KR20200135760A - Ssea4에 결합하는 키메라 항원 수용체 및 이의 용도 - Google Patents
Ssea4에 결합하는 키메라 항원 수용체 및 이의 용도 Download PDFInfo
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Abstract
서열번호 3의 폴리펩타이드를 암호화하는 뉴클레오타이드 서열을 함유하는 단리된 핵산. 서열번호 3의 폴리펩타이드는 단계-특이적 배아 항원 4(SSEA4)에 특이적으로 결합한다. 상기 설명한 단리된 핵산을 포함하는 재조합 세포, 상기 단리된 핵산을 함유하는 바이러스 벡터, 및 서열번호 3의 서열을 포함하는 단리된 폴리펩타이드가 또한 개시된다. 서열번호 3의 서열을 갖고 SSEA4에 특이적으로 결합하는 단일 사슬 Fv를 포함하는 키메라 항원 수용체 (CAR)가 또한 제공된다. 더욱이, SSEA4를 발현하는 종양을 갖는 대상체의 T 세포를 CAR을 암호화하는 벡터로 시험관 내에서 형질도입하고, 형질도입된 T 세포를 확장시키고, 확장되고 형질도입된 T 세포를 대상체 내로 주입하여, 이에 의해 항-종양 T 세포 반응을 일으키는, 종양을 치료하는 방법이 개시된다.
Description
화학요법(chemotherapy)과 비교하여, 표적화된 암 면역요법(immunotherapy)은 단기적 및 장기적 둘 다의 보다 양호한 효능뿐만 아니라, 더 적은 부작용의 전망을 갖는다.
예를 들어, 종양 특이적 탄수화물 항원, 예컨대 Globo H, 단계 특이적 배아 항원(stage-specific embryonic antigen) 3("SSEA3"), 및 단계-특이적 배아 항원 4("SSEA4")를 표적화하는 항암 백신은 이러한 항원에 대한 항체를 개발하도록 환자 자신의 면역계를 자극하도록 개발되어왔고, 이는 항체-의존성 세포성 세포독성, 항체-의존성 식균작용, 보체-의존성 세포 용해 뿐만 아니라, 직접적인 세포 증식 억제 및/또는 세포독성 효과로 이어진다.
이러한 접근법은 종종 종양에서 억제 환경의 결과로서 시간 경과에 따라 유효성을 상실한다. 억제 환경은 하나 또는 모든 항체, NK 세포, 대식세포 및 보체가 종양으로 진입하는 것을 차단한다.
최근에, 상기 언급된 약점을 제거하기 위해 키메라 항원 수용체("CAR")가 개발되었다. CAR은 (i) 종양 항원에 결합하는 세포외 도메인(extracellular domain) 및 (ii) T 세포에 1차 및 공동자극 신호 둘 다를 제공하는 하나 이상의 세포내 도메인을 함유한다. T 세포는 선택된 세포외 도메인을 갖는 CAR을 발현하도록 시험관 내에서 가공될 수 있다.
CAR 접근법은 효과적이지만, 심각한 부작용이 없지는 않은 것으로 입증되었다. 예를 들어, CAR을 발현하는 다수의 T 세포의 활성화가 사이토킨 방출 증후군을 유발한다. 고열, 저혈압, 저산소증을 특징으로 하는 이러한 증후군은, 다발성 장기 부전 및 심지어 죽음을 초래할 수 있다.
현재 사용되는 것보다 더 안전하고 더 효과적인 CAR-기반 종양 요법을 개발할 필요가 있다.
상기 논의된 필요를 충족시키기 위해, 서열번호 3의 폴리펩타이드를 암호화하는 뉴클레오타이드 서열을 함유하는 단리된 핵산(isolated nucleic acid)이 개시된다. 서열번호 3의 폴리펩타이드는 단계-특이적 배아 항원 4 (SSEA4)에 특이적으로 결합한다.
상기 기재된 단리된 핵산을 포함하는 재조합 세포(recombinant cell)로서, 서열번호 2의 폴리펩타이드를 발현하는 재조합 세포가 또한 개시된다.
추가로, 상기 단리된 핵산을 함유하는 바이러스 벡터가 본 발명의 범위 내에 있다. 바이러스 벡터는 렌티바이러스 벡터, 감마-레트로바이러스 벡터, 또는 아데노-연관 바이러스 벡터이다.
더욱이, 서열번호 3의 서열을 포함하는 단리된 폴리펩타이드, 다시, 단리된 폴리펩타이드는 SSEA4에 특이적으로 결합한다.
서열번호 3의 서열을 갖고 SSEA4에 특이적으로 결합하는 단일 사슬 Fv(scFv), 및 CD3ζ 또는 FcεRIγ로부터의 제1 엔도도메인(endodomain)을 포함하는 키메라 항원 수용체(CAR)가 또한 제공된다.
최종적으로, 대상체에서 종양을 치료하기 위한 방법으로서, (i) 종양을 갖는 대상체로부터 T 세포를 수득하는 단계; (ii) SSEA-4를 특이적으로 인식하는 scFv를 포함하는 CAR을 암호화하는 핵산을 함유하는 벡터로 T 세포를 시험관 내에서 형질도입하여, 이에 의해 형질도입된 T 세포가 CAR을 발현하는 단계; (iii) 시험관 내에서 형질도입된 T 세포를 확장시키는 단계; 및 (iv) 확장되고 형질도입된 T 세포를 종양을 갖는 대상체 내로 주입하여, 이에 의해 항-종양 T 세포 반응을 일으키는 단계를 포함하는 방법이 개시된다. scFv는 서열번호 3의 아미노산 서열을 갖고 종양 내의 세포는 SSEA4를 발현한다.
본 발명의 하나 이상의 실시양태의 세부사항은 하기 상세한 설명 및 도면에서 설명된다. 본 발명의 다른 특징, 목적, 및 이점은 상세한 설명으로부터 및 청구범위로부터 명백해질 것이다.
하기의 설명은 첨부된 도면을 참조한다:
도 1은 상이한 효과기(effector) 대 표적 비에서, 지시된 효과기 T 세포에 의한 표적 세포의 용해 백분율(percent lysis)의 막대 그래프이다.
도 2a는 상이한 효과기 대 표적 비에서, 지시된 효과기 T 세포를 표적 MCF-7 세포와 함께 공동 배양(coculturing)한 후 지시된 효과기 T 세포에 의해 방출된 IL-2의 양을 나타내는 막대 그래프이다.
도 2b는 상이한 효과기 대 표적 비에서, 지시된 효과기 T 세포를 표적 MCF-7 세포와 함께 공동 배양한 후 지시된 효과기 T 세포에 의해 방출된 IFN-γ의 양을 나타내는 막대 그래프이다.
도 1은 상이한 효과기(effector) 대 표적 비에서, 지시된 효과기 T 세포에 의한 표적 세포의 용해 백분율(percent lysis)의 막대 그래프이다.
도 2a는 상이한 효과기 대 표적 비에서, 지시된 효과기 T 세포를 표적 MCF-7 세포와 함께 공동 배양(coculturing)한 후 지시된 효과기 T 세포에 의해 방출된 IL-2의 양을 나타내는 막대 그래프이다.
도 2b는 상이한 효과기 대 표적 비에서, 지시된 효과기 T 세포를 표적 MCF-7 세포와 함께 공동 배양한 후 지시된 효과기 T 세포에 의해 방출된 IFN-γ의 양을 나타내는 막대 그래프이다.
상기 언급한 바와 같이, CAR-기반 종양 요법을 개발할 필요를 충족시키기 위해, 서열번호 3의 폴리펩타이드를 암호화하는 뉴클레오타이드 서열을 포함하는 단리된 핵산이 제공된다. 서열번호 3의 폴리펩타이드는 SSEA4에 특이적으로 결합하는 scFv이다. 특정 실시예에서, 단리된 핵산은 서열번호 1의 뉴클레오타이드 서열을 갖는다.
서열번호 1의 뉴클레오타이드 서열을 갖는 단리된 핵산을 함유하는 재조합 세포가 또한 본 발명의 범위 내에 있다. 재조합 세포는 서열번호 2의 폴리펩타이드, 즉, 서열번호 3의 scFv를 포함하는 CAR 작제물(construct)을 발현한다. 재조합 세포는 T 세포, 예를 들어, CD4+ 또는 CD8+ T 세포일 수 있다. 사용될 수 있는 다른 세포는 NK, iNKT, 단핵구, 대식세포, 미세아교세포, 수지상세포, 및 호중구를 포함한다.
서열번호 3의 폴리펩타이드, 예를 들어 CAR 작제물을 암호화하는 뉴클레오타이드 서열을 포함하는 단리된 핵산은 바이러스 벡터 내 함유될 수 있다.
예시적인 바이러스 벡터는 렌티바이러스 벡터, 감마-레트로바이러스 벡터, 및 아데노-연관 바이러스 벡터를 포함한다. 렌티바이러스 또는 감마 레트로바이러스를 기반으로 한 바이러스 벡터는 문헌 [Dai et al. 2016, J. Natl. Cancer Inst. 108:1-14 ("Dai et al."); Jin et al. 2016, EMBO Mol. Med. 8:702-711; Liechtenstein et al. 2013, Cancers 5:815-837; and Schonfeld et al. 2015, Mol. Therapy 23:330-338]에서 설명된다. 이러한 바이러스 벡터는 CAR-암호화 핵산을 T 세포 게놈 DNA로 통합시켜 CAR의 안정한 발현을 생산하기 위해 사용된다.
특정 실시예에서, 바이러스 벡터는 서열번호 1의 뉴클레오타이드 서열을 포함하는 렌티바이러스 벡터이다.
대안적으로, CAR 작제물은 CAR-암호화 핵산, 예를 들어, 서열번호 1의 T 세포 내로의 트랜스포손-매개된(transposon-mediated) 게놈 통합을 용이하게 하는 서열을 함유하는 벡터 내에 포함될 수 있다. 이러한 발현 벡터의 예는 소위 "PiggyBac" 및 "슬리핑 뷰티(Sleeping Beauty)" 발현 벡터이다. 문헌 [Nakazawa et al. 2011, Mol. Ther. 19:2133-2143 and Maiti et al. 2013, J. Immunotherapy 36:112-123] 참조.
또 다른 대안에서, CAR 작제물을 함유하는 벡터는 T 세포의 게놈으로 CAR 작제물의 짧은 회문구조 반복서열 (clustered regularly interspaced short palindromic repeat; CRISPR)-매개된 삽입을 가능하게 하는 CAR 작제물에 인접하는(flanking) 게놈 핵산 서열을 또한 함유한다. CAR을 게놈 내로 삽입하기 위한 CRISPR 작제물의 예는 예를 들어, 문헌 [Miura et al. 2018, Nature Protocols13:195-215] 및 [He et al. 2016, Nucl. Acids Res. 44:1-14]에서 찾을 수 있다.
서열번호 3의 서열을 함유하는 단리된 폴리펩타이드가 추가로 개시된다. 단리된 폴리펩타이드인 scFv는, SSEA-4에 특이적으로 결합한다.
단계-특이적 배아 항원 4에 특이적으로 결합하는 scFv를 포함하는 CAR이 추가적으로 제공된다. scFv는 서열번호 3의 서열을 가질 수 있다. CAR은 CD3ζ 또는 FcεRIγ로부터의 제1 엔도도메인을 추가로 포함한다. 예시적인 CAR에서, 제1 도메인은 CD3ζ으로부터의 것이다.
CAR은 또한 제2 엔도도메인을 함유할 수 있다. 제2 엔도도메인은 CD28, CD137, CD4, OX40, 및 ICOS로부터의 엔도도메인일 수 있으나, 이에 제한되지 않는다. 제2 엔도도메인이 CAR에 존재하는 경우, scFv는 제2 엔도도메인에 융합(fusing)되고 제2 엔도도메인은 제1 엔도도메인에 융합된다. CAR의 특정한 실시예는 CD137로부터의 제2 엔도도메인을 갖는다. 다른 특이적인 예에서, CAR은 서열번호 4의 아미노산 서열을 갖는다.
상기 언급한 바와 같이, 특히, 종양을 갖는 대상체로부터 T 세포를 수득하는 단계 및 SSEA4를 특이적으로 인식하는 scFv를 포함하는 CAR을 암호화하는 핵산을 함유하는 벡터로 T 세포를 시험관 내에서 형질도입하는 단계를 포함하는 종양 치료 방법이 제공된다.
T 세포를 수득하는 과정이 당해 분야에 공지되어 있다. 문헌 [예를 들면, Kaiser et al. 2015, Cancer Gene Therapy 22:72-78 ("Kaiser et al.")] 참조. T 세포는 CD4+, CD8+, 또는 NK 세포일 수 있다. 예시적인 방법에서, CD8+ 세포는 대상체로부터 수득된다.
T 세포는 상기 기재된 CAR 벡터로 시험관 내에서 형질도입된다. T 세포의 형질도입은 사용된 CAR 벡터의 유형에 따라 전기천공, 리포펙션(lipofection), 렌티바이러스 감염, 감마 레트로바이러스 감염, 또는 아데노-연관 바이러스 감염에 의해 수행될 수 있다.
