JP2018042564A - 親和性増強型t細胞受容体およびその作製方法 - Google Patents
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Abstract
Description
本出願は、2012年5月3日に出願された米国特許仮出願第61/642,358号における米国特許法§119(e)の下で利益を請求し、本出願は、その全体が本開示に参照によって組み込まれる。
本出願に関する配列表は、紙の写しに代えてテキスト形式で提供され、これにより参照によって本明細書に組み込まれる。配列表を含むテキストファイルの名前は、360056_412WO_SEQUENCE_LISTING.TXT.である。テキストファイルは129KBであり、2013年5月2日に作製され、EFS−Webにより電子的に提出されている。
本発明は、米国国立衛生研究所によって授与された助成金番号P01 CA 18029による国庫補助によってなされた。政府は、この発明における特定の権利を有する。
本開示は、親和性増強型T細胞受容体(TCR)(enhanced affinity T cell)、より詳細には抗原特異的TCRαを発現する造血前駆細胞のアゴニスト選択を使用し、親和性増強型TCRを生成すること、およびそれらの使用に関する。
TCR遺伝子治療は、従来のT細胞養子免疫療法に関連する障害、例えば、腫瘍抗原特異的T細胞クローンの単離、特徴づけおよび増殖に必要な莫大な時間および労力の多くを克服することができる新たな処置手法である(Schmitt,Ragnarsson,&Greenberg,2009,Hum.Gene Ther.20:1240−1248)。遺伝子治療のさらなる利点には、インビボでの長時間持続可能な定義されたT細胞集団を利用する特性がある(Berger et al.,2008,J.Clin.Invest.118:294−305;Hinrichs et al.,2009,Proc.Natl.Acad.Sci.USA106:17469−17474)。このようなT細胞を、腫瘍抗原に高い親和性を有する十分に特徴づけられたTCRをコードする遺伝子を用いて形質導入し、それにより抗腫瘍効果を取り成す可能性を増大させることができる。実際に、自己/腫瘍抗原を標的とする高親和性キメラ受容体を発現する遺伝的に改変されたT細胞を用いた進行期B細胞白血病を標的とする治療の最近の報告では、白血病の処置用に操作された高親和性T細胞を使用する可能性が強調されている(Kalos et al.,2011,Sci.Transl.Med.3:95ra73)。しかし、T細胞免疫療法で標的となるほとんどの腫瘍抗原は、過剰発現した自己タンパク質であるため、これらの抗原に特異的な高親和性T細胞は一般に、胸腺で負の選択が行われる。それゆえ、一般のT細胞系免疫療法の大きな制限の1つには、突然変異していない腫瘍抗原に十分に高い親和性を有する内因性TCRを発現するT細胞の可用性の制限がある。
本発明はまた、以下の項目を提供する。
(項目1)
親和性増強型T細胞受容体(TCR)を生成する方法であって、
a.造血前駆細胞と間質細胞およびペプチド抗原を諸条件下および造血前駆細胞のDN
TCRαβ+胸腺細胞への分化を誘導するのに十分な時間接触させること、
b.該DN TCRαβ+胸腺細胞由来の種々のTCRβ鎖をコードする核酸配列を単離し、細胞表面上にTCRを発現することができ、ステップ(a)からのTCRα鎖をコードする核酸配列を含む細胞に該TCRβ鎖をコードする核酸配列を導入すること、および
c.親和性増強型TCRを同定すること
を含む方法であって、該造血前駆細胞が該ペプチド抗原に特異的な親TCR由来のTCRα鎖をコードする非内因性核酸配列を含み、
該間質細胞がデルタ様1またはデルタ様4をコードする非内因性核酸配列およびMHC分子をコードする核酸配列を含む、方法。
(項目2)
前記TCRβ鎖が親TCRから単離される、項目1に記載の方法。
(項目3)
前記造血前駆細胞が胸腺前駆細胞または胚性幹細胞を含む、項目1に記載の方法。
(項目4)
前記造血前駆細胞が骨髄または臍帯血由来の造血幹細胞を含む、項目1に記載の方法。
(項目5)
ウイルスベクターを使用し、前記ペプチド抗原に特異的な前記TCRα鎖をコードする前記非内因性核酸配列を前記造血前駆細胞に導入する、項目1に記載の方法。
(項目6)
前記ウイルスベクターがレトロウイルスベクターである、項目5に記載の方法。
(項目7)
前記ウイルスベクターがレンチウイルスベクターである、項目5に記載の方法。
(項目8)
前記ウイルスベクターが形質導入のための遺伝子マーカーをさらに含む、項目5に記載の方法。
(項目9)
