KR20170142995A - 키메라 항원 수용체 및 키메라 항원 수용체가 발현된 t 세포 - Google Patents
키메라 항원 수용체 및 키메라 항원 수용체가 발현된 t 세포 Download PDFInfo
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Abstract
항원 결합 도메인; 힌지 영역; 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체가 개시된다.
Description
본 발명은 암세포 표면 항원을 인식하는 키메라 항원 수용체 및 이것이 발현된 T 세포에 관한 것이다. 구체적으로는, 본 발명은 발현율이 우수한 키메라 항원 수용체 및 이것이 발현된 T 세포에 관한 것이다. 보다 구체적으로, 본 발명은 암세포 표면 항원 결합 도메인(antigen binding domain); 힌지 영역(hinge region); 막통과 도메인(transmembrane domain); 보조 자극 도메인(costimulatory domain) 및 세포질 신호 도메인(signaling domain)을 포함하는 키메라 항원 수용체에 있어서, 보조 자극 도메인이 돌연변이된 CD28 또는 TNFRSF9로 이루어지는 것을 특징으로 하는 키메라 항원 수용체 및 이것이 발현된 T 세포에 관한 것이다. 추가적으로, 본 발명은 상기 키메라 항원 수용체 및 이것이 발현된 T 세포에 있어서, 상기 항원 결합 도메인이 IL13Rα2, 혈관 신생 작용과 관련된 항원, EGFRvlll, EphA2, αVβ3, 및 glypican1으로 이루어지는 군으로부터 선택되는 항원과 결합하는 것을 특징으로 하는 키메라 항원 수용체 및 이것이 발현된 T 세포에 관한 것이다.
또한, 본 발명은 상기 키메라 항원 수용체 및 이것이 발현된 T 세포에 있어서, 상기 항원 결합 도메인과 힌지 영역 사이에 3개의 글리신이 추가로 도입된 것을 특징으로 하는 키메라 항원 수용체 및 이것이 발현된 T 세포에 관한 것이다.
또한, 본 발명은 상기 키메라 항원 수용체 및 이것이 발현된 T 세포에 있어서, 세포질 신호도메인이 Jurkat T세포의 CD3ζ 신호전달 도메인이 아닌, 추가의 글루타민(extra Glutamine)이 포함된 정상 인간(normal person)의 CD3ζ 신호전달 도메인 사용을 특징으로 하는 키메라 항원 수용체 및 이것이 발현된 T 세포에 관한 것이다.
나아가, 본 발명은, 상기에 개시된 소정의 항원 결합 도메인, 보조 자극 도메인 및 세포질 신호 도메인의 어느 하나를 포함하거나, 또는, 모두를 포함하는 키메라 항원 수용체 및 이것이 발현된 T 세포에 관한 것이다.
키메라 항원 수용체(이하 본 명세서에서는 이를 「CAR」라 약칭하는 경우가 있다)를 발현하는 T 세포(이하 본 명세서에서는 이를 「CAR-T 세포」라 약칭하는 경우가 있다)는, 암세포의 표면에 특이적으로 발현되는 암세포 표면 항원을 인식하는 수용체를 코딩하는 유전자를 T 세포에 도입하여 암세포를 사멸시킬 수 있도록 유전자가 재조합된 T 세포를 의미한다. 이스라엘의 Weizmann Institute of Science의 화학자이면서 면역학자인 Dr. Zelig Eshhar 등이 암세포에서 특이적으로 발현하는 항원과 결합하는 수용체를 갖는 T세포를 인위적으로 만들면 암세포만 표적하여 면역반응을 일으켜 암세포를 죽일 수 있다는 지견을 도출하여, 키메라 항원 수용체를 장착한 T세포를 만드는데 성공하였고 1989년 PNAS에 발표한 바 있다.
그러나, 초창기에 제조된 CAR-T 세포, 즉 1세대 CAR-T 세포는 신호 전달 도메인으로서 CD3ζ만을 이용하였는데, 그 치료효과가 미미했고, 또한, 지속시간도 짧다는 단점이 있었다. 이에, CAR-T 세포의 반응성을 향상시키기 위한 노력이 행해졌으며, 보조 자극 도메인(CD28 또는 CD137/4-1BB)과 CD3ζ를 결합한 2세대 CAR-T 세포가 제조되었는데 1세대 CAR-T 세포와 비교하여 체내에 잔존하는 CAR-T 세포의 수가 현저히 증가하였다. 한편, 2세대 CAR-T 세포는 한 가지의 보조 자극 도메인을 이용하였는데, 두 가지의 보조 자극 도메인을 이용하는 CAR-T 세포를 3세대 CAR-T라 지칭하며, 현재 연구는 2세대 및 3세대 CAR-T 세포에 집중되어 있다. 한편, CAR-T세포를 이용해서 암을 치료하는 방법과 관련하여, 3명의 말기 만성림프성백혈병(CCL, chronic lymphoid leukemia) 환자에게 CD19를 인지할 수 있도록 변형된 세포독성 T세포(Cytotoxic T cell)을 주사했더니, 그 중 2명에서 백혈병이 완전히 치료되었고, 그 상태가 10개월 정도 지속되었다는 보고가 있고, (N. Engl J Med 2011; 365:725-733 August 25, 2011, Sic. Transl. Med 2011 Aug 10;3(95):95ra73) 여기에서 사용된 CAR-T는 2세대에 해당되는 것으로서 보조 자극 도메인으로서 4-1BB를, 신호 전달 도메인으로서 CD3ζ를 이용한 것이다. 상기 CAR-T세포의 항원 결합 도메인은 백혈병 암세포의 표면에서 발견되는 CD19를 항원으로 인식한다.
또한, 급성 백혈병 환자에게 CTL019를 투여하여 치료하였더니, 환자 30명중 27명이 완전 관해를 경험하였고, 전체 환자의 67%가 2년동안 완전관해, 78%가 2년간 생존하였다는 보고가 있으며, 대상 환자가 재발성 혹은 불응성환자였음을 고려한다면, 이는 매우 놀라운 것이다.(N Engl J Med 2014; 371:1507-1517, October 16, 2014)
현재, 다양한 CAR-T세포를 이용한 치료법에 대하여 lymphoma, myeloma 등 다양한 혈액암을 대상으로 임상시험이 진행중에 있고, 사용가능한 의약품으로서의 CAR-T가 시장에 등장할 것으로 예상된다. CAR-T 세포를 이용한 암치료는 자가 유래 방식이어서 대량생산되는 제품은 아니지만, 환자 맞춤형으로서 그 치료효과가 기존의 항암제와 비교할 수 없을 정도로 높다.
Immunol Rev, 2014, 257(1):107-126
N Engl J Med 2014; 371:1507-1517, October 16, 2014
Science Translational Medicine 18 Feb 2015: Vol. 7, Issue 275, pp. 275ra22
본 발명은 종래에 알려졌던 CAR-T 세포와 비교하여 발현율과 치료효과가 현저히 우수한 CAR 및 CAR-T 세포의 제공을 해결과제로 한다. 구체적으로, 본 발명에서는, 2세대 및 3세대 CAR-T 세포에 있어서, 그 기능의 주요역할을 담당하는 보조 자극 도메인으로서 다양한 CAR-T 세포에 도입가능한 보조 자극 도메인을 제공하는 것을 해결과제로 한다. 나아가, 특정한 암 세포의 표면에 발현되는 항원과 결합가능하고, 또한, CAR-T 세포의 형성이 가능한 다양한 항원 결합 도메인을 제공하는 것을 해결과제로 한다. 또한, 다양한 CAR-T 세포에 있어서, 항원 결합 도메인과 힌지 영역 사이에 추가적으로 도입가능한 추가의 아미노산 서열을 갖는 것을 특징으로 하는 키메라 항원 수용체로서, CAR-T 세포의 발현율 및 그 치료효과의 향상 방법을 제공하는 것을 기술적 과제로 한다.
상기 과제의 해결 수단으로서, 본 발명에서는 하기와 같은 기술사상을 개시한다.
항원 결합 도메인; 힌지 영역; 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체에 있어서, 특정한 보조 자극 도메인, 또는 특정한 항원 결합 도메인, 항원 결합 도메인과 힌지 영역 사이에 추가되는 특정한 아미노산 서열을 독립적으로 포함하거나, 또는 세포질 신호 도메인이 Jurkat T세포의 CD3ζ 신호전달 도메인이 아닌, 추가의글루타민(extra Glutamine)이 포함된 정상 인간(normal person)의 CD3ζ 신호전달 도메인 사용을 특징으로 하는, 또는 이들을 조합하여 포함하는 키메라 항원 수용체, 그리고, 이것이 발현된 CAR-T 세포를 개시한다.
본 발명에서 개시하고 있는 항원 결합 도메인; 또는 보조 자극 도메인; 또는 신호 전달 도메인을 포함하는 CAR-T 세포는 치료효능 및 발현율이 현저히 우수하다는 효과를 갖는다.
본 발명을 예시할 목적으로, 현재 실시형태가 도면에 도시되어 있다. 그러나 본 발명은 도면에 도시된 실시형태의 정확한 배열 및 방편에 제한되지 않는 것으로 이해되어야 한다.
도 1은 본 발명에서 개시하는 CAR-T세포의 일 실시예의 주요 기능 요소를 나타내는 레트로바이러스 벡터 및 이식 유전자를 나타낸다. 구체적으로 IL13의 2가지 아미노산 치환(Glu-11, Arg-107)보다 높은 항원 친화력를 부여하기 위해 돌연변이 된 IL13(E11K.R64D.S67D.R107K), 인간 CD8α 힌지 및 인간 CD8/인간 CD3 막통과 도메인, CAR 발현율을 증가시키기 위해 돌연변이 인간 CD28(RLLH → RGGH), 인간 TNFRSF9, 및 건강한 사람의 CD3 제타 신호전달 도메인의 발현을 지시하는 임상적 등급 레트로바이러스 벡터를 도시했다. 도면은 일정한 축적으로 도시되지 않았다.
도 2는 CAR단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 부위 사이에 3개의 글리신을 첨가한 후 발현율이 증가함을 보이는 도면이다.
도 3은 CAR단백질의 키메라 항원 수용체의 발현을 증가시키기 위하여 인간CD28의 돌연변이 (RLLH → RGGH) 사용시 발현율이 증가함을 보이는 도면이다.
도 4는 임상을 위해 설정된 제조공정으로 생산된 CAR-T 세포 순도 및 CAR 발현율 확인을 위해 형질전환한 T 세포를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과를 나타내는 도면으로 CAR 발현율 및 T 세포 순도를 나타내는 도면이다.
도 5는 2개 위치가 치환된 IL13 (Glu-11, Arg-107)과 4개 위치가 치환된 IL13(IL13.E11K.R64D.S67D.R107K)이 도입된 T-세포의 세포독성(Cytotoxicity)을 비교한 도면이다.
도 6은 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K).TNFRSF9.CD3ζ로 구성되는 CAR-T 세포의 인간 뇌암세포주 U251에서 CAR 발현율 의존적으로 항암 활성 증가를 보임을 나타내는 도면이다.
도 7은 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ로 이루어지는 CAR-T 세포와 타겟세포인 인간 뇌암세포주 U251 (IL13Rα2 과발현) 또는 normal cell control인 HUVEC (IL13Rα2 발현의 결여)를 0.5 : 1 비율로 19시간 배양한 후 IFN-γ cytokine 생성을 나타내는 도면이다.
도 8은 4개 위치가 치환된 (IL13.E11K.R64D.S67D.R107K).TNFRSF9.CD3ζ을 포함하는 CAR-T 세포와 타겟세포인 인간 뇌암세포주 U251를 19시간 배양한 후 IFN-γ cytokine 생성이 CAR-T 세포수 의존적으로 항암 활성 증가를 보임을 나타내는 도면이다.
도 9A는 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ을 포함하는 CAR-T 세포를 이용한 누드 마우스 in vivo 효력실험 방법을 개략적으로 보여주는 이미지이고, 도 9B는 상기 CAR-T 세포 또는 PBS 처리 12일 후에 동물의 종양 크기를 측정한 결과를 나타내는 도면이다.
도 9C는 상기 CAR-T 세포 또는 PBS 처리 15일 후에 누드 마우스로부터 제거된 암조직의 형태, 크기, 그리고 무게를 나타내는 도면이다.
도 10A은 TMZ+PBS(PBS는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스 로부터 제거된 암조직을 anti-human CD3 antibody를 이용하여 T 세포를 염색한 이미지이다.
도 10B는 TMZ+YYB103(TMZ 및 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ을 포함하는 CAR-T 세포는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스 로부터 제거된 암조직을 anti-human CD3 antibody를 이용하여 T 세포를 염색한 이미지이다.
도 11A는 TMZ+PBS(PBS는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스로부터 제거된 암조직을 H&E 염색을 실시한 이미지이다.
도 11B는 TMZ+YYB103(TMZ 및 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ을 포함하는 CAR-T 세포는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스로부터 제거된 암조직을 H&E 염색을 실시한 이미지이다.
도 12는 성공적인 항암 CAR 치료법은, 항원 특이적인 CAR-T 세포뿐만 아니라 암세포에 대한 CAR-T세포의 접근 및 CAR-T 세포 기능 유지를 위한 면역기능 강화(immunosupportive) 환경을 필요로 하므로, 이러한 목표를 달성하기 위하여 항-혈관신생(anti-angiogenic) CAR를 제작한 것을 나타낸다. 도 12A는 주요 기능 요소를 나타내는 Anti-Angiogenic CAR이식 유전자를 나타내고, 도 12B는 Anti-Angiogenic CAR의 세포표면에서의 발현을 위한 유전자 구조체들을 이용하여 형질 전환한 세포를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과를 나타내는 도면이다.
도 13 내지 도 16은 다양한 암의 주요한 종양 항원을 타겟으로 하는 CAR 제작을 나타낸다. 각 도면의 A는 주요 기능 요소를 나타내는 CAR이식 유전자를 나타내고, 각 도면의 B는 CAR의 세포표면에서의 발현을 위한 유전자 구조체들을 이용하여 형질 전환한 세포를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과를 나타내는 도면이다.