더욱 구체적으로, CAR 벡터가 PiggyBac, 슬리핑 뷰티, 또는 CRISPR-기반 발현 벡터인 경우, 전기천공 또는 리포펙션을 통해 T 세포 내로 형질도입될 수 있다. CRISPR-기반 발현 벡터는 T 세포 내 의도된 게놈 삽입 부위에서 프로토스페이서(protospacer) 인접 모티프(motif)에 인접한 서열과 상보적인 가이드 RNA를 발현하는 벡터와 함께 공동 형질감염된다.
CAR 벡터가 바이러스 기반인 경우, 바이러스 입자가 제조되어 T 세포를 감염시키는데 사용된다.
종양 치료 방법은 또한 형질도입된 T 세포를 시험관 내에서 확장시키는 단계 및 확장되고 형질도입된 T 세포를 종양을 갖는 대상체 내로 주입하는 단계를 포함한다.
형질도입된 T 세포는 당해 분야에 공지된 방법을 사용하여 시험관 내에서 확장된다. 문헌 [Kaiser et al.] 참조. 확장된 T 세포는 이후에 1개의 배치(batch)로 또는 2개 이상의 배치로 종양을 갖는 대상체 내에 주입된다.
종양-치료 방법의 구체적인 대안에서, 방법은 바로 언급된 주입 단계 전에 수행되는 예비 조절(preconditioning) 단계를 추가로 포함한다. 예비 조절 단계는 림프구 제거(lymphodepletion)를 유도하는 약물로 대상체를 치료함으로써 달성된다. 이러한 약물의 예는 시클로포스파미드(cyclophosphamide) 및 플루다라빈(fludarabine)를 포함한다. 추가적인 약물의 예는 문헌 [Dai et al. and Han et al. 2013, J. Hematol. Oncol. 6:47-53]에서 찾을 수 있다.
종양-치료 방법에서, 형질도입된 T 세포는 CAR 이외에, 서열번호 5의 폴리펩타이드, 즉, 상피 성장 인자 수용체 t 도메인 III-IV (EGFRt)를 추가로 발현할 수 있다. 이러한 방식으로, 주입되고 확장된 T 세포는 EGFRt에 결합하는 항-상피 성장 인자 수용체 항체에 의해 생체 내에서 결실될 수 있다. 예를 들어, 세툭시맙(cetuximab)은 대상체에게 투여되어 생체 내에서 주입된 T 세포를 사멸시킨다. CAR과 EGFRt를 함께 암호화하는 예시적인 핵산은 서열번호 1의 핵산 서열을 갖는다.
상기 설명된 방법은 SSEA4를 발현하는 세포를 함유하는 종양을 치료하기 위해 사용될 수 있다. 치료될 수 있는 종양은 유방, 결장, 위장, 신장, 폐, 간, 난소, 췌장, 직장, 위, 고환, 흉선, 자궁 경부, 전립선, 방광, 피부, 비인두, 식도, 경구, 두경부, 뼈, 연골, 근육, 림프절, 골수, 또는 뇌 종양을 포함하나, 이에 제한되지 않는다.
추가의 상세한 설명 없이, 당해 분야 숙련가는, 본원의 개시내용에 기초하여, 본 개시내용을 최대한 활용할 수 있는 것으로 고려된다. 따라서, 하기의 구체적인 실시예는 단지 설명적인 것이고, 어떤 식으로든 본 개시내용의 나머지를 제한하는 것이 아닌 것으로 해석되어야한다. 본원에 인용된 모든 간행물 및 특허 문헌은 그 전문이 참고로 포함된다.
실시예
실시예 1: 항-SSEA4 CAR 작제물을 함유하는 렌티바이러스의 제조
항-SSEA4 CAR을 암호화하는 렌티바이러스 벡터의 작제
렌티바이러스 작제물을 표준 재조합 DNA 기술을 사용하여 E. coli에서 제조하였고 DNA 서열분석에 의해 검증하였다. 더욱 구체적으로, 서열번호 3의 서열을 갖는 scFv를 암호화하는 핵산을 EF-1 알파 프로모터 및 신호 펩티드 암호화 서열의 하부(downstream) 및 CD8 힌지(hinge)-암호화 서열의 상부(upstream) 렌티바이러스 플라스미드 벡터 내로 클로닝하여 CAR 카세트(cassette)를 생성하였다. CAR 카세트는 또한 CD8 막관통(transmembrane) 도메인, CD137 세포내 신호전달 도메인, CD3ζ엔도도메인, 토시아 아시그나(Thosea asigna) 자가-절단 펩타이드 T2A, 및 EGFRt 도메인 III-IV를 암호화한다. CAR 카세트는 서열번호 1의 핵산 서열을 갖는다. 렌티바이러스 플라스미드 벡터는 추가적인 서열을 함유하여 렌티바이러스 입자의 생성을 용이하게 한다.
렌티바이러스 팩키징(packaging) 및 생산
렌티바이러스의 팩키징 및 생산은 확립된 기술을 사용하여 수행되었다. 팩키징 세포, 즉, 293T 세포를, 10 cm 배양 접시 내 10 mL의 완전 배양 배지에 5 x 106 개 세포로 플레이팅(plating)하였다. 세포를 37℃에서 5% CO2로 밤새 배양(incubating)하였다. PBS에 형질감염 시약, 상기 기재된 렌티바이러스 벡터, 팩키징 벡터, 및 엔벨로프 벡터(envelope vector)를 조합함으로써 형질감염 복합체를 제조하였다. 형질감염 복합체를 팩키징 세포를 함유하는 배양 접시에 첨가하고 세포를 37℃에서 5% CO2로 6 내지 8 시간 동안 배양하였다. 배지를 교체하고 세포를 24시간 동안 배양하였다. 배양 배지를 수집하고 신선한 배지로 교체하였다. 이러한 24시간 배양 및 배지 수집을 2회 반복하였다. 수집된 모든 배지를 조합하고 0.45 μm 필터를 통과시켰다. 여액을 50,000 x g에서 2시간 동안 원심분리하여 렌티바이러스 입자를 펠렛화(pellet)하였다. 렌티바이러스 스톡(stock)을 PBS에서 현탁하고 -80℃에서 저장하였다.
렌티바이러스 적정
감염된 세포의 게놈 내로 통합된 렌티바이러스 DNA의 양을 측정하여 렌티바이러스 역가를 측정하였다. 293T 세포를 50,000개 세포/웰(cell/sell)의 밀도로 24-웰 플레이트에 플레이팅하고 밤새 배양하였다. 농축된 렌티바이러스 스톡을 폴리브렌(polybrene)과 함께 6 μg/mL의 농도로 각 웰에 첨가하였다. 플레이트를 짧게 원심분리한 다음 37℃에서 5% CO2로 72시간 동안 인큐베이터 속에 두었다. 렌티바이러스-형질도입된 세포로부터의 게놈 DNA를 상업적 키트(kit)를 사용하여 추출하였다.
실시간 정량적 PCR(RT-PCR)을 사용하여 추출된 게놈 DNA에 존재하는 렌티바이러스 DNA의 카피 수를 측정하였다. 알부민 유전자를 또한 측정하여 결과를 정규화하였다. RT-QPCR에 사용된 프라이머 및 탐침(probe)을 하기 표 1에 나타낸다.
프라이머 | 서열 (형광 표지) | 서열번호 |
LTR Fa | TGACAGCCGCCTAGCATTTC | 6 |
LTR Ra | GCTCGATATCAGCAGTTCTTGAAG | 7 |
LTR Probea | CACGTGGCCCGAGAGCTGCATC (5'-FAM-BHQ1-3') |
8 |
ALB Fb | GCTGTCATCTCTTGTGGGCTGT | 9 |
ALB Rb | ACTCATGGGAGCTGCTGGTTC | 10 |
ALB Probeb | CCTGTCATGCCCACACAAATCTCTCC (5'-FAM-BHQ1-3') |
11 |
a LTR = 긴 말단 반복(long terminal repeat). 이 프라이머는 렌티바이러스 서열을 특이적으로 증폭시킨다.
b ALB = 알부민. 이 프라이머는 알부민 유전자를 특이적으로 증폭시킨다.
상기 기재된 RT-QPCR 프라이머를 사용하여 알부민 또는 LTR 유전자 서열을 보유하는 플라스미드 DNA의 공지된 양을 증폭시킴으로써 표준 곡선을 작제하였다. 게놈 DNA 내 렌티바이러스 DNA의 카피 수를 LTR 서열의 양을 알부민 서열의 양으로 나눈 비로 계산하였다.
이후 렌티바이러스 역가를 하기 식을 사용하여 계산하였다:
예시적인 렌티바이러스 제제는 2.6 x 108 개 형질도입 단위/mL를 함유하였다.
실시예 2: 항-SSEA4 CAR T 세포의 제조
항-SSEA4 CAR을 발현하는 T 세포를 확립된 기술을 사용하여 제조하였다. 첫 째로, 말초 혈액 단핵 세포(PBMC)를 표준 혈액 분리 튜브를 사용하여 전혈(whole blood)로부터 단리하고 세포를 완전 배양 배지에 세포를 재현탁시켰다. T 세포를 표준 자기 비드 분리 기술을 사용하여 PBMC로부터 단리하였다.
단리된 T 세포를 조직 배양 플레이트 내로 분배하고 200 IU/mL IL2, 10 ng/mL IL7, 5 ng/mL IL15, 및 5 ng/mL IL21로 보충된 성장 배지를 첨가하여 세포 밀도가 0.5 x 106 내지 1 x 106 개 세포/mL가 되도록 하였다. 플레이트를 37℃에서 5% CO2로 3일 동안 배양시켰다. 실시예 1에서 상기 기재된 바와 같이 생성된 렌티바이러스 제제를 T 세포에 첨가하고, 폴리브렌을 6 μg/ml의 최종 농도로 또한 첨가하였다. 플레이트를 800 x g로 1시간 동안 실온에서 원심분리하고, 이후 37℃에서 5% CO2로 5일 동안 배양하였다. 5일의 배양 동안, T 세포를 0.5 x 106개 세포/mL의 세포 밀도로 유지시켰다. 항-SSEA4 CAR을 발현하는 T 세포의 백분율을 EGFR 도메인 III-IV에 대한 항체를 사용하는 형광-활성화 세포 분류에 의해 측정하였다.
예시적인 제조에서, T 세포의 45.7%가 항-SSEA4 CAR을 발현하였다.
실시예 3: 항-SSEA4 CAR T 효과기 세포에 의한 MCF-7 표적 세포의 용해
표적 세포를 용해하는 항-SSEA4 CAR T 세포의 능력을 공동 배양 분석에 의해 평가하였다. SSEA4를 발현하는, MCF-7 유방암 세포를 표적 세포로 사용하였다. 5 x 105 개 세포/mL의 100 μL의 MCF-7 표적 세포를 96-웰 플레이트의 각 웰에 옮기고 37℃에서 5% CO2로 밤새 배양하였다. 효과기 세포, 즉, 항-SSEA4 CAR T 세포, 비형질도입된 T 세포, 및 음성 대조군 렌티바이러스로 형질도입된 T 세포를 무혈청 RPMI1640 배지에 각각 현탁시켰다. 96 웰 플레이트로부터의 배양 배지를 제거하고 표적 세포를 PBS로 1회 세척하였다. T 세포를 1:1, 2:1, 5:1 및 10:1의 효과기 대 표적(E/T) 비로 별도의 웰에 첨가하였다. 각 웰에서 배지의 최종 용적을 RPMI1640을 사용하여 100 μL/웰로 조정하였다. 공동 배양물을 37℃에서 5% CO2로 6시간 동안 배양하였다.
상업용 키트(CytoTox 96® non-radioactive cytotoxicity assay; 미국 위스콘신주 프로메가(Promega) 소재)를 사용하여 용해 중 이러한 세포로부터 방출된 락테이트 디히드로게네이스(LDH)의 수준을 측정함으로써 표적 MCF-7 세포의 용해를 측정하였다. 공동 배양한 후, 96-웰 플레이트를 1200 x g로 5분 동안 실온에서 원심분리하고, 각 웰로부터 50μL의 상청액을 새로운 96 웰 플레이트로 옮겼다. 각 상청액에서 LDH 수준을 제조업자에 의해 지시된 대로 측정하였다. 표적 세포만 함유하는 특정 웰은 원심분리 단계 전 용해 완충제로 처리하였다. 이 웰로부터의 상청액을 사용하여 MCF-7 세포에 의해 방출된 LDH의 최대량을 측정하였다. 결과는 도 1에 나타낸다.
데이터는 비형질도입된 T 세포 및 빈(empty) 렌티바이러스 형질도입된 T 세포와 비교하여, 모든 E/T 비에서 항-SSEA4 CAR-T 세포가 유의하게 더 많은 표적 MCF-7 세포를 용해시켰다는 것을 보여준다.
