KR20210049916A - 고형암을 위한 키메라 항원 수용체 및 키메라 항원 수용체가 발현된 t세포 - Google Patents
고형암을 위한 키메라 항원 수용체 및 키메라 항원 수용체가 발현된 t세포 Download PDFInfo
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Abstract
지속성이 향상된 키메라 항원 수용체를 개시한다.
Description
본 발명은 혈액암 또는 고형암을 효과적으로 치료하기 위한 신규의 키메릭 항원 수용체(CAR: Chimeric Antigen Receptor) 및 특정 암항원을 타겟으로 하는 키메릭 항원 수용체가 발현된 CAR-T 세포에 관한 것이다. 또한, 본 발명은 혈액암 또는 고혈암을 효과적으로 치료하기 위한 신규의 CAR를 발현하는 벡터에 관한 것이다.
보다 구체적으로, 본 발명은 항원결합 도메인(antigen binding domain); 힌지영역(hinge region); 막통과 도메인(transmembrane domain); 보조자극 도메인(costimulatory domain); 및 세포질 신호 도메인(signaling domain)을 포함하는 키메라 항원 수용체에 있어서, CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과를 위하여, 세포질 신호 도메인인 CD3ζ 도메인 내에 존재하는 어느 하나의 면역수용체 티로신-기반 활성화 모티프(immunoreceptor tyrosine-based activation motif; 이하 'ITAM'이라고 기재함)가 돌연변이된 키메릭 항원 수용체 및 이것이 발현된 CAR-T 세포에 관한 것이다.
또한, 암항원 자극시 항원-의존적으로 CAR 유전자에 CD3ζ 신호 전달 도메인 및 4-1BB 보조 자극 도메인에 더하여 사이토카인(cytokine) 신호를 유도할 수 있도록 인터루킨(interleukin)-7 receptor-α (IL7Rα) 또는 interleukin-2 receptor-β (IL-2Rβ)의 절단된 세포질 도메인을 추가하여 CAR 토닉 신호전달(tonic signaling)로 인한 CAR-T 세포의 분화(differentiation)와 탈진(exhaustion)을 감소시켜 CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과를 나타내도록 하였다.
또한, 본 발명에서는 적대적 종양 미세환경의 면역 억제 신호를 CAR-T 세포내에서 활성화 신호로 바꿔주도록 하는 키메라 스위치 수용체(chimeric switch receptor)를 도입하였다.
또한, 본 발명에서는 선천성 면역 관련 세포들의 활성화를 도와주고, 분화가 덜 된 기억 CAR-T 세포의 함유량이 증가될 수 있도록 사이토카인 IL-21이 CAR-T 세포 밖으로 분비된다.
본 발명에 따른 키메릭 항원 수용체는 적대적 종양 미세환경에서 CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과를 보여주며, 동시에 독성을 저하시켜 환자에게 부작용이 적게 나타나고 치료 효과를 높일 수 있다. 또한, 본 발명에 따른 키메릭 항원 수용체가 장착된 동종 타가유래 CAR-T 치료제를 제작하여 본 발명의 활용 범위를 넓힐 수 있다.
키메라 항원 수용체(CAR)를 발현하는 T 세포(CAR-T 세포)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.
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 증가하였다.
2세대 CAR-T 세포는 한 가지의 보조 자극 도메인을 이용하였는데, 두 가지의 보조 자극 도메인을 이용하는 CAR-T 세포는 3세대 CAR-T라 지칭된다.
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 림프종(lymphoma), 골수종(myeloma) 등 다양한 혈액암을 대상으로 임상시험이 진행중에 있고, 혈액암을 대상으로 사용가능한 의약품으로서의 CAR-T가 시장에 등장했다.
그러나, CAR-T 세포를 이용한 고형암 치료에는 몇 가지 장애물이 있다. 예를 들어, CAR-T 세포를 암환자에 정맥 투여한 경우에 CAR-T 세포가 종양 부위로 이동하는데 어려움이 있고; 적대적 종양 미세 환경 내에서 CAR-T 세포가 기능적으로 억제됨과 동시에 제한된 지속성(persistence) 및 증식을 나타낸다.
따라서, 이와 같은 문제점을 극복하여 고형암 치료가 가능한 CAR-T 세포를 개발할 필요가 있다.
본 발명은 종래에 알려져 있던 CAR-T 세포와 비교하여, 고형암에서의 치료효과가 현저히 우수한 CAR 플랫폼들, CAR-T 세포 및 CAR 발현 벡터를 제공하기 위한 것이다.
고형암을 치료하기 위한 본 발명의 CAR-T 세포 치료제는 (1) CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과를 위하여 돌연변이된 ITAM을 세포질 신호 도메인에 도입하고, 및/또는 (2) 항원-의존적으로 CAR 유전자에 CD3ζ 신호 전달 도메인, 4-1BB 보조 자극 도메인에 더하여 사이토카인 신호를 유도할 수 있도록 IL-7Rα 또는 IL-2Rβ의 절단된 세포질 도메인을 추가하여 CAR 토닉 신호전달(tonic signaling)을 조절하고, 및/또는 (3) 적대적 종양미세환경의 면역 억제 신호를 CAR-T 세포내에서 활성화 신호로 바꿔주도록 키메라 스위치 수용체(chimeric switch receptor)를 도입하고, 및/또는 (4) 선천성 면역 관련 세포들의 활성화를 도와주고, 분화가 덜 된 기억 CAR-T 세포의 함유량이 증가될 수 있도록 하기 위하여 사이토카인 IL-21이 CAR-T 세포 밖으로 분비되도록 하였다.
CAR-T 세포는 CAR 토닉 신호전달로 인해 아네르기(anergy), 분화, 소진, 활성화-유도된 CAR-T 세포 사멸을 촉진한다. CAR-T 세포의 고형암 치료 효능을 높이기 위해서는 CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과가 필수적이므로, 고형암 치료 전략에 있어서 CAR 토닉 신호체계를 조절하는 것이 필요하다.
CAR 토닉 신호전달은 CAR-T 세포 내 신호 전달 도메인의 치환에 의해 조절될 수 있으므로, 암항원-의존적으로 CAR-T 세포내에 사이토카인 신호전달을 추가하였다. 또한, CD3ζ 도메인 내에 조절되지 않은 과한 ITAM 기반 신호로 인하여 발생할 수 있는 CAR 토닉 신호전달을 조절하기 위해, 돌연변이된 하나의 ITAM을 세포질 신호 도메인에 도입하였다. CAR 토닉 신호전달을 조절함으로써, CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과가 더 오래 지속되도록 하였다.
또한, 종양 미세환경에서 과발현되는 면역억제 사이토카인(immunosuppressive cytokine)인 TGF-베타의 억제 신호를 CAR-T 세포내에서 사이토카인 IL-18의 활성화 신호로 바꾸어 주는 키메라 스위치 리셉터를 도입하였다. 또한, 선천성 면역 관련 세포들의 활성화를 도와주고, 분화가 덜 된 기억 CAR-T 세포의 함유량이 증가될 수 있도록 하기 위하여 사이토카인 IL-21을 CAR-T 세포 밖으로 분비할 수 있게 제작하였다.
본 발명의 키메릭 항원 수용체는 항원 결합 도메인의 암항원 타깃을 변경함으로써 다양한 암종에 대한 CAR-T 세포 치료제를 제조할 수 있다.
상기 과제를 해결하기 위하여, 본 발명은 항원결합 도메인; 힌지영역; 막통과 도메인; 보조자극 도메인; 및 신호 전달 도메인을 포함하는 키메라 항원 수용체가 포함된 폴리펩타이드를 제공한다. 여기에서, 상기 보조자극 도메인은 4-1BB 도메인 또는 CD28 도메인을 포함하거나, 4-1BB 도메인과 CD28 도메인을 모두 포함할 수 있고, 상기 신호 전달 도메인은 CD3ζ도메인을 포함한다.
본 발명에서, 상기 4-1BB 도메인과 상기 CD3ζ도메인 사이에는 IL-7Rα 또는 그의 일부, 또는 IL-2Rβ또는 그의 일부를 포함한다. 여기에서, IL-7Rα의 일부는 서열번호 15의 서열이고, IL-2Rβ의 일부는 서열번호 17의 서열일 수 있다. 상기 IL-7Rα의 세포질 도메인 중 일부(서열번호 15)는 서열번호 14의 IL-7Rα 전체 서열 중 266번 내지 328번 사이의 서열이고, 상기 IL-2Rβ의 세포질 도메인 중 일부(서열번호 17)는 서열번호 16의 IL-2Rβ 전체 서열 중 266번 내지 369번 사이의 서열이다.
예를 들어, 공지의 anti-IL13Ra2 CAR-T 세포(서열번호 22의 YYB-103: PCT 국제공개공보 WO 2017/023138호 참조)을 기반으로 하여 IL-13Ra2에 특이적인 CAR에, 절단된 사이토카인 IL-7Rα (아미노산 위치 265-328; 서열번호 15)의 세포질 도메인 또는 절단된 사이토카인 IL2Rβ(아미노산 위치 266-369; 서열번호 17)의 세포질 도메인을, 보조 자극 도메인으로서 4-1BB (서열번호 11)와 mutant CD3ζ (서열번호 18의 91번 내지 113번 위치가 서열번호 31 또는 서열번호 32로 치환됨) 사이에 연결하여 CAR 토닉 신호전달을 조절함으로써 CAR-T 세포의 생체 내 지속성 및 종양 치료 효능을 높였다.
본 발명에서, 상기 CD3ζ도메인 내에는 3개의 ITAM(면역수용체 티로신-기반 활성화 모티프: immunoreceptor tyrosine-based activation motif)가 포함되어 있는데, 이 중에서 3번째에 위치한 ITAM 부위의 첫번째 YxxL 및 두번째 YxxL이 치환되어 있는 것이 바람직하다(여기에서 x, y는 임의의 아미노산을 의미한다)(도 3 참조).
일반적으로 CD3ζ도메인 내의 ITAM은 루신(L) 또는 이소루신(I)으로부터 아미노산 2개 서열만큼 떨어져 있는 티로신(Y)을 함유하는 YxxL(또는 I)의 형태를 2개 포함한다. 상기 YxxL/I 형태는 통상적으로 아미노산 6 내지 8개만큼 떨어져 존재하므로, ITAM은 YxxL/Ix(6-8)YxxL/I 의 구조로 표시할 수 있다.
본 발명에서 서열번호 18로 표시되는 CD3ζ도메인에는 3개의 ITAM(서열번호 18의 21번 내지 35번; 60번 내지 75번; 및 91번 내지 105 위치)가 포함되어 있는데, 이 중에서 3번째에 위치한 ITAM의 첫번째 모티프 YxxL(서열번호 18의 91번 내지 94번 위치)이 YxxQ로 치환되고, 두번째 모티프 부위 YxxLHM(서열번호 18의 102번 내지 107번 위치)가 YxYVTM, 또는 3번째에 위치한 ITAM의 첫번째 모티프 YxxL(서열번호 18의 91번 내지 94번 위치)이 YyyL로 치환되고, 두번째 모티프 YxxL(서열번호 18의 102번 내지 105번 위치)이 YxxQ로 치환되어 있는 것이 바람직하다(여기에서 x, y는 임의의 아미노산을 의미한다).
예를 들어, 본 발명에서 CD3ζ도메인의 3번째에 위치한 ITAM을 포함하는 부위는 서열번호 31 또는 32의 서열로 돌연변이될 수 있다.
구체적으로, 공지의 anti-IL13Ra2 CAR-T 세포(YYB-103)의 신호전달 도메인인 CD3ζ도메인(서열번호 18 참조) 내에 존재하는 3개의 ITAM 모티프 중 3번째에 위치한 ITAM 모티프(즉, 서열번호 18의 91번 내지 106번) 부위의 서열을 Y Q G L S T A T K D T Y D A L H M Q A L P P R 에서 Y L P Q S T A T K D T Y D Y V T M Q A L P P R (서열번호 31) 또는 공지의 anti-IL13Ra2 CAR-T 세포(YYB-103)의 신호전달 도메인인 CD3ζ도메인(서열번호 18 참조) 내에 존재하는 3개의 ITAM 모티프 중 3번째에 위치한 ITAM 모티프(즉, 서열번호 18의 91번 내지 105번) 부위의 서열을 Y Q G L S T A T K D T Y D A L H M Q A L P P R 에서 Y L S L S T A T K D T Y L P Q H M Q A L P P R (서열번호 32)로 돌연변이시킨 키메릭 항원 수용체를 사용할 수 있다(도 3 참조).
특히, 본 발명에서 CD3ζ도메인의 3번째에 위치한 ITAM의 첫번째 모티프 YxxL(서열번호 18의 91번 내지 94번 위치)은 YxxQ로 치환되고, 두번째 모티프 부위 YxxLHM(서열번호 18의 102번 내지 106번 위치)가 YxYVTM, 또는 본 발명에서 CD3ζ도메인의 3번째에 위치한 ITAM의 첫번째 모티프 YxxL(서열번호 18의 91번 내지 94번 위치)이 YyyL로 치환되고, 두번째 모티프 YxxL(서열번호 18의 102번 내지 105번 위치)이 YxxQ로 치환되어 있는 것이 바람직하다(여기에서 x, y는 임의의 아미노산을 의미한다).
본 발명의 폴리펩타이드는 추가로 사이토카인을 포함할 수 있다. 예를 들어, 본 발명의 폴리펩타이드는 추가되는 사이토카인으로서 IL-21을 포함할 수 있다. 여기에서, 상기 사이토카인은 자기 절단형 펩타이드(self-cleaving peptide)에 의하여 키메라 항원 수용체와 연결되어 있는 것이 바람직하다.
자기 절단형 펩타이드는 예를 들어 공지의 서열번호 40 내지 43 의 2A 펩타이드를 사용할 수 있다. 자기 절단형 펩타이드는 번역(translation) 후에 절단되게 되는데, C-말단의 프롤린(P)과 글리신(G) 사이에 있는 펩타이드 결합이 분해됨으로써 절단이 이루어진다. 따라서, 자기 절단형 펩타이드 전후의 단백질은 서로 독립적으로 발현하게 된다.
따라서, 본 발명에 따른 폴리펩타이드는 T 세포 내에서 발현 시, 상기 사이토카인이 키메라 항원 수용체(CAR)와 분리되며, 분리된 사이토카인은 T 세포 외부로 분비될 수 있다. 분리된 사이토카인(예를 들어, IL-21)에 의하여 선천성 면역 관련 세포들을 활성화되고, 분화가 덜 된 CAR-T 세포의 함량이 증가될 수 있다(도 5 참조).
즉, IL-21 발현으로 인하여 CAR-T 세포 제조 공정시 시험관 내에서 분화를 막아, 분화가 덜 된 기억 CAR-T 세포의 함유량을 증가시켜 CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과를 높할 수 있고, 또한 고형암 주위의 선천성 면역 세포들을 활성화시켜 고형암을 더 효과적으로 치료 가능하게 하였다.
본 발명의 폴리펩타이드는 키메라 항원 수용체에 더하여 추가로 TGF-βR2 엑소도메인, IL18R 막통과 도메인 및 IL18R 엔도도메인을 포함할 수 있다. 여기에서, 상기 TGF-βR2 엑소도메인 및 IL18R 엔도도메인 사이에는 IL18R 막통과 도메인이 포함되어 있는 것이 바람직하다(도 4 참조).
