JP2018520679A - 免疫チェックポイントキメラ抗原受容体療法 - Google Patents
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Abstract
Description
本願は、2015年6月29日に出願された米国仮出願第62/186,108号の優先権を主張し、その全体が参照によって本明細書に組み込まれる。
悪性腫瘍患者の大多数は、それらの疾患で死亡する。これらの患者を処置する1つのアプローチは、キメラ抗原受容体(「CAR」)の発現を介して腫瘍細胞において発現される抗原をターゲティングするようにT細胞を遺伝子改変することである。CARは、ヒト白血球抗原非依存的に細胞表面抗原を認識するように設計された抗原受容体である。CD19ターゲティングアプローチの成功の他、CARを発現する遺伝子改変細胞を使用して他の悪性腫瘍を処置する試みは、限定的に成功している。
いくつかの態様では、実施形態は、阻害受容体の細胞外ドメインと、免疫応答を活性化し得る細胞内シグナリングドメインとを含むキメラ膜貫通タンパク質に関する。細胞外ドメインは、例えば、CTLA−4、PD−1、LAG−3またはTim−3由来の細胞外ドメインであり得る。細胞内シグナリングドメインは、例えば、CD3ζ、4−1BBまたはCD28の細胞内シグナリングドメインであり得る。いくつかの態様では、実施形態は、本明細書に記載されるキメラ膜貫通タンパク質をコードする核酸に関する。
CAR療法は、これまでに大きな展望を示している。慢性リンパ球性白血病(CLL)およびより最近では急性リンパ芽球性白血病(ALL)をターゲティングするCD19 CARは、顕著な成功を収めている。興味深いことに、他の抗原をターゲティングするCARは、同様の臨床応答を提供しなかった。このような抗原標的アプローチの1つの限界は、特定の表面受容体を発現する疾患のみに限定されるというそれらの治療適用性であり、単一の腫瘍抗原をターゲティングするという限界は、抗原喪失変異体では再発をもたらしている。
形質導入の16〜24時間前に、T細胞を適切な培地にプレーティングし、CD3、CD28およびIL−2で刺激した。次いで、細胞をインキュベーター(37℃/5%CO2)に一晩入れた。16〜24時間後、細胞を損なわずに、可能な限り多くの培地を除去した。次いで、CARウイルスを細胞に追加し、インキュベーターに4〜12時間戻した。4〜12時間後、IL−2を含有する適切な体積の培地を細胞に戻し、次いで、インキュベーターに戻した。細胞をインキュベーター内で放置し、必要な場合には培地を分割および交換して、3〜12日間成長させた。限定されないが、フローサイトメトリー、ウエスタンブロッティング、または蛍光レポーター遺伝子を使用した場合には蛍光顕微鏡法を含む様々な方法によって、CAR形質導入をチェックし得る。
DMEM+10%FBS中、80%コンフルエントを決して超えない細胞密度で、293T細胞を2日毎に少なくとも3継代にわたって継代した。トランスフェクションの1日前に、24時間後(トランスフェクションの日)に約80%コンフルエントになる密度で、293T細胞を播種した。トランスフェクションの日に培地を除去し、十分な新鮮培地を追加して細胞をカバーした。別のチューブにおいて、VSV−G、Gag、Pol&Revプラスミド、トランスフェクション試薬およびCARプラスミドを混ぜ合わせ、室温で10〜20分間インキュベートした。次いで、この混合物を293T細胞に滴下し、一晩インキュベートした。トランスフェクションの12〜24時間後、培地を完全に交換し、またはさらなる新鮮培地を追加した。トランスフェクションの48時間後および72時間後の両方に、細胞由来のウイルス含有培地を収集し、新鮮培地を細胞に補充した。収集した培地中の細胞を、遠心分離またはろ過によって除去した。次いで、収集した培地を超遠心分離でスピンして、ウイルスをペレット化した。過剰な培地を除去し、ウイルスをDMEMまたはHBSSに再懸濁し、滅菌チューブに等分し、使用まで−80℃で保存した。
被験体から得たMILを、本明細書に記載されるように活性化およびエクスパンションした。簡潔に言えば、被験体から骨髄サンプルを得た後、国際公開第2016037054号(これは、参照により本明細書に組み込まれる)に記載されているように、低酸素条件下、抗CD3/抗CD28ビーズおよびサイトカインの存在下で、細胞をインキュベートした。次いで、配列番号11を含むキメラ膜貫通タンパク質をコードする核酸分子を含むウイルスをMILに感染させた。次いで、正常酸素圧条件下で細胞を成長させ、エクスパンションした。対照MILおよび感染MILを異なる細胞型と接触させた。MILのエクスパンションおよびMILの抗原認識能力は、キメラ膜貫通タンパク質の存在によって悪影響を受けなかった。これらの結果は、MILへのキメラ膜貫通タンパク質の添加が、その機能および成長に有害ではないことを実証している。結果は、2人の異なる患者からの図6パネルAおよびBに示されている。
Claims (54)
- 阻害受容体の細胞外ドメインと、
免疫応答を活性化し得る細胞内シグナリングドメインであって、細胞内シグナリングタンパク質の一部を含む細胞内シグナリングドメインとを含む、キメラ膜貫通タンパク質。 - 配列番号10の配列を含む、請求項1に記載のタンパク質。
- 配列番号11の配列を含む、請求項2に記載のタンパク質。
- 配列番号7および配列番号8の配列を含む、請求項1に記載のタンパク質。
- 配列番号9の配列を含む、請求項1に記載のタンパク質。
- 前記細胞内シグナリングドメインがキナーゼ活性を含む、上記請求項のいずれか一項に記載のタンパク質。
- 前記細胞内シグナリングドメインがリン酸化部位を含む、上記請求項のいずれか一項に記載のタンパク質。
- 前記阻害受容体の膜貫通ドメインまたは前記細胞内シグナリングタンパク質の膜貫通ドメインを含む、上記請求項のいずれか一項に記載のタンパク質。
- 前記阻害受容体がヒト阻害受容体またはマウス阻害受容体である、上記請求項のいずれか一項に記載のタンパク質。
- 天然のアゴニストの結合により、前記阻害受容体が免疫活性を減少させる、上記請求項のいずれか一項に記載のタンパク質。
- 天然のアゴニストの結合により、前記阻害受容体が、T細胞増殖、T細胞生存、サイトカイン分泌または免疫細胞溶解活性を減少させ得る、上記請求項のいずれか一項に記載のタンパク質。
- 前記阻害受容体がリンパ球阻害受容体である、上記請求項のいずれか一項に記載のタンパク質。
- 前記阻害受容体が、CTLA−4、PD−1、LAG−3またはTim−3である、請求項12に記載のタンパク質。
- 前記阻害受容体がPD−1である、請求項13に記載のタンパク質。
- 前記細胞内シグナリングタンパク質がヒトタンパク質またはマウスタンパク質である、上記請求項のいずれか一項に記載のタンパク質。
- 前記細胞内シグナリングタンパク質が免疫活性を増加させる、上記請求項のいずれか一項に記載のタンパク質。
- 前記細胞内シグナリングタンパク質が、T細胞増殖、T細胞生存、サイトカイン分泌または免疫細胞溶解活性を増強し得る、上記請求項のいずれか一項に記載のタンパク質。
- 前記細胞内シグナリングタンパク質が膜貫通タンパク質であるか、または前記細胞内シグナリングタンパク質が天然の膜貫通タンパク質に結合し得る、上記請求項のいずれか一項に記載のタンパク質。
- 前記細胞内シグナリングタンパク質がリンパ球タンパク質である、上記請求項のいずれか一項に記載のタンパク質。
- 前記細胞内シグナリングタンパク質がCD3ζ、4−1BBまたはCD28である、請求項19に記載のタンパク質。
- 前記細胞内シグナリングタンパク質が4−1BBである、請求項19に記載のタンパク質。
- 自殺ドメインをさらに含む、上記請求項のいずれか一項に記載のタンパク質。
- 前記自殺ドメインがチミジンキナーゼ活性を有するか、または前記自殺ドメインがカスパーゼである、請求項22に記載のタンパク質。
- 前記自殺ドメインがHSVチミジンキナーゼのチミジンキナーゼドメインであるか、または前記自殺ドメインがカスパーゼ9の一部を含む、請求項23に記載のタンパク質。
- 請求項1〜24のいずれか一項に記載のキメラ膜貫通タンパク質をコードする、核酸。
- 請求項25に記載の核酸を含む、組換え細胞。
- 請求項1〜24のいずれか一項に記載のキメラ膜貫通タンパク質を含む、組換え細胞。
- リンパ球である、請求項26または27に記載の細胞。
- T細胞である、請求項27に記載の細胞。
- 腫瘍浸潤リンパ球(「TIL」)である、請求項27に記載の細胞。
- 骨髄浸潤リンパ球(「MIL」)である、請求項27に記載の細胞。
- 前記MILが低酸素MILである、請求項31に記載の細胞。
- 組換え細胞を作製するための方法であって、細胞に請求項1〜24のいずれか一項に記載のキメラ膜貫通タンパク質をコードする核酸分子をトランスフェクトまたは感染することを含む、方法。
- 前記細胞がMILである、請求項33に記載の方法。
- 前記細胞に前記キメラ膜貫通タンパク質をコードする核酸分子をトランスフェクトまたは感染する前に、低酸素条件下で前記MILをインキュベートすることをさらに含む、請求項33または34に記載の方法。
- 前記低酸素条件が約0.5%〜約5%の酸素ガスを含む、請求項35に記載の方法。
- 前記低酸素条件が約1%〜約2%の酸素ガスを含む、請求項35に記載の方法。
- 前記低酸素インキュベーションの後に、正常酸素圧条件下で前記細胞をインキュベートすることをさらに含む、請求項35〜37のいずれか一項に記載の方法。
- 前記細胞と抗CD3/抗CD28ビーズとを接触させることをさらに含む、請求項33〜38のいずれか一項に記載の方法。
- 被験体における免疫応答を増加させるための方法であって、請求項26〜32のいずれか一項に記載の組換え細胞を前記被験体に投与することを含む、方法。
- 前記組換え細胞を作製することをさらに含み、前記組換え細胞の作製が、細胞に前記キメラ膜貫通タンパク質をコードする核酸をトランスフェクトすることを含む、請求項40に記載の方法。
- 前記被験体から前記細胞を単離することをさらに含む、請求項40に記載の方法。
- 前記被験体が新生物を有する、請求項40に記載の方法。
- 前記新生物が白血病、リンパ腫または多発性骨髄腫である、請求項43に記載の方法。
- 前記被験体がヒトである、請求項40に記載の方法。
- 被験体における新生物を処置するための方法であって、請求項26〜32のいずれか一項に記載の組換え細胞を前記被験体に投与することを含む、方法。
- 前記組換え細胞を作製することをさらに含み、前記組換え細胞の作製が、細胞に前記キメラ膜貫通タンパク質をコードする核酸をトランスフェクトすることを含む、請求項46に記載の方法。
- 前記被験体から前記細胞を単離することをさらに含む、請求項46に記載の方法。
- 前記被験体が新生物を有する、請求項46に記載の方法。
- 前記新生物が多発性骨髄腫、白血病またはリンパ腫である、請求項49に記載の方法。
- 前記被験体がヒトである、請求項46に記載の方法。
- 前記細胞を前記被験体に投与する前に、
前記細胞と抗CD3/抗CD28ビーズとを接触させること;
低酸素条件下で前記細胞をインキュベートすること;および
正常酸素圧条件下で前記細胞をインキュベートすること
をさらに含む、請求項46に記載の方法。 - 低酸素条件下で前記細胞を約0.5〜約4日間インキュベートする、請求項52に記載の方法。
- 正常酸素圧条件下で前記細胞を約0.5〜約4日間インキュベートする、請求項52に記載の方法。
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KR20190067765A (ko) | 2016-07-27 | 2019-06-17 | 오비아이 파머 인코퍼레이티드 | 면역원성/치료 글리칸 조성물 및 그의 용도 |
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