JP2021522844A - キメラ抗原受容体 - Google Patents
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- JP2021522844A JP2021522844A JP2020564248A JP2020564248A JP2021522844A JP 2021522844 A JP2021522844 A JP 2021522844A JP 2020564248 A JP2020564248 A JP 2020564248A JP 2020564248 A JP2020564248 A JP 2020564248A JP 2021522844 A JP2021522844 A JP 2021522844A
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Abstract
Description
がん処置での使用のためのいくつかの免疫治療剤(治療用モノクローナル抗体(mAb)、二重特異性T細胞エンゲージャー、およびキメラ抗原受容体(CAR)が含まれる)が記載されている。
a)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
b)以下の配列を有する相補性決定領域(CDR)を有する軽鎖可変領域(VL):
。
a)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
b)以下の配列を有する相補性決定領域(CDR)を有する軽鎖可変領域(VL):
。
VH−CH−spacer−TM−endo−coexpr−VL−CL
を有し得、
ここで、
VHは、第1のポリペプチドの重鎖可変ドメインをコードする核酸配列であり;
CHは、前記第1のポリペプチドの重鎖定常ドメインをコードする核酸配列であり;
spacerは、前記第1のポリペプチドのスペーサーをコードする核酸配列であり;
TMは、前記第1のポリペプチドの膜貫通領域をコードする核酸配列であり;
endoは、前記第1のポリペプチドのエンドドメインをコードする核酸配列であり;
VLは、第2のポリペプチドの軽鎖可変ドメインをコードする核酸配列であり;
CLは、前記第2のポリペプチドの軽鎖定常ドメインをコードする核酸配列であり;
coexprは、前記第1および第2のポリペプチドの共発現が可能な核酸配列である。
キメラ抗原受容体
CARは、以下の一般構造を有し得る:
抗原結合ドメイン
VH−CH−スペーサー−膜貫通ドメイン−細胞内シグナル伝達ドメイン;および
VL−CL
または
VL−CL−スペーサー−膜貫通ドメイン−細胞内シグナル伝達ドメイン;および
VH−CH
定常領域ドメイン
配列番号3(ヒトIgG1ヒンジ):
膜貫通ドメイン
エンドドメイン
(i)ITAM含有エンドドメイン(CD3ゼータ由来のエンドドメインなど);および/または
(ii)共刺激ドメイン(CD28またはICOS由来のエンドドメインなど);および/または
(iii)生存シグナルを伝達するドメイン(例えば、TNF受容体ファミリーエンドドメイン(OX−40、4−1BB、CD27、またはGITRなど)。
標的抗原
CD22
表1
CD21
CEACAM5
MUC1
FCRL5
本発明のCARを、1またはそれより多くの他の賦活性または抑制性のキメラ抗原受容体と組み合わせて使用してよい。例えば、本発明のCARを、「論理ゲート」において1またはそれより多くのCARと組み合わせて使用してよく、CAR組み合わせは、T細胞などの細胞によって発現されるとき、少なくとも2つの標的抗原の特定の発現パターンを検出することができる。少なくとも2つの標的抗原が抗原Aおよび抗原Bとして任意に示される場合、3つの可能な選択肢は以下の通りである:
「ORゲート」−T細胞は、抗原Aまたは抗原Bのいずれかが標的細胞上に存在するときに引き起こす
「ANDゲート」−T細胞は、抗原AおよびBの両方が標的細胞上に存在するときに引き起こす
「AND NOTゲート」−T細胞は、抗原Aが単独で標的細胞上に存在する場合に引き起こすが、T細胞は、抗原AおよびBの両方が標的細胞上に存在する場合に引き起こさない
(i)抗CD22 FabCAR;
(ii)抗CD79 dAb CAR);および
(iii)抗CD19 scFv CAR(図7bを参照のこと)。
デュアルCAR
VH−CL−spacer−TM−endo−coexpr−VL−CHまたは
VL−CH−spacer−TM−endo−coexpr−VH−CL
ここで、
VHは、重鎖可変領域をコードする核酸配列であり;
CHは、重鎖定常領域をコードする核酸配列であり
spacerは、スペーサーをコードする核酸であり;
TMは、膜貫通ドメインをコードする核酸配列であり;
endoは、エンドドメインをコードする核酸配列であり;
coexprは、第1および第2のポリペプチドの共発現を可能にする核酸配列であり;
VLは、軽鎖可変領域をコードする核酸配列であり;
CLは、軽鎖定常領域をコードする核酸配列である。
CD79バインダー
CD79aイソ型1−配列番号67
CD79bイソ型2−配列番号68
