KR20210129125A - Baff-r/cd19 표적화된 키메라 항원 수용체-변형된 t 세포 및 그의 용도 - Google Patents
Baff-r/cd19 표적화된 키메라 항원 수용체-변형된 t 세포 및 그의 용도 Download PDFInfo
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Abstract
BAFF-R 및 CD19 둘 모두를 표적화하는 키메라 항원 수용체를 그의 사용 방법과 같이 기술한다.
Description
조작된 T 세포를 이용하는 요법을 비롯한, 종양 특이적 T 세포 기반 면역요법이 항-종양 치료를 위해 연구되어 왔다.
CD19 CAR-T 세포 요법은 많은 B-ALL 및 림프종 환자에서 효과적이다. 그러나, CD19-지시된 CAR-T 요법을 회피하는 항원 손실 변이체로 인한 재발은 환자의 최대 20-30%에서 발생할 수 있다. CD22 CAR-T 세포 요법은 CD19-음성 B-ALL 환자에서 임상 반응의 달성에 의해 입증된 바와 같이, CD19 항원 손실로부터의 재발을 극복하기 위한 하나의 대안 전략법으로서 제안되었다. 그러나, CD22 발현 밀도는 특히 혼합 계통 백혈병 (MLL)에서 다양할 수 있으며, 그의 발현은 CD22-표적화된 요법 후에 감소하는 것으로 보고되었다.
본원에서는 B 세포 활성화 인자 수용체 (BAFF-R) 및 CD19로 표적화된 키메라 항원 수용체 (CAR)를 발현하는 T 세포를 이용하는, B-ALL 및 림프종을 비롯한 B 세포 악성종양을 치료하는 방법을 기술한다. 일부 경우에, 단일 CAR은 BAFF-R 및 CD19 둘 모두를 표적화한다. BAFF-R 및 CD19 둘 모두를 표적화하는 단일 CAR의 경우, 세포외 표적화 부분은 표적 중 하나에 대한 scFv가 다른 scFv보다 앞에 있는 탠덤 포맷, 또는 두 표적 중 하나에 대한 scFv가 나머지 다른 표적에 대한 scFv의 VL 및 VH 도메인 사이에 배치되어 있는 루프 포맷을 가질 수 있다. 상기 포맷 중 어느 것에서든, CAR은 막횡단 도메인 (예컨대, CD8 막횡단 도메인), 공동자극 도메인 (예컨대, 4-1BB 공동자극 도메인) 및 CD3 제타 신호전달 도메인을 포함한다. CAR은 또한 예를 들어, scFv 도메인(들)과 막횡단 도메인 사이, 막횡단 도메인과 공동자극 도메인 사이, 및/또는 공동자극 도메인과 CD3 제타 신호전달 도메인 사이에 스페이서 서열을 포함할 수 있다.
본원에서는 BAFF-R 및 CD19 둘 모두로 표적화된 키메라 항원 수용체를 코딩하는 뉴클레오티드 서열을 포함하는 핵산 분자이며, 여기서 키메라 항원 수용체는 아미노에서 카르복시 말단으로 BAFF-R 및 CD19를 표적화하기 위한 표적화 도메인; 스페이서 도메인; 막횡단 도메인; 공동자극 도메인; 및 CD3ζ 신호전달 도메인을 포함하는 것인, 핵산 분자를 기술한다.
다양한 실시양태에서: (1) 표적화 도메인은 아미노에서 카르복시 말단으로 a) BAFF-R로 표적화된 scFv 및 CD19로 표적화된 scFv; 또는 b) CD19로 표적화된 scFv 및 BAFF-R로 표적화된 scFv를 포함하고; (2) 표적화 도메인은 아미노에서 카르복시 말단으로 a) CD19 scFv의 VL 도메인; BAFF-R로 표적화된 scFv; 및 CD19 scFv의 VH; 또는 b) CD19 scFv의 VH 도메인; BAFF-R로 표적화된 scFv; 및 CD19 scFv의 VL을 포함하고; (3) 표적화 도메인은 아미노에서 카르복시 말단으로 a) BAFF-R scFv의 VL 도메인; CD19로 표적화된 scFv; 및 BAFF-R scFv의 VH; 또는 b) BAFF-R scFv의 VH 도메인; CD19로 표적화된 scFv; 및 BAFF-R scFv의 VL을 포함한다.
본원에서는 또한 두 BAFF-R로 표적화된 키메라 항원 수용체 및 CD19로 표적화된 키메라 항원 수용체를 코딩하는 뉴클레오티드 서열을 포함하는 핵산 분자이며, 여기서 BAFF-R로 표적화된 키메라 항원 수용체는 아미노에서 카르복시 말단으로 BAFF-R scFv; 스페이서 도메인; 막횡단 도메인; 공동자극 도메인; 및 CD3ζ 신호전달 도메인을 포함하고; CD19로 표적화된 키메라 항원 수용체는 아미노에서 카르복시 말단으로 CD19 scFv; 스페이서 도메인; 막횡단 도메인; 공동자극 도메인; 및 CD3ζ 신호전달 도메인을 포함하는 것인, 핵산 분자를 기술한다.
다양한 실시양태에서: 공동자극 도메인은 CD28 공동자극 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, 4-1BB 공동자극 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, 및 OX40 공동자극 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체로 이루어진 군으로부터 선택되고; 막횡단 도메인은 CD4 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, CD8 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, CD28 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, 및 CD3ζ 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체; 공동자극 도메인; 및 CD3ζ 신호전달 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체로부터 선택되고; 스페이서 도메인은 IgG4 힌지 (S→P), IgG4 힌지, IgG4 힌지 (S228P)+링커, CD28 힌지, CD8 힌지-48aa, CD8 힌지-45aa, IgG4(HL-CH3), IgG4(L235E,N297Q), IgG4(S228P, L235E,N297Q), 및 IgG4(CH3), 및 1-5개의 아미노산 변형을 갖는 IgG4 힌지 (S→P), IgG4 힌지, IgG4 힌지 (S228P)+링커, CD28 힌지, CD8 힌지-48aa, CD8 힌지-45aa, IgG4(HL-CH3), IgG4(L235E,N297Q), IgG4(S228P, L235E,N297Q), 및 IgG4(CH3) 각각의 변이체로 이루어진 군으로부터 선택된다.
다양한 실시양태에서: (1) BAFF-R scFv는 경쇄 가변 영역 및 중쇄 가변 영역을 포함하고, 여기서 경쇄 가변 영역은 CDR L1 (서열식별번호(SEQ ID NO:) 1), CDR L2 (서열식별번호 2) 및 CDR L3 (서열식별번호 3)을 포함하고; 중쇄 가변 영역은 CDR H1 (서열식별번호 4), CDR H2 (서열식별번호 5), 및 CDR H3 (서열식별번호 6)을 포함하고; (2) BAFF-R scFv는 경쇄 가변 영역 및 중쇄 가변 영역을 포함하고, 여기서 경쇄 가변 영역은 CDR L1 (서열식별번호 7), CDR L2 (서열식별번호 8) 및 CDR L3 (서열식별번호 9)을 포함하고; 중쇄 가변 영역은 CDR H1 (서열식별번호 10), CDR H2 (서열식별번호 11), 및 CDR H3 (서열식별번호 12)을 포함하고; (3) BAFF-R scFv는 Chi90 HC, Hu90 HC-1, Hu90 HC-2, Hu90 HC-3, Chi55 HC, Hu55 HC-1, Hu55 HC-2, 및 Hu55 HC-3으로부터 선택되는 중쇄 가변 도메인, 및 Chi90 LC, Hu90 LC-1, Hu90 LC-2, Hu90 LC-3, Chi55 LC, Hu55 LC-1, Hu55 LC-2, 및 Hu55 LC-3으로부터 선택되는 경쇄 가변 도메인을 포함하고; (4) BAFF-R scFv는 서열식별번호 17-20 및 25-28로부터 선택되는 아미노산 서열을 갖는 경쇄 가변 도메인을 포함하고; (5) BAFF-R scFv는 서열식별번호 13-16 및 21-24로부터 선택되는 아미노산 서열을 갖는 중쇄 가변 도메인을 포함하고; (6) CD19 scFv는 아미노산 서열 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPYTFGGGTKLEIT (서열식별번호 30)를 포함하는 VL, 및 아미노산 서열 EVK LQESGPGLVAPSQSLSVTCTVSGVSLPDYG VSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGG SYAMDYWGQGTSVTVSS (서열식별번호 31)를 포함하는 VH를 포함한다.
본원에서는 또한 상기 기술된 핵산 분자 중 하나 이상의 것을 포함하는 벡터를 기술한다. 다양한 실시양태에서, 벡터는 렌티바이러스 벡터이다. 본원에 기술된 벡터에 의해 형질도입된 인간 T 세포 집단 또한 기술한다.
대상체에게 치료 유효량의, 본원에 기술된 바와 같은 인간 T 세포 집단을 포함하는 조성물을 투여하는 단계를 포함하는, 암 치료를 필요로 하는 대상체에서 암을 치료하는 방법 또한 기술한다. 본 방법의 다양한 실시양태에서: 암은 림프종, 백혈병 또는 골수종이고; 림프종은 외투 세포 림프종, 여포성 림프종, 미만성 거대 B 세포 림프종, 변연부 림프종 또는 버킷 림프종이고; 백혈병은 급성 림프모구성 백혈병, 만성 림프구성 백혈병 또는 모발 세포 백혈병이고; 골수종은 다발성 골수종이고; T 세포 집단은 환자에 대해 자가 또는 동종이계이고; 인간 T 세포 집단은 CD4+ 세포 및 CD8+ 세포를 포함하는 세포를 포함한다.
일부 실시양태에서, BAFF-R scFv는 경쇄 가변 영역 및 중쇄 가변 영역을 포함하고, 여기서 경쇄 가변 영역은 서열식별번호 7에 기재된 바와 같은 CDR L1, 서열식별번호 8에 기재된 바와 같은 CDR L2, 및 서열식별번호 9에 기재된 바와 같은 CDR L3을 포함하고; 중쇄 가변 영역은 서열식별번호 10에 기재된 바와 같은 CDR H1, 서열식별번호 11에 기재된 바와 같은 CDR H2, 및 서열식별번호 12에 기재된 바와 같은 CDR H3을 포함한다. 실시양태에서, 항체는 인간화 항체이다.
일부 실시양태에서, BAFF-R scFv는 서열식별번호 1 또는 7의 CDR L1, 서열식별번호 2 또는 8의 CDR L2, 서열식별번호 3 또는 9의 CDR L3, 서열식별번호 4 또는 10의 CDR H1, 서열식별번호 5 또는 11의 CDR H2, 및 서열식별번호 7 또는 13의 CDR H3을 포함한다.
일부 실시양태에서, BAFF-R scFv의 일부는 모노클로날 항체 H90의 경쇄 가변 도메인 및 모노클로날 항체 H90의 중쇄 가변 도메인, 또는 모노클로날 항체 H55의 경쇄 가변 도메인 및 모노클로날 항체 H55의 중쇄 가변 도메인을 포함한다. 중쇄 및 경쇄 가변 도메인은 5-100, 10-50 또는 10-20개의 아미노산 (예컨대, GGGGSGGGGSGGGGS)으로 이루어진 링커에 의해 연결될 수 있다.
일부 실시양태에서, BAFF-R scFv는 a) 모노클로날 항체 H90의 경쇄 가변 도메인의 인간화 변이체 및 모노클로날 항체 H90의 중쇄 가변 도메인의 인간화 변이체; 또는 b) 모노클로날 항체 H55의 경쇄 가변 도메인의 인간화 변이체 및 모노클로날 항체 H55의 중쇄 가변 도메인의 인간화 변이체를 포함한다. 중쇄 및 경쇄 가변 도메인은 10-20개의 아미노산 (예컨대, GGGGSGGGGSGGGGS)으로 이루어진 링커에 의해 연결될 수 있다. 일부 경우에, H90 경쇄 가변 도메인의 인간화 변이체는 Hu90 LC-1, Hu90 LC-2 및 Hu90 LC-3으로부터 선택되고, H90 중쇄 가변 도메인의 인간화 변이체는 Hu90 HC-1, Hu90 HC-2 및 Hu90 HC-3으로부터 선택된다. 일부 경우에, H55 경쇄 가변 도메인의 인간화 변이체는 Hu55 LC-1, Hu55 LC-2 및 Hu55 LC-3으로부터 선택되고, H55 중쇄 가변 도메인의 인간화 변이체는 Hu55 HC-1, Hu55 HC-2 및 Hu90 HC-3으로부터 선택된다.
실시양태에서, BAFF-R scFv 경쇄 가변 영역은 카바트(Kabat) 위치 7에 상응하는 위치에 세린을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 8에 상응하는 위치에 프롤린을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 15에 상응하는 위치에 발린을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 22에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 24에 상응하는 위치에 글루타민을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 41에 상응하는 위치에 글리신을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 42에 상응하는 위치에 리신을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 43에 상응하는 위치에 알라닌을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 44에 상응하는 위치에 프롤린을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 56에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 72에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 73에 상응하는 위치에 페닐알라닌을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 79에 상응하는 위치에 글루타민을 포함한다. 실시양태에서, 경쇄 가변 영역은 카바트 위치 104에 상응하는 위치에 발린을 포함한다.