도 1은 본 발명에서 개시하는 CAR-T세포의 일 실시예의 주요 기능 요소를 나타내는 레트로바이러스 벡터 및 이식 유전자를 나타낸다. 구체적으로 IL13의 2가지 아미노산 치환(Glu-11, Arg-107)보다 높은 항원 친화력를 부여하기 위해 돌연변이 된 IL13(E11K.R64D.S67D.R107K), 인간 CD8α 힌지 및 인간 CD8/인간 CD3 막통과 도메인, CAR 발현율을 증가시키기 위해 돌연변이 인간 CD28(RLLH → RGGH), 인간 TNFRSF9, 및 건강한 사람의 CD3 제타 신호전달 도메인의 발현을 지시하는 임상적 등급 레트로바이러스 벡터를 도시했다. 도면은 일정한 축적으로 도시되지 않았다.
도 2는 CAR단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 부위 사이에 3개의 글리신을 첨가한 후 발현율이 증가함을 보이는 도면이다.
도 3은 CAR단백질의 키메라 항원 수용체의 발현을 증가시키기 위하여 인간CD28의 돌연변이 (RLLH → RGGH) 사용시 발현율이 증가함을 보이는 도면이다.
도 4는 임상을 위해 설정된 제조공정으로 생산된 CAR-T 세포 순도 및 CAR 발현율 확인을 위해 형질전환한 T 세포를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과를 나타내는 도면으로 CAR 발현율 및 T 세포 순도를 나타내는 도면이다.
도 5는 2개 위치가 치환된 IL13 (Glu-11, Arg-107)과 4개 위치가 치환된 IL13(IL13.E11K.R64D.S67D.R107K)이 도입된 T-세포의 세포독성(Cytotoxicity)을 비교한 도면이다.
도 6은 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K).TNFRSF9.CD3ζ로 구성되는 CAR-T 세포의 인간 뇌암세포주 U251에서 CAR 발현율 의존적으로 항암 활성 증가를 보임을 나타내는 도면이다.
도 7은 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ로 이루어지는 CAR-T 세포와 타겟세포인 인간 뇌암세포주 U251 (IL13Rα2 과발현) 또는 normal cell control인 HUVEC (IL13Rα2 발현의 결여)를 0.5 : 1 비율로 19시간 배양한 후 IFN-γ cytokine 생성을 나타내는 도면이다.
도 8은 4개 위치가 치환된 (IL13.E11K.R64D.S67D.R107K).TNFRSF9.CD3ζ을 포함하는 CAR-T 세포와 타겟세포인 인간 뇌암세포주 U251를 19시간 배양한 후 IFN-γ cytokine 생성이 CAR-T 세포수 의존적으로 항암 활성 증가를 보임을 나타내는 도면이다.
도 9A는 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ을 포함하는 CAR-T 세포를 이용한 누드 마우스 in vivo 효력실험 방법을 개략적으로 보여주는 이미지이고, 도 9B는 상기 CAR-T 세포 또는 PBS 처리 12일 후에 동물의 종양 크기를 측정한 결과를 나타내는 도면이다.
도 9C는 상기 CAR-T 세포 또는 PBS 처리 15일 후에 누드 마우스로부터 제거된 암조직의 형태, 크기, 그리고 무게를 나타내는 도면이다.
도 10A은 TMZ+PBS(PBS는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스 로부터 제거된 암조직을 anti-human CD3 antibody를 이용하여 T 세포를 염색한 이미지이다.
도 10B는 TMZ+YYB103(TMZ 및 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ을 포함하는 CAR-T 세포는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스 로부터 제거된 암조직을 anti-human CD3 antibody를 이용하여 T 세포를 염색한 이미지이다.
도 11A는 TMZ+PBS(PBS는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스로부터 제거된 암조직을 H&E 염색을 실시한 이미지이다.
도 11B는 TMZ+YYB103(TMZ 및 4개 위치가 치환된 IL13(E11K.R64D.S67D.R107K)TNFRSF9.CD3ζ을 포함하는 CAR-T 세포는 정맥 내 한번 투여하였으며, TMZ 및 IL-2는 각각 복강 및 정맥 내 하루에 한번씩 4일간 투여) 15일 후에 누드 마우스로부터 제거된 암조직을 H&E 염색을 실시한 이미지이다.
도 12는 성공적인 항암 CAR 치료법은, 항원 특이적인 CAR-T 세포뿐만 아니라 암세포에 대한 CAR-T세포의 접근 및 CAR-T 세포 기능 유지를 위한 면역기능 강화(immunosupportive) 환경을 필요로 하므로, 이러한 목표를 달성하기 위하여 항-혈관신생(anti-angiogenic) CAR를 제작한 것을 나타낸다. 도 12A는 주요 기능 요소를 나타내는 Anti-Angiogenic CAR이식 유전자를 나타내고, 도 12B는 Anti-Angiogenic CAR의 세포표면에서의 발현을 위한 유전자 구조체들을 이용하여 형질 전환한 세포를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과를 나타내는 도면이다.
도 13 내지 도 16은 다양한 암의 주요한 종양 항원을 타겟으로 하는 CAR 제작을 나타낸다. 각 도면의 A는 주요 기능 요소를 나타내는 CAR이식 유전자를 나타내고, 각 도면의 B는 CAR의 세포표면에서의 발현을 위한 유전자 구조체들을 이용하여 형질 전환한 세포를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과를 나타내는 도면이다.
발명의 실시를 위한 최선의 형태
본 발명에 따른 CAR-T 세포는 암세포를 항원으로 인식하는 수용체 유전자를 도입한 유전자 재조합 된 T 세포로서, 항원을 인식하는 항원 결합 도메인; 항원 결합 도메인과 막통과 도메인을 연결하는 힌지 영역(또는 스페이서); 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인으로 구성된다.
항원 결합 도메인은 주신호가 전달되는 부위로 세포막 외부에 있으며 특정 항원을 발현하는 암세포를 인식하는 부분이다. 따라서, CAR-T 세포를 이용한 암 치료에 있어서, 구체적인 치료대상은 항원 결합 도메인에 의하여 결정되는데, 본 발명은, 이와 같은 항원 결합 도메인을 특정한 것으로 제한하지 않지만, 예를 들면, 교묘세포종에 과발현되는 IL13Rα2에 특이적으로 결합할 수 있는 키메라 항원 수용체를 개시한다. 교모세포종(Glioblastoma, GBM) 또는 다형성아교모세포종(glioblastoma multiforme)는 뇌종양의 약 12~15%를 차지하는 가장 일반적인 뇌종양 중 하나로서, 일반적인 악성 뇌암에 해당한다. 대장암이나 폐암에 비해서 상대적으로 드문 편이므로 그 치료법에 대한 연구가 활발하지 않은 편이다. 교모세포종의 세포는 성상세포(astrocyte)와 유사한데, 성상세포는 신경 세포를 유지하고 신경에 영양을 주고, 뇌 조직의 손상에 대한 방어 반응을 담당하고 있다. 교모세포종의 발생과 악성화에는 줄기 세포 또는 미성숙한 성상 세포의 유전자 이상이 관여하고 있다고 생각되어지고 있다. 교모세포종의 치료는, 수술, 방사선 치료 및 화학항암요법제가 사용된다. 화학항암요법제로서는, 테모졸로미드, 로무스틴 및 카르무스틴등을 사용하고 있고, 최근에는 종양 백신 치료 및 분자 표적 치료등의 임상시험이 진행되고 있다. 그러나, 여전히 교모세포종 치료에 대해서 유용한 치료제는 없는 실정이며, 특히, 11번 위치가 E11Y로 치환된 돌연변이 IL13을 이용한 CAR-T 세포를 이용해서 IL13Rα2를 과발현하는 교모세포종 치료에 대한 시도가 있었지만, Baylor college of medicine groupd의 11번 위치가 E11Y로 치환된 돌연변이 IL13을 이용한 CAR-T 세포는 in vivo에서는 치료효과가 좋지않다고 보고되었는데, 본 발명에서 개시하는 CAR-T 세포는 교모세포종 치료효과가 우수하다.
IL13Rα2와 결합하는 항원 결합 도메인의 서열은 서열번호 1과 같은데, 특히, 11번, 64번, 67번 및 107번 위치가 각각 E11K.R64D.S67D.R107K로 치환된 돌연변이 IL13이 본 발명을 통해서 새롭게 개시된다. 다만, 해당 위치에서 치환되는 아미노산은 상기 특정된 아미노산과 유사한 성질의 아미노산으로 대체될 수 있음을 유념해야 한다. 따라서, 11번에서는 리신(K) 대신에 아르기닌(R) 또는 히스티딘(H)으로; 64번 및 67번에서는 아스파르트산(D) 대신에 글루탐산(E)으로; 107번에서는 리신(K) 대신에 히스티딘(H)으로 대체될 수 있다.
본 발명에서 개시하고 있는 4개 위치가 돌연변이 된 IL13(E11K.R64D.S67D.R107K) 및 동일한 위치에서 동일 성질의 아미노산으로 치환된 유사체는 항원 친화력이 증가한다.
본 발명의 항원 결합 도메인은, 교모종세포에 과발현되는 IL13Rα2 뿐만 아니라, 다양한 암 세포에 발현되는 항원과 결합하게 제작될 수 있다. 예를 들면, 혈관 신생 작용과 관련된 항원과 결합할 수 있는 항원 결합 도메인(서열번호 2); 교모세포종과 폐암 등의 주요한 종양 항원(tumor antigen)인 EGFRvlll와 결합하는 항원 결합 도메인(서열번호 3); 교모세포종, 유방암, 전립선암 등의 종양 항원인 EphA2와 결합하는 항원 결합 도메인(서열번호 4); 췌장암, 폐암, 유방암의 암종 줄기세포능(carcinoma stemness)과 엘로티닙(erlotinib) 등 티로신 키나제 (RTKIs; receptor tyrosine kinase inhibitors) 저항 마커(resistant marker)인 αVβ3와 결합하는 항원 결합 도메인(서열번호 5); 췌장암, 교모세포종, 유방암등에 과발현되는 글리피칸1(glypican1)과 결합하는 항원 결합 도메인(서열번호 6)이 본 발명에서 개시되고, 도 12 내지 16에는 위 항원 결합 도메인을 포함하는 CAR-T 세포를 제작하기 위한 유전자 및 세포표면에서의 발현을 위한 유전자 구조체들을 이용하여 형질 전환한 세포를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과를 제시한다.
본 발명의 다른 특징은, CAR 단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위해서 항원 결합 도메인과 힌지 영역 사이에 3개의 글리신을 추가적으로 도입한 것이다. 본 발명자의 연구에 따르면, 항원 결합 도메인과 힌지 영역 사이에 3개의 글리신을 도입한 것과 도입하지 않는 경우, 그 용해도의 차이가 약 10배가 나타나는 것을 확인하였고, 이로 인하여 CAR-T 세포의 제조와 관련하여 발현율에서 큰 차이를 보이고, 이와 같은 발현률의 차이는 궁극적으로 치료효과와 직결된다는 점에서 이는 매우 진보한 기술적 도약이라 할 수 있다. 또한, 위 3개의 글리신(K)은 이와 유사한 성질의 아미노산인 알라닌(A), 발린(V), 류신(L) 또는 이소류신(I)으로 치환될 수 있다.
본 발명의 또 다른 특징은 특정의 보조 자극 도메인의 사용에 있다. CAR-T 세포에 있어서, 항원 결합 도메인과 항원이 결합하면 그 신호가 세포질 신호 도메인(CD3ζ)을 통해서 T 세포 면역반응을 활성화 시킨다. 보조 자극 도메인은 보조 자극 신호가 전달되는 부위로서 항원 결합 도메인과 결합한 특정 항원을 인식한 CAR-T 세포가 면역반응을 일으키며 자가 증식을 돕고, 체내에 잔존하는 시간을 늘리도록 신호를 전달하는 역할을 한다. 한편, 이와 같은 보조 자극 도메인은 1세대 CAR-T 세포에서는 존재하지 않던 구성요소였고, 2세대 CAR-T 세포에서는 하나의 보조 자극 도메인을 이용하며, 3세대 CAR-T 세포에서는 2개의 보조자극도메인을 이용한다. CAR-T 세포는 1세대, 2세대, 3세대 등 세대가 지남에 따라 세포 내부의 보조자극 도메인(Co-stimulatory domain) 부분에서 CAR-T 세포의 자가 증식 능력 및 체내에 잔존하는 시간을 늘려 작은 세포 수를 주사해도 몸 안에서 암세포에 대항하는 CAR-T 세포들이 많이 만들어 내고, 주입 후에도 오랜 시간 체내에서 지속될 수 있도록 하는 유전자들로 재조합 되어 개발되고 있다. 즉, 1세대의 경우 보조자극신호 도메인이 없이 CD3ζ 밖에 없어 신호 전달의 한계가 있었지만, 2세대, 3세대에는 이 도메인 부위에 4-1BB 또는 OX40 등이 추가로 도입되어 암세포 특이적 인식 능력을 향상시키고자 하였다.
또한, CAR-T 세포의 발현률 향상으로 적은 CAR-T 세포를 사용해도 치료효과를 보일 수 있도록, 본 발명자는 CD28의 소정의 위치에 돌연변이를 발생시킨 보조 자극 도메인을사용하였고, 나아가, 돌연변이된 CD28과 TNFRSF9를 결합한 2개의 보조 자극 도메인을 사용함으로써, '암세포 항원 인식 능력'이 높아져 정상세포를 공격하는 부작용이 최소화되고, 또한, 발현율이 극대화됨으로써 치료효능이 비약적으로 상승함을 알게 되었다.
