JP2020525408A - 共通キメラ抗原受容体発現免疫細胞のためのターゲティングモジュールならびに癌、感染および自己免疫障害の処置における使用 - Google Patents
共通キメラ抗原受容体発現免疫細胞のためのターゲティングモジュールならびに癌、感染および自己免疫障害の処置における使用 Download PDFInfo
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Abstract
Description
ペプチドターゲティングモジュール(pTM)は、ある特定のヒト細胞表面のタンパク質またはタンパク質複合体に特異的な結合部分と、UniCARの結合部分によって認識されるタグという2つのドメインを含む。pTMは、当業者に公知の技術によって製造されることができる。これらの技術には、ポリペプチド鎖の人工的な合成または固相および液相の化学合成が含まれるが、それらに限定されない。
a)本発明による少なくとも1つのターゲティングモジュールと
b)共通キメラ抗原受容体をコードする核酸を含むベクターまたは細胞と
を含むキットをさらに含み、この中で、共通キメラ抗原受容体は、3つのドメインを含み、この中で、
第一のドメインは、タグ結合ドメインであり、
第二のドメインは、細胞外ヒンジおよび膜貫通ドメインであり、かつ
第三のドメインは、シグナル伝達ドメインであり、
この中で、タグ結合ドメインは、本発明によるターゲティングモジュールのタグへ結合する。
免疫細胞は、種々の方法によってUniCARを発現するよう遺伝子操作することができる。UniCARをコードするポリヌクレオチドベクターおよび遺伝子操作された免疫細胞内でのUniCARの発現を確実にするすべての必要な要素は、免疫細胞内へと移入される。ベクターの移入は、電気穿孔法、または核酸のトランスフェクション、またはアデノウイルス、アデノ随伴ウイルス、レトロウイルス、泡沫状ウイルスもしくはレンチウイルスのウイルス遺伝子移入のようなウイルスベクター系の助力によって実施することができる。
・哺乳類動物へ共通キメラ抗原受容体をコードする核酸を含む有効量のベクターまたは細胞を投与することであって、共通キメラ抗原受容体は、3つのドメインを含み、第一のドメインがタグ結合ドメインであり、第二のドメインが細胞外ヒンジおよび膜貫通ドメインであり、かつ第三のドメインがシグナル伝達ドメインであり、タグ結合ドメインがヒト核タンパク質由来のタグへ結合することと
・本発明によるターゲティングモジュールを投与することと
を含む方法であって、
ターゲティングモジュールが、共通キメラ抗原受容体を発現するエフェクター細胞の投与の前に、またはその投与と同時に、またはその投与の後に対象へ投与される。
1 タグ結合ドメインである第一のドメイン
2 細胞外ヒンジおよび膜貫通ドメインである第二のドメイン
3 シグナル伝達ドメインである第三のドメイン
4 短鎖ペプチドリンカーである任意の第四のドメイン
Claims (17)
- ヒト細胞表面のタンパク質またはタンパク質複合体に特異的な化学的に合成されたペプチド結合部分と、タグとを含む、ターゲティングモジュールであって、前記タグが、タンパク質由来のペプチドであり、前記ターゲティングモジュールが、10〜120個のアミノ酸を含むペプチドであり、前記化学的に合成されたペプチド結合部分が、ソマトスタチンおよびソマトスタチン類似体、ソマトスタチンアンタゴニスト、ボンベシンおよびボンベシン類似体、ガストリン放出ペプチド(GRP)およびGRP類似体、ニューロメジンBおよびニューロメジンB類似体、血管作用性セクレチンファミリー、メラニン細胞刺激ホルモン(MSH)およびMSH類似体、コレシストキニン(CCK)、ガストリン、ニューロテンシンおよびニューロテンシン類似体、生殖腺刺激ホルモン放出ホルモンファミリー、ニューロカイン、エキセンジンもしくはエキセナチド、Arg−Gly−Asp(RGD)ペプチドおよびAsn−Gly−Arg(NGR)ペプチド、ニューレグリンから選択され、または前記化学的に合成されたペプチド結合部分が、膜受容体に対する結合特異性を有する、ターゲティングモジュール。
- 前記タグが、ヒトタンパク質由来のペプチドである、請求項1記載のターゲティングモジュール。
- 前記タグが、ヒト核タンパク質由来のペプチドである、請求項1または2記載のターゲティングモジュール。
