JP7495385B2 - 生体関連の直交性サイトカイン/受容体ペア - Google Patents
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Description
本方法及び組成物について説明する前に、本発明は説明されている特定の方法や組成物には限定されず、したがって当然ながら変わり得ることを理解すべきである。また、本明細書で使う術語は、具体的な実施形態を説明するという目的しかなく、限定の意図はない。本発明の範囲は添付の請求項によってのみ定められるからである。
改変された直交性サイトカイン受容体/リガンドペア、及びその使用方法を提供する。改変された(直交性)サイトカインは、カウンターパートの改変された(直交性)受容体に特異的に結合する。結合すると、直交性受容体はシグナル伝達を活性化させ、これが未変性の細胞エレメントを通じて伝わって、天然の応答を模倣する生物学的活性をもたらすが、それは直交性受容体を発現している改変された細胞に特異的である。直交性受容体は、直交性サイトカインの未変性カウンターパートも含めて内在性カウンターパートサイトカインには結合せず、直交性サイトカインは、直交性受容体の未変性カウンターパートも含めてどの内在性受容体にも結合しない。いくつかの実施形態では、直交性サイトカインの直交性受容体に対する親和性は、未変性サイトカインの未変性受容体に対する親和性に匹敵する。
レシピエントまたはドナーからの細胞を、本発明のオルソロガスな受容体の導入によって改変し、改変された細胞を同族のオルソロガスなサイトカインと接触させることにより該オルソロガスな受容体を刺激することによって、細胞応答を高める方法を提供する。本方法には、標的細胞、たとえばT細胞、造血幹細胞等を得るステップが含まれ、該細胞は生体検体から単離してもよいし、または前駆細胞ソースからインビトロで誘導してもよい。細胞は、オルソロガスな受容体をコードする配列を含む発現ベクターにより形質導入またはトランスフェクトされ、このステップは任意の好適な培養培地で実施することができる。
改変されたT細胞は、治療用の、たとえばヒトの治療に好適な、医薬組成物中で提供することができる。そのような細胞を含む治療製剤は、凍結される場合もあるし、または生理学的に許容される担体、賦形剤、または安定剤と一緒に水溶液として調製され投与される場合もある(Remington’s Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))。細胞は、然るべき医療行為に即して製剤され、処方され、投与される。この場合に考慮すべき要素としては、治療対象である特定の障害、治療対象である特定の哺乳類、患者個人の臨床的状態、障害の原因、剤の送達部位、投与方法、投与スケジュール、及び医療従事者には既知のその他の要素が挙げられる。
本方法で使用されるキットも提供する。このキットには、オルソロガスなサイトカイン受容体をコードする発現ベクター、または該発現ベクターを含む細胞が含まれる。キットはさらに、同族のオルソロガスなサイトカインを含む場合もある。いくつかの実施形態では、これらの構成要素が、任意の便利な包装(たとえば、スティック状包装、用量包装等)の液体または固体の剤形(たとえば治療有効剤形)として提供される。たとえば増殖因子、分化因子、組織培養試薬等、細胞の選択またはインビトロ誘導のための試薬も提供される場合がある。
オルソロガスなIL-2及びIL-2Rβ
ここでは、エクスビボ養子細胞治療の設定で所望の細胞サブセットの選択的増殖を可能にする改変されたサイトカイン及び受容体が含まれる発明を説明する。この特定の発明は、サイトカインであるインターロイキン-2(IL-2)と、その受容体IL-2Rβ鎖(IL-2Rβ)とについて説明するが、これは養子細胞治療において特にT細胞の増殖を可能にするもので、したがって免疫治療において未だ満たされていない必要性に取り組むものである。本明細書で説明するこの手法は、細胞が特定の受容体-リガンドペアによって刺激を受けるあらゆる設定の養子細胞治療、たとえば骨髄移植や幹細胞移植、及び多くの他のモダリティーへと一般化することができる。
本願は、2016年9月11日に出願された米国特許仮出願第62/217,364号、及び2016年8月15日に出願された米国特許仮出願第62/375,089号の利益を主張し、これらの出願の全文を参照により本明細書に援用するものとする。
