JP2021529539A - 特定の自己免疫疾患を治療するためのcd6標的キメラ抗原受容体 - Google Patents
特定の自己免疫疾患を治療するためのcd6標的キメラ抗原受容体 Download PDFInfo
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Abstract
Description
[0100] NP_001552.2
[0106] NP_003318.1
[0102]一態様では、本明細書で提供される組換えタンパク質は、本明細書で提供される単離された核酸により発現されるタンパク質を含み、その実施形態を含む。従って、ある態様では、CD6を標的とする一本鎖可変断片及び膜貫通ドメインを含む、キメラ抗原受容体(CAR)のような組換えタンパク質が提供される。ある態様では、本明細書では、膜貫通ドメインがないCD6を標的とするscFvが提供される。ある態様では、本明細書では、CARを発現するように操作された細胞(例えば、免疫エフェクター細胞の集団等の細胞の集団)であって、CARが抗原結合ドメイン及び膜貫通ドメインを含む、細胞が提供される。ある場合、抗原結合ドメインは、CD6を標的とする抗体断片又は変異体を含む。ある場合、抗原結合ドメインはCD6を標的とする一本鎖可変断片(scFv)である。ある場合、CARは、細胞内シグナル伝達ドメインをさらに含む。ある場合、CARを発現する細胞はTリンパ球(CAR T細胞)又はNK細胞である。ある場合、CARを発現する細胞はTリンパ球(CAR T細胞)又はNK細胞である。ある場合、細胞はCD4+ T細胞又はCD8+ T細胞である。ある場合、T細胞は調節性T細胞(Treg)である。
DSVKGRFTISRDNVKNTLYLQMSSLRSEDT
AMYYCARRDYDLDYFDSWGQGTLVTVSS(配列番号35)。ある場合、抗原結合ドメインは、以下のVL配列、又はその変異体を含む:DIQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKPGKAPKTLIYYATSLADGVPSRF
SGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGSGTKLEIKRA(配列番号34)。ある場合、抗原結合ドメインは、以下のVH配列又はその変異体を含む:EVQLVESGGGL
VKPGGSLKLSCAASGFKFSRYAMSWVRQTPEKRLEWVATISSGGSYIYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYFDSWGQGTTLTVSS(配列番号68)。ある場合、抗原結合ドメインは、以下のVL配列又はその変異体を含む:
DIKMTQSPSSMYASLGERVTITCKASRDIRSYLTWYQQKPWKSPKTLIYYATSLADGVPSRF
SGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGSGTKLEIKRA(配列番号69)。ある場合、VLは、以下の配列又はその変異体を含む:IQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKPGKAPKTLIYYATSLADGVPSRFSGSGSGQ(配列番号75)。ある場合、VLは、DIQMTQSPSSLSASVGDRVTITCKASRDIRSY(配列番号76)の配列又はその変異体を含む。ある場合、VLは、以下の配列又はその変異体を含む:LTWYQQKPGKAPKTLIYYATSLADGVPSRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFT(配列番号77)。ある場合、VLは、以下の配列又はその変異体を含む:FGSGTKLEIKRA(配列番号78)。ある場合、VHは、以下の配列又はその変異体:EVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMS(配列番号79)を含む。ある場合、VHは、以下の配列又はその変異体:WVRQAPGKRLEWVATISSGG(配列番号80)を含む。ある場合、VHは、以下の配列又はその変異体:SYIYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYFDS(配列番号81)を含む。ある場合、VHは、以下の配列又はその変異体を含む:WGQGTLVTVSS(配列番号82)。ある場合、本明細書で提供されるVH又はVL配列の変異体は、当該配列と比較して5、4、3、2、1、又は0の欠失がある。ある場合、本明細書で提供されるVH又はVL配列の変異体は、当該配列と比較して5、4、3、2、1、又は0の挿入がある。ある場合、本明細書中で提供されるVH又はVL配列の変異体は、配列と比較して5、4、3、2、1、又は0の置換がある。実施形態では、本明細書で提供されるVH又はVL配列の変異体は、当該配列と比較して10、9、8、7、6、5、4、3、2、又は1の置換がある。ある場合、置換の1又はそれ以上又は全てが保存的置換である。
[0104]ある場合、配置は、ダイアボディ又は多量体等の多量体であってよい。ある場合、多量体は、軽鎖及び重鎖の可変領域をいわゆるダイアボディに交差対合することで形成される可能性がとても高い。ある場合、構築物のヒンジ部分は、完全欠失されるか、第1システインは保持されるか、セリン置換ではなくプロリン置換であるか、第1システインまで切断されるといった、複数の選択肢がありうる。ある場合、Fc部分を削除しうる。ある場合、安定なタンパク質や二量体化したタンパク質がこの目的に機能しうる。ある場合、CARは、Fcドメインの1つ、例えば、ヒト免疫グロブリン由来のCH2又はCH3ドメインのいずれかを含む。ある場合、CARは、二量体化の改良のために修飾されたヒト免疫グロブリンのヒンジ、CH2及びCH3領域を用いる。ある場合、免疫グロブリンのヒンジ部分だけが用いられる。ある場合、発現されると、抗原結合ドメインは、CARの細胞膜への発現を指向するシグナルペプチドを含む。ある場合、シグナルペプチドが細胞の表面上にあると、CARに存在しない。ある場合、シグナルペプチドは、抗原結合ドメインのCDRを有する抗体からのシグナルペプチドと同一であるか、又は異なる。
[0106]ある場合、scFvは、特定の配向(例えば、N末端からC末端へのVH−VL又はVL−VH)を有するように設計されうる。ある場合、scFvのVHとVLはN末端からC末端へVH−VLと配向する。ある場合、scFvのVHとVLは、N末端からC末端へVL−VHと配向する。ある場合、発現されたタンパク質のVH部分とVL部分は、その配向に依存して立体配座がわずかに異なる。ある場合、VHとVLの関係の配向によりリガンド(例えば、CD6)に対する親和性が異なる場合がある。ある場合、ある配向と他の配向との間の差次的な親和性は、1桁又はそれ以上である。
[0116]ある場合、本明細書中に提供される膜貫通ドメインは、生物膜(例えば、スパニング)の部分を形成するポリペプチドをいう。ある場合、本明細書中に提供される膜貫通ドメインは、生体膜(例えば、細胞膜)を膜の一方の側から膜の他方の側へ拡張しうる。ある場合、膜貫通ドメインは膜の部分にのみ及ばないが、抗原結合ドメインの膜への固定には十分である。ある場合、膜貫通ドメインは細胞膜の細胞内側から細胞外側に及ぶ。ある場合、膜貫通ドメインは、生物学的膜(例えば、T細胞の細胞膜)中の、その実施形態を含む本明細書で提供されるタンパク質を固定する非極性の疎水性残基を含んでよい。その実施形態を含む本明細書で提供されるタンパク質を固定しうるいかなる膜貫通ドメインが考えられる。膜貫通ドメインの非限定的な例としては、CD28、CD8、CD4、又はCD3−ゼータ(CD3ζ)の膜貫通ドメインがあげられる。
[0129]「high(高い)」及び「low(低い)」発現の決定は、当業界で周知である。上記マーカーの高発現及び低発現、並びに高発現及び低発現の決定及び定量の説明は、例えば、以下の:
[0144]その実施形態を含む本明細書で提供される組成物は、自己免疫疾患の有効な治療として企図される。すなわち、ある態様では、自己免疫疾患(例えば、I型糖尿病、移植片対宿主病、ループス)を治療する方法が提供され、その方法は、その実施形態を含む本明細書において提供される有効量のTリンパ球(例えば、CART細胞)を、それを必要とする被験体に投与することを含む。
〔実施例〕
[0147]以下の実施例は、本開示の特定の実施形態をさらに例示することを意図する。当該実施例は、当業者に提供するように示され、その範囲を限定することを意図するものではない。