본 발명에서 상기 TGF-βR2 엑소도메인은 자기 절단형 펩타이드에 의하여 키메라 항원 수용체와 연결되어 있는 것이 바람직하다. 따라서, 본 발명에 따른 폴리펩타이드는 T 세포 내에서 발현 시, 상기 TGF-βR2 엑소도메인, IL18R 막통과 도메인 및 IL18R 엔도도메인을 포함하는 폴리펩타이드가 키메라 항원 유도체(CAR)와 분리된다. 분리된 폴리펩타이드의 TGF-βR2 도메인은 T 세포의 외부로 노출되고, IL18R 막통과 도메인은 T 세포의 세포막에 위치하며, IL18R 엔도도메인은 T 세포의 세포질 내에 위치하게 된다.
따라서, T 세포의 외부에서 면역 억제 사이토카인인 TGF-β가 존재하는 경우, TGF-β가 상기 TGF-βR2 엑소도메인에 결합하고, 이에 의하여 상기 IL18R 엔도도메인이 활성화된다. 즉, 적대적 종양 미세환경의 면역 억제 사이토카인인 TGF-베타의 억제 신호가 CAR-T 세포 내에서 사이토카인 IL-18의 활성화 신호로 바뀌게 된다. 따라서, 상기 TGF-βR2 엑소도메인, IL18R 막통과 도메인 및 IL18R 엔도도메인을 포함하는 폴리펩타이드는 키메라 스위치 수용체(chimeric switch receptor)가 된다.
사이토카인 IL-18은 T 세포내에서 면역억제물질의 발현과 조절 T 세포의 분화를 억제하고, 암세포에 대한 면역반응을 증진시킨다. IL-18에 의한 진행성 고형암(advanced solid tumors)에서의 CAR-T 세포 치료제의 효과를 확인해 본 결과, IL-18에 의해서 CD4+ T 세포의 FoxO1 발현이 감소되고, 또한 CD8+ T 세포에서는 IL-18에 의해서 T-bet 발현은 증가함을 확인하였다.
결과적으로 IL-18은 T-bethigh FoxO1low CAR-T 즉, CAR-T 세포의 지속성(persistence)을 통해서 진행성 고형암에서 우수한 항암 효과를 나타낸다. 특히, 본 발명에서는 고형암 주위의 면역억제 사이토카인(immunosuppressive cytokine)인 TGF-β와 결합하기 위한 수용체인 TGF-βR2 엑소도메인(아미노산 위치 23-166; 서열번호 19)과 사이토카인 수용체인 IL-18R(아미노산 위치 323-541; 서열번호 20)의 막통과 도메인 및 엔도도메인을 포함하는 키메라 스위치 수용체(chimeric switch receptor)가 CAR-T 세포 내에서 발현되도록 제작하여, 적대적 종양미세환경을 역이용하여 면역 억제 신호를 CAR-T 세포내에서 활성화 신호가 되도록 바꿔주었다.
상기와 같이 키메라 항원 수용체에 추가로 TGF-βR2 엑소도메인, IL18R 막통과 도메인 및 IL18R 엔도도메인이 포함되어 있는 폴리펩타이드에도, 위에서 설명한 바와 같은 사이토카인(예를 들어, IL-21)이 추가로 포함될 수 있다.
즉, 키메라 항원 수용체에 추가로 TGF-βR2 엑소도메인, IL18R 막통과 도메인 및 IL18R 세포질 엔도도메인이 포함되어 있는 폴리펩타이드의 IL18R 엔도도메인에 상기 사이토카인(예를 들어, IL-21)이 자기 절단형 펩타이드에 의하여 연결될 수 있다.
따라서, 본 발명에 따른 폴리펩타이드는 T 세포 내에서 발현 시, 상기 TGF-βR2 엑소도메인, IL18R 막통과 도메인 및 IL18R 엔도도메인을 포함하는 폴리펩타이드가 키메라 항원 수용체(CAR)와 분리되고, 또한 사이토카인도 별도로 분리될 수 있다. 따라서, 분리된 사이토카인은 T 세포 외부로 분비되며, TGF-βR2 엑소도메인은 T 세포의 외부로 노출되고, IL18R 막통과 도메인은 T 세포의 세포막에 위치하며, IL18R 엔도도메인은 T 세포의 세포질 내에 위치하게 된다.
본 발명에 따른 폴리펩타이드는 예를 들어, 서열번호 24 내지 30 및 34 내지 37 중 어느 하나의 서열로 표시되는 폴리펩타이드일 수 있다.
또한, 본 발명은 상기와 같은 CAR 함유 폴리펩타이드가 발현된 CAR-T 세포에 관한 것이다.
또한, 본 발명은 항원결합 도메인; 힌지영역; 막통과 도메인; 보조자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체(CAR)를 발현하는 벡터에 관한 것이다. 여기에서, 상기 CAR 발현 벡터는 CAR를 코딩하는 핵산을 포함하며, 여기에서 상기 CAR 코딩 핵산은 상기 보조자극 도메인으로서 4-1BB 도메인을 코딩하는 핵산 및 상기 신호 전달 도메인으로 CD3ζ도메인을 코딩하는 핵산을 포함하되, 추가로 상기 4-1BB 도메인을 코딩하는 핵산과 상기 CD3ζ도메인을 코딩하는 핵산 사이에는 IL-7Rα 또는 그의 일부, 또는 IL-2Rβ또는 그의 일부를 코딩하는 핵산을 포함한다. 여기에서, IL-7Rα의 일부는 예를 들어 서열번호 15의 서열일 수 있고, IL-2Rβ의 일부는 예를 들어 서열번호 17의 서열일 수 있다.
본 발명에서, 상기 CD3ζ도메인을 코딩하는 핵산은, CD3ζ도메인 내에 존재하는 3개의 ITAM 중 3번째에 위치한 ITAM 부위의 첫번째 YxxL 및 두번째 YxxL이 치환된 CD3ζ도메인을 코딩하는 핵산일 수 있다. 바람직하게는, 상기 3번째에 위치한 ITAM 부위의 첫번째 모티프 YxxL은 YxxQ로 치환되고, 두번째 모티프 부위 YxxLHM은 YxYVTM 또는 첫번째 모티프 YxxL은 YyyL로 치환되고, 두번째 모티프 부위 YxxL는 YxxQ로 치환된 CD3ζ도메인을 코딩하는 핵산일 수 있다(여기에서 x, y는 임의의 아미노산을 의미한다).
또한, 본 발명의 CAR 발현 벡터는, 추가로 사이토카인 IL-21을 코딩하는 핵산을 더 포함할 수 있다. 여기에서, 상기 사이토카인 IL-21을 코딩하는 핵산은 자기 절단형 펩타이드를 코딩하는 핵산을 통하여 CAR를 코딩하는 핵산과 연결된다.
또한, 본 발명의 CAR 발현 벡터는, 추가로 TGF-βR2 엑소도메인을 코딩하는 핵산, IL18R 막통과 도메인을 코딩하는 핵산 및 IL18R 엔도도메인을 코딩하는 핵산을 포함할 수 있다. 여기에서, 상기 TGF-βR2 엑소도메인을 코딩하는 핵산은 자기 절단형 펩타이드를 코딩하는 핵산에 의하여 CAR를 코딩하는 핵산과 연결된다.
이와 같이 TGF-βR2 엑소도메인을 코딩하는 핵산, IL18R 막통과 도메인을 코딩하는 핵산 및 IL18R 엔도도메인을 코딩하는 핵산을 포함하는 CAR 발현 벡터는, 추가로 사이토카인 IL-21을 코딩하는 핵산을 포함할 수 있다. 여기에서, 상기 사이토카인 IL-21을 코딩하는 핵산은 자기 절단형 펩타이드를 코딩하는 핵산을 통하여 IL18R 엔도도메인을을 코딩하는 핵산과 연결된다.
본 발명은 상기와 같은 CAR 발현 벡터를 도입하여 제조된 CAR-T 세포에 관한 것이다.
또한, 본 발명은 상기와 같인 CAR-T 세포를 함유하는 항암제에 관한 것이다. 본 발명의 CAR-T 세포 함유 항암제는 필요에 따라 약제학적으로 허용되는 첨가제를 더 포함할 수 있다.
본 발명에 따른 CAR 함유 폴리펩타이드에서 항원 결합 도메인의 암항원 타깃을 필요에 따라 선택하여 변경함으로써 다양한 암종에 대한 CAR-T 세포를 제조할 수 있다. 예를 들어, 상기 항원 결합 도메인은 IL13Rα2, 혈관 신생 작용과 관련된 항원(anti-angiogenesis), EFGRvIII, EphA2, αVβMesothelin 및 글리피칸1(glypican1) 등의 항원과 결합하는 것으로 제조할 수 있다. 즉, IL-13Ra2, anti-angiogenesis, EGFRvIII, EphA2, aVβglypican1 및 mesothelin 등을 타겟으로 하는 리간드 또는 항체(서열번호 1 내지 7 및 33 참조)를 도입하면 이 타깃에 대한 항암제로 활용할 수 있다. 따라서, 특정 암종에 대하여 항암 효과를 갖는 CAR-T 세포를 제조할 수 있다.
교모세포종과 폐암 등의 주요한 종양 항원(tumor antigen)인 EGFRvIII의 경우, 비특이적 결합을 통해 나타나는 CAR-T 세포의 부작용을 줄이기 위하여 EGFRvIII에 대한 특이성은 유지하면서 EGFR wild type과의 결합력을 최소화하도록 타깃 서열을 변경시킴과 동시에 CAR-T 세포에서의 CAR 발현률 및 지속성(persistence)을 최적화시켰다.
타겟 서열(서열번호 33)는 서열번호 3의 52번 내지 57번을 STGGYN에서 DPENDE로(HEAVY CHAIN CDR2 부분), 서열번호 3의 101번을 S에서 G로(HEAVY CHAIN CDR3 부분), 서열번호 3의 229번을 V에서 G로 (LIGHT CHAIN CDR3 부분) 변경시킴과 동시에 CAR-T 세포에서의 CAR 발현률 및 지속성을 CD8 신호 서열(signal sequence)을 사용하여 향상시켰다(서열번호 34 및 35).
aVβ를 타겟으로 하는 CAR-T 세포에서의 CAR 발현률 및 지속성을 높이기 위하여, Gaussia princeps luciferase signal sequence 또는 CD8 signal sequence를 사용하였다(서열번호 36 및 37).
본 발명에서 개시하고 있는 CAR-T 세포는 발현율 및 지속성이 우수하여, 인체 내 지속성 및 항 종양 효과를 보여주어, 고형암 등에 대한 향상된 치료 효과를 갖는다.
도 1은 본 발명에 따른 CAR 함유 폴리펩타이드가 고형암을 효과적으로 치료하는 과정을 도시한 것이다.
도 2은 본 발명에 따른 CAR 함유 폴리펩타이드 플랫폼에 사용 가능한 항원 결합 도메인을 설명하는 도면이다.
도 3은 본 발명에 따른 CAR 함유 폴리펩타이드에서 CAR 토닉 시그널링 조절을 위하여 CAR-T 세포 내에 사이토카인 신호전달 도메인을 도입한 것을 설명하기 위한 도면이다.
도 4는 적대적 종양 미세환경의 면역 억제 신호를 CAR-T 세포 내에서 활성화 신호로 바꿔주도록 키메라 스위치 수용체를 도입한 것을 설명하기 위한 도면이다.
도 5는 선천성 면역 관련 세포들의 활성화를 도와주고, 분화가 덜 된 기억 CAR-T 세포의 함유량이 증가될 수 있도록 사이토카인 IL-21이 CAR-T 세포 밖으로 분비되는 것을 설명하기 위한 도면이다.
도 6은 본 발명에 따른 CAR 함유 폴리펩타이드의 구조를 도시한 것이다.
도 7은 본 발명에 따른 CAR 함유 폴리펩타이드에서 사용된 자기 절단형 펩타이드를 도시한 것이다.
도 8은 본 발명의 CAR로 형질 변형된 CAR-T 세포의 성장속도 및 생존율를 나타낸 그래프 및 표이다.
도 9는 본 발명의 CAR로 형질 변형된 CAR-T 세포의 CAR 발현율을 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 10은 본 발명의 CAR로 형질 변형된 CAR-T 세포의 TGF-βR2와 IL-18R의 키메라 스위치 수용체 발현율을 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 11은 본 발명의 CAR로 형질 변형된 CAR-T 세포의 Day10 표현형(phenotype)을 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 12는 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h 후 LDH assay를 통하여 세포 독성(cytotoxicity)을 확인한 그래프와 CAR-T 세포독성 시험에 사용된 CAR-T 세포 순도 및 생존율를 나타낸 표이다.
도 13은 본 발명의 CAR로 형질 변형된 CAR-T의 24h 또는 96h 후 자발적 독성(spontaneous toxicity)를 분석한 결과이다.
도 14 내지 16은 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h(도 14), 48h(도 15), 96h(도 16)후 CAR-T 세포의 CAR 발현율 변화를 유세포 분석기를 사용해서 분석한 결과이다.
도 17은 본 발명의 키메릭 항원 수용체로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h(A)후 CAR-T 세포의 TGF-Rβ2와 IL-18R의 chimeric switch receprtor 발현율 변화를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 18은 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h와 48h후 IFN-γ사이토카인 생성을 비교한 그래프이다.
도 19는 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h와 48h후 IL-21 사이토카인 생성을 비교한 그래프이다.
도 20은 암항원 EGFRvIII 타겟인 경우, 비특이적 결합을 통해 나타나는 CAR-T 세포의 부작용을 줄이기 위하여 EGFRvIII에 대한 특이성은 유지하면서 EGFR wild type과의 결합력을 최소화하도록 타깃 서열을 변경시킴과 동시에 CAR-T 세포에서의 CAR 발현률 및 지속성을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포의 성장속도 및 생존율를 나타낸 그래프 및 표이다(YYB105, #13, #14). 암항원이 aVβ타겟인 경우, CAR-T 세포에서의 CAR 발현율을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포의 성장속도 및 생존율를 나타낸 그래프 및 표이다(YYB107, #15, #16).
도 21은 암항원 EGFRvIII 타겟인 경우, 비특이적 결합을 통해 나타나는 CAR-T 세포의 부작용을 줄이기 위하여 EGFRvIII에 대한 특이성은 유지하면서 EGFR wild type과의 결합력을 최소화하도록 타깃 서열을 변경시킴과 동시에 CAR-T 세포에서의 CAR 발현률을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포에서의 CAR 발현율을 나타낸 그래프이다(YYB105, #13, #14). 암항원이 aVβ타겟인 경우, CAR-T 세포에서의 CAR 발현율을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포에서의 CAR 발현율을 나타낸 그래프이다(YYB107, #15, #16).
도 2은 본 발명에 따른 CAR 함유 폴리펩타이드 플랫폼에 사용 가능한 항원 결합 도메인을 설명하는 도면이다.
도 3은 본 발명에 따른 CAR 함유 폴리펩타이드에서 CAR 토닉 시그널링 조절을 위하여 CAR-T 세포 내에 사이토카인 신호전달 도메인을 도입한 것을 설명하기 위한 도면이다.
도 4는 적대적 종양 미세환경의 면역 억제 신호를 CAR-T 세포 내에서 활성화 신호로 바꿔주도록 키메라 스위치 수용체를 도입한 것을 설명하기 위한 도면이다.
도 5는 선천성 면역 관련 세포들의 활성화를 도와주고, 분화가 덜 된 기억 CAR-T 세포의 함유량이 증가될 수 있도록 사이토카인 IL-21이 CAR-T 세포 밖으로 분비되는 것을 설명하기 위한 도면이다.
도 6은 본 발명에 따른 CAR 함유 폴리펩타이드의 구조를 도시한 것이다.