실시예 4: 항-SSEA4 CAR-T 세포에 의한 사이토카인 방출
상기 기재된 CAR-T 세포를 10% FBS로 보충된 RPMI1640 배지에서 상이한 E/T 비로 24시간 동안 96-웰 플레이트에서 37℃에서 5% CO2로 표적 세포주 MCF7와 함께 공동 배양하였다. CAR-T 세포에 의한 사이토카인 방출을 측정하기 위해 배양 배지를 수확(harvesting)하였다. 요약하면, 96-웰 플레이트를 1200 x g로 5분 동안 실온에서 원심분리하고, 이후 각 웰로부터 50μL의 상청액을 새로운 96 웰 플레이트로 옮겼다. 사이토카인 IL-2 및 IFN-γ의 농도를 제조업자의 설명서에 따라 상업용 ELISA 키트를 사용하여 측정하였다. 결과는 도 2a 및 도 2b에 나타낸다. 데이터는 SSEA4-특이적 CAR-T 세포가 표적 종양 세포에 관여한 후 IL-2 및 IFN-γ 둘 다를 강력하게 분비하고 이 분비 수준은 비형질도입된 T 세포 또는 CAR 작제물이 결여된 렌티바이러스로 형질도입된 T 세포보다 유의하게 크다는 것을 나타낸다.
기타 실시양태
본 명세서에 개시된 모든 특징들은 임의의 조합으로 조합될 수 있다. 본 명세서에 개시된 각각의 특징은 동일하거나, 동등하거나, 유사한 목적을 제공하는 대안적인 특징으로 대체될 수 있다. 달리 명시되지 않는 한, 개시된 각각의 특징은 일반적인 일련의 동등하거나 유사한 특징의 예일 뿐이다.
상기 설명으로부터, 당해 분야 숙련가는 본 발명의 본질적인 특징을 쉽게 확인할 수 있고, 본 발명의 사상 및 범위를 벗어나지 않으면서, 본 발명의 다양한 변경 및 수정을 행하여 다양한 용도 및 조건에 적응시킬 수 있다. 따라서, 기타 실시양태도 다음의 청구범위의 범위 내에 있다.
SEQUENCE LISTING
<110> CHEN, LAN, BO
<120> CHIMERIC ANTIGEN RECEPTORS THAT BIND TO SSEA4 AND USES THEREOF
<130> IPA200392-US
<150> US 15/926,382
<151> 2018-03-20
<160> 11
<170> PatentIn version 3.5
<210> 1
<211> 3972
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<220>
<221> CDS
<222> (1354)..(3972)
<400> 1
gagtaattca tacaaaagga ctcgcccctg ccttggggaa tcccagggac cgtcgttaaa 60
ctcccactaa cgtagaaccc agagatcgct gcgttcccgc cccctcaccc gcccgctctc 120
gtcatcactg aggtggagaa gagcatgcgt gaggctccgg tgcccgtcag tgggcagagc 180
gcacatcgcc cacagtcccc gagaagttgg ggggaggggt cggcaattga accggtgcct 240
agagaaggtg gcgcggggta aactgggaaa gtgatgtcgt gtactggctc cgcctttttc 300
ccgagggtgg gggagaaccg tatataagtg cagtagtcgc cgtgaacgtt ctttttcgca 360
acgggtttgc cgccagaaca caggtaagtg ccgtgtgtgg ttcccgcggg cctggcctct 420
ttacgggtta tggcccttgc gtgccttgaa ttacttccac gcccctggct gcagtacgtg 480
attcttgatc ccgagcttcg ggttggaagt gggtgggaga gttcgaggcc ttgcgcttaa 540
ggagcccctt cgcctcgtgc ttgagttgag gcctggcttg ggcgctgggg ccgccgcgtg 600
cgaatctggt ggcaccttcg cgcctgtctc gctgctttcg ataagtctct agccatttaa 660
aatttttgat gacctgctgc gacgcttttt ttctggcaag atagtcttgt aaatgcgggc 720
caagatctgc acactggtat ttcggttttt ggggccgcgg gcggcgacgg ggcccgtgcg 780
tcccagcgca catgttcggc gaggcggggc ctgcgagcgc ggccaccgag aatcggacgg 840
gggtagtctc aagctggccg gcctgctctg gtgcctggcc tcgcgccgcc gtgtatcgcc 900
ccgccctggg cggcaaggct ggcccggtcg gcaccagttg cgtgagcgga aagatggccg 960
cttcccggcc ctgctgcagg gagctcaaaa tggaggacgc ggcgctcggg agagcgggcg 1020
ggtgagtcac ccacacaaag gaaaagggcc tttccgtcct cagccgtcgc ttcatgtgac 1080
tccacggagt accgggcgcc gtccaggcac ctcgattagt tctcgagctt ttggagtacg 1140
tcgtctttag gttgggggga ggggttttat gcgatggagt ttccccacac tgagtgggtg 1200
gagactgaag ttaggccagc ttggcacttg atgtaattct ccttggaatt tgcccttttt 1260
gagtttggat cttggttcat tctcaagcct cagacagtgg ttcaaagttt ttttcttcca 1320
tttcaggtgt cgtgattcga attcgccgcc acc atg gcc tta cca gtg acc gcc 1374
Met Ala Leu Pro Val Thr Ala
1 5
ttg ctc ctg ccg ctg gcc ttg ctg ctc cac gcc gcc agg ccg cag ctg 1422
Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Gln Leu
10 15 20
caa gag tct ggc cct gga ctg gtc aag cct agc gag aca ctg agc ctg 1470
Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu
25 30 35
acc tgt acc gtg tcc ggc ttt agc ctg aca agc tac ggc gtg gac tgg 1518
Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr Gly Val Asp Trp
40 45 50 55
gtc cga cag cct cct gga aaa ggc ctg gaa tgg atc ggc gtt atc tgg 1566
Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Trp
60 65 70
ggc gga ggc agc acc aac tac aac agc gcc ctg atg agc cgg ctg acc 1614
Gly Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser Arg Leu Thr
75 80 85
atc agc aag gac aac agc aag agc cag gtg tcc ctg aag ctg agc agc 1662
Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu Lys Leu Ser Ser
90 95 100
gtg aca gcc gct gat acc gcc gtg tac tac tgt gcc aag cac gag gtg 1710
Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Glu Val
105 110 115
ctg aga ggc tac gcc ctg gat tat tgg ggc cag ggc aca ctg gtc aca 1758
Leu Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
120 125 130 135
gtg tct agc gga ggc gga gga agt ggt ggc gga gga tca ggc ggt ggt 1806
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
140 145 150
gga tct ctg aca cag tct ccc gct aca ctg tct ctg agc cct ggc gaa 1854
Gly Ser Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu
155 160 165
aga gcc aca ctg agc tgt tct gcc tct cct agc gtg tcc tac atg cac 1902
Arg Ala Thr Leu Ser Cys Ser Ala Ser Pro Ser Val Ser Tyr Met His
170 175 180
tgg tat cag cag aag ccc gga cag gcc cct aga ctg ctg atc tac gac 1950
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp
185 190 195
acc tac aag ctg gcc tct ggc atc ccc gcc aga ttt tct ggc tct ggc 1998
Thr Tyr Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
200 205 210 215
agc ggc acc gat ttc acc ctg acc ata agc agc ctg gaa cct gag gac 2046
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp
220 225 230
ttc gct gtc tac tac tgc ttc caa ggc agc ggc ttc cct ctg aca ttt 2094
Phe Ala Val Tyr Tyr Cys Phe Gln Gly Ser Gly Phe Pro Leu Thr Phe
235 240 245
gga cag ggc acc aag gtg gaa atc aag acc act acc cca gca ccg agg 2142
Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg
250 255 260
cca ccc acc ccg gct cct acc atc gcc tcc cag cct ctg tcc ctg cgt 2190
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
265 270 275
ccg gag gca tgt aga ccc gca gct ggt ggg gcc gtg cat acc cgg ggt 2238
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
280 285 290 295
ctt gac ttc gcc tgc gat atc tac att tgg gcc cct ctg gct ggt act 2286
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
300 305 310
tgc ggg gtc ctg ctg ctt tca ctc gtg atc act ctt tac tgt atc tac 2334
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Ile Tyr
315 320 325
att tgg gcc cct ctg gct ggt act tgc ggg gtc ctg ctg ctt tca ctc 2382
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
330 335 340
gtg atc act ctt tac tgt aag cgc ggt cgg aag aag ctg ctg tac atc 2430
Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
345 350 355
ttt aag caa ccc ttc atg agg cct gtg cag act act caa gag gag gac 2478
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
360 365 370 375
ggc tgt tca tgc cgg ttc cca gag gag gag gaa ggc ggc tgc gaa ctg 2526
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
380 385 390
cgc gtg aaa ttc agc cgc agc gca gat gct cca gcc tac aag cag ggg 2574
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
395 400 405
cag aac cag ctc tac aac gaa ctc aat ctt ggt cgg aga gag gag tac 2622
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
410 415 420
gac gtg ctg gac aag cgg aga gga cgg gac cca gaa atg ggc ggg aag 2670
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
425 430 435
ccg cgc aga aag aat ccc caa gag ggc ctg tac aac gag ctc caa aag 2718
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
440 445 450 455