[0148]イトリズマブから誘導されたscFvを含む様々なCARを図1〜図4に示す。各々は、VL又はVH配向のscFvに加えて、特定の変異を有するIgG4の部分に由来するスペーサー、CD4膜貫通ドメイン、CTLA4又は4−1BBシグナル伝達ドメイン、及びCD3ゼータシグナル伝達ドメインを含む。酵母表面ディスプレイ技術により、すでに、VH−VL scFvのヒトCD6に対する親和性は、イトリズマブのヒトCD6に対する親和性に類似するが、VL−VH scFvはヒトCD6に対する親和性は低いことが示唆されるため(Garner et al.(2018)Immunology155:273)、VH−VL又はVL−VH配向のscFvを用いてCARを調製した。図5は、CD6low/−であるTregs及びTregsの単離に用いられる方法の概略図である。Tregは、いかなる適当な方法を用いて単離しうる(Fuchs et al.(2018)Front Immunol.8:1844;Duggleby et al.)2018)Front Immunol. 9:252)。Tregの比較、CD6 CAR(CTLA4)及びCD6 CAR(4−1BB)を発現するTreg、は、CTLA4シグナル伝達ドメインを有するCD6 CARが、Teff(CD4+)増殖を低下させるのに優れていることを示す(図6)。さらに、CTLA4シグナル伝達ドメインを有するCD6 CARは、標的Teff増殖を低下させるのに優れる(図7)。CD6を発現するTregは抗炎症性サイトカインを誘導した(図8)。図10に示すように、CTLA4シグナル伝達ドメインを有するCD6 CARを発現するTregは、Teffの存在下で培養することができ、比較的低いレベルの枯渇マーカーを発現する。
[0196]CD6標的CARはレンチウイルスベクターを用いてTregsで発現させることができる。適当なレンチウイルスベクターは、国際公開第2016/044811号に記載される。CARを発現するヌクレオチド配列は、T2Aをコードする配列(LEGGGEGRGSLLTCGDVEENPGPR;配列番号71)及び切断されたCD19受容体であって、以下の配列番号73:
非公式部分配列リスト
Claims (54)
- CD6を標的とする一本鎖可変断片(scFv)、ヒンジ領域、膜貫通ドメイン、CTLA4シグナル伝達ドメイン及びCD3ゼータシグナル伝達ドメインを含む、キメラ抗原受容体(CAR)をコードする単離された核酸。
- 前記膜貫通ドメインは、CD4膜貫通ドメイン若しくはその変異体、CD8膜貫通ドメイン若しくはその変異体、CD28膜貫通ドメイン若しくはその変異体、又はCD3ζ膜貫通ドメイン若しくはその変異体を含む、請求項1に記載の単離された核酸。
- 前記CARは、配列番号83〜88のいずれかと少なくとも95%同一のアミノ酸配列を含むか、又はからなる、請求項1に記載の単離された核酸。
- 前記CARは、5個以下の単一アミノ酸置換を有する配列番号83〜86のいずれかのアミノ酸配列を含むか、又はからなる、請求項1に記載の単離された核酸。
- 前記scFvは、配列番号34で表されるアミノ酸配列を含む軽鎖可変領域(VL)を含む、請求項1記載の単離された核酸。
- 前記scFvは、配列番号35で表されるアミノ酸配列を含む重鎖可変領域(VH)を含む、請求項1記載の単離された核酸。
- 前記scFvは、配列番号31で表されるアミノ酸配列を含む軽鎖可変領域(VL)相補性決定領域(CDR)1(VL−CDR1)、配列番号32で表されるアミノ酸配列を含むVL−CDR2、及び配列番号33で表されるアミノ酸配列を含むVL−CDR3を含む、請求項1に記載の単離された核酸。
- 前記scFvは、配列番号28で表されるアミノ酸配列を含む重鎖可変領域(VH)相補性決定領域(CDR)1(VH−CDR1)、配列番号29で表されるアミノ酸配列を含むVH−CDR2、及び配列番号30で表されるアミノ酸配列を含むVH−CDR3を含む、請求項1に記載の単離された核酸。
- 前記scFvは、軽鎖可変領域アミノ末端から重鎖可変領域に配向された軽鎖可変領域及び重鎖可変領域を含む、請求項1に記載の単離された核酸。
- 前記scFvは、重鎖可変領域のアミノ末端が軽鎖可変領域に配向された軽鎖可変領域及び重鎖可変領域を含む、請求項1に記載の単離された核酸。
- 前記scFvは、リンカーにより分離された軽鎖可変領域及び重鎖可変領域を含む、請求項1記載の単離された核酸。
- 前記リンカーは、配列番号26で表される配列を含む、請求項11に記載の単離された核酸。
- 前記リンカーは、配列番号27で表される配列配列を含む、請求項11記載の単離された核酸。
- 前記scFvは、図1に示される、請求項1に記載の単離された核酸。
- 前記scFvは、図2に示される、請求項1に記載の単離された核酸。
- 前記ヒンジ領域は、ヒトIgG Fcである、請求項14記載の単離された核酸。
- 前記ヒトIgG Fcは、ヒトIgG4 Fcである、請求項16に記載の単離された核酸。
- 前記ヒトIgG Fcは、ヒトIgG1 Fcである、請求項16に記載の単離された核酸。
- 前記scFvは、図10に示される、請求項1に記載の単離された核酸。
- 前記ヒンジは、図1に示されるIgGヒンジである、請求項1に記載の単離された核酸。