따라서, 본 발명의 또 다른 기술적 특징은, 항원 결합 도메인; 막통과 도메인; 보조 자극 도메인 및 세포질 신호 도메인으로 구성되는 키메라 항원 수용체 및 이것이 발현된 CAR-T 세포에 있어서, 상기 보조 자극 도메인이 CD28 또는 TNFRSF9를 포함하거나, 또는, CD28과 TNFRSF9를 포함하는 것이다. 여기에서, CD28은 키메라 항원 수용체의 발현을 증가시키기 위한 돌연변이 (서열번호 6 내지 9가 RLLH에서 RGGH로 치환)를 포함할 수 있다. 본 발명의 보조 자극 도메인으로 포함될 수 있는 와일드 타입의 CD28 및 TNFRSF9의 아미노산 서열이 각각 서열번호 7 및 8로 표시된다. 또한, 돌연변이된 CD28(서열번호 6 내지 9가 RLLH에서 RGGH로 치환) 에 있어서, 치환된 아미노산은 글리신(G)이지만, 이와 유사한 아미노산, 예를 들면 알라닌(A), 발린(V), 류신(L) 또는 이소류신(I)로 대체될 수 있다. 본 발명의 힌지 영역은 항원 결합 도메인과 막투과 도메인을 연결하는 부분이며 스페이서라고도 불리우는데, T 세포막으로부터 항원 결합 도메인을 확장하기 위한 목적을 갖는다. 본 발명의 힌지 부분은 본 기술분야에서 통상적으로 사용하는 힌지 영역을 사용할 수 있고, 예를 들면, CD8 힌지 영역에서 유래될 수 있다(서열번호 9, 서열번호 10). 본 발명의 또 다른 기술적 특징이 항원 결합 도메인과 힌지 영역 사이에 추가로 도입된 3개의 글리신에 있음은 앞서 설명한 바와 같다.
본 발명의 막투과 도메인은 CAR 분자의 지지대 역할을 함과 동시에 항원 결합 도메인으로부터 받은 신호를 보조 자극 도메인과 세포질 신호 도메인으로 전달하는 역할을 한다. 본 발명의 막투과 도메인에 한정되지 않고 CAR 제조에 사용되는 통상적인 막투과 도메인을 사용할 수 있는데, 예를 들면, 인간 CD8/CD3 막투과 도메인을 사용할 수 있다(서열번호 11, 서열번호 12).
본 발명의 세포질 신호 도메인은 Jurkat T세포의 CD3ζ 신호전달 도메인이 아닌, 추가의 글루타민이 포함된 정상 인간(normal person)의 CD3ζ 신호전달 도메인을 사용하였고, 상기 추가의 글루타민은 서열번호 13에 있어서 50번 위치의 글루타민(Q)를 의미한다.
본 발명의 기술사상은, 위에서 개시한 기술적 특징을 독자적으로 사용하는 것과 조합하여 사용하는 것을 모두 포함한다. 즉, 본 발명의 기술적 특징의 구현은, 본 발명에서 개시하는 소정의 항원 결합 부위를 포함하는 CAR-T 세포; 소정의 항원 결합 도메인과 소정의 힌지 영역 사이에 3개의 글리신을 추가로 도입한 CAR-T 세포; 본 발명에서 개시하는 보조 자극 도메인을 포함하는 CAR-T 세포를 모두 포함한다.
본 명세서에서 개시하는 도메인을 구성하는 폴리펩타이드의 핵산 서열은 당해 기술분야에 공지된 재조합 방법을 이용하여 수득될 수 있으며, 예를 들어 표준 기법을 이용하여 상기 유전자를 발현하는 세포로부터 라이브러리를 스크리닝하거나, 상기 동일한 유전자를 포함하도록 공지된 벡터로부터 유전자를 유도하거나, 상기 동일한 유전자를 포함하는 세포 및 조직으로부터 직접 단리함으로써 수득될 수 있다. 대안적으로는, 상기 관심이 있는 유전자는 클로닝이 아닌 합성에 의해 생성될 수 있다.
세포 내로 유전자를 도입하고 발현하는 방법은 당해 기술분야에 공지되어 있다. 발현 벡터는 당해 기술분야에 공지된 임의의 방법에 의해 숙주 세포 내로 신속하게 도입될 수 있다. 예를 들면, 본 발명에서는 최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켜 CAR-T 세포를 제조할 수 있다. 본 발명은 구조체의 성분 각각에 대한 다수의 임의의 변이체를 포함하는 것으로 이해되어야 한다.
치료될 수 있는 암은 교모세포종뿐만 아니라, 비-고형 종양(예를 들어, 혈액학적 종양, 예를 들어 백혈병 및 림프종)을 포함할 수 있거나, 고형 종양을 포함할 수 있다.
이와 같이 유전자 재조합 된 CAR-T 세포를 제조하여 암 환자에게 주입하기까지는 여러 단계를 거친다. 환자의 혈액에서 백혈구성분 분리채집 과정을 거쳐 T 세포를 추출한 뒤, 발현 벡터를 이용하여 CAR로 디자인된 DNA를 T세포에 주입하고 이 CAR-T 세포를 증식시킨 후, 이를 환자에게 주입하게 된다.
발명의 실시를 위한 형태
이하, 실시예를 통해서 본 발명을 구체화한다. 다만, 하기 실시예는 본 발명의 기술적 범위를 어떤 의미에서든지 제한하는 것은 아님을 유의해야 한다.
실시예 1: 암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하는 2세대(YYB-103, IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ) 및 3세대(YYB-103A, IL13.E11K.R64D.S67D. R107K.28.TNFRSF9.CD3ζ) 키메라 항원 수용체를 갖는 발현 벡터의 구축
본 발명자는 IL13의 2가지 아미노산 치환(Glu-11, Arg-107)보다 높은 항원 친화력을 부여하기 위해 돌연변이 IL13(E11K.R64D.S67D.R107K)를 제작하였으며, T 세포 활성화를 위한 세포질 신호 도메인을 1가지(TNFRSF9) 및 2가지(CD28, TNFRSF9)를 포함하는 키메라 항원 수용체를 제작하였다(도 1). 본 발명에서는 CAR단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 사이에 3개의 글리신(GGG)을 첨가하였다(도 2). 본 발명에서 사용된 CD28 신호 세포질 도메인은 CAR 단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위한 돌연변이 (RLLH → RGGH) 인간 CD28 염기 서열들을 포함한다(도 3). 인간 TNFRSF9 및 건강한 사람의 CD3 제타 신호전달 도메인을 사용 하였다. 인간 IL13(P35225.1), 인간 CD3(P20963-1), 인간 CD8α(P01732), 인간 CD28(P10747), 인간 TNFRSF9(Q07011), 그리고 인간 카파 경쇄 신호 서열(HuVHCAMP)을 과학문헌 및 공공이 이용가능한 데이터베이스를 이용하여 최적화 하였으며, codon-optimized synthetic DNA로 구성된 2세대 및 3세대 키메라 항원 수용체(YYB-103, IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ 및 YYB-103A, IL13.E11K.R64D.S67D.R107K.28.TNFRSF9.CD3ζ)를 제작하였다(도 1). 완성된 구조체는 kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP), 인간 IL13.E11K.R64D.S67D.R107K 성숙 단백질 서열(human IL13(E11K.R64D.S67D.R107K)), CAR단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 사이에 3개의 글리신 (GGG)첨가(도 2), 인간 CD8α의 힌지 영역, 인간 CD8/CD3 막 통과 도메인, 돌연변이(RLLH → RGGH)로 변형된 세포질 CD28의 보조 자극 신호 도메인, 세포질 TNFRSF9의 보조 자극 신호 도메인, 건강한 사람의 CD3ζ 세포질 신호 도메인 서열과 XhoI/NotI 절단 부분을 포함한다. YYB-103 및 YYB-103A의 전체 서열을 서열번호 14 및 15에 나타냈다. 최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(Emtage PC 등, Clin Cancer Res, 2008, 14:8112-8122)(도 1). 본 실시예에서 키메라 항원 수용체의 활성을 비교하기 위해, IL13의 2가지 아미노산 치환(Glu-11, Arg-107) 3세대 키메라 항원 수용체(YYB-103B, IL13(E11K.R107K).28.TNFRSF9.CD3ζ)를 추가적으로 제작하였다 (서열번호 16).
실시예 2: 암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하는 2세대(YYB-103, IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ) 및 3세대(YYB-103A, IL13.E11K.R64D.S67D.R107K.28.TNFRSF9.CD3ζ) 키메라 항원 수용체로 형질 변형된 T 세포의 제조
CAR를 발현하는 높은 역가의 PG13 클론은 일시적으로 피닉스-엠포 및 피닉스-에코 세포를 실시예 1 에서 제작된 레트로바이러스 발현 벡터 YYB-103 또는 YYB-103A를 이용하여 감염시켰으며, 그 이후에 감염된 피닉스-엠포 및 피닉스-에코 세포로부터 무세포 벡터 스탁을 PG13 세포에 감염시킴으로써 만들었다. 높은 역가의 단일 클론은 항-IL-13 단일클로 항체(BD Pharmingen)를 사용하여 PG13/YYB-103 세포를 염색한 후에 유세포분석기에 의하여 단일 클론을 분리하였다. 높은 역가의 PG13/YYB-103클론은 한계희석법에 의하여 2번째 서브클로닝에 의하여 만들어졌다. 서브클론 PG13/YYB-103-13는 높은 CAR발현을 안정적으로 보여주었으며, 말초혈액에 효율적인 형질도입 능력을 위하여 선택되어졌다. 항-IL-13 단일클론 항체 (BD Pharmingen)를 이용하여 형질도입된 PG13/YYB-103-13 세포를 유세포 분석기(Flow cytometry analysis)를 사용하여 형질 도입 정도를 분석하였다. 형질도입된 PG13/YYB-103-13 세포의 상층 액은 레트로 바이러스를 포함하며 T 세포의 유전적 변형을 위해 수거 하였다. 말초 혈액 단핵 세포(peripheral blood mononuclear cells, PBMC)는 건강한 공여자로부터 얻은 전혈(whole blood)을 Ficoll Paque(GE Healthcare)에 넣고 원심분리를 사용하여 분리하였다. 분리된 PBMC를 Human IL-2(NOVARTIS) 100IU/mL 조건으로 있는 상태에서 anti-CD3 단일클론 항체 (eBioscience) 100ng/mL을 첨가하여 배양함으로써 T 세포 분획을 활성화시켰다(BL Levine, Cancer Gene Therapy, 2015, 22:79-84). 배양 2-3일 후에, 세포의 대부분은 T 세포이었으며 일부 자연 살해 세포(natural killer cell)가 0~2% 비율로 포함되어 있었다. 활성화 단계 2~3일 후, T 세포에 retroviral 상층액을 사용하여 2일에 걸쳐 2회 형질도입 진행 및 세척 후 플라스크에서 4 내지 7일 동안 세포를 증식하였다. 세포는 12내지 14일 동안 교반용 플랫폼 장치 (WAVE 생물 반응기 시스템) 상에서 배양하였다. IL-2를 100IU/mL로 유지하였다. 이러한 방식으로 변형된 T 세포는 분석 실험에 사용되였다 (도 4).
실험예 1: 키메라 항원 수용체로 형질 변형된 T 세포표면의 CAR 발현률 체크
실험방법 (flow cytometric analysis)
유세포 분석(>30,000 events)를 위해 BD LSRII 장비(Becton Dickinson)와 BD FACSDiva 소프트웨어(Becton Dickinson)을 사용하였다. 구체적으로는 PE-conjugated anti-human IL-13 단일클론 항체(BD Pharmingen)를 첨가하기 전 세포를 2% bovine serum albumin을 함유한 PBS에 1회 세척을 진행하였다. 세척 후에 빛이 차단된 상태에서 4℃에서 30 분간 각각의 항체와 반응한 후, 세포를 1회 세정하고, 형질 도입 된 T 세포 표면 CAR의 발현률을 체크하였다. 또한 IL13Rα2 및 IL13Rα1의 세포 표면 발현을 확인하기 위해, anti-human IL13Rα2 항체(R&D systems), donkey anti-goat IgG phycoerythrin secondary antibody(R&D systems), 및 anti-human IL13Rα1 phycoerythrin(R&D systems)을 사용하였으며, 대조군으로 isotype antibody를 포함시켰다.
실험결과
실시예 1에서 제작한 IL13Rα2 특이적인 CAR(YYB-103, IL13.E11K.R107K.TNFRSF9.CD3ζ; YYB-103A, IL13.E11K.R64D.S67D.R107K.28.TNFRSF9.CD3ζ; YYB-103B, IL13.E11K.R107K.28.TNFRSF9.CD3ζ,)가 T 세포 표면에서 발현되는지 확인하기 위해 실시예 2에 따라 T 세포 배양을 12-14일 동안 진행한 후 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다. 분석 결과, 살아있는 T 세포 표면에 발현된 키메라 항원 수용체의 발현률은 7명의 혈액 donor에서 모두 90.5% ~ 92.8%로 나타났다. 배양을 유지할 경우, 추가적인 T 세포 활성화나 형질도입이 없이도 IL13Rα2 특이적 키메라 항원 수용체의 발현은 4주까지 안정적으로 유지되었다. 또한, 배양된 세포에서 전체 T 세포, CD4 T 세포, CD8 T 세포, B 세포, 그리고 Monocyte의 비율을 분석하였다. 그 결과, B 세포의 경우 0.5 ~ 1.2%가 존재하였으며, Monocyte의 경우 존재하지 않는 것을 확인하였다.
실시예 3: 암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하는 2세대(YYB-103, IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ) 및 3세대(YYB-103A, IL13.E11K.R64D.S67D.R107K.28.TNFRSF9.CD3ζ) 키메라 항원 수용체로 형질 변형된 T 세포의 세포독성 및 IFN-γ 분비 측정
실시예 2에서 제작된 CAR-T 세포를 이용하여 IL13Rα2 특이적인 세포독성 및 IFN-γ 의 분비를 측정하였다. IL13Rα2 특이적인 세포독성 및 IFN-γ 분비를 측정하기 위하여 IL13Rα2를 과발현하는 glioblastoma 인간 세포주인 U251과 normal cell control로 IL13Rα2를 발현하지 않는 primary HUVEC을 사용하였다.
실험예 1: IL13Rα2가 과발현되는 교모세포종에 대한 세포독성 체크
실험방법
IL13Rα2 특이적인 CAR-T 세포 effector(IL13Rα2-specific CAR+ T cell effector)의 세포 용해 활성을 측정하기 위해 DELFIA(Perkin Elmer) 키트를 사용하여 세포독성 분석(cytotoxicity assay)을 진행하였다. 구체적으로는 CAR-T 세포 effector 세포는 anti-CD3로 세포 활성화 후 12~14일 후에 사용하였으며, IL13Rα2 표적 세포가 있는 96 well plate에 5:1(effector:target)의 비율과 0.625:1(effector:target) 비율로 effector 세포를 넣고 37℃에서 2시간 동안 반응하는 조건을 3반복 실험으로 구성하여 진행하였다. 분석 실험에 사용된 96 well plate에는 well 당 5,000개의 표적 세포가 첨가되었으며, 사용된 표적 세포는 IL13Rα2를 과발현하는 glioblastoma 세포주인 U251과 normal cell control로 primary HUVEC을 사용하였다.
실험결과
본 발명을 통해 제작된 IL13Rα2 특이적인 CAR(YYB-103, IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ; YYB-103A, IL13.E11K.R64D.S67D.R107K.28.TNFRSF9.CD3ζ; YYB-103B, IL13.E11K.R107K.28.TNFRSF9.CD3ζ) T 세포에 의해 IL13Rα2가 과발현되는 표적 암세포(U251)을 효과적으로 사멸시키는지 분석하였다. 실험방법은 앞서 언급한 표적 암세포(U251)과 정상세포(HUVEC)을 각각의 활성화된 CAR-T 세포와 함께 배양하여 세포독성을 비교 분석하는 방법을 사용하였다. 도 5에 나타낸 바와 같이, 모든 경우에서 IL13Rα2에 특이적인 CAR가 발현된 경우 형질도입이 되지 않은 활성화된 T 세포와 비교하여 높은 수준으로 IL13Rα2를 발현하는 교모세포 종 U251 세포의 사멸을 유도하는 결과를 나타내었다(도 5). 구체적으로 본 발명의 실시예 2에서 제작한 YYB-103 (IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ), YYB-103A(IL13.E11K.R64D.S67D.R107K.28.TNFRSF9.CD3ζ), 및 YYB-103B(IL13.E11K.R107K.28.TNFRSF9.CD3ζ) CAR를 발현하는 T 세포의 경우 E:T 비율이 증가함에 따라 세포 독성이 점차 증가하였으나 CAR를 발현하지 않는 T 세포의 경우 세포독성이 거의 증가하지 않았다. 또한, IL13의 2가지 아미노산이 치환된 YYB-103B(IL13.E11K.R107K.28.TNFRSF9.CD3ζ) CAR와 보다 높은 항원 친화력(affinity)를 부여하기 위하여 사용된 IL13의 4가지 아미노산이 치환된 YYB-103 (IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ)와 YYB-103A(IL13.E11K.R64D.S67D.R107K.28.TNFRSF9.CD3ζ)를 비교한 결과 2가지 아미노산만 치환된 YYB-103B의 경우 5:1의 E:T 비율에서 67.4%의 세포독성을 나타내었으나 IL13의 4가지 아미노산이 치환된 mutant IL13.E11K.R64D.S67D.R107K이 사용된 YYB-103와 YYB-103A를 사용하였을 경우 각각 85.6% 및 87.7%의 세포독성이 나타났다. 이는 IL13의 4가지 아미노산이 치환된 mutant IL13.E11K.R64D.S67D.R107K가 도입된 T-세포의 세포독성이 IL13의 2가지 아미노산이 치환된 mutant IL13.E11K.R107K가 도입된 T-세포의 세포독성보다 2nd Generation 및 3rd Generation 모두에서 우월하다는 것을 보여준다.
표적 세포에 대한 비교 대상으로 IL13Rα2를 발현하지 않지만, IL13Rα1은 minimally 발현되는 HUVEC 세포를 normal cell control로 사용한 실험 결과에서는 IL13Rα2에 특이적인 CAR-T 세포(12.3~14% cytotoxicity)의 경우 매우 약한 세포독성을 가지는 것을 확인하였다(도 5). 이는 IL13Rα1가 발현되고 IL13Rα2는 발현되지 않는 HUVEC 세포의 특성으로 인하여 실험에 사용된 키메라 항원 수용체가 IL13Rα2에 특이적으로 결합한다는 것을 보여준다. 본 실험 예를 통해 IL13Rα2 특이적인 키메라 항원 수용체 T 세포가 정상세포(HUVEC)에는 독성을 나타내지 않으며, IL13Rα2를 발현하는 표적 암세포(U251)를 현저하게 사멸시킬 수 있음을 증명하였다.
실험예 2: CAR 발현률에 따른 항암 활성 변화 측정
실험방법
IL13Rα2 특이적인 CAR의 발현률에 따른 항암 활성 변화를 측정하기 위해 세포독성 분석을 진행하였다. 구체적으로 CAR-T 세포로는 YYB-103인 2nd Generation IL13.E11K.R64D.S67D.R107K.TNFSFR9.CD3ζ을 effector 세포로 사용하였으며, Target 세포로는 IL13Rα2를 과발현하는 U251 세포주를 사용하였다. 세포독성 분석을 위하여 Effector 세포와 표적 세포의 비율은 0.625:1 과 5:1을 사용하였으며, CAR를 발현하는 T 세포의 비율은 0 ~ 70%를 사용하였다. 세포독성 분석의 자세한 방법은 실험예 2의 실험방법과 같다.
실험결과
IL13Rα2 특이적인 CAR를 발현하는 T 세포가 존재하지 않을 경우 5:1과 0.625:1 비율에서 각각 16.4% 및 2.5%의 세포독성을 나타내었다. 하지만 IL13Rα2 특이적인 CAR를 발현하는 T 세포의 비율이 증가함에 따라 세포독성이 증가하는 것을 볼 수 있었으며, IL13Rα2 특이적인 CAR를 발현하는 T 세포의 비율이 70%일 때 5:1과 0.625:1 비율에서 각각 86% 및 26%의 세포독성을 나타내어 IL13Rα2 특이적인 키메라 항원 수용체 T 세포가 IL13Rα2 특이적으로 표적 암세포(U251)를 사멸시킬 수 있음을 확인하였다 (도 6).
실험예 3: IL13Rα2 특이적 키메라 항원 수용체로 형질 변형된 T 세포의 사이토카인(IFN-γ) 생성 체크
실험방법
96 well tissue culture plate에 well당 배양 배지를 200ul씩 넣고 표적 세포(1×10^5)를 첨가하였다. CAR 발현율에 따른 세포독성을 측정하기 위하여, 준비된 96 well tissue culture plate에 형질도입이 되지 않은 상태로 활성화된 T 세포(untransduced activated T cell)와 10 ~ 70%의 IL13Rα2에 특이적인 CAR-T 세포를 effector(0.5×10^5)로 넣고 2반복(duplicate) 실험으로 구성하여 동시 배양하였다. 또한 CAR-T 세포가 number 의존적으로 항암 활성 증가를 보이는지 확인하기 위하여 7500개의 CAR-T 부터 계단희석하여 effector로 넣고 2반복(duplicate) 실험으로 구성하여 동시 배양하였다. 배양 19시간 후, 배양 상층액을 사용하여 분석기 제조사의 지침에 따라 ELISA 분석기(R&D systems)로 IFN-γ 분석 실험을 진행하였다 (도 7, 도 8).
실험결과
일반적으로 활성화 된 T 세포는 자신의 성장 및 활성에 도움이 되는 사이토카인(cytokine)을 생성하며, 그 중 IFN-γ는 CD8 T 세포, CD4 T 세포, 그리고 NK 세포 등이 분비하며, 선천 면역 및 적응 면역 반응에 있어서 중요한 역할을 수행한다. 특히 암의 발생을 억제할 뿐만 아니라 T 세포를 종양부위로 이동하게 하는 중요한 역할을 수행한다. 본 실험 예를 통해 IL13Rα2 특이적인 CAR를 발현하는 T 세포가 표적세포를 만났을 때 IFN-γ의 생성이 증가되는지를 확인하였다. 실험 방법에 따라 IL13Rα2 특이적인 CAR-T 세포를 표적 세포(HUVEC 세포, U251 세포)와 동시 배양한 후 ELISA 분석을 통해 IFN-γ를 정량하였다.
도 7는 제작된 키메라 항원 수용체의 transduction비율에 따라 IL13Rα2 항원 결합 시 증가된 IFN-γ를 나타낸 것으로, CAR-T 세포의 비율에 따라 IFN-γ의 생성 양상이 다름을 알 수 있다. 표적 암세포인 U251을 사용한 경우 키메라 항원 수용체가 형질도입 되지 않은 T 세포는 IFN-γ를 거의 생성하지 못하였다. 키메라 항원 수용체가 형질도입 된 T 세포의 경우 30% 비율까지 IFN-γ의 생성이 증가하였으며, 그 이후에는 더 이상 증가하지 않은 것으로 보아 30% 비율의 CAR-T 세포 만으로도 표적 암세포를 제거하는데 충분하다고 판단된다. IL13Rα2 를 과발현 하지 않는 세포주인 HUVEC의 경우 CAR-T의 비율이 증가하여도 크게 IFN-γ의 생성이 증가하지 않는 것으로 보아 CAR-T에 의한 IFN-γ의 생성은 IL13Rα2 항원 특이적인 것으로 보인다. 도 8은 제작된 키메라 항원 수용체를 가지는 T 세포의 수에 따라 증가된 IFN-γ를 나타낸 것으로 YY6 및 YY7 두 공여자 모두에서 세포수가 증가함에 따라 IFN-γ가 증가하였다. 이는 CAR-T 세포가 암세포를 죽이는데 있어서 세포 수에 의존적이라는 것을 나타낸다.
실시예 4: YYB-103을 이용한 in vivo 효능 평가
YYB-103이 실제 in vivo에서 효능을 나타내는지 평가하기 위하여 누드 마우스에 암세포를 피하주입하여 종양을 유도하였으며, YYB-103을 처리 후 종양 크기의 변화 및 종양부위에서 CAR-T 세포의 존재를 확인하였다.
실험예 1: U251 세포주를 이용한 종양 누드 마우스 제작 및 YYB-103의 효능 체크
U251 세포주를 누드 마우스에 피하로 주입하였다. 9일 후에 대조군 PBS와 치료군 YYB-103을 정맥 내 한번 투여하였다. Temozolomide (TMZ)와 IL-2를 각각 복강 및 정맥 내 하루에 한번씩 4일간 대조군과 실험군에 똑같이 투여하였다. 치료 시작일과 치료 12일 후에 종양의 크기를 측정하였으며, 치료 15일후에 부검을 실시하여 종양의 무게 측정 및 조직학 분석을 수행하였다 (도 9).
실험결과
종양 누드 마우스동물 모델에 투여한 YYB-103의 효능 측정을 위하여 치료 12일 후에 종양의 크기를 측정한 결과 대조군의 경우 종양의 크기가 234.8 mm3에서 132.4 mm3로 약 44% 감소하였다. 하지만 치료군으로 YYB-103을 투여한 경우 종양의 크기가 288.2 mm3에서 64.6 mm3로 약 78% 감소하였다. 따라서 대조군과 비교할 경우 약 1.8배의 치료효과를 나타내는 것을 볼 수 있었다 (도 9B). 치료 15일후에 부검을 실시하여 암조직의 무게 측정 결과 대조군보다 치료군으로 YYB-103을 처리한 누드 마우스의 종양의 무게가 더 가벼운 것을 볼 수 있었다 (도 9C). 이와 더불어 YYB-103을 처리할 경우 대조군과 다르게 암조직에서 혈관신생이 억제 되는 것으로 보였다 (도 11A, 도 11B).
치료 15일후에 암조직에서 YYB-103이 존재하는지 확인하기 위하여 T 세포 마커인 anti-human CD3 antibody를 이용하여 염색을 실시하였다. 그 결과 대조군 누드 마우스는 human T 세포가 없어 염색이 되지 않았음을 나타냈다. (도 10A).
YYB-103을 처리한 그룹에서는 많은 T 세포가 존재하고 있는 것이 확인되었으며, 이는 종양의 크기 감소에 직접적으로 영향을 준 것으로 판단된다(도 10B).
치료 15일후 암조직을 H&E 염색을 통하여 조직을 관찰한 결과 YYB-103을 처리하지 않은 군에서 많은 혈관이 관찰되는 것을 볼 수 있었다. 따라서 YYB-103으로 인하여 종양부위에서 혈관신생이 억제 되어 less aggressive tumor가 될 수 있다고 보인다 (도 11A, 도 11B).
실시예 5: 다양한 고형 종양 및 신생혈관을 인식 할 수 있는 CAR 구축 및 CAR를 안정적으로 발현하는 PG13 생산 세포주 제조
새로운 혈관이 종양부위로 자라도록 하는 혈관 신생을 억제한다면 암세포의 전이 및 성장을 억제할 수 있다. 성공적인 항암 CAR 치료법은, 항원 특이적인 CAR-T 세포뿐만 아니라 암세포에 대한 CAR-T 세포의 접근 및 CAR-T 세포 기능 유지를 위한 면역기능 강화(immunosupportive) 환경을 필요로 하므로, 이러한 목표를 달성하기 위하여 항-혈관신생(anti-angiogenic) CAR를 제작하였다(도 12A).
교모세포종과 폐암 등의 주요한 종양 항원(tumor antigen)인 EGFRvlll를 타겟으로 하는 CAR를 제작하였다(도 13A).
EphA2 (Membrane-bound erythropoietin-producing hepatocellular receptor tyrosine kinase class A2)는 유방암, 전립선암, 방광암, 피부암, 폐암, 난소암, 그리고 뇌암 등에서 과발현 되어 있어, EphA2를 타겟으로 하는 CAR를 제작하였다(도 14A).
Integrin alpha(V) beta(3) (αVβ3)는 당단백 막 수용체로써 활성화된 종양 상피세포에 높게 발현하고 있다. 췌장암, 폐암, 유방암의 암종 줄기세포능(carcinoma stemness)과 엘로티닙(erlotinib) 등 티로신 키나제 (RTKIs; receptor tyrosine kinase inhibitors) 저항 마커(resistant marker)를 타켓(target)으로 하는 CAR를 제작하였다(도 15A).
GPC1은 암세포의 효율적인 성장, 전이, 그리고 혈관신생을 위해 중요하며, GPC1의 경우 췌장암, 유방암, 교모세포종에서 과발현되어 있다(도 16A).
실험예 1: Angiogenic blood vessels, EGFRvIII, EphA2, Integrin αVβ3, 또는 GPC1를 인식할 수 있는 CAR로 형질변형된 PG13 세포주 표면의 CAR 발현률 체크
실험방법 (flow cytometric analysis)
유세포 분석(>30,000 events)를 위해 BD LSRII 장비(Becton Dickinson)와 BD FACSDiva 소프트웨어(Becton Dickinson)을 사용하였다. 구체적으로는 항체를 첨가하기 전 세포를 2% bovine serum albumin을 함유한 PBS에 1회 세척을 진행하였다. 세척 후에 빛이 차단된 상태에서 4℃에서 30 분간 각각의 항체와 반응한 후, 세포를 1회 세정하고, 형질 도입 된 T 세포 표면 CAR의 발현률을 체크하기 위해 anti-human Fibronectin monoclonal antibody, PE-conjugated anti-human c-Myc monoclonal antibody (Santa Cruz Biotechnoloby), PE-conjugated anti-human EphA2 monoclonal antibody (R&D Systems) PE-conjugated anti-human alpha v beta 3 monoclonal antibody (BioLegend)를 사용하였으며 형광이 결합되어있지 않은 항체의 경우 추가로 PE conjugated anti-mouse IgG1 monoclonal antibody (Santa Cruz Biotechnology) 또는 donkey anti-goat IgG phycoerythrin secondary antibody (R&D systems)를 사용하여 형광염색을 수행하였으며, 염색 후에 유세포 분석 (flow cytometric analysis)을 실시하였다.
실험결과
각각의 CAR가 형질전환 된 PG13 세포주에서 발혈률을 확인한 결과 거의 모든 살아있는 PG13 세포주의 표면에 키메라 항원 수용체가 발현되는 것으로 나타났다(도 12B, 도 13B,도 14B, 도 15B, 도 16B).
본 발명은 암 치료분야에서 급속하게 발전하고 있는 CAR-T 세포에 관한 것으로서, 맞춤형 암 치료분야에서 의료산업에 이용가능하다.
서열번호 1 {IL13Rα2와 결합하는 항원 결합 wild type IL-13 도메인의 서열}
길이: 112
타입: ligand protein
생물명: human
서열:
G P V P P S T A L R E L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q R M L S G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F R E G Q F N
서열번호 2 {혈관 신생 작용과 관련된 항원과 결합할 수 있는 항원 결합 도메인}
길이: 92
타입: ligand protein
생물명: human
서열:
E V V A A T P T S L L I S W R H P H F P T R Y Y R I T Y G E T G G N S P V Q E F T V L Q P P S T A T I S G L K P G V D Y T I T V Y A V V E R N G R E L N T P P I S I N Y R T H H H H H H
서열번호 3 {EGFRvlll와 결합하는 항원 결합 도메인}
길이: 252
타입: scFv protein
생물명: human
서열:
Q V Q L Q E S G G G L V K P G G S L K L S C A A S G F T F S K F G M S W V R Q T P D K R L E W V A S I S T G G Y N T F Y S D N V K G R F T I S R D N A K N T L Y L Q M S S L K S E D T A M Y Y C A R G Y S S T S F A M D Y W G Q G T M V T V S S G S T S G S G K P G S G E G S D I Q M T Q S P S S L S A S V G D R V T I T C M T S T D I D D D M N W Y Q Q K P G K T P K L L I Y E G N T L R P G V P S R F S G S G S G T D F I F T I S S L Q P E D I A T Y Y C L Q S F N V P L T F G G G T K V E I K E Q K L I S E E D L
서열번호 4 {EphA2와 결합하는 항원 결합 도메인}
길이: 141
타입: ligand protein
생물명: human
서열:
D R H T V F W N S S N P K F R N E D Y T I H V Q L N D Y V D I I C P H Y E D H S V A D A A M E Q Y I L Y L V E H E E Y Q L C Q P Q S K D Q V R W Q C N R P S A K H G P E K L S E K F Q R F T A F A L A K E F K A G H S Y Y Y I S K P I H Q H E D R C L R L K V T V S G E Q K L I S E E D L
서열번호 5 {αVβ3와 결합하는 항원 결합 도메인}
길이: 104
타입: ligand protein
생물명: human
서열:
V S D V P R D L E V V A A T P T S L L I S W D A P A V T V R Y Y R I T Y G E T G G N S P V Q E F T V P G S K S T A T I S G L K P G V D Y T I T V Y A V T P R G D W N E G S K P I S I N Y R T E Q K L I S E E D L
서열번호 6 {글리피칸1(glypican1)과 결합하는 항원 결합 도메인}
길이: 418
타입: ligand protein
생물명: human
서열:
T S P C D N F D C Q N G A Q C I V R I N E P I C Q C L P G Y Q G E K C E K L V S V N F I N K E S Y L Q I P S A K V R P Q T N I T L Q I A T D E D S G I L L Y K G D K D H I A V E L Y R G R V R A S Y D T G S H P A S A I Y S V E T I N D G N F H I V E L L A L D Q S L S L S V D G G N P K I I T N L S K Q S T L N F D S P L Y V G G M P G K S N V A S L R Q A P G Q N G T S F H G C I R N L Y I N S E L Q D F Q K V P M Q T G I L P G C E P C H K K V C A H G T C Q P S S Q A G F T C E C Q E G W M G P L C D Q R T N D P C L G N K C V H G T C L P I N A F S Y S C K C L E G H G G V L C D E E E D L F N P C Q A I K C K H G K C R L S G L G Q P Y C E C S S G Y T G D S C D R E I S C R G E R I R D Y Y Q K Q Q G Y A A C Q T T K K V S R L E C R G G C A G G Q C C G P L R S K R R K Y S F E C T D G S S F V D E V E K V V K C G C T R C V S E Q K L I S E E D L
서열번호 7 {Wild type CD28}
길이: 41
타입: protein
생물명: human
서열:
R S K R S R L L H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S
서열번호 8 {TNFRSF9}
길이: 42
타입: protein
생물명: human
서열;
K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L
서열번호 9 {힌지영역 서열-1}
길이: 47
타입: protein
생물명: human
서열:
K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D
서열번호 10 {힌지영역 서열-2}
길이: 45
타입: protein
생물명: human
서열:
K P T T T P A P R P P T P A P T I A S Q P L S L R P E A A R P A A G G A V H T R G L D F A
서열번호 11 {막통과 도메인서열-1}
길이: 21
타입: protein
생물명: human
서열:
I Y I W A P L A G T C G V L L L S L V I T
서열번호 12 {막통과 도메인서열-2}
길이: 23
타입: protein
생물명: human
서열:
L A Y L L D G I L F I Y G V I L T A L F L R V
서열번호 13 {추가의 글루타민을 포함하는 CD3ζ}
길이: 113
타입: protein
생물명: human
서열:
R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 14 {YYB 103}
길이: 359
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S G P V P P S T A L R K L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q D M L D G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F K E G Q F N G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 15 {YYB 103A}
길이: 400
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S G P V P P S T A L R K L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q D M L D G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F K E G Q F N G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 16 {YYB-103B, IL13(E11K.R107K).28.TNFRSF9.CD3ζ}
길이: 400
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S G P V P P S T A L R K L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q R M L S G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F K E G Q F N G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 17 {YYB 104}
길이: 339
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S E V V A A T P T S L L I S W R H P H F P T R Y Y R I T Y G E T G G N S P V Q E F T V L Q P P S T A T I S G L K P G V D Y T I T V Y A V V E R N G R E L N T P P I S I N Y R T H H H H H H G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 18 {YYB 104-1}
길이: 380
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S E V V A A T P T S L L I S W R H P H F P T R Y Y R I T Y G E T G G N S P V Q E F T V L Q P P S T A T I S G L K P G V D Y T I T V Y A V V E R N G R E L N T P P I S I N Y R T H H H H H H G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 19 {YYB 105}
길이: 497
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S Q V Q L Q E S G G G L V K P G G S L K L S C A A S G F T F S K F G M S W V R Q T P D K R L E W V A S I S T G G Y N T F Y S D N V K G R F T I S R D N A K N T L Y L Q M S S L K S E D T A M Y Y C A R G Y S S T S F A M D Y W G Q G T M V T V S S G S T S G S G K P G S G E G S D I Q M T Q S P S S L S A S V G D R V T I T C M T S T D I D D D M N W Y Q Q K P G K T P K L L I Y E G N T L R P G V P S R F S G S G S G T D F I F T I S S L Q P E D I A T Y Y C L Q S F N V P L T F G G G T K V E I K E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A A R P A A G G A V H T R G L D F A L A Y L L D G I L F I Y G V I L T A L F L R V K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 20 {YYB 105-1}
길이: 538
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S Q V Q L Q E S G G G L V K P G G S L K L S C A A S G F T F S K F G M S W V R Q T P D K R L E W V A S I S T G G Y N T F Y S D N V K G R F T I S R D N A K N T L Y L Q M S S L K S E D T A M Y Y C A R G Y S S T S F A M D Y W G Q G T M V T V S S G S T S G S G K P G S G E G S D I Q M T Q S P S S L S A S V G D R V T I T C M T S T D I D D D M N W Y Q Q K P G K T P K L L I Y E G N T L R P G V P S R F S G S G S G T D F I F T I S S L Q P E D I A T Y Y C L Q S F N V P L T F G G G T K V E I K E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A A R P A A G G A V H T R G L D F A L A Y L L D G I L F I Y G V I L T A L F L R V R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 21 {YYB 106}
길이: 388
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S D R H T V F W N S S N P K F R N E D Y T I H V Q L N D Y V D I I C P H Y E D H S V A D A A M E Q Y I L Y L V E H E E Y Q L C Q P Q S K D Q V R W Q C N R P S A K H G P E K L S E K F Q R F T A F A L A K E F K A G H S Y Y Y I S K P I H Q H E D R C L R L K V T V S G E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 22 {YYB 106-1}
길이: 429
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S D R H T V F W N S S N P K F R N E D Y T I H V Q L N D Y V D I I C P H Y E D H S V A D A A M E Q Y I L Y L V E H E E Y Q L C Q P Q S K D Q V R W Q C N R P S A K H G P E K L S E K F Q R F T A F A L A K E F K A G H S Y Y Y I S K P I H Q H E D R C L R L K V T V S G E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 23 {YYB 107}
길이: 351
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S V S D V P R D L E V V A A T P T S L L I S W D A P A V T V R Y Y R I T Y G E T G G N S P V Q E F T V P G S K S T A T I S G L K P G V D Y T I T V Y A V T P R G D W N E G S K P I S I N Y R T E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 24 {YYB 107-1}
길이: 392
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S V S D V P R D L E V V A A T P T S L L I S W D A P A V T V R Y Y R I T Y G E T G G N S P V Q E F T V P G S K S T A T I S G L K P G V D Y T I T V Y A V T P R G D W N E G S K P I S I N Y R T E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 25 {YYB 108}
길이: 665
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S T S P C D N F D C Q N G A Q C I V R I N E P I C Q C L P G Y Q G E K C E K L V S V N F I N K E S Y L Q I P S A K V R P Q T N I T L Q I A T D E D S G I L L Y K G D K D H I A V E L Y R G R V R A S Y D T G S H P A S A I Y S V E T I N D G N F H I V E L L A L D Q S L S L S V D G G N P K I I T N L S K Q S T L N F D S P L Y V G G M P G K S N V A S L R Q A P G Q N G T S F H G C I R N L Y I N S E L Q D F Q K V P M Q T G I L P G C E P C H K K V C A H G T C Q P S S Q A G F T C E C Q E G W M G P L C D Q R T N D P C L G N K C V H G T C L P I N A F S Y S C K C L E G H G G V L C D E E E D L F N P C Q A I K C K H G K C R L S G L G Q P Y C E C S S G Y T G D S C D R E I S C R G E R I R D Y Y Q K Q Q G Y A A C Q T T K K V S R L E C R G G C A G G Q C C G P L R S K R R K Y S F E C T D G S S F V D E V E K V V K C G C T R C V S E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 26 {YYB 108-1}
길이: 706
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S T S P C D N F D C Q N G A Q C I V R I N E P I C Q C L P G Y Q G E K C E K L V S V N F I N K E S Y L Q I P S A K V R P Q T N I T L Q I A T D E D S G I L L Y K G D K D H I A V E L Y R G R V R A S Y D T G S H P A S A I Y S V E T I N D G N F H I V E L L A L D Q S L S L S V D G G N P K I I T N L S K Q S T L N F D S P L Y V G G M P G K S N V A S L R Q A P G Q N G T S F H G C I R N L Y I N S E L Q D F Q K V P M Q T G I L P G C E P C H K K V C A H G T C Q P S S Q A G F T C E C Q E G W M G P L C D Q R T N D P C L G N K C V H G T C L P I N A F S Y S C K C L E G H G G V L C D E E E D L F N P C Q A I K C K H G K C R L S G L G Q P Y C E C S S G Y T G D S C D R E I S C R G E R I R D Y Y Q K Q Q G Y A A C Q T T K K V S R L E C R G G C A G G Q C C G P L R S K R R K Y S F E C T D G S S F V D E V E K V V K C G C T R C V S E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
길이: 112
타입: ligand protein
생물명: human
서열:
G P V P P S T A L R E L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q R M L S G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F R E G Q F N
서열번호 2 {혈관 신생 작용과 관련된 항원과 결합할 수 있는 항원 결합 도메인}
길이: 92
타입: ligand protein
생물명: human
서열:
E V V A A T P T S L L I S W R H P H F P T R Y Y R I T Y G E T G G N S P V Q E F T V L Q P P S T A T I S G L K P G V D Y T I T V Y A V V E R N G R E L N T P P I S I N Y R T H H H H H H
서열번호 3 {EGFRvlll와 결합하는 항원 결합 도메인}
길이: 252
타입: scFv protein
생물명: human
서열:
Q V Q L Q E S G G G L V K P G G S L K L S C A A S G F T F S K F G M S W V R Q T P D K R L E W V A S I S T G G Y N T F Y S D N V K G R F T I S R D N A K N T L Y L Q M S S L K S E D T A M Y Y C A R G Y S S T S F A M D Y W G Q G T M V T V S S G S T S G S G K P G S G E G S D I Q M T Q S P S S L S A S V G D R V T I T C M T S T D I D D D M N W Y Q Q K P G K T P K L L I Y E G N T L R P G V P S R F S G S G S G T D F I F T I S S L Q P E D I A T Y Y C L Q S F N V P L T F G G G T K V E I K E Q K L I S E E D L
서열번호 4 {EphA2와 결합하는 항원 결합 도메인}
길이: 141
타입: ligand protein
생물명: human
서열:
D R H T V F W N S S N P K F R N E D Y T I H V Q L N D Y V D I I C P H Y E D H S V A D A A M E Q Y I L Y L V E H E E Y Q L C Q P Q S K D Q V R W Q C N R P S A K H G P E K L S E K F Q R F T A F A L A K E F K A G H S Y Y Y I S K P I H Q H E D R C L R L K V T V S G E Q K L I S E E D L
서열번호 5 {αVβ3와 결합하는 항원 결합 도메인}
길이: 104
타입: ligand protein
생물명: human
서열:
V S D V P R D L E V V A A T P T S L L I S W D A P A V T V R Y Y R I T Y G E T G G N S P V Q E F T V P G S K S T A T I S G L K P G V D Y T I T V Y A V T P R G D W N E G S K P I S I N Y R T E Q K L I S E E D L
서열번호 6 {글리피칸1(glypican1)과 결합하는 항원 결합 도메인}
길이: 418
타입: ligand protein
생물명: human
서열:
T S P C D N F D C Q N G A Q C I V R I N E P I C Q C L P G Y Q G E K C E K L V S V N F I N K E S Y L Q I P S A K V R P Q T N I T L Q I A T D E D S G I L L Y K G D K D H I A V E L Y R G R V R A S Y D T G S H P A S A I Y S V E T I N D G N F H I V E L L A L D Q S L S L S V D G G N P K I I T N L S K Q S T L N F D S P L Y V G G M P G K S N V A S L R Q A P G Q N G T S F H G C I R N L Y I N S E L Q D F Q K V P M Q T G I L P G C E P C H K K V C A H G T C Q P S S Q A G F T C E C Q E G W M G P L C D Q R T N D P C L G N K C V H G T C L P I N A F S Y S C K C L E G H G G V L C D E E E D L F N P C Q A I K C K H G K C R L S G L G Q P Y C E C S S G Y T G D S C D R E I S C R G E R I R D Y Y Q K Q Q G Y A A C Q T T K K V S R L E C R G G C A G G Q C C G P L R S K R R K Y S F E C T D G S S F V D E V E K V V K C G C T R C V S E Q K L I S E E D L
서열번호 7 {Wild type CD28}
길이: 41
타입: protein
생물명: human
서열:
R S K R S R L L H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S
서열번호 8 {TNFRSF9}
길이: 42
타입: protein
생물명: human
서열;
K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L
서열번호 9 {힌지영역 서열-1}
길이: 47
타입: protein
생물명: human
서열:
K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D
서열번호 10 {힌지영역 서열-2}
길이: 45
타입: protein
생물명: human
서열:
K P T T T P A P R P P T P A P T I A S Q P L S L R P E A A R P A A G G A V H T R G L D F A
서열번호 11 {막통과 도메인서열-1}
길이: 21
타입: protein
생물명: human
서열:
I Y I W A P L A G T C G V L L L S L V I T
서열번호 12 {막통과 도메인서열-2}
길이: 23
타입: protein
생물명: human
서열:
L A Y L L D G I L F I Y G V I L T A L F L R V
서열번호 13 {추가의 글루타민을 포함하는 CD3ζ}
길이: 113
타입: protein
생물명: human
서열:
R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 14 {YYB 103}
길이: 359
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S G P V P P S T A L R K L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q D M L D G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F K E G Q F N G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 15 {YYB 103A}
길이: 400
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S G P V P P S T A L R K L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q D M L D G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F K E G Q F N G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 16 {YYB-103B, IL13(E11K.R107K).28.TNFRSF9.CD3ζ}
길이: 400
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S G P V P P S T A L R K L I E E L V N I T Q N Q K A P L C N G S M V W S I N L T A G M Y C A A L E S L I N V S G C S A I E K T Q R M L S G F C P H K V S A G Q F S S L H V R D T K I E V A Q F V K D L L L H L K K L F K E G Q F N G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 17 {YYB 104}
길이: 339
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S E V V A A T P T S L L I S W R H P H F P T R Y Y R I T Y G E T G G N S P V Q E F T V L Q P P S T A T I S G L K P G V D Y T I T V Y A V V E R N G R E L N T P P I S I N Y R T H H H H H H G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 18 {YYB 104-1}
길이: 380
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S E V V A A T P T S L L I S W R H P H F P T R Y Y R I T Y G E T G G N S P V Q E F T V L Q P P S T A T I S G L K P G V D Y T I T V Y A V V E R N G R E L N T P P I S I N Y R T H H H H H H G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 19 {YYB 105}
길이: 497
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S Q V Q L Q E S G G G L V K P G G S L K L S C A A S G F T F S K F G M S W V R Q T P D K R L E W V A S I S T G G Y N T F Y S D N V K G R F T I S R D N A K N T L Y L Q M S S L K S E D T A M Y Y C A R G Y S S T S F A M D Y W G Q G T M V T V S S G S T S G S G K P G S G E G S D I Q M T Q S P S S L S A S V G D R V T I T C M T S T D I D D D M N W Y Q Q K P G K T P K L L I Y E G N T L R P G V P S R F S G S G S G T D F I F T I S S L Q P E D I A T Y Y C L Q S F N V P L T F G G G T K V E I K E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A A R P A A G G A V H T R G L D F A L A Y L L D G I L F I Y G V I L T A L F L R V K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 20 {YYB 105-1}
길이: 538
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S Q V Q L Q E S G G G L V K P G G S L K L S C A A S G F T F S K F G M S W V R Q T P D K R L E W V A S I S T G G Y N T F Y S D N V K G R F T I S R D N A K N T L Y L Q M S S L K S E D T A M Y Y C A R G Y S S T S F A M D Y W G Q G T M V T V S S G S T S G S G K P G S G E G S D I Q M T Q S P S S L S A S V G D R V T I T C M T S T D I D D D M N W Y Q Q K P G K T P K L L I Y E G N T L R P G V P S R F S G S G S G T D F I F T I S S L Q P E D I A T Y Y C L Q S F N V P L T F G G G T K V E I K E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A A R P A A G G A V H T R G L D F A L A Y L L D G I L F I Y G V I L T A L F L R V R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 21 {YYB 106}
길이: 388
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S D R H T V F W N S S N P K F R N E D Y T I H V Q L N D Y V D I I C P H Y E D H S V A D A A M E Q Y I L Y L V E H E E Y Q L C Q P Q S K D Q V R W Q C N R P S A K H G P E K L S E K F Q R F T A F A L A K E F K A G H S Y Y Y I S K P I H Q H E D R C L R L K V T V S G E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 22 {YYB 106-1}
길이: 429
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S D R H T V F W N S S N P K F R N E D Y T I H V Q L N D Y V D I I C P H Y E D H S V A D A A M E Q Y I L Y L V E H E E Y Q L C Q P Q S K D Q V R W Q C N R P S A K H G P E K L S E K F Q R F T A F A L A K E F K A G H S Y Y Y I S K P I H Q H E D R C L R L K V T V S G E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 23 {YYB 107}
길이: 351
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S V S D V P R D L E V V A A T P T S L L I S W D A P A V T V R Y Y R I T Y G E T G G N S P V Q E F T V P G S K S T A T I S G L K P G V D Y T I T V Y A V T P R G D W N E G S K P I S I N Y R T E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 24 {YYB 107-1}
길이: 392
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S V S D V P R D L E V V A A T P T S L L I S W D A P A V T V R Y Y R I T Y G E T G G N S P V Q E F T V P G S K S T A T I S G L K P G V D Y T I T V Y A V T P R G D W N E G S K P I S I N Y R T E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 25 {YYB 108}
길이: 665
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S T S P C D N F D C Q N G A Q C I V R I N E P I C Q C L P G Y Q G E K C E K L V S V N F I N K E S Y L Q I P S A K V R P Q T N I T L Q I A T D E D S G I L L Y K G D K D H I A V E L Y R G R V R A S Y D T G S H P A S A I Y S V E T I N D G N F H I V E L L A L D Q S L S L S V D G G N P K I I T N L S K Q S T L N F D S P L Y V G G M P G K S N V A S L R Q A P G Q N G T S F H G C I R N L Y I N S E L Q D F Q K V P M Q T G I L P G C E P C H K K V C A H G T C Q P S S Q A G F T C E C Q E G W M G P L C D Q R T N D P C L G N K C V H G T C L P I N A F S Y S C K C L E G H G G V L C D E E E D L F N P C Q A I K C K H G K C R L S G L G Q P Y C E C S S G Y T G D S C D R E I S C R G E R I R D Y Y Q K Q Q G Y A A C Q T T K K V S R L E C R G G C A G G Q C C G P L R S K R R K Y S F E C T D G S S F V D E V E K V V K C G C T R C V S E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
서열번호 26 {YYB 108-1}
길이: 706
타입: protein
생물명: human
서열:
M G W S C I I L F L V A T A T G V H S T S P C D N F D C Q N G A Q C I V R I N E P I C Q C L P G Y Q G E K C E K L V S V N F I N K E S Y L Q I P S A K V R P Q T N I T L Q I A T D E D S G I L L Y K G D K D H I A V E L Y R G R V R A S Y D T G S H P A S A I Y S V E T I N D G N F H I V E L L A L D Q S L S L S V D G G N P K I I T N L S K Q S T L N F D S P L Y V G G M P G K S N V A S L R Q A P G Q N G T S F H G C I R N L Y I N S E L Q D F Q K V P M Q T G I L P G C E P C H K K V C A H G T C Q P S S Q A G F T C E C Q E G W M G P L C D Q R T N D P C L G N K C V H G T C L P I N A F S Y S C K C L E G H G G V L C D E E E D L F N P C Q A I K C K H G K C R L S G L G Q P Y C E C S S G Y T G D S C D R E I S C R G E R I R D Y Y Q K Q Q G Y A A C Q T T K K V S R L E C R G G C A G G Q C C G P L R S K R R K Y S F E C T D G S S F V D E V E K V V K C G C T R C V S E Q K L I S E E D L G G G P R K P T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F A C D I Y I W A P L A G T C G V L L L S L V I T R S K R S R G G H S D Y M N M T P R R P G P T R K H Y Q P Y A P P R D F A A Y R S K R G R K K L L Y I F K Q P F M R P V Q T T Q E E D G C S C R F P E E E E G G C E L R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
<110> YOO YOUNG PHARM CO.,LTD.
<120> CHIMERIC ANTIGEN RECEPTOR AND T CELLS EXPRESSING THE CHIMERIC
ANTIGEN RECEPTOR
<130> KR15P0802PCT
<150> 10-2015-0110788
<151> 2015-08-05
<160> 26
<170> KoPatentIn 3.0
<210> 1
<211> 112
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 1
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile Glu Glu Leu
1 5 10 15
Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn Gly Ser Met
20 25 30
Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu Glu
35 40 45
Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln Arg
50 55 60
Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe Ser
65 70 75 80
Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val Lys
85 90 95
Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly Gln Phe Asn
100 105 110
<210> 2
<211> 92
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 2
Glu Val Val Ala Ala Thr Pro Thr Ser Leu Leu Ile Ser Trp Arg His
1 5 10 15
Pro His Phe Pro Thr Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly
20 25 30
Gly Asn Ser Pro Val Gln Glu Phe Thr Val Leu Gln Pro Pro Ser Thr
35 40 45
Ala Thr Ile Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val
50 55 60
Tyr Ala Val Val Glu Arg Asn Gly Arg Glu Leu Asn Thr Pro Pro Ile
65 70 75 80
Ser Ile Asn Tyr Arg Thr His His His His His His
85 90
<210> 3
<211> 252
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 3
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Thr Gly Gly Tyr Asn Thr Phe Tyr Ser Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Ser Ser Thr Ser Phe Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys
115 120 125
Pro Gly Ser Gly Glu Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Met Thr
145 150 155 160
Ser Thr Asp Ile Asp Asp Asp Met Asn Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Thr Pro Lys Leu Leu Ile Tyr Glu Gly Asn Thr Leu Arg Pro Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ile Phe
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu
210 215 220
Gln Ser Phe Asn Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
225 230 235 240
Ile Lys Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 4
<211> 141
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 4
Asp Arg His Thr Val Phe Trp Asn Ser Ser Asn Pro Lys Phe Arg Asn
1 5 10 15
Glu Asp Tyr Thr Ile His Val Gln Leu Asn Asp Tyr Val Asp Ile Ile
20 25 30
Cys Pro His Tyr Glu Asp His Ser Val Ala Asp Ala Ala Met Glu Gln
35 40 45
Tyr Ile Leu Tyr Leu Val Glu His Glu Glu Tyr Gln Leu Cys Gln Pro
50 55 60
Gln Ser Lys Asp Gln Val Arg Trp Gln Cys Asn Arg Pro Ser Ala Lys
65 70 75 80
His Gly Pro Glu Lys Leu Ser Glu Lys Phe Gln Arg Phe Thr Ala Phe
85 90 95
Ala Leu Ala Lys Glu Phe Lys Ala Gly His Ser Tyr Tyr Tyr Ile Ser
100 105 110
Lys Pro Ile His Gln His Glu Asp Arg Cys Leu Arg Leu Lys Val Thr
115 120 125
Val Ser Gly Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135 140
<210> 5
<211> 104
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 5
Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr
1 5 10 15
Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr
20 25 30
Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe
35 40 45
Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys Pro
50 55 60
Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Pro Arg Gly Asp
65 70 75 80
Trp Asn Glu Gly Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu Gln
85 90 95
Lys Leu Ile Ser Glu Glu Asp Leu
100
<210> 6
<211> 418
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 6
Thr Ser Pro Cys Asp Asn Phe Asp Cys Gln Asn Gly Ala Gln Cys Ile
1 5 10 15
Val Arg Ile Asn Glu Pro Ile Cys Gln Cys Leu Pro Gly Tyr Gln Gly
20 25 30
Glu Lys Cys Glu Lys Leu Val Ser Val Asn Phe Ile Asn Lys Glu Ser
35 40 45
Tyr Leu Gln Ile Pro Ser Ala Lys Val Arg Pro Gln Thr Asn Ile Thr
50 55 60
Leu Gln Ile Ala Thr Asp Glu Asp Ser Gly Ile Leu Leu Tyr Lys Gly
65 70 75 80
Asp Lys Asp His Ile Ala Val Glu Leu Tyr Arg Gly Arg Val Arg Ala
85 90 95
Ser Tyr Asp Thr Gly Ser His Pro Ala Ser Ala Ile Tyr Ser Val Glu
100 105 110
Thr Ile Asn Asp Gly Asn Phe His Ile Val Glu Leu Leu Ala Leu Asp
115 120 125
Gln Ser Leu Ser Leu Ser Val Asp Gly Gly Asn Pro Lys Ile Ile Thr
130 135 140
Asn Leu Ser Lys Gln Ser Thr Leu Asn Phe Asp Ser Pro Leu Tyr Val
145 150 155 160
Gly Gly Met Pro Gly Lys Ser Asn Val Ala Ser Leu Arg Gln Ala Pro
165 170 175
Gly Gln Asn Gly Thr Ser Phe His Gly Cys Ile Arg Asn Leu Tyr Ile
180 185 190
Asn Ser Glu Leu Gln Asp Phe Gln Lys Val Pro Met Gln Thr Gly Ile
195 200 205
Leu Pro Gly Cys Glu Pro Cys His Lys Lys Val Cys Ala His Gly Thr
210 215 220
Cys Gln Pro Ser Ser Gln Ala Gly Phe Thr Cys Glu Cys Gln Glu Gly
225 230 235 240
Trp Met Gly Pro Leu Cys Asp Gln Arg Thr Asn Asp Pro Cys Leu Gly
245 250 255
Asn Lys Cys Val His Gly Thr Cys Leu Pro Ile Asn Ala Phe Ser Tyr
260 265 270
Ser Cys Lys Cys Leu Glu Gly His Gly Gly Val Leu Cys Asp Glu Glu
275 280 285
Glu Asp Leu Phe Asn Pro Cys Gln Ala Ile Lys Cys Lys His Gly Lys
290 295 300
Cys Arg Leu Ser Gly Leu Gly Gln Pro Tyr Cys Glu Cys Ser Ser Gly
305 310 315 320
Tyr Thr Gly Asp Ser Cys Asp Arg Glu Ile Ser Cys Arg Gly Glu Arg
325 330 335
Ile Arg Asp Tyr Tyr Gln Lys Gln Gln Gly Tyr Ala Ala Cys Gln Thr
340 345 350
Thr Lys Lys Val Ser Arg Leu Glu Cys Arg Gly Gly Cys Ala Gly Gly
355 360 365
Gln Cys Cys Gly Pro Leu Arg Ser Lys Arg Arg Lys Tyr Ser Phe Glu
370 375 380
Cys Thr Asp Gly Ser Ser Phe Val Asp Glu Val Glu Lys Val Val Lys
385 390 395 400
Cys Gly Cys Thr Arg Cys Val Ser Glu Gln Lys Leu Ile Ser Glu Glu
405 410 415
Asp Leu
<210> 7
<211> 41
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 7
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> 8
<211> 42
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 8
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> 9
<211> 47
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 9
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 10
<211> 45
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 10
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ala Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
35 40 45
<210> 11
<211> 21
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 11
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> 12
<211> 23
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 12
Leu Ala Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu
1 5 10 15
Thr Ala Leu Phe Leu Arg Val
20
<210> 13
<211> 113
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 13
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 Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 14
<211> 359
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 14
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg
195 200 205
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
210 215 220
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
225 230 235 240
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
290 295 300
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
305 310 315 320
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
325 330 335
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
340 345 350
Met Gln Ala Leu Pro Pro Arg
355
<210> 15
<211> 400
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 15
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg
195 200 205
Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
210 215 220
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
225 230 235 240
Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
245 250 255
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
260 265 270
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
275 280 285
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
290 295 300
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
305 310 315 320
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
325 330 335
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
340 345 350
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
355 360 365
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
370 375 380
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
385 390 395 400
<210> 16
<211> 400
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 16
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg
195 200 205
Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
210 215 220
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
225 230 235 240
Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
245 250 255
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
260 265 270
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
275 280 285
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
290 295 300
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
305 310 315 320
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
325 330 335
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
340 345 350
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
355 360 365
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
370 375 380
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
385 390 395 400
<210> 17
<211> 339
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 17
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Val Ala Ala Thr Pro Thr Ser Leu Leu Ile Ser
20 25 30
Trp Arg His Pro His Phe Pro Thr Arg Tyr Tyr Arg Ile Thr Tyr Gly
35 40 45
Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe Thr Val Leu Gln Pro
50 55 60
Pro Ser Thr Ala Thr Ile Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr
65 70 75 80
Ile Thr Val Tyr Ala Val Val Glu Arg Asn Gly Arg Glu Leu Asn Thr
85 90 95
Pro Pro Ile Ser Ile Asn Tyr Arg Thr His His His His His His Gly
100 105 110
Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
115 120 125
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
130 135 140
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
145 150 155 160
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
165 170 175
Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg Lys Lys Leu Leu
180 185 190
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
195 200 205
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
210 215 220
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
225 230 235 240
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
245 250 255
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
260 265 270
Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
275 280 285
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
290 295 300
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
305 310 315 320
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
325 330 335
Pro Pro Arg
<210> 18
<211> 380
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 18
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Val Ala Ala Thr Pro Thr Ser Leu Leu Ile Ser
20 25 30
Trp Arg His Pro His Phe Pro Thr Arg Tyr Tyr Arg Ile Thr Tyr Gly
35 40 45
Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe Thr Val Leu Gln Pro
50 55 60
Pro Ser Thr Ala Thr Ile Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr
65 70 75 80
Ile Thr Val Tyr Ala Val Val Glu Arg Asn Gly Arg Glu Leu Asn Thr
85 90 95
Pro Pro Ile Ser Ile Asn Tyr Arg Thr His His His His His His Gly
100 105 110
Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
115 120 125
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
130 135 140
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
145 150 155 160
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
165 170 175
Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg Ser Arg Gly Gly
180 185 190
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
195 200 205
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
210 215 220
Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
225 230 235 240
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
245 250 255
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
260 265 270
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
275 280 285
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
290 295 300
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys
305 310 315 320
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
325 330 335
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
340 345 350
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
355 360 365
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
370 375 380
<210> 19
<211> 497
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 19
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Lys Phe Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu
50 55 60
Glu Trp Val Ala Ser Ile Ser Thr Gly Gly Tyr Asn Thr Phe Tyr Ser
65 70 75 80
Asp Asn Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Gly Tyr Ser Ser Thr Ser Phe Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Ser Thr Ser Gly
130 135 140
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Asp Ile Gln Met Thr Gln
145 150 155 160
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
165 170 175
Cys Met Thr Ser Thr Asp Ile Asp Asp Asp Met Asn Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Lys Thr Pro Lys Leu Leu Ile Tyr Glu Gly Asn Thr Leu
195 200 205
Arg Pro Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Phe Ile Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Tyr Cys Leu Gln Ser Phe Asn Val Pro Leu Thr Phe Gly Gly Gly Thr
245 250 255
Lys Val Glu Ile Lys Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly
260 265 270
Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
275 280 285
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
290 295 300
Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
305 310 315 320
Ala Leu Ala Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile
325 330 335
Leu Thr Ala Leu Phe Leu Arg Val Lys Arg Gly Arg Lys Lys Leu Leu
340 345 350
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
355 360 365
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
370 375 380
Glu Leu Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
385 390 395 400
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
405 410 415
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
420 425 430
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
435 440 445
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
450 455 460
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
465 470 475 480
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
485 490 495
Arg
<210> 20
<211> 538
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 20
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Lys Phe Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu
50 55 60
Glu Trp Val Ala Ser Ile Ser Thr Gly Gly Tyr Asn Thr Phe Tyr Ser
65 70 75 80
Asp Asn Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Gly Tyr Ser Ser Thr Ser Phe Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Ser Thr Ser Gly
130 135 140
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Asp Ile Gln Met Thr Gln
145 150 155 160
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
165 170 175
Cys Met Thr Ser Thr Asp Ile Asp Asp Asp Met Asn Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Lys Thr Pro Lys Leu Leu Ile Tyr Glu Gly Asn Thr Leu
195 200 205
Arg Pro Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Phe Ile Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Tyr Cys Leu Gln Ser Phe Asn Val Pro Leu Thr Phe Gly Gly Gly Thr
245 250 255
Lys Val Glu Ile Lys Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly
260 265 270
Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
275 280 285
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
290 295 300
Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
305 310 315 320
Ala Leu Ala Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile
325 330 335
Leu Thr Ala Leu Phe Leu Arg Val Arg Ser Lys Arg Ser Arg Gly Gly
340 345 350
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
355 360 365
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
370 375 380
Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
385 390 395 400
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
405 410 415
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Lys Phe Ser Arg Ser
420 425 430
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
435 440 445
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
450 455 460
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro
465 470 475 480
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
485 490 495
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
500 505 510
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
515 520 525
Ala Leu His Met Gln Ala Leu Pro Pro Arg
530 535
<210> 21
<211> 388
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 21
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Arg His Thr Val Phe Trp Asn Ser Ser Asn Pro Lys
20 25 30
Phe Arg Asn Glu Asp Tyr Thr Ile His Val Gln Leu Asn Asp Tyr Val
35 40 45
Asp Ile Ile Cys Pro His Tyr Glu Asp His Ser Val Ala Asp Ala Ala
50 55 60
Met Glu Gln Tyr Ile Leu Tyr Leu Val Glu His Glu Glu Tyr Gln Leu
65 70 75 80
Cys Gln Pro Gln Ser Lys Asp Gln Val Arg Trp Gln Cys Asn Arg Pro
85 90 95
Ser Ala Lys His Gly Pro Glu Lys Leu Ser Glu Lys Phe Gln Arg Phe
100 105 110
Thr Ala Phe Ala Leu Ala Lys Glu Phe Lys Ala Gly His Ser Tyr Tyr
115 120 125
Tyr Ile Ser Lys Pro Ile His Gln His Glu Asp Arg Cys Leu Arg Leu
130 135 140
Lys Val Thr Val Ser Gly Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
145 150 155 160
Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro
165 170 175
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
180 185 190
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
195 200 205
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
210 215 220
Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg Lys Lys Leu
225 230 235 240
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
245 250 255
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
260 265 270
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
275 280 285
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
290 295 300
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
305 310 315 320
Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
325 330 335
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
340 345 350
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
355 360 365
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
370 375 380
Leu Pro Pro Arg
385
<210> 22
<211> 429
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 22
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Arg His Thr Val Phe Trp Asn Ser Ser Asn Pro Lys
20 25 30
Phe Arg Asn Glu Asp Tyr Thr Ile His Val Gln Leu Asn Asp Tyr Val
35 40 45
Asp Ile Ile Cys Pro His Tyr Glu Asp His Ser Val Ala Asp Ala Ala
50 55 60
Met Glu Gln Tyr Ile Leu Tyr Leu Val Glu His Glu Glu Tyr Gln Leu
65 70 75 80
Cys Gln Pro Gln Ser Lys Asp Gln Val Arg Trp Gln Cys Asn Arg Pro
85 90 95
Ser Ala Lys His Gly Pro Glu Lys Leu Ser Glu Lys Phe Gln Arg Phe
100 105 110
Thr Ala Phe Ala Leu Ala Lys Glu Phe Lys Ala Gly His Ser Tyr Tyr
115 120 125
Tyr Ile Ser Lys Pro Ile His Gln His Glu Asp Arg Cys Leu Arg Leu
130 135 140
Lys Val Thr Val Ser Gly Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
145 150 155 160
Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro
165 170 175
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
180 185 190
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
195 200 205
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
210 215 220
Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg Ser Arg Gly
225 230 235 240
Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
245 250 255
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
260 265 270
Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
275 280 285
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
290 295 300
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
305 310 315 320
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
325 330 335
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
340 345 350
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
355 360 365
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
370 375 380
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
385 390 395 400
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
405 410 415
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
420 425
<210> 23
<211> 351
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 23
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala
20 25 30
Thr Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val
35 40 45
Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val
50 55 60
Gln Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly
65 70 75 80
Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Pro
85 90 95
Arg Gly Asp Trp Asn Glu Gly Ser Lys Pro Ile Ser Ile Asn Tyr Arg
100 105 110
Thr Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Gly Pro Arg
115 120 125
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
130 135 140
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
145 150 155 160
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
165 170 175
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
180 185 190
Leu Val Ile Thr Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
195 200 205
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
210 215 220
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
225 230 235 240
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
245 250 255
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
260 265 270
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln
275 280 285
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
290 295 300
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
305 310 315 320
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
325 330 335
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
340 345 350
<210> 24
<211> 392
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 24
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala
20 25 30
Thr Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val
35 40 45
Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val
50 55 60
Gln Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly
65 70 75 80
Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Pro
85 90 95
Arg Gly Asp Trp Asn Glu Gly Ser Lys Pro Ile Ser Ile Asn Tyr Arg
100 105 110
Thr Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Gly Pro Arg
115 120 125
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
130 135 140
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
145 150 155 160
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
165 170 175
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
180 185 190
Leu Val Ile Thr Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr
195 200 205
Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln
210 215 220
Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly
225 230 235 240
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
245 250 255
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
260 265 270
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
275 280 285
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
290 295 300
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
305 310 315 320
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
325 330 335
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
340 345 350
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
355 360 365
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
370 375 380
His Met Gln Ala Leu Pro Pro Arg
385 390
<210> 25
<211> 665
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 25
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Thr Ser Pro Cys Asp Asn Phe Asp Cys Gln Asn Gly Ala
20 25 30
Gln Cys Ile Val Arg Ile Asn Glu Pro Ile Cys Gln Cys Leu Pro Gly
35 40 45
Tyr Gln Gly Glu Lys Cys Glu Lys Leu Val Ser Val Asn Phe Ile Asn
50 55 60
Lys Glu Ser Tyr Leu Gln Ile Pro Ser Ala Lys Val Arg Pro Gln Thr
65 70 75 80
Asn Ile Thr Leu Gln Ile Ala Thr Asp Glu Asp Ser Gly Ile Leu Leu
85 90 95
Tyr Lys Gly Asp Lys Asp His Ile Ala Val Glu Leu Tyr Arg Gly Arg
100 105 110
Val Arg Ala Ser Tyr Asp Thr Gly Ser His Pro Ala Ser Ala Ile Tyr
115 120 125
Ser Val Glu Thr Ile Asn Asp Gly Asn Phe His Ile Val Glu Leu Leu
130 135 140
Ala Leu Asp Gln Ser Leu Ser Leu Ser Val Asp Gly Gly Asn Pro Lys
145 150 155 160
Ile Ile Thr Asn Leu Ser Lys Gln Ser Thr Leu Asn Phe Asp Ser Pro
165 170 175
Leu Tyr Val Gly Gly Met Pro Gly Lys Ser Asn Val Ala Ser Leu Arg
180 185 190
Gln Ala Pro Gly Gln Asn Gly Thr Ser Phe His Gly Cys Ile Arg Asn
195 200 205
Leu Tyr Ile Asn Ser Glu Leu Gln Asp Phe Gln Lys Val Pro Met Gln
210 215 220
Thr Gly Ile Leu Pro Gly Cys Glu Pro Cys His Lys Lys Val Cys Ala
225 230 235 240
His Gly Thr Cys Gln Pro Ser Ser Gln Ala Gly Phe Thr Cys Glu Cys
245 250 255
Gln Glu Gly Trp Met Gly Pro Leu Cys Asp Gln Arg Thr Asn Asp Pro
260 265 270
Cys Leu Gly Asn Lys Cys Val His Gly Thr Cys Leu Pro Ile Asn Ala
275 280 285
Phe Ser Tyr Ser Cys Lys Cys Leu Glu Gly His Gly Gly Val Leu Cys
290 295 300
Asp Glu Glu Glu Asp Leu Phe Asn Pro Cys Gln Ala Ile Lys Cys Lys
305 310 315 320
His Gly Lys Cys Arg Leu Ser Gly Leu Gly Gln Pro Tyr Cys Glu Cys
325 330 335
Ser Ser Gly Tyr Thr Gly Asp Ser Cys Asp Arg Glu Ile Ser Cys Arg
340 345 350
Gly Glu Arg Ile Arg Asp Tyr Tyr Gln Lys Gln Gln Gly Tyr Ala Ala
355 360 365
Cys Gln Thr Thr Lys Lys Val Ser Arg Leu Glu Cys Arg Gly Gly Cys
370 375 380
Ala Gly Gly Gln Cys Cys Gly Pro Leu Arg Ser Lys Arg Arg Lys Tyr
385 390 395 400
Ser Phe Glu Cys Thr Asp Gly Ser Ser Phe Val Asp Glu Val Glu Lys
405 410 415
Val Val Lys Cys Gly Cys Thr Arg Cys Val Ser Glu Gln Lys Leu Ile
420 425 430
Ser Glu Glu Asp Leu Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro
435 440 445
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
450 455 460
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
465 470 475 480
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
485 490 495
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg
500 505 510
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
515 520 525
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
530 535 540
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
545 550 555 560
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
565 570 575
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
580 585 590
Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln
595 600 605
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
610 615 620
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
625 630 635 640
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
645 650 655
Leu His Met Gln Ala Leu Pro Pro Arg
660 665
<210> 26
<211> 706
<212> PRT
<213> Unknown
<220>
<223> HUMAN
<400> 26
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Thr Ser Pro Cys Asp Asn Phe Asp Cys Gln Asn Gly Ala
20 25 30
Gln Cys Ile Val Arg Ile Asn Glu Pro Ile Cys Gln Cys Leu Pro Gly
35 40 45
Tyr Gln Gly Glu Lys Cys Glu Lys Leu Val Ser Val Asn Phe Ile Asn
50 55 60
Lys Glu Ser Tyr Leu Gln Ile Pro Ser Ala Lys Val Arg Pro Gln Thr
65 70 75 80
Asn Ile Thr Leu Gln Ile Ala Thr Asp Glu Asp Ser Gly Ile Leu Leu
85 90 95
Tyr Lys Gly Asp Lys Asp His Ile Ala Val Glu Leu Tyr Arg Gly Arg
100 105 110
Val Arg Ala Ser Tyr Asp Thr Gly Ser His Pro Ala Ser Ala Ile Tyr
115 120 125
Ser Val Glu Thr Ile Asn Asp Gly Asn Phe His Ile Val Glu Leu Leu
130 135 140
Ala Leu Asp Gln Ser Leu Ser Leu Ser Val Asp Gly Gly Asn Pro Lys
145 150 155 160
Ile Ile Thr Asn Leu Ser Lys Gln Ser Thr Leu Asn Phe Asp Ser Pro
165 170 175
Leu Tyr Val Gly Gly Met Pro Gly Lys Ser Asn Val Ala Ser Leu Arg
180 185 190
Gln Ala Pro Gly Gln Asn Gly Thr Ser Phe His Gly Cys Ile Arg Asn
195 200 205
Leu Tyr Ile Asn Ser Glu Leu Gln Asp Phe Gln Lys Val Pro Met Gln
210 215 220
Thr Gly Ile Leu Pro Gly Cys Glu Pro Cys His Lys Lys Val Cys Ala
225 230 235 240
His Gly Thr Cys Gln Pro Ser Ser Gln Ala Gly Phe Thr Cys Glu Cys
245 250 255
Gln Glu Gly Trp Met Gly Pro Leu Cys Asp Gln Arg Thr Asn Asp Pro
260 265 270
Cys Leu Gly Asn Lys Cys Val His Gly Thr Cys Leu Pro Ile Asn Ala
275 280 285
Phe Ser Tyr Ser Cys Lys Cys Leu Glu Gly His Gly Gly Val Leu Cys
290 295 300
Asp Glu Glu Glu Asp Leu Phe Asn Pro Cys Gln Ala Ile Lys Cys Lys
305 310 315 320
His Gly Lys Cys Arg Leu Ser Gly Leu Gly Gln Pro Tyr Cys Glu Cys
325 330 335
Ser Ser Gly Tyr Thr Gly Asp Ser Cys Asp Arg Glu Ile Ser Cys Arg
340 345 350
Gly Glu Arg Ile Arg Asp Tyr Tyr Gln Lys Gln Gln Gly Tyr Ala Ala
355 360 365
Cys Gln Thr Thr Lys Lys Val Ser Arg Leu Glu Cys Arg Gly Gly Cys
370 375 380
Ala Gly Gly Gln Cys Cys Gly Pro Leu Arg Ser Lys Arg Arg Lys Tyr
385 390 395 400
Ser Phe Glu Cys Thr Asp Gly Ser Ser Phe Val Asp Glu Val Glu Lys
405 410 415
Val Val Lys Cys Gly Cys Thr Arg Cys Val Ser Glu Gln Lys Leu Ile
420 425 430
Ser Glu Glu Asp Leu Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro
435 440 445
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
450 455 460
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
465 470 475 480
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
485 490 495
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser
500 505 510
Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg
515 520 525
Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg
530 535 540
Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr
545 550 555 560
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
565 570 575
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
580 585 590
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
595 600 605
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
610 615 620
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
625 630 635 640
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
645 650 655
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
660 665 670
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
675 680 685
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
690 695 700
Pro Arg
705
Claims (22)
- 항원 결합 도메인; 힌지 영역; 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체에 있어서, 보조 자극 도메인이 돌연변이된 CD28 또는 TNFRSF9인 것을 특징으로 하는 키메라 항원 수용체.
- 제 1항에 있어서, 상기 돌연변이된 CD28은 서열번호 7번에 기재된 아미노산 서열의 6번 내지 9번 위치의 아미노산이 RLLH에서 RGGH 또는 RGGH와 유사한 성질의 아미노산으로 치환 된 것을 특징으로 하는 키메라 항원 수용체.
- 제 2항에 있어서, RGGH와 유사한 성질의 아미노산은, 글리신(G)이 알라닌(A), 발린(V), 류신(L) 또는 이소류신(I)으로 치환된 것을 특징으로 하는 키메라 항원 수용체.
- 제 1항 내지 제 3항 중 어느 한 항에 있어서, 보조 자극 도메인은 돌연변이된 CD28 및 TNFRSF9으로 이루어지는 것을 특징으로 하는 키메라 항원 수용체.
- 항원 결합 도메인; 힌지 영역; 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체에 있어서, 항원 결합 도메인과 힌지 영역 수용체 사이에 추가로 3개의 글리신(G) 또는 글리신과 유사한 성질의 아미노산이 도입된 것을 특징으로 하는 키메라 항원 수용체.
- 제 5항에 있어서, 글리신과 유사한 성질의 아미노산은 알라닌(A), 발린(V), 류신(L) 또는 이소류신(I)인 것을 특징으로 하는 키메라 항원 수용체.
- 항원 결합 도메인; 힌지 영역; 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체에 있어서, 항원 결합 도메인이 IL13Rα2, 혈관 신생 작용과 관련된 항원, EGFRvlll, EphA2, αVβ3, 및 glypican1으로 이루어지는 군으로부터 선택되는 항원과 결합하는 것을 특징으로 하는 키메라 항원 수용체.
- 제 7항에 있어서, 상기 항원 결합 도메인은 IL13Rα2와 결합하는 것을 특징으로 하는 키메라 항원 수용체.
- 제 8항에 있어서, 상기 항원 결합 도메인은 서열번호 1번으로 표시되는 아미노산 서열의 11번 위치가 리신으로 치환되고, 107번 위치가 리신으로 치환된 아미노산 서열을 갖는 것을 특징으로 하는 키메라 항원 수용체.
- 제 8항에 있어서, 상기 항원 결합 도메인은 서열번호 1번으로 표시되는 아미노산 서열의 11번, 64번, 67번 및 107번 위치가 각각 리신(K), 아스파르트산(D), 아스파르트산(D) 및 리신(K) 또는 이와 유사한 아미노산으로 치환된 것을 특징으로 하는 키메라 항원 수용체.
- 제 10항에 있어서, 이와 유사한 아미노산으로 치환된 것은, 11번에서는 리신(K) 대신에 아르기닌(R) 또는 히스티딘(H)로; 64번 및 67번에서는 아스파르트산(D) 대신에 글루탐산(E)으로; 107번에서는 리신(K) 대신에 히스티딘(H)으로 치환된 것을 특징으로 하는 키메라 항원 수용체.
- 항원 결합 도메인; 힌지 영역; 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체에 있어서, 상기 세포질 신호 도메인이 추가의 글루타민(extra Glutamine)이 포함된 정상 인간(normal person)의 CD3ζ 신호전달 도메인인 것을 특징으로 하는 키메라 항원 수용체.
- 제 12항에 있어서, 상기 추가의 글루타민(extra Glutamine)은 정상 인간(normal person)의 CD3ζ 신호전달 도메인의 서열 50번째 위치에 존재하는 글루타민인 것을 특징으로 하는 키메라 항원 수용체.
- 제 13항에 있어서, 상기 CD3ζ 신호전달 도메인은 서열번호 13으로 표시되는 서열인 것을 특징으로 하는 카메라 항원 수용체.
- 제 1항에 있어서, 서열번호 14으로 표시되는 키메라 항원 수용체.
- 제 1항에 있어서, 서열번호 15으로 표시되는 키메라 항원 수용체.
- 제 1항, 제 5항, 제 7항, 제 10항, 제 12항 또는 제 16항 중 어느 한항에 따른 키메라 항원 수용체가 발현된 CAR-T 세포.
- 제 7항에 있어서, 서열번호 17 또는 서열번호 18로 표시되는 혈관 신생 작용과 관련된 항원과 결합하는 키메라 항원 수용체.
- 제 7항에 있어서, 서열번호 19 또는 서열번호 20으로 표시되는 EGFRvIII와 결합하는 키메라 항원 수용체.
- 제 7항에 있어서, 서열번호 21 또는 서열번호 22로 표시되는 EphA2와 결합하는 키메라 항원 수용체.
- 제 7항에 있어서, 서열번호 23 또는 서열번호 24로 표시되는 αVβ3와 결합하는 키메라 항원 수용체.
- 제 7항에 있어서, 서열번호 25 또는 서열번호 26으로 표시되는 글리피칸1(glypican1)과 결합하는 키메라 항원 수용체.
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WO2023200266A1 (ko) * | 2022-04-14 | 2023-10-19 | 주식회사 셀랩메드 | 키메릭 항원 수용체 및 hgf 중화항체의 조합 요법 |
WO2023200267A1 (ko) * | 2022-04-14 | 2023-10-19 | 주식회사 셀랩메드 | 키메릭 항원 수용체 및 hgf 결합 억제 물질의 조합 요법 |
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EP4081552A4 (en) * | 2020-02-17 | 2024-01-24 | Univ Virginia Patent Foundation | CAR-T CELLS AGAINST THE INTEGRIN ALPHAV-BETA3 WITH ROBUST ANTI-TUMOR RESPONSE AGAINST GLIOMAS AND OTHER SOLID TUMORS |
CN113402612A (zh) | 2020-03-17 | 2021-09-17 | 西比曼生物科技(香港)有限公司 | 靶向cd19和cd20的联合嵌合抗原受体及其应用 |
CN116178562A (zh) * | 2021-11-29 | 2023-05-30 | 四川大学华西医院 | 基于efna1构建的嵌合抗原受体免疫细胞制备及其应用 |
CN114573711A (zh) * | 2022-03-04 | 2022-06-03 | 陕西师范大学 | 一种TanCAR的构建及其应用 |
WO2023220128A1 (en) * | 2022-05-10 | 2023-11-16 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Targeting myeloid-derived suppressor cells (mdscs) in bladder cancer to enhance efficacy of adoptive cell therapy (act) |
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KR102011789B1 (ko) | 2019-08-19 |
US10975148B2 (en) | 2021-04-13 |
US20180265585A1 (en) | 2018-09-20 |
RU2724738C2 (ru) | 2020-06-25 |
AU2016301932B2 (en) | 2020-02-27 |
CN108026534B (zh) | 2021-08-31 |
RU2018107535A3 (ko) | 2019-09-05 |
EP3333264A1 (en) | 2018-06-13 |
JP6751493B2 (ja) | 2020-09-09 |
EP3575403A1 (en) | 2019-12-04 |
EP3333264B1 (en) | 2021-03-31 |
AU2016301932A1 (en) | 2018-03-01 |
CA2994797C (en) | 2021-07-20 |
SG11201800872QA (en) | 2018-03-28 |
CA2994797A1 (en) | 2017-02-09 |
EP3333264A4 (en) | 2019-01-02 |
MX2018001502A (es) | 2018-08-01 |
ES2877090T3 (es) | 2021-11-16 |
CN108026534A (zh) | 2018-05-11 |
JP2018522904A (ja) | 2018-08-16 |
WO2017023138A1 (ko) | 2017-02-09 |
IL257295B (en) | 2022-05-01 |
SG10201912734PA (en) | 2020-02-27 |
RU2018107535A (ru) | 2019-09-05 |
IL257295A (en) | 2018-03-29 |
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