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
CD19バインダー
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
配列番号84(マウスCD19ALAb scFv配列)
配列番号85(ヒト化CD19ALAb scFv配列−重鎖19、カッパ16)
配列番号86(ヒト化CD19ALAb scFv配列−重鎖19、カッパ7)
配列番号89(マウスCD19ALAb VL配列)
配列番号90(ヒト化CD19ALAb VL配列、カッパ16)
配列番号91(ヒト化CD19ALAb VL配列、カッパ7)
核酸構築物
VH−CH−spacer−TM−endo−coexpr−VL−CLまたは
VL−CL−spacer−TM−endo−coexpr−VH−CH
ここで、
VHは、重鎖可変領域をコードする核酸配列であり;
CHは、重鎖定常領域をコードする核酸配列であり
spacerは、スペーサーをコードする核酸であり;
TMは、膜貫通ドメインをコードする核酸配列であり;
endoは、エンドドメインをコードする核酸配列であり;
coexprは、第1および第2のポリペプチドの共発現を可能にする核酸配列であり;
VLは、軽鎖可変領域をコードする核酸配列であり;
CLは、軽鎖定常領域をコードする核酸配列である。
VH−CH−spacer1−TM1−endo1−coexpr1−VL−CL−coexpr2−AgBD−spacer2−TM2−endo2;または
VL−CL−spacer−TM1−endo1−coexpr1−VH−CH−coexpr2−AgBD−spacer2−TM2−endo2
ここで、
VHは、第1のCARの重鎖可変領域をコードする核酸配列であり;
CHは、第1のCARの重鎖定常領域をコードする核酸配列であり;
spacer1は、第1のCARのスペーサーをコードする核酸配列であり;
TM1は、第1のCARの膜貫通ドメインをコードする核酸配列であり;
endo1は、第1のCARのエンドドメインをコードする核酸配列であり;
coexpr1およびcoexpr2は、同一でも異なっていてもよく、第1のCAR;ならびに第1および第2のCARの第1および第2のポリペプチドの共発現が可能な核酸配列であり;
VLは、第1のCARの軽鎖可変領域をコードする核酸配列であり;
CLは、第1のCARの軽鎖定常領域をコードする核酸配列であり;
AgBDは、第2のCARの抗原結合ドメインをコードする核酸配列であり;
spacer2は、第2のCARのスペーサーをコードする核酸配列であり;
TM2は、第2のCARの膜貫通ドメインをコードする核酸配列であり;
endo2は、第2のCARのエンドドメインをコードする核酸配列である。
VH−CH−spacer1−TM1−endo1−coexpr1−VL−CL−coexpr2−AgBD2−spacer2−TM2−endo2−coexpr3−AgBD3−spacer3−TM3−endo3;または
VL−CL−spacer1−TM1−endo1−coexpr1−VH−CH−coexpr2−AgBD2−spacer2−TM2−endo2−coexpr3−AgBD3−spacer3−TM3
ここで、
VHは、第1のCARの重鎖可変領域をコードする核酸配列であり;
CHは、第1のCARの重鎖定常領域をコードする核酸配列であり;
spacer1は、第1のCARのスペーサーをコードする核酸配列であり;
TM1は、第1のCARの膜貫通ドメインをコードする核酸配列であり;
endo1は、第1のCARのエンドドメインをコードする核酸配列であり;
coexpr1、coexpr2、およびcoexpr3は、同一でも異なっていてもよく、第1のCAR;ならびに第1、第2、および第3のCARの第1および第2のポリペプチドの共発現が可能な核酸配列であり;
VLは、第1のCARの軽鎖可変領域をコードする核酸配列であり;
CLは、第1のCARの軽鎖定常領域をコードする核酸配列であり;
AgBD2は、第2のCARの抗原結合ドメインをコードする核酸配列であり;
spacer2は、第2のCARのスペーサーをコードする核酸配列であり;
TM2は、第2のCARの膜貫通ドメインをコードする核酸配列であり;
endo2は、第2のCARのエンドドメインをコードする核酸配列であり;
AgBD3は、第3のCARの抗原結合ドメインをコードする核酸配列であり;
spacer3は、第3のCARのスペーサーをコードする核酸配列であり;
TM3は、第3のCARの膜貫通ドメインをコードする核酸配列であり;
endo3は、第3のCARのエンドドメインをコードする核酸配列である。
ベクター
細胞
(i)上記列挙の被験体または他の供給源からのTまたはNK細胞を含む試料の単離;および
(ii)キメラポリペプチドをコードする1またはそれより多くの核酸配列でのTまたはNK細胞の形質導入またはトランスフェクション。
医薬組成物
処置方法
(i)TまたはNK細胞を含む試料を単離するステップ;
(ii)かかる細胞を、本発明によって提供された核酸配列またはベクターで形質導入するかトランスフェクトするステップ;