도 7은 본 발명에 따른 CAR 함유 폴리펩타이드에서 사용된 자기 절단형 펩타이드를 도시한 것이다.
도 8은 본 발명의 CAR로 형질 변형된 CAR-T 세포의 성장속도 및 생존율를 나타낸 그래프 및 표이다.
도 9는 본 발명의 CAR로 형질 변형된 CAR-T 세포의 CAR 발현율을 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 10은 본 발명의 CAR로 형질 변형된 CAR-T 세포의 TGF-βR2와 IL-18R의 키메라 스위치 수용체 발현율을 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 11은 본 발명의 CAR로 형질 변형된 CAR-T 세포의 Day10 표현형(phenotype)을 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 12는 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h 후 LDH assay를 통하여 세포 독성(cytotoxicity)을 확인한 그래프와 CAR-T 세포독성 시험에 사용된 CAR-T 세포 순도 및 생존율를 나타낸 표이다.
도 13은 본 발명의 CAR로 형질 변형된 CAR-T의 24h 또는 96h 후 자발적 독성(spontaneous toxicity)를 분석한 결과이다.
도 14 내지 16은 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h(도 14), 48h(도 15), 96h(도 16)후 CAR-T 세포의 CAR 발현율 변화를 유세포 분석기를 사용해서 분석한 결과이다.
도 17은 본 발명의 키메릭 항원 수용체로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h(A)후 CAR-T 세포의 TGF-Rβ2와 IL-18R의 chimeric switch receprtor 발현율 변화를 유세포 분석기(Flow cytometry analysis)를 사용해서 분석한 결과이다.
도 18은 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h와 48h후 IFN-γ사이토카인 생성을 비교한 그래프이다.
도 19는 본 발명의 CAR로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h와 48h후 IL-21 사이토카인 생성을 비교한 그래프이다.
도 20은 암항원 EGFRvIII 타겟인 경우, 비특이적 결합을 통해 나타나는 CAR-T 세포의 부작용을 줄이기 위하여 EGFRvIII에 대한 특이성은 유지하면서 EGFR wild type과의 결합력을 최소화하도록 타깃 서열을 변경시킴과 동시에 CAR-T 세포에서의 CAR 발현률 및 지속성을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포의 성장속도 및 생존율를 나타낸 그래프 및 표이다(YYB105, #13, #14). 암항원이 aVβ타겟인 경우, CAR-T 세포에서의 CAR 발현율을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포의 성장속도 및 생존율를 나타낸 그래프 및 표이다(YYB107, #15, #16).
도 21은 암항원 EGFRvIII 타겟인 경우, 비특이적 결합을 통해 나타나는 CAR-T 세포의 부작용을 줄이기 위하여 EGFRvIII에 대한 특이성은 유지하면서 EGFR wild type과의 결합력을 최소화하도록 타깃 서열을 변경시킴과 동시에 CAR-T 세포에서의 CAR 발현률을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포에서의 CAR 발현율을 나타낸 그래프이다(YYB105, #13, #14). 암항원이 aVβ타겟인 경우, CAR-T 세포에서의 CAR 발현율을 최적화한 키메릭 항원 수용체로 형질 변형된 CAR-T 세포에서의 CAR 발현율을 나타낸 그래프이다(YYB107, #15, #16).
이하, 실시예를 통해서 본 발명을 구체적으로 설명한다. 다만, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 사상 및 기술적 범위가 어떤 의미에서든지 제한되는 것은 아님을 유의해야 한다. 또한, 본 발명은 참조로서 인용되는 도면에 도시된 실시형태의 정확한 배열 및 방편에 제한되지 않는 것으로 이해되어야 한다.
실시예 1: 고형암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하여 효과적으로 치료하기 위한 신규의 키메릭 항원 수용체(CAR) 플랫폼 제조
인간 IL13(P35225.1), 인간 CD3(P20963-1), 인간 CD8A(P01732), 인간 CD28(P10747), 인간 CD3ζ(P20963), 인간 4-1BB(Q07011), IL7RA(P16871), IL2RB(P14784), TGFR2(P37173), IL18R(Q13478), IL21(Q9HBE4), IL2(P60568), T2A, P2A, 및 인간 카파 경쇄 신호 서열(HuVHCAMP)을 과학문헌 및 공공이 이용가능한 데이터베이스를 이용하여, 코돈-최적화 합성 DNA(codon-optimized synthetic DNA)로 구성된, 키메라 항원 수용체 함유 폴리펩타이드(서열번호 23 내지 30 및 34 내지 37 및 도 6의 #1, #2, #5, #6, #7, #8, #11, #12 참조) 발현 벡터를 이용하여 CAR 함유 폴리펩타이드를 제작하였다(도 6 및 도 7 참조).
구체적으로, 합성 DNA를 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합하여, CAR 함유 폴리펩타이드를 발현하는 벡터를 제작하고, 이 벡터를 T 세포에 형질 도입함으로써, CAR 함유 폴리펩타이드가 발현된 T 세포를 제작할 수 있다.
도 6의 폴리펩타이드 #1의 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); PCT 국제공개공보 WO 2017/023138호의 YYB-103 참조), CAR 단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 사이에 도입되는 3개의 글리신(GGG)(PCT 국제공개공보 WO 2017/023138호의 YYB-103 참조), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단된 사이토카인 IL-7RA (아미노산 위치 265-328; 서열번호 15)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 31의 서열로 돌연변이됨), T2A, CD8A 신호 서열(leader sequence), TGF-βR2 엑소도메인(아미노산 위치 23-166; 서열번호 19)과 사이토카인 수용체인 IL-18R (아미노산 위치 323-541; 서열번호 20)의 막통과 도메인 및 엔도도메인을 포함하는 키메라 스위치 수용체(chimeric switch receptor), P2A, 인간 IL2 신호 서열(leader sequence), IL-21(아미노산 위치 23-155; 서열번호 21) 서열과 XhoI/NotI 절단 부분을 포함한다(도 6의 CAR 함유 폴리펩타이드 #1 및 도 7 참조).
도 6의 CAR 함유 폴리펩타이드 #2의 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 도입된 3개의 글리신 (GGG), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단된 사이토카인 IL-7RA (아미노산 위치 265-328; 서열번호 15)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 31의 서열로 돌연변이됨), T2A, CD8A 신호 서열, TGF-βR2 엑소도메인(아미노산 위치 23-166; 서열번호 19)과 사이토카인 수용체인 IL-18R (아미노산 위치 323-541; 서열번호 20)의 막통과 도메인 및 엔도도메인을 포함하는 키메라 스위치 수용체 서열과 XhoI/NotI 절단 부분을 포함한다(도 6의 CAR 함유 폴리펩타이드 #2 및 도 7 참조).
도 6의 CAR 함유 폴리펩타이드 #5의 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 도입된 3개의 글리신 (GGG), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단된 사이토카인 IL-7RA (아미노산 위치 265-328; 서열번호 15)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 31의 서열로 돌연변이됨), T2A, 인간 IL2 신호 서열, IL-21(아미노산 위치 23-155: 서열번호 21) 서열과 XhoI/NotI 절단 부분을 포함한다(도 6의 CAR 함유 폴리펩타이드 #5 및 도 7 참조).
도 6의 CAR 함유 폴리펩타이드 #6의 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 도입된 3개의 글리신 (GGG), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단 된 사이토카인 IL-7RA (아미노산 위치 265-328; 서열번호 15)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 31의 서열로 돌연변이됨) 서열과 XhoI/NotI 절단 부분을 포함한다(도 6의 CAR 함유 폴리펩타이드 #6 및 도 7 참조).
도 6의 CAR 함유 폴리펩타이드 #7의 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 도입된 3개의 글리신(GGG), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단된 사이토카인 IL2Rβ(아미노산 위치 266-369; 서열번호 17)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 32의 서열로 돌연변이됨), T2A, CD8A 신호 서열, TGF-βR2 엑소도메인(아미노산 위치 23-166; 서열번호 19)과 사이토카인 수용체인 IL-18R (아미노산 위치 323-541; 서열번호 20)의 막통과 도메인 및 엔도도메인을 포함하는 키메라 스위치 수용체, P2A, 인간 IL2 신호 서열, IL-21(아미노산 위치 23-155) 서열과 XhoI/NotI 절단 부분을 포함한다(도 6 #7, 도 7).
도 6의 CAR 함유 폴리펩타이드 #8의 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 도입된 3개의 글리신(GGG), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단된 사이토카인 IL2Rβ(아미노산 위치 266-369; 서열번호 19)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 32의 서열로 돌연변이됨), T2A, CD8A 신호 서열, TGF-βR2 엑소도메인(아미노산 위치 23-166; 서열번호 19)과 사이토카인 수용체인 IL-18R (아미노산 위치 323-541; 서열번호 20)의 막통과 도메인 및 엔도도메인을 포함하는 키메라 스위치 수용체 서열과 XhoI/NotI 절단 부분을 포함한다(도 6의 CAR 함유 폴리펩타이드 #8 및 도 7 참조).
도 6의 CAR 함유 폴리펩타이드 #11의 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 도입된 3개의 글리신(GGG), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단 된 사이토카인 IL2Rβ(아미노산 위치 266-369; 서열번호 17)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 32의 서열로 돌연변이됨), T2A, 인간 IL2 신호 서열, IL-21(아미노산 위치 23-155: 서열번호 21) 서열과 XhoI/NotI 절단 분을 포함한다(도 6의 CAR 함유 폴리펩타이드 #11 및 도 7 참조).
도 6의 CAR 함유 폴리펩타이드 #12의 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 도입된 3개의 글리신(GGG), 인간 CD8α의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, 절단 된 사이토카인 IL2Rβ(아미노산 위치 266-369; 서열번호 17)의 세포질 도메인, mutant CD3ζ (서열번호 18의 91번 내지 113번 위치는 서열번호 32의 서열로 돌연변이됨), 서열과 XhoI/NotI 절단 부분을 포함한다(도 6 #12, 도 7).
CAR 함유 폴리펩타이드 #1, #2, #5, #6, #7, #8, #11 및 #12의 전체 서열을 서열번호 23 내지 30에 나타내었다.
최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(Emtage PC 등, Clin Cancer Res, 2008, 14:8112-8122). 본 실시예에서 키메라 항원 수용체의 활성을 비교하기 위해, YYB103(서열번호 22)를 추가적으로 제작하였다.
실시예 2: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 제조
CAR를 발현하는 높은 역가의 PG13 클론은 일시적으로 피닉스-엠포 및 피닉스-에코 세포를 실시예 1 에서 제작된 레트로바이러스 발현 벡터 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/#1, PG13/#2, PG13/#5, PG13/#6, PG13/#7, PG13/#8, PG13/#11, 또는 PG13/#12 세포를 염색한 후에 유세포분석기에 의하여 단일 클론을 분리하였다. 높은 역가의 PG13/#1, PG13/#2, PG13/#5, PG13/#6, PG13/#7, PG13/#8, PG13/#11, 또는 PG13/#12 클론은 한계희석법에 의하여 2번째 서브클로닝에 의하여 만들어졌다. 서브클론은 높은 CAR 발현을 안정적으로 보여주었으며, 말초혈액에 효율적인 형질도입 능력을 위하여 선택되었다.
항-IL-13 단일클론 항체 (BD Pharmingen)를 이용하여 형질도입된 PG13/#1, PG13/#2, PG13/#5, PG13/#6, PG13/#7, PG13/#8, PG13/#11, 또는 PG13/#12 세포를 유세포 분석기(Flow cytometry analysis)를 사용하여 형질 도입 정도를 분석하였다. 형질도입된 PG13/#1, PG13/#2, PG13/#5, PG13/#6, PG13/#7, PG13/#8, PG13/#11, 또는 PG13/#12세포의 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 28일 동안 교반용 플랫폼 장치 (WAVE 생물 반응기 시스템) 상에서 배양하였다. IL-2를 100IU/mL로 유지하였다. 이러한 방식으로 변형된 T 세포는 분석 실험에 사용되였다.
실험예 1: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 성장속도 및 생존율 체크
실험결과
상기 실시예 2에서 제조된 T 세포에 대하여 세포 수를 계수하여 CAR-T의 성장속도(cell growth) 및 생존율(viability)을 확인하고, 그 결과를 도 8에 나타내었다.
모든 군(#1, #2, #5, #6, #7, #8, #11 또는 #12)의 세포 수, 성장속도는 요일에 따라 대조군인 YYB103 보다 높게 나타났고, 배양 12일때부터 세포가 급속하게 성장함을 알 수 있고, 생존율도 90% 이상으로 나타났다 (도 8 참조).
실험예 2: 신규 키메라 항원 수용체로 형질 변형된 CAR-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.
실험결과
실시예 2에서 제조된 IL13Rα2 특이적인 8종의 CAR 함유 폴리펩타이드 (#1, #2, #5, #6, #7, #8, #11 또는 #12)가 T 세포 표면에서 발현되는지 확인하기 위해 실시예 2에 따라 T 세포 배양을 28일 동안 진행한 후 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다.
분석 결과, 도 9에 도시되어 있는 바와 같이, 살아있는 T 세포 표면에 발현된 키메라 항원 수용체의 발현률은 24.5% ~ 84.2%로 추가적인 T 세포 활성화나 형질도입이 없이도 IL13Rα2 특이적 키메라 항원 수용체의 발현은 4주까지 안정적으로 유지되었다 (도 9 참조).
실험예 3: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포표면의 TGF-βR2와 IL-18R의 chimeric switch receptor 발현율 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 Human TGF-beta RII Fluorescein-conjugated Antibody (FAB2411F) (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 표면의 TGFβR2와 IL-18R의 chimeric switch receprtor 발현율을 체크하였다.
실험결과
실시예 2에서 제조된 CAR-T (#1, #2, #5, #6, #7, #8, #11 또는 #12) 세포 표면에서 TGFβR2와 IL-18R의 chimeric switch receprtor가 발현되는지 확인하기 위해 실시예 2에 따라 T 세포 배양을 14일 동안 진행한 후 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다. 분석 결과, 살아있는 T 세포 표면에 발현된 TGFβR2와 IL-18R의 chimeric switch receprtor의 발현률은 ~ 85%로 나타났다 (도 10 참조).
실험예 4: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포표면의 표현형(phenotype) 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 FITC-conjugated CD45RA Ab (HI100) (Biolegend), PE-conjugated CCR7Ab (G043H7) (Biolegend), PE-Cy7-conjugated CD62L Ab (DREG-56) (Biolegend)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 표면의 분화가 덜 된 기억 CAR-T 세포의 함유량, CCR7+CD45RA+CD62L+ phenotype을 체크하였다.
실험결과
실시예 2에서 제조된 CAR-T (#1, #2, #5, #6, #7, #8, #11 또는 #12) 세포 표면에서 분화가 덜 된 기억 CAR-T 세포의 함유량을 확인하기 위해 실시예 2에 따라 T 세포 배양을 10일 동안 진행한 후 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다. 분석 결과, 살아있는 T 세포 표면에 발현된 CCR7+CD45RA+CD62L+ phenotype은 실시예 2에서 제작한 CAR-T 모든 군(#1, #2, #5, #6, #7, #8, #11 또는 #12) 세포 표면에서 대조군인 비-형질도입 시료(untrasnduced sample)보다 ~ 5 %이상, 형질도입 시료 CAR-T 대조군인 YYB103보다 ~ 10 % 이상 CCR7+CD45RA+CD62L+ phenotype을 보이는 분화가 덜 된 기억 CAR-T 세포의 함유량을 확인했다 (도 11 참조).
