KR20230123515A - Fc-수용체 car 작제물 및 세포 (fc-receptor car constructsand cells) - Google Patents
Fc-수용체 car 작제물 및 세포 (fc-receptor car constructsand cells) Download PDFInfo
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Abstract
항체-결합 도메인을 갖는 키메라 항원 수용체(chimeric antigen receptor)가 제시되며, 이는 바람직하게는 치료 세포, 특히 NK-92 세포 또는 이의 유도체에서 재조합 세포로부터 발현된다. 이러한 변형된 세포는 다수의 세포독성 모드, 향상된 표적상 세포 사멸화, 저하된 표적외 세포 사멸화를 가지며, 재조합 CAR의 유의한 발현 및/또는 증가된 CAR-매개 세포독성을 보여준다는 점이 주지된다.
Description
본 출원은 2020년 12월 22일에 출원되었고 그 전체 내용이 본원에 참조로 포함되는 일련 번호 63/129,340호를 갖는 본 발명자들의 동시계류중인(copending) 미국 임시 특허 출원에 대해 우선권을 주장한다.
서열 목록
서열 목록 명칭은 104077.0021_REV005_ST25.txt이며, 크기가 144 KB이고, 2021년 12월 16일에 생성되었으며 본 출원과 함께 EFS-웹을 통해 전자적으로 제출된 ASCII 텍스트 파일의 내용은 그 전체 내용이 본원에 참조로 포함된다.
기술분야
본 발명의 분야는 키메라 항원 수용체(CAR) 및 이러한 CAR을 발현하는 재조합 세포에 관한 것이며, 특히 항체의 Fc 부분에 결합하는 항원 결합 도메인, 예컨대 CD16 Fc 결합 도메인, CD32 Fc 결합 도메인 또는 CD64 Fc 결합 도메인을 갖는 CAR에 관한 것이다.
배경기술 설명은 본 발명의 이해에 유용할 수 있는 정보를 포함한다. 이는 본원에 제공된 임의의 정보가 선행 기술이거나 본원에 청구된 발명과 관련이 있거나 구체적으로 또는 함축적으로 참조된 임의의 공보가 선행 기술임을 인정하는 것이 아니다.
본원의 모든 공보 및 특허 출원은 각각의 개별 공보 또는 특허 출원이 구체적으로 그리고 개별적으로 참조로 포함되는 것으로 지시되는 바와 동일한 정도까지 참조로 포함된다. 포함된 참조문헌의 정의 또는 용어의 사용이 본원에 제공된 해당 용어의 정의와 일관되지 않거나 대조를 이루는 경우, 본원에 제공된 해당 용어의 정의가 적용되고 참조문헌의 해당 용어의 정의는 적용되지 않는다.
많은 경우, 치료 항체는 유전적으로 변형된 NK 세포를 사용하는 다양한 암의 면역 치료법에 유망한 통로가 된 효과 항체-의존적 세포-매개 세포독성(ADCC)에 사용될 수 있다. ADCC는 치료 항체에 결합하고 항체-결합 표적 세포에 대한 그랜자임 및 그래눌리신(granulysin) 방출을 촉발하는 CD16 수용체에 의해 매개된다. 그러나 안타깝게도, CD16 수용체의 발현은 종종 빠르게 하향조절되고, 따라서 천연 NK 세포를 사용하는 이들 항체의 치료 유용성을 제한한다. 이에 더하여, 천연 NK 세포 상의 CD16은 항체의 Fc 부분에 대해 상대적으로 낮은 친화도를 가지며, 따라서 치료 용도를 추가로 제한한다. 보다 최근에, CD16의 고 친화도 버전을 발현하는 재조합 NK 세포(NantKwest사로부터 haNK 세포로서 상업적으로 입수 가능함)가 개발되었으며, 따라서 재조합 CD16 변이체로서의 치료 잠재성을 유의하게 증가시키는 것이 하향조절을 거치지 않고 항체의 Fc 부분에 대해 더 높은 친화도를 갖는다.
또 다른 접근법에서, CD16 세포내 및 막관통 부분과 CD64 세포외 부분을 가져서 CD64 부분으로 인해 증가된 친화도를 갖는 ADCC 능력을 유지시키는 키메라 단백질이 생산되었다(예를 들어, 문헌[Frontiers in Immunology, December 2018, Vol. 9, Article 2873] 참조). 개념적으로는 매력적이지만, 다양한 단점이 여전하였다. 무엇보다도, 생체내 항종양 활성은 입증되지 않았고, 저자들은 CD64/16A를 발현하는 NK 세포가 연쇄 사멸화에서 덜 효율적일 수 있다고 상정하였다. 추가 시도에서, WO 2015/179833호에 기재된 바와 같이, CD64의 다량체가 막관통 도메인 및 세포내 T-세포 신호전달 도메인에 연결되어 T 세포를 키메라 수용체로 무장시킨(arm) 하이브리드 작제물이 생산되었으며, 이는 항체 결합에 의해 유도된 T 세포의 세포독성 세포 사멸화를 활성화시킬 수 있었다.
더욱 또 다른 접근법에서, US 2018/0133252호에 기재된 바와 같이 다양한 신호전달 도메인에 연결된 CD16V 도메인을 포함한 키메라 항원 수용체가 생산되었다. 유사하게는, US 7618817호는 CD16 부분이 NK-92 세포에서 레트로바이러스 작제물로부터 발현된 CAR에서 결합 특이성을 제공하는 데 사용된 특정한 CAR 작제물을 기재하였다. 이러한 접근법은 항체에 결합할 수 있는 재조합 세포독성 세포를 유발하긴 하였지만, 이러한 세포주의 생성은 종종, 심지어 CAR 작제물 중 적어도 일부가 2세대 또는 3세대 CAR 작제물인 경우 이러한 작제물에 대해 천연 NK 세포와 비교하여 천연 세포독성의 소실 또는 감소, 저하된 표적상 세포 사멸화 및/또는 증가된 표적외 세포 사멸사, 재조합 CAR의 약화된 발현 및/또는 저하된 CAR-매개 세포독성과 연관이 있다.
그러므로, 항체의 Fc 부분에 결합하는 CAR의 다양한 시스템 및 방법이 당업계에 알려져 있더라도, 이들 모두 또는 거의 모두는 여러 결점을 갖고 있다. 따라서, 다수의 세포독성 모드, 향상된 표적상 세포 사멸화, 저하된 표적외 세포 사멸화, 재조합 CAR의 유의한 발현 및/또는 증가된 CAR-매개 세포독성을 갖는 향상된 CAR 및 CAR 발현 세포를 위한 조성물 및 방법에 대한 필요성이 존재한다.
본 발명의 주제는 재조합 CAR 및 이러한 CAR을 발현하는 세포의 다양한 조성물 및 방법에 관한 것이며, 여기서 이러한 세포는 다수의 세포독성 모드, 향상된 표적상 세포 사멸화, 저하된 표적외 세포 사멸화, 재조합 CAR의 유의한 발현 및/또는 증가된 CAR-매개 세포독성을 나타낸다.
본 발명의 주제의 일 양태에서, 발명자들은 SEQ ID NO:12, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:22, SEQ ID NO:25, SEQ ID NO:28 및 SEQ ID NO:31로 이루어진 군으로부터 선택되는 서열을 갖는 폴리펩타이드의 항체-결합 부분을 갖는 항체 결합 도메인을 포함하는 재조합 키메라 항원 수용체(CAR)를 고려한다. 이러한 CAR에서, 항체 결합 도메인은 추가로 선택적인 힌지 부분, 막관통 부분 및 신호전달 도메인을 서열에 포함하는 폴리펩타이드에 연결된다.
선택된 구현예에서, 항체 결합 도메인은 SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:29 및 SEQ ID NO:32로 이루어진 군으로부터 선택되는 펩타이드 서열을 갖는다. 전형적으로, 힌지 부분은 SEQ ID NO:3의 펩타이드 서열을 갖고/갖거나, 막관통 부분은 SEQ ID NO:5, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82 또는 SEQ ID NO:84의 펩타이드 서열을 갖고/갖거나, 신호전달 도메인은 SEQ ID NO:1의 펩타이드 서열을 갖는다. 추가의 고려되는 구현예에서, CAR은 적어도 하나의 제2 신호전달 도메인을 포함할 수 있으며, 이는 초기 신호전달 도메인와 별개일 수 있다. 예를 들어, 일부 구현예에서, 신호전달 도메인은 SEQ ID NO:7, SEQ ID NO:8 및 SEQ ID NO:9로 이루어진 군으로부터 선택되는 펩타이드 서열을 갖는다.
추가의 예시적인 구현예에서, 이러한 CAR 내 항체 결합 도메인은 SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:29 및 SEQ ID NO:32로 이루어진 군으로부터 선택되는 펩타이드 서열을 갖고, 신호전달 도메인은 SEQ ID NO:1의 펩타이드 서열을 갖는다. 바람직하게는, 힌지 부분은 SEQ ID NO:3의 펩타이드 서열을 갖고/갖거나 막관통 부분은 SEQ ID NO:5, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82 또는 SEQ ID NO:84의 펩타이드 서열을 갖는다. 원한다면, CAR은 적어도 하나의 추가의 신호전달 도메인(예를 들어 SEQ ID NO:1의 서열 또는 다른 신호전달 도메인을 가짐)을 추가로 포함할 수 있다.
추가의 고려되는 양태에서, 발명자들은 본원에 제시된 바와 같은 키메라 항원 수용체를 인코딩하는 재조합 핵산을 고려한다. 바람직하게는, 필수적인것은 아니지만, 핵산은 인간 코돈 용법으로 코돈-최적화된다. 더욱이, 핵산은 또한 시토카인, CD16, 귀소 수용체 및/또는 TGF-베타 트랩(TGF-beta trap)(이들은 모두 다시스트론성(polycistronic) 위치배열로 배열될 수 있음)을 인코딩하는 서열 부분을 포함할 수 있는 것으로 고려된다. 예를 들어, 재조합 핵산은 렌티바이러스 벡터의 일부 또는 DNA 벡터의 일부일 수 있다.
더욱 추가의 고려되는 양태에서, 발명자들은 본원에 제시된 바와 같은 재조합 핵산으로 형질주입된 (전형적으로 포유류) 세포를 고려한다. 예를 들어, 세포는 NK 세포(예를 들어 NK-92 세포, 유전적으로 변형된 NK-92 세포, 또는 자가 NK 세포) 또는 T 세포이다. 상이한 관점에서 볼 때, 발명자들은 또한 본원에 기재된 바와 같은 재조합 키메라 항원 수용체를 인코딩하는 재조합 핵산으로 형질주입된 재조합 NK 세포(예를 들어 NK-92 세포, 유전적으로 변형된 NK-92 세포, 또는 자가 NK 세포)를 고려한다.
결과적으로, 본 발명자들은 또한 치료를 필요로 하는 환자에서 암을 치료하는 방법을 고려하며, 치료적 유효량의 본원에 제시된 세포를 환자에게 투여하고, 이에 따라 암을 치료하는 단계를 포함한다. 가장 전형적으로, 환자의 체표면적 m2당 약 1x108 내지 약 1x1011개 세포가 환자에게 투여된다. 이에 더하여, 적어도 하나의 추가의 치료 엔티티(entity), 예컨대 바이러스 암 백신, 박테리아 암 백신, 효모 암 백신, N-803, 항체, 줄기 세포 이식물 및/또는 종양 표적화된 시토카인이 환자에게 투여될 수 있다. 예를 들어, 치료될 것으로 고려되는 암은 백혈병(leukemia), 급성 림프구성 백혈병(acute lymphocytic leukemia), 급성 골수구성 백혈병(acute myelocytic leukemia), 만성 백혈병(chronic leukemia), 만성 골수구성(과립구성) 백혈병(chronic myelocytic(granulocytic) leukemia), 만성 림프구성 백혈병(chronic lymphocytic leukemia), 진성 적혈구증가증(polycythemia vera), 림프종(lymphoma), 호지킨 질환(Hodgkin's disease), 비호지킨 질환(non-Hodgkin's disease), 다발성 골수종(multiple myeloma), 발덴스트롬 마크로글로불린혈증(Waldenstrom's macroglobulinemia), 중쇄 질환(heavy chain disease), 육종(sarcoma) 및 암종(carcinoma), 예컨대 섬유육종(fibrosarcoma), 점액육종(myxosarcoma), 지방육종(liposarcoma), 연골육종(chondrosarcoma), 골원성 육종(osteogenic sarcoma), 척색종(chordoma), 혈관육종(angiosarcoma), 내피육종(endotheliosarcoma), 림프관육종(lymphangiosarcoma), 림프관내피육종(lymphangioendotheliosarcoma), 윤활막종(synovioma), 중피종(mesothelioma), 에윙 종양(Ewing's tumor), 평활근육종(leiomyosarcoma), 횡문근육종(rhabdomyo sarcoma), 결장 암종(colon carcinoma), 췌장암, 유방암, 난소암, 전립선암, 편평 세포 암종(squamous cell carcinoma), 기저 세포 암종(basal cell carcinoma), 선암종(adenocarcinoma), 한선 암종(sweat gland carcinoma), 피지선 암종(sebaceous gland carcinoma), 유두상 암종(papillary carcinoma), 유두상 선암종(papillary adenocarcinoma), 낭선암종(cystadenocarcinoma), 수질 암종(medullary carcinoma), 기관지원성 암종(bronchogenic carcinoma), 신세포 암종(renal cell carcinoma), 간종양(hepatoma), 담관 암종(bile duct carcinoma), 융모막 암종(choriocarcinoma), 정상피종(seminoma), 배아 암종(embryonal carcinoma), 윌름 종양(Wilm's tumor), 자궁경부암, 고환 종양, 폐암종(lung carcinoma), 소세포 폐암종(small cell lung carcinoma), 방광 암종(bladder carcinoma), 상피 암종(epithelial carcinoma), 신경교종(glioma), 성상세포종(astrocytoma), 수모세포종(medulloblastoma), 두개인두종(craniopharyngioma), 뇌실막종(ependymoma), 송과체종(pinealoma), 혈관아세포종(hemangioblastoma), 청신경종(acoustic neuroma), 희소돌기아교세포종(oligodendroglioma), 수막종(menangioma), 흑색종(melanoma), 신경아세포종(neuroblastoma) 및 망막아세포종(retinoblastoma)을 포함하지만 이로 제한되지 않는 고형 종양(solid tumor)을 포함한다.
그러므로, 본원에 제시된 바와 같은 세포의 용도는 암의 치료에서 고려된다.
본 발명의 주제의 다양한 목적, 특징, 양태 및 이점은 첨부된 도면과 함께 바람직한 구현예의 하기 상세한 설명으로부터 더 명백해질 것이며, 유사한 숫자는 유사한 구성요소를 나타낸다.
도1은 본원에 제시된 다양한 키메라 항원 수용체의 개략적인 예시이다.
도2는 aNK 세포, haNK 세포 및 CD16-CAR 28.E 세포에 대한 예시적인 CD16 FACS 스캔 결과를 도시한다.
도3은 haNK 세포와 비교하여 NK 민감성 K562 세포에 대한 CD16-CAR 28.E 세포의 세포독성에 대한 예시적인 결과를 도시한다.
도4는 표적상 및 표적외 항체의 존재 및 부재 하에 SUP-B15CD20+ 세포에 대한 CD16-CAR 28.E 세포의 ADCC 활성의 예시적인 결과를 도시한다.
도2는 aNK 세포, haNK 세포 및 CD16-CAR 28.E 세포에 대한 예시적인 CD16 FACS 스캔 결과를 도시한다.
도3은 haNK 세포와 비교하여 NK 민감성 K562 세포에 대한 CD16-CAR 28.E 세포의 세포독성에 대한 예시적인 결과를 도시한다.
도4는 표적상 및 표적외 항체의 존재 및 부재 하에 SUP-B15CD20+ 세포에 대한 CD16-CAR 28.E 세포의 ADCC 활성의 예시적인 결과를 도시한다.
발명자들은 재조합 CAR 및 이러한 CAR을 발현하는 세포의 다양한 조성물 및 방법을 발견하였으며, 이러한 세포는 다수의 세포독성 모드, 향상된 표적상 세포 사멸화, 저하된 표적외 세포 사멸화, 재조합 CAR의 유의한 발현 및/또는 증가된 CAR-매개 세포독성을 나타낸다.
1세대-유형 작제물에서 신호전달 도메인으로서 FcεRIγ를 사용하는 다양한 CAR 작제물이 이러한 CAR 작제물을 발현하는 NK-92 세포에서 향상된 발현을 가졌고 증가된 표적 특이적 사멸화를 부여하였다는 발명자들의 이전의 발견에 기초하여, 발명자들은 항체(특히 IgG 항체)의 Fc 부분에 결합할 고 친화도 CAR 작제물 및 이러한 CAR을 발현하는 세포의 증강된 세포독성 효과로 다양한 세포, 특히 NK-92 세포 및 유전적으로 변형된 NK-92 세포를 무장시키기 위해 이러한 세포를 변형시키도록 설정하였다. 실제로, 이들 CAR이 NK 세포 상에서 발현되는 경우, 이들 세포의 ADCC는 비변형된 NK 세포에 비해 실질적으로 증가되었다.
예상치 못하게도 그리고 아래에 더 상세히 기재된 바와 같이, 이렇게 생성된 재조합 NK 세포는 비변형된 NK 세포, NK-92 세포와 비교하는 경우 및 일부 경우, CD16을 발현하고 FcεRIγ 신호전달 폴리펩타이드 또는 CD3ζ 사슬을 공동발현하는(예를 들어 US 9181322호에 교시된 바와 같음) NK 세포와 비교하는 경우에도 다수의 세포독성 모드, 향상된 표적상 세포 사멸화, 저하된 표적외 세포 사멸화, 재조합 CAR의 유의한 발현 및/또는 증가된 CAR-매개 세포독성을 가졌다.
바람직한 구현예에서, 발명자들은 항체-결합 부분을 갖는 항체 결합 도메인을 단일 폴리펩타이드 사슬에 포함하고, 뒤이어 세포외 선택적인 힌지 부분, 막관통 부분 및 세포내 신호전달 도메인을 서열에 포함하는 CAR 작제물을 고려한다. 세포내 신호전달 도메인의 특정 용도 및/또는 배열에 따라, 이렇게 제조된 CAR 작제물은 1세대, 2세대 또는 3세대 CAR일 수 있는 것으로 이해되어야 한다. 도 1은 본원에 제시된 교시와 관련하여 유용한 고려되는 CAR을 예시적으로 도시한다. 예를 들어, 1세대 CA 작제물은 단일 신호전달 도메인, 예컨대 CD3ζ 세포내 신호전달 도메인, 더 바람직하게는 FcεRIγ 신호전달 도메인을 포함할 수 있다. 주목할 만하게는, CAR 작제물이 1세대 구조를 가진 경우, FcεRIγ 신호전달 도메인을 갖는 이러한 CAR은 다른 CAR 작제물과 비교하여 NK 세포에서 우수한 특성을 가졌다. 이러한 발견은 특히 T 세포에서 지금까지 알려진 1세대 CAR이 2세대 및 3세대 CAR에서 보편적으로 발견되는 바와 같은 CD3ζ, 4-1BB 또는 CD28 신호전달 도메인 및 선택적으로 추가의 신호전달 도메인을 갖는 CAR과 비교하여 상대적으로 불량하게 수행하였기 때문에 예상치 못한 것이었다. 쉽게 이해할 수 있는 바와 같이, 고려되는 CAR은 또한 다수의 FcεRIγ 및/또는 CD3ζ 세포내 신호전달 도메인을 포함할 수 있다.
추가 예에서, CAR 작제물은 적어도 2개의 별개의 세포내 신호전달 도메인을 포함할 수 있으며, 이러한 CAR 작제물에 대한 전형적인 예는 CD3ζ 세포내 신호전달 도메인이 도 1의 2세대 CAR 작제물에 예시적으로 도시된 바와 같이 CD28 신호전달 도메인 또는 4-1BB 신호전달 도메인에 연결되는 것을 포함한다. 더욱이, 고려되는 CAR 작제물은 2개 초과의 신호전달 도메인(즉, 전형적으로 별개임)을 포함할 수 있고, 예시적인 3세대 CAR 작제물은 CD3ζ 세포내 신호전달 도메인이 CD28 신호전달 도메인 및 4-1BB 신호전달 도메인에 연결되는 것을 포함함을 주지한다. 당연하게도, 세포내 신호전달 도메인의 특정 서열 순서는 다양할 수 있고, 모든 배열은 본원에 사용하기에 적합한 것으로 여겨지는 것으로 인식되어야 한다.
항체 결합 도메인에 관하여, 본원에 제시된 CAR은 항체의 Fc 부분, 가장 바람직하게는 IgG의 Fc 부분에 결합할 적어도 하나의 항체-결합 부분을 갖는 것으로 일반적으로 고려된다. 그러나, 대안적인 양태에서, Fc 부분은 또한 IgA, IgM 및 IgE를 포함하는, IgG 이외의 항체 부류에 속할 수 있다. 따라서, 적합한 항체 결합 도메인은 바람직하게는 CD16A, CD16B, CD32A, CD32B, CD64A, CD64B 및 CD64C의 전장 폴리펩타이드 또는 항체-결합 부분을 포함할 것이고 덜 바람직한 양태에서는 단백질 A 및 단백질 G를 또한 포함할 것이다. 따라서, 적합한 전장 폴리펩타이드 또는 항체-결합 부분은 SEQ ID NO:12, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:22, SEQ ID NO:25, SEQ ID NO:28 및 SEQ ID NO:31에 따른 아미노산 서열(또는 이들 서열 각각의 부분)을 갖거나 포함할 것이다. 항체-결합 부분이 CD16, CD32 또는 CD64의 세포외 도메인인 경우, 특히 고려되는 세포외 도메인은 SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:29 및 SEQ ID NO:32에 따른 아미노산 서열(또는 이들 서열 각각의 부분)을 갖거나 포함할 것이다.
항체 결합 도메인의 유형에 상관없이, 대부분의 경우 항체 결합 도메인은 막관통 부분에 관해 항체 결합 도메인의 가요성(flexibility)을 제공하기 위해 힌지 부분을 통해 막관통 부분에 연결될 것으로 이해되어야 한다. 그러나, 특정한 구현예에서 힌지 부분은 아래 예시적인 서열 중 일부에 제시된 바와 같이 생략되는 것으로 인식되어야 한다. 힌지 부분은 존재하는 경우 가장 전형적으로 그러나 본질적이지는 않은, 약 5 내지 100개의 (주로 친수성) 아미노산 잔기를 갖는 짧은 가요성 폴리펩타이드이다. 따라서, 적합한 높은 부분 특수성은 SEQ ID NO:3에 따른 아미노산 서열을 갖거나 포함하는 CD8 힌지 부분(특히 인간 CD8 힌지 부분)(또는 이의 부분)을 포함한다.
추가의 고려되는 양태에서, 항체, 예컨대 IgG, IgA, IgM, IgE 또는 IgD 항체의 힌지 도메인은 또한 본원에 기재된 키메라 수용체에 사용하기에 적합한 것으로 여겨진다. 일부 구현예에서, 힌지 도메인은 항체의 불변 도메인 CH1 및 CH2를 접합시키는(join) 힌지 도메인이다. 다른 구현예에서, 힌지 도메인은 항체를 가지며, 항체의 힌지 도메인 및 항체의 하나 이상의 불변 영역을 포함한다. 추가 구현예에서, 힌지 도메인은 항체의 힌지 도메인 및 항체의 CH3 불변 영역을 포함한다. 더욱 추가의 구현예에서, 힌지 도메인은 항체의 힌지 도메인 및 항체의 CH2 및 CH3 불변 영역을 포함한다.
추가의 바람직한 양태에서, 항체 결합 도메인 및 힌지 부분(존재하는 경우)은 막관통 부분을 통해 세포막에 고정(anchor)될 수 있다. 예를 들어, 일부 구현예에서, 본원에 기재된 키메라 수용체의 막관통 도메인은 유형 I 단일-통과 막 단백질로부터 유래될 수 있다. 단일-통과 막 단백질은 CD8α, CD8β, 4-1BB/CD137, CD28, CD34, CD4, FcεRIγ, CD16, OX40/CD134, CD3ζ, CD3, CD3γ, CD3δ, TCRα, TCRβ, TCRζ, CD32, CD64, CD45, CDS, CD9, CD22, CD37, CD80, CD86, CD40, CD4OL/CD154, VEGFR2, FAS 및 FGFR2B를 포함한다. 바람직한 예에서, 막관통 도메인은 CD8α, CD28 또는 CD34로부터 유래된다. 따라서, 특히 바람직한 막관통 부분은 SEQ ID NO:5, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82 또는 SEQ ID NO:84에 따른 아미노산 서열(또는 임의의 바로 앞의 아미노산 서열에 관하여 이의 부분)을 갖거나 포함할 것이다.
더욱 추가의 양태에서, 다중-통과 막 단백질로부터의 막관통 도메인은 또한 본원에 기재된 키메라 수용체에 사용과 양립될 수 있다. 다중-통과 막 단백질은 복잡한(적어도 2, 3, 4, 5, 6, 7개 이상의) 알파 나선 또는 베타 시트 구조를 포함할 수 있다. 바람직하게는, 다중-통과 막 단백질의 N-말단 및 C-말단은 지질 이중층의 반대면 상에 존재하며, 예를 들어, 단백질의 N-말단은 지질 이중층의 세포질면 상에 존재할 수 있고, 단백질의 C-말단은 세포외면 상에 존재할 수 있다. 다중-통과 막 단백질로부터의 하나의 또는 다수의 나선 경로는 본원에 기재된 키메라 수용체를 작제하는 데 사용될 수 있다.
본원에 기재된 키메라 수용체에 사용하기 위한 막관통 도메인은 또한 합성, 비천연 발생 단백질 분절의 적어도 일부를 포함할 수 있다. 일부 구현예에서, 막관통 도메인은 합성, 비천연 발생 알파 나선 또는 베타 시트이다. 일부 구현예에서, 단백질 분절은 적어도 대략 20개 아미노산, 예를 들어 적어도 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 이상의 아미노산이다. 합성 막관통 도메인의 예는 당업계, 예를 들어 US 7052906호 및 WO 2000/032776호에 알려져 있으며, 이들 둘 모두는 본원에 참조로 포함된다.
적합한 신호전달 도메인에 관하여, 모든 신호전달 부분(전형적으로 세포내)은 본원에 사용하기에 적합한 것으로 여겨지며, 이는 표면 수용체의 신호전달 부분, 예컨대 CD3ζ 및 FcεRIγ, 뿐만 아니라 공동자극성 단백질의 신호전달 부분, 예컨대 B7/CD28 패밀리의 구성원(예를 들어 B7-1/CD80, B7-2/CD86, B7-H1/PD-L1, B7-H2, B7-H3, B7-H4, B7-H6, B7-H7, BTLA/CD272, CD28, CTLA-4, Gi24/VISTA/B7-H5, ICOS/CD278, PD-1, PD-L2/B7-DC 및 PDCD6), TNF 슈퍼패밀리의 구성원(예를 들어 4-1BB/TNFSF9/CD137, 4-1BB 리간드/TNFSF9, BAFF/BLyS/TNFSF13B, BAFF R/TNFRSF13C, CD27/TNFRSF7, CD27 리간드/TNFSF7, CD30/TNFRSF8, CD30 리간드/TNFSF8, CD40/TNFRSF5, CD40/TNFSF5, CD40 리간드/TNFSF5, DR3/TNFRSF25, GITR/TNFRSF18, GITR 리간드/TNFSF18, HVEM/TNFRSF14, LIGHT/TNFSF14, 림포톡신-알파/TNF-베타, OX40/TNFRSF4, OX40 리간드/TNFSF4, RELT/TNFRSF19L, TACl/TNFRSF13B, TL1A/TNFSF15, TNF-알파 및 TNF RII/TNFRSF1B), SLAM 패밀리의 구성원(예를 들어 2B4/CD244/SLAMF4, BLAME/SLAMF8, CD2, CD2F-10/SLAMF9, CD48/SLAMF2, CD58/LFA-3, CD84/SLAMFS, CD229/SLAMF3, CRACC/SLAMF7, NTB-A/SLAMF6 및 SLAM/CD150) 및 임의의 다른 공동자극성 분자, 예컨대 CD2, CD7, CD53, CD82/Kai-1, CD90/Thyl, CD96, CD160, CD200, CD300a/LMIR1, HLA 부류 I, HLA-DR, Ikaros, 인테그린 알파 4/CD49d, 인테그린 알파 4 베타 1, 인테그린 알파 4 베타 7/LPAM-1, LAG-3, TCL1A, TCL1B, CRTAM, DAP12, Dectin-1/CLEC7A, DPPIV/CD26, EphB6, TIM-1/KIM-1/HAVCR, TIM-4, TSLP, TSLP R, 림프구 기능 연관 항원-1(LFA-1) 및 NKG2C를 포함할 수 있는 일반적으로 고려된다.
그러나, 특히 바람직한 신호전달 도메인은 SEQ ID NO:9에 따른 아미노산 서열(또는 이의 부분)을 갖거나 포함하는 CD3ζ, SEQ ID NO:1에 따른 아미노산 서열(또는 이의 부분)을 갖거나 포함하는 FcεRIγ, SEQ ID NO:7에 따른 아미노산 서열(또는 이의 부분)을 갖거나 포함하는 CD28 및 SEQ ID NO:8에 따른 아미노산 서열(또는 이의 부분)을 갖거나 포함하는 4-1BB로부터의 것을 포함한다.
따라서 그리고 더욱 또 다른 관점에서 봤을 때, 발명자들은 임의의 하나의 도메인이 본원에 제시된 아미노산 서열 중 하나 이상을 사용하여 구축될 수 있는 표 1에 따른 다양한 CAR 작제물을 고려한다. 더욱이, 아래의 표가 예시적인 서열을 나열하긴 하지만, 식별된 바와 같은 각각의 서열은 아미노산 변화가 표에 제시된 서열과 적어도 70%, 또는 적어도 75%, 또는 적어도 80%, 또는 적어도 85%, 또는 적어도 90%, 또는 적어도 91%, 또는 적어도 92%, 또는 적어도 93%, 또는 적어도 94%, 또는 적어도 95%, 또는 적어도 96%, 또는 적어도 97%, 또는 적어도 98%, 또는 적어도 91%의 동일성을 갖도록 하는 하나 이상의 아미노산 변화를 포함할 수 있는 것으로 이해되어야 한다. 더욱이, 또한 절단된 서열이 지시된 기능을 여전히 보유하는 한, 표에 제시된 서열은 (어느 한쪽 말단에서 또는 양쪽 말단 모두에서) 더 짧은 서열로 절단될 수 있는 것으로 인식되어야 한다. 당연하게도, 이들 서열은 외수송 또는 트래피킹(trafficking)을 위한 임의의 추가 서열 부분(예를 들어 리더 펩타이드)이 없는 성숙한 폴리펩타이드 서열을 나타내는 것으로 인식되어야 한다.
표 1
본 발명의 주제의 추가 양태에서, 본원에 제시된 폴리펩타이드 서열뿐만 아니라 본원에 고려되는 서열을 인코딩하는 핵산 서열 및 작제물도 고려되는 것으로 인식되어야 한다. 당연하게도, 쉽게 이해하게 될 바와 같이, 고려되는 핵산 서열은 모든 코돈 용법 패턴, 특히 인간 코돈 용법을 사용할 수 있다. 이에 더하여, 재조합 핵산은 또한 재조합 핵산을 사용하여 형질주입된 세포에서 CAR 작제물의 발현을 발휘하기 위해 모든 필요한 조절 요소를 포함할 것이다. 사이토메갈로바이러스(CMV) 즉각 초기 프로모터(intermediate early promoter), 바이러스 LTR, 예컨대 라우스 육종(Rous sarcoma) 바이러스 LTR, HIV-LTR, HTLV-1 LTR, 시미안 바이러스 40(SV40: simian virus 40) 초기 프로모터, 단순 포진 tk 바이러스 프로모터 등을 포함한 다양한 알려진 프로모터가 본원에 기재된 CAR 작제물의 발현에 사용될 수 있다. 키메라 수용체의 발현을 위한 추가의 프로모터는 면역 세포에서 임의의 항시적으로(constitutively) 활성인 프로모터를 포함한다. 대안적으로, 임의의 조절 가능한 프로모터가 사용될 수 있으며, 따라서 이의 발현은 면역 세포 내에서 조절될 수 있다.
더욱이 그리고 원하는 경우, 재조합 핵산은 원하는 기능을 갖는 하나 이상의 추가의 단백질을 인코딩할 수 있는 하나 이상의 추가의 서열 부분을 포함할 수 있다. 예를 들어, 적합한 추가의 서열 부분은 시토카인, 특히 NK 세포의 자가분비 성장 자극에 필요한 시토카인, 예컨대 소포체 체류 서열을 통해 세포내로 보유될 수 있는 IL-2 및/또는 IL15, 면역 자극성 시토카인, 예컨대 N-801, 인터페론 감마 등, 뿐만 아니라 세포 이동(예를 들어 케모카인 수용체) 또는 종양 미세환경의 변형(예를 들어 IL-8 또는 TGF-β 트랩)에 일조하는 하나 이상의 기능성 단백질을 포함할 것이다.
추가로, 재조합 핵산은 추가의 기능성 요소, 예컨대 선택 가능한 마커 유전자(예를 들어 숙주 세포에서 안정한 또는 일시적인 형질주입제의 선택을 위한 네오마이신 유전자), mRNA 안정성을 위한 SV40으로부터의 증가된 수준의 전사, 전사 종결 및 RNA 프로세싱 신호를 위한 인간 CMV의 즉각 초기 유전자로부터의 하나 이상의 인핸서/프로모터 서열, SV40 폴리오마(polyoma) 복제 기원 및 박테리아에서의 복제를 위한 ColEl, 하나 이상의 내부 리보솜 결합 부위(IRESes), 다중 클로닝 부위, 센스 및 안티센스 RNA의 시험관내 전사를 위한 T7 및 SP6 RNA 프로모터, 촉발된 경우 벡터를 운반하는(carrying) 세포의 사망을 야기 하는 "자살 스위치" 또는 "자살 유전자"(예를 들어 HSV 티미딘 키나제, 유도적 카스파제, 예컨대 iCasp9) 및/또는 CAR 작제물의 발현을 평가하기 위한 하나 이상의 리포터 유전자를 함유할 수 있다. 예시적인 다시스트론성 작제물은 WO 2019/226708호에 기재되어 있으며, 이는 참조로 본원에 포함된다. 이를 위해, 고려되는 핵산 작제물은 동일한 mRNA에 의해 인코딩되는 폴리펩타이드를 등몰 수준으로 생산하기 위해 2A 펩타이드, 예컨대 T2A, P2A, E2A 또는 F2A 펩타이드를 인코딩하는 서열을 포함할 수 있다.
다양한 다른 핵산 서열 중에서, 예시적인 핵산 서열은 SEQ ID NO:2(FcεRIγ 세포내 신호전달 도메인을 인코딩함), SEQ ID NO:4(인간 CD8 힌지를 인코딩함), SEQ ID NO:6(인간 CD28 막관통 부분을 인코딩함), SEQ ID NO:10(CD3ζ 세포내 신호전달 도메인을 인코딩함), SEQ ID NO:11(저 친화도 CD16A를 인코딩함), SEQ ID NO:13(고 친화도 CD16A를 인코딩함), SEQ ID NO:15(CD64A를 인코딩함), SEQ ID NO:18(CD64B를 인코딩함), SEQ ID NO:21(CD64C를 인코딩함), SEQ ID NO:24(CD32A를 인코딩함), SEQ ID NO:27(CD32B를 인코딩함) 및 SEQ ID NO:30(CD16B를 인코딩함)에 따른 서열을 가질 것이다. 추가의 고려되는 핵산 서열은 SEQ ID NO:73(CD16A 막관통 도메인을 인코딩함), SEQ ID NO:75(CD32A 막관통 도메인을 인코딩함), SEQ ID NO:77(CD32B 막관통 도메인을 인코딩함), SEQ ID NO:79(CD64A 막관통 도메인을 인코딩함), SEQ ID NO:81(CD64B 막관통 도메인을 인코딩함) 또는 SEQ ID NO:83(CD16C 막관통 도메인을 인코딩함)에 따른 핵산 서열을 가질 것이다. 주지된 바와 같이, 상기 나열된 바와 같은 핵산 서열은 예를 들어 코돈 우선도(codon preference) 및 하나 이상의 아미노산 교환(바람직하게는, 동시에 이의 각각의 기능을 유지함)로 인해 어느 정도 다양할 수 있는 것으로 인식되어야 한다. 따라서, 본원에 고려되는 핵산 서열은 또한 본원에 개시된 핵산 서열과 적어도 99%, 또는 적어도 98%, 또는 적어도 97%, 또는 적어도 96%, 또는 적어도 95%, 또는 적어도 94%, 또는 적어도 93%, 또는 적어도 92%, 또는 적어도 91%, 또는 적어도 90%의 서열 동일성을 갖는 핵산 서열을 포함한다. 결과적으로, 본원에 고려되는 아미노산 서열은 또한 본원에 개시된 아미노산 서열과 적어도 99%, 또는 적어도 98%, 또는 적어도 97%, 또는 적어도 96%, 또는 적어도 95%, 또는 적어도 94%, 또는 적어도 93%, 또는 적어도 92%, 또는 적어도 91%, 또는 적어도 90%의 서열 동일성을 갖는 아미노산 서열을 포함한다.
따라서, 고려되는 핵산 서열은 또한, CAR 작제물의 형질주입, 전파(propagation) 및/또는 발현에 적합한 다양한 재조합 작제물을 포함할 것이다. 예를 들어, 이러한 재조합 핵산은 선형 또는 환형 DNA 및 RNA, 이러한 선형화된 DNA 및 RNA, 클로닝 벡터, 발현 벡터 및 심지어 재조합 바이러스를 포함할 것이다. 다른 바람직한 옵션 중에서, 이러한 작제물은 전형적으로 선형화된 형태, 바이러스 형태(예를 들어 아데노바이러스 또는 렌티바이러스) 또는 바이러스 발현 벡터에서 다시스트론성 작제물로서 구성될 것이다.
더욱 추가의 고려되는 양태에서, 본원에 제시되는 CAR 작제물은 전형적으로 포유류 세포에서, 가장 바람직하게는 치료용 세포, 또는 세포를 수용하는 개체에 관하여 자가 또는 이종성일 수 있는 면역 적격 세포에서 발현될 것이다. 예를 들어, 본원에 제시된 CAR 작제물의 발현에 적합한 세포는 특히 T 세포, NK 세포 및 NKT 세포를 포함한다.
적합한 NK 세포에 관하여, 모든 NK 세포는 본원에 사용하기에 적합한 것으로 여겨지고 따라서 아래에서 더 상세히 기재된 바와 같이 1차 NK 세포(보존된, 확장된 및/또는 신선한 세포), 불멸화된 2차 NK 세포, 자가 또는 이종성 NK 세포(보관된(banked), 보존된, 신선한 등) 및 변형된 NK 세포를 포함하는 것으로 주지되어야 한다. 일부 구현예에서, NK 세포는 NK-92 세포인 것이 바람직하다. NK-92 세포주는 인터루킨 2(IL-2)의 존재 하에 증식하는 것으로 발견된 독특한 세포주이다(예를 들어 문헌[Gong et al., Leukemia 8:652-658 (1994)] 참조). NK-92 세포는 넓은 항종양 세포독성 및 적합한 배양 배지에서 확장 후 추측 가능한 수율을 갖는 암성 NK 세포이다. 유리하게는, NK-92 세포는 다양한 암에 대해 높은 세포용해 활성을 갖는다.
원래의 NK-92 세포주는 CD56bright, CD2, CD7, CD11a, CD28, CD45 및 CD54 표면 마커를 발현하였으며, CD1, CD3, CD4, CD5, CD8, CD10, CD14, CD16, CD19, CD20, CD23 및 CD34 마커를 나타내지 않았다. 배양물에서 이러한 NK-92 세포의 성장은 인터루킨 2(예를 들어 rIL-2)의 존재에 의존적이고, 1 IU/mL만큼 낮은 용량이 증식을 유지하기에 충분하다. IL-7 및 IL-12는 장기간 성장을 지지하지 않으며, IL-1α, IL-6, 종양 괴사 인자 α, 인터페론 α 및 인터페론 γ를 포함하여 시험된 다양한 다른 시토카인을 갖지 않는다. 1차 NK 세포와 비교하여, NK-92는 전형적으로 심지어 상대적으로 낮은 이펙터:표적(E:T) 비, 예를 들어 1:1에서 높은 세포독성을 갖는다. 대표적인 NK-92 세포는 CRL-2407 명칭 하에 American Type Culture Collection(ATCC)에 기탁된다. 더욱 추가의 고려되는 NK-92 세포는 자가분비 성장 자극을 위한 시토카인을 발현하도록 유전적으로 조작되었고/되었거나 CD16의 고-친화도 버전을 발현하도록 유전적으로 조작된 것을 포함한다.
더욱 추가의 구현예에서, 발명자들은 질환(예를 들어 암, 바이러스 감염, 박테리아 감염 등), 특히 치료 항체가 이용 가능한 질환의 치료에서 본원에 제시된 하나 이상의 CAR 작제물을 발현하는 재조합 세포의 용도를 고려한다. 이러한 치료 용도 및 방법에서, 치료적 유효량의 재조합 세포는 단독으로 또는 치료 항체와 함께 투여될 것이다.
고려되는 질환은 특히 백혈병, 급성 림프구성 백혈병, 급성 골수구성 백혈병, 만성 백혈병, 만성 골수구성(과립구성) 백혈병, 만성 림프구성 백혈병, 진성 적혈구증가증, 림프종, 호지킨 질환, 비호지킨 질환, 다발성 골수종, 발덴스트롬 마크로글로불린혈증, 중쇄 질환, 육종 및 암종, 예컨대 섬유육종, 점액육종, 지방육종, 연골육종, 골원성 육종, 척색종, 혈관육종, 내피육종, 림프관육종, 림프관내피육종, 윤활막종, 중피종, 에윙 종양, 평활근육종, 횡문근육종, 결장 암종, 췌장암, 유방암, 난소암, 전립선암, 편평 세포 암종, 기저 세포 암종, 선암종, 한선 암종, 피지선 암종, 유두상 암종, 유두상 선암종, 낭선암종, 수질 암종, 기관지원성 암종, 신세포 암종, 간종양, 담관 암종, 융모막 암종, 정상피종, 배아 암종, 윌름 종양, 자궁경부암, 고환 종양, 폐암종, 소세포 폐암종, 방광 암종, 상피 암종, 신경교종, 성상세포종, 수모세포종, 두개인두종, 뇌실막종, 송과체종, 혈관아세포종, 청신경종, 희소돌기아교세포종, 수막종, 흑색종, 신경아세포종 및 망막아세포종을 포함하지만 이로 제한되지 않는 고형 종양을 포함한다.
고려되는 형질주입된 세포(예를 들어 형질주입된 NK-92) 세포는 절대수의 세포에 의해 개체에게 투여될 수 있다. 예를 들어, 개체는 약 1,000개 세포/주사 내지 최대 약 100억개의 세포/주사, 예컨대 주사당 약, 적어도 약 또는 최대 약 1x108, 1x107, 5x107, 1x106, 5x106, 1x105, 5x105, 1x104, 5x104, 1x103, 5x103개 또는 종점을 포함하여 임의의 2개의 숫자 사이의 임의의 범위로 투여받을 수 있다. 다른 구현예에서, 세포는 상대수의 세포에 의해 개체에게 투여될 수 있으며, 예를 들어 상기 개체는 개체의 킬로그램당 약 1,000개 세포 내지 최대 약 100억개의 세포, 예컨대 개체의 킬로그램당 약, 적어도 약 또는 최대 약 1x108, 1x107, 5x107, 1x106, 5x106, 1x105, 5x105, 1x104, 5x104, 1x103, 5x103개 또는 종점을 포함하여 임의의 2개의 숫자 사이의 임의의 범위로 투여받을 수 있다. 다른 구현예에서, 총 용량은 체표면적 m2에 의해, m2당 1x1011, 1x1010, 1x109, 1x108, 1x107를 포함하거나 종점을 포함하여 임의의 2개의 숫자 사이의 임의의 범위에 의해 계산될 수 있다. 평균 사람은 약 1.6 내지 약 1.8 m2이다. 바람직한 구현예에서, 약 10억 내지 약 30억개의 NK-92 세포가 환자에게 투여된다.
형질주입된 세포(예를 들어 형질주입된 NK-92 세포) 및 선택적으로 다른 항암제 또는 항바이러스제는 암을 갖거나 바이러스로 감염된 환자에게 치료법 동안 1회 투여될 수 있거나 여러 번, 예를 들어 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 또는 23시간마다 1회 또는 1, 2, 3, 4, 5, 6 또는 7일마다 1회 또는 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 이상의 주마다 1회 또는 종점을 포함하여 임의의 2개의 숫자 사이의 임의의 범위로 투여될 수 있다.
실시예
본원에 제시된 교시와 함께 사용되는 예시적인 핵산 및 아미노산 서열은 SEQ ID NO:33 내지 72를 포함한다. 더 구체적으로, SEQ ID NO:33은 ECD - CD16a TM - FceRIg 도메인을 갖는 예시적인 CD16aV CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:34는 ECD - CD16a TM - FceRIg 도메인을 갖는 예시적인 CD16aV CAR에 대한 아미노산을 보여주고, SEQ ID NO:35는 ECD - CD28 TM - FceRIg 도메인을 갖는 예시적인 CD16aV CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:36은 ECD - CD28 TM - FceRIg 도메인을 갖는 예시적인 CD16aV CAR에 대한 아미노산을 보여주고, SEQ ID NO:37은 ECD - CD8 - CD28 TM - FceRIg 도메인을 갖는 예시적인 CD16aV CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:38은 CD16aV ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:39는 CD16b ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:40은 CD16b ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:41은 CD16b ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:42는 CD16b ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:43은 CD64a ECD - CD64 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:44는 CD64a ECD - CD64 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:45는 CD64a ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:46은 CD64a ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:47은 CD64a ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:48은 CD64a ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:49는 CD64b ECD - CD64 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:50은 CD64b ECD - CD64 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:51은 CD64b ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:52는 CD64b ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:53은 CD64b ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:54는 CD64b ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:55는 CD64c ECD - CD64 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:56은 CD64c ECD - CD64 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:57은 CD64c ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:58은 CD64c ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:59는 CD64c ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 인코딩하는 핵산을 보여주며, SEQ ID NO:60은 CD64c ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:61은 CD32a ECD - CD32a TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:62는 CD32a ECD - CD32a TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:63은 CD32a ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:64는 CD32a ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:65는 CD32a ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:66은 CD32a ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:67은 CD32b ECD - CD32b TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:68은 CD32b ECD - CD32b TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:69는 CD32b ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:70은 CD32b ECD - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여주고, SEQ ID NO:71은 CD32b ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR을 인코딩하는 핵산을 보여주며, SEQ ID NO:72는 CD32b ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR에 대한 아미노산을 보여준다.
본원에서 ECD는 Fc 수용체의 세포외 도메인(이는 예를 들어 CD32B Fc 수용체의 세포외 도메인에 대해 'CD32b ECD'로서 또는 CD16a Fc 수용체의 세포외 도메인에 대해 ECD - CD16a로서 정규화(qualified)될 수 있음)을 지칭하며, TM은 막관통 도메인(예를 들어 CD28 막관통 도메인 CD28 TM)을 지칭하고, FceRIg는 FceRIg로부터의 신호전달 도메인을 지칭하며, CD8은 CD8 힌지 도메인을 지칭한다.
본원에 제시된 교시와 함께 사용되는 추가의 예시적인 핵산 및 아미노산 서열은 SEQ ID NO:73 내지 84를 포함한다. 더 구체적으로, SEQ ID NO:73은 예시적인 CD16A 막관통 도메인을 인코딩하는 핵산을 보여주며, SEQ ID NO:74는 예시적인 CD16A 막관통 도메인에 대한 아미노산을 보여주고, SEQ ID NO:75는 예시적인 CD32A 막관통 도메인을 인코딩하는 핵산을 보여주며, SEQ ID NO:76은 예시적인 CD32A 막관통 도메인에 대한 아미노산을 보여주고, SEQ ID NO:77은 예시적인 CD32B 막관통 도메인을 인코딩하는 핵산을 보여주며, SEQ ID NO:78은 예시적인 CD32B 막관통 도메인에 대한 아미노산을 보여주고, SEQ ID NO:79는 예시적인 CD64A 막관통 도메인을 인코딩하는 핵산을 보여주며, SEQ ID NO:80은 예시적인 CD64A 막관통 도메인에 대한 아미노산을 보여주고, SEQ ID NO:81은 예시적인 CD64B 막관통 도메인을 인코딩하는 핵산을 보여주며, SEQ ID NO:82는 예시적인 CD64B 막관통 도메인에 대한 아미노산을 보여주고, SEQ ID NO:83은 예시적인 CD64C 막관통 도메인을 인코딩하는 핵산을 보여주며, SEQ ID NO:84는 예시적인 CD64C 막관통 도메인에 대한 아미노산을 보여준다. 이러한 맥락에서, 모든 막관통 도메인 서열은 본원에 기재된 바와 같이 CAR 작제물에서 상호 교환적으로 사용될 수 있는 것으로 이해되어야 한다. 따라서 그리고 예를 들어, CD32b ECD - CD8 - CD28 TM - FceRIg 도메인을 포함하는 예시적인 CAR은 또한, CD28 TM 도메인 대신에 SEQ ID NO:73 내지 84에 상기 제시된 바와 같은 CD16A, CD32A, CD32B, CD64A, CD64B 또는 CD64C TM 도메인 중 임의의 하나를 포함하는 CAR로서 제조될 수 있다.
실시예 1. aNK 세포의 형질주입: Fc-CAR 및 IL-2에 대한 서열을 함유하는 비시스트론성(bicistronic) 플라스미드-기초 벡터로 aNK 세포를 전기천공함으로써 Fc-CAR aNK 세포를 생성한다. IL-2 서열을 소포체 체류 신호인 KDEL로 태깅하여 소포체(ER)로부터의 IL-2 단백질 분비를 방지하고, ERIL-2로 지칭한다.
다양한 Fc-CAR 작제물을 인코딩하는 핵산은 서열 목록에 제공되며, 힌지 영역을 포함할 수 있거나 포함하지 않을 수 있다. 이들 작제물을 GeneWiz, Inc에 의해 생성된 PCR 생성물 및 합성 올리고뉴클레오타이드로부터 조립할 것이다. 앰피실린 내성 카세트, EF-1알파 프로모터 및 SV40 폴리아데닐화 서열을 함유하는 비시스트론성 pNEUKv1 IRES_ERIL2 벡터 백본 내로 작제물을 클로닝할 것이다. 생성된 플라스미드 DNA를 형질전환된 박테리아로부터 정제할 것이고, 이의 농도를 UV 분광법에 의해 결정할 것이다. 네온(Neon) 전기천공기 장치를 사용하여 aNK 세포를 다양한 정제된 Fc-CAR 플라스미드로 전기천공할 것이다. 전기천공된 세포를 IL-2의 첨가 없이 5% 열-비활성화된 인간 AB 혈청이 보충된 X-VIVO 10 배지 내로 다시 넣고 5% CO2 인큐베이터에서 37℃에서 인큐베이션할 것이다.
예상된 결과: 플라스미드 작제물을 성공적으로 혼입한 다클론 aNK 세포는 배양 배지에서 IL-2의 부재 하에 성장할 수 있을 것이다. Fc-CAR aNK 세포의 확장하는 집단은 전기천공의 3주 내지 5주 내에 검출 가능하고 또 다른 2주 내지 3주 내에 시험을 받을 수 있어야 한다.
실시예 2. 표현형 분석: 유세포측정법 분석을 실시하여, 전기천공된 aNK 세포 상에서의 Fc-CAR의 표면 발현을 측정할 것이다. 세포를, 인간 CD16, CD32 또는 CD64를 인식하는 형광단-접합 항체를 제조업체의 설명서에 따라 이용하여 염색하고 유세포측정 장치 상에서 분석할 것이다.
예상된 결과: Fc-CAR 분자의 표면 발현은 전기천공 후 3주 내지 5주의 배양 후 적어도 30%의 세포에서 관찰되어야 한다. 더 구체적으로, 선택된 실험 결과에서, 도 2는 aNK 세포(CD16-CAR.28E 세포)에서 발현되는 CD16-CAR.28E 작제물에 대한 데이터를 도시하며, 여기서 CAR을 FCGRIIIA의 CD16A-158V 변이체의 세포외 도메인, CD28의 막관통 도메인 및 FCERIG의 신호전달 도메인으로부터 작제하였다. 이러한 작제물을 인코딩하는 핵산을 pNEUKv1-IRES-ERIL2 플라스미드 내로 서브클로닝하였다. NeonTM 전기천공기 장치를 사용하여 aNK 세포를 이러한 플라스미드로 전기천공하였다. 전기천공 3주 후에, 세포를 항-CD16 항체로 염색하고, 유세포측정법에 의해 분석하였다. 전기천공된 세포를 비전기천공된 aNK 및 haNK 세포와 비교하였다. 스캔으로부터 쉽게 알 수 있는 바와 같이, aNK 세포는 이의 세포 표면 상에 CD16을 발현하지 않은 반면, haNK 세포는 세포 표면 상에 유의한 CD16 발현을 나타내었다. 마찬가지로, CD16-CAR 28.E 세포는 CD16 표면 제시를 위한 강한 신호를 가졌다.
실시예 3. 직접적 또는 천연 세포독성: K562 세포를 10% 열-비활성화된 FBS(Gibco/Thermofisher)가 보충된 RPMI-1640 배지(Gibco/Thermofisher)에서 성장시키고 37℃에서 5% CO2 인큐베이터에서 인큐베이션할 것이다. K562 세포를 녹색 형광 염료(PKH67-GL)로 염색할 것이고, Fc-CAR aNK 이펙터 세포를 96-웰 플레이트에서 상이한 이펙터 : 표적(E:T) 비로 조합하고, 간략하게 원심분리하고, 37℃에서 5% CO2 인큐베이터에서 4시간 동안 인큐베이션할 것이다. 인큐베이션 후, 세포를 1% BSA/PBS 완충제 중 프로피디움 요오다이드(PI)로 1 μg/ml에서 염색하고, 유세포측정법에 의해 즉시 분석할 것이다. 표적 세포 및 이펙터 세포를 또한 PI로 별도로 염색하여 자발적 세포 용해를 평가할 것이다.
사멸된 표적 세포를 PKH67-GL 및 PI에 대한 이중 양성으로서 식별할 것이다. 사멸된 세포의 백분율을 PKH67+ 표적 세포 집단 내 PI+의 백분율에 의해 결정할 것이다. 사멸화 %를 하기와 같이 계산할 것이다 = [시료 내 사멸된 표적 세포% - 자발적으로 사멸된 표적 세포%]/[100 - 자발적으로 사멸된 표적 세포%].
예상된 결과: K562 표적 세포의 사멸화 백분율은 최고 E:T 비에서 50% 초과여야 한다. 더 구체적으로, 선택된 실험 결과에서, 도 3은 NK-민감성 인간 세포주 K562에 대한 유동(flow) 기초 시험관내 세포독성 검정에 의해 결정되고 haNK 세포와 비교한 바와 같은 CD16-CAR.28E 세포의 세포독성 활성에 대한 데이터를 도시한다. 이펙터 및 표적 세포를 10:1 내지 0.06:1 범위의 E:T 비로 혼합하고, 37℃에서 4시간 동안 인큐베이션하였다. 도 3의 그래프로부터 쉽게 알 수 있는 바와 같이, 세포독성은 유사하였고, 심지어 더 높은 E:T 비에서 haNK 세포의 세포독성보다 더 양호하였다.
실시예 4. ADCC: NK-내성 SUP-B15 표적 세포의 CD20-발현 변이체를 검정에 사용할 것이다. CD20+ SUP-B15 표적 세포를 20% 열-비활성화된 FBS(Gibco/Thermofisher) 및 0.2% 베타-머캅토에탄올이 보충된 RPMI-1640 배지(Gibco/Thermofisher)에서 성장시키고, 37℃에서 5% CO2 인큐베이터에서 인큐베이션할 것이다. CD20+ SUP-B15 세포를 녹색 형광 염료(PKH67-GL)로 염색할 것이다. 그 후에, 염색된 표적 세포를 단일클론 항체 리툭시맙(rituximab)(항-CD20 항체) 또는 트라스투주맙(trastuzumab)(항-HER2/neu 대조군 항체, SUP-B15 세포는 HER2/neu 음성임)으로 2 ug/ml의 농도에서 20분 동안 또는 항체 없이 사전인큐베이션할 것이다. 사전인큐베이션된 염색된 표적 세포를 Fc-CAR aNK 이펙터 세포와 상이한 이펙터 : 표적(E:T) 비로 96-웰 플레이트에서 조합하고, 간략하게 원심분리하고, 37℃에서 5% CO2 인큐베이터에서 4시간 동안 인큐베이션할 것이다. 인큐베이션 후, 세포를 1% BSA/PBS 완충제 중 프로피디움 요오다이드(PI)로 1 μg/ml에서 염색하고, 유세포측정법에 의해 즉시 분석할 것이다. 표적 세포 및 이펙터 세포를 또한 PI로 별도로 염색하여 자발적 세포 용해를 평가할 것이다. 사멸된 표적 세포를 PKH67-GL 및 PI에 대한 이중 양성으로서 식별한다. 항체-의존적 세포-매개 세포독성(ADCC%)을 하기와 같이 계산할 것이다 = [(시료 E+T 플러스 mAb 내 사멸된 표적 세포%) - (시료 E+T 마이너스 mAb 내 사멸된 표적 세포%)]/[100 - (시료 E+T 마이너스 mAb 내 사멸된 표적 세포%)], (E = 이펙터, T = 표적, mAb = 단일클론 항체).
예상된 결과: CD20+ SUP-B15 표적 세포의 ADCC 사멸화 백분율은 트라스투주맙의 존재 하에서보다 리툭시맙의 존재 하에 유의하게 더 높아야 한다. ADCC%는 최고 E:T 비에서 적어도 20%여야 한다. 더 구체적으로, 선택된 실험 결과에서, 도 4는 CD20-양성, HER2-음성, NK-내성 인간 세포주 SUP-B15CD20+에 대한 유동 기초 시험관내 세포독성 검정에 의해 결정된 바와 같은 CD16-CAR.28E 세포의 항체-의존적 세포-매개 세포독성(ADCC) 활성에 대한 데이터를 도시한다. 표적 세포를 리툭시맙(표적상 항-CD20) 또는 트라스투주맙(표적외 항-HER2) 항체와 함께 2 μg/mL에서 또는 항체 없이 실온에서 20분 동안 사전인큐베이션하였다. 그 후에, 이펙터 및 사전인큐베이션된 표적 세포를 10:1 내지 0.06:1 범위의 E:T 비로 혼합하고, 37℃에서 4시간 동안 인큐베이션하였다. haNK 세포를 비교용 검정에 포함시켰다. 도 4의 그래프로부터 분명하게 알 수 있는 바와 같이, haNK 세포와 CD16-CAR.28E 세포 둘 모두는 표적외 항체의 존재 하에 어떠한 ADCC 활성도 갖지 않았다. 대조적으로, haNK 세포와 CD16-CAR.28E 세포는 둘 다 표적상 항체의 존재 하에 유의한 ADCC 활성을 가졌고, CD16-CAR.28E 세포는 haNK 세포를 유의하게 능가하였다. 상이한 관점에서 봤을 때, CD16-CAR.28E 작제물은 예상치 못하게도 세포 표면 상에 CD16 158V 고 친화도 변이체를 발현하는 유사한 NK 세포보다 더 강한 ADCC 활성을 제공하였다.
본원에 제시된 교시와 함께 사용하기에 적합한 추가의 양태, 고려사항 및 방법은 US 2018/0133252호 및 US 2016/0067356호에 기재되어 있으며, 이들 둘 모두는 본원에 참조로 포함된다.
일부 구현예에서, 본 발명의 특정한 구현예를 설명하고 주장하는 데 사용되는 성분의 양, 특성, 예컨대 농도, 반응 조건 등을 표현하는 숫자는 일부 경우 용어 "약"에 의해 수식되는 것으로 이해되어야 한다. 따라서, 일부 구현예에서, 작성된 상세한 설명 및 첨부된 청구범위에 제시된 수치 파라미터는 특정 구현예에 의해 수득되고자 하는 원하는 특성에 따라 다양할 수 있는 근사치이다. 본원에서 값의 범위의 언급은 범위 내에 속하는 각각의 별도의 값을 개별적으로 지칭하는 속기 방법으로서 역할을 하는 것으로 의도될 뿐이다. 본원에서 달리 지시되지 않는 한, 각각의 개별 값은 이것이 본원에서 개별적으로 언급된 바와 같이 명세서 내에 포함된다.
본원에 사용된 바와 같이, 약학적 조성물 또는 약물을 "투여하는"이라는 용어는 약학적 조성물 또는 약물의 직접 투여와 간접 투여 둘 모두를 지칭하며, 약학적 조성물 또는 약물의 직접 투여는 전형적으로 의료 전문가(예를 들어 의사, 간호사 등)에 의해 수행되고, 간접 투여는 (예를 들어, 주사, 주입, 경구 전달, 국소 전달 등을 통한) 직접 투여를 위해 약학적 조성물 또는 약물을 의료 전문가에게 제공하거나 이용 가능하게 만드는 단계를 포함한다. 추가로, 질병, 질환의 발증 감수성(susceptibility) 또는 의도된 치료에 대한 반응을 "예후하는(prognosing)" 또는 "예측하는"이라는 용어는 대상체에서 질병의 진행 속도, 향상 및/또는 기간을 포함한 질병, 감수성 및/또는 반응을 예측하는 행위 또는 예측(그러나 이의 치료 또는 진단은 아님)을 망라하는 것으로 의미됨에 주지해야 한다.
본원에 기재된 모든 방법은 본원에서 달리 지시되지 않는 한 또는 맥락에 의해 명확하게 상충되지 않는 한 임의의 적합한 순서로 수행될 수 있다. 본원의 특정한 구현예에 관하여 제공된 임의의 그리고 모든 예 또는 예시적인 언어(예를 들어 "예컨대")의 사용은 본 발명을 더 양호하게 예시하는 것으로 의도될 뿐이며, 달리 청구되지 않는 본 발명의 범위에 제한을 부여하지는 아니다. 명세서에서 어떠한 언어도 본 발명을 실시하는 데 필수적인 임의의 비청구된 요소를 지시하는 것으로 간주되어서는 안 된다.
본원의 상세한 설명에서 그리고 후속하는 청구범위 전반에 걸쳐 사용된 바와 같이, 단수형("a," "an," 및 "the")의 의미는 맥락상 명확하게 달리 지시하지 않는 한 복수형을 포함한다. 또한, 본원의 상세한 설명에 사용된 바와 같이, "내에(in)"의 의미는 맥락상 명확하게 달리 지시하지 않는 한 "내에" 및 "상에"를 포함한다. 본원에서 또한 사용된 바와 같이 그리고 맥락상 달리 지시하지 않는 한, "~에 연결된"이라는 용어는 직접 연결(서로 연결되는 2개의 요소가 서로 접촉함)과 간접 연결(적어도 하나의 추가 요소가 2개의 요소 사이에 위치함)둘 모두를 포함하는 것으로 의도된다. 따라서, "~에 연결된" 및 "~와 연결된"이라는 용어는 동의어로 사용된다.
이미 기재된 것 외에도 더 많은 변형이 본원의 발명의 개념으로부터 벗어나지 않으면서 가능하다는 것이 당업자에게 분명해져야 한다. 따라서, 본 발명의 주제는 첨부된 청구범위의 범위를 제외하고는 제한되지 않는다. 더욱이, 명세서와 청구범위 둘 모두의 해석에서, 모든 용어는 맥락과 일관되는 가장 넓은 가능한 방식으로 해석되어야 한다. 특히, "포함한다" 및 "포함하는"이라는 용어는 요소, 구성요소 또는 단계를 비배타적인 방식으로 지칭하는 것으로 해석되어야 하며, 이는 인용된 요소, 구성요소 또는 단계가 표현적으로 인용되지 않은 다른 요소, 구성요소 또는 단계와 함께 존재하거나 활용되거나 조합될 수 있음을 나타낸다. 명세서 및/또는 청구범위가 A, B, C ... 및 N으로 이루어진 군으로부터 선택되는 것 중 적어도 하나를 지칭하는 경우, 이 텍스트는 A 플러스 N 또는 B 플러스 N 등이 아니라 상기 군으로부터 단지 하나의 요소를 필요로 하는 것으로 해석되어야 한다.
<110> NantKwest, Inc.
<120> Fc-Receptor CAR Constructs and Cells
<130> 104077.0021PRO
<160> 84
<170> PatentIn version 3.5
<210> 1
<211> 41
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(41)
<223> FceRIgamma Intracellular Domain peptide
<400> 1
Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser
1 5 10 15
Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu
20 25 30
Thr Leu Lys His Glu Lys Pro Pro Gln
35 40
<210> 2
<211> 123
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(123)
<223> FceRIgamma Intracellular Domain
<400> 2
ctgaagatcc aggtccgaaa ggccgccatc accagctacg agaagtctga tggcgtgtac 60
accggcctga gcaccagaaa ccaggaaacc tacgagacac tgaagcacga gaagcccccc 120
cag 123
<210> 3
<211> 64
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(64)
<223> CD8 Hinge (Human)
<400> 3
Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu
1 5 10 15
Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
20 25 30
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
35 40 45
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
50 55 60
<210> 4
<211> 192
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(192)
<223> CD8 Hinge DNA (Human)
<400> 4
ctgagcaaca gcatcatgta cttcagccac ttcgtgcctg tgttcctgcc tgccaagcct 60
acaacaacac cagcccctag acctccaacc cctgccccta caattgcctc tcagcctctg 120
tctctgaggc ccgaagcttg tagacctgct gctggcggag ctgtgcacac cagaggactg 180
gatttcgcct gc 192
<210> 5
<211> 28
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(28)
<223> Human CD28 Transmembrane domain
<400> 5
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg
20 25
<210> 6
<211> 84
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(84)
<223> Human CD28 Transmembrane domain (nt)
<400> 6
ttttgggtgc tggtggtcgt gggcggagtg ctggcttgtt attctctgct ggtcaccgtg 60
gccttcatca tcttttgggt ccga 84
<210> 7
<211> 41
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(41)
<223> CD28 signaling domain
<400> 7
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 8
<211> 42
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(42)
<223> 4-1BB signaling domain
<400> 8
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 9
<211> 113
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(113)
<223> CD3 zeta signaling domain
<400> 9
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> 10
<211> 339
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(339)
<223> Human CD3 zeta
<400> 10
gtgaagttca gcaggagcgc agacgccccc gcgtaccagc agggccagaa ccagctctat 60
aacgagctca atctaggacg aagagaggag tacgatgttt tggacaagag acgtggccgg 120
gaccctgaga tggggggaaa gccgcagaga aggaagaacc ctcaggaagg cctgtacaat 180
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
tacgacgccc ttcacatgca ggccctgccc cctcgctaa 339
<210> 11
<211> 765
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(765)
<223> Polynucleotide Encoding the Low Affinity Immunoglobulin Gamma Fc
Region Receptor III-A
<400> 11
atgtggcagc tgctcctccc aactgctctg ctacttctag tttcagctgg catgcggact 60
gaagatctcc caaaggctgt ggtgttcctg gagcctcaat ggtacagggt gctcgagaag 120
gacagtgtga ctctgaagtg ccagggagcc tactcccctg aggacaattc cacacagtgg 180
tttcacaatg agagcctcat ctcaagccag gcctcgagct acttcattga cgctgccaca 240
gtcgacgaca gtggagagta caggtgccag acaaacctct ccaccctcag tgacccggtg 300
cagctagaag tccatatcgg ctggctgttg ctccaggccc ctcggtgggt gttcaaggag 360
gaagacccta ttcacctgag gtgtcacagc tggaagaaca ctgctctgca taaggtcaca 420
tatttacaga atggcaaagg caggaagtat tttcatcata attctgactt ctacattcca 480
aaagccacac tcaaagacag cggctcctac ttctgcaggg ggctttttgg gagtaaaaat 540
gtgtcttcag agactgtgaa catcaccatc actcaaggtt tggcagtgtc aaccatctca 600
tcattctttc cacctgggta ccaagtctct ttctgcttgg tgatggtact cctttttgca 660
gtggacacag gactatattt ctctgtgaag acaaacattc gaagctcaac aagagactgg 720
aaggaccata aatttaaatg gagaaaggac cctcaagaca aatga 765
<210> 12
<211> 254
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(254)
<223> High Affinity Variant Ig gamma FcRIII-A amino acid sequence
<400> 12
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln
195 200 205
Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
210 215 220
Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp
225 230 235 240
Lys Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys
245 250
<210> 13
<211> 765
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(765)
<223> High Affinity Variant IgGamma FcRIII-A nucleic acid sequence
<400> 13
atgtggcagc tgctgctgcc tacagctctc ctgctgctgg tgtccgccgg catgagaacc 60
gaggatctgc ctaaggccgt ggtgttcctg gaaccccagt ggtacagagt gctggaaaag 120
gacagcgtga ccctgaagtg ccagggcgcc tacagccccg aggacaatag cacccagtgg 180
ttccacaacg agagcctgat cagcagccag gccagcagct acttcatcga cgccgccacc 240
gtggacgaca gcggcgagta tagatgccag accaacctga gcaccctgag cgaccccgtg 300
cagctggaag tgcacatcgg atggctgctg ctgcaggccc ccagatgggt gttcaaagaa 360
gaggacccca tccacctgag atgccactct tggaagaaca ccgccctgca caaagtgacc 420
tacctgcaga acggcaaggg cagaaagtac ttccaccaca acagcgactt ctacatcccc 480
aaggccaccc tgaaggactc cggctcctac ttctgcagag gcctcgtggg cagcaagaac 540
gtgtccagcg agacagtgaa catcaccatc acccagggcc tggccgtgtc taccatcagc 600
agctttttcc cacccggcta ccaggtgtcc ttctgcctcg tgatggtgct gctgttcgcc 660
gtggacaccg gcctgtactt cagcgtgaaa acaaacatca gaagcagcac ccgggactgg 720
aaggaccaca agttcaagtg gcggaaggac ccccaggaca agtga 765
<210> 14
<211> 135
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(135)
<223> Human T-cell surface glycoprotein CD3 zeta
<400> 14
Pro Lys Leu Cys Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val
1 5 10 15
Ile Leu Thr Ala Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
20 25 30
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
35 40 45
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
50 55 60
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
65 70 75 80
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
85 90 95
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
100 105 110
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
115 120 125
Met Gln Ala Leu Pro Pro Arg
130 135
<210> 15
<211> 1336
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(1336)
<223> Human FCGR1A (CD64A) nt sequence
<400> 15
aatatcttgc atgttacaga tttcactgct cccaccagct tggagacaac atgtggttct 60
tgacaactct gctcctttgg gttccagttg atgggcaagt ggtagacacc acaaaggcag 120
tgatcacttt gcagcctcca tgggtcagcg tgttccaaga ggaaaccgta accttgcact 180
gtgaggtgct ccatctgcct gggagcagct ctacacagtg gtttctcaat ggcacagcca 240
ctcagacctc gacccccagc tacagaatca cctctgccag tgtcaatgac agtggtgaat 300
acaggtgcca gagaggtctc tcagggcgaa gtgaccccat acagctggaa atccacagag 360
gctggctact actgcaggtc tccagcagag tcttcacgga aggagaacct ctggccttga 420
ggtgtcatgc gtggaaggat aagctggtgt acaatgtgct ttactatcga aatggcaaag 480
cctttaagtt tttccactgg aattctaacc tcaccattct gaaaaccaac ataagtcaca 540
atggcaccta ccattgctca ggcatgggaa agcatcgcta cacatcagca ggaatatctg 600
tcactgtgaa agagctattt ccagctccag tgctgaatgc atctgtgaca tccccactcc 660
tggaggggaa tctggtcacc ctgagctgtg aaacaaagtt gctcttgcag aggcctggtt 720
tgcagcttta cttctccttc tacatgggca gcaagaccct gcgaggcagg aacacatcct 780
ctgaatacca aatactaact gctagaagag aagactctgg gttatactgg tgcgaggctg 840
ccacagagga tggaaatgtc cttaagcgca gccctgagtt ggagcttcaa gtgcttggcc 900
tccagttacc aactcctgtc tggtttcatg tccttttcta tctggcagtg ggaataatgt 960
ttttagtgaa cactgttctc tgggtgacaa tacgtaaaga actgaaaaga aagaaaaagt 1020
gggatttaga aatctctttg gattctggtc atgagaagaa ggtaatttcc agccttcaag 1080
aagacagaca tttagaagaa gagctgaaat gtcaggaaca aaaagaagaa cagctgcagg 1140
aaggggtgca ccggaaggag ccccaggggg ccacgtagca gcggctcagt gggtggccat 1200
cgatctggac cgtcccctgc ccacttgctc cccgtgagca ctgcgtacaa acatccaaaa 1260
gttcaacaac accagaactg tgtgtctcat ggtatgtaac tcttaaagca aataaatgaa 1320
ctgacttcaa ctggga 1336
<210> 16
<211> 374
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(374)
<223> Human FCGR1A (CD64A) a.a. sequence
<400> 16
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala Pro
180 185 190
Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu Val
195 200 205
Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu Gln
210 215 220
Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg Asn
225 230 235 240
Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser Gly
245 250 255
Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys Arg
260 265 270
Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr Pro
275 280 285
Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu
290 295 300
Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys Arg Lys
305 310 315 320
Lys Lys Trp Asp Leu Glu Ile Ser Leu Asp Ser Gly His Glu Lys Lys
325 330 335
Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu Leu Lys
340 345 350
Cys Gln Glu Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His Arg Lys
355 360 365
Glu Pro Gln Gly Ala Thr
370
<210> 17
<211> 292
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(292)
<223> Human FCGR1A (CD64A) extracellular domain
<400> 17
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala Pro
180 185 190
Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu Val
195 200 205
Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu Gln
210 215 220
Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg Asn
225 230 235 240
Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser Gly
245 250 255
Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys Arg
260 265 270
Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr Pro
275 280 285
Val Trp Phe His
290
<210> 18
<211> 904
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(904)
<223> Human FCGR1B (CD64B)
<400> 18
gtacaaaaaa gcagaagggc cgtcaaggcc caccatgtgg ttcttgacaa ctctgctcct 60
ttgggttcca gttgatgggc aagtggacac cacaaaggca gtgatcactt tgcagcctcc 120
atgggtcagc gtgttccaag aggaaaccgt aaccttgcac tgtgaggtgc tccatctgcc 180
tgggagcagc tccacacagt ggtttctcaa tggcacagcc actcagacct cgacccccag 240
ctacagaatc acctctgcca gtgtcaatga cagtggtgaa tacaggtgcc agagaggtct 300
ctcagggcga agtgacccca tacagctgga aatccacaga ggctggctac tactgcaggt 360
ctccagcaga gtcttcatgg aaggagaacc tctggccttg aggtgtcatg cgtggaagga 420
taagctggtg tacaatgtgc tttactatcg aaatggcaaa gcctttaagt ttttccactg 480
gaattctaac ctcaccattc tgaaaaccaa cataagtcac aatggcacct accattgctc 540
aggcatggga aagcatcgct acacatcagc aggaatatca caatacactg tgaaaggcct 600
ccagttacca actcctgtct ggtttcatgt ccttttctat ctggcagtgg gaataatgtt 660
tttagtgaac actgttctct gggtgacaat acgtaaagaa ctgaaaagaa agaaaaagtg 720
gaatttagaa atctctttgg attctggtca tgagaagaag gtaatttcca gccttcaaga 780
agacagacat ttagaagaag agctgaaatg tcaggaacaa aaagaagaac agctgcagga 840
aggggtgcac cggaaggagc cccagggggc cacgtaaggc ctcatgggcc cagctttctt 900
gtac 904
<210> 19
<211> 280
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(280)
<223> Human FCGR1B (CD64B)
<400> 19
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Met Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met
195 200 205
Phe Leu Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys
210 215 220
Arg Lys Lys Lys Trp Asn Leu Glu Ile Ser Leu Asp Ser Gly His Glu
225 230 235 240
Lys Lys Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu
245 250 255
Leu Lys Cys Gln Glu Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His
260 265 270
Arg Lys Glu Pro Gln Gly Ala Thr
275 280
<210> 20
<211> 198
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(198)
<223> Human FCGR1B (CD64B) extracellular domain
<400> 20
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Met Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His
195
<210> 21
<211> 1068
<212> DNA
<213> Homo sapiens
<400> 21
aatatcttgc atgttacaga tttcactgct cccaccagct tggagacaac atgtggttct 60
tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca aaggcagtga 120
tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc ttgcactgtg 180
aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc acagccactc 240
agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt ggtgaataca 300
ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc cacagaggct 360
ggccactact gcaggtctcc agcagagtct tcacggaagg agaacctctg gccttgaggt 420
gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat ggcaaagcct 480
ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata agtcacaatg 540
gcacctacca ttgctcaggc aagggaaagc atcactacac atcagcagga atatcacaat 600
acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatgtcctt ttctatctgg 660
cagtgggaat aatgttttta gtgaacactg ttctctgggt gacaatacgt aaagaactga 720
aaagaaagaa aaagtggaat ttagaaatct ctttggattc tggtcatgag aagaaggtaa 780
tttccagcct tcaagaagac agacatttag aagaagagct gaaatgtcag gaacaaaaag 840
aagaacagct gcaggaaggg gtgcaccgga aggagcccca gggggccacg tagcagcggc 900
tcagtgggtg gccatcgatc tggaccgtcc cctgtccact tgctccccgt gagcactgcg 960
tacaaacatc caaaagttca acaacaccag aactgtgtgt ctcatggtat ataactctta 1020
aggcaaataa atgaactgac ttcaactggg aaaaaaaaaa aaaaaaaa 1068
<210> 22
<211> 280
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(280)
<223> Human FCGR1C
<400> 22
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Pro Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Lys Gly Lys His His Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met
195 200 205
Phe Leu Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys
210 215 220
Arg Lys Lys Lys Trp Asn Leu Glu Ile Ser Leu Asp Ser Gly His Glu
225 230 235 240
Lys Lys Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu
245 250 255
Leu Lys Cys Gln Glu Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His
260 265 270
Arg Lys Glu Pro Gln Gly Ala Thr
275 280
<210> 23
<211> 198
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(198)
<223> Human FCGR1C extracellular domain
<400> 23
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Pro Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Lys Gly Lys His His Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His
195
<210> 24
<211> 2643
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(2643)
<223> Human FCGR2A (CD32A)
<400> 24
acagtgctgg gatgactatg gagacccaaa tgtctcagaa tgtatgtccc agaaacctgt 60
ggctgcttca accattgaca gttttgctgc tgctggcttc tgcagacagt caagctgctc 120
ccccaaaggc tgtgctgaaa cttgagcccc cgtggatcaa cgtgctccag gaggactctg 180
tgactctgac atgccagggg gctcgcagcc ctgagagcga ctccattcag tggttccaca 240
atgggaatct cattcccacc cacacgcagc ccagctacag gttcaaggcc aacaacaatg 300
acagcgggga gtacacgtgc cagactggcc agaccagcct cagcgaccct gtgcatctga 360
ctgtgctttc cgaatggctg gtgctccaga cccctcacct ggagttccag gagggagaaa 420
ccatcatgct gaggtgccac agctggaagg acaagcctct ggtcaaggtc acattcttcc 480
agaatggaaa atcccagaaa ttctcccatt tggatcccac cttctccatc ccacaagcaa 540
accacagtca cagtggtgat taccactgca caggaaacat aggctacacg ctgttctcat 600
ccaagcctgt gaccatcact gtccaagtgc ccagcatggg cagctcttca ccaatgggga 660
tcattgtggc tgtggtcatt gcgactgctg tagcagccat tgttgctgct gtagtggcct 720
tgatctactg caggaaaaag cggatttcag ccaattccac tgatcctgtg aaggctgccc 780
aatttgagcc acctggacgt caaatgattg ccatcagaaa gagacaactt gaagaaacca 840
acaatgacta tgaaacagct gacggcggct acatgactct gaaccccagg gcacctactg 900
acgatgataa aaacatctac ctgactcttc ctcccaacga ccatgtcaac agtaataact 960
aaagagtaac gttatgccat gtggtcatac tctcagcttg ctgagtggat gacaaaaaga 1020
ggggaattgt taaaggaaaa tttaaatgga gactggaaaa atcctgagca aacaaaacca 1080
cctggccctt agaaatagct ttaactttgc ttaaactaca aacacaagca aaacttcacg 1140
gggtcatact acatacaagc ataagcaaaa cttaacttgg atcatttctg gtaaatgctt 1200
atgttagaaa taagacaacc ccagccaatc acaagcagcc tactaacata taattaggtg 1260
actagggact ttctaagaag atacctaccc ccaaaaaaca attatgtaat tgaaaaccaa 1320
ccgattgcct ttattttgct tccacatttt cccaataaat acttgcctgt gacattttgc 1380
cactggaaca ctaaacttca tgaattgcgc ctcagatttt tcctttaaca tctttttttt 1440
ttttgacaga gtctcaatct gttacccagg ctggagtgca gtggtgctat cttggctcac 1500
tgcaaacccg cctcccaggt ttaagcgatt ctcatgcctc agcctcccag tagctgggat 1560
tagaggcatg tgccatcata cccagctaat ttttgtattt tttatttttt ttttttagta 1620
gagacagggt ttcgcaatgt tggccaggcc gatctcgaac ttctggcctc tagcgatctg 1680
cccgcctcgg cctcccaaag tgctgggatg accagcatca gccccaatgt ccagcctctt 1740
taacatcttc tttcctatgc cctctctgtg gatccctact gctggtttct gccttctcca 1800
tgctgagaac aaaatcacct attcactgct tatgcagtcg gaagctccag aagaacaaag 1860
agcccaatta ccagaaccac attaagtctc cattgttttg ccttgggatt tgagaagaga 1920
attagagagg tgaggatctg gtatttcctg gactaaattc cccttgggga agacgaaggg 1980
atgctgcagt tccaaaagag aaggactctt ccagagtcat ctacctgagt cccaaagctc 2040
cctgtcctga aagccacaga caatatggtc ccaaatgact gactgcacct tctgtgcctc 2100
agccgttctt gacatcaaga atcttctgtt ccacatccac acagccaata caattagtca 2160
aaccactgtt attaacagat gtagcaacat gagaaacgct tatgttacag gttacatgag 2220
agcaatcatg taagtctata tgacttcaga aatgttaaaa tagactaacc tctaacaaca 2280
aattaaaagt gattgtttca aggtgatgca attattgatg acctatttta tttttctata 2340
atgatcatat attacctttg taataaaaca ttataaccaa aacattctgt ttaccttttc 2400
agggctgtat tgattggggt gtagactgaa ctatccgggg tctgtttctt ttcggtgatg 2460
aaagtcttga gaaggtagta atggataaga tgtgagggag aggagagagg gagatttgga 2520
gtgtagggtg agtgcccctc ttcttagaac tgaatactct tcttctaatg aacttgtatt 2580
cttgtttcca tgtcttcttc cctttccttc tatagcaaat aaagcattca ctttgttttg 2640
gaa 2643
<210> 25
<211> 316
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(316)
<223> Human FCGR2A (CD32A)
<400> 25
Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu
1 5 10 15
Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp
20 25 30
Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp
35 40 45
Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala
50 55 60
Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu
65 70 75 80
Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn
85 90 95
Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp
100 105 110
Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro
115 120 125
His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser
130 135 140
Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys
145 150 155 160
Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala
165 170 175
Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr
180 185 190
Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro Ser
195 200 205
Met Gly Ser Ser Ser Pro Met Gly Val Ile Val Ala Val Val Ile Ala
210 215 220
Thr Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr Cys
225 230 235 240
Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala
245 250 255
Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln
260 265 270
Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met
275 280 285
Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu
290 295 300
Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn
305 310 315
<210> 26
<211> 216
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(216)
<223> Human FCGR2A (CD32A) extracellular domain
<400> 26
Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu
1 5 10 15
Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp
20 25 30
Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp
35 40 45
Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala
50 55 60
Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu
65 70 75 80
Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn
85 90 95
Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp
100 105 110
Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro
115 120 125
His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser
130 135 140
Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys
145 150 155 160
Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala
165 170 175
Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr
180 185 190
Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro Ser
195 200 205
Met Gly Ser Ser Ser Pro Met Gly
210 215
<210> 27
<211> 2068
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(2068)
<223> Human FCGR2B (CD32B)
<400> 27
gcagaccaag tggcttaagg gtagaatccg ccaagctttg agagaaggct gtgactgctg 60
tgctctgggc gccagctcgc tccagggagt gatgggaatc ctgtcattct tacctgtcct 120
tgccactgag agtgactggg ctgactgcaa gtccccccag ccttggggtc atatgcttct 180
gtggacagct gtgctattcc tggctcctgt tgctgggaca cctgcagctc ccccaaaggc 240
tgtgctgaaa ctcgagcccc agtggatcaa cgtgctccag gaggactctg tgactctgac 300
atgccggggg actcacagcc ctgagagcga ctccattcag tggttccaca atgggaatct 360
cattcccacc cacacgcagc ccagctacag gttcaaggcc aacaacaatg acagcgggga 420
gtacacgtgc cagactggcc agaccagcct cagcgaccct gtgcatctga ctgtgctttc 480
tgagtggctg gtgctccaga cccctcacct ggagttccag gagggagaaa ccatcgtgct 540
gaggtgccac agctggaagg acaagcctct ggtcaaggtc acattcttcc agaatggaaa 600
atccaagaaa ttttcccgtt cggatcccaa cttctccatc ccacaagcaa accacagtca 660
cagtggtgat taccactgca caggaaacat aggctacacg ctgtactcat ccaagcctgt 720
gaccatcact gtccaagctc ccagctcttc accgatgggg atcattgtgg ctgtggtcac 780
tgggattgct gtagcggcca ttgttgctgc tgtagtggcc ttgatctact gcaggaaaaa 840
gcggatttca gccaatccca ctaatcctga tgaggctgac aaagttgggg ctgagaacac 900
aatcacctat tcacttctca tgcacccgga tgctctggaa gagcctgatg accagaaccg 960
tatttagtct ccattgtctt gcattgggat ttgagaagaa aatcagagag ggaagatctg 1020
gtatttcctg gcctaaattc cccttgggga ggacagggag atgctgcagt tccaaaagag 1080
aaggtttctt ccagagtcat ctacctgagt cctgaagctc cctgtcctga aagccacaga 1140
caatatggtc ccaaataacc gactgcacct tctgtgcttc agctcttctt gacatcaagg 1200
ctcttccgtt ccacatccac acagccaatc caattaatca aaccactgtt attaacagat 1260
aatagcaact tgggaaatgc ttatgttaca ggttacgtga gaacaatcat gtaaatctat 1320
atgatttcag aaatgttaaa atagactaac ctctaccagc acattaaaag tgattgtttc 1380
tgggtgataa aattattgat gatttttatt ttctttattt ttctataaag atcatatatt 1440
acttttataa taaaacatta taaaaacaac attctgttta ccttttcaag gctgtattgg 1500
ttggagtgta gactgaactg cctggggtct gtttctcttc agtgatgaga ctcttaggaa 1560
ggcaggaatg gataggatag ggggaggaga ggagagatgg ggatttagaa tgtagagtga 1620
gtgccccttt tcttaaaact gaatacagtc acgcaccaca taatgatgtt tagttcaaca 1680
acagactgca tatatgatgg tgatcccata aaattataat accatatttc tattgtacct 1740
tttctattcc tatgtttaga tatatgagta cttaccattg tgttacaatt gcctaaagta 1800
ttcagtacag tagcatgctg tacaggtttg tagcctaggg gcaataggct atacgctaca 1860
gcctaggtgt gtagtaggcc acaccattta ggtttgtata agtacctgct atgatgttca 1920
cacaacaaaa ttgcctgcat ttctcaaaat gtatccccat atttcaacaa tgcatgactg 1980
tactcttctg ccaatgacct tgtattcttg tttccatgtc ttcttctctt tcctcctatg 2040
gcaaataaaa cactgttttg caacacaa 2068
<210> 28
<211> 310
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(310)
<223> Human FCGR2B (CD32B)
<400> 28
Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp
1 5 10 15
Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr
20 25 30
Ala Val Leu Phe Leu Ala Pro Val Ala Gly Thr Pro Ala Ala Pro Pro
35 40 45
Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu
50 55 60
Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp
65 70 75 80
Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln
85 90 95
Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr
100 105 110
Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val
115 120 125
Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu
130 135 140
Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu
145 150 155 160
Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg
165 170 175
Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly
180 185 190
Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys
195 200 205
Pro Val Thr Ile Thr Val Gln Ala Pro Ser Ser Ser Pro Met Gly Ile
210 215 220
Ile Val Ala Val Val Thr Gly Thr Ala Val Ala Ala Ile Val Ala Ala
225 230 235 240
Val Val Ala Leu Ile Tyr Cys Arg Lys Lys Arg Ile Ser Ala Leu Pro
245 250 255
Gly Tyr Pro Glu Cys Arg Glu Met Gly Glu Thr Leu Pro Glu Lys Pro
260 265 270
Ala Asn Pro Thr Asn Pro Asp Glu Ala Asp Lys Val Gly Ala Glu Asn
275 280 285
Thr Ile Thr Tyr Ser Leu Leu Met His Pro Asp Ala Leu Glu Glu Pro
290 295 300
Asp Asp Gln Asn Arg Ile
305 310
<210> 29
<211> 217
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(217)
<223> Human FCGR2B (CD32B) extracellular domain
<400> 29
Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp
1 5 10 15
Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr
20 25 30
Ala Val Leu Phe Leu Ala Pro Val Ala Gly Thr Pro Ala Ala Pro Pro
35 40 45
Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu
50 55 60
Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp
65 70 75 80
Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln
85 90 95
Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr
100 105 110
Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val
115 120 125
Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu
130 135 140
Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu
145 150 155 160
Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg
165 170 175
Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly
180 185 190
Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys
195 200 205
Pro Val Thr Ile Thr Val Gln Ala Pro
210 215
<210> 30
<211> 2300
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1)..(2300)
<223> Human FCGR3B (CD16B)
<400> 30
agatgctcag ccgcagacct ttgggagagt aaagggggca cacccaccca ccttgcctcc 60
aggctctttc cttcctattc ctgttctatg gtggggctcc attgcgagac ttcagattga 120
gaaatcagat gaagtttcaa gaaaaggaaa ctggcaggtg acagagatgg gtggagggac 180
tggggaaagg ctgtttactc cctcctgtct agtcggcttg gtccctttag ggctccggat 240
atctttggtg acttgtccac tccagtgtgg catcatgtgg cagctgctcc tcccaactgc 300
tctgctactt ctagtttcag ctggcatgcg gactgaagat ctcccaaagg ctgtggtgtt 360
cctggagcct caatggtaca gcgtgcttga gaaggacagt gtgactctga agtgccaggg 420
agcctactcc cctgaggaca attccacaca gtggtttcac aatgagaacc tcatctcaag 480
ccaggcctcg agctacttca ttgacgctgc cacagtcaac gacagtggag agtacaggtg 540
ccagacaaac ctctccaccc tcagtgaccc ggtgcagcta gaagtccata tcggctggct 600
gttgctccag gcccctcggt gggtgttcaa ggaggaagac cctattcacc tgaggtgtca 660
cagctggaag aacactgctc tgcataaggt cacatattta cagaatggca aagacaggaa 720
gtattttcat cataattctg acttccacat tccaaaagcc acactcaaag atagcggctc 780
ctacttctgc agggggcttg ttgggagtaa aaatgtgtct tcagagactg tgaacatcac 840
catcactcaa ggtttggcag tgtcaaccat ctcatcattc tctccacctg ggtaccaagt 900
ctctttctgc ttggtgatgg tactcctttt tgcagtggac acaggactat atttctctgt 960
gaagacaaac atttgaagct caacaagaga ctggaaggac cataaactta aatggagaaa 1020
ggaccctcaa gacaaatgac ccccatccca tgggagtaat aagagcagtg gcagcagcat 1080
ctctgaacat ttctctggat ttgcaacccc atcatcctca ggcctctcta caagcagcag 1140
gaaacataga actcagagcc agatccttta tccaactctc gatttttcct tggtctccag 1200
tggaagggaa aagcccatga tcttcaagca gggaagcccc agtgagtagc tgcattccta 1260
gaaattgaag tttcagagct acacaaacac tttttctgtc ccaaccattc cctcacagca 1320
aagcaacaat acaggctagg gatggtaatc ctttaaacat acaaaaattg ctcgtattat 1380
aaattaccca gtttagaggg aaaaaaagaa aataattatt cctaaacaaa tggataagta 1440
gaattaatgg ttgaggcagg accctacaga gtgtgggaac tgctggggat ctagagaatt 1500
cagtgggacc aatgaaagca tggctgagaa atagcagggt agtccaggat agtctaaggg 1560
aggtgttccc atctgagccc agagataagg gtgtcttcct agaacattag ccgtagtgga 1620
attaacagga aatcatgagg gtgacgtaga attgagtctt ccaggggact ctatcagaac 1680
tggaccattt ccaagtatat aacgatgagc cctctaatgc taggagtagc aaatggtcct 1740
aggaagggga ctgaggattg gggtgggggt ggggtggaaa agaaagtaca gaacaaaccc 1800
tgtgtcactg tcccaagtta agctaagtga acagaactat ctcagcatca gaatgagaaa 1860
gcctgagaag aaagaaccaa ccacaagcac acaggaagga aagcgcagga ggtgaaaatg 1920
ctttcttggc cagggtagta agaattagag gttaatgcag ggactgtaaa accacctttt 1980
ctgcttcaat gtctagttcc tgtatagctt tgttcattgc atttattaaa caaatgttgt 2040
ataaccaata ctaaatgtac tactgagctt cactgagtta cgctgtgaaa ctttcaaatc 2100
cttcttcatg tcagttccaa tgaggtgggg atggagaaga caattgttgc ttatgaaaga 2160
aagctttagc tgtctctgtt ttgtaagctt tcagtgcaac atttcttggt tccaataaag 2220
cattttacaa gatcttgcat gctactctta gatagaagat ggcaaaacca tggtaataaa 2280
atatgaatga taaaaaaaaa 2300
<210> 31
<211> 233
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(233)
<223> Human FCGR3B (CD16B)
<400> 31
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Ser Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Ser Pro Pro Gly Tyr Gln
195 200 205
Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
210 215 220
Leu Tyr Phe Ser Val Lys Thr Asn Ile
225 230
<210> 32
<211> 200
<212> PRT
<213> Homo sapiens
<220>
<221> MISC_FEATURE
<222> (1)..(200)
<223> Human FCGR3B (CD16B) extracellular domain
<400> 32
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Ser Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser
195 200
<210> 33
<211> 810
<212> DNA
<213> Artificial Sequence
<220>
<223> CD16aV CAR with ECD - CD16a TM - FceRIg portions
<220>
<221> misc_feature
<222> (1)..(810)
<223> CD16aV CAR with ECD - CD16a TM - FceRIg domains
<400> 33
atgtggcagc tgctgctgcc tacagctctc ctgctgctgg tgtccgccgg catgagaacc 60
gaggatctgc ctaaggccgt ggtgttcctg gaaccccagt ggtacagagt gctggaaaag 120
gacagcgtga ccctgaagtg ccagggcgcc tacagccccg aggacaatag cacccagtgg 180
ttccacaacg agagcctgat cagcagccag gccagcagct acttcatcga cgccgccacc 240
gtggacgaca gcggcgagta tagatgccag accaacctga gcaccctgag cgaccccgtg 300
cagctggaag tgcacatcgg atggctgctg ctgcaggccc ccagatgggt gttcaaagaa 360
gaggacccca tccacctgag atgccactct tggaagaaca ccgccctgca caaagtgacc 420
tacctgcaga acggcaaggg cagaaagtac ttccaccaca acagcgactt ctacatcccc 480
aaggccaccc tgaaggactc cggctcctac ttctgcagag gcctcgtggg cagcaagaac 540
gtgtccagcg agacagtgaa catcaccatc acccagggcc tggccgtgtc taccatcagc 600
agctttttcc cacccggcta ccaggtgtcc ttctgcctcg tgatggtgct gctgttcgcc 660
gtggacaccg gcctgtactt cagcgtgctg aagatccagg tccgaaaggc cgccatcacc 720
agctacgaga agtctgatgg cgtgtacacc ggcctgagca ccagaaacca ggaaacctac 780
gagacactga agcacgagaa gcccccccag 810
<210> 34
<211> 270
<212> PRT
<213> Artificial Sequence
<220>
<223> CD16aV CAR with ECD - CD16a TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(270)
<223> CD16aV CAR with ECD - CD16a TM - FceRIg domains
<400> 34
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln
195 200 205
Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
210 215 220
Leu Tyr Phe Ser Val Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr
225 230 235 240
Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn
245 250 255
Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
260 265 270
<210> 35
<211> 825
<212> DNA
<213> Artificial Sequence
<220>
<223> CD16aV CAR with ECD - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(825)
<223> CD16aV CAR with ECD - CD28 TM - FceRIg domains
<400> 35
atgtggcagc tgctgctgcc tacagctctc ctgctgctgg tgtccgccgg catgagaacc 60
gaggatctgc ctaaggccgt ggtgttcctg gaaccccagt ggtacagagt gctggaaaag 120
gacagcgtga ccctgaagtg ccagggcgcc tacagccccg aggacaatag cacccagtgg 180
ttccacaacg agagcctgat cagcagccag gccagcagct acttcatcga cgccgccacc 240
gtggacgaca gcggcgagta tagatgccag accaacctga gcaccctgag cgaccccgtg 300
cagctggaag tgcacatcgg atggctgctg ctgcaggccc ccagatgggt gttcaaagaa 360
gaggacccca tccacctgag atgccactct tggaagaaca ccgccctgca caaagtgacc 420
tacctgcaga acggcaaggg cagaaagtac ttccaccaca acagcgactt ctacatcccc 480
aaggccaccc tgaaggactc cