KR20230148433A - 키메릭 항원 수용체 및 hgf 중화항체의 조합 요법 - Google Patents
키메릭 항원 수용체 및 hgf 중화항체의 조합 요법 Download PDFInfo
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Abstract
본 발명은 HGF의 중화가능 에피토프에 결합하는 중화 항체와 조합하여 대상체에서 암의 치료에 사용하기 위한 키메릭 항원 수용체(CAR)를 발현하는 면역 이펙터 세포의 집단을 포함하는 CAR 요법제에 관한 것으로서, HGF 중화항체를 조합함으로써 암세포와 면역계의 상호 작용에 있어서 치료효과를 상승시켜 CAR-T 세포치료제의 항암 효과를 증가시켜 혈액암 뿐만 아니라 고형암 치료에 효과적으로 사용될 수 있다.
Description
본 발명은 3세대 면역항암제인 CAR-T 세포치료제의 고형암 예방 또는 치료에 관한 것이다. 구체적으로, 간세포성장인자 (Hepatocyte growth factor, HGF) 중화항체를 조합하여 암세포와 면역계의 상호 작용에 영향을 줌으로써 CAR-T 세포치료제의 항암 효과를 증가시키는 것을 특징으로 한다.
본 발명의 CAR-T 세포치료제는 면역항암제가 활용되기 어렵다고 인식되어 있는 고형암 치료에도 효과적으로 사용될 수 있다.
수십 년 동안 암을 치료하는 방법들은 꾸준히 변화하고 발전해왔다. 1800년대에서부터 1900년대까지는 외과적인 수술 (Surgery), 화학요법 (Chemotherapy), 그리고 방사선 요법 (Radiation therapy)과 같은 방법들이 주로 이뤄졌지만, 이들에 대한 한계점들이 드러나기 시작하여, 최근 면역세포 요법으로 체내의 면역세포를 꺼내서, 강화시키거나 유전공학적으로 변형시켜 다시 넣어주는 세포치료 방식이 개발되고 있다.
보다 구체적으로, 암을 치료하기 위한 1세대 화학항암제의 경우 세포독성물질로 암세포를 공격해 사멸시키는 방법인데, 암세포 뿐만 아니라 정상세포도 같이 손상을 주기 때문에 부작용이 심한 문제가 있다. 이러한 1세대 화학항암제의 단점을 극복하기 위한 2세대 표적항암제의 경우 암세포의 특정 물질을 목표로 공격하기 때문에 1세대 화학항암제에 비해 부작용은 적지만 내성이 생긴다는 큰 단점을 지니고 있다. 반면, 3세대 면역항암제는 우리 몸의 면역체계를 이용하기 때문에 1세대 화학항암제의 독성 문제와 2세대 표적항암제의 내성 문제가 적고 부작용도 현저히 적다. 또한, 2세대 표적항암제는 초기에 높은 생존율을 보이지만, 내성문제로 지속성이 떨어지는 반면 면역항암제는 항암효과가 유지돼 면역항암제에 대한 반응이 좋은 환자는 완치에 가까워진다. 이처럼 3세대 면역항암제는 탁월한 효능과 적은 부작용으로 인해 암환자의 장기 생존율은 물론 암환자의 삶의 질을 높이는데 기여한다.
키메릭 항원 수용체(chimeric antigen receptor, CAR)는 항체의 단편, 힌지 영역, 막통과 도메인 및 세포 내 신호전달 도메인으로 구성되는데, 상기 키메릭 항원 수용체가 발현된 T 세포는 암세포만 공격하게 설계된 면역항암제 중 하나이다. CAR-T 세포치료제는 암세포를 특이적으로 공격하는 면역 T 세포의 공격성을 크게 높였기 때문에 정상세포의 손상은 줄이고 암세포만을 표적 삼아 공격한다는 점에서 매우 중요한 세포치료제이다.
현재까지 CAR T 세포치료제와 같은 면역세포치료가 일부 혈액암에서 높은 완치율을 보였지만, 암 대부분을 차지하는 고형암에서는 제대로 치료효과를 발휘하지 못하였는데, 이는 인체가 강한 면역반응을 억제하는 경향이 있어 투여된 면역세포가 충분히 활동할 수 없기 때문으로 알려져 있다.
이에, 본 발명자들은 CAR-T 세포치료제를 난소암 등 고형암에서도 치료 효과가 발휘될 수 있도록 하는 치료 방법을 연구한 결과, 1세대 화학항암제의 독성 문제와 2세대 표적항암제의 내성 문제가 적은 3세대 면역항암제인 CAR-T 세포치료제에 HGF의 중화가능 에피토프에 결합하는 중화항체를 조합할 경우 CAR-T 세포치료제 단독에 비해 종양 진행의 억제 또는 감소의 개선을 초래할 수 있다는 것을 확인하고, 본 발명을 완성하였다.
따라서, 본 발명은 난소암을 포함한 고형암 치료를 위한 CAR 요법제를 제공하는 것을 해결과제로 하며, HGF의 중화가능 에피토프에 결합하는 중화 항체와 조합하여 대상체에서 암의 치료에 사용하기 위한 키메릭 항원 수용체(CAR)를 발현하는 면역 이펙터 세포의 집단을 포함하는 CAR 요법제를 제공하는 것을 구체적인 해결과제로 한다.