gat aag atg gca gaa gcc tat agc gag att ggt atg aaa ggg gaa cgc 2766
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
460 465 470
aga aga ggc aaa ggc cac gac gga ctg tac cag gga ctc agc acc gcc 2814
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
475 480 485
acc aag gac acc tat gac gct ctt cac atg cag gcc ctg ccg cct cgg 2862
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
490 495 500
gag ggc aga ggc agc ctg ctg aca tgt ggc gac gtg gaa gag aac cct 2910
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
505 510 515
ggc ccc atg tgg ctg cag agc ctg ctg ctc ttg ggc act gtg gcc tgc 2958
Gly Pro Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys
520 525 530 535
agc atc tct cgc aaa gtg tgt aac gga ata ggt att ggt gaa ttt aaa 3006
Ser Ile Ser Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys
540 545 550
gac tca ctc tcc ata aat gct acg aat att aaa cac ttc aaa aac tgc 3054
Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys
555 560 565
acc tcc atc agt ggc gat ctc cac atc ctg ccg gtg gca ttt agg ggt 3102
Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly
570 575 580
gac tcc ttc aca cat act cct cct ctg gat cca cag gaa ctg gat att 3150
Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile
585 590 595
ctg aaa acc gta aag gaa atc aca ggg ttt ttg ctg att cag gct tgg 3198
Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp
600 605 610 615
cct gaa aac agg acg gac ctc cat gcc ttt gag aac cta gaa atc ata 3246
Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile
620 625 630
cgc ggc agg acc aag caa cat ggt cag ttt tct ctt gca gtc gtc agc 3294
Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser
635 640 645
ctg aac ata aca tcc ttg gga tta cgc tcc ctc aag gag ata agt gat 3342
Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp
650 655 660
gga gat gtg ata att tca gga aac aaa aat ttg tgc tat gca aat aca 3390
Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr
665 670 675
ata aac tgg aaa aaa ctg ttt ggg acc tcc ggt cag aaa acc aaa att 3438
Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile
680 685 690 695
ata agc aac aga ggt gaa aac agc tgc aag gcc aca ggc cag gtc tgc 3486
Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys
700 705 710
cat gcc ttg tgc tcc ccc gag ggc tgc tgg ggc ccg gag ccc agg gac 3534
His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp
715 720 725
tgc gtc tct tgc cgg aat gtc agc cga ggc agg gaa tgc gtg gac aag 3582
Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys
730 735 740
tgc aac ctt ctg gag ggt gag cca agg gag ttt gtg gag aac tct gag 3630
Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu
745 750 755
tgc ata cag tgc cac cca gag tgc ctg cct cag gcc atg aac atc acc 3678
Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr
760 765 770 775
tgc aca gga cgg gga cca gac aac tgt atc cag tgt gcc cac tac att 3726
Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile
780 785 790
gac ggc ccc cac tgc gtc aag acc tgc ccg gca gga gtc atg gga gaa 3774
Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu
795 800 805
aac aac acc ctg gtc tgg aag tac gca gac gcc ggc cat gtg tgc cac 3822
Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His
810 815 820
ctg tgc cat cca aac tgc acc tac gga tgc act ggg cca ggt ctt gaa 3870
Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu
825 830 835
ggc tgt cca acg aat ggg cct aag atc ccg tcc atc gcc act ggg atg 3918
Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met
840 845 850 855
gtg ggg gcc ctc ctc ttg ctg ctg gtg gtg gcc ctg ggg atc ggc ctc 3966
Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu
860 865 870
ttc atg 3972
Phe Met
<210> 2
<211> 873
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 2
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Thr Ser Tyr Gly Val Asp Trp Val Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Val Ile Trp Gly Gly Gly Ser Thr Asn Tyr Asn Ser
65 70 75 80
Ala Leu Met Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Lys His Glu Val Leu Arg Gly Tyr Ala Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Thr Gln Ser Pro Ala Thr
145 150 155 160
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser
165 170 175
Pro Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala
180 185 190
Pro Arg Leu Leu Ile Tyr Asp Thr Tyr Lys Leu Ala Ser Gly Ile Pro
195 200 205
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
210 215 220
Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Phe Gln Gly
225 230 235 240
Ser Gly Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
245 250 255
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
260 265 270
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
275 280 285
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
290 295 300
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
305 310 315 320
Ile Thr Leu Tyr Cys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
325 330 335
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
340 345 350
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
355 360 365
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
370 375 380
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
385 390 395 400
Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
405 410 415
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
420 425 430
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
435 440 445
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
450 455 460
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
465 470 475 480
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
485 490 495
Met Gln Ala Leu Pro Pro Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys
500 505 510
Gly Asp Val Glu Glu Asn Pro Gly Pro Met Trp Leu Gln Ser Leu Leu
515 520 525
Leu Leu Gly Thr Val Ala Cys Ser Ile Ser Arg Lys Val Cys Asn Gly
530 535 540
Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn
545 550 555 560
Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile
565 570 575
Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu
580 585 590
Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly
595 600 605
Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala
610 615 620
Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln
625 630 635 640
Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg
645 650 655
Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys
660 665 670
Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr
675 680 685
Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys
690 695 700
Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys
705 710 715 720
Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg
725 730 735
Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg
740 745 750
Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu
755 760 765
Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys
770 775 780
Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys
785 790 795 800
Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala
805 810 815
Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly
820 825 830
Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile
835 840 845
Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val
850 855 860
Val Ala Leu Gly Ile Gly Leu Phe Met
865 870
<210> 3
<211> 235
<212> PRT
<213> Artificial Sequence
<220>
<223> single chain Fv
<400> 3
Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu
1 5 10 15
Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr Gly Val
20 25 30
Asp Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val
35 40 45
Ile Trp Gly Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser Arg
50 55 60
Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu Lys Leu
65 70 75 80
Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His
85 90 95
Glu Val Leu Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro
130 135 140
Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Pro Ser Val Ser Tyr
145 150 155 160
Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
165 170 175
Tyr Asp Thr Tyr Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly
180 185 190
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
195 200 205
Glu Asp Phe Ala Val Tyr Tyr Cys Phe Gln Gly Ser Gly Phe Pro Leu
210 215 220
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 4
<211> 490
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 4
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Thr Ser Tyr Gly Val Asp Trp Val Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Val Ile Trp Gly Gly Gly Ser Thr Asn Tyr Asn Ser
65 70 75 80
Ala Leu Met Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Lys His Glu Val Leu Arg Gly Tyr Ala Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Thr Gln Ser Pro Ala Thr
145 150 155 160
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser
165 170 175
Pro Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala
180 185 190
Pro Arg Leu Leu Ile Tyr Asp Thr Tyr Lys Leu Ala Ser Gly Ile Pro
195 200 205
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
210 215 220
Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Phe Gln Gly
225 230 235 240
Ser Gly Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
245 250 255
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
260 265 270
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
275 280 285
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Lys Arg Gly
290 295 300
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
305 310 315 320
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
325 330 335
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
340 345 350
Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
355 360 365
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
370 375 380
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
385 390 395 400
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
405 410 415
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
420 425 430
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
435 440 445
Met Gln Ala Leu Pro Pro Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys
450 455 460
Gly Asp Val Glu Glu Asn Pro Gly Pro Met Trp Leu Gln Ser Leu Leu
465 470 475 480
Leu Leu Gly Thr Val Ala Cys Ser Ile Ser
485 490
<210> 5
<211> 352
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic ploypeptide
<400> 5
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser
20 25 30
Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser
35 40 45
Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser
50 55 60
Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys
65 70 75 80
Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu
85 90 95
Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly
100 105 110
Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn
115 120 125
Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp
130 135 140
Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn
145 150 155 160
Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser
165 170 175
Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala
180 185 190
Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val
195 200 205
Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn
210 215 220
Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile
225 230 235 240
Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr
245 250 255
Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly
260 265 270
Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn
275 280 285
Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys
290 295 300
His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys
305 310 315 320
Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly
325 330 335
Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met
340 345 350
<210> 6
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic primer
<400> 6
tgacagccgc ctagcatttc 20
<210> 7
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic primer
<400> 7
gctcgatatc agcagttctt gaag 24
<210> 8
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic probe
<400> 8
cacgtggccc gagagctgca tc 22
<210> 9
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic primer
<400> 9
gctgtcatct cttgtgggct gt 22
<210> 10
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic primer
<400> 10
actcatggga gctgctggtt c 21
<210> 11
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic probe
<400> 11
cctgtcatgc ccacacaaat ctctcc 26
Claims (20)
- 서열번호 3의 폴리펩타이드를 암호화하는 뉴클레오타이드를 포함하는, 단리된 핵산(isolated nucleic acid).
- 제1항에 있어서, 뉴클레오타이드 서열이 서열번호 1인, 단리된 핵산.
- 제2항의 단리된 핵산을 포함하는 재조합 세포로서, 서열번호 2의 폴리펩타이드를 발현하는, 재조합 세포(recombinant cell).
- 제3항에 있어서, 세포가 T 세포인, 재조합 세포.
- 제1항의 단리된 핵산을 포함하는 바이러스 벡터로서, 바이러스 벡터가 렌티바이러스 벡터, 감마-레트로바이러스 벡터, 또는 아데노-연관 바이러스 벡터인, 바이러스 벡터.
- 제5항에 있어서, 뉴클레오타이드 서열이 서열번호 1인, 바이러스 벡터.
- 서열번호 3의 서열을 포함하는 단리된 폴리펩타이드로서, 단계-특이적 배아 항원 4에 특이적으로 결합하는, 단리된 폴리펩타이드.
- 단계-특이적 배아 항원 4에 특이적으로 결합하는 단일 사슬 Fv(scFv), 및 CD3ζ 또는 FcεRIγ로부터의 제1 엔도도메인(endodomain)을 포함하고, 여기서 scFv가 서열번호 3의 서열을 갖는 것인, 키메라 항원 수용체.
- 제8항에 있어서, CD28, CD137, CD4, OX40, 또는 ICOS로부터의 제2 엔도도메인을 추가로 포함하고, 여기서 scFv가 제2 엔도도메인에 융합(fusing)되고 제2 엔도도메인이 제1 엔도도메인에 융합되는 것인, 키메라 항원 수용체.
- 제9항에 있어서, 서열번호 4의 서열을 갖는, 키메라 항원 수용체.
- 종양을 갖는 대상체로부터 T 세포를 수득하는 단계;
단계-특이적 배아 항원 4(SSEA4)를 특이적으로 인식하는 scFv를 포함하는 키메라 항원 수용체(CAR)를 암호화하는 핵산을 함유하는 벡터로 T 세포를 시험관 내에서 형질도입하여, 이에 의해 형질도입된 T 세포가 CAR을 발현하는 단계;
형질도입된 T 세포를 시험관 내에서 확장시키는 단계; 및
확장되고 형질도입된 T 세포를 종양을 갖는 대상체 내로 주입하여, 이에 의해 항-종양 T 세포 반응을 일으키는 단계를 포함하여, 대상체에서 종양을 치료하는 방법으로서,
여기서 scFv가 서열번호 3의 아미노산 서열을 갖고 종양 내의 세포가 SSEA4를 발현하는, 방법. - 제11항에 있어서, CAR이 서열번호 4의 아미노산 서열을 갖는, 방법.
- 제12항에 있어서, 벡터가 렌티바이러스, 감마 레트로바이러스, 또는 아데노-연관 바이러스인, 방법.
- 제13항에 있어서, 종양이 유방, 결장, 위장, 신장, 폐, 간, 난소, 췌장, 직장, 위, 고환, 흉선, 자궁 경부, 전립선, 방광, 피부, 비인두, 식도, 경구, 두경부, 뼈, 연골, 근육, 림프절, 골수, 또는 뇌 종양인, 방법.
- 제11항에 있어서, 형질도입된 T 세포가 서열번호 5의 폴리펩타이드를 추가로 발현하여, 주입된 확장된 T 세포가 항-표피 성장 인자 수용체 항체에 의해 생체 내에서 결실될 수 있는, 방법.
- 제15항에 있어서, CAR이 서열번호 4의 아미노산 서열을 갖는, 방법.
- 제16항에 있어서, 핵산이 서열번호 1의 서열을 갖는, 방법.
- 제15항에 있어서, 종양이 유방, 결장, 위장, 신장, 폐, 간, 난소, 췌장, 직장, 위, 고환, 흉선, 자궁 경부, 전립선, 방광, 피부, 비인두, 식도, 경구, 두경부, 뼈, 연골, 근육, 림프절, 골수, 또는 뇌 종양인, 방법.
- 제16항에 있어서, 종양이 유방, 결장, 위장, 신장, 폐, 간, 난소, 췌장, 직장, 위, 고환, 흉선, 자궁 경부, 전립선, 방광, 피부, 비인두, 식도, 경구, 두경부, 뼈, 연골, 근육, 림프절, 골수, 또는 뇌 종양인, 방법.
- 제17항에 있어서, 종양이 유방, 결장, 위장, 신장, 폐, 간, 난소, 췌장, 직장, 위, 고환, 흉선, 자궁 경부, 전립선, 방광, 피부, 비인두, 식도, 경구, 두경부, 뼈, 연골, 근육, 림프절, 골수, 또는 뇌 종양인, 방법.
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US15/926,382 | 2018-03-20 | ||
US15/926,382 US10751399B2 (en) | 2018-03-20 | 2018-03-20 | Chimeric antigen receptors that bind to SSEA4 and uses thereof |
PCT/US2019/022861 WO2019183025A1 (en) | 2018-03-20 | 2019-03-19 | Chimeric antigen receptors that bind to ssea4 and uses thereof |
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EP (1) | EP3678711A4 (ko) |
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CN (1) | CN111629762A (ko) |
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CA (1) | CA3078304A1 (ko) |
IL (1) | IL274258B (ko) |
SG (1) | SG11202002994SA (ko) |
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US20210332448A1 (en) * | 2020-03-09 | 2021-10-28 | Janssen Pharmaceutica Nv | Compositions and methods for quantifying integration of recombinant vector nucleic acid |
US20240066125A1 (en) * | 2021-02-09 | 2024-02-29 | Obi Pharma, Inc. | Globo series antigens-binding chimeric antigen receptors and uses thereof |
WO2022178040A1 (en) * | 2021-02-16 | 2022-08-25 | City Of Hope | Truncated domain iv egfr and uses thereof |
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WO2007149269A2 (en) * | 2006-06-12 | 2007-12-27 | Oncomethylome Sciences S.A. | Methylation markers for early detection and prognosis of colon cancers |
RU2582266C2 (ru) * | 2009-07-02 | 2016-04-20 | Мерц Фарма Гмбх Унд Ко. Кгаа | Нейротоксины, проявляющие сокращенную биологическую активность |
KR102135239B1 (ko) * | 2012-08-20 | 2020-07-17 | 프레드 헛친슨 켄서 리서치 센터 | 세포 면역요법을 위한 방법 및 조성물 |
TWI654206B (zh) | 2013-03-16 | 2019-03-21 | 諾華公司 | 使用人類化抗-cd19嵌合抗原受體治療癌症 |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
TWI570483B (zh) * | 2014-07-21 | 2017-02-11 | 友達光電股份有限公司 | 顯示器 |
CA2958757C (en) | 2014-08-19 | 2021-04-27 | Miltenyi Biotec Gmbh | Chimeric antigen receptor specific for ssea4 antigen |
CN107254453B (zh) * | 2014-12-22 | 2019-10-25 | 武汉康复得生物科技股份有限公司 | 一种在生理pH条件下有活力的草酸氧化酶及其应用 |
TW201631152A (zh) | 2014-12-29 | 2016-09-01 | 諾華公司 | 製造嵌合抗原受體-表現細胞之方法 |
CN109311995A (zh) | 2016-03-29 | 2019-02-05 | 台湾浩鼎生技股份有限公司 | 抗体、药物组合物和方法 |
US20180028633A1 (en) | 2016-07-29 | 2018-02-01 | Lan Bo Chen | Chimeric antigen receptor combination therapy for treating tumors |
US20180028631A1 (en) * | 2016-07-29 | 2018-02-01 | Lan Bo Chen | Anti-ssea4 chimeric antigen receptors and their use for treating cancer |
WO2018023121A1 (en) | 2016-07-29 | 2018-02-01 | Obi Pharma, Inc. | Human antibodies, pharmaceutical compositions and methods |
JP7213549B2 (ja) | 2016-08-22 | 2023-01-27 | シーエイチオー ファーマ インコーポレイテッド | 抗体、結合性断片、および使用の方法 |
CN107188968A (zh) | 2017-05-08 | 2017-09-22 | 上海神因生物科技有限公司 | 一种靶向pdpn基因的人源嵌合抗原受体及其用途 |
CN107759700A (zh) * | 2017-10-18 | 2018-03-06 | 银丰生物工程集团有限公司 | 靶向cd19抗原的转基因t细胞及其制备方法与应用 |
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US10751399B2 (en) | 2020-08-25 |
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BR112020015723A2 (pt) | 2020-12-08 |
CN111629762A (zh) | 2020-09-04 |
IL274258B (en) | 2022-04-01 |
EP3678711A4 (en) | 2021-06-02 |
SG11202002994SA (en) | 2020-04-29 |
US20200338177A1 (en) | 2020-10-29 |
CA3078304A1 (en) | 2019-09-26 |
IL274258A (en) | 2020-06-30 |
US11628210B2 (en) | 2023-04-18 |
TWI817997B (zh) | 2023-10-11 |
US20190290744A1 (en) | 2019-09-26 |
JP2021517450A (ja) | 2021-07-26 |
AU2019239730A1 (en) | 2020-04-23 |
TW202003049A (zh) | 2020-01-16 |
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