該形質導入のための前記遺伝子マーカーが緑色蛍光タンパク質またはヒトCD2の細胞外ドメインを含む、項目8に記載の方法。
(項目10)
前記間質細胞がデルタ様1を発現する、項目1に記載の方法。
(項目11)
前記間質細胞がOP9由来である、項目1に記載の方法。
(項目12)
前記方法がステップ(b)に起因して前記細胞表面上にTCRを発現することができる細胞を、MHCペプチド四量体染色を用いて選択することをさらに含む、項目1に記載の方法。
(項目13)
ステップ(b)に起因して前記細胞表面上にTCRを発現することができる前記細胞が複数回のMHCペプチド四量体染色を用いて選択される、項目12に記載の方法。
(項目14)
ウイルスベクターを使用し、ステップ(b)由来の前記種々のTCRβ鎖をコードする核酸配列を前記細胞表面上にTCRを発現することができる前記細胞に導入する、項目1に記載の方法。
(項目15)
前記ウイルスベクターがレトロウイルスベクターである、項目14に記載の方法。
(項目16)
前記ウイルスベクターがレンチウイルスベクターである、項目14に記載の方法。
(項目17)
前記ウイルスベクターが形質導入のための遺伝子マーカーをさらに含む、項目14に記載の方法。
(項目18)
形質導入のための前記遺伝子マーカーが緑色蛍光タンパク質を含む、項目17に記載の方法。
(項目19)
前記細胞表面上にTCRを発現することができる前記細胞がTCRα−/β−58T細胞ハイブリドーマ由来である、項目1に記載の方法。
(項目20)
前記親和性増強型TCRがヒトTCRである、項目1に記載の方法。
(項目21)
前記MHC分子がクラスI MHC分子またはクラスII MHC分子を含む、項目1に記載の方法。
(項目22)
前記MHC分子がHLA−A2およびヒトベータ2マイクログロブリン(β2M)を含む、項目21に記載の方法。
(項目23)
前記ペプチド抗原がウイルス抗原、細菌抗原、癌抗原、および自己免疫抗原からなる群から選択される、項目1に記載の方法。
(項目24)
前記ペプチド抗原がWT1ペプチド抗原またはメソテリンペプチド抗原である、項目23に記載の方法。
(項目25)
前記WT1ペプチド抗原がアミノ酸配列RMFPNAPYL(配列番号2)を含む、請求項24に記載の方法。
(項目26)
前記メソテリンペプチド抗原がアミノ酸配列GQKMNAQAI(配列番号31)を含む、項目24に記載の方法。
(項目27)
前記ペプチド抗原を培養物中の前記造血前駆細胞および間質細胞に添加する、項目1に記載の方法。
(項目28)
前記間質細胞が前記ペプチド抗原をコードする核酸配列を含む、項目1に記載の方法。
(項目29)
前記DN TCRαβ+胸腺細胞由来の前記種々のTCRβ鎖をコードする核酸配列の単離が、前記選択されたTCRβ鎖を前記細胞表面上にTCRを発現することのできる細胞に導入する前に前記親TCRβ鎖と同じVβ遺伝子を含むTCRβ鎖を選択することをさらに含む、項目1に記載の方法。
(項目30)
項目1に記載の方法により生成される親和性増強型TCR。
(項目31)
前記項目1に記載の方法により生成される親和性増強型TCRおよび細胞毒性構成要素または検出可能な構成要素を含む融合タンパク質。
(項目32)
前記項目23または24に記載の方法により生成される親和性増強型TCR。
(項目33)
項目1に記載の方法により生成される親和性増強型TCR、および薬学的に許容され得る担体、希釈剤、または賦形剤を含む、薬学的組成物。
(項目34)
項目1に記載の方法により作製される親和性増強型TCRを投与することを含む、被験体の疾患を処置する方法。
(項目35)
前記疾患がウイルス感染、細菌感染、癌、および自己免疫疾患からなる群から選択される、項目34に記載の方法。
(項目36)
前記被験体がヒトである、項目34に記載の方法。
(項目37)
前記増強型TCRを可溶性TCRとして前記被験体に投与する、項目34に記載の方法。
(項目38)
前記被験体に前記親和性増強型TCRを含むT細胞を投与する、項目34に記載の方法。
(項目39)
前記T細胞が制御性T細胞を含む、項目38に記載の方法。
(項目40)
前記T細胞がCD8+T細胞またはCD4+T細胞を含む、項目38に記載の方法。
(項目41)
前記T細胞が自己T細胞である、項目38に記載の方法。