상기 과제를 해결하기 위하여, 본 발명에서는 하기와 같은 수단을 개시한다.
본 발명은 HGF의 중화가능 에피토프에 결합하는 중화 항체와 조합하여 대상체에서 암의 치료에 사용하기 위한 키메릭 항원 수용체(chimeric antigen receptor, CAR)를 발현하는 면역 이펙터 세포의 집단을 포함하는 CAR 요법제를 개시한다.
본 발명에서 CAR는 IL13Rα2 항원 결합 도메인; 힌지 영역; 막관통 도메인; 보조 자극 도메인; 및 세포질 신호 전달 도메인을 포함할 수 있으며, 이에 한정되는 것은 아니다.
상기 CAR는 서열번호 9 또는 서열번호 10의 아미노산 서열로 표시된다.
상기 HGF 중화 항체의 중쇄는 서열번호 13, 경쇄는 서열번호 14의 아미노산 서열로 표시된다. 또한, 공지의 링커 서열이 추가될 수 있다.
본 발명은 HGF의 중화가능 에피토프에 결합하는 중화 항체와 조합하여 대상체에서 암의 치료에 사용하기 위한 키메릭 항원 수용체(CAR)를 발현하는 면역 이펙터 세포의 집단을 포함하는 CAR 요법제를 개시한다.
본 발명에서, 상기 CAR는 항원 결합 도메인; 힌지 영역; 막관통 도메인; 보조 자극 도메인; 및 세포질 신호 전달 도메인을 포함할 수 있으며, 이에 한정되는 것은 아니다.
상기 CAR의 항원 결합 도메인은 CD19, MUC16, MUCl, CAlX, CEA, CDS, CD7, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD133, CD138, 사이토메갈로바이러스(CMV) 감염된 세포 항원, EGP-2, EGP-40, EpCAM, erb-B2,3,4, FBP, 태아 아세틸콜린 수용체, 폴레이트 수용체-a, GD2, GD3, HER-2, hTERT, K-경쇄, KDR, LeY, L1 세포 부착 분자, MAGE-A1, 메소텔린, NKG2D 리간드, NY-ES0-1, 암태아 항원(h5T4), PSCA, PSMA, ROR1, TAG-72, VEGF-R2, WT-1, CD276 또는 IL13Ra2로부터 선택되는 항원과 결합하는 항원 결합 도메인을 포함할 수 있다.
상기 CAR의 막관통 도메인은 T-세포 수용체의 알파, 베타 또는 제타 쇄, CD28, CD3엡실론, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 또는 CD154로부터 선택되는 막관통 도메인을 포함할 수 있다.
상기 CAR의 보조 자극 도메인은 MHC 클래스 I 분자, TNF 수용체 단백질, 이뮤노글로불린-유사 단백질, 시토카인 수용체, 인테그린, 신호전달 림프구성 활성화 분자 (signaling lymphocytic activation molecule, SLAM), 활성화 NK 세포 수용체, BTLA(B an T lymphocyte attenuator), 톨-유사 리간드 수용체(Tolllike ligand receptor), OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8알파, CD8베타, IL2R 베타, IL2R 감마, IL7R 알파, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, 또는 CD83과 특이적으로 결합하는 리간드로부터 선택되는 보조 자극 도메인을 포함할 수 있다.
상기 CAR의 세포질 신호 전달 도메인은 4-1BB, CD28, OX40, CD3ζ의 기능적 신호 전달 도메인, 또는 이들의 조합으로부터 선택되는 세포질 신호 전달 도메인을 포함할 수 있다.
구체적인 양태에서, 본 발명의 CAR는 IL13Rα2 항원 결합 도메인; 힌지 영역; 막관통 도메인; 보조 자극 도메인; 및 세포질 신호 전달 도메인을 포함할 수 있다. 이때, 상기 CAR는 서열번호 9의 아미노산 서열 또는 서열번호 10의 아미노산 서열로 표시될 수 있다.
또한, 본 발명의 HGF 중화항체는 중쇄가 서열번호 13, 경쇄가 서열번호 14의 아미노산 서열로 표시될 수 있다.
본 발명에서 암은 난소암, 유방암, 위암, 폐암, 간암, 담도암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 신장암, 대장암, 결장암, 자궁경부암, 뇌암, 전립선암, 골암, 두경부암, 피부암, 갑상선암, 부갑상선암 또는 요관암일 수 있다.
본 발명에 따른 “키메릭 항원 수용체(chimeric antigen receptor, CAR)”는 항원을 인식하는 항원 결합 도메인; 항원 결합 도메인과 막통과 도메인을 연결하는 힌지 영역(또는 스페이서); 막통과 도메인; 보조 자극 도메인; 및 세포질 신호 도메인으로 구성된 2세대 CAR이다.
본 발명의 CAR 구조에서 항원 결합 도메인은 주신호가 전달되는 부위로 세포막 외부에 있으며 특정 항원을 발현하는 암세포를 인식하는 부분이다. 따라서, CAR-T 세포를 이용한 암 치료에 있어서, 구체적인 치료대상은 항원 결합 도메인에 의하여 결정되는데, 본 발명에서, 이와 같은 항원 결합 도메인에 결합하는 항원은 CD19, MUC16, MUCl, CAlX, CEA, CDS, CD7, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD133, CD138, 사이토메갈로바이러스(CMV) 감염된 세포 항원, EGP-2, EGP-40, EpCAM, erb-B2,3,4, FBP, 태아 아세틸콜린 수용체, 폴레이트 수용체-a, GD2, GD3, HER-2, hTERT, K-경쇄, KDR, LeY, L1 세포 부착 분자, MAGE-A1, 메소텔린, NKG2D 리간드, NY-ES0-1, 암태아 항원(h5T4), PSCA, PSMA, ROR1, TAG-72, VEGF-R2, WT-1, CD276 또는 IL13Ra2가 포함될 수 있으며, 이에 제한되지 않고, 바람직하게는 IL13Rα2에 특이적으로 결합할 수 있는 키메릭 항원 수용체를 개시한다.
본 발명에 따른 CAR에서 IL13Rα2와 결합하는 항원 결합 도메인의 서열은 서열번호 2와 같은데, IL13Rα2와 결합하는 항원 결합 wild type IL-13 서열의 11번, 64번, 67번 및 107번 위치가 각각 E11K.R64D.S67D.R107K로 치환된 돌연변이다. 해당 위치에서 치환되는 아미노산은 상기 특정된 아미노산과 유사한 성질의 아미노산으로 대체될 수 있다.
또한, 본 발명에 따른 CAR는 CAR 단백질의 용해도를 높여 키메릭 항원 수용체의 발현을 증가시키기 위해서 항원 결합 도메인과 힌지 영역 사이에 3개의 글리신을 추가적으로 도입한 것이다. 위 3개의 글리신(G)은 이와 유사한 성질의 아미노산인 알라닌(A), 발린(V), 류신(L) 또는 이소류신(I)으로 치환될 수 있다.
본 발명에 따른 CAR의 보조 자극 도메인은 보조 자극 신호가 전달되는 부위로서 항원 결합 도메인과 결합한 특정 항원을 인식한 CAR-T 세포가 면역반응을 일으키며 자가 증식을 돕고, 체내에 잔존하는 시간을 늘리도록 신호를 전달하는 역할을 한다. 본 발명에서는 서열번호 6의 보조 자극 도메인을 사용한다.
본 발명에 따른 CAR의 세포질 신호 전달 도메인은 Jurkat T 세포의 CD3ζ 신호전달 도메인이 아닌, 추가의 글루타민이 포함된 정상 인간(normal person)의 CD3ζ 신호전달 도메인을 사용하였고, 상기 추가의 글루타민은 서열번호 7에 있어서 50번 위치의 글루타민(Q)를 의미한다. 또한, CD3ζ는 총 3개의 면역 수용체 티로신 기반 활성화 모티프 (Immunoreceptor tyrosine-based activation motif, ITAM- YxxL/Ix6-8YxxL/I) 서열을 지니고 있는데, 3개의 YxxL/Ix6-8YxxL/I 중 2번째와 3번째의 tyrosine (Y)을 phenylalanine (F)으로 돌연변이(Mutation) 하여 사용될 수 있다 (서열번호 8). 이와 같은 돌연변이는 WO 2019/133969에 개시된 내용으로 제작되었고, 이 전문은 참고로 통합된다.
본 명세서에서 개시하는 도메인을 구성하는 폴리펩타이드의 핵산 서열은 당해 기술분야에 공지된 재조합 방법을 이용하여 수득될 수 있으며, 예를 들어 표준 기법을 이용하여 상기 유전자를 발현하는 세포로부터 라이브러리를 스크리닝하거나, 상기 동일한 유전자를 포함하도록 공지된 벡터로부터 유전자를 유도하거나, 상기 동일한 유전자를 포함하는 세포 및 조직으로부터 직접 단리함으로써 수득될 수 있다. 대안적으로는, 상기 관심이 있는 유전자는 클로닝이 아닌 합성에 의해 생성될 수 있다.
세포 내로 유전자를 도입하고 발현하는 방법은 당해 기술분야에 공지되어 있다. 발현 벡터는 당해 기술분야에 공지된 임의의 방법에 의해 숙주 세포 내로 신속하게 도입될 수 있다. 예를 들면, 본 발명에서는 최종적으로 제작된 CAR 유전자 단편을 BamH1/NotI로 절단된 MFG 레트로바이러스 발현 벡터에 접합시켜 CAR-T 세포를 제조할 수 있다. 본 발명은 구조체의 성분 각각에 대한 다수의 임의의 변이체를 포함하는 것으로 이해되어야 한다.
또한, 본 발명에 따른 CAR는 서열번호 9 또는 서열번호 10의 아미노산 서열로 표시될 수 있으며, 국제공개특허 WO 2017/023138에 개시된 내용을 반영하여 제작되었으며, 이 전문은 참조로 통합된다.
본 발명의 HGF 중화항체는 중화가능 에피토프에 결합하여 HGF를 중화시킬 수 있는 활성을 나타내는 것으로, HGF에 특이적으로 결합하는 항체 또는 그의 항원 결합 단편을 포함한다.
본 발명의 HGF에 특이적으로 결합하는 항체 또는 그의 항원 결합 단편은 서열번호 11의 아미노산 서열로 표시되는 VH 영역 및 서열번호 12의 아미노산 서열로 표시되는 VL 영역을 갖는 것으로, 4개의 프레임워크 영역(framework region; FR)과 3개의 항원결합부위(complementarity determining region; CDR)가 존재(서열번호 15 내지 20)한다.
구체적으로, 본 발명의 CAR 요법제와 조합하여 사용되는 HGF 중화항체의 중쇄는 서열번호 13, 경쇄는 서열번호 14의 아미노산 서열로 표시될 수 있으며, 대한민국 등록특허 제556660호에 개시된 내용으로 제작되었으며, 이 전문은 참조로 통합된다.
본 발명의 CAR 요법제에 의해 예방 또는 치료될 수 있는 암은 당업계에 공지된 다양한 암을 포함하며, 예를 들어 난소암, 유방암, 위암, 폐암, 간암, 담도암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 신장암, 대장암, 결장암, 자궁경부암, 뇌암, 전립선암, 골암, 두경부암, 피부암, 갑상선암, 부갑상선암 또는 요관암을 포함하나, 이에 한정되는 것은 아니다.
구체적으로, 본 발명의 CAR 요법제에 의해 예방 또는 치료될 수 있는 암은 IL13Ra2 를 발현하면서 HGF를 분비하는 암이고, 보다 구체적으로 IL13Ra2를 발현하면서 HGF를 분비하는 난소암이다.
본 발명의 CAR-T 세포치료제는 암 환자에게 주입하기까지는 여러 단계를 거친다. 환자의 혈액에서 백혈구성분 분리채집 과정을 거쳐 T 세포를 추출한 뒤, 발현 벡터를 이용하여 CAR로 디자인된 유전자를 T 세포에 주입하고 이 CAR-T 세포를 증식시킨 후, 이를 환자에게 주입하게 된다.
또한, 본 발명의 HGF 중화항체는 CAR-T 세포치료제 주입과 동시에 또는 순차적으로,예를 들어 임의의 순서로 투여된다. 일 실시형태에서, 조합물은 소정의 치료 간격에서 투여된다. 본 발명의 구체적인 구현예에 따르면, HGF 중화항체의 투여는 CAR-T 세포치료제의 투여 전/후 2주 이내 또는 CAR-T 세포치료제와 동시에 투여된다.
본 발명의 CAR-T 세포치료제 및 HGF 중화항체의 적합한 투여량은 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 본 발명의 구체적인 구현예에 따르면, 본 발명의 CAR-T 세포치료제의 1회 투여량은 1 x 107~108 cells/ kg 이고, HGF 중화항체의 1회 투여량은 10~30 mg/kg 이다.
본 발명에 CAR 요법제는 난소암을 포함하는 고형암의 예방 또는 치료 효과를 나타낸다. 보다 특별하게는, HGF 중화항체를 조합함으로써 암세포와 면역계의 상호 작용에 있어서 치료 효과 상승을 통해 CAR-T 세포치료제의 항암 효과를 증가시켜 난소암을 포함하는 고형암의 예방 또는 치료제로서 유용하게 활용될 수 있다. 특히, 1세대 화학항암제의 독성 문제와 2세대 표적항암제의 내성 문제가 적은 3세대 면역항암제인 CAR-T 세포치료제를 고형암에 활용할 수 있다는 특별한 효과가 있다.
도 1은 난소암 세포주 (A2780)에서 IL13Ra2 (human interleukin 13 receptor alpha 2)발현률을 나타내는 유세포 분석 결과이다.
도 2는 난소암 세포주 (A2780)에서 간세포 성장인자 (Hepatocyte growth factor, HGF) ELISA 분석 결과이다.
도 3은 YYB-103 및 YYB-103-1XX의 구조를 나타낸 도면이다.
도 4는 YYB-103 CAR-T 및 YYB-103-1XX CAR-T 세포의 IL13 발현률을 확인한 유세포 분석 결과이다.
도 5는 CAR-T 또는 YYB-101 단독투여 및 CAR-T와 YYB-101 병용투여에 의한 생존을 관찰한 결과이다.
도 6은 고농도로 CAR-T 단독 투여한 경우 생존을 관찰한 결과이다.
도 7은 본 출원의 YYB-101, YYB-103 및 YYB-103-1XX의 서열에 대한 것이다.
도 2는 난소암 세포주 (A2780)에서 간세포 성장인자 (Hepatocyte growth factor, HGF) ELISA 분석 결과이다.
도 3은 YYB-103 및 YYB-103-1XX의 구조를 나타낸 도면이다.