- 前記化学的に合成されたペプチド結合部分が、ソマトスタチン、ボンベシン、ガストリン放出ペプチド(GRP)、血管作用性小腸ペプチド(VIP)、α−メラニン細胞刺激ホルモン(α−MSH)、メラノタン2(α−M2)、コレシストキニン(CCK)、ガストリン、ニューロテンシン、ノイロペプチドY、黄体形成ホルモン放出ホルモン(LHRH)、サブスタンスP、エキセンジン、Arg−Gly−Asp(RGD)ペプチド、Asn−Gly−Arg(NGR)ペプチドから選択される、請求項1から3までのいずれか1項記載のターゲティングモジュール。
- 前記化学的に合成されたペプチド結合部分が、ソマトスタチンおよびソマトスタチン類似体、ソマトスタチンアンタゴニスト、ボンベシンおよびボンベシン類似体、ガストリン放出ペプチド(GRP)およびGRP類似体、ニューロメジンBおよびニューロメジンB類似体、血管作用性セクレチンファミリー、メラニン細胞刺激ホルモン(MSH)およびMSH類似体、コレシストキニン(CCK)、ガストリン、ニューロテンシンおよびニューロテンシン類似体、生殖腺刺激ホルモン放出ホルモンファミリー、ニューロカイン、エキセンジンもしくはエキセナチド、Arg−Gly−Asp(RGD)ペプチドおよびAsn−Gly−Arg(NGR)ペプチド、ニューレグリンから選択される少なくとも2つのペプチドを含み、または前記化学的に合成されたペプチド結合部分が、膜受容体に対する結合特異性を有する、請求項1から4までのいずれか1項記載のターゲティングモジュール。
- 前記化学的に合成されたペプチド結合部分および/もしくは前記タグが、D型アミノ酸、擬ペプチド結合(pseudo peptide bond)、アミノアルコール、非タンパク質原性アミノ酸、修飾された側鎖を有するアミノ酸を含み、かつ/または前記化学的に合成されたペプチド結合部分および/もしくは前記タグが、環状ペプチドである、請求項1から5までのいずれか1項記載のターゲティングモジュール。
- 前記タグが、ヒト核Laタンパク質由来のペプチドであり、好ましくは前記タグが、配列番号25または配列番号27によるヒト核Laタンパク質由来の短鎖線状エピトープである、請求項1から6までのいずれか1項記載のターゲティングモジュール。
- 配列番号26、式(I)または式(II)による請求項1から3まで記載のターゲティングモジュール。
- キレーターをさらに含む、請求項1から8までのいずれか1項記載のターゲティングモジュール。
- 癌、感染症、炎症性障害および自己免疫障害の処置における使用のための、請求項1から9までのいずれか1項記載のターゲティングモジュール。
- a)請求項1から10までのいずれか1項記載のターゲティングモジュールと、
b)共通キメラ抗原受容体をコードする核酸を含むベクターまたは細胞と、
を含むキットであって、前記共通キメラ抗原受容体が3つのドメインを含み、
前記第一のドメインが、タグ結合ドメインであり、
前記第二のドメインが、細胞外ヒンジおよび膜貫通ドメインであり、かつ
前記第三のドメインが、シグナル伝達ドメインであり、
タグ結合ドメインが、請求項1から10まで記載のターゲティングモジュールの前記タグへ結合する、キット。 - タグ結合ドメインが、ヒト核Laタンパク質由来のタグへ結合し、好ましくは前記タグ結合ドメインが抗体または抗原結合フラグメントであり、前記タグ結合ドメインが、抗LaエピトープscFv、より好ましくは配列番号21および22または配列番号23および24による抗LaエピトープscFvを構成する、請求項11記載のキット。
- 前記細胞外ヒンジおよび膜貫通ドメインが、ヒトCD28分子、CD8a鎖NK細胞受容体、好ましくはナチュラルキラー基NKG2Dのヒンジおよび膜貫通ドメイン、または抗体の定常領域の部分、ならびにこれらの組み合わせから選択される、請求項11または12記載のキット。
- 前記シグナル伝達ドメインが、CD28、CD137(4−1BB)、CD134(OX40)、DAP10およびCD27、プログラム細胞死1(PD−1)、細胞毒性Tリンパ球抗原4(CTLA−4)、CD3鎖の細胞質領域、DAP12および活性化Fc受容体の細胞質領域から選択される、請求項11から13までのいずれか1項記載のキット。
- 前記核酸が、配列番号17、18、19または20によるアミノ酸配列を有する共通キメラ抗原受容体のためにコードする配列番号1、9、13または16である、請求項11から14までのいずれか1項記載のキット。
- 請求項11から15までのいずれか1項記載のキットを含む、医薬組成物。
- 癌、感染症、炎症性障害および自己免疫障害の処置における使用のための、請求項11から15までのいずれか1項記載のキットまたは請求項16記載の医薬組成物。
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