JP7141725B2 - 変異cd28共刺激ドメインを有するキメラ抗原受容体 - Google Patents
変異cd28共刺激ドメインを有するキメラ抗原受容体 Download PDFInfo
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Description
本出願は、2017年7月7日に出願された米国仮特許出願第62/529,919号の利益を主張し、該出願の全体が参照により本明細書に組み込まれる。
本出願は、2018年7月7日に作成された「320803-2160 Sequence listing_ST25」という名称のASCII.txtファイルとして電子形式で出願された配列表を含む。この配列表の内容は、その全体が本明細書に組み込まれる。
CARは、一般に、リンパ球活性化に関与する膜貫通シグナル伝達モチーフを有するモノクローナル抗体(mAb)の単鎖可変断片(scFv)由来の抗原認識ドメインを組み込む(Sadelain M,et al.Nat Rev Cancer 2003 3:35-45)。癌に対する抗腫瘍活性を増強するために免疫エフェクター細胞中で発現させることができるキメラ抗原受容体(CAR)が本明細書に開示される。
SP-TAA-HG-TM-CSR-ISD;
式中、「SP」は、任意選択のシグナルペプチドを表し、
「TAA」は、TAA結合領域を表し、
「HG」は、任意選択のヒンジドメインを表し、
「TM」は、膜貫通ドメインを表し、
「CSR」は、共刺激シグナル伝達領域を表し、
「ISD」は、細胞内シグナル伝達ドメインを表し、
「-」は、ペプチド結合またはリンカーを表す。
開示される免疫エフェクター細胞におけるCARの発現を可能にする、開示されるCARをコードするポリヌクレオチドおよびポリヌクレオチドベクターもまた開示される。
開示されるCAR(本明細書で「CAR-T細胞」とも呼ばれる。)を発現するために操作された免疫エフェクター細胞も開示される。これらの細胞は、治療される対象から入手することが好ましい(即ち、自己)。しかしながら、いくつかの実施形態では、免疫エフェクター細胞株またはドナーエフェクター細胞(同種異系)が使用される。免疫エフェクター細胞は、末梢血単核細胞、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位由来の組織、腹水、胸水、脾臓組織、および腫瘍を含む多くの供給源から得ることができる。免疫エフェクター細胞は、Ficoll(商標)分離のような、当業者に公知の任意の数の技術を使用して、対象から収集された血液から得ることができる。例えば、個体の循環血液由来の細胞は、アフェレーシスによって得ることができる。いくつかの実施形態では、免疫エフェクター細胞は、赤血球を溶解し、単球を枯渇させることによって、例えば、PERCOLL(商標)勾配を通した遠心分離によって、または向流遠心分離エルトリエーションによって、末梢血リンパ球から単離される。免疫エフェクター細胞の特定の亜集団は、陽性または陰性選択技術によってさらに単離され得る。例えば、免疫エフェクター細胞は、例えば、所望の免疫エフェクター細胞の陽性選択のために十分な期間、抗体結合ビーズとインキュベートすることによって、陽性選択された細胞に独特の表面マーカーに対する抗体の組み合わせを使用して単離され得る。あるいは、免疫エフェクター細胞集団の富化は、陰性に選択された細胞に独特の表面マーカーに対する抗体の組み合わせを使用する陰性選択によって達成され得る。
開示されるCARを発現する免疫エフェクター細胞は、TAA発現癌細胞に対する抗腫瘍免疫応答を誘発することができる。開示されるCAR修飾免疫エフェクター細胞によって誘発される抗腫瘍免疫応答は、能動免疫応答でも受動免疫応答でもよい。さらに、CAR媒介免疫応答は、CAR修飾免疫エフェクター細胞がTAAに特異的な免疫応答を誘導する養子免疫療法アプローチの一部であり得る。
用語「アミノ酸配列」は、アミノ酸残基を表す略語、文字、符号または単語のリストを指す。本明細書で使用されるアミノ酸の略語は、アミノ酸についての通常の1文字コードであり、以下のように表される:A、アラニン;B、アスパラギンまたはアスパラギン酸;C、システイン;D、アスパラギン酸;E、グルタメート、グルタミン酸;F、フェニルアラニン;G、グリシン;H、ヒスチジン;I、イソロイシン;K、リジン;L、ロイシン;M、メチオニン;N、アスパラギン;P、プロリン;Q、グルタミン;R、アルギニン;S、セリン;T、トレオニン;V、バリン;W、トリプトファン;Y、チロシン;Z、グルタミンまたはグルタミン酸。