- 前記scFvは、配列番号20、21、22、23、24、及び25で表されるCDR配列を含む、請求項1記載の単離された核酸。
- 請求項1〜21のいずれか一項に記載の核酸を含む、ベクター。
- 前記ベクターは、ウイルスベクターである、請求項22記載のベクター。
- 請求項22に記載のベクターを含む、Tリンパ球。
- 前記Tリンパ球は、調節性T細胞である、請求項24に記載のTリンパ球。
- CD6を標的とする一本鎖可変断片(scFv)、ヒンジ領域、膜貫通ドメイン、CTLA4シグナル伝達ドメイン及びCD3ゼータシグナル伝達ドメインを含む、キメラ抗原受容体(CAR)ポリペプチド。
- 前記膜貫通ドメインは、CD4膜貫通ドメイン若しくはその変異体、CD8膜貫通ドメイン若しくはその変異体、CD28膜貫通ドメイン若しくはその変異体、又はCD3ζ膜貫通ドメイン若しくはその変異体を含む、請求項26に記載のCARポリペプチド。
- 前記svFvは、図1又は図2に示される、請求項26に記載のCARポリペプチド。
- 前記scFvは、図10に示される、請求項28に記載のCARポリペプチド。
- 前記scFvは、配列番号34で表される軽鎖可変領域を含む、請求項26記載のCARポリペプチド。
- 前記scFvは、配列番号35で表される重鎖可変領域を含む、請求項26記載のCARポリペプチド。
- 前記scFvは、配列番号31で表されるアミノ酸配列を含む軽鎖可変領域(VL)相補性決定領域(CDR)1(VL−CDR1)、配列番号32で表されるアミノ酸配列を含むVL−CDR2、及び配列番号33で表されるアミノ酸配列を含むVL−CDR3を含む、請求項26に記載のCARポリペプチド。
- 前記scFvは、配列番号28で表されるアミノ酸配列を含む重鎖可変領域(VH)相補性決定領域(CDR)1(VH−CDR1)、配列番号29で表されるアミノ酸配列を含むVH−CDR2、及び配列番号30で表されるアミノ酸配列を含むVH−CDR3を含む、請求項26に記載のCARポリペプチド。
- 前記scFvは、N末端で前記軽鎖可変領域に配向され、その後に重鎖可変領域が続く、請求項26に記載のCARポリペプチド。
- 前記scFvは、N末端の重鎖可変領域に配向され、その後に軽鎖可変領域が続く、請求項26のCARポリペプチド。
- 前記scFvは、リンカーにより分離された軽鎖可変領域及び重鎖可変領域を含む、請求項26に記載のCARポリペプチド。
- 前記リンカーは、配列番号36で表される配列配列を含む、請求項36に記載のCARポリペプチド。
- 前記リンカーは、配列番号37で表される配列配列を含む、請求項36に記載のCARポリペプチド。
- 前記膜貫通ドメインは、ヒンジ領域を介して前記scFvの軽鎖可変領域に共有結合する、請求項26記載のCARポリペプチド。
- 前記膜貫通ドメインは、ヒンジ領域を介して前記scFvの重鎖可変領域に共有結合する、請求項26記載のCARポリペプチド。
- 前記ヒンジ領域は、ヒトIgG Fcである、請求項40に記載のCARポリペプチド。
- 前記ヒトIgG Fcは、ヒトIgG4 Fcである、請求項40に記載のCARポリペプチド。
- 前記ヒトIgG Fcは、ヒトIgG1 Fcである、請求項40に記載のCARポリペプチド。
- さらに、細胞内T細胞シグナル伝達ドメインを含む、請求項26に記載のCARポリペプチド。
- 前記細胞内T細胞シグナル伝達ドメインは、CD3ζ細胞内T細胞シグナル伝達ドメインである、請求項44に記載のCARポリペプチド。
- 前記scFvは、配列番号28、29、30、31、32、及び33で表されるCDR配列を含む、請求項26に記載のCARポリペプチド。
- キメラ抗原受容体(CAR)である、請求項26に記載のCARポリペプチド。
- 請求項26〜46のいずれか一項に記載のCARポリペプチドを含む、Tリンパ球。
- 前記Tリンパ球は、調節性T細胞である、請求項48に記載のTリンパ球。
- それを必要とする被験体に有効量の請求項24又は48に記載のTリンパ球を投与することを含む、自己免疫疾患を治療する方法。
- Tリンパ球は、自己Tリンパ球又は同種Tリンパ球である、請求項50に記載の方法。
- 自己免疫疾患は、I型糖尿病又は移植片対宿主病である、請求項50に記載の方法。
- 前記細胞の少なくとも70%、80%又は90%は、CD4+/CD25high/CD127low/−である、請求項49に記載のTリンパ球。
- 細胞の少なくとも70%、80%又は90%はCD6low/−である、請求項53に記載のTリンパ球。
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