JP2021516996A - 生物学的に関連する直交サイトカイン/受容体対 - Google Patents
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Abstract
Description
本方法および組成物を記載する前に、本発明は記載の特定の方法または組成物に限定されず、そのため、勿論、異なる場合があることが理解されるべきである。本明細書で使用される用語は、特定の実施形態のみを説明するためのものであり、本発明の範囲が添付の特許請求の範囲によってのみ限定されるため、限定することを意図するものではないことも理解されたい。
直交IL−2およびIL−2Rβ
ここでは、エクスビボ養子細胞療法の設定において、所望の細胞サブセットの選択的拡大を可能にする操作されたサイトカインおよび受容体を伴う発明を説明する。特定の発明は、サイトカインインターロイキン−2(IL−2)およびその受容体であるIL−2Rβ鎖(IL−2Rβ)について記載されており、これは、養子細胞療法におけるT細胞の特定の拡大を可能にし、したがって、免疫療法における満たされていないニーズに対処する。本明細書に記載のアプローチは、骨髄および幹細胞移植、ならびに多くの他のモダリティを含む、細胞が特定の受容体−リガンド対によって刺激される養子細胞療法の任意の設定に一般化することができる。
ヒトIL−2オルソログ
材料および方法
タンパク質産生。野生型ヒトIL−2をコードするDNAを、親和性精製のためにC末端8xHISタグを含む昆虫発現ベクターpAcGP67−Aにクローニングした。マウス血清アルブミン(MSA)をコードするDNAを、Integrated DNA Technologies(IDT,Coralville,Iowa 52241)から購入し、hIL−2のN末端とMSAのC末端との間の融合物としてpAcGP67−Aにクローニングした。活性スクリーンから単離されたorthoヒトIL−2の変異型を、GBlock(IDT)として合成し、オーバーラップ伸長によりpAcGP67−A−MSAベクターにクローニングした。
本出願は、2018年3月9日に出願された米国一部継続特許出願第15/916,689号の利益を主張するものであり、本出願は参照によりその全体が本明細書に組み込まれる。
本発明は、国立衛生研究所により授与された契約AI513210に基づく政府の支援を受けて行われた。政府は本発明において一定の権利を有する。
Claims (30)
- (i)天然ヒトCD122への大幅に低減された結合を有し、かつ(ii)残基T51、R81において天然タンパク質以外のアミノ酸による少なくとも1つのアミノ酸置換を含むか、またはアミノ酸置換M23Aを含み、かつ(iii)E15、H16、L19、D20のそれぞれにおいてアミノ酸置換を含む、操作されたヒトIL−2ポリペプチド。
- [E15D、E15T、E15A、E15S]、[H16N、H16Q]、[L19V、L19I、L19A]、[D20L、D20M]、[Q22S、Q22T、Q22E、Q22K、Q22E]、[M23A、M23W、M23H、M23Y、M23F、M23Q、M23Y]、[G27K、G27S]、[R81D、R81Y]、[N88E、N88Q]、[T51I]から選択される1つ以上のアミノ酸置換を含む、請求項1に記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換E15S;H16Q;L19VおよびD20Lを含む、請求項1または請求項2に記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換Q22Kをさらに含む、請求項1〜3のいずれかに記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換T51Iを含む、請求項1〜4のいずれかに記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換R81DまたはR81Yを含む、請求項1〜5のいずれかに記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換のセット[E15D、H16N、L19V、D20L、Q22T、M23A]を含む、請求項1に記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換のセット[E15D、H16N、L19V、D20L、Q22K、M23A]を含む、請求項1に記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換のセット[E15S、H16Q、L19V、D20L、M23Q、R81D、T51I]を含む、請求項1に記載の操作されたヒトIL−2ポリペプチド。
- アミノ酸置換のセット[E15S、H16Q、L19V、D20L、M23Q、R81Y]を含む、請求項1に記載の操作されたヒトIL−2ポリペプチド。
- 直交ヒトCD122タンパク質に結合し、それを活性化する、請求項1〜10のいずれかに記載の操作されたヒトIL−2ポリペプチド。
- 前記直交ヒトCD122タンパク質が、R41、R42、Q70、K71、T73、T74、V75、S132、H133、Y134、F135、E136、Q214から選択される1つ以上の残基で修飾される、請求項11に記載の操作されたヒトIL−2ポリペプチド。
- 前記直交ヒトCD122タンパク質が、H133およびY134で修飾される、請求項12に記載の操作されたヒトIL−2ポリペプチド。
- 前記直交ヒトCD122タンパク質が、アミノ酸置換H133DおよびY134Fを含む、請求項13に記載の操作されたヒトIL−2ポリペプチド。
- 細胞における受容体の選択的活性化のための系であって、
(a)H133およびY134におけるアミノ酸置換を含む直交ヒトCD122受容体と、
(b)請求項1〜10のいずれかに記載の操作されたヒトIL−2ポリペプチドと
を含む、系。 - 前記直交ヒトCD122受容体が、哺乳類細胞によって発現される、請求項15に記載の系。
- 前記細胞が、免疫細胞または幹細胞である、請求項16に記載の系。
- 前記免疫細胞が、T細胞である、請求項17に記載の系。
- 前記T細胞が、CAR−T細胞である、請求項18に記載の系。
- 請求項1〜10のいずれかに記載の操作されたヒトIL−2ポリペプチドと、薬学的に許容される賦形剤とを含む、医薬組成物。
- 請求項1〜10のいずれかに記載の操作されたヒトIL−2ポリペプチドをコードする、核酸。
- 請求項21に記載の核酸を含む、発現ベクター。
- 請求項22に記載の発現ベクターを含むように遺伝子操作された、細胞。
- 個体を治療する方法であって、
H133およびY134においてアミノ酸置換を含む直交ヒトCD122受容体を発現する免疫エフェクター細胞を導入することと、
請求項1〜10のいずれかに記載の操作されたヒトIL−2ポリペプチドと接触させることによって、前記免疫エフェクター細胞を選択的に活性化することと
を含む、方法。 - 前記免疫エフェクター細胞が、T細胞である、請求項24に記載の方法。
- 前記T細胞が、CAR−T細胞である、請求項25に記載の方法。
- 前記個体が、癌のために治療される、請求項24〜26のいずれかに記載の方法。
- 前記個体が、自己免疫疾患のために治療される、請求項24〜26のいずれかに記載の方法。
- 前記個体が、感染のために治療される、請求項24〜26のいずれかに記載の方法。
- 請求項15に記載の系を含む、キット。
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