(iii)(ii)由来の細胞を被験体に投与するステップ。
さらなる態様
a)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
VH−CH−spacer1−TM1−endo1−coexpr1−VL−CL−coexpr2−AgBD−spacer2−TM2−endo2;
VL−CL−spacer−TM1−endo1−coexpr1−VH−CH−coexpr2−AgBD−spacer2−TM2−endo2;
AgBD−spacer2−TM2−endo2−VH−CH−spacer1−TM1−endo1−coexpr2−VL−CL;
AgBD−spacer2−TM2−endo2−coexpr1−VL−CL−spacer−TM1−endo1−coexpr2−VH−CH
VL−CL−coexpr1−VH−CH−spacer1−TM1−endo1−−coexpr2−AgBD−spacer2−TM2−endo2;
VH−CH−coexpr1−VL−CL−spacer−TM1−endo1−coexpr2−AgBD−spacer2−TM2−endo2;
AgBD−spacer2−TM2−endo2−VL−CL−coexpr2−VH−CH−spacer1−TM1−endo1;または
AgBD−spacer2−TM2−endo2−coexpr1−VH−CH−coexpr2−VL−CL−spacer−TM1−endo1
ここで、
VHは、第1のCARの重鎖可変領域をコードする核酸配列であり;
CHは、第1のCARの重鎖定常領域をコードする核酸配列であり;
spacer1は、第1のCARのスペーサーをコードする核酸配列であり;
TM1は、第1のCARの膜貫通ドメインをコードする核酸配列であり;
endo1は、第1のCARのエンドドメインをコードする核酸配列であり;
coexpr1およびcoexpr2は、同一でも異なっていてもよく、第1のCAR;および第2のCARの第1および第2のポリペプチドの共発現が可能な核酸配列であり;
VLは、第1のCARの軽鎖可変領域をコードする核酸配列であり;
CLは、第1のCARの軽鎖定常領域をコードする核酸配列であり;
AgBDは、第2のCARの抗原結合ドメインをコードする核酸配列であり;
spacer2は、第2のCARのスペーサーをコードする核酸配列であり;
TM2は、第2のCARの膜貫通ドメインをコードする核酸配列であり;
endo2は、第2のCARのエンドドメインをコードする核酸配列である。
AgBD1−spacer1−TM1−endo1−coexpr−AgBD2−spacer2−TM2−endo2;または
AgBD2−spacer2−TM2−endo2−coexpr−AgBD1−spacer1−TM1−endo1
ここで、
AgBD1は、第1のCARの抗原結合ドメインをコードする核酸配列であり;
spacer1は、第1のCARのスペーサーをコードする核酸配列であり;
TM1は、第1のCARの膜貫通ドメインをコードする核酸配列であり;
endo1は、第1のCARのエンドドメインをコードする核酸配列であり、
coexprは、第1および第2のCARの共発現が可能な核酸配列であり;
AgBD2は、第2のCARの抗原結合ドメインをコードする核酸配列であり;
spacer2は、第2のCARのスペーサーをコードする核酸配列であり;
TM2は、第2のCARの膜貫通ドメインをコードする核酸配列であり;
endo2は、第2のCARのエンドドメインをコードする核酸配列である。
a)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
b)以下の配列を有するCDRを有する軽鎖可変領域(VL):
。
a)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
b)以下の配列を有する相補性決定領域(CDR)を有する軽鎖可変領域(VL):
。
ai)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
bi)以下の配列を有する相補性決定領域(CDR)を有する軽鎖可変領域(VL):
または
aii)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
bii)以下の配列を有する相補性決定領域(CDR)を有する軽鎖可変領域(VL):
または
aiii)以下の配列を有する相補性決定領域(CDR)を有する重鎖可変領域(VH):
および
biii)以下の配列を有する相補性決定領域(CDR)を有する軽鎖可変領域(VL):
。
実施例1−FACsに基づく殺滅(FBK)
NT:非形質導入
10C1−D9 Fab:10C1mAbに基づいたFabCAR
実施例2−増殖アッセイ(PA)
NT:非形質導入
3B4:3B4mAbに基づいたFabCAR
9A8:9A8−1mAbに基づいたFabCAR
CARパネルを以下にまとめているように作製した:
NT:非形質導入
Fmc63:抗CD19 CAR(負の対照)
10C1:10C1mAbに基づいた抗CD22 FabCAR
3B4:3B4mAbに基づいた抗CD22 FabCAR