실시양태에서, BAFF-R scFv 경쇄 가변 영역은 카바트 위치 7에 상응하는 위치에 세린, 카바트 위치 8에 상응하는 위치에 프롤린, 카바트 위치 15에 상응하는 위치에 발린, 카바트 위치 22에 상응하는 위치에 트레오닌, 카바트 위치 24에 상응하는 위치에 글루타민 또는 세린, 카바트 위치 41에 상응하는 위치에 글리신, 카바트 위치 42에 상응하는 위치에 리신, 카바트 위치 43에 상응하는 위치에 알라닌 또는 트레오닌, 카바트 위치 44에 상응하는 위치에 프롤린, 카바트 위치 56에 상응하는 위치에 트레오닌, 카바트 위치 72에 상응하는 위치에 트레오닌, 카바트 위치 73에 상응하는 위치에 페닐알라닌 또는 리신, 카바트 위치 79에 상응하는 위치에 글루타민, 또는 카바트 위치 104에 상응하는 위치에 발린을 포함한다.
실시양태에서, BAFF-R scFv 경쇄 가변 영역은, 카바트 위치 7에 상응하는 위치가 세린, 카바트 위치 8에 상응하는 위치가 프롤린, 카바트 위치 15에 상응하는 위치가 발린, 카바트 위치 22에 상응하는 위치가 트레오닌, 카바트 위치 24에 상응하는 위치가 글루타민 또는 세린, 카바트 위치 41에 상응하는 위치가 글리신, 카바트 위치 42에 상응하는 위치가 리신, 카바트 위치 43에 상응하는 위치가 알라닌 또는 트레오닌, 카바트 위치 44에 상응하는 위치가 프롤린, 카바트 위치 56에 상응하는 위치가 트레오닌, 카바트 위치 72에 상응하는 위치가 트레오닌, 카바트 위치 73에 상응하는 위치가 페닐알라닌 또는 리신, 카바트 위치 79에 상응하는 위치가 글루타민, 또는 카바트 위치 104에 상응하는 위치가 발린인 결합 프레임워크 영역 잔기를 포함한다.
실시양태에서, BAFF-R scFv 중쇄 가변 영역은 카바트 위치 10에 상응하는 위치에 트레오닌 또는 알라닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 11에 상응하는 위치에 리신을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 12에 상응하는 위치에 발린을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 15에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 19에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 23에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 41에 상응하는 위치에 프롤린을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 44에 상응하는 위치에 알라닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 61에 상응하는 위치에 프롤린 또는 트레오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 66에 상응하는 위치에 아르기닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 70에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 75에 상응하는 위치에 리신을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 79에 상응하는 위치에 발린을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 81에 상응하는 위치에 트레오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 82에 상응하는 위치에 메티오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 82B에 상응하는 위치에 아스파라긴을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 82C에 상응하는 위치에 메티오닌을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 84에 상응하는 위치에 프롤린을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 85에 상응하는 위치에 발린을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 108에 상응하는 위치에 리신을 포함한다. 실시양태에서, 중쇄 가변 영역은 카바트 위치 109에 상응하는 위치에 발린을 포함한다.
실시양태에서, BAFF-R scFv 중쇄 가변 영역은 카바트 위치 10에 상응하는 위치에 트레오닌 또는 알라닌, 카바트 위치 11에 상응하는 위치에 리신, 카바트 위치 12에 상응하는 위치에 발린, 카바트 위치 15에 상응하는 위치에 트레오닌, 카바트 위치 19에 상응하는 위치에 트레오닌, 카바트 위치 23에 상응하는 위치에 트레오닌, 카바트 위치 41에 상응하는 위치에 프롤린, 카바트 위치 44에 상응하는 위치에 알라닌, 카바트 위치 61에 상응하는 위치에 프롤린 또는 트레오닌, 카바트 위치 66에 상응하는 위치에 아르기닌, 카바트 위치 70에 상응하는 위치에 트레오닌, 카바트 위치 75에 상응하는 위치에 리신, 카바트 위치 79에 상응하는 위치에 발린, 카바트 위치 81에 상응하는 위치에 트레오닌, 카바트 위치 82에 상응하는 위치에 메티오닌, 카바트 위치 82B에 상응하는 위치에 아스파라긴, 카바트 위치 82C에 상응하는 위치에 메티오닌, 카바트 위치 84에 상응하는 위치에 프롤린, 카바트 위치 85에 상응하는 위치에 발린, 카바트 위치 108에 상응하는 위치에 리신, 카바트 위치 109에 상응하는 위치에 발린을 포함한다.
실시양태에서, BAFF-R scFv 중쇄 가변 영역은 카바트 위치 10에 상응하는 위치가 트레오닌 또는 알라닌, 카바트 위치 11에 상응하는 위치가 리신, 카바트 위치 12에 상응하는 위치가 발린, 카바트 위치 15에 상응하는 위치가 트레오닌, 카바트 위치 19에 상응하는 위치가 트레오닌, 카바트 위치 23에 상응하는 위치가 트레오닌, 카바트 위치 41에 상응하는 위치가 프롤린, 카바트 위치 44에 상응하는 위치가 알라닌, 카바트 위치 61에 상응하는 위치가 프롤린 또는 트레오닌, 카바트 위치 66에 상응하는 위치가 아르기닌, 카바트 위치 70에 상응하는 위치가 트레오닌, 카바트 위치 75에 상응하는 위치가 리신, 카바트 위치 79에 상응하는 위치가 발린, 카바트 위치 81에 상응하는 위치가 트레오닌, 카바트 위치 82에 상응하는 위치가 메티오닌, 카바트 위치 82B에 상응하는 위치가 아스파라긴, 카바트 위치 82C에 상응하는 위치가 메티오닌, 카바트 위치 84에 상응하는 위치가 프롤린, 카바트 위치 85에 상응하는 위치가 발린, 카바트 위치 108에 상응하는 위치가 리신, 카바트 위치 109에 상응하는 위치가 발린인 결합 프레임워크 영역 잔기를 포함한다.
도 1은 탠덤 구축물의 2가지 예, 및 BAFF-R/CD19 이중 CAR에 대한 루프 구축물의 1가지 예를 나타낸 개략도를 도시한 것이다. 단일 세포가, 하나는 BAFF-R로 표적화되고, 하나는 CD19로 표적화되는 것인 2개의 CAR을 발현하는 비시스트로닉 구축물의 예 또한 제시되어 있다.
도 2는 신호 서열을 포함하는, 미성숙 1250 이중 CAR의 아미노산 서열 (서열식별번호 58)을 도시한 것이다. 성숙한 CAR (서열식별번호 59)은 아미노에서 카르복시 말단으로 BAFF-R scFv, 링커, CD19 scFv (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 4-1BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 3은 신호 서열을 포함하는, 미성숙 1296 이중 CAR의 아미노산 서열 (서열식별번호 60)을 도시한 것이다. 성숙한 CAR (서열식별번호 61)은 아미노에서 카르복시 말단으로 CD19 scFv (FMC63으로부터 유래), 링커, BAFF-R scFv, IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 4-1BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 4는 신호 서열을 포함하는, 미성숙 1316 이중 CAR의 아미노산 서열 (서열식별번호 62)을 도시한 것이다. 성숙한 CAR (서열식별번호 63)은 아미노에서 카르복시 말단으로 CD19 VL (FMC63으로부터 유래), GGGS 링커, BAFF-R scFv, CD19 VH (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 41BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 5는 (A) 신호 서열을 포함하는, 미성숙 CD19 CAR의 아미노산 서열 (서열식별번호 64) 및 B 신호 서열을 포함하는, 미성숙 BAFF-R CAR의 아미노산 서열 (서열식별번호 66)을 도시한 것이다. 성숙한 CD19 CAR (서열식별번호 65)은 아미노에서 카르복시 말단으로 CD19 scFv (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD28 막횡단 도메인, CD28(GG) 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다. 성숙한 BAFF-R CAR (서열식별번호 67)은 아미노에서 카르복시 말단으로 BAFF-R scFv, IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 4-1BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 6은 BAFF-R/CD19 이중 CAR을 발현하기 위한 벡터의 한 예에 대한 개략도이다. 상이한 배열의 이중 CAR을 발현하도록 하기 위해 BAFF-R 및 CD19 scFv 요소는 달라질 수 있다. 말단절단된 EGFR (EGFRt)은 선별 마커로서 발현된다.
도 7은 이중 CAR 발현 연구 결과를 도시한 것이다. T 세포 (주르카트(Jurkat))에 각 CAR 구축물 또는 공 벡터 (모의)를 형질도입하였다. 세포를 프로테인 L- 또는 EGFR-APC 접합된 항체로 염색하였다. 프로테인 L은 scFv의 가변 경쇄를 표적화하고, 말단절단된 EGFR은 CAR 벡터에 의해 공동 발현된다. 이중 CAR을 적절하게 발현할 수 있는 구축물을 추가로 연구하였다. 이중 CAR 1296 및 이중 CAR 1316은 무손상 CAR 및 EGFRt 선별 마커를 발현한 반면, 이중 CAR 1250은 무손상 CAR을 발현하지 못했다.
도 8은 표적 세포와의 인큐베이션 후, 1250 이중 CAR T 세포 탈과립화를 평가하는 FACS 검정 결과를 도시한 것이다. 표적 세포는 BAFF-R 단일 양성, CD19 단일 양성, 또는 BAFF-R 및 CD19 이중 음성이다. 대조군 BAFF-R 단일 CAR 및 비-형질도입된 T 세포 (비-CAR)를 대조군으로서 사용하였다. 1250 이중 CAR은 BAFF-R-양성 L 세포에 대한 반응을 유도하지 못했으며, 이는 BAFF-R-표적화 scFv가 적절하게 발현되지 않았다는 것을 시사하는 것이다.
도 9는 BAFF-R/CD19 이중 CAR 연구를 위한 모델을 개발하는 데 사용된 세포주 발생과 관련된 분석 결과를 도시한 것이다. 이중 CAR 모델 개발을 위해 사용된 Nalm-6 넉아웃 세포주의 FACS 히스토그램. Nalm-6 B-ALL 종양 세포주를 CRISPR로 유전자 편집하여 BAFF-R (좌측) 또는 CD19 (우측)를 넉아웃시켰다. 시판용 BAFF-R 및 CD19 항체를 이용한 FACS 염색에 의해 표면 단백질 발현을 확인하였다. Nalm-6 야생형 (WT)을 대조군으로서 사용하였다.
도 10A-10B는 BAFF-R/CD19 이중 CAR의 CTL 기능 분석 결과를 도시한 것이다. 그래프는 Nalm-6 ALL 종양 세포주에 대한 세포독성 T 림프구 검정법으로부터 플롯팅된 비(specific) 용해 산출치를 보여주는 것이다. 표적 세포주 Nalm-6 (WT, CD19 넉아웃, 또는 BAFF-R 넉아웃 변이체)을 크로뮴-51로 표지하고, 이펙터 CAR T 세포와 함께 인큐베이션시켰다. CAR은 BAFF-R/CD19 이중 표적화 CAR을 포함하였고: A). 1296 및 1250, 또는 B). 1296 및 1316; 두 패널 모두에서 대조군은 단일 표적화 CAR을 포함한다: BAFF-R CAR 및 CD19 CAR 및 비-형질도입된 T 세포 (비-CAR, 동종이계 대조군). 각 패널에서 T 세포 모두 1명의 건강한 공여자로부터 유래된 것이었다. 이펙터 T 세포 기능에 기인한 표적 세포에 의해 방출된 크로뮴은 감마 계수기에 의해 측정하였고, 최대 가능 방출률(%)로서 산출하였다. 실험을 삼중으로 수행하였고, 스튜던츠 t 검정(Student's t-test)에 의해 분석하였다; A. ** P<0.001 (이중 CAR 간의 비교); 및 B). ** P<0.001 (c/w 비-CAR 대조군). 1250 이중 CAR CTL 데이터는 잠재적인 BAFF-R 표적화 결핍을 시사한다.
도 11A-11B는 BAFF-R- + CD19-결핍 혼합 B-ALL 종양에서 BAFF-R/CD19 이중 CAR의 활성을 도시한 것이다. A) 0일째 1 x 105개의 RFP-음성, 루시페라제 발현 Nalm-6-CD19KO + 2.5 x 105개의 RFP-양성, 루시페라제 발현 Nalm-6-BAFF-RKO 종양 세포의 혼합물에 의한 IV 종양 챌린지 후 NSG 마우스의 생체발광 영상. 이어서, 종양을 보유하는 마우스 5마리로 이루어진 각 군을 무작위로 10일째 IV로 단일 주입으로서 2.5 x 106개의 CD4 TN CAR-T + 106개의 CD8 TN 1296 또는 1316 이중 CAR T 세포/마우스를 이용하는 처리로 배정하였다. 동일 공여자로부터의 비-형질도입된 CD4/CD8 T 세포를 동종이계 대조군 (비-CAR)으로서 사용하였다. B) 전체 생존율의 카플란 마이어(Kaplan-Meier) 플롯이 제시되어 있다. 로그-순위 검정은 제시된 바와 같이 실험군을 비교한다. 1296 처리와 비교하여 1316 처리는 유의하게 연장된 생존을 부여하였다.