完全マウス抗マウスCD19構築物を開発して、CD19標的CAR T細胞に対する標的としてB-ALLを検証した(Davila et al.,2013 PLoS One 8:e61338)。これは、CD28共刺激ドメインを含む第2世代m1928z CARを含んでいた(図1)。CAR T細胞において使用されるCD28共刺激ドメインは内因性酵素活性を有さないが、T細胞シグナル伝達を調節するサブドメインまたはモチーフを含む、CD28の細胞質尾部に由来する。YMNM(配列番号1)モチーフはPI3kのp85サブユニットに対する結合部位であり、CD28共刺激は細胞周期進行、抗アポトーシス、および細胞代謝をもたらすPI3k活性化を支持する(Rudd and Schneider,2003 Nat Rev Immunol 3:544-556;Sasaki et al.,2000 Science 287:1040-1046;Wang and Rudd,2008 Trends Cell Biol 18:486-493)。変異YMNM(配列番号1)ドメインを有するマウスの研究は、他の関連するインビボ欠損なしにPI3kシグナル伝達を排除する(Dodson et al.,2009)。CD28のPYAP(配列番号3)モチーフはLCKに結合し、T細胞活性化およびIL2産生を生じる(Holdorf et al.,1999 J Exp Med 190:375-384;Kim et al.,1998 J Biol Chem 273:296-301)。Fyn、Grb2およびGADSを含むSH3ドメインを有する他の分子もまた、PYAP(配列番号3)およびPRRP(配列番号2)モチーフに結合する(Ellis et al.,2000 J Immunol 164:5805-5814;Okkenhaug and Rottapel,1998 J Biol Chem 273:21194-21202)。PYAP(配列番号3)ドメインに変異を有するマウスは、CD28依存性増殖、サイトカイン分泌、および適応免疫を著しく損なう(Burr et al.,2001 J Immunol 166:5331-5335;Dodson et al.,2009 Mol Cell Biol 29:3710-3721;Friend et al.,2006 J Exp Med 203:2121-2133)。まとめると、これらの結果は、CD28サブドメインが異なるシグナル伝達および機能経路を媒介し、T細胞機能に差次的に必要とされることを実証する。さらに、CD28は低レベルのTCRシグナルを増幅することが知られており(Acuto and Michel,2003 Nat Rev Immunol 3:939-951)、データは低レベルの緊張性CARシグナル伝達がCD28によって増幅され、インビボでCAR T細胞枯渇をもたらすモデルを支持する。これらのサブドメインおよびそれらのシグナル伝達経路がどのようにCAR-T細胞機能を調節するかは不明であったので、実験を行って、それらの役割を定義し、ヒト翻訳のための最適なシグナル伝達構築物を設計した。従って、YMNM(配列番号1)、PRRP(配列番号2)、またはPYAP(配列番号3)サブドメインにおける一連の7つの変異体を設計した(図2A)。これらのCAR構築物は、単一のサブドメインのヌル変異(Mut01-Mut03)または単一の機能的サブドメインのみを残す2つの変異サブドメイン(Mut04-Mu06)のいずれかを含む。三重変異体(Mut07)もまた、3つのサブドメイン全てが変異した状態で作製した。CD28Mut CARはNur77GFPマウス由来のT細胞で評価され、支持されている全てのCARシグナル伝達が決定されたが、二重変異体(Mut04-Mut06)は第1世代m19z CARと類似したレベルでNur77GFPが低かった(図14B)。これらのCD28変異体および他の新規CAR設計を使用して、CAR T細胞枯渇のメカニズムをCD28共刺激によって評価し、枯渇を減少させて持続性を増強する方法を同定した。