7G6:7G6mAbに基づいた抗CD22 FabCAR
9F8−2:9F8−2mAbに基づいた抗CD22 FabCAR
9A8−1:9A8−1mAbに基づいた抗CD22 FabCAR
1G3−4:1G3−4mAbに基づいた抗CD22 FabCAR
9F9−6:9F9−6mAbに基づいた抗CD22 FabCAR
形質導入
NK細胞およびNKT細胞の枯渇
細胞傷害性アッセイ
サイトカイン放出
Claims (25)
- 嵩高い細胞外ドメインを有する標的抗原に結合するキメラ抗原受容体(CAR)であって、前記CARがFab抗原結合ドメインを含む、キメラ抗原受容体(CAR)。
- 前記標的抗原が、少なくとも約150Åの細胞外ドメインを有する、請求項1に記載のCAR。
- 前記標的抗原が、少なくとも約400個のアミノ酸の細胞外ドメインを有する、請求項1または2に記載のCAR。
- 前記標的抗原が、CD22、CD21、CEACAM5、MUC1、またはFcRL5である、前記請求項のいずれかに記載のCAR。
- 前記標的抗原がCD22である、請求項4に記載のCAR。
- 配列番号65として示した配列を有するVHドメイン;および配列番号66として示した配列を有するVLドメインを含む、請求項6に記載のCAR。
- 配列番号99として示した配列を有するVHドメイン;および配列番号100として示した配列を有するVLドメインを含む、請求項6に記載のCAR。
- 前記請求項のいずれかに記載のCARをコードする核酸配列。
- 以下の一般構造:
VH−CH−spacer−TM−endo−coexpr−VL−CL
を有し、
ここで、
VHは、第1のポリペプチドの重鎖可変ドメインをコードする核酸配列であり;
CHは、前記第1のポリペプチドの重鎖定常ドメインをコードする核酸配列であり;
spacerは、前記第1のポリペプチドのスペーサーをコードする核酸配列であり;
TMは、前記第1のポリペプチドの膜貫通領域をコードする核酸配列であり;
endoは、前記第1のポリペプチドのエンドドメインをコードする核酸配列であり;
VLは、第2のポリペプチドの軽鎖可変ドメインをコードする核酸配列であり;
CLは、前記第2のポリペプチドの軽鎖定常ドメインをコードする核酸配列であり;
coexprは、前記第1および第2のポリペプチドの共発現が可能な核酸配列である、請求項10に記載の核酸配列。 - 請求項10または11に記載の第1の核酸配列、およびドメイン抗体(dAb)抗原結合ドメインまたはscFv抗原結合ドメインを有する第2のキメラ抗原受容体をコードする第2の核酸配列を含む、核酸構築物。
- 請求項10または11に記載の第1の核酸配列;ドメイン抗体(dAb)抗原結合ドメインを有する第2のキメラ抗原受容体をコードする第2の核酸配列;およびscFv抗原結合ドメインを有する第3のCARをコードする第3の核酸配列を含む、核酸構築物。
- 前記第1の核酸配列が抗CD22 Fab CARをコードし;前記第2の核酸配列が抗CD79 dAb CARをコードし;前記第3の核酸配列が抗CD19 scFv CARをコードする、請求項13に記載の核酸構築物。
- 請求項10または11に記載の核酸配列または請求項12〜14のいずれかに記載の核酸構築物を含む、ベクター。
- 請求項1〜9のいずれかに記載のCARを発現する細胞。
- 請求項1〜9のいずれかに記載の第1のCAR、およびドメイン抗体(dAb)抗原結合ドメインまたはscFv抗原結合ドメインを有する第2のキメラ抗原受容体を発現する細胞。
- 請求項1〜9のいずれかに記載の第1のCAR、およびドメイン抗体(dAb)抗原結合ドメインを有する第2のCAR;およびscFv抗原結合ドメインを有する第3のCARを発現する細胞。
- 前記第1のCARが抗CD22 Fab CARであり;前記第2のCARが抗CD79 dAb CARであり;前記第3のCARが抗CD19 scFv CARである、請求項16に記載の細胞。
- 請求項10または11に記載の核酸配列;請求項12〜14のいずれかに記載の核酸構築物;または請求項15に記載のベクターを細胞にex vivoで導入するステップを含む、請求項16〜19のいずれかに記載の細胞を作製する方法。
- 請求項16〜19のいずれかに記載の細胞の複数を、薬学的に許容され得る担体、希釈剤、または賦形剤と共に含む、医薬組成物。
- 請求項19に記載の医薬組成物を被験体に投与するステップを含む、がんを処置する方法。
- 前記がんがB細胞リンパ腫または白血病である、請求項22に記載の方法。
- がんの処置で使用するための請求項21に記載の医薬組成物。
- がんを処置するための医薬組成物の製造における請求項16〜19のいずれかに記載の細胞の使用。
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CN111072776A (zh) * | 2019-12-26 | 2020-04-28 | 成都欧林生物科技股份有限公司 | 抗SpA5蛋白的单克隆抗体及其应用和包含其的试剂盒 |
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