도 12는 넉-아웃 종양에 대한 1316 BAFF-R/CD19 이중 CAR의 활성을 도시한 것이다. CD107a 탈과립화 검정법에 의해 측정된, BAFF-R CAR T 세포 기능적 효능에 관한 FACS 플롯. CD4 또는 CD8 BAFF-R CAR T 세포를 CD19-BAFF-R+ Nalm-6 또는 CD19+BAFF-R- Nalm-6 세포주와 함께 공동으로 인큐베이션시켰다. 단일 표적화 CD19 또는 BAFF-R CAR T 세포를 대조군으로서 사용하였다.
도 13A-13B는 혼합 B-ALL 종양에서의 TN/ MEM 1316 BAFF-R/CD19 이중 CAR의 활성을 도시한 것이다. A) 0일째 1 x 105개의 RFP-음성, 루시페라제 발현 Nalm-6-CD19KO + 1 x 105개의 RFP-양성, 루시페라제 발현 Nalm-6-BAFF-RKO 종양 세포의 혼합물에 의한 IV 종양 챌린지 후 NSG 마우스의 생체발광 영상. 이어서, 종양을 보유하는 마우스 5마리로 이루어진 각 군을 무작위로 9일째 IV로 저용량 (2.8 x 106개 TN/MEM), 고용량 (5.6 x 106개 TN/ MEM)의 단일 주입으로서 1316 이중 CAR T 세포/마우스를 이용하는 처리로 배정하였고, 각각 1 x 106 및 2 x 106개의 BAFF-R CAR T 세포를 얻었다. 동일 공여자로부터의 2.5 또는 5 x 106개의 비-형질도입된 TN/ MEM 세포를 동종이계 대조군 (비-CAR)으로서 사용하였다. B) 전체 생존율의 카플란 마이어 플롯이 제시되어 있다. 로그-순위 검정은 제시된 바와 같이 실험군을 비교한다. 두 투약 사이의 생존율에 있어 어떤 유의한 차이도 관찰되지 않았다.
도 2는 신호 서열을 포함하는, 미성숙 1250 이중 CAR의 아미노산 서열 (서열식별번호 58)을 도시한 것이다. 성숙한 CAR (서열식별번호 59)은 아미노에서 카르복시 말단으로 BAFF-R scFv, 링커, CD19 scFv (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 4-1BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 3은 신호 서열을 포함하는, 미성숙 1296 이중 CAR의 아미노산 서열 (서열식별번호 60)을 도시한 것이다. 성숙한 CAR (서열식별번호 61)은 아미노에서 카르복시 말단으로 CD19 scFv (FMC63으로부터 유래), 링커, BAFF-R scFv, IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 4-1BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 4는 신호 서열을 포함하는, 미성숙 1316 이중 CAR의 아미노산 서열 (서열식별번호 62)을 도시한 것이다. 성숙한 CAR (서열식별번호 63)은 아미노에서 카르복시 말단으로 CD19 VL (FMC63으로부터 유래), GGGS 링커, BAFF-R scFv, CD19 VH (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 41BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 5는 (A) 신호 서열을 포함하는, 미성숙 CD19 CAR의 아미노산 서열 (서열식별번호 64) 및 B 신호 서열을 포함하는, 미성숙 BAFF-R CAR의 아미노산 서열 (서열식별번호 66)을 도시한 것이다. 성숙한 CD19 CAR (서열식별번호 65)은 아미노에서 카르복시 말단으로 CD19 scFv (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD28 막횡단 도메인, CD28(GG) 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다. 성숙한 BAFF-R CAR (서열식별번호 67)은 아미노에서 카르복시 말단으로 BAFF-R scFv, IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 4-1BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함한다.
도 6은 BAFF-R/CD19 이중 CAR을 발현하기 위한 벡터의 한 예에 대한 개략도이다. 상이한 배열의 이중 CAR을 발현하도록 하기 위해 BAFF-R 및 CD19 scFv 요소는 달라질 수 있다. 말단절단된 EGFR (EGFRt)은 선별 마커로서 발현된다.
도 7은 이중 CAR 발현 연구 결과를 도시한 것이다. T 세포 (주르카트(Jurkat))에 각 CAR 구축물 또는 공 벡터 (모의)를 형질도입하였다. 세포를 프로테인 L- 또는 EGFR-APC 접합된 항체로 염색하였다. 프로테인 L은 scFv의 가변 경쇄를 표적화하고, 말단절단된 EGFR은 CAR 벡터에 의해 공동 발현된다. 이중 CAR을 적절하게 발현할 수 있는 구축물을 추가로 연구하였다. 이중 CAR 1296 및 이중 CAR 1316은 무손상 CAR 및 EGFRt 선별 마커를 발현한 반면, 이중 CAR 1250은 무손상 CAR을 발현하지 못했다.
도 8은 표적 세포와의 인큐베이션 후, 1250 이중 CAR T 세포 탈과립화를 평가하는 FACS 검정 결과를 도시한 것이다. 표적 세포는 BAFF-R 단일 양성, CD19 단일 양성, 또는 BAFF-R 및 CD19 이중 음성이다. 대조군 BAFF-R 단일 CAR 및 비-형질도입된 T 세포 (비-CAR)를 대조군으로서 사용하였다. 1250 이중 CAR은 BAFF-R-양성 L 세포에 대한 반응을 유도하지 못했으며, 이는 BAFF-R-표적화 scFv가 적절하게 발현되지 않았다는 것을 시사하는 것이다.
도 9는 BAFF-R/CD19 이중 CAR 연구를 위한 모델을 개발하는 데 사용된 세포주 발생과 관련된 분석 결과를 도시한 것이다. 이중 CAR 모델 개발을 위해 사용된 Nalm-6 넉아웃 세포주의 FACS 히스토그램. Nalm-6 B-ALL 종양 세포주를 CRISPR로 유전자 편집하여 BAFF-R (좌측) 또는 CD19 (우측)를 넉아웃시켰다. 시판용 BAFF-R 및 CD19 항체를 이용한 FACS 염색에 의해 표면 단백질 발현을 확인하였다. Nalm-6 야생형 (WT)을 대조군으로서 사용하였다.
도 10A-10B는 BAFF-R/CD19 이중 CAR의 CTL 기능 분석 결과를 도시한 것이다. 그래프는 Nalm-6 ALL 종양 세포주에 대한 세포독성 T 림프구 검정법으로부터 플롯팅된 비(specific) 용해 산출치를 보여주는 것이다. 표적 세포주 Nalm-6 (WT, CD19 넉아웃, 또는 BAFF-R 넉아웃 변이체)을 크로뮴-51로 표지하고, 이펙터 CAR T 세포와 함께 인큐베이션시켰다. CAR은 BAFF-R/CD19 이중 표적화 CAR을 포함하였고: A). 1296 및 1250, 또는 B). 1296 및 1316; 두 패널 모두에서 대조군은 단일 표적화 CAR을 포함한다: BAFF-R CAR 및 CD19 CAR 및 비-형질도입된 T 세포 (비-CAR, 동종이계 대조군). 각 패널에서 T 세포 모두 1명의 건강한 공여자로부터 유래된 것이었다. 이펙터 T 세포 기능에 기인한 표적 세포에 의해 방출된 크로뮴은 감마 계수기에 의해 측정하였고, 최대 가능 방출률(%)로서 산출하였다. 실험을 삼중으로 수행하였고, 스튜던츠 t 검정(Student's t-test)에 의해 분석하였다; A. ** P<0.001 (이중 CAR 간의 비교); 및 B). ** P<0.001 (c/w 비-CAR 대조군). 1250 이중 CAR CTL 데이터는 잠재적인 BAFF-R 표적화 결핍을 시사한다.
도 11A-11B는 BAFF-R- + CD19-결핍 혼합 B-ALL 종양에서 BAFF-R/CD19 이중 CAR의 활성을 도시한 것이다. A) 0일째 1 x 105개의 RFP-음성, 루시페라제 발현 Nalm-6-CD19KO + 2.5 x 105개의 RFP-양성, 루시페라제 발현 Nalm-6-BAFF-RKO 종양 세포의 혼합물에 의한 IV 종양 챌린지 후 NSG 마우스의 생체발광 영상. 이어서, 종양을 보유하는 마우스 5마리로 이루어진 각 군을 무작위로 10일째 IV로 단일 주입으로서 2.5 x 106개의 CD4 TN CAR-T + 106개의 CD8 TN 1296 또는 1316 이중 CAR T 세포/마우스를 이용하는 처리로 배정하였다. 동일 공여자로부터의 비-형질도입된 CD4/CD8 T 세포를 동종이계 대조군 (비-CAR)으로서 사용하였다. B) 전체 생존율의 카플란 마이어(Kaplan-Meier) 플롯이 제시되어 있다. 로그-순위 검정은 제시된 바와 같이 실험군을 비교한다. 1296 처리와 비교하여 1316 처리는 유의하게 연장된 생존을 부여하였다.
도 12는 넉-아웃 종양에 대한 1316 BAFF-R/CD19 이중 CAR의 활성을 도시한 것이다. CD107a 탈과립화 검정법에 의해 측정된, BAFF-R CAR T 세포 기능적 효능에 관한 FACS 플롯. CD4 또는 CD8 BAFF-R CAR T 세포를 CD19-BAFF-R+ Nalm-6 또는 CD19+BAFF-R- Nalm-6 세포주와 함께 공동으로 인큐베이션시켰다. 단일 표적화 CD19 또는 BAFF-R CAR T 세포를 대조군으로서 사용하였다.
도 13A-13B는 혼합 B-ALL 종양에서의 TN/ MEM 1316 BAFF-R/CD19 이중 CAR의 활성을 도시한 것이다. A) 0일째 1 x 105개의 RFP-음성, 루시페라제 발현 Nalm-6-CD19KO + 1 x 105개의 RFP-양성, 루시페라제 발현 Nalm-6-BAFF-RKO 종양 세포의 혼합물에 의한 IV 종양 챌린지 후 NSG 마우스의 생체발광 영상. 이어서, 종양을 보유하는 마우스 5마리로 이루어진 각 군을 무작위로 9일째 IV로 저용량 (2.8 x 106개 TN/MEM), 고용량 (5.6 x 106개 TN/ MEM)의 단일 주입으로서 1316 이중 CAR T 세포/마우스를 이용하는 처리로 배정하였고, 각각 1 x 106 및 2 x 106개의 BAFF-R CAR T 세포를 얻었다. 동일 공여자로부터의 2.5 또는 5 x 106개의 비-형질도입된 TN/ MEM 세포를 동종이계 대조군 (비-CAR)으로서 사용하였다. B) 전체 생존율의 카플란 마이어 플롯이 제시되어 있다. 로그-순위 검정은 제시된 바와 같이 실험군을 비교한다. 두 투약 사이의 생존율에 있어 어떤 유의한 차이도 관찰되지 않았다.
BAFF-R/CD19 이중 CAR 및 BAFF-R/CD19 비시스트로닉 CAR은 다양한 BAFF-R scFv 및 CD19 scFv 중 임의의 것을 사용할 수 있고, 제1 scFv가 제2 scFv의 가변 도메인 사이에 위치하는 BAFF-R/CD19 이중 CAR의 경우, 다양한 VL 및 VH 중 임의의 것이 사용될 수 있다.
도 1은, 하나는 BAFF-R scFv가 CD19 scFv에 대하여 아미노 말단에 위치하고, 하나는 CD19 scFv가 BAFF-R scFv에 대하여 아미노 말단에 위치하는 것인, 탠덤 구축물의 2가지 예를 나타낸 개략도를 도시한 것이다. BAFF-R/CD29 이중 CAR에 대한 루프 구축물의 한 예도 또한 도시되어 있다. 본 예에서, BAFF-R은 CD19 VL (scFv에 대해 아미노 말단에 위치)과 CD19 VH 도메인 (scFv에 대해 카르복시 말단에 위치) 사이에 위치한다. 또한, 단일 세포가, 하나는 BAFF-R로 표적화되고, 하나는 CD19로 표적화되는 것인 2개의 CAR을 발현하는 비시스트로닉 구축물의 예도 제시되어 있다.
BAFF
-R
scFv
서열
BAFF-R/CD19 이중 CAR에서 사용된 BAFF-R scFv 서열은 US PCT/US2017/036181에 더욱 상세하게 기술되어 있는 클론 90 및 클론 55인 2개의 모노클로날 항체로부터 유래될 수 있다. 예를 들어, VL은 하기 기술되는 C90 CDR 서열 또는 C55 CDR 서열을 포함할 수 있다.
C90 CDR L1: ESVDNYGISF (서열식별번호 1)
C90 CDR L2: AAS (서열식별번호 2)
C90 CDR L3: QQSKEVPWT (서열식별번호 3)
C90 CDR H1: GDSITSGY (서열식별번호 4)
C90 CDR H2: ISYSGST (서열식별번호 5)
C90 CDR H3: ASPNYPFYAMDY (서열식별번호 6)
C55 CDR L1: QDISNY (서열식별번호 7)
C55 CDR L2: YTS (서열식별번호 8)
C55 CDR L3: FSELPWT (서열식별번호 9)
C55 CDR H1: GFSLSTSGMG (서열식별번호 10)
C55 CDR H2: IWWDDDK (서열식별번호 11)
C55 CDR H3: ARSFGYGLDY (서열식별번호 12)
이중 CAR의 BAFF-R scFv에서 사용하는 데 적합한 중쇄 가변 도메인 (VH) 중에는 모노클로날 항체 클론 90 (PCT/US2017/036181에 더욱 상세하게 기술)으로부터 유래된 하기 중쇄 가변 도메인이 있다. 이들 중, Hu90 HC-1, HC-2 및 HC-3은 인간화된 것이다.