실험예 5: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 IL13Rα2가 과발현되는 교모세포종에 대한 세포독성 체크
실험방법
실시예 2에서 제조된 CAR-T (#1, #2, #5, #6, #7, #8, #11 또는 #12) IL13Rα2 특이적인 CAR-T 세포의 세포독성을 측정하기 위해 LDH (Promega) 키트를 사용하여 세포독성 분석(cytotoxicity assay)을 진행하였다. 구체적으로, CAR-T 세포 (effector 세포)는 anti-CD3 Ab로 세포 활성화 후 10일 후에 사용하였으며 CAR 발현율이 20~40%인 CAR-T 세포를 6-well plate에 1:2 (effector: target=1 x 106 cells : 2 x 106 cells)의 비율로 세포를 넣고 37℃에서 24시간 동안 반응시켰다. 사용된 표적 세포는 IL13Rα2를 발현하는 U87세포와 정상세포 대조군인 293FT 세포를 사용하였다.
실험결과
본 발명을 통해 제작된 IL13Rα2 특이적인 CAR-T 세포가 표적 암세포(U87)세포를 효과적으로 사멸시키는지 분석하였다. 앞서 언급한 표적 암세포(U87)와 정상세포(293FT)를 각각의 활성화된 CAR-T 세포와 함께 배양하여 세포 독성을 비교 분석하는 방법을 사용하였다. 도 12에 도시되어 있는 바와 같이, 본 발명에 따라 제조된 모든 CAR-T 세포는, 형질도입이 되지 않은 활성화된 T 세포와 비교할 때 50~70% 높은 수준으로 표적 암세포(U87) 사멸을 유도하는 결과를 나타내었다. 특히, 본 발명의 CAR-T #5, #6, #11에서 세포 독성이 높게 나왔다. 또한, IL-7Rα를 포함하는 CAR-T 세포(#1,2,5,6)가, IL-2Rβ를 포함하는 CAR-T 세포 (#7,8,11,12)보다 전체적으로 높은 세포 독성을 보였다.
표적 세포에 대한 비교 대상으로 IL13Rα2를 발현하지 않는 293FT 세포를 정상세포 대조군으로 사용한 실험 결과에서는, IL13Rα2에 특이적인 CAR-T 세포의 경우 매우 약한 세포독성(2~4%)을 보이는 것을 확인하였다. 이는 본 실험에 사용된 키메라 항원 수용체가 IL13Rα2에 특이적으로 결합한다는 것을 보여준다.
본 실험예를 통해 IL13Rα2 특이적인 키메라 항원 수용체 T 세포가 정상세포(293FT)에는 독성을 나타내지 않으며, IL13Rα2를 발현하는 표적 암세포(U87)만을 현저하게 사멸시킬 수 있음을 알 수 있다.
도 13은 본 발명의 키메릭 항원 수용체로 형질 변형된 CAR-T 세포의 표적 세포와의 공 배양 없이 24h 또는 96h후 LDH assay를 통한 spontaneous toxicity를 확인한 결과이다. YYB103 spontaneous toxicity가 다른 군보다 높기 때문에, U87 공배양에서는 8개의 군이 YYB103보다 높은 세포독성을 보일 것으로 예상되며, 본 발명의 키메릭 항원 수용체로 형질 변형된 CAR-T 세포 (#1, #2, #5, #6, #7, #8, #11 또는 #12)는 안전성 및 안정성 면에서 비교우위에 있다고 예상된다.
실험예 6: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 IL13Rα2가 과발현되는 교모세포종과 공배양시 CAR 발현율 변화 체크
실험방법
실시예 2에서 제조된 CAR-T (#1, #2, #5, #6, #7, #8, #11 또는 #12) 세포의 IL13Rα2가 과발현되는 교모세포종과 공배양시 CAR 발현율 변화를 체크하기위해, CAR 발현율이 20~40%인 CAR-T 세포 (effector 세포)는 anti-CD3 Ab로 세포 활성화 후 10일 후에 사용하였으며 6-well plate에 1:2 (effector: target=1 x 106 cells : 2 x 106 cells)의 비율로 세포를 넣고 37℃에서 24시간, 48시간, 96시간 동안 반응시켰다. 96시간 샘플은 48시간후 target 2 x 106 cells을 add후, 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, CAR 발현률 변화를 체크하였다.
실험결과
실시예 2에서 제조된 IL13Rα2 특이적인 8종의 CAR (#1, #2, #5, #6, #7, #8, #11 또는 #12)가 IL13Rα2가 과발현되는 교모세포종과 공배양시 CAR 발현율 변화를 확인하기 위해 실시예 2에 따라 T 세포 배양을 10일 동안 진행한 후, 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다. 분석 결과, 도 14에 도시되어 있는 바와 같이, 24시간 U87과의 공배양에서는 8종의 모든군에서 CAR 발현 변화가 YYB103 보다 적게 나타났다(도 14).
48시간 U87과의 공배양에서는 8종의 모든군에서 CAR 발현 변화가 YYB103 보다 적게 나타났다(도 15).
96시간 U87과의 공배양에서는 #1, #2 #5, #6, #7, 5종의 군에서 발현 변화가 YYB103 보다 적게 나타났다(도 16). 96시간 U87과의 공배양후 YYB103의 CAR 발현은 미미한 수준을 보였다(도 16).
IL13Rα2가 과발현되는 교모세포종에 대한 공배양시 CAR 발현율 변화는, 표적 세포와의 공 배양 없이, 또는 정상 세포 대조군으로 사용된 293FT 세포와의 공 배양시 CAR 발현율 변화 확인으로, 본 발명에 따른 키메릭 항원 수용체는 적대적 종양 미세환경에서 CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과를 보여주며, 동시에 독성을 저하시킬 것으로 기대된다.
실험예 7: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 IL13Rα2가 과발현되는 교모세포종과 공배양시 TGFβR2와 IL-18R의 chimeric switch receprtor 발현율 변화 체크
실험방법
실시예 2에서 제조된 CAR-T (#1, #2, #5, #6, #7, #8, #11 또는 #12) 세포의 IL13Rα2가 과발현되는 교모세포종과 공배양시 TGFβR2와 IL-18R의 chimeric switch receprtor 발현율 변화를 체크하기위해, CAR 발현율이 20~40%인 CAR-T 세포 (effector 세포)는 anti-CD3 Ab로 세포 활성화 후 10일 후에 사용하였으며 6-well plate에 1:2 (effector: target=1 x 106 cells : 2 x 106 cells)의 비율로 세포를 넣고 37℃에서 24시간, 48시간, 96시간 동안 반응시켰다. 96시간 샘플은 48시간후 target 2 x 106 cells을 add후, 유세포 분석(>30,000 events)를 위해 BD LSRII 장비(Becton Dickinson)와 BD FACSDiva 소프트웨어(Becton Dickinson)을 사용하였다. 구체적으로는 Human TGF-beta RII Fluorescein-conjugated Antibody (FAB2411F) (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, TGFβR2와 IL-18R의 chimeric switch receprtor 발현율 변화를 체크하였다.
실험결과
실시예 2에서 제조된 IL13Rα2 특이적인 8종의 CAR (#1, #2, #5, #6, #7, #8, #11 또는 #12)가IL13Rα2가 과발현되는 교모세포종과 공배양시 TGFβR2와 IL-18R의 chimeric switch receprtor 발현율 변화를 확인하기 위해 실시예 2에 따라 T 세포 배양을 10일 동안 진행한 후, 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다.
분석 결과, 도 17에 도시되어 있는 바와 같이, 24시간 공배양후 4종의 군(#1, #2, #7, #8)에서 TGFβR2와 IL-18R의 chimeric switch receprtor 발현이 CAR-T cell only보다 U87 공배양 군에서 감소하는 양상을 보이나 평균 30%의 발현을 보였다(도 17). 48시간 공배양후 4종의 군(#1, #2, #7, #8)에서 TGFβR2와 IL-18R의 chimeric switch receprtor 발현이 CAR-T cell only보다 U87 공배양 군에서 감소하는 양상을 보이나 평균 25%의 발현을 보였다. 96시간 공배양후 4종의 군(#1, #2, #7, #8)에서 TGFβR2와 IL-18R의 chimeric switch receprtor 발현이 CAR-T cell only보다 U87 공배양 군에서 감소하는 양상을 보이나 평균 15%의 발현을 보였다. 표적 세포와의 공 배양 없이, 또는 정상 세포 대조군으로 사용된 293FT 세포와의 공 배양시 보다는 발현율 변화가 많았지만, IL13Rα2가 과발현되는 교모세포종에 대한 공배양시 TGFβR2와 IL-18R의 chimeric switch receprtor 발현율 변화 확인으로, 본 발명에 따른 키메릭 항원 수용체는 적대적 종양 미세환경에서 CAR-T 세포의 우수한 생체 내 지속성 및 항 종양 효과를 보여줄 것으로 기대된다.
실험예 8: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 target 세포에 대한 사이토카인 (IFN-gamma) 생성 확인
실험 방법
실시예 2에서 제조된 CAR-T (#1, #2, #5, #6, #7, #8, #11 또는 #12) 세포와 IL13Rα2가 과발현되는 교모세포종 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h후와 48h후 IFN-γ사이토카인 생성을 확인하기위해, CAR 발현율이 20~40%인 CAR-T 세포 (effector 세포)는 anti-CD3 Ab로 세포 활성화 후 10일 후에 사용하였으며, 6-well plate에 1:2 (effector : target=1 x 106 cells : 2 x 106 cells)의 비율로 세포를 넣고, 6 well culture plate의 well당 배양배지 6 mL을 넣고 37℃에서 24 시간 배양 후 상층액 100 ul을 취하여 1.5 ml tube에 옮겨준 후, 48 시간까지 추가 배양하여 상층액 100 ul을 동일하게 취했다.
ELISA 분석기(R&D systems) 제조사의 지침에 따라 아래와 같이 IFN-gamma 분석 실험을 진행 하였다. IFN-gamma standard bottle에 3 ml calibrator diluent RD6-21을 넣어준 후 진탕기(shaker)에서 15분 동안 섞어주고 1.5 ml tube에 1ml씩 분주하여 standard 1을 2개를 만들었다. 분주한 1ml의 standard 1로부터 500 ul 취하여 계단 희석하여 standard 7까지 만들었다. Blank를 만들어 주기 위해서 배양배지 500 ul와 calibrator diluent RD6-21 500 ul 섞어 준비했다.
Sample을 1/20 희석하기 위해서, Sample 수만큼의 새로운 1.5 ml tube에 190 ul의 calibrator diluent RD6-21을 넣어주고, sample의 상층액 10 ul를 취하여 total volume이 200 ul로 assay 시료를 준비했다. Wash buffer을 만들기 위해서 500 ml storage bottle에 증류수 500 ml과 20ml의 wash buffer concentrate를 잘 섞어서 준비했다.
IFN-gamma microplate에 assay diluent RD1-51(blue dye)를 standard 1~7과 blank, sample well에 100 ul씩 넣어 주었다. 위에서 준비한 blank, standard와 sample을 100 ul씩 넣어준 후 plate sealer를 부착하여 상온에서 2시간 반응 시켰다. 반응 후 반응액을 버리고 준비해 둔 wash buffer 400 ul를 넣고 well을 4회 wash 했다. IFN-gamma conjugate를 각 well당 200 ul 넣고 plate sealer를 부착하여 상온에서 2시간 반응시켰다. 반응액을 버리고 400 ul wash buffer을 이용하여 4회 wash했다. 발색 시약(Color reagent) A:B 를 1:1 비율로 섞은 후 well당 200 ul씩 넣어주고 plate sealer 부착 후 호일로 빛을 차단시킨 후 30분간 상온에서 반응했다. 반응 후 stop solution 50 ul를 각 well에 넣고 30분 이내에 450nm로 측정했다.
실험 결과
YYB103이 상대적으로 다른 시료에 비해 더 많은 양의 IFN-gamma를 분비하는 것으로 나타났으며, U87 cell 존재 하에 CAR-T 세포 배양시 IL-7Rα 신호전달도메인을 포함한 CAR-T(#1,2,5,6)가 IL-2Rβ 신호전달도메인을 포함한 CAR-T(#7,8,11,12)보다 IFN-gamma를 더 많이 분비하는 것으로 나타났다. 24 시간과 48 시간 배양 후의 시료 간 결과는 유사한 양상을 나타냈다 (도 18).
도 12에서와 같이 본 발명의 키메릭 항원 수용체로 형질 변형된 CAR-T 세포와 인간 뇌암세포주 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h 후 LDH assay를 통한 세포 독성(cytotoxicity) 확인한 결과, 8 개군의 표적세포 살상능력은 비슷하게 나타났으나, IFN-γ의 생성이 적은 것을 미루어 볼 때 cytokine에 의한 악영향 (Cytokine release syndrome, CRS) 없이 표적세포를 살상할 수 있다는 점에서 안전성 면에서, CAR-T 세포치료제의 효과가 부작용이 적으며 치료효과는 우수할 것으로 예측 된다.
실험예 9: 신규 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 사이토카인(IL-21) 생성 체크
실험 방법
실시예 2에서 제조된 CAR-T (#1, #2, #5, #6, #7, #8, #11 또는 #12) 세포와 IL13Rα2가 과발현되는 교모세포종 U87 세포 및 정상 세포 대조군으로 사용된 293FT 표적 세포와의 공 배양 24h후와 48h후 사이토카인 IL-21 생성을 확인하기위해, CAR 발현율이 20~40%인 CAR-T 세포 (effector 세포)는 anti-CD3 Ab로 세포 활성화 후 10일 후에 사용하였으며, 6-well plate에 1:2 (effector : target=1 x 106 cells : 2 x 106 cells)의 비율로 세포를 넣고, 6 well culture plate의 well당 배양배지 6 mL을 넣고 37℃에서 24 시간 배양 후 상층액 100 ul을 취하여 1.5 ml tube에 옮겨준 후, 48 시간까지 추가 배양하여 상층액 100 ul을 동일하게 취했다.
ELISA 분석기 (Invitrogen) 제조사의 지침에 따라 아래와 같이 IL-21 분석 실험을 진행 하였다. 96 well ELISA plate에 well당 100 ul capture antibody를 넣고 4 ℃에서 overnight 동안 반응 시켰다. 반응 후 250 ul wash buffer을 이용하여 well을 3회 wash 한다. Well당 200 ul씩 ELISA/ELISASPOT diluent를 넣고 실온에서 1시간동안 반응시켰다. 반응 후 준비한 blank, cytokine IL-21 standard와 sample을 100 ul씩 넣어준 후 well당 100ul씩 ELISA/ELISASPOT diluent를 넣고 plate sealer를 부착하여 상온에서 2시간 반응 시켰다. 반응 후 250ul wash buffer을 이용하여 well을 3회 wash 했다. Well당 100 ul씩 detection antibody를 넣고 plate sealer를 부착하여 상온에서 1시간 반응 시켰다. 반응 후 250 ul wash buffer을 이용하여 well을 3 회 wash 했다. Well당 100 ul씩 Avidin-HRP를 넣고 plate sealer를 부착하여 상온에서 30분 반응 시켯다. 반응 후 250 ul wash buffer을 이용하여 well을 5회 wash 했다. Well당 100 ul씩 1x TMB solution를 넣고 plate sealer를 부착하여 상온에서 30분 반응 시켰다. 반응 후 stop solution 50 ul를 각 well에 넣고 30분 이내에 450nm로 측정했다.
실험 결과
IL-21 유전자를 포함하고 있는 #1, #5, #7, #11 CAR-T 세포에서 IL-21이 분비됨을 확인하였다. U87 cell과 공배양시 더 많은 양의 IL-21이 분비되었으며, 전체적으로 24시간과 48시간에서의 실험 결과 양상이 유사하게 나타난 점으로 보아 배양시간에 따른 차이는 보이지 않았다. 48시간에서의 실험 결과가 24시간에서의 실험 결과에 비해 IL-21의 농도가 높아진 것으로 보아 IL-21의 분비는 꾸준히 진행되는 것으로 보였다 (도 19).