도 4는 YYB-103 CAR-T 및 YYB-103-1XX CAR-T 세포의 IL13 발현률을 확인한 유세포 분석 결과이다.
도 5는 CAR-T 또는 YYB-101 단독투여 및 CAR-T와 YYB-101 병용투여에 의한 생존을 관찰한 결과이다.
도 6은 고농도로 CAR-T 단독 투여한 경우 생존을 관찰한 결과이다.
도 7은 본 출원의 YYB-101, YYB-103 및 YYB-103-1XX의 서열에 대한 것이다.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.
실시예 1. 난소암 세포주 (A2780)에서 IL13Ra2 (human interleukin 13 receptor alpha 2) 발현 확인
실험 방법
유세포 분석을 위해, FITC-conjugated anti-human IL13Ra2 단일클론 항체 (R&D, Cat. No., FAB614F)를 첨가하기 전 세포를 2% bovine serum albumin을 함유한 PBS에 1회 세척하였다. 세척 후 빛이 차단된 상태에서 4℃, 30 분간 각각의 항체와 반응한 후, 세포를 1회 세정하고, 난소암 세포주 (A2780)에서 IL13Ra2 발현률을 체크하였다. 대조군으로 isotype control 시료 (R&D, Cat. No., IC108F)를 포함시켰다.
실험 결과
실험방법에 따라 난소암 세포주 (A2780)을 이용하여 IL13Ra2 발현률을 확인한 결과를 표 1 및 도 1에 나타내었다. 난소암 세포주 (A2780)의 IL13Ra2의 발현률은 69.1% 이고, 대조군으로 사용한 isotype control의 경우 0.9%로 확인되었다.
난소암 세포주(A2780) | IL13Ra2 발현률 |
Unstained | 0.7% |
Isotype control | 0.9% |
Anti-IL13Ra2 | 69.1% |
실시예 2.
난소암 세포주 (A2780)에서 간세포 성장인자 (Hepatocyte growth factor, HGF) 분석
실험 방법
난소암 세포주 (A2780)에서 간세포 성장인자 (Hepatocyte growth factor, HGF)가 분비되는 양을 확인하기 위해서 2% Fetal bovine serum (FBS, Gibco, 10082-147)가 포함된 RPMI 배지를 이용하여 난소암 세포주 (A2780)을 32℃, 6% CO2 조건에서 2일간 배양하였다. 2일후 배양 배지를 1,500 rpm 조건으로 5분간 원심분리 한 후 상층액을 새로운 1.5 mL tube에 옮겼다. 난소암 세포주 (A2780)에서 분비되는 HGF의 양을 확인하기 위해서 human HGF Quantikine ELISA kit (R&D system, DHG00B)을 이용하였다. ELISA 분석 결과에 대한 대조군으로 난소암 세포주 (A2780)의 배양액인 RPMI을 포함시켰다.
실험 결과
ELISA 분석 결과를 도 2에 나타내었다. 대조군으로 사용한 난소암 세포주 (A2780)의 배양액인 RPMI의 경우 4 ng/mL의 농도로 HGF 양이 확인되었으며, 난소암 세포주 (A2780)의 경우 164 ng/mL 농도로 약 41배 높은 HGF 양이 확인되었다.
실시예 1 및 실시예 2의 결과를 종합하여, IL13Ra2 발현 및 HGF를 분비하는 난소암 세포주 (A2780)가 YYB-103 CAR-T 세포와 YYB-101의 병용 시험을 위해 선정되었다.
실시예 3. YYB-103 그리고 YYB-103-1XX 유전자 발현 T세포의 제작
YYB-103 발현 T 세포의 제작
IL13Ra2에 특이적으로 결합하는 2세대 (IL13.E11K.R64D.S67D.R107K.TNFRSF9.CD3ζ) 키메릭 항원 수용체인 YYB-103은 항원 결합 도메인과 힌지 영역 사이에 추가로 3개의 글리신(G)이 도입되어 있으며, 항원 결합 도메인은 IL13Rα2와 결합하되, 서열번호 2와 같이 IL13Rα2와 결합하는 항원 결합 wild type IL-13 서열의 11번, 64번, 67번 및 107번 위치가 각각 리신(K), 아스파르트산(D), 아스파르트산(D) 및 리신(K)으로 치환되었다(서열번호 9). YYB-103 발현 T 세포는 국제공개특허 WO2017/023138에 개시된 내용으로 제작되었으며(도 3), 이 전문은 참조로 통합된다.
YYB-103-1XX 발현 T 세포의 제작
T 세포의 구성요소인 CD3ζ 는 총 3개의 면역 수용체 티로신 기반 활성화 모티프 (Immunoreceptor tyrosine-based activation motif, ITAM- YxxL/Ix6-8YxxL/I) 서열을 지니고 있는데, YYB-103-1XX는 YYB-103의 3개의 YxxL/Ix6-8YxxL/I 중 2번째와 3번째의 tyrosine (Y)을 phenylalanine (F)로 돌연변이(Mutation) 하였다(서열번호 10). YYB-103-1XX는 국제공개특허 WO 2019/133969에 개시된 내용으로 제작되었고(도 3), YYB-103-1XX 발현 T 세포는 국제공개특허 WO2017/023138에 개시된 내용으로 제작되었으며, 이 전문들은 참고로 통합된다.
실험방법
T 세포 배양 배지에 배양 중인 YYB-103 CAR-T 및 YYB-103-1XX CAR-T (공여자 번호, YY93) 1 x 106 세포를 원심분리 하였다. 그 후 상층액을 제거하고, 2% bovine serum albumin을 함유한 PBS을 이용하여 YYB-103 CAR-T 및 YYB-103-1XX CAR-T 세포를 2회 세척하였다. 세척이 완료된 후 형질 도입된 T 세포의 발현은 IL13을 통해서 YYB-103 CAR-T 및 YYB-103-1XX CAR-T의 surface IL13 발현을 유세포 분석을 통해 체크하였으며, 그 결과는 표 2 및 도 4에 나타내었다. 유세포 분석 결과에 대한 대조군으로 YYB-103 CAR 또는 YYB-103-1XX CAR 바이러스에 형질도입 되지 않은 (Untransduced T 세포) 시료를 포함시켰다.
공여자 번호 (YY93) | CAR-T 발현 (%, IL13) |
Untransduced T 세포 | 0.3 |
YYB-103 CAR-T | 60.6 |
YYB-103-1XX CAR-T | 54.9 |
실험 결과
YYB-103 CAR-T 또는 YYB-103-1XX CAR-T 세포 (공여자 번호, YY93)의 발현을 확인하기 위해서 유세포 분석을 진행한 결과, YYB-103 CAR 또는 YYB-103-1XX CAR에 형질도입 되지 않은 untransduced T 세포의 IL13 발현은 DAY 11에서 0.3% 이하로 IL13이 발현하지 않았는데 반해, YYB-103 CAR-T 또는 YYB-103-1XX CAR-T 세포의 IL13의 발현률은 DAY 11에서 YYB-103 CAR-T는 60.6%, YYB-103-1XX CAR-T는 54.9%을 보였다.
실시예 4. HGF(hepatocyte growth factor; 간세포성장인자)의 중화가능 에피토프에 결합하는 중화 항체(YYB-101)의 제작
HGF와 그 수용체간의 결합을 방해하는 HGF 중화 항체인 YYB-101(서열번호 13 및 서열번호 14)은 대한민국 등록특허 제556660호에 개시된 내용으로 제작되었으며, 이 전문은 참조로 통합된다.
실험예 1. CAR-T 또는 YYB-101 단독투여 및 CAR-T와 YYB-101 병용 투여
난소암 세포주 (A2780) 준비
IL13Rα2 발현 및 HGF 분비하는 난소암 세포주 (A2780)를 10% FBS와 1% antibiotics가 포함된 DMEM 배지를 사용하여 CO2 incubator (Thermo, 371) 내에서 32℃, 6% CO2 조건에서 배양하였다.
난소암 세포주 (A2780) 종양이식 및 군구성
1x105 A2780 세포 8 ul와 matrigel 2 ul를 이용하여 NSGA 마우스의 난소에 직접 이식하여 생착을 유도하였다. 생착 3일 후, 시험동물의 체중 측정 및 in vivo luciferase 이미징을 이용하여 종양의 크기가 고르게 분포되도록 분배하였다. 시험군은 1개의 대조군 (Vehicle)과 5개의 시험물질의 투여군 (Untransduced T 세포, YYB-103 CAR-T, YYB-103-1XX CAR-T, YYB-101 및 YYB-103-1XX CAR-T와 YYB-101 병용)으로 구성하였으며, 각 군당 3마리씩 분배하였다.
시험물질 조제
CAR-T 세포치료제에 대하여 PBS을 이용하여 2회 세척 후 각각의 Untransduced T 세포 및 CAR-T 세포를 PBS로 희석한 후 준비하였다.
실험 방법
종양이식 후 3일에 CAR 바이러스에 형질도입 되지 않은 T 세포 (Untransduced T 세포), YYB-103 CAR-T 및 YYB-103-1XX CAR-T 세포를 1.5 x 107 세포 농도로 정맥으로 단회 투여하였다. 또한, YYB-103-1XX CAR-T와 YYB-101 병용군의 경우 YYB-101은 YYB-103-1XX CAR-T와 동시에 투여(1차)를 시작하여 추가(2차)로 1회 더 투여하여 총 주 2회 (20 mpk) 정맥으로 반복 투여하였다.
실험 결과
Untransduced T 세포군과 YYB-101만을 처리한 군의 경우 종양 생착 후 20~30일 안에 모든 개체가 사망하였다. 반면, YYB-103 CAR-T 및 YYB-103-1XX CAR-T의 경우 마지막 개체가 50일 이후 사망함에 따라서 Untransduced T 세포 군보다 약 20일 생존이 길어질 수 있음을 확인하였다. YYB-103-1XX CAR-T와 YYB-101을 병용한 경우에는 마지막 개체의 사망일 기준으로 YYB-103-1XX CAR-T 단독군에 비해서 17일정도 더 생존하였다.
그 결과는 도 5에 나타난 바와 같이, YYB-103-1XX CAR-T 세포치료제와 HGF을 특이적으로 인식하는 항체인 YYB-101의 병용하였을 때 CAR-T 세포치료제 단독 투여군에 비해 항암 효과가 증가하는 것을 확인할 수 있었다.
실험예 2. 고용량 CAR-T 단독 투여
난소암 세포주 (A2780) 준비
난소암 세포주 (A2780)를 10% FBS와 1% antibiotics가 포함된 DMEM 배지를 사용하여 CO2 incubator (Thermo, 371) 내에서 32℃6% CO2 조건에서 배양하였다.
난소암 세포주 (A2780) 종양이식 및 군구성
NSGA 마우스에 1x105 A2780 세포 8 ul와 matrigel 2 ul를 이용하여 NSGA 마우스의 난소에 직접 이식하여 생착을 유도하였다. 생착 3일 후, 시험동물의 체중 측정 및 in vivo luciferase 이미징을 이용하여 종양의 크기가 고르게 분배되었음을 확인하였다. 시험군은 1개의 대조군 (Vehicle)과 1개의 시험물질의 투여군 (YYB-103 CAR-T)으로 구성하였으며, 각 군당 5마리씩 분배하였다.
시험물질 조제
CAR-T 세포치료제에 대하여 PBS을 이용하여 2회 세척 후 CAR-T 세포를 PBS로 희석한 후 준비하였다.
실험 방법
종양이식 후 3일에, YYB-103 CAR-T 세포를 5 x 107 세포 농도로 정맥으로 단회 투여하였다.
실험 결과
YYB-103 CAR-T 세포를 고농도(5 x 107 세포)로 정맥으로 단회 투여한 경우, 도 6에 나타난 바와 같이 마지막 개체가 약 70일에 사망함을 확인할 수 있었다. 즉, 5 x 107 CAR-T 세포 투여에 의한 마우스의 중간 생존이 상기 실험예 1의 1.5 x 107 YYB-103-1XX CAR-T와 YYB-101의 병용과 유사한 결과를 나타냄을 알 수 있었다. 이와 같은 결과는, YYB-103-1XX CAR-T와 YYB-101의 병용을 통해 저용량의 CAR-T로도 효과적으로 암세포를 사멸시킬 수 있기 때문에, 면역 효과 세포 관련 신경 독성 증후군(ICANS) 및 사이토카인 방출 증후군(CRS)와 같은 CAR-T 주입에 따른 부작용을 최소화 할 수 있다는 것을 의미한다.
본 발명에 따른 CAR 요법제는 난소암을 포함하는 고형암에 대한 항암 효과를 나타내므로, 항암제와 같은 의약품으로 이용 가능하다.
<110> CellabMED Inc.
<120> Combination therapies of chimeric antigen receptors and HGF
neutralizing antibody
<130> OKR21P0130-CMED
<160> 20
<170> KoPatentIn 3.0
<210> 1
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> hVHCAMP signal peptide
<400> 1
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 2
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Human IL13 ligand
<400> 2
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys 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 Asp
50 55 60
Met Leu Asp 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 Lys Glu Gly Gln Phe Asn
100 105 110
<210> 3
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker
<400> 3
Gly Gly Gly Pro Arg
1 5
<210> 4
<211> 47
<212> PRT
<213> Artificial Sequence
<220>
<223> Human CD8a hinge
<400> 4
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> 5
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> Human CD8a transmembrane domain
<400> 5
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> 6
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Human CD137 topological domain
<400> 6
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> 7
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Human CD3 zeta
<400> 7
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> 8
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Human CD3 zeta containing point-mutated ITAM
<400> 8
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 Phe Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Phe Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 9
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-103
<400> 9
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> 10
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-103-1XX
<400> 10
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 Phe Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Phe 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
Phe Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His
340 345 350
Met Gln Ala Leu Pro Pro Arg
355
<210> 11
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> amino acid sequence of VH region
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Gly Thr Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Gly Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Arg Ile Asn Leu Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 12
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> amino acid sequence of VL region
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Ile
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Gly Tyr Tyr Ser Arg Gly
85 90 95
Ala Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 443
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Heavy chain
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Gly Thr Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Gly Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Arg Ile Asn Leu Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 14
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Light chain
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Ile
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Gly Tyr Tyr Ser Arg Gly
85 90 95
Ala Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 15
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Light chain_CDR 1
<400> 15
Arg Ala Ser Gln Gly Ile Ser Asn Ile Leu Ala
1 5 10
<210> 16
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Light chain_CDR 2
<400> 16
Gly Ala Ser Asn Leu Glu Ser
1 5
<210> 17
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Light chain_CDR 3
<400> 17
Gln Ser Gly Tyr Tyr Ser Arg Gly Ala Thr
1 5 10
<210> 18
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Heavy chain_CDR 1
<400> 18
Thr Tyr Tyr Met Ser
1 5
<210> 19
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Heavy chain_CDR 2
<400> 19
Tyr Ile Gly Thr Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 20
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> YYB-101 Heavy chain_CDR 3
<400> 20
Gly Leu Gly Arg Ile Asn Leu
1 5
Claims (11)
- HGF의 중화가능 에피토프에 결합하는 중화 항체와 조합하여 대상체에서 암의 치료에 사용하기 위한 키메릭 항원 수용체(CAR)를 발현하는 면역 이펙터 세포의 집단을 포함하는 CAR 요법제.
- 제 1항에 있어서, 상기 CAR가 항원 결합 도메인; 힌지 영역; 막관통 도메인; 보조 자극 도메인; 및 세포질 신호 전달 도메인을 포함하는 CAR 요법제.
- 제 2항에 있어서, 상기 CAR의 항원 결합 도메인이 CD19, MUC16, MUCl, CAlX, CEA, CDS, CD7, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD133, CD138, 사이토메갈로바이러스(CMV) 감염된 세포 항원, EGP-2, EGP-40, EpCAM, erb-B2,3,4, FBP, 태아 아세틸콜린 수용체, 폴레이트 수용체-a, GD2, GD3, HER-2, hTERT, K-경쇄, KDR, LeY, L1 세포 부착 분자, MAGE-A1, 메소텔린, NKG2D 리간드, NY-ES0-1, 암태아 항원(h5T4), PSCA, PSMA, ROR1, TAG-72, VEGF-R2, WT-1, CD276 또는 IL13Ra2로부터 선택되는 항원과 결합하는 항원 결합 도메인을 포함하는 CAR 요법제.
- 제 2항에 있어서, 상기 CAR의 막관통 도메인이 T-세포 수용체의 알파, 베타 또는 제타 쇄, CD28, CD3엡실론, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 또는 CD154로부터 선택되는 막관통 도메인을 포함하는 CAR 요법제.
- 제 2항에 있어서, 상기 CAR의 보조 자극 도메인이 MHC 클래스 I 분자, TNF 수용체 단백질, 이뮤노글로불린-유사 단백질, 시토카인 수용체, 인테그린, 신호전달 림프구성 활성화 분자 (signaling lymphocytic activation molecule, SLAM), 활성화 NK 세포 수용체, BTLA(B an T lymphocyte attenuator), 톨-유사 리간드 수용체(Tolllike ligand receptor), OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8알파, CD8베타, IL2R 베타, IL2R 감마, IL7R 알파, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, 또는 CD83과 특이적으로 결합하는 리간드로부터 선택되는 보조 자극 도메인을 포함하는 CAR 요법제.
- 제 2항에 있어서, 상기 CAR의 세포질 신호 전달 도메인이 4-1BB, CD28, OX40, CD3ζ의 기능적 신호 전달 도메인, 또는 이들의 조합으로부터 선택되는 세포질 신호 전달 도메인을 포함하는 CAR 요법제.
- 제 2항에 있어서, 상기 CAR가 IL13Rα2 항원 결합 도메인; 힌지 영역; 막관통 도메인; 보조 자극 도메인; 및 세포질 신호 전달 도메인을 포함하는 CAR 요법제.
- 제 7항에 있어서, 상기 CAR가 서열번호 9의 아미노산 서열로 표시되는 CAR 요법제.
- 제 7항에 있어서, 상기 CAR가 서열번호 10의 아미노산 서열로 표시되는 CAR 요법제.
- 제 1항에 있어서, 상기 HGF 중화항체의 중쇄가 서열번호 13, 경쇄가 서열번호 14의 아미노산 서열로 표시되는 CAR 요법제.
- 제 1항 내지 제10항 중 어느 한 항에 있어서, 상기 암이 난소암, 유방암, 위암, 폐암, 간암, 담도암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 신장암, 대장암, 결장암, 자궁경부암, 뇌암, 전립선암, 골암, 두경부암, 피부암, 갑상선암, 부갑상선암 또는 요관암인 CAR 요법제.
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KR1020220046299A KR20230148433A (ko) | 2022-04-14 | 2022-04-14 | 키메릭 항원 수용체 및 hgf 중화항체의 조합 요법 |
PCT/KR2023/004996 WO2023200266A1 (ko) | 2022-04-14 | 2023-04-13 | 키메릭 항원 수용체 및 hgf 중화항체의 조합 요법 |
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KR1020220046299A KR20230148433A (ko) | 2022-04-14 | 2022-04-14 | 키메릭 항원 수용체 및 hgf 중화항체의 조합 요법 |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100556660B1 (ko) | 2003-11-11 | 2006-03-10 | 국립암센터 | Hgf의 중화가능 에피토프 및 이에 결합하는 중화 항체 |
KR102011789B1 (ko) | 2015-08-05 | 2019-08-19 | 주식회사 셀랩메드 | 키메라 항원 수용체 및 키메라 항원 수용체가 발현된 t 세포 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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KR100556660B1 (ko) | 2003-11-11 | 2006-03-10 | 국립암센터 | Hgf의 중화가능 에피토프 및 이에 결합하는 중화 항체 |
KR102011789B1 (ko) | 2015-08-05 | 2019-08-19 | 주식회사 셀랩메드 | 키메라 항원 수용체 및 키메라 항원 수용체가 발현된 t 세포 |
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