Chi90 HC: MYRMQLLSCIALSLALVTNSEVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWNWIRKFPGNKLEYMGYISYSGSTYYNPSLKSRISITRDTSKNQYYLQLNSVTPEDTATYYCASPNYPFYAMDYWGQGTSVTVSSDI (서열식별번호 13)
Hu90 HC-1: MDPKGSLSWRILLFLSLAFELSYGQVQLQESGPGLVKPSQTLSLTCTVSGDSITSGYWNWIRQHPGKGLEYIGYISYSGSTYYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCASPNYPFYAMDYWGQGTLVTVSS (서열식별번호 14)
Hu90 HC-2: MDPKGSLSWRILLFLSLAFELSYGEVQLQESGPGLVKPSQTLSLTCTVSGDSITSGYWNWIRQHPGKGLEYIGYISYSGSTYYNPSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCASPNYPFYAMDYWGQGTLVTVSS (서열식별번호 15)
Hu90 HC-3: MDPKGSLSWRILLFLSLAFELSYGEVQLQESGPGLVKPSETLSLTCSVSGDSITSGYWNWIRQPPGKGLEYIGYISYSGSTYYNPSLKSRVTISRDTSKNQYSLRLSSVTAADTALYYCASPNYPFYAMDYWGQGTRVTVSS (서열식별번호 16)
이중 CAR의 BAFF-R scFv에서 사용하는 데 적합한 경쇄 가변 도메인 (VL) 중에는 모노클로날 항체 클론 90 (PCT/US2017/036181에 더욱 상세하게 기술)으로부터 유래된 하기 중쇄 가변 도메인이 있다. 이들 중, Hu90 LC-1, LC-2 및 LC-3은 인간화된 것이다.
Chi90 LC: MYRMQLLSCIALSLALVTNSDIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGQPPKLLIYAASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIKTMEIKR (서열식별번호 17)
HuC90 LC-1: METDTLLLWVLLLWVPGSTGEIVLTQSPATLSLSPGERATLSCRASESVDNYGISFLNWFQQKPGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKVEIKRTV (서열식별번호 18)
Hu90 LC-2: METDTLLLWVLLLWVPGSTGDIVLTQSPATLSLSPGERATLSCRASESVDNYGISFMNWFQQKPGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKVEIKRTV (서열식별번호 19)
HuC90 LC-3: METDTLLLWVLLLWVPGSTGDIVMTQSPSSLSASVGDRVTITCRASESVDNYGISFMNWFQQKPGKAPKLLIYAASNLGSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSKEVPWTFGQGTKVEIKRTV (서열식별번호 20)
또한, 이중 CAR의 BAFF-R scFv에서 사용하는 데 적합한 중쇄 가변 도메인 (VH) 중에는 모노클로날 항체 클론 55 (PCT/US2017/036181에 더욱 상세하게 기술)로부터 유래된 하기 중쇄 가변 도메인이 있다. 이들 중, Hu55 HC-1, HC-2 및 HC-3은 인간화된 것이다.
Chi55 HC: MYRMQLLSCIALSLALVTNSQVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYYNSSLKSHLTISKDTSRNQVFLKITSVDTADTATYYCARSFGYGLDYWGQGTTLTVSSAS (서열식별번호 21)
Hu55 HC-1: MDPKGSLSWRILLFLSLAFELSYGQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARSFGYGLDYWGQGTLVTVSS (서열식별번호 22)
Hu55 HC-2: MDPKGSLSWRILLFLSLAFELSYGQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNSSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARSFGYGLDYWGQGTLVTVSS (서열식별번호 23)
Hu55 HC-3: MDPKGSLSWRILLFLSLAFELSYGQVTLKESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNTSLKSRLTITKDTSKNQVVLKMTNMDPVDTATYYCARSFGYGLDYWGQGTLVTVSS (서열식별번호 24)
또한, 이중 CAR의 BAFF-R scFv에서 사용하는 데 적합한 경쇄 가변 도메인 (VL) 중에는 모노클로날 항체 클론 90 (PCT/US2017/036181에 더욱 상세하게 기술)으로부터 유래된 하기 중쇄 가변 도메인이 있다. 이들 중, Hu55 LC-1, LC-2 및 HC-3은 인간화된 것이다.
Chi55 LC: MYRMQLLSCIALSLALVTNSDIQMTQTTSSLSASLGDRVTISCSASQDISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYSLTISSLEPEDIATYYCHQFSELPWTFGGGTKLEIKRT (서열식별번호 25)
Hu55 LC-1: METDTLLLWVLLLWVPGSTGDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYYTSSLHTGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCHQFSELPWTFGGGTKVEIKRTV (서열식별번호 26)
Hu55 LC-2: METDTLLLWVLLLWVPGSTGDIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSSLHTGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCHQFSELPWTFGGGTKVEIKRTV (서열식별번호 27)
Hu55 LC-3: METDTLLLWVLLLWVPGSTGDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKTPKLLIYYTSSLHTGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCHQFSELPWTFGGGTKVEIKRTV (서열식별번호 28)
BAFF-R scFv의 VH 및 VL 도메인은 변형될 수 있다. 따라서, scFv에서 Hu90 LC-1, Hu90 LC-2, Hu90 LC-3, Hu90 HC-1, Hu90 HC-2 및 Hu90 HC-3, Hu55 LC-1, Hu55 LC-2, Hu55 LC-3, Hu55 HC-1, Hu55 HC-2 및 Hu90 HC-3은 각각 1, 2, 3, 4 또는 5개의 단일 아미노산 치환을 포함할 수 있다. 일부 경우에, 치환은 CDR보다는 프레임워크 영역 (FR)으로 한정된다. 일부 경우에, 치환은 보존적 치환이다.
CDR 및 FR의 위치는 카바트 넘버링 체계에 의해 정의될 수 있다 (Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, U.S. Government Printing Office (1991)). 유사하게, 항체의 경쇄 또는 중쇄 내의 개별 잔기에 의해 점유된 위치도 카바트 넘버링 체계에 의해 정의될 수 있다. 그러므로, 인간화 항체의 인간화 경쇄 및 인간화 중쇄 내의 결합을 위해 요구되는 잔기의 위치는 관련 기술분야에 널리 공지된 바와 같은 카바트 넘버링 체계에 따른 잔기의 위치에 의해 정의될 수 있다. 상기 기술된 바와 같이, 인간화 항체는 공여자 항체 (예컨대, 마우스)로부터의 CDR, 및 인간 항체로부터의 가변 영역 프레임워크 (FR)를 갖는 항체일 수 있다. 프레임워크 영역 (FR)은 CDR을 인간화 항체에서 제자리에 그대로 유지한다고 한다. 아미노-말단에서부터 진행하여, 이들 영역은 각각 경쇄의 경우, FR L1, FR L2, FR L3, 및 FR L4, 및 중쇄의 경우, FR H1, FR H2, FR H3, 및 FR H4로 지정된다.
CD19
scFv
서열
다양한 scFv 표적화 CD19가 BAFF-R/CD19 이중 CAR에서 사용될 수 있다.
FMC63 scFv: IPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ KPDGTVKLLI YHTSRLHSGV PSRFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVA PSQSLSVTCT VSGVSLPDYG VSWIRQPPRKGLEWLGVIWGSETTYYNSAL KSRLTIIKDN SKSQVFLKMN SLQTDDTAIYYCAKHYYYGGSYAMDYWGQG TSVTVSS (서열식별번호 29).
FMC63 VL: DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ KPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPYTFGGGTKLEIT (서열식별번호 30).
FMC63 VH: EVK LQESGPGLVAPSQSLSVTCTVSGVSLPDYG VSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDN SKSQVFLKMN SLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS (서열식별번호 31).
CD19에 결합하는 추가의 scFv는 US 2016/0152723 및 WO 2016/033570에 기술되어 있다.
스페이서
영역
본원에 기술된 이중 CAR 및 비시스트로닉 CAR은 표적화 도메인 (예컨대, scFv) 및 막횡단 도메인 사이에 위치하는 스페이서를 포함할 수 있다. 각종의 상이한 스페이서가 사용될 수 있다. 이들 중 일부는 인간 Fc 영역의 적어도 일부, 예를 들어 인간 Fc 영역 또는 CH3 도메인의 힌지 부분, 또는 그의 변이체를 포함한다. 하기 표 1은 본원에 기술된 CAR에서 사용될 수 있는 다양한 스페이서를 제공한다.
표 1:
스페이서의
예
일부 스페이서 영역은 면역글로불린 (예컨대, IgG1, IgG2, IgG3, IgG4) 힌지 영역 힌지 영역 머드 또는 일부, 즉, 면역글로불린의 CH1 및 CH2 도메인 사이에 있는 서열, 예컨대, IgG4 Fc 힌지 또는 CD8 힌지를 포함한다. 일부 스페이서 영역은 면역글로불린 CH3 도메인, 또는 CH3 도메인 및 CH2 도메인, 둘 모두를 포함한다. 면역글로불린 유래 서열은 하나 이상의 아미노산 변형, 예를 들어, 1, 2, 3, 4 또는 5개의 치환, 예컨대, 표적외 결합을 감소시키는 치환을 포함할 수 있다.
힌지/링커 영역은 또한 서열 ESKYGPPCPSCP (서열식별번호 34) 또는 ESKYGPPCPPCP (서열식별번호 33)를 갖는 IgG4 힌지 영역을 포함할 수 있다.
힌지/링커 영역은 또한 서열 ESKYGPPCPPCP (서열식별번호 33), 이어서, 링커 서열 GGGSSGGGSG (서열식별번호 32), 이어서, IgG4 CH3 서열 GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (서열식별번호 41)를 포함할 수 있다. 따라서, 전체 링커/스페이서 영역은 서열: ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (서열식별번호 _)를 포함할 수 있다. 일부 경우에, 스페이서는 서열식별번호 __와 비교하여 1,2,3,4, 또는 5개의 단일 아미노산 변이 (예컨대, 보존적 변이)를 갖는다. 일부 경우에, IgG4 Fc 힌지/링커 영역은 Fc 수용체 (FcR)에 의한 결합을 감소시키는 방식으로 2개 위치에서 돌연변이화된다 (L235E; N297Q).
막횡단
도메인
다양한 막횡단 도메인이 본원에 기술된 이중 CAR 및 비시스트로닉 CAR에서 사용될 수 있다. 표 2는 적합한 막횡단 도메인의 예를 포함한다. 스페이서 영역이 존재하는 경우, 막횡단 도메인은 스페이서 영역에 대해 카르복시 말단에 위치한다.
표 2:
막횡단
도메인의 예
공동자극 및
CD3제타
도메인
공동자극 도메인은 CD3ζ 신호전달 도메인과 함께 사용하기에 적합한 임의의 도메인일 수 있다. 일부 경우에, 공동자극 도메인은 RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (서열식별번호 52; LL에서 GG로의 아미노산 변이, 이중 밑줄체로 표시)과 적어도 90%, 적어도 95%, 적어도 98% 동일하거나, 또는 그와 동일한 서열을 포함하는 CD28 공동자극 도메인이다. 일부 경우에, CD28 공-신호전달 도메인은 서열식별번호 23과 비교하여 1, 2, 3, 4 또는 5개의 아미노산 변이를 갖는다 (바람직하게, 보존적 변이이고, 바람직하게, 밑줄체로 표시된 GG 서열에서의 변이는 아님). 일부 경우에, 공-신호전달 도메인은 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (서열식별번호 54)과 적어도 90%, 적어도 95%, 적어도 98% 동일하거나, 또는 그와 동일한 서열을 포함하는 4-1BB 공-신호전달 도메인이다. 일부 경우에, 4-1BB 공-신호전달 도메인은 서열식별번호 24와 비교하여 1, 2, 3, 4 또는 5개의 아미노산 변이를 갖는다 (바람직하게, 보존적 변이).
공동자극 도메인(들)은 막횡단 도메인과 CD3ζ 신호전달 도메인 사이에 위치한다. 표 3은 CD3ζ 신호전달 도메인 서열과 함께 적합한 공동자극 도메인의 예를 포함한다.