バックグランドとして、胸腺でT細胞が成長する間、前駆胸腺細胞は、多くのTCR介在性チェックポイント下に置かれる。これらの1つ目はβ選択と呼ばれ、マウスT細胞成長のダブルネガティブ3(DN3)の段階で生じる。Tcrb遺伝子座で再構成を成功させるDN3細胞は、インバリアントプレTαタンパク質と対合する細胞表面でTCRβタンパク質を発現することができる。この受容体はプレTCRと呼ばれ、リガンドに依存しない形式でシグナル伝達し、増殖、αβ系統細胞のCD4/CD8ダブルポジティブ(DP)段階への分化、およびTcra遺伝子座での再構成を促進する(Boehmer et al.,1999,Curr.Opin.Immunol.11:135−142)。TCRα遺伝子座はβ選択の前では不活性であり、TCR遺伝子再構成が行われないが、TCRγおよびδ遺伝子座はともに、成長中のDN3段階で再構成を行い、これら両方の遺伝子座の再構成の成功により成熟γδTCRの発現が得られ、これにより成長中のDP段階を通して分化しないγδT細胞系統−γδT細胞への分化を促進するシグナルがもたらされ、一般にDNまたはCD8αα+のままとなり得る。成長中のT細胞が、成熟γδTCRと関連するより強いシグナルによりプレTCRシグナルとγδTCRシグナルを識別するとき、αβ/γδ細胞の運命決定が成長中のこの段階のTCRシグナルの強度により決定される(Pennington,Silva−Santos,&Hayday,2005,Curr.Opin.Immunol.17:108−115)。興味深いことに、多くのαβTCR遺伝子導入マウスは、胸腺に大きな成熟CD24−TCRαβポジティブCD4/CD8ダブルネガティブ(DN)細胞集団を有し、β選択チェックポイントで成熟αβ遺伝子導入TCRからのより強いシグナルの結果として成長する「γδ志願(wanna−be)」細胞を表すことが示されている(Egawa et al.,2000,PLOS One3:1512)。
別の態様において、本明細書に開示の方法により生成された親和性増強型TCRを提供する。親和性増強型TCRは、細胞結合状態(例えば、成熟T細胞の表面に発現)、または可溶形態であってよい。特定の実施形態において、親和性増強型TCRをコドン最適化し、T細胞の発現を増強することができる(Scholten et al.,2006,Clin.Immunol.119:135−145)。
用途
ヒトクラスI MHC分子HLA−A2(Genbank受託番号U18930.1(配列番号50)およびAAA87076.1(配列番号51)、それぞれ転写産物およびタンパク質配列)およびヒトクラスI MHCβ2マイクログロブリン(β2M)分子(Genbank受託番号NM_004048.2(配列番号52)およびNP_004039.1(配列番号53)、それぞれ転写産物およびタンパク質配列)を発現する実施例1に記載のOP9−DL1細胞株の変異体を生成した。C4 TCRクローンのTCRα鎖を形質導入マーカーとして緑色蛍光タンパク質(GFP)もコードするレトロウイルスベクターを用いたレトロウイルス形質導入により臍帯血由来造血前駆細胞に安定して形質導入した。GFPを発現する前駆細胞をフローサイトメトリーにより選別し、WT1ペプチドRMFPNAPYL(配列番号2)の存在下または非存在下においてOP9−DL1−A2/β2M間質細胞上で培養した。ヒト造血細胞前駆細胞は容易に増殖し、OP9−DL1培養において、表現型CD34+CD1a+CD4+を特徴とするヒトT細胞成長段階に(La Motte−Mohs et al.,2005,Blood 105:1431−1439)、β、γ、およびδ遺伝子座でTCR遺伝子再構成を行う点にて分化する(Spits,2002,Nat.Rev.Immunol.2:760−772)。マウス対応物のように、TCRβ遺伝子座でインフレーム再構成を生じるTCRα発現ヒトT細胞前駆細胞は、2つの細胞運命の1つである、遺伝子導入TCRαと十分に対合しないTCRβまたは遺伝子導入TCRαと対合するが、そのαβTCRを介して強いシグナルを受け取らないTCRβ鎖を発現するものがプレTCRを介したシグナル伝達に応答してDP段階に分化する運命、もう一方は、遺伝子導入TCRαと対合し、この成熟αβTCRを介して十分に強いシグナルを受け取ることができるTCRβを生成するものにシグナル伝達され、DN TCRαβ+γδ様系統に分化する運命に適合すると仮定する。DP細胞のみがポジティブ選択シグナルなしで約3〜4日間生存するため、かつ有効なポジティブ選択がOP9−DL1培養において生じないため、αβTCRを介したアゴニストシグナルを受け取らない膨大な細胞が培養物から排除され、初期αβTCRシグナル伝達により成長するγδ様細胞を蓄積させることを可能にする。
候補TCRβ鎖の単離
高親和性WT1特異的TCRのスクリーニング
増強型TCRのオフターゲット活性の評価
インビボでの正常組織の親和性増強型TCR活性
親和性増強型と標的認識および機能の改善との相関
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