암세포의 환경에서 IL-21의 분비는 선천성 면역 관련 세포들의 활성화를 도와 암세포의 사멸능력을 높일 것으로 판단된다.
실시예 3: 암항원 EGFRvIII 타겟 CAR 및 aVβ 타겟 CAR 벡터 제작
교모세포종과 폐암 등의 주요한 종양 항원(tumor antigen)인 EGFRvIII의 경우, 비특이적 결합을 통해 나타나는 CAR-T 세포의 부작용을 줄이기 위하여 EGFRvIII에 대한 특이성은 유지하면서 EGFR wild type과의 결합력을 최소화하도록 서열번호 33은 먼저 서열번호 3의 52번 내지 57번을 STGGYN에서 DPENDE로 (HEAVY CHAIN CDR2 부분), 서열번호 3의 101번을 S에서 G로 (HEAVY CHAIN CDR3 부분),, 서열번호 3의 229번을 V에서 G로 (LIGHT CHAIN CDR3 부분) 변경시켰다.
인간 CD3(P20963-1), 인간 CD8A(P01732), 인간 4-1BB(Q07011), 인간 CD3Z(P20963), Gaussia princeps luciferase, 그리고 인간 카파 경쇄 신호 서열(HuVHCAMP)을 과학문헌 및 공공이 이용가능한 데이터베이스를 이용하여 최적화 하였으며, codon-optimized synthetic DNA로 구성된 키메라 항원 수용체 함유 폴리펩타이드(서열번호 34 내지 37의 #13, #14, #15, #16) 를 제작하였다.
CAR 함유 폴리펩타이드 #13의 완성된 구조체는 kozak consensus ribosome-binding sequence, CD8A signal sequence, 서열번호 3 EGFRvlll와 결합하는 항원 결합 도메인, CAR 단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 사이에 도입된 3개의 글리신(GGG), 인간 CD8A의 힌지 영역, 인간 CD3 막 통과 도메인, 세포질 4-1BB의 보조 자극 신호 도메인, CD3ζ 세포질 도메인 (서열번호 18) 서열과 XhoI/NotI 절단 부분을 포함한다.
최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(Emtage PC 등, Clin Cancer Res, 2008, 14:8112-8122). 본 실시예에서 키메라 항원 수용체의 활성을 비교하기 위해, YYB105(서열번호 39: PCT 국제공개공보 WO 2017/023138호 참조)를 추가적으로 제작하였다.
CAR 함유 폴리펩타이드 #14의 완성된 구조체는 kozak consensus ribosome-binding sequence, CD8A signal sequence, 서열번호 32 EGFRvlll와 결합하는 항원 결합 도메인, CAR 단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 사이에 3개의 글리신 (GGG)첨가, 인간 CD8A의 힌지 영역, 인간 CD3 막 통과 도메인, 세포질 41BB의 보조 자극 신호 도메인, CD3ζ 세포질 도메인 (서열번호 18) 서열과 XhoI/NotI 절단 부분을 포함한다. 최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(Emtage PC 등, Clin Cancer Res, 2008, 14:8112-8122).
aVβanti-angiogenic의 경우, 이들을 타깃하는 CAR-T 세포에서의 CAR 발현률 및 persistence를 최적화 시켰다. aVβ의 경우, 이들을 타깃하는 CAR-T 세포에서의 CAR 발현률 및 지속성을 Gaussia princeps luciferase signal sequence 또는 CD8 signal sequence를 사용하여 향상시켰다 (서열번호 36과 서열번호 37)
CAR 함유 폴리펩타이드 #15의 완성된 구조체는 kozak consensus ribosome-binding sequence, Gaussia princeps luciferase signal sequence, 서열번호 5 {αVβ와 결합하는 항원 결합 도메인}, CAR 단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 사이에 도입된 3개의 글리신(GGG), 인간 CD8A의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 41BB의 보조 자극 신호 도메인, CD3ζ 세포질 도메인 (서열번호 18) 서열과 XhoI/NotI 절단 부분을 포함한다. 최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(Emtage PC 등, Clin Cancer Res, 2008, 14:8112-8122). 본 실시예에서 키메라 항원 수용체의 활성을 비교하기 위해, YYB107(서열번호 38: PCT 국제공개공보 WO 2017/023138호 참조)를 추가적으로 제작하였다.
#16 완성된 구조체는 kozak consensus ribosome-binding sequence, CD8A signal sequence, 서열번호 5 {αVβ와 결합하는 항원 결합 도메인}, CAR 단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위하여 항원 결합 도메인과 힌지 사이에 3개의 글리신 (GGG)첨가, 인간 CD8A의 힌지 영역, 인간 CD8 막 통과 도메인, 세포질 41BB의 보조 자극 신호 도메인, CD3ζ 세포질 도메인 (서열번호 18) 서열과 XhoI/NotI 절단 부분을 포함한다. 최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(Emtage PC 등, Clin Cancer Res, 2008, 14:8112-8122).
실시예 4: 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 제조
CAR를 발현하는 높은 역가의 PG13 클론은 일시적으로 피닉스-엠포 및 피닉스-에코 세포를 실시예 1 에서 제작된 레트로바이러스 발현 벡터 감염시켰으며, 그 이후에 감염된 피닉스-엠포 및 피닉스-에코 세포로부터 무세포 벡터 스탁을 PG13 세포에 감염시킴으로써 만들었다. 높은 역가의 단일 클론은 anti-myc Ab (BD Pharmingen)를 사용하여 PG13/#13, PG13/#14, PG13/#15, PG13/#16 세포를 염색한 후에 유세포분석기에 의하여 단일 클론을 분리하였다. anti-myc Ab를 이용하여 형질도입된 PG13/#13, PG13/#14, PG13/#15, PG13/#16세포를 유세포 분석기(Flow cytometry analysis)를 사용하여 형질 도입 정도를 분석하였다. 형질도입된 PG13/#13, PG13/#14, PG13/#15, PG13/#16 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 14일 동안 세포를 증식하였다. IL-2를 100IU/mL로 유지하였다. 이러한 방식으로 변형된 T 세포는 분석 실험에 사용되였다.
실험예 1: 키메라 항원 수용체로 형질 변형된 CAR-T 세포의 성장속도 및 생존율 체크
실험결과
상기 실시예 4에서 제조된 T 세포에 대하여 세포 수를 계수하여 CAR-T의 성장속도 및 생존율을 확인하고, 그 결과를 도 20에 나타내었다. 모든 군(#13, #14, #15, #16)의 세포 수, 성장속도는 요일에 따라 대조군인 YYB105 또는 대조군인 YYB107과 비슷했고, 생존율(viability)도 90% 이상으로 나타났다 (도 20).
실험예 2: 키메라 항원 수용체로 형질 변형된 CAR-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-myc 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 체크하였다.
실험결과
실시예 3에서 제조된 4종의 CAR (#13, #14, #15, #16)가 T 세포 표면에서 발현되는지 확인하기 위해 실시예 4에 따라 T 세포 배양을 14일 동안 진행한 후 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다.
분석 결과, 도 21에 도시되어 있는 바와 같이, 살아있는 T 세포 표면에 발현된 키메라 항원 수용체의 발현률이 대조군 YYB105 (37.4%) 보다 #13 (43.0%), #14 (50.8%)로 증가하였다(도 21). 대조군 YYB107 (24.6%) 보다 #15 (45.9%), #16 (40.0%)로 증가하였다(도 21).
본 발명은 암 치료분야에서 급속하게 발전하고 있는 CAR-T 세포에 관한 것으로서, 본 발명에 따른 CAR-T 세포는 발현율 및 지속성이 현저히 우수하여, 고형암 등에 대한 향상된 치료 효과를 가지며, 맞춤형 암 치료분야에서 유용하게 사용될 수 있다.
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 {αVβ와 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 {mesothelin과 결합하는 항원 결합 도메인}
길이: 262
타입: scFv protein
생물명: human
서열:
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CAREGKNGAFDIWGQGTMVTVSS GSTSGSGKPGSGEGSQVQLQQSGPGLVTPSQTLSLTCAISGDSVSSNSATWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRMSINPDTSKNQFSLQLNSVTPEDTAVYYCARGMMTYYYGMDV WGQGTTVTVSSGILGS
서열번호 8 {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 9 {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 10 {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 11 {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 12 {4-1BB}
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 13 {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 14 {IL-7Rα}
길이: 459
타입: protein
생물명: human
서열:
MTILGTTFGMVFSLLQVVSGESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEVKCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYREGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMDPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ
서열번호 15 {IL-7Rα의 일부}
길이: 64
타입: protein
생물명: human
서열:
KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTF
서열번호 16 {IL-2Rβ}
길이: 551
타입: protein
생물명: human
서열:
MAAPALSWRLPLLILLLPLATSWASAAVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDTIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGPREGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV
서열번호 17 {IL-2Rβ의 일부}
길이: 104
타입: protein
생물명: human
서열:
NCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHL
서열번호 18 {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 19 {TGF-βR2 엑소도메인}
길이: 137
타입: protein
생물명: human
서열:
TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPD
서열번호 20 {IL-18R의 막통과 도메인 및 엔도도메인}
길이: 219
타입: protein
생물명: human
서열:
PGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES
서열번호 21 {IL-21}
길이: 133
타입: protein
생물명: human
서열:
QGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 22 {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 23 {#1}
길이: 998
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPREGRGSLLTCGDVEENPGPMALPVTALLLPLALLLHAARPTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSESRRKRSGSGATNFSLLKQAGDVEENPGPMYRMQLLSCIALSLALVTNSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 24 {#2}
길이: 818
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPREGRGSLLTCGDVEENPGPMALPVTALLLPLALLLHAARPTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES
서열번호 25 {#5}
길이: 594
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPREGRGSLLTCGDVEENPGPMYRMQLLSCIALSLALVTNSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 26 {#6}
길이: 423
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPR
서열번호 27 {#7}
길이: 1038
타입: protein
생물명: human
서열:
KMIHQHLSSRTHGSEDS
서열번호 28 {#8}
길이: 858
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELNCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLSLSTATKDTYLPQHMQALPPREGRGSLLTCGDVEENPGPMALPVTALLLPLALLLHAARPTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES
서열번호 29 {#11}
길이: 634
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELNCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLSLSTATKDTYLPQHMQALPPREGRGSLLTCGDVEENPGPMYRMQLLSCIALSLALVTNSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 30 {#12}
길이: 463
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELNCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLSLSTATKDTYLPQHMQALPPR
서열번호 31 {mutated 3rd ITAM-1}
길이: 23
타입: protein
생물명: human
서열:
Y L P Q S T A T K D T Y D Y V T M Q A L P P R
서열번호 32 {mutated 3rd ITAM-2}
길이: 23
타입: protein
생물명: human
서열:
Y L S L S T A T K D T Y L P Q H M Q A L P P R
서열번호 33 {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 D P E N D E 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 G 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 G P L T F G G G T K V E I K E Q K L I S E E D L
서열번호 34 {#13}
길이: 499
타입: protein
생물명: human
서열:
M A L P V T A L L L P L A L L L H A A R P 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 35 {#14}
길이: 499
타입: protein
생물명: human
서열:
M A L P V T A L L L P L A L L L H A A R P 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 D P E N D E 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 G 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 G 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 36 {#15}
길이: 349
타입: protein
생물명: human
서열:
M G V K V L F A L I C I A V A E A 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 37 {#16}
길이: 353
타입: protein
생물명: human
서열:
M A L P V T A L L L P L A L L L H A A R P 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 38 {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 39 {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 40 {T2A 펩타이드}
길이: 21
타입: protein
생물명: human
서열:
GSG E G R G S L L T C G D V E E N P G P
서열번호 41 {P2A 펩타이드}
길이: 22
타입: protein
생물명: human
서열:
GSG A T N F S L L K Q A G D V E E N P G P
서열번호 42 {E2A 펩타이드}
길이: 23
타입: protein
생물명: human
서열:
GSG Q C T N Y A L L K L A G D V E S N P G P
서열번호 43 {F2A 펩타이드}
길이: 25
타입: protein
생물명: human
서열:
GSG V K Q T L N F D L L K L A G D V E S N P G P
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 {αVβ와 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 {mesothelin과 결합하는 항원 결합 도메인}
길이: 262
타입: scFv protein
생물명: human
서열:
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CAREGKNGAFDIWGQGTMVTVSS GSTSGSGKPGSGEGSQVQLQQSGPGLVTPSQTLSLTCAISGDSVSSNSATWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRMSINPDTSKNQFSLQLNSVTPEDTAVYYCARGMMTYYYGMDV WGQGTTVTVSSGILGS
서열번호 8 {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 9 {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 10 {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 11 {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 12 {4-1BB}
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 13 {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 14 {IL-7Rα}
길이: 459
타입: protein
생물명: human
서열:
MTILGTTFGMVFSLLQVVSGESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEVKCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYREGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMDPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ
서열번호 15 {IL-7Rα의 일부}
길이: 64
타입: protein
생물명: human
서열:
KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTF
서열번호 16 {IL-2Rβ}
길이: 551
타입: protein
생물명: human
서열:
MAAPALSWRLPLLILLLPLATSWASAAVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDTIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGPREGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV
서열번호 17 {IL-2Rβ의 일부}
길이: 104
타입: protein
생물명: human
서열:
NCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHL
서열번호 18 {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 19 {TGF-βR2 엑소도메인}
길이: 137
타입: protein
생물명: human
서열:
TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPD
서열번호 20 {IL-18R의 막통과 도메인 및 엔도도메인}
길이: 219
타입: protein
생물명: human
서열:
PGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES
서열번호 21 {IL-21}
길이: 133
타입: protein
생물명: human
서열:
QGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 22 {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 23 {#1}
길이: 998
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPREGRGSLLTCGDVEENPGPMALPVTALLLPLALLLHAARPTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSESRRKRSGSGATNFSLLKQAGDVEENPGPMYRMQLLSCIALSLALVTNSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 24 {#2}
길이: 818
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPREGRGSLLTCGDVEENPGPMALPVTALLLPLALLLHAARPTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES
서열번호 25 {#5}
길이: 594
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPREGRGSLLTCGDVEENPGPMYRMQLLSCIALSLALVTNSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 26 {#6}
길이: 423
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLPQSTATKDTYDYVTMQALPPR
서열번호 27 {#7}
길이: 1038
타입: protein
생물명: human
서열:
KMIHQHLSSRTHGSEDS
서열번호 28 {#8}
길이: 858
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELNCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLSLSTATKDTYLPQHMQALPPREGRGSLLTCGDVEENPGPMALPVTALLLPLALLLHAARPTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES
서열번호 29 {#11}
길이: 634
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELNCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLSLSTATKDTYLPQHMQALPPREGRGSLLTCGDVEENPGPMYRMQLLSCIALSLALVTNSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
서열번호 30 {#12}
길이: 463
타입: protein
생물명: human
서열:
MGWSCIILFLVATATGVHSGPVPPSTALRKLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQDMLDGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGQFNGGGPRKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELNCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYLSLSTATKDTYLPQHMQALPPR
서열번호 31 {mutated 3rd ITAM-1}
길이: 23
타입: protein
생물명: human
서열:
Y L P Q S T A T K D T Y D Y V T M Q A L P P R
서열번호 32 {mutated 3rd ITAM-2}
길이: 23
타입: protein
생물명: human
서열:
Y L S L S T A T K D T Y L P Q H M Q A L P P R
서열번호 33 {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 D P E N D E 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 G 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 G P L T F G G G T K V E I K E Q K L I S E E D L
서열번호 34 {#13}
길이: 499
타입: protein
생물명: human
서열:
M A L P V T A L L L P L A L L L H A A R P 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 35 {#14}
길이: 499
타입: protein
생물명: human
서열:
M A L P V T A L L L P L A L L L H A A R P 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 D P E N D E 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 G 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 G 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 36 {#15}
길이: 349
타입: protein
생물명: human
서열:
M G V K V L F A L I C I A V A E A 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 37 {#16}
길이: 353
타입: protein
생물명: human
서열:
M A L P V T A L L L P L A L L L H A A R P 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 38 {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 39 {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 40 {T2A 펩타이드}
길이: 21
타입: protein
생물명: human
서열:
GSG E G R G S L L T C G D V E E N P G P
서열번호 41 {P2A 펩타이드}
길이: 22
타입: protein
생물명: human
서열:
GSG A T N F S L L K Q A G D V E E N P G P
서열번호 42 {E2A 펩타이드}
길이: 23
타입: protein
생물명: human
서열:
GSG Q C T N Y A L L K L A G D V E S N P G P
서열번호 43 {F2A 펩타이드}
길이: 25
타입: protein
생물명: human
서열:
GSG V K Q T L N F D L L K L A G D V E S N P G P
<110> KONG, Seogkyoung
<120> CHIMERIC ANTIGEN RECEPTORS AND T CELLS EXPRESSING THE CHIMERIC
ANTIGEN RECEPTOR FOR SOLID TUMORS
<130> KR18P0902pct
<150> US 62/727254
<151> 2018-09-05
<160> 43
<170> KoPatentIn 3.0
<210> 1
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> antigen binding wild type IL13 domain binding to IL13Ra2
<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> Artificial Sequence
<220>
<223> antigen binding domain capable of binding to an antigen
associated with an angiogenic activity
<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> Artificial Sequence
<220>
<223> antigen binding domain binding to EGFRvIII
<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> Artificial Sequence
<220>
<223> antigen binding domain binding to EphA2
<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> Artificial Sequence
<220>
<223> antigen binding domain binding to alphaVbeta3
<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> Artificial Sequence
<220>
<223> antigen binding domain binding to glypican one
<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> 262
<212> PRT
<213> Artificial Sequence
<220>
<223> antigen binding domain binding to mesothelin
<400> 7
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro
115 120 125
Gly Ser Gly Glu Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Pro Gly
130 135 140
Leu Val Thr Pro Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly
145 150 155 160
Asp Ser Val Ser Ser Asn Ser Ala Thr Trp Asn Trp Ile Arg Gln Ser
165 170 175
Pro Ser Arg Gly Leu Glu Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys
180 185 190
Trp Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Met Ser Ile Asn
195 200 205
Pro Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr
210 215 220
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Met Met Thr Tyr
225 230 235 240
Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
245 250 255
Ser Gly Ile Leu Gly Ser
260
<210> 8
<211> 47
<212> PRT
<213> Artificial Sequence
<220>
<223> hinge region sequence 1
<400> 8
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> 9
<211> 45
<212> PRT
<213> Artificial Sequence
<220>
<223> hinge region sequence 2
<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 Ala Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
35 40 45
<210> 10
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> transmembrane domain sequence 1
<400> 10
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> 11
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> transmembrane domain sequence 2
<400> 11
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> 12
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> 4-1BB
<400> 12
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> 13
<211> 41
<212> PRT
<213> Artificial Sequence
<220>
<223> wild type CD28
<400> 13
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> 14
<211> 459
<212> PRT
<213> Artificial Sequence
<220>
<223> IL7Ra
<400> 14
Met Thr Ile Leu Gly Thr Thr Phe Gly Met Val Phe Ser Leu Leu Gln
1 5 10 15