표 3:
CD3ζ
도메인 및 공동자극 도메인의 예
다양한 실시양태에서: 공동자극 도메인은 표 3에 제시된 공동자극 도메인, 또는 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형을 갖는 그의 변이체, CD28 공동자극 도메인, 또는 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형을 갖는 그의 변이체, 4-1BB 공동자극 도메인, 또는 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형을 갖는 그의 변이체, 및 OX40 공동자극 도메인, 또는 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형을 갖는 그의 변이체로 이루어진 군으로부터 선택된다. 특정 실시양태에서, 4-1BB 공동자극 도메인, 또는 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형을 갖는 그의 변이체가 존재한다. 일부 실시양태에서, 2개의 공동자극 도메인, 예를 들어, CD28 공동자극 도메인, 또는 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형 (예컨대, 치환)을 갖는 그의 변이체 및 4-1BB 공동자극 도메인, 또는 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형 (예컨대, 치환)을 갖는 그의 변이체가 존재한다. 다양한 실시양태에서, 1-5개의 (예컨대, 1 또는 2개의) 아미노산 변형은 치환이다. 공동자극 도메인은 CD3ζ 신호전달 도메인에 대해 아미노 말단에 위치하고, 일부 경우에, 2 - 10개, 예컨대, 3개의 아미노산 (예컨대, GGG)으로 이루어진 짧은 링커가 공동자극 도메인과 CD3ζ 신호전달 도메인 사이에 위치한다.
CD3ζ
신호전달 도메인
CD3ζ 신호전달 도메인은 CD3ζ 신호전달 도메인과 함께 사용하기에 적합한 임의의 도메인일 수 있다. 일부 경우에, CD3ζ 신호전달 도메인은 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (서열식별번호 51)과 적어도 90%, 적어도 95%, 적어도 98% 동일하거나, 또는 그와 동일한 서열을 포함한다. 일부 경우에, CD3ζ 신호전달은 서열식별번호 51과 비교하여 1, 2, 3, 4 또는 5개의 아미노산 변이를 갖는다 (바람직하게, 보존적 변이).
말단절단된
EGFR
CD3ζ 신호전달 도메인 다음으로 리보솜 스킵 서열 (예컨대, LEGGGEGRGSLLTCGDVEENPGPR; 서열식별번호 56), 및 LVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM (서열식별번호 57)과 적어도 90%, 적어도 95%, 적어도 98% 동일하거나, 또는 그와 동일한 서열을 갖는 말단절단된 EGFR이 존재할 수 있다. 일부 경우에, 말단절단된 EGFR은 서열식별번호 57과 비교하여 1, 2, 3, 4 또는 5개의 아미노산 변이를 갖는다 (바람직하게, 보존적 변이).
아미노산 변형은 단백질 또는 펩티드 서열에서 아미노산 치환, 삽입 및/또는 결실을 지칭한다. "아미노산 치환" 또는 "치환"은 모체 펩티드 또는 단백질 서열의 특정 위치에 있는 아미노산을 또 다른 아미노산으로 대체하는 것을 지칭한다. 비보존적 방식으로 (즉, 특정 크기 또는 특징을 갖는 아미노산 그룹에 속하는 아미노산에서 또 다른 그룹에 속하는 아미노산으로 코돈을 변이시킴으로써) 또는 보존적 방식으로 (즉, 특정 크기 또는 특징을 갖는 아미노산 그룹에 속하는 아미노산에서 동일한 그룹에 속하는 아미노산으로 코돈을 변이시킴으로써) 생성된 단백질 중의 아미노산을 변이시키는 치환이 이루어질 수 있다. 상기 보존적 변이는 일반적으로 생성된 단백질의 구조 및 기능을 더 적게 변화시킨다. 하기는 다양한 아미노산 그룹의 예이다: 1) 비극성 R 기를 갖는 아미노산: 알라닌, 발린, 류신, 이소류신, 프롤린, 페닐알라닌, 트립토판, 메티오닌; 2) 비하전된 극성 R 기를 갖는 아미노산: 글리신, 세린, 트레오닌, 시스테인, 티로신, 아스파라긴, 글루타민; 3) 하전된 극성 R 기를 갖는 아미노산 (pH 6.0에서 음으로 하전): 아스파르트산, 글루탐산; 4) 염기성 아미노산 (pH 6.0에서 양으로 하전): 리신, 아르기닌, 히스티딘 (pH 6.0에서). 또 다른 그룹은 페닐 기를 갖는 아미노산일 수 있다: 페닐알라닌, 트립토판 및 티로신.
CAR은 도 9에 제시된 성숙한 아미노산 서열 (서열식별번호 29-40)과 적어도 90%, 적어도 95%, 적어도 98% 동일하거나, 또는 그와 동일한 서열로서, GMCSFRa 신호 서열을 포함 또는 배제하고, T2A 리보솜 스킵 서열 및 말단절단된 EGFRt를 포함 또는 배제하는 것인 서열을 포함할 수 있다.
일부 경우에, CAR은, CAR 오픈 리딩 프레임 다음으로 T2A 리보솜 스킵 서열 및 말단절단된 EGFR (EGFRt)이 존재하고, 세포질 신호전달 테일은 없는 벡터를 사용하여 제조될 수 있다. 상기 배열에서, EGFRt의 공동-발현은, 유전자 변형 세포의 정확한 측정을 허용하고, 유전자 변형 세포의 양성 선별을 가능하게 할 뿐만 아니라, 입양 전달 후 생체내에서 치료 T 세포의 효율적인 세포 추적도 가능하게 하는, 불활성, 비-면역원성 표면 마커를 제공한다. 시토카인 스톰 및 표적외 독성을 피하기 위해 증식을 효율적으로 제어하는 것이 T 세포 면역요법의 성공을 위해서는 중요한 장애물이 된다. CAR 렌티바이러스 벡터에 도입된 EGFRt는 치료 관련 독성의 경우 CAR+ T 세포를 절제하는 자살 유전자로 작용할 수 있다.
본원에 기술된 CAR은 비록 바람직하게는 재조합 DNA 기술을 이용하여 제조되지만, 관련 기술분야에 공지된 임의의 수단에 의해 제조될 수 있다. 키메라 수용체의 여러 영역을 코딩하는 핵산은 편의상 관련 기술분야에 공지된 분자 클로닝의 표준 기술 (게놈 라이브러리 스크리닝, 중첩 PCR, 프라이머 지원 라이게이션, 부위 지정 돌연변이유발법 등)에 의해 완전한 코딩 서열로 제조 및 어셈블리될 수 있다. 생성된 코딩 영역은 바람직하게 발현 벡터 내로 삽입되고, 적합한 발현 숙주 세포주, 바람직하게, T 림프구 세포주, 가장 바람직하게, 자가 T 림프구 세포주를 형질전환시키는 데 사용된다.
환자로부터 단리된 다양한 T 세포 서브세트는 CAR 발현을 위한 벡터로 형질도입될 수 있다. 중심 기억 T 세포는 한 유용한 T 세포 서브세트이다. 중심 기억 T 세포는 예를 들어, 원하는 수용체를 발현하는 세포를 면역자기적으로 선별하는 CliniMACS® 장치를 사용하여 CD45RO+/CD62L+ 세포를 선별함으로써 말초 혈액 단핵 세포 (PBMC)로부터 단리될 수 있다. 중심 기억 T 세포에 대해 농축된 세포는 항-CD3/CD28로 활성화될 수 있고, 예를 들어, CAR의 발현을 지시하는 렌티바이러스 벡터 뿐만 아니라, 생체내 검출, 절제, 및 잠재적인 생체외 선별을 위한 비-면역원성 표면 마커로 형질도입될 수 있다. 활성화된/유전적으로 변형된 중심 기억 T 세포는 시험관내에서 IL-2/IL-15로 확장된 후, 동결보존될 수 있다.
실시예 1: 이중 CAR 발현을 위한 T 세포 집단 제조
BAFF-CD19 이중 CAR의 발현을 위해 하기 T 세포 집단을 제조하였다: CD4+ 나이브 T 세포 (CD4+ TN), CD8+ 나이브 T 세포 (CD8+ TN), CD8+ 중심 기억 T 세포 (CD8+ TCM), CD8+ 기억 줄기 세포 (CD8+ MSC) 및 Pan T 세포 (Pan T). 간략하면, 5 mL의 혈액 샘플을 5 mL 히스토파크-1077 (시그마 알드리치(Sigma Aldrich))에 첨가한다. 혼합물을 2,500 RPM (실온 (RT), 브레이크 없음)으로 20 min 동안 원심분리한다. 중간 말초 혈액 단핵 세포 (PBMC) 층을 수집하고, 50 mL PBS (코닝(Corning))로 세척하고, 1,500 RPM (RT)으로 5 min 동안 원심분리한다. 수집된 세포를 10 mL RBC 용해 완충제 (퀴아젠)와 함께 조합하고, 7 min 동안 인큐베이션시킨다. 이어서, 세포를 PBS로 세척하고, 5 min 동안 (1,500 RPM, RT) 원심분리한다.
제조사의 설명서를 사용하여 스템셀 테크놀러지즈, 인크.(StemCell Technologies, Inc.)로부터 이용가능한 하기 키트: 이지셉(EasySep)™ 인간 나이브 CD4+ T 세포 농축 키트 (CD4+ TN), 이지셉™ 인간 나이브 CD8+ T 세포 농축 키트 (CD8+ TN), 및 이지셉™ 인간 T 세포 농축 키트 (Pan T)를 이용하여 다양한 T 세포 집단을 제조할 수 있다. CD8+ TCM은 제조사의 설명서를 사용하여 스템셀 테크놀러지즈, 인크.로부터 이용가능한 이지셉™ 인간 CD8+ T 세포 농축 키트를 이용하여 CD8+ T 세포를 단리시킴으로써 제조할 수 있고, 이어서, CD8-PerCP-Cy5.5, CD45 RO-APC, 및 CD62L-PE로 염색할 수 있다. 이어서, 염색된 세포를 분류하여 CD8+/CD45+/CD62L+ 삼중 양성 세포를 단리시킨다. 표 4에 제시된 배양 조건을 사용하여 CD8+ TN으로부터 CD8+ 기억 줄기 세포 (CD8+ MSC)를 생성할 수 있다. 표 4에 제시된 바와 같이 다른 T 세포 집단을 배양할 수 있다.
실시예 2: BAFF -R/CD19 이중 CAR의 서열
다양한 BAFF-R/CD19 이중 CAR을 제조하였다. 1250 이중 CAR (서열식별번호 59)은 아미노에서 카르복시 말단으로 BAFF-R scFv, 링커, CD19 scFv (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 41BB 세포질 도메인, GGG 링커, 및 CD3 제타 신호전달 도메인을 포함한다 (도 2). 1296 이중 CAR (서열식별번호 61)은 아미노에서 카르복시 말단으로 CD19 scFv (FMC63으로부터 유래), 링커, BAFF-R scFv, IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 41BB 세포질 도메인, GGG 링커, 및 CD3 제타 신호전달 도메인을 포함한다 (도 3). 1316 이중 CAR (서열식별번호 63)은 아미노에서 카르복시 말단으로 CD19 VL (FMC63으로부터 유래), GGGS 링커, BAFF-R scFv, CD19 VH (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 41BB 세포질 도메인, GGG 링커, 및 CD3 제타 신호전달 도메인을 포함한다.
비시스트로닉 CAR은 렌티바이러스 벡터를 사용하여 BAFF-R CAR 및 CD19 CAR을 발현한다. 두 CAR은 동일한 T 세포에서 발현된다. 성숙한 CD19 CAR (서열식별번호 65)은 아미노에서 카르복시 말단으로 CD19 scFv (FMC63으로부터 유래), IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD28 막횡단 도메인, CD28(GG) 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함할 수 있다. 성숙한 BAFF-R CAR (서열식별번호 67)은 아미노에서 카르복시 말단으로 BAFF-R scFv, IgG4 (SmP/L235E,N297Q) 스페이서 도메인, CD4 막횡단 도메인, 4-1BB 세포질 도메인, GGG 링커, 및 CD3 신호전달 도메인을 포함할 수 있다.
실시예 2: BAFF -R/CD19 이중 CAR을 발현하는 렌티바이러스 벡터의 제조
도 5는 1250 이중 CAR을 발현하는 데 사용된 렌티바이러스 벡터의 개략적 다이어그램이다. 유사한 렌티바이러스 벡터 (svFv 부분 대체)를 이용하여 1296 이중 CAR, 및 1316 이중 CAR을 제조하였다.
실시예 3: CAR 발현 세포 제조
1:1 비드 대 세포 비로 세포를 CD3/CD28 인간 T 세포 활성화 비드 (써모 피셔)와 함께 조합하고, 밤새도록 (습윤화된 상태, 5% CO2, 37℃) 인큐베이션시켜 이중 CAR을 발현하는 렌티바이러스 벡터로의 형질도입을 위한 제제 중에서 세포를 활성화시켰다. 인큐베이션 후, 세포를 계수하고, 48 웰 플레이트 중에 1 x 106개의 세포/웰로 분포시켰다. 세포를 MOI = 1로 감염시켰다. 각 경우에, 전체 배양 배지를 250 ㎕가 될 때까지 보충하고, 30 min 동안 (800 g, RT) 원심분리하였다. 세포를 밤새도록 (습윤화된 상태, 5% CO2, 37℃) 인큐베이션시킨 후, 이어서, 표 1에 명시된 배지 중에서 10일 동안 배양한다. CD4+ TN, CD8+ TN, CD8+ TCM, 및 Pan T 세포 배양물은 1:1 세포 대 비드 비로 CD3/CD28 비드를 포함하였다. CD8+ T MSC 배양물은 CD3/CD28 비드를 포함하지 않았다. 유세포 분석법을 이용하여 GFP 양성 세포의 비율(%)에 의해 CAR의 발현을 평가하였다.
실시예 4: CAR 발현
T 세포 (주르카트)에 각 CAR 구축물 또는 공 벡터를 형질도입하였다. CAR 발현을 평가하기 위해, 세포를 프로테인 L- 또는 EGFR-APC 접합된 항체로 염색하였다. 프로테인 L은 scFv의 가변 경쇄를 표적화하고, 말단절단된 EGFR은 CAR 벡터에 의해 공동 발현된다. 이중 CAR을 적절하게 발현할 수 있는 구축물을 추가로 연구하였다. 도 7에서 알 수 있는 바와 같이, 이중 CAR 1296 및 이중 CAR 1316은 무손상 CAR 및 EGFRt 선별 마커를 발현한 반면, 이중 CAR 1250은 무손상 CAR을 발현하지 못했다.
실시예 5: BAFF -R 표적화된 CAR T 세포에 의한 시험관내 세포 사멸
1296 이중 CAR, 1316 이중 CAR, CD19 CAR 또는 BAFF-R CAR 세포를 발현하는 다양한 T 세포 집단을 이용한 시험관내 검정법. 표적 세포주 Nalm-6 (WT, CD19 넉아웃, 또는 BAFF-R 넉아웃 변이체)을 크로뮴-31로 표지하고, 이펙터 CAR T 세포와 함께 인큐베이션시켰다. CAR은 BAFF-R/CD19 이중 표적화 CAR: 1296 및 1316; 단일 표적화 CAR: BAFF-R CAR 및 CD19 CAR을 포함하였다. 비-형질도입된 T 세포 (비-CAR)를 동종이계 대조군으로서 사용하였다. T 세포 모두 1명의 건강한 공여자로부터 유래된 것이었다. 이펙터 T 세포 기능에 기인한 표적 세포에 의해 방출된 크로뮴은 감마 계수기에 의해 측정하였고, 최대 가능 방출률 (%)로서 산출하였다. 도 8에서 알 수 있는 바와 같이, 1250 이중 CAR은 BAFF-R-양성 L 세포에 대한 반응을 유도하지 못했으며, 이는 BAFF-R-표적화 scFv가 적절하게 발현되지 않았다는 것을 시사하는 것이다.
실시예 6: BAFF -R- 및 CD19-결핍 뮤린 모델
Nalm-6 B-ALL 종양 세포주를 CRISPR로 유전자 편집하여 BAFF-R 또는 CD19를 넉아웃시켰다. 시판용 BAFF-R 및 CD19 항체를 이용한 FACS 염색에 의해 표면 단백질 발현을 확인하였다. Nalm-6 야생형 (WT)을 대조군으로서 사용하였다. 도 9에 제시된 바와 같이, FACS 분석을 통해 넉아웃을 확인한다.
실시예 7: 이중 CAR T 세포의 CTL 기능
결과가 도 10에 제시되어 있는 본 연구에서, 표적 세포주 Nalm-6, WT, CD19 넉아웃, 또는 BAFF-R 넉아웃 변이체를 크로뮴-51로 표지하고, 이펙터 CAR T 세포와 함께 인큐베이션시켰다. CAR은 BAFF-R/CD19 이중 표적화 CAR을 포함하였다. 1250 이중 CAR CTL 데이터는 잠재적인 BAFF-R 표적화 결핍을 시사한다.
실시예 8: BAFF -R-양성 CD19-음성 혼합 B-ALL 종양에서의 BAFF -R/CD19 이중 CAR의 활성
도 11A-11B는 0일째 1 x 105개의 RFP-음성, 루시페라제 발현 Nalm-6-CD19KO + 2.5 x 105개의 RFP-양성, 루시페라제 발현 Nalm-6-BAFF-RKO 종양 세포의 혼합물에 의한 IV 종양 챌린지 후 1316 이중 CAR 및 1296NSG 마우스의 영향을 조사한 연구 결과를 보여주는 것이다. 이어서, 종양을 보유하는 마우스 5마리로 이루어진 각 군을 무작위로 10일째 IV로 단일 주입으로서 2.5 x 106개의 CD4 TN CAR-T + 106개의 CD8 TN 1296 또는 1316 이중 CAR T 세포/마우스를 이용하는 처리로 배정하였다. 동일 공여자로부터의 비-형질도입된 CD4/CD8 T 세포를 동종이계 대조군 (비-CAR)으로서 사용하였다. 알 수 있는 바와 같이, 1296 처리와 비교하여 1316 처리는 유의하게 연장된 생존을 부여하였다.
실시예 9: 넉-아웃 종양에 대한 1316 BAFF -R/CD19 이중 CAR의 탈과립화
CD107a 탈과립화를 이용하여 넉아웃 종양에 대한 이중 CAR 1316 효능을 평가하였다. CD4 또는 CD8 BAFF-R CAR T 세포를 CD19-BAFF-R+ Nalm-6 또는 CD19+BAFF-R- Nalm-6 세포주와 함께 인큐베이션시켰다. 단일 표적화 CD19 또는 BAFF-R CAR T 세포를 대조군으로서 사용하였다.
실시예 10: 혼합 B-ALL 종양에서의 TN/ MEM 1316 BAFF -R/CD19 이중 CAR의 활성
NSG 마우스를 0일째 1 x 105개의 RFP-음성, 루시페라제 발현 Nalm-6-CD19KO + 1 x 105개의 RFP-양성, 루시페라제 발현 Nalm-6-BAFF-RKO 종양 세포주의 혼합물로 챌린지하였다. 이어서, 종양을 보유하는 마우스 5마리로 이루어진 각 군을 무작위로 9일째 IV로 저용량 (2.8 x 106개 TN/MEM), 고용량 (5.6 x 106개 TN/MEM)의 단일 주입으로서 1316 이중 CAR T 세포/마우스를 이용하는 처리로 배정하였고, 각각 1 x 106 및 2 x 106개의 BAFF-R CAR T 세포를 얻었다. 동일 공여자로부터의 2.5 또는 5 x 106개의 비-형질도입된 TN/MEM 세포를 동종이계 대조군 (비-CAR)으로서 사용하였다. 1316 이중 CAR은 유의하게 더 긴 생존을 부여하였다. 두 투약 사이의 생존율에 있어 어떤 유의한 차이도 관찰되지 않았다.
SEQUENCE LISTING
<110> Qin, Hong
Wang, Xiuli
Kwak, Larry Wonshin
Forman, Stephen J.
<120> BAFF-R/CD19 TARGETED CHIMERIC ANTIGEN RECEPTOR-MODIFIED T CELLS
AND USE THEREOF
<130> 40056-0045WO1
<140> PCT/US2020/019082
<141> 2020-02-20
<150> US 62/808,222
<151> 2019-02-20
<160> 68
<170> PatentIn version 3.5
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Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe
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Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
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Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
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Pro Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val
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Pro Gly Lys Gly Leu Glu Tyr Ile Gly Tyr Ile Ser Tyr Ser Gly Ser
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Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Arg Asp
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Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
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Asp Thr Ala Val Tyr Tyr Cys Ala Ser Pro Asn Tyr Pro Phe Tyr Ala
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Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
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Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
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Pro Gly Lys Gly Leu Glu Tyr Ile Gly Tyr Ile Ser Tyr Ser Gly Ser
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Thr Ser Lys Asn Gln Tyr Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
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Asp Thr Ala Val Tyr Tyr Cys Ala Ser Pro Asn Tyr Pro Phe Tyr Ala
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Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
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Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
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Leu Ala Phe Glu Leu Ser Tyr Gly Glu Val Gln Leu Gln Glu Ser Gly
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Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ser Val
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Ser Gly Asp Ser Ile Thr Ser Gly Tyr Trp Asn Trp Ile Arg Gln Pro
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Pro Gly Lys Gly Leu Glu Tyr Ile Gly Tyr Ile Ser Tyr Ser Gly Ser
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Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Arg Asp
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Thr Ser Lys Asn Gln Tyr Ser Leu Arg Leu Ser Ser Val Thr Ala Ala
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Asp Thr Ala Leu Tyr Tyr Cys Ala Ser Pro Asn Tyr Pro Phe Tyr Ala
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Met Asp Tyr Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ser
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Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
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Val Thr Asn Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
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Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
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Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro
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Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser
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Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser
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Leu Asn Ile His Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys
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Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
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Glu Ile Lys Thr Met Glu Ile Lys Arg
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
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Gly Ser Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
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Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser
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Val Asp Asn Tyr Gly Ile Ser Phe Leu Asn Trp Phe Gln Gln Lys Pro
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Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser Asn Arg Ala Thr
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Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
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Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
100 105 110
Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val
115 120 125
Glu Ile Lys Arg Thr Val
130
<210> 19
<211> 134
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<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu90 LC-2
<400> 19
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro
50 55 60
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser Asn Arg Ala Thr
65 70 75 80
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
100 105 110
Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val
115 120 125
Glu Ile Lys Arg Thr Val
130
<210> 20
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu90 LC-3
<400> 20
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro
50 55 60
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gly Ser
65 70 75 80
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
115 120 125
Glu Ile Lys Arg Thr Val
130
<210> 21
<211> 140
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Chi55 HC
<400> 21
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu
20 25 30
Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser
35 40 45
Leu Ser Thr Ser Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly
50 55 60
Lys Gly Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr
65 70 75 80
Tyr Asn Ser Ser Leu Lys Ser His Leu Thr Ile Ser Lys Asp Thr Ser
85 90 95
Arg Asn Gln Val Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr
100 105 110
Ala Thr Tyr Tyr Cys Ala Arg Ser Phe Gly Tyr Gly Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser
130 135 140
<210> 22
<211> 142
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu55 HC-1
<400> 22
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Thr Leu Lys Glu Ser Gly
20 25 30
Pro Thr Leu Val Lys Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe
35 40 45
Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Gly Trp Ile Arg
50 55 60
Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Trp Trp Asp
65 70 75 80
Asp Asp Lys Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Thr
85 90 95
Lys Asp Thr Ser Lys Asn Gln Val Val Leu Thr Met Thr Asn Met Asp
100 105 110
Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ser Phe Gly Tyr Gly
115 120 125
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135 140
<210> 23
<211> 142
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu55 HC-2
<400> 23
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Thr Leu Lys Glu Ser Gly
20 25 30
Pro Thr Leu Val Lys Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe
35 40 45
Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Gly Trp Ile Arg
50 55 60
Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Trp Trp Asp
65 70 75 80
Asp Asp Lys Tyr Tyr Asn Ser Ser Leu Lys Ser Arg Leu Thr Ile Thr
85 90 95
Lys Asp Thr Ser Lys Asn Gln Val Val Leu Thr Met Thr Asn Met Asp
100 105 110
Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ser Phe Gly Tyr Gly
115 120 125
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135 140
<210> 24
<211> 142
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu55 HC-3
<400> 24
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Thr Leu Lys Glu Ser Gly
20 25 30
Pro Ala Leu Val Lys Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe
35 40 45
Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Gly Trp Ile Arg
50 55 60
Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Trp Trp Asp
65 70 75 80
Asp Asp Lys Tyr Tyr Asn Thr Ser Leu Lys Ser Arg Leu Thr Ile Thr
85 90 95
Lys Asp Thr Ser Lys Asn Gln Val Val Leu Lys Met Thr Asn Met Asp
100 105 110
Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ser Phe Gly Tyr Gly
115 120 125
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135 140
<210> 25
<211> 129
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Chi55 LC
<400> 25
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser
85 90 95
Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys His Gln Phe Ser
100 105 110
Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Thr
<210> 26
<211> 130
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu55 LC-1
<400> 26
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Thr Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys His Gln Phe Ser
100 105 110
Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val
130
<210> 27
<211> 130
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu55 LC-2
<400> 27
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Thr Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys His Gln Phe Ser
100 105 110
Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val
130
<210> 28
<211> 130
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Hu55 LC-3
<400> 28
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Thr Pro
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Thr Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys His Gln Phe Ser
100 105 110
Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val
130
<210> 29
<211> 247
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> FMC63 scFv
<400> 29
Ile Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser
1 5 10 15
Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser
20 25 30
Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu
35 40 45
Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu
65 70 75 80
Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu
85 90 95
Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr
100 105 110
Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu
115 120 125
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
130 135 140
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
145 150 155 160
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
165 170 175
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
180 185 190
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
195 200 205
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
210 215 220
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Ser Val Thr Val Ser Ser
245
<210> 30
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> FMC63 scFv Vl
<400> 30
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 31
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> FMC63 scFv Vh
<400> 31
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
1 5 10 15
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
20 25 30
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
35 40 45
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
50 55 60
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
65 70 75 80
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
85 90 95
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 32
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> Linker 10aa
<400> 32
Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly
1 5 10
<210> 33
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4 hinge
<400> 33
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 34
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4 hinge
<400> 34
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro
1 5 10
<210> 35
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4 hinge
<400> 35
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser
1 5 10 15
Ser Gly Gly Gly Ser Gly
20
<210> 36
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD28 hinge
<400> 36
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 37
<211> 48
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD8 hinge-48aa
<400> 37
Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
1 5 10 15
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
20 25 30
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 38
<211> 45
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD8 hinge-45aa
<400> 38
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 39
<211> 129
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4(HL-CH3) (includes S228P in hinge)
<400> 39
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser
1 5 10 15
Ser Gly Gly Gly Ser Gly Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
20 25 30
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
35 40 45
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
50 55 60
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
65 70 75 80
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
85 90 95
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
100 105 110
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
115 120 125
Lys
<210> 40
<211> 229
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4(L235E,N297Q)
<400> 40
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
1 5 10 15
Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Gln Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 41
<211> 229
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4(S228P, L235E,N297Q)
<400> 41
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Gln Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 42
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4(CH3)
<400> 42
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
100 105
<210> 43
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD3z
<400> 43
Leu Cys Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu
1 5 10 15
Thr Ala Leu Phe Leu
20
<210> 44
<211> 27
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD28
<400> 44
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 45
<211> 28
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD28(M)
<400> 45
Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
1 5 10 15
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 46
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD4
<400> 46
Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile
1 5 10 15
Gly Leu Gly Ile Phe Phe
20
<210> 47
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD8tm
<400> 47
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr
20
<210> 48
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD8tm2
<400> 48
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr
20
<210> 49
<211> 24
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD8tm3
<400> 49
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 50
<211> 27
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 41BB
<400> 50
Ile Ile Ser Phe Phe Leu Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu
1 5 10 15
Leu Phe Phe Leu Thr Leu Arg Phe Ser Val Val
20 25
<210> 51
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD3
<400> 51
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 52
<211> 41
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD28
<400> 52
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 53
<211> 41
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD28gg
<400> 53
Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 54
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 4-1BB
<400> 54
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 55
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> OX40
<400> 55
Ala Leu Tyr Leu Leu Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His
1 5 10 15
Lys Pro Pro Gly Gly Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln
20 25 30
Ala Asp Ala His Ser Thr Leu Ala Lys Ile
35 40
<210> 56
<211> 24
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> ribosomal skip sequence
<400> 56
Leu Glu Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp
1 5 10 15
Val Glu Glu Asn Pro Gly Pro Arg
20
<210> 57
<211> 354
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated EGFR
<400> 57
Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala Phe Leu
1 5 10 15
Leu Ile Pro Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys
20 25 30
Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys
35 40 45
Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly
50 55 60
Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile
65 70 75 80
Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp
85 90 95
Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile
100 105 110
Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser
115 120 125
Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp
130 135 140
Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr
145 150 155 160
Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile
165 170 175
Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys
180 185 190
His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp
195 200 205
Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys
210 215 220
Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu
225 230 235 240
Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr
245 250 255
Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile
260 265 270
Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu
275 280 285
Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His
290 295 300
Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu
305 310 315 320
Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met
325 330 335
Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu
340 345 350
Phe Met
<210> 58
<211> 940
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 1250 dual CAR, including signal sequence
<400> 58
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Gln Glu Ser Gly Pro Gly
20 25 30
Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
35 40 45
Asp Ser Ile Thr Ser Gly Tyr Trp Asn Trp Ile Arg Gln His Pro Gly
50 55 60
Lys Gly Leu Glu Tyr Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr
65 70 75 80
Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser
85 90 95
Lys Asn Gln Tyr Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Ser Pro Asn Tyr Pro Phe Tyr Ala Met Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
165 170 175
Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met
180 185 190
Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
195 200 205
Ala Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser
210 215 220
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
225 230 235 240
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys Glu Val Pro Trp Thr
245 250 255
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly Ser
260 265 270
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
275 280 285
Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp
290 295 300
Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu
305 310 315 320
Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr
325 330 335
His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
340 345 350
Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu
355 360 365
Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr
370 375 380
Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly Ser
385 390 395 400
Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys Leu
405 410 415
Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val
420 425 430
Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp
435 440 445
Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp
450 455 460
Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr
465 470 475 480
Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser
485 490 495
Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr
500 505 510
Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
515 520 525
Thr Val Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
530 535 540
Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
545 550 555 560
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
565 570 575
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
580 585 590
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
595 600 605
Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
610 615 620
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
625 630 635 640
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
645 650 655
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
660 665 670
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
675 680 685
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
690 695 700
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
705 710 715 720
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
725 730 735
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
740 745 750
Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val Leu Gly
755 760 765
Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys
770 775 780
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
785 790 795 800
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
805 810 815
Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val Lys Phe
820 825 830
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
835 840 845
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
850 855 860
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
865 870 875 880
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
885 890 895
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
900 905 910
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
915 920 925
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
930 935 940
<210> 59
<211> 918
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 1250 dual CAR
<400> 59
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Tyr Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Tyr Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Pro Asn Tyr Pro Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser Asn Arg Ala
180 185 190
Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr
260 265 270
Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys
275 280 285
Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys
290 295 300
Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His
305 310 315 320
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
325 330 335
Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe
340 345 350
Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys
355 360 365
Leu Glu Ile Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly
370 375 380
Glu Gly Ser Thr Lys Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly
385 390 395 400
Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly
405 410 415
Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg
420 425 430
Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr
435 440 445
Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser
450 455 460
Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr
465 470 475 480
Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala
485 490 495
Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Glu Ser
500 505 510
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly
515 520 525
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
530 535 540
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
545 550 555 560
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
565 570 575