本発明は、AI513210号の契約により国立衛生研究所から拠出される政府助成金を受けてなされた。政府は本発明に対し一定の権利を有する。
Claims (21)
- 細胞内で受容体を選択的に活性化させるためのシステムであって、
(a)位置133でのアミノ酸置換H133Dと位置134でのアミノ酸置換Y134Fとを含み、哺乳類細胞により発現される直交性ヒトCD122受容体であって、前記アミノ酸置換はCD122ポリペプチドへの未変性ヒトインターロイキン-2(IL-2)の結合を阻害する、直交性ヒトCD122受容体、ならびに
(b)E15S、E15T、E15Q及びE15Hからなる群から選択された位置15でのアミノ酸置換と、H16Qからなる群から選択された位置16でのアミノ酸置換と、L19V及びL19Iからなる群から選択された位置19でのアミノ酸置換と、D20T、D20S、D20M及びD20Lからなる群から選択された位置20でのアミノ酸置換と、Q22K及びQ22Nからなる群から選択された位置22でのアミノ酸置換と、M23L、M23S、M23V、M23A及びM23Tからなる群から選択された位置23でのアミノ酸置換との群から選択された少なくとも4つのアミノ酸置換を含み、前記直交性ヒトCD122受容体に結合して前記直交性ヒトCD122受容体を活性化させる、直交性ヒトIL-2サイトカイン
を含んでいる、システム。 - 前記哺乳類細胞は、免疫細胞または幹細胞である、請求項1に記載のシステム。
- 前記免疫細胞は、T細胞である、請求項2に記載のシステム。
- 前記細胞は、ヒト細胞またはマウス細胞である、請求項2または請求項3に記載のシステム。
- 前記直交性ヒトIL-2サイトカインは、
[E15S;H16Q;L19V;D20S;Q22K;M23L]、
[E15S;H16Q;L19V;D20T;Q22K;M23L]、
[E15S;H16Q;L19V;D20T;Q22K;M23S]、
[E15S;H16Q;L19V;D20S;Q22K;M23S]、
[E15S;H16Q;L19I;D20S;Q22K;M23L]、
[E15S;L19V;D20M;Q22K;M23S]、
[E15T;H16Q;L19V;D20S;M23S]、
[E15Q;L19V;D20M;Q22K;M23S]、
[E15Q;H16Q;L19V;D20T;Q22K;M23V]、
[E15H;H16Q;L19I;D20S;Q22K;M23L]、
[E15H;H16Q;L19I;D20L;Q22K;M23T]、及び
[L19V;D20M;Q22N;M23S]
からなる群から選択されるアミノ酸置換の組を含む、請求項1に記載のシステム。 - 請求項1における直交性ヒトCD122受容体を含んでいる、組成物。
- 請求項6における直交性ヒトCD122受容体をコードする、核酸。
- 請求項7の核酸を含んでいる、発現ベクター。
- 請求項8の発現ベクターを含むように遺伝子改変されている、細胞。
- 請求項1または請求項5における直交性ヒトIL-2サイトカインを含んでいる、組成物。
- 請求項10における直交性ヒトIL-2サイトカインをコードする、核酸。
- 請求項11の核酸を含んでいる、発現ベクター。
- 請求項12の発現ベクターを含むように遺伝子改変されている、細胞。
- 個体を治療するために、請求項9に記載の細胞を前記個体に導入すること、及び、前記細胞を請求項10における直交性ヒトIL-2サイトカインに接触させて前記直交性ヒトCD122受容体に係る前記細胞を選択的に活性化させることを有する方法に使用される、請求項1~請求項5のいずれか1項に記載のシステム。
- 前記細胞は、T細胞である、請求項14に記載の使用のためのシステム。
- 前記個体は、癌を治療される、請求項15に記載の使用のためのシステム。
- 前記個体は、自己免疫疾患を治療される、請求項14に記載の使用のためのシステム。
- 前記自己免疫疾患は、全身性エリテマトーデスである、請求項17に記載の使用のためのシステム。
- 前記個体は、感染症を治療される、請求項14に記載の使用のためのシステム。
- 請求項1~請求項5のいずれか1項に記載のシステムを含んでいる、キット。
- 請求項7または請求項8の核酸または発現ベクターと、請求項10に記載の組成物とを含んでいる、請求項20に記載のキット。
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