Val Val Ser Gly Glu Ser Gly Tyr Ala Gln Asn Gly Asp Leu Glu Asp
20 25 30
Ala Glu Leu Asp Asp Tyr Ser Phe Ser Cys Tyr Ser Gln Leu Glu Val
35 40 45
Asn Gly Ser Gln His Ser Leu Thr Cys Ala Phe Glu Asp Pro Asp Val
50 55 60
Asn Ile Thr Asn Leu Glu Phe Glu Ile Cys Gly Ala Leu Val Glu Val
65 70 75 80
Lys Cys Leu Asn Phe Arg Lys Leu Gln Glu Ile Tyr Phe Ile Glu Thr
85 90 95
Lys Lys Phe Leu Leu Ile Gly Lys Ser Asn Ile Cys Val Lys Val Gly
100 105 110
Glu Lys Ser Leu Thr Cys Lys Lys Ile Asp Leu Thr Thr Ile Val Lys
115 120 125
Pro Glu Ala Pro Phe Asp Leu Ser Val Val Tyr Arg Glu Gly Ala Asn
130 135 140
Asp Phe Val Val Thr Phe Asn Thr Ser His Leu Gln Lys Lys Tyr Val
145 150 155 160
Lys Val Leu Met His Asp Val Ala Tyr Arg Gln Glu Lys Asp Glu Asn
165 170 175
Lys Trp Thr His Val Asn Leu Ser Ser Thr Lys Leu Thr Leu Leu Gln
180 185 190
Arg Lys Leu Gln Pro Ala Ala Met Tyr Glu Ile Lys Val Arg Ser Ile
195 200 205
Pro Asp His Tyr Phe Lys Gly Phe Trp Ser Glu Trp Ser Pro Ser Tyr
210 215 220
Tyr Phe Arg Thr Pro Glu Ile Asn Asn Ser Ser Gly Glu Met Asp Pro
225 230 235 240
Ile Leu Leu Thr Ile Ser Ile Leu Ser Phe Phe Ser Val Ala Leu Leu
245 250 255
Val Ile Leu Ala Cys Val Leu Trp Lys Lys Arg Ile Lys Pro Ile Val
260 265 270
Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys
275 280 285
Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu
290 295 300
Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp Glu Val
305 310 315 320
Glu Gly Phe Leu Gln Asp Thr Phe Pro Gln Gln Leu Glu Glu Ser Glu
325 330 335
Lys Gln Arg Leu Gly Gly Asp Val Gln Ser Pro Asn Cys Pro Ser Glu
340 345 350
Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg Asp Ser Ser Leu Thr
355 360 365
Cys Leu Ala Gly Asn Val Ser Ala Cys Asp Ala Pro Ile Leu Ser Ser
370 375 380
Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly Pro His Val
385 390 395 400
Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser Thr Leu Pro
405 410 415
Pro Pro Phe Ser Leu Gln Ser Gly Ile Leu Thr Leu Asn Pro Val Ala
420 425 430
Gln Gly Gln Pro Ile Leu Thr Ser Leu Gly Ser Asn Gln Glu Glu Ala
435 440 445
Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln
450 455
<210> 15
<211> 64
<212> PRT
<213> Artificial Sequence
<220>
<223> part of IL7Ra
<400> 15
Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys
1 5 10 15
Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val
20 25 30
Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp
35 40 45
Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp Thr Phe
50 55 60
<210> 16
<211> 551
<212> PRT
<213> Artificial Sequence
<220>
<223> IL2Rb
<400> 16
Met Ala Ala Pro Ala Leu Ser Trp Arg Leu Pro Leu Leu Ile Leu Leu
1 5 10 15
Leu Pro Leu Ala Thr Ser Trp Ala Ser Ala Ala Val Asn Gly Thr Ser
20 25 30
Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp
35 40 45
Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp
50 55 60
Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser
65 70 75 80
Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln
85 90 95
Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu
100 105 110
Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu
115 120 125
Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu
130 135 140
Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr
145 150 155 160
Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His
165 170 175
Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp
180 185 190
Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val
195 200 205
Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser
210 215 220
Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr
225 230 235 240
Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu Ser Gly Ala Phe Gly
245 250 255
Phe Ile Ile Leu Val Tyr Leu Leu Ile Asn Cys Arg Asn Thr Gly Pro
260 265 270
Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe
275 280 285
Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu
290 295 300
Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro
305 310 315 320
Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu
325 330 335
Leu Leu Gln Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn
340 345 350
His Ser Leu Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His
355 360 365
Leu Pro Asp Ala Leu Glu Ile Glu Ala Cys Gln Val Tyr Phe Thr Tyr
370 375 380
Asp Pro Tyr Ser Glu Glu Asp Pro Asp Glu Gly Val Ala Gly Ala Pro
385 390 395 400
Thr Gly Ser Ser Pro Gln Pro Leu Gln Pro Leu Ser Gly Glu Asp Asp
405 410 415
Ala Tyr Cys Thr Phe Pro Ser Arg Asp Asp Leu Leu Leu Phe Ser Pro
420 425 430
Ser Leu Leu Gly Gly Pro Ser Pro Pro Ser Thr Ala Pro Gly Gly Ser
435 440 445
Gly Ala Gly Glu Glu Arg Met Pro Pro Ser Leu Gln Glu Arg Val Pro
450 455 460
Arg Asp Trp Asp Pro Gln Pro Leu Gly Pro Pro Thr Pro Gly Val Pro
465 470 475 480
Asp Leu Val Asp Phe Gln Pro Pro Pro Glu Leu Val Leu Arg Glu Ala
485 490 495
Gly Glu Glu Val Pro Asp Ala Gly Pro Arg Glu Gly Val Ser Phe Pro
500 505 510
Trp Ser Arg Pro Pro Gly Gln Gly Glu Phe Arg Ala Leu Asn Ala Arg
515 520 525
Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly
530 535 540
Gln Asp Pro Thr His Leu Val
545 550
<210> 17
<211> 104
<212> PRT
<213> Artificial Sequence
<220>
<223> part of IL2Rb
<400> 17
Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn
1 5 10 15
Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His Gly
20 25 30
Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe
35 40 45
Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu Glu Val Leu Glu
50 55 60
Arg Asp Lys Val Thr Gln Leu Leu Leu Gln Gln Asp Lys Val Pro Glu
65 70 75 80
Pro Ala Ser Leu Ser Ser Asn His Ser Leu Thr Ser Cys Phe Thr Asn
85 90 95
Gln Gly Tyr Phe Phe Phe His Leu
100
<210> 18
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> CD3zeta
<400> 18
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> 19
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> TGF bR2 exodomain
<400> 19
Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val
1 5 10 15
Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys
20 25 30
Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn
35 40 45
Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala
50 55 60
Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His
65 70 75 80
Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser
85 90 95
Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe
100 105 110
Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser
115 120 125
Glu Glu Tyr Asn Thr Ser Asn Pro Asp
130 135
<210> 20
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> transmembrane domain and endodomain of IL18R
<400> 20
Pro Gly His Val Phe Thr Arg Gly Met Ile Ile Ala Val Leu Ile Leu
1 5 10 15
Val Ala Val Val Cys Leu Val Thr Val Cys Val Ile Tyr Arg Val Asp
20 25 30
Leu Val Leu Phe Tyr Arg His Leu Thr Arg Arg Asp Glu Thr Leu Thr
35 40 45
Asp Gly Lys Thr Tyr Asp Ala Phe Val Ser Tyr Leu Lys Glu Cys Arg
50 55 60
Pro Glu Asn Gly Glu Glu His Thr Phe Ala Val Glu Ile Leu Pro Arg
65 70 75 80
Val Leu Glu Lys His Phe Gly Tyr Lys Leu Cys Ile Phe Glu Arg Asp
85 90 95
Val Val Pro Gly Gly Ala Val Val Asp Glu Ile His Ser Leu Ile Glu
100 105 110
Lys Ser Arg Arg Leu Ile Ile Val Leu Ser Lys Ser Tyr Met Ser Asn
115 120 125
Glu Val Arg Tyr Glu Leu Glu Ser Gly Leu His Glu Ala Leu Val Glu
130 135 140
Arg Lys Ile Lys Ile Ile Leu Ile Glu Phe Thr Pro Val Thr Asp Phe
145 150 155 160
Thr Phe Leu Pro Gln Ser Leu Lys Leu Leu Lys Ser His Arg Val Leu
165 170 175
Lys Trp Lys Ala Asp Lys Ser Leu Ser Tyr Asn Ser Arg Phe Trp Lys
180 185 190
Asn Leu Leu Tyr Leu Met Pro Ala Lys Thr Val Lys Pro Gly Arg Asp
195 200 205
Glu Pro Glu Val Leu Pro Val Leu Ser Glu Ser
210 215
<210> 21
<211> 133
<212> PRT
<213> Artificial Sequence
<220>
<223> IL21
<400> 21
Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
<210> 22
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB 103 CAR
<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 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> 23
<211> 998
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 1
<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 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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro
245 250 255
Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro
260 265 270
Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys
275 280 285
Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly
290 295 300
Phe Leu Gln Asp Thr Phe Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
305 310 315 320
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
325 330 335
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
340 345 350
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
355 360 365
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
370 375 380
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
385 390 395 400
Tyr Leu Pro Gln Ser Thr Ala Thr Lys Asp Thr Tyr Asp Tyr Val Thr
405 410 415
Met Gln Ala Leu Pro Pro Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys
420 425 430
Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala
435 440 445
Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Thr Ile
450 455 460
Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp
465 470 475 480
Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val
485 490 495
Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser
500 505 510
Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp
515 520 525
Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro
530 535 540
Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys
545 550 555 560
Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys
565 570 575
Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu
580 585 590
Tyr Asn Thr Ser Asn Pro Asp Pro Gly His Val Phe Thr Arg Gly Met
595 600 605
Ile Ile Ala Val Leu Ile Leu Val Ala Val Val Cys Leu Val Thr Val
610 615 620
Cys Val Ile Tyr Arg Val Asp Leu Val Leu Phe Tyr Arg His Leu Thr
625 630 635 640
Arg Arg Asp Glu Thr Leu Thr Asp Gly Lys Thr Tyr Asp Ala Phe Val
645 650 655
Ser Tyr Leu Lys Glu Cys Arg Pro Glu Asn Gly Glu Glu His Thr Phe
660 665 670
Ala Val Glu Ile Leu Pro Arg Val Leu Glu Lys His Phe Gly Tyr Lys
675 680 685
Leu Cys Ile Phe Glu Arg Asp Val Val Pro Gly Gly Ala Val Val Asp
690 695 700
Glu Ile His Ser Leu Ile Glu Lys Ser Arg Arg Leu Ile Ile Val Leu
705 710 715 720
Ser Lys Ser Tyr Met Ser Asn Glu Val Arg Tyr Glu Leu Glu Ser Gly
725 730 735
Leu His Glu Ala Leu Val Glu Arg Lys Ile Lys Ile Ile Leu Ile Glu
740 745 750
Phe Thr Pro Val Thr Asp Phe Thr Phe Leu Pro Gln Ser Leu Lys Leu
755 760 765
Leu Lys Ser His Arg Val Leu Lys Trp Lys Ala Asp Lys Ser Leu Ser
770 775 780
Tyr Asn Ser Arg Phe Trp Lys Asn Leu Leu Tyr Leu Met Pro Ala Lys
785 790 795 800
Thr Val Lys Pro Gly Arg Asp Glu Pro Glu Val Leu Pro Val Leu Ser
805 810 815
Glu Ser Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu
820 825 830
Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Tyr Arg
835 840 845
Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu Val Thr Asn
850 855 860
Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp
865 870 875 880
Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe
885 890 895
Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe
900 905 910
Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn
915 920 925
Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro
930 935 940
Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser
945 950 955 960
Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe
965 970 975
Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr
980 985 990
His Gly Ser Glu Asp Ser
995
<210> 24
<211> 818
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 2
<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 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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro
245 250 255
Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro
260 265 270
Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys
275 280 285
Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly
290 295 300
Phe Leu Gln Asp Thr Phe Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
305 310 315 320
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
325 330 335
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
340 345 350
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
355 360 365
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
370 375 380
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
385 390 395 400
Tyr Leu Pro Gln Ser Thr Ala Thr Lys Asp Thr Tyr Asp Tyr Val Thr
405 410 415
Met Gln Ala Leu Pro Pro Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys
420 425 430
Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala
435 440 445
Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Thr Ile
450 455 460
Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp
465 470 475 480
Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val
485 490 495
Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser
500 505 510
Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp
515 520 525
Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro
530 535 540
Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys
545 550 555 560
Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys
565 570 575
Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu
580 585 590
Tyr Asn Thr Ser Asn Pro Asp Pro Gly His Val Phe Thr Arg Gly Met
595 600 605
Ile Ile Ala Val Leu Ile Leu Val Ala Val Val Cys Leu Val Thr Val
610 615 620
Cys Val Ile Tyr Arg Val Asp Leu Val Leu Phe Tyr Arg His Leu Thr
625 630 635 640
Arg Arg Asp Glu Thr Leu Thr Asp Gly Lys Thr Tyr Asp Ala Phe Val
645 650 655
Ser Tyr Leu Lys Glu Cys Arg Pro Glu Asn Gly Glu Glu His Thr Phe
660 665 670
Ala Val Glu Ile Leu Pro Arg Val Leu Glu Lys His Phe Gly Tyr Lys
675 680 685
Leu Cys Ile Phe Glu Arg Asp Val Val Pro Gly Gly Ala Val Val Asp
690 695 700
Glu Ile His Ser Leu Ile Glu Lys Ser Arg Arg Leu Ile Ile Val Leu
705 710 715 720
Ser Lys Ser Tyr Met Ser Asn Glu Val Arg Tyr Glu Leu Glu Ser Gly
725 730 735
Leu His Glu Ala Leu Val Glu Arg Lys Ile Lys Ile Ile Leu Ile Glu
740 745 750
Phe Thr Pro Val Thr Asp Phe Thr Phe Leu Pro Gln Ser Leu Lys Leu
755 760 765
Leu Lys Ser His Arg Val Leu Lys Trp Lys Ala Asp Lys Ser Leu Ser
770 775 780
Tyr Asn Ser Arg Phe Trp Lys Asn Leu Leu Tyr Leu Met Pro Ala Lys
785 790 795 800
Thr Val Lys Pro Gly Arg Asp Glu Pro Glu Val Leu Pro Val Leu Ser
805 810 815
Glu Ser
<210> 25
<211> 594
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 5
<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 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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro
245 250 255
Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro
260 265 270
Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys
275 280 285
Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly
290 295 300
Phe Leu Gln Asp Thr Phe Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
305 310 315 320
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
325 330 335
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
340 345 350
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
355 360 365
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
370 375 380
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
385 390 395 400
Tyr Leu Pro Gln Ser Thr Ala Thr Lys Asp Thr Tyr Asp Tyr Val Thr
405 410 415
Met Gln Ala Leu Pro Pro Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys
420 425 430
Gly Asp Val Glu Glu Asn Pro Gly Pro Met Tyr Arg Met Gln Leu Leu
435 440 445
Ser Cys Ile Ala Leu Ser Leu Ala Leu Val Thr Asn Ser Gln Gly Gln
450 455 460
Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln
465 470 475 480
Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro
485 490 495
Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln
500 505 510
Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile
515 520 525
Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala
530 535 540
Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr
545 550 555 560
Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu
565 570 575
Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu
580 585 590
Asp Ser
<210> 26
<211> 423
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 6
<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 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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro
245 250 255
Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro
260 265 270
Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys
275 280 285
Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly
290 295 300
Phe Leu Gln Asp Thr Phe Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
305 310 315 320
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
325 330 335
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
340 345 350
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
355 360 365
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
370 375 380
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
385 390 395 400
Tyr Leu Pro Gln Ser Thr Ala Thr Lys Asp Thr Tyr Asp Tyr Val Thr
405 410 415
Met Gln Ala Leu Pro Pro Arg
420
<210> 27
<211> 1038
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 7
<400> 27
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 Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys
245 250 255
Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln
260 265 270
Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro
275 280 285
Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser
290 295 300
Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Gln
305 310 315 320
Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn His Ser Leu
325 330 335
Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His Leu Arg Val
340 345 350
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
355 360 365
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