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr
580 585 590
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
595 600 605
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
610 615 620
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
625 630 635 640
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
645 650 655
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
660 665 670
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
675 680 685
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
690 695 700
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
705 710 715 720
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
725 730 735
Leu Gly Lys Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu
740 745 750
Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu
755 760 765
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
770 775 780
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
785 790 795 800
Cys Glu Leu Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
805 810 815
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
820 825 830
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
835 840 845
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
850 855 860
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
865 870 875 880
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
885 890 895
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
900 905 910
Gln Ala Leu Pro Pro Arg
915
<210> 60
<211> 940
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 1296 dual CAR, including signal sequence
<400> 60
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser
20 25 30
Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly
50 55 60
Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr
85 90 95
Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln
100 105 110
Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
115 120 125
Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser
130 135 140
Thr Lys Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala
145 150 155 160
Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu
165 170 175
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
180 185 190
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
195 200 205
Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln
210 215 220
Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr
225 230 235 240
Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
245 250 255
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
260 265 270
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
275 280 285
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
290 295 300
Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly Tyr
305 310 315 320
Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Tyr Ile Gly
325 330 335
Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
340 345 350
Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Tyr Ser Leu Lys
355 360 365
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Ser
370 375 380
Pro Asn Tyr Pro Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
385 390 395 400
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
405 410 415
Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
420 425 430
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser
435 440 445
Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro
450 455 460
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser Asn Arg Ala Thr
465 470 475 480
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
485 490 495
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
500 505 510
Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val
515 520 525
Glu Ile Lys Arg Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
530 535 540
Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
545 550 555 560
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
565 570 575
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
580 585 590
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
595 600 605
Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
610 615 620
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
625 630 635 640
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
645 650 655
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
660 665 670
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
675 680 685
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
690 695 700
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
705 710 715 720
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
725 730 735
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
740 745 750
Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val Leu Gly
755 760 765
Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys
770 775 780
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
785 790 795 800
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
805 810 815
Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val Lys Phe
820 825 830
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
835 840 845
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
850 855 860
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
865 870 875 880
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
885 890 895
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
900 905 910
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
915 920 925
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
930 935 940
<210> 61
<211> 918
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 1296 dual CAR
<400> 61
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys
115 120 125
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
130 135 140
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
145 150 155 160
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
165 170 175
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
180 185 190
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
195 200 205
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
210 215 220
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
225 230 235 240
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Glu Ser
260 265 270
Gly Pro Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr
275 280 285
Val Ser Gly Asp Ser Ile Thr Ser Gly Tyr Trp Asn Trp Ile Arg Gln
290 295 300
His Pro Gly Lys Gly Leu Glu Tyr Ile Gly Tyr Ile Ser Tyr Ser Gly
305 310 315 320
Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Arg
325 330 335
Asp Thr Ser Lys Asn Gln Tyr Ser Leu Lys Leu Ser Ser Val Thr Ala
340 345 350
Ala Asp Thr Ala Val Tyr Tyr Cys Ala Ser Pro Asn Tyr Pro Phe Tyr
355 360 365
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
385 390 395 400
Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg
405 410 415
Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile
420 425 430
Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
435 440 445
Leu Ile Tyr Ala Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe
450 455 460
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
465 470 475 480
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys Glu Val
485 490 495
Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Glu Ser
500 505 510
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly
515 520 525
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
530 535 540
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
545 550 555 560
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
565 570 575
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr
580 585 590
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
595 600 605
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
610 615 620
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
625 630 635 640
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
645 650 655
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
660 665 670
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
675 680 685
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
690 695 700
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
705 710 715 720
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
725 730 735
Leu Gly Lys Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu
740 745 750
Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu
755 760 765
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
770 775 780
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
785 790 795 800
Cys Glu Leu Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
805 810 815
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
820 825 830
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
835 840 845
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
850 855 860
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
865 870 875 880
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
885 890 895
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
900 905 910
Gln Ala Leu Pro Pro Arg
915
<210> 62
<211> 914
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 1316 dual CAR, including signal sequence
<400> 62
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser
20 25 30
Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly
50 55 60
Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr
85 90 95
Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln
100 105 110
Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
115 120 125
Thr Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Glu Ser Gly Pro Gly
130 135 140
Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
145 150 155 160
Asp Ser Ile Thr Ser Gly Tyr Trp Asn Trp Ile Arg Gln His Pro Gly
165 170 175
Lys Gly Leu Glu Tyr Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr
180 185 190
Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser
195 200 205
Lys Asn Gln Tyr Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Ser Pro Asn Tyr Pro Phe Tyr Ala Met Asp
225 230 235 240
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser
245 250 255
Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile
260 265 270
Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg
275 280 285
Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile
290 295 300
Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
305 310 315 320
Leu Ile Tyr Ala Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe
325 330 335
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
340 345 350
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys Glu Val
355 360 365
Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly Gly
370 375 380
Gly Gly Ser Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala
385 390 395 400
Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu
405 410 415
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
420 425 430
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
435 440 445
Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln
450 455 460
Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr
465 470 475 480
Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
485 490 495
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Glu Ser Lys Tyr Gly
500 505 510
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser
515 520 525
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
530 535 540
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
545 550 555 560
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
565 570 575
Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val
580 585 590
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
595 600 605
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
610 615 620
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
625 630 635 640
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
645 650 655
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
660 665 670
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
675 680 685
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
690 695 700
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
705 710 715 720
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
725 730 735
Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile
740 745 750
Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
755 760 765
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
770 775 780
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
785 790 795 800
Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
805 810 815
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
820 825 830
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
835 840 845
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
850 855 860
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
865 870 875 880
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
885 890 895
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
900 905 910
Pro Pro
<210> 63
<211> 892
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> 1316 dual CAR
<400> 63
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
100 105 110
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
115 120 125
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly
130 135 140
Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Tyr Ile
145 150 155 160
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
165 170 175
Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Tyr Ser Leu
180 185 190
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
195 200 205
Ser Pro Asn Tyr Pro Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
210 215 220
Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly
225 230 235 240
Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Val Leu Thr Gln Ser Pro
245 250 255
Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg
260 265 270
Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe
275 280 285
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser
290 295 300
Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
305 310 315 320
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala
325 330 335
Val Tyr Tyr Cys Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly
340 345 350
Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly Ser Glu Val Lys
355 360 365
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
370 375 380
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
385 390 395 400
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
405 410 415
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
420 425 430
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
435 440 445
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
450 455 460
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
465 470 475 480
Val Thr Val Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
485 490 495
Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
500 505 510
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
515 520 525
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
530 535 540
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
545 550 555 560
Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
565 570 575
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
580 585 590
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
595 600 605
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
610 615 620
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
625 630 635 640
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
645 650 655
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
660 665 670
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
675 680 685
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
690 695 700
Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val Leu
705 710 715 720
Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe
725 730 735
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
740 745 750
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
755 760 765
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val Lys
770 775 780
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
785 790 795 800
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
805 810 815
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
820 825 830
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
835 840 845
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
850 855 860
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
865 870 875 880
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
885 890
<210> 64
<211> 680
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD19 CAR, including signal sequence
<400> 64
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser
20 25 30
Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly
50 55 60
Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr
85 90 95
Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln
100 105 110
Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
115 120 125
Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser
130 135 140
Thr Lys Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala
145 150 155 160
Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu
165 170 175
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
180 185 190
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
195 200 205
Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln
210 215 220
Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr
225 230 235 240
Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
245 250 255
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Glu Ser Lys Tyr Gly
260 265 270
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser
275 280 285
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
290 295 300
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
305 310 315 320
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
325 330 335
Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val
340 345 350
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
355 360 365
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
370 375 380
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
385 390 395 400
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
405 410 415
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
420 425 430
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
435 440 445
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
450 455 460
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
465 470 475 480
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
485 490 495
Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
500 505 510
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg
515 520 525
Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
530 535 540
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
545 550 555 560
Ala Ala Tyr Arg Ser Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala
565 570 575
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
580 585 590
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
595 600 605
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
610 615 620
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
625 630 635 640
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
645 650 655
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
660 665 670
His Met Gln Ala Leu Pro Pro Arg
675 680
<210> 65
<211> 658
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> CD19 CAR
<400> 65
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys
115 120 125
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
130 135 140
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
145 150 155 160
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
165 170 175
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
180 185 190
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
195 200 205
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
210 215 220
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
225 230 235 240
Val Thr Val Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
245 250 255
Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
370 375 380
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Phe Trp Val Leu Val
465 470 475 480
Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala
485 490 495
Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser
500 505 510
Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His
515 520 525
Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Gly
530 535 540
Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
545 550 555 560
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
565 570 575
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
580 585 590
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
595 600 605
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
610 615 620
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
625 630 635 640
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
645 650 655
Pro Arg
<210> 66
<211> 675
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> BAFF-R CAR including a signal sequence
<400> 66
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Gln Glu Ser Gly Pro Gly
20 25 30
Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
35 40 45
Asp Ser Ile Thr Ser Gly Tyr Trp Asn Trp Ile Arg Gln His Pro Gly
50 55 60
Lys Gly Leu Glu Tyr Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr
65 70 75 80
Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser
85 90 95
Lys Asn Gln Tyr Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Ser Pro Asn Tyr Pro Phe Tyr Ala Met Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
165 170 175
Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met
180 185 190
Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
195 200 205
Ala Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser
210 215 220
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
225 230 235 240
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys Glu Val Pro Trp Thr
245 250 255
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Glu Ser Lys Tyr Gly
260 265 270
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser
275 280 285
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
290 295 300
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
305 310 315 320
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
325 330 335
Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val
340 345 350
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
355 360 365
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
370 375 380
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
385 390 395 400
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
405 410 415
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
420 425 430
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
435 440 445
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
450 455 460
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
465 470 475 480
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
485 490 495
Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile
500 505 510
Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
515 520 525
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
530 535 540
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
545 550 555 560
Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
565 570 575
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
580 585 590
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
595 600 605
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
610 615 620
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
625 630 635 640
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
645 650 655
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
660 665 670
Pro Pro Arg
675
<210> 67
<211> 653
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> BAFF-R CAR
<400> 67
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Tyr Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Tyr Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Pro Asn Tyr Pro Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser Asn Arg Ala
180 185 190
Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Arg Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
245 250 255
Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
370 375 380
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val Leu
465 470 475 480
Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe
485 490 495
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
500 505 510
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
515 520 525
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val Lys
530 535 540
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
545 550 555 560
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
565 570 575
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
580 585 590
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
595 600 605
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
610 615 620
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
625 630 635 640
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
645 650
<210> 68
<211> 129
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<220>
<221> MISC_FEATURE
<223> IgG4 hinge
<400> 68
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser
1 5 10 15
Ser Gly Gly Gly Ser Gly Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
20 25 30
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
35 40 45
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
50 55 60
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
65 70 75 80
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
85 90 95
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
100 105 110
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
115 120 125
Lys
Claims (33)
- BAFF-R 및 CD19 둘 모두로 표적화된 키메라 항원 수용체를 코딩하는 뉴클레오티드 서열을 포함하는 핵산 분자이며, 여기서 키메라 항원 수용체는 임의 순서로 CD19 결합 scFv의 VL 도메인, CD19 결합 scFv의 VH 도메인, BAFF-R 결합 scFv의 VL 도메인, BAFF-R 결합 scFv의 VH 도메인을 포함하는 표적화 도메인; 이어서, 스페이서 도메인, 막횡단 도메인, 공동자극 도메인 및 CD3ζ 신호전달 도메인을 포함하는 것인 핵산 분자.
