求項12に記載のTCR認識がん特異的抗原に結合する治療抗体。
- 前記治療抗体は抗体フラグメントである、請求項13に記載の治療抗体。
- (d)前記捕捉した免疫活性化リンパ球の前記TCRの全てまたは一部を提示する改変リンパ球を作製することであって、前記改変リンパ球は、前記候補抗原配列を含む前記ペプチドに結合したMHCを提示する抗原提示細胞を認識する、前記作製すること、
を更に含む、請求項1から請求項11のうちの1項に記載の方法。 - 前記改変リンパ球はCD8+細胞傷害性リンパ球である、請求項15に記載の方法。
- 前記捕捉した免疫活性化リンパ球の前記TCRの全てまたは一部を提示する改変リンパ球を作製することは、
(i)前記捕捉した免疫活性化リンパ球の前記TCRの前記一部をコードする核酸配列をベクターにクローニングすることと、
(ii)前記ベクターを宿主リンパ球に導入することと、
(iii)前記捕捉した免疫活性化リンパ球の前記TCRの前記一部が前記改変リンパ球上に発現及び提示されるような条件下で、前記宿主リンパ球を培養することと、
を更に含む、請求項15に記載の方法。 - 前記TCRの前記一部は前記TCR−α鎖及び/またはTCR−β鎖を含む、請求項17に記載の方法。
- 前記TCRの前記一部は、前記TCR−α鎖及び/またはTCR−β鎖の1つまたは複数の相補性決定領域(CDR)を含む、請求項18に記載の方法。
- シークエンスした前記TCRの前記一部は、前記TCR−α鎖及び/またはTCR−β鎖のCDR3を含む、請求項19に記載の方法。
- シークエンスした前記TCRの前記一部は、配列番号:45〜132からなる群から選択されるアミノ酸配列を含む、請求項20に記載の方法。
- 前記改変リンパ球は、配列番号45及び46、47及び48、49及び50、51及び52、53及び54、55及び56、57及び58、59及び60、61及び62、63及び64、65及び66、67及び68、69及び70、71及び72、73及び74、75及び76、77及び78、79及び80、81及び82、83及び84、85及び86、87及び88、89及び90、91及び92、93及び94、95及び96、97及び98、99及び100、101及び102、103及び104、105及び106、107及び108、109及び110、111及び112、113及び114、115及び116、117及び118、119及び120、121及び122、123及び124、125及び126、127及び128、129及び130、及び、131及び132、からなる群から選択されるアミノ酸配列ペアを含むα鎖及びβ鎖を含むTCRを提示する、請求項21に記載の方法。
- 前記ベクターは、健康ドナー宿主に由来する宿主リンパ球に導入される、請求項17に記載の方法。
- 前記ベクターは、前記改変リンパ球で治療されるがん患者に由来する宿主リンパ球に導入される、請求項17に記載の方法。
- 請求項15から請求項24のうちの1項に記載の方法により作製される改変リンパ球。
- 前記改変リンパ球はCD8+細胞傷害性リンパ球である、請求項25に記載の改変リンパ球。
- 請求項25に記載の改変CD8+リンパ球を対象に投与することを含む、対象内におけるがんを治療するための方法。
- (d)前記捕捉した免疫活性化リンパ球の前記TCRの前記配列の全てまたは一部を含む治療抗体を作製すること、
を更に含む、請求項1から請求項11のうちの1項に記載の方法。 - 前記TCRの前記一部は前記TCR−α鎖及び/またはTCR−β鎖を含む、請求項28に記載の方法。
- 前記TCRの前記一部は、前記TCR−α鎖及び/またはTCR−β鎖の1つまたは複数の相補性決定領域(CDR)を含む、請求項29に記載の方法。
- シークエンスした前記TCRの前記一部は、前記TCR−α鎖及び/またはTCR−β鎖のCDR3を含む、請求項30に記載の方法。
- シークエンスした前記TCRの前記一部は、配列番号:45〜132からなる群から選択されるアミノ酸配列を含む、請求項31に記載の方法。
- 前記治療抗体は、配列番号45及び46、47及び48、49及び50、51及び52、53及び54、55及び56、57及び58、59及び60、61及び62、63及び64、65及び66、67及び68、69及び70、71及び72、73及び74、75及び76、77及び78、79及び80、81及び82、83及び84、85及び86、87及び88、89及び90、91及び92、93及び94、95及び96、97及び98、99及び100、101及び102、103及び104、105及び106、107及び108、109及び110、111及び112、113及び114、115及び116、117及び118、119及び120、121及び122、123及び124、125及び126、127及び128、129及び130、及び、131及び132、からなる群から選択されるアミノ酸配列ペアを含むCDR3を含む、請求項32に記載の方法。
- 前記抗体は抗体フラグメントである、請求項28に記載の方法。
- 請求項28から請求項34のうちの1項に記載の方法により作製される抗体。
- 請求項35に記載の抗体を対象に投与することを含む、対象内におけるがんを治療するための方法。
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