CD28変異CAR細胞のインビトロおよびインビボ機能をさらに評価するために、T細胞マウスT細胞をCARで修飾し、生存率(図4)および増殖(図5)に対するそれらの影響を決定した。分泌されたサイトカイン産生はまた、正常な野生型マウスからCAR T細胞を作製し、3T3-mCD19と一晩インキュベートし、次いで分泌されたサイトカインレベルを測定することによって特徴付けられた。Mut06 CAR T細胞は非変異1928zと比較して有意に少ないサイトカインを産生するが、第一世代CARと比較して有意に多いサイトカインを産生する(図6A~6D)。標的細胞毒性はまた、正常野生型マウスからCAR T細胞を作製し、3T3-mCD19とインキュベートし、1週間にわたってRTCAによる標的死滅を測定することによって特徴付けられた。CD28変異CAR T細胞は、非変異CAR T細胞と同様に殺傷するが、低E:T比では、mut06死滅が優位である(図7Aおよび7B)。1x106 CAR T細胞(CD3+ CAR+)をシトキサン(300mg/kg)前処理野生型C57BL/6マウスに静脈注射した後、血液のシリアルフローサイトメトリーによりB細胞死滅およびCAR T細胞残存を監視した。1週目(図8A、8B)、2週目(図8C、8D)、4週目(図8E、8F)、および6週目(図8G、8H)において、マウスMut06および1928z CAR T細胞は、インビボで類似のB細胞殺傷およびCAR T細胞数を示す(図8A~8H、9A~9D)。種々のCD19標的CAR T細胞による白血病のインビボ殺傷も比較した。Eu-ALL細胞を野生型C57BL/6マウスに注射して6日後にシトキサン(300mg/kg)をi.p.投与した後、1日後に3x105のCAR T細胞を経静脈投与した。Eu-ALL腫瘍を有するマウスは、mut06 CAR T細胞を与えた場合、1928z CRA T細胞と比較して有意に長い生存を有する(図10)。これらの観察はまた、ヒトCD28変異、ヒトCD19標的CAR T細胞にも拡張された。健康なドナーから得られ、ヒトCD19標的化CAR T細胞構築物で修飾されたT細胞を用いて、生存率、増殖、および細胞毒性を評価した。CD28変異ヒトCAR T細胞の生存率および増殖は、トリパンブルー細胞計数によってアッセイした場合、産生の終わりに非変異CAR T細胞に類似している(図11Aおよび11B)。また、全てのヒトCAR T細胞は、ヒトCD19を発現する3T3細胞での刺激後、インビトロで同様の増殖を示した(図12)。非変異CAR T細胞と比較して、ヒトmut06 CAR T細胞は、RTCAによって測定した場合、同様に3T3-ヒトCD19細胞を死滅させる(図13)。
Claims (12)
- リガンド結合ドメイン、膜貫通ドメイン、細胞内シグナル伝達ドメイン、および共刺激シグナル伝達領域を含むキメラ抗原受容体(CAR)ポリペプチドであって、前記共刺激シグナル伝達領域が、(i)YMNMサブドメインを欠くか、または前記YMNMサブドメインにヌル変異を有し、且つ(ii)PRRPサブドメインを欠くか、または前記PRRPサブドメインにヌル変異を有するCD28の細胞質ドメインの変異型を含む、キメラ抗原受容体(CAR)ポリペプチド。
- 前記CD28の細胞質ドメインの変異型が更に、PYAPサブドメインを欠くか、または前記PYAPサブドメインにヌル変異を有する、請求項1に記載のポリペプチド。
- 前記CARポリペプチドが式:
SP-TAA-HG-TM-CSR-ISD;または
SP-TAA-HG-TM-ISD-CSR
(式中、「SP」は、シグナルペプチドを表し、
「TAA」は、腫瘍関連抗原と結合するリガンド結合ドメインを表し、
「HG」は、ヒンジドメインを表し、
「TM」は、膜貫通ドメインを表し、
「CSR」は、前記共刺激シグナル伝達領域を表し、
「ISD」は、細胞内シグナル伝達ドメインを表し、
「-」は、二価リンカーを表す)
によって定義される、請求項1又は2に記載のポリペプチド。 - 前記細胞内シグナル伝達ドメインがCD3ゼータ(CD3ζ)シグナル伝達ドメインを含む、請求項1~3のいずれか1項に記載のポリペプチド。
- 請求項1~4のいずれか1項に記載のポリペプチドをコードする単離されたポリヌクレオチド。
- 請求項5に記載の単離されたポリヌクレオチドを含むベクター。
- 請求項6に記載のベクターを含む細胞。
- 前記細胞が、細胞傷害性Tリンパ球(CTL)である、請求項7に記載の細胞。
- 前記CARのリガンド結合ドメインが腫瘍関連抗原に結合する場合、細胞が抗腫瘍免疫を示す、請求項8に記載の細胞。
- 腫瘍関連抗原発現癌を有する対象において抗腫瘍免疫を提供するための医薬であって、請求項1~4のいずれか1項に記載のCARポリペプチドを発現するように遺伝子改変された有効量の細胞傷害性Tリンパ球を含み、前記CARポリペプチドのリガンド結合ドメインが腫瘍関連抗原と結合する、医薬。
- 前記医薬の投与が、チェックポイント阻害剤を前記対象に投与することをさらに含む、請求項10に記載の医薬。
- 前記チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、またはそれらの組み合わせを含む、請求項11に記載の医薬。
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