- BAFF-R 및 CD19 둘 모두로 표적화된 키메라 항원 수용체를 코딩하는 뉴클레오티드 서열을 포함하는 핵산 분자이며, 여기서 표적화 도메인은 아미노에서 카르복시 말단으로 a) BAFF-R로 표적화된 scFv 및 CD19로 표적화된 scFv; 또는 b) CD19로 표적화된 scFv 및 BAFF-R로 표적화된 scFv를 포함하는 표적화 도메인; 스페이서 도메인; 막횡단 도메인; 공동자극 도메인; 및 CD3ζ 신호전달 도메인을 포함하는 것인 핵산 분자.
- 제1항에 있어서, 표적화 도메인이 아미노 말단에서 카르복시 말단으로 CD19 결합 scFv의 VL 도메인, BAFF-R 결합 scFv의 VH 도메인, BAFF-R 결합 scFv의 VL 도메인 및 CD19 결합 scFv의 VH 도메인을 포함하는 것인 핵산 분자.
- 제1항에 있어서, 표적화 도메인이 아미노 말단에서 카르복시 말단으로 CD19 결합 scFv의 VH 도메인, BAFF-R 결합 scFv의 VH 도메인, BAFF-R 결합 scFv의 VL 도메인, 및 CD19 결합 scFv의 VL 도메인을 포함하는 것인 핵산 분자.
- 제1항에 있어서, 표적화 도메인이 아미노 말단에서 카르복시 말단으로 CD19 결합 scFv의 VL 도메인, BAFF-R 결합 scFv의 VL 도메인, BAFF-R 결합 scFv의 VH 도메인, 및 CD19 결합 scFv의 VH 도메인을 포함하는 것인 핵산 분자.
- 제1항에 있어서, 표적화 도메인이 아미노 말단에서 카르복시 말단으로 CD19 결합 scFv의 VH 도메인, BAFF-R 결합 scFv의 VL 도메인, BAFF-R 결합 scFv의 VH 도메인, 및 CD19 결합 scFv의 VL 도메인을 포함하는 것인 핵산 분자.
- 제1항 내지 제6항 중 어느 한 항에 있어서, BAFF-R VH가 서열식별번호(SEQ ID NO:) 13-16으로 이루어진 군으로부터 선택되는 아미노산 서열을 포함하고, BAFF-R VL이 서열식별번호 17-20으로 이루어진 군으로부터 선택되는 아미노산 서열을 포함하는 것인 핵산 분자.
- 제1항 내지 제7항 중 어느 한 항에 있어서, BAFF-R VH가 서열식별번호 21-24로 이루어진 군으로부터 선택되는 아미노산 서열을 포함하고, BAFF-R VL이 서열식별번호 25-28로 이루어진 군으로부터 선택되는 아미노산 서열을 포함하는 것인 핵산 분자.
- 제1항에 있어서, 키메라 항원 수용체가 서열식별번호 58-63으로부터 선택되는 아미노산 서열을 포함하는 것인 핵산 분자.
- 제1항 내지 제9항 중 어느 한 항에 있어서, 링커가 각 VL 및 VH 도메인 사이에 4-15개의 아미노산을 포함하는 것인 핵산 분자.
- 제9항에 있어서, 링커가 오직 G 및 S만을 포함하는 것인 핵산 분자.
- 제1항에 있어서, 표적화 도메인이 아미노에서 카르복시 말단으로 a) CD19 scFv의 VL 도메인; BAFF-R로 표적화된 scFv; 및 CD19 scFv의 VH; 또는 b) CD19 scFv의 VH 도메인; BAFF-R로 표적화된 scFv; 및 CD19 scFv의 VL을 포함하는 것인 핵산 분자.
- 제1항에 있어서, 표적화 도메인이 아미노에서 카르복시 말단으로 a) BAFF-R scFv의 VL 도메인; CD19로 표적화된 scFv; 및 BAFF-R scFv의 VH; 또는 b) BAFF-R scFv의 VH 도메인; CD19로 표적화된 scFv; 및 BAFF-R scFv의 VL을 포함하는 것인 핵산 분자.
- 두 BAFF-R로 표적화된 키메라 항원 수용체 및 CD19로 표적화된 키메라 항원 수용체를 코딩하는 뉴클레오티드 서열을 포함하는 핵산 분자이며, 여기서 BAFF-R로 표적화된 키메라 항원 수용체는 아미노에서 카르복시 말단으로 BAFF-R scFv; 스페이서 도메인; 막횡단 도메인; 공동자극 도메인; 및 CD3ζ 신호전달 도메인을 포함하고; CD19로 표적화된 키메라 항원 수용체는 아미노에서 카르복시 말단으로 CD19 scFv; 스페이서 도메인; 막횡단 도메인; 공동자극 도메인; 및 CD3ζ 신호전달 도메인을 포함하는 것인 핵산 분자.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 공동자극 도메인이 CD28 공동자극 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, 4-1BB 공동자극 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, 및 OX40 공동자극 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체로 이루어진 군으로부터 선택되는 것인 핵산 분자.
- 제1항 내지 제15항 중 어느 한 항에 있어서, 막횡단 도메인이 CD4 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, CD8 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, CD28 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체, 및 CD3ζ 막횡단 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체; 공동자극 도메인; 및 CD3ζ 신호전달 도메인 또는 1-5개의 아미노산 변형을 갖는 그의 변이체로부터 선택되는 것인 핵산 분자.
- 제1항 내지 제16항 중 어느 한 항에 있어서, 스페이서 도메인이 IgG4 힌지 (S→P), IgG4 힌지, IgG4 힌지 (S228P)+링커, CD28 힌지, CD8 힌지-48aa, CD8 힌지-45aa, IgG4(HL-CH3), IgG4(L235E,N297Q), IgG4(S228P,L235E,N297Q), 및 IgG4(CH3), 및 1-5개의 아미노산 변형을 갖는 IgG4 힌지 (S→P), IgG4 힌지, IgG4 힌지 (S228P)+링커, CD28 힌지, CD8 힌지-48aa, CD8 힌지-45aa, IgG4(HL-CH3), IgG4(L235E,N297Q), IgG4(S228P,L235E,N297Q), 및 IgG4(CH3) 각각의 변이체로 이루어진 군으로부터 선택되는 것인 핵산 분자.
- 제1항 내지 제17항 중 어느 한 항에 있어서, BAFF-R scFv가 경쇄 가변 영역 및 중쇄 가변 영역을 포함하고, 여기서 경쇄 가변 영역이 CDR L1 (서열식별번호 1), CDR L2 (서열식별번호 2) 및 CDR L3 (서열식별번호 3)을 포함하고; 중쇄 가변 영역이 CDR H1 (서열식별번호 4), CDR H2 (서열식별번호 5), 및 CDR H3 (서열식별번호 6)을 포함하는 것인 핵산 분자.
- 제1항 내지 제18항 중 어느 한 항에 있어서, BAFF-R scFv가 경쇄 가변 영역 및 중쇄 가변 영역을 포함하고, 여기서 경쇄 가변 영역이 CDR L1 (서열식별번호 7), CDR L2 (서열식별번호 8) 및 CDR L3 (서열식별번호 9)을 포함하고; 중쇄 가변 영역이 CDR H1 (서열식별번호 10), CDR H2 (서열식별번호 11), 및 CDR H3 (서열식별번호 12)을 포함하는 것인 핵산 분자.
- 제1항 내지 제19항 중 어느 한 항에 있어서, BAFF-R scFv가 Chi90 HC, Hu90 HC-1, Hu90 HC-2, Hu90 HC-3, Chi55 HC, Hu55 HC-1, Hu55 HC-2, 및 Hu55 HC-3으로부터 선택되는 중쇄 가변 도메인, 및 Chi90 LC, Hu90 LC-1, Hu90 LC-2, Hu90 LC-3, Chi55 LC, Hu55 LC-1, Hu55 LC-2, 및 Hu55 LC-3으로부터 선택되는 경쇄 가변 도메인을 포함하는 것인 핵산 분자.
- 제1항 내지 제20항 중 어느 한 항에 있어서, BAFF-R scFv가 서열식별번호 17-20 및 25-28로부터 선택되는 아미노산 서열을 갖는 경쇄 가변 도메인을 포함하는 것인 핵산 분자.
- 제1항 내지 제21항 중 어느 한 항에 있어서, BAFF-R scFv가 서열식별번호 13-16 및 21-24로부터 선택되는 아미노산 서열을 갖는 중쇄 가변 도메인을 포함하는 것인 핵산 분자.
- 제1항 내지 제22항 중 어느 한 항에 있어서, CD19 scFv가 아미노산 서열 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ KPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPYTFGGGTKLEIT (서열식별번호 30)를 포함하는 VL, 및 아미노산 서열 EVK LQESGPGLVAPSQSLSVTCTVSGVSLPDYG VSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDN SKSQVFLKMN SLQTDDTAIYYCAKHYYYGG SYAMDYWGQGTSVTVSS (서열식별번호 31)를 포함하는 VH를 포함하는 것인 핵산 분자.
- 제1항 내지 제23항 중 어느 한 항의 핵산 분자를 포함하는 벡터.
- 제24항에 있어서, 렌티바이러스 벡터인 벡터.
- 제25항의 벡터에 의해 형질도입된 인간 T 세포 또는 NK 세포의 집단.
- 대상체에게 치료 유효량의, 제17항의 인간 T 세포 집단을 포함하는 조성물을 투여하여 대상체에서 암을 치료하는 단계를 포함하는, 암 치료를 필요로 하는 대상체에서 암을 치료하는 방법.
- 제27항에 있어서, 암이 림프종, 백혈병 또는 골수종인 방법.
- 제28항에 있어서, 림프종이 외투 세포 림프종, 여포성 림프종, 미만성 거대 B 세포 림프종, 변연부 림프종 또는 버킷 림프종인 방법.
- 제28항에 있어서, 백혈병이 급성 림프모구성 백혈병, 만성 림프구성 백혈병 또는 모발 세포 백혈병인 방법.
- 제19항에 있어서, 골수종이 다발성 골수종인 방법.
- 제27항 내지 제31항 중 어느 한 항에 있어서, T 세포 집단이 환자에 대해 자가 또는 동종이계인 방법.
- 제27항 내지 제32항 중 어느 한 항에 있어서, 인간 T 세포 집단이 CD4+ 세포 및 CD8+ 세포를 포함하는 세포를 포함하는 것인 방법.
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