370 375 380
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln
385 390 395 400
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
405 410 415
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
420 425 430
Arg Gly Lys Gly His Asp Gly Leu Tyr Leu Ser Leu Ser Thr Ala Thr
435 440 445
Lys Asp Thr Tyr Leu Pro Gln His Met Gln Ala Leu Pro Pro Arg Glu
450 455 460
Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly
465 470 475 480
Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu
485 490 495
Leu His Ala Ala Arg Pro Thr Ile Pro Pro His Val Gln Lys Ser Val
500 505 510
Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro
515 520 525
Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln
530 535 540
Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro
545 550 555 560
Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr
565 570 575
Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile
580 585 590
Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys
595 600 605
Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn
610 615 620
Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Pro
625 630 635 640
Gly His Val Phe Thr Arg Gly Met Ile Ile Ala Val Leu Ile Leu Val
645 650 655
Ala Val Val Cys Leu Val Thr Val Cys Val Ile Tyr Arg Val Asp Leu
660 665 670
Val Leu Phe Tyr Arg His Leu Thr Arg Arg Asp Glu Thr Leu Thr Asp
675 680 685
Gly Lys Thr Tyr Asp Ala Phe Val Ser Tyr Leu Lys Glu Cys Arg Pro
690 695 700
Glu Asn Gly Glu Glu His Thr Phe Ala Val Glu Ile Leu Pro Arg Val
705 710 715 720
Leu Glu Lys His Phe Gly Tyr Lys Leu Cys Ile Phe Glu Arg Asp Val
725 730 735
Val Pro Gly Gly Ala Val Val Asp Glu Ile His Ser Leu Ile Glu Lys
740 745 750
Ser Arg Arg Leu Ile Ile Val Leu Ser Lys Ser Tyr Met Ser Asn Glu
755 760 765
Val Arg Tyr Glu Leu Glu Ser Gly Leu His Glu Ala Leu Val Glu Arg
770 775 780
Lys Ile Lys Ile Ile Leu Ile Glu Phe Thr Pro Val Thr Asp Phe Thr
785 790 795 800
Phe Leu Pro Gln Ser Leu Lys Leu Leu Lys Ser His Arg Val Leu Lys
805 810 815
Trp Lys Ala Asp Lys Ser Leu Ser Tyr Asn Ser Arg Phe Trp Lys Asn
820 825 830
Leu Leu Tyr Leu Met Pro Ala Lys Thr Val Lys Pro Gly Arg Asp Glu
835 840 845
Pro Glu Val Leu Pro Val Leu Ser Glu Ser Arg Arg Lys Arg Ser Gly
850 855 860
Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu
865 870 875 880
Glu Asn Pro Gly Pro Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala
885 890 895
Leu Ser Leu Ala Leu Val Thr Asn Ser Gln Gly Gln Asp Arg His Met
900 905 910
Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr
915 920 925
Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu
930 935 940
Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu
945 950 955 960
Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile
965 970 975
Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln
980 985 990
Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro
995 1000 1005
Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile
1010 1015 1020
His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser
1025 1030 1035
<210> 28
<211> 858
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 8
<400> 28
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 Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys
245 250 255
Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln
260 265 270
Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro
275 280 285
Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser
290 295 300
Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Gln
305 310 315 320
Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn His Ser Leu
325 330 335
Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His Leu Arg Val
340 345 350
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
355 360 365
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
370 375 380
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln
385 390 395 400
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
405 410 415
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
420 425 430
Arg Gly Lys Gly His Asp Gly Leu Tyr Leu Ser Leu Ser Thr Ala Thr
435 440 445
Lys Asp Thr Tyr Leu Pro Gln His Met Gln Ala Leu Pro Pro Arg Glu
450 455 460
Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly
465 470 475 480
Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu
485 490 495
Leu His Ala Ala Arg Pro Thr Ile Pro Pro His Val Gln Lys Ser Val
500 505 510
Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro
515 520 525
Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln
530 535 540
Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro
545 550 555 560
Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr
565 570 575
Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile
580 585 590
Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys
595 600 605
Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn
610 615 620
Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Pro
625 630 635 640
Gly His Val Phe Thr Arg Gly Met Ile Ile Ala Val Leu Ile Leu Val
645 650 655
Ala Val Val Cys Leu Val Thr Val Cys Val Ile Tyr Arg Val Asp Leu
660 665 670
Val Leu Phe Tyr Arg His Leu Thr Arg Arg Asp Glu Thr Leu Thr Asp
675 680 685
Gly Lys Thr Tyr Asp Ala Phe Val Ser Tyr Leu Lys Glu Cys Arg Pro
690 695 700
Glu Asn Gly Glu Glu His Thr Phe Ala Val Glu Ile Leu Pro Arg Val
705 710 715 720
Leu Glu Lys His Phe Gly Tyr Lys Leu Cys Ile Phe Glu Arg Asp Val
725 730 735
Val Pro Gly Gly Ala Val Val Asp Glu Ile His Ser Leu Ile Glu Lys
740 745 750
Ser Arg Arg Leu Ile Ile Val Leu Ser Lys Ser Tyr Met Ser Asn Glu
755 760 765
Val Arg Tyr Glu Leu Glu Ser Gly Leu His Glu Ala Leu Val Glu Arg
770 775 780
Lys Ile Lys Ile Ile Leu Ile Glu Phe Thr Pro Val Thr Asp Phe Thr
785 790 795 800
Phe Leu Pro Gln Ser Leu Lys Leu Leu Lys Ser His Arg Val Leu Lys
805 810 815
Trp Lys Ala Asp Lys Ser Leu Ser Tyr Asn Ser Arg Phe Trp Lys Asn
820 825 830
Leu Leu Tyr Leu Met Pro Ala Lys Thr Val Lys Pro Gly Arg Asp Glu
835 840 845
Pro Glu Val Leu Pro Val Leu Ser Glu Ser
850 855
<210> 29
<211> 634
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 11
<400> 29
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 Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys
245 250 255
Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln
260 265 270
Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro
275 280 285
Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser
290 295 300
Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Gln
305 310 315 320
Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn His Ser Leu
325 330 335
Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His Leu Arg Val
340 345 350
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
355 360 365
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
370 375 380
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln
385 390 395 400
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
405 410 415
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
420 425 430
Arg Gly Lys Gly His Asp Gly Leu Tyr Leu Ser Leu Ser Thr Ala Thr
435 440 445
Lys Asp Thr Tyr Leu Pro Gln His Met Gln Ala Leu Pro Pro Arg Glu
450 455 460
Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly
465 470 475 480
Pro Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala
485 490 495
Leu Val Thr Asn Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg
500 505 510
Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu
515 520 525
Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu
530 535 540
Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn
545 550 555 560
Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys
565 570 575
Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu
580 585 590
Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe
595 600 605
Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu
610 615 620
Ser Ser Arg Thr His Gly Ser Glu Asp Ser
625 630
<210> 30
<211> 463
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 12
<400> 30
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 Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys
245 250 255
Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln
260 265 270
Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro
275 280 285
Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser
290 295 300
Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Gln
305 310 315 320
Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn His Ser Leu
325 330 335
Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His Leu Arg Val
340 345 350
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
355 360 365
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
370 375 380
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln
385 390 395 400
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
405 410 415
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
420 425 430
Arg Gly Lys Gly His Asp Gly Leu Tyr Leu Ser Leu Ser Thr Ala Thr
435 440 445
Lys Asp Thr Tyr Leu Pro Gln His Met Gln Ala Leu Pro Pro Arg
450 455 460
<210> 31
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> mutated 3rd ITAM 1
<400> 31
Tyr Leu Pro Gln Ser Thr Ala Thr Lys Asp Thr Tyr Asp Tyr Val Thr
1 5 10 15
Met Gln Ala Leu Pro Pro Arg
20
<210> 32
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> mutated 3rd ITAM 2
<400> 32
Tyr Leu Ser Leu Ser Thr Ala Thr Lys Asp Thr Tyr Leu Pro Gln His
1 5 10 15
Met Gln Ala Leu Pro Pro Arg
20
<210> 33
<211> 252
<212> PRT
<213> Artificial Sequence
<220>
<223> antigen binding domain binding to EGFRvIII
<400> 33
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 Asp Pro Glu Asn Asp Glu 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 Gly 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 Gly 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> 34
<211> 499
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 13
<400> 34
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu
20 25 30
Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys
50 55 60
Arg Leu Glu Trp Val Ala Ser Ile Ser Thr Gly Gly Tyr Asn Thr Phe
65 70 75 80
Tyr Ser Asp Asn Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr
100 105 110
Ala Met Tyr Tyr Cys Ala Arg Gly Tyr Ser Ser Thr Ser Phe Ala Met
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Ser Thr
130 135 140
Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Asp Ile Gln Met
145 150 155 160
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
165 170 175
Ile Thr Cys Met Thr Ser Thr Asp Ile Asp Asp Asp Met Asn Trp Tyr
180 185 190
Gln Gln Lys Pro Gly Lys Thr Pro Lys Leu Leu Ile Tyr Glu Gly Asn
195 200 205
Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Asp Phe Ile Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala
225 230 235 240
Thr Tyr Tyr Cys Leu Gln Ser Phe Asn Val Pro Leu Thr Phe Gly Gly
245 250 255
Gly Thr Lys Val Glu Ile Lys Glu Gln Lys Leu Ile Ser Glu Glu Asp
260 265 270
Leu Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
275 280 285
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
290 295 300
Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
305 310 315 320
Asp Phe Ala Leu Ala Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly
325 330 335
Val Ile Leu Thr Ala Leu Phe Leu Arg Val Lys Arg Gly Arg Lys Lys
340 345 350
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
355 360 365
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
370 375 380
Gly Cys Glu Leu Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
385 390 395 400
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
405 410 415
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
420 425 430
Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 35
<211> 499
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 14
<400> 35
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu
20 25 30
Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys
50 55 60
Arg Leu Glu Trp Val Ala Ser Ile Asp Pro Glu Asn Asp Glu Thr Phe
65 70 75 80
Tyr Ser Asp Asn Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr
100 105 110
Ala Met Tyr Tyr Cys Ala Arg Gly Tyr Gly Ser Thr Ser Phe Ala Met
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Ser Thr
130 135 140
Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Asp Ile Gln Met
145 150 155 160
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
165 170 175
Ile Thr Cys Met Thr Ser Thr Asp Ile Asp Asp Asp Met Asn Trp Tyr
180 185 190
Gln Gln Lys Pro Gly Lys Thr Pro Lys Leu Leu Ile Tyr Glu Gly Asn
195 200 205
Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Asp Phe Ile Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala
225 230 235 240
Thr Tyr Tyr Cys Leu Gln Ser Phe Asn Gly Pro Leu Thr Phe Gly Gly
245 250 255
Gly Thr Lys Val Glu Ile Lys Glu Gln Lys Leu Ile Ser Glu Glu Asp
260 265 270
Leu Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
275 280 285
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
290 295 300
Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
305 310 315 320
Asp Phe Ala Leu Ala Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly
325 330 335
Val Ile Leu Thr Ala Leu Phe Leu Arg Val Lys Arg Gly Arg Lys Lys
340 345 350
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
355 360 365
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
370 375 380
Gly Cys Glu Leu Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
385 390 395 400
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
405 410 415
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
420 425 430
Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 36
<211> 349
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 15
<400> 36
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro
20 25 30
Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr
35 40 45
Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu
50 55 60
Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys
65 70 75 80
Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Pro Arg Gly
85 90 95
Asp Trp Asn Glu Gly Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu
100 105 110
Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Gly Pro Arg Lys Pro
115 120 125
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
130 135 140
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
145 150 155 160
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
165 170 175
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
180 185 190
Ile Thr Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
195 200 205
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
210 215 220
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
225 230 235 240
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
245 250 255
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
260 265 270
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
275 280 285
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
290 295 300
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
305 310 315 320
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
325 330 335
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
340 345
<210> 37
<211> 353
<212> PRT
<213> Artificial Sequence
<220>
<223> polypeptide No 16
<400> 37
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Val Ser Asp Val Pro Arg Asp Leu Glu Val Val
20 25 30
Ala Ala Thr Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val
35 40 45
Thr Val Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser
50 55 60
Pro Val Gln Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile
65 70 75 80
Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val
85 90 95
Thr Pro Arg Gly Asp Trp Asn Glu Gly Ser Lys Pro Ile Ser Ile Asn
100 105 110
Tyr Arg Thr Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Gly
115 120 125
Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
130 135 140
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
145 150 155 160
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
165 170 175
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
180 185 190
Leu Ser Leu Val Ile Thr Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
195 200 205
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
210 215 220
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
225 230 235 240
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
245 250 255
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
260 265 270
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
275 280 285
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
290 295 300
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
305 310 315 320
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
325 330 335
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
340 345 350
Arg
<210> 38
<211> 351
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB 107 CAR
<400> 38
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> 39
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB 105 CAR
<400> 39
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> 40
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> T2A peptide
<400> 40
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
1 5 10 15
Glu Asn Pro Gly Pro
20
<210> 41
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> P2A peptide
<400> 41
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
1 5 10 15
Glu Glu Asn Pro Gly Pro
20
<210> 42
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> E2A peptide
<400> 42
Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp
1 5 10 15
Val Glu Ser Asn Pro Gly Pro
20
<210> 43
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> F2A peptide
<400> 43
Gly Ser Gly Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala
1 5 10 15
Gly Asp Val Glu Ser Asn Pro Gly Pro
20 25
Claims (49)
- 항원결합 도메인; 힌지영역; 막통과 도메인; 보조자극 도메인; 및 신호 전달 도메인을 포함하는 키메라 항원 수용체가 포함된 폴리펩타이드로서,
상기 신호 전달 도메인은 CD3ζ 도메인을 포함하는 폴리펩타이드. - 제1항에 있어서, 상기 보조자극 도메인과 상기 CD3ζ 도메인 사이에 IL-7Rα 또는 그의 일부를 포함하는 폴리펩타이드.
- 제1항에 있어서, 상기 보조자극 도메인과 상기 CD3ζ 도메인 사이에 IL-2Rβ 또는 그의 일부를 포함하는 폴리펩타이드.
- 제2항에 있어서, IL-7Rα의 일부는 서열번호 15의 서열인 폴리펩타이드.
- 제3항에 있어서, IL-2Rβ의 일부는 서열번호 17의 서열인 폴리펩타이드.
- 제2항에 있어서, 상기 CD3ζ 도메인 내에는 3개의 ITAM(면역수용체 티로신-기반 활성화 모티프: immunoreceptor tyrosine-based activation motif)가 포함되어 있고,
여기에서, 3번째에 위치한 ITAM 부위의 첫번째 모티프 YxxL이 YxxQ로 치환되고, 두번째 모티프 부위 YxxLHM이 YxYVTM로 치환된 폴리펩타이드. - 제3항에 있어서, 상기 CD3ζ 도메인 내에는 3개의 ITAM(면역수용체 티로신-기반 활성화 모티프: immunoreceptor tyrosine-based activation motif)가 포함되어 있고,
여기에서, 3번째에 위치한 ITAM 부위의 첫번째 모티프 YxxL이 YyyL로 치환되고, 두번째 모티프 YxxL이 YxxQ로 치환된 폴리펩타이드. - 제4항에 있어서, 상기 CD3ζ 도메인 내에는 3개의 ITAM가 포함되어 있고,
여기에서, 3번째에 위치한 ITAM 부위는 서열번호 31의 서열로 돌연변이된 것인 폴리펩타이드. - 제5항에 있어서, 상기 CD3ζ 도메인 내에는 3개의 ITAM가 포함되어 있고,
여기에서, 3번째에 위치한 ITAM 부위는 32의 서열로 돌연변이된 것인 폴리펩타이드. - 제4항 또는 제5항에 있어서, 상기 CD3ζ 도메인은 서열번호 18로 표시되는 서열인 폴리펩타이드.
- 제4항 또는 제5항에 있어서, 상기 3번째에 위치한 ITAM 부위는 서열번호 18로 표시되는 서열의 91번 내지 113번 사이의 서열인 폴리펩타이드.
- 제4항에 있어서,
상기 3번째에 위치한 ITAM 부위의 첫번째 모티프 YxxL은 YxxQ로 치환되고, 두번째 모티프 부위 YxxLHM이 YxYVTM로 치환되며, 여기에서, x는 임의의 아미노산인 폴리펩타이드. - 제5항에 있어서,
상기 3번째에 위치한 ITAM 부위의 첫번째 모티프 YxxL이 YyyL로 치환되고, 두번째 모티프 YxxL은 YxxQ로 치환되며,
여기에서, x, y는 임의의 아미노산인 폴리펩타이드. - 제2항 내지 제7항 중 어느 한 항에 있어서, 추가로 사이토카인을 포함하는 폴리펩타이드.
- 제14항에 있어서, 상기 사이토카인은 IL-21인 폴리펩타이드.
- 제15항에 있어서, 상기 사이토카인은 자기 절단형 펩타이드에 의하여 키메라 항원 수용체와 연결되어 있는 폴리펩타이드.
- 제14항에 있어서, T 세포 내에서 발현된 상기 사이토카인은 상기 키메라 항원 유도체와 분리된 후, T 세포 외부로 분비되는 것을 특징으로 하는 폴리펩타이드.
- 제2항 내지 제7항 중 어느 한 항에 있어서, 추가로 TGF-βR2 엑소도메인 및 IL18R 엔도도메인을 포함하고, 상기 TGF-βR2 엑소도메인과 상기 IL18R 엔도도메인 사이에 IL18R 막통과 도메인을 포함하는 폴리펩타이드.
- 제18항에 있어서, 상기 TGF-βR2 엑소도메인은 자기 절단형 펩타이드에 의하여 키메라 항원 수용체와 연결되어 있는 폴리펩타이드.
- 제19항에 있어서,
T 세포내에서 발현된 TGF-β엑소도메인, IL18R의 막통과 도메인 및 IL18R의 엔도도메인은 상기 키메라 항원 수용체와 분리되고, 이 중 TGF-βR2 도메인은 T 세포의 외부로 노출되며,
T 세포의 외부에 존재하는 TGF-β 가 상기 TGF-β엑소도메인에 결합함에 의하여 상기 IL18R 엔도도메인이 활성화되는 것을 특징으로 하는 폴리펩타이드. - 제18항에 있어서, 추가로 사이토카인을 포함하는 폴리펩타이드.
- 제21항에 있어서, 상기 사이토카인은 IL-21인 폴리펩타이드.
- 제21항에 있어서, 상기 사이토카인은 자기 절단형 펩타이드에 의하여 IL18R의 엔도도메인과 연결되어 있는 폴리펩타이드.
- 제23항에 있어서, T 세포 내에서 발현된 상기 사이토카인은 상기 IL18R의 엔도도메인과 분리된 후, T 세포 외부로 분비되는 것을 특징으로 하는 폴리펩타이드.
- 제2항 또는 제3항에 있어서, 상기 항원 결합 도메인은 IL13Rα2, 혈관 신생 작용과 관련된 항원, EFGRvIII, EphA2, αVβ3, mesothelin, 및 글리피칸(glypican)으로 구성된 군으로부터 선택되는 항원과 결합하는 것인 폴리펩타이드.
- 제1항에 있어서, 상기 보조자극 도메인은 4-1BB 및 CD28 도메인으로 구성된 군으로부터 선택되는 1종 이상을 포함하는 것을 특징으로 하는 폴리펩타이드.
- 서열번호 23 내지 30 및 34 내지 37 중 어느 하나의 서열로 표시되는 폴리펩타이드.
- 제1항 내지 제26항 중 어느 한 항에 있어서, 고형암을 치료하기 위한 폴리펩타이드.
- 제1항 내지 제26항 중 어느 한 항에 따른 키메라 항원 수용체 함유 폴리펩타이드가 발현된 CAR-T 세포.
- 제27항에 따른 키메라 항원 수용체 함유 폴리펩타이드가 발현된 CAR-T 세포.
- 항원결합 도메인; 힌지영역; 막통과 도메인; 보조자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체(CAR)를 발현하는 벡터로서,
상기 CAR 발현 벡터는 CAR를 코딩하는 핵산을 포함하며,
여기에서 상기 CAR 코딩 핵산은 상기 보조자극 도메인을 코딩하는 핵산 및 상기 신호 전달 도메인으로 CD3ζ도메인을 코딩하는 핵산을 포함하되, 추가로 상기 보조자극 도메인을 코딩하는 핵산과 상기 CD3ζ 도메인을 코딩하는 핵산 사이에는 IL-7Rα 또는 그의 일부를 코딩하는 핵산을 포함하는 CAR 발현 벡터. - 항원결합 도메인; 힌지영역; 막통과 도메인; 보조자극 도메인; 및 세포질 신호 도메인을 포함하는 키메라 항원 수용체(CAR)를 발현하는 벡터로서,
상기 CAR 발현 벡터는 CAR를 코딩하는 핵산을 포함하며,
여기에서 상기 CAR 코딩 핵산은 상기 보조자극 도메인을 코딩하는 핵산 및 상기 신호 전달 도메인으로 CD3ζ도메인을 코딩하는 핵산을 포함하되, 추가로 상기 보조자극 도메인을 코딩하는 핵산과 상기 CD3ζ 도메인을 코딩하는 핵산 사이에는 IL-2Rβ 또는 그의 일부를 코딩하는 핵산을 포함하는 CAR 발현 벡터. - 제31항에 있어서, IL-7Rα의 일부는 서열번호 15의 서열인 CAR 발현 벡터.
- 제32항에 있어서, IL-2Rβ의 일부는 서열번호 17의 서열인 CAR 발현 벡터.
- 제31항에 있어서, 상기 CD3ζ 도메인을 코딩하는 핵산은, CD3ζ 도메인 내에 존재하는 3개의 ITAM 중 3번째에 위치한 ITAM 부위의 첫번째 YxxL 및 두번째 YxxLHM이 치환된 CD3ζ 도메인을 코딩하는 핵산인 CAR 발현 벡터.
- 제32항에 있어서, 상기 CD3ζ 도메인을 코딩하는 핵산은, CD3ζ 도메인 내에 존재하는 3개의 ITAM 중 3번째에 위치한 ITAM 부위의 첫번째 YxxL 및 두번째 YxxL이 치환된 CD3ζ 도메인을 코딩하는 핵산인 CAR 발현 벡터.
- 제35항에 있어서, 상기 CD3ζ 도메인을 코딩하는 핵산은
상기 3번째에 위치한 ITAM 부위의 첫번째 모티프 YxxL은 YxxQ로 치환되고, 두번째 모티프 부위 YxxLHM은 YxYVTM로 치환된 CD3ζ 도메인을 코딩하는 핵산이며,
여기에서, x는 임의의 아미노산인 CAR 발현 벡터. - 제36항에 있어서, 상기 CD3ζ 도메인을 코딩하는 핵산은
상기 3번째에 위치한 ITAM 부위의 첫번째 모티프 YxxL은 YyyL로 치환되고, 두번째 모티프 YxxL이 YxxQ로 치환된 CD3ζ 도메인을 코딩하는 핵산이며,
여기에서, x, y는 임의의 아미노산인 CAR 발현 벡터. - 제31항 내지 제36항 중 어느 한 항에 있어서, 추가로 사이토카인 IL-21을 코딩하는 핵산을 더 포함하는 CAR 발현 벡터.
- 제39항에 있어서, 상기 사이토카인 IL-21을 코딩하는 핵산은 자기 절단형 펩타이드를 코딩하는 핵산을 통하여 CAR를 코딩하는 핵산과 연결되어 있는 CAR 발현 벡터.
- 제31항 내지 제36항 중 어느 한에 있어서, 추가로 TGF-βR2 엑소도메인을 코딩하는 핵산과, IL18R의 막통과 도메인 및 IL18R의 엔도도메인을 코딩하는 핵산을 포함하는 CAR 발현 벡터.
- 제41항에 있어서, 상기 TGF-βR2 엑소도메인을 코딩하는 핵산은 자기 절단형 펩타이드를 코딩하는 핵산에 의하여 CAR를 코딩하는 핵산과 연결되는 CAR 발현 벡터.
- 제41항에 있어서, 추가로 사이토카인 IL-21을 코딩하는 핵산을 더 포함하는 CAR발현 벡터.
- 제43항에 있어서, 상기 사이토카인 IL-21을 코딩하는 핵산은, 자기 절단형 펩타이드를 코딩하는 핵산을 통하여 IL18R 엔도도메인 코딩 핵산과 연결되어 있는 CAR 발현 벡터.
- 제31항 내지 제39항 중 어느 한 항에 따른 벡터를 도입하여 제조된 CAR-T 세포.
- 제41항에 따른 벡터를 도입하여 제조된 CAR-T 세포.
- 제43항에 따른 벡터를 도입하여 제조된 CAR-T 세포.
- 제45항에 따른 CAR-T 세포를 함유하는 항암제.
- 제37항 또는 제38항에 있어서, 상기 보조자극 도메인은 4-1BB 및 CD28 도메인으로 이루어진 군으로부터 1종 이상 선택되는 것인 CAR 발현 벡터.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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KR102532266B1 (ko) * | 2022-05-31 | 2023-05-15 | 주식회사 유틸렉스 | 돌연변이 egfr를 타겟하는 키메라 항원 수용체 |
WO2023234461A1 (ko) * | 2022-05-31 | 2023-12-07 | 주식회사 유틸렉스 | 돌연변이 egfr를 타겟하는 키메라 항원 수용체 |
KR102532260B1 (ko) * | 2022-07-07 | 2023-05-16 | 주식회사 유틸렉스 | 돌연변이 EGFR 및 EphA2를 동시 타겟하는 키메라 항원 수용체 |
WO2024010119A1 (ko) * | 2022-07-07 | 2024-01-11 | 주식회사 유틸렉스 | 돌연변이 egfr 및 epha2를 동시 타겟하는 키메라 항원 수용체 |
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US20220387503A1 (en) | 2022-12-08 |
CA3111978A1 (en) | 2020-03-12 |
IL281232A (en) | 2021-04-29 |
EP3848387A4 (en) | 2022-06-22 |
KR20240046644A (ko) | 2024-04-09 |
EP3848387A1 (en) | 2021-07-14 |
JP2021536266A (ja) | 2021-12-27 |
BR112021004289A2 (pt) | 2021-08-03 |
JP2023134640A (ja) | 2023-09-27 |
AU2019336031A1 (en) | 2021-04-15 |
US20230056345A1 (en) | 2023-02-23 |
CN113272318A (zh) | 2021-08-17 |
US20210252069A1 (en) | 2021-08-19 |
US20230055761A1 (en) | 2023-02-23 |
KR102663253B1 (ko) | 2024-05-23 |
KR20240046645A (ko) | 2024-04-09 |
WO2020050667A1 (ko) | 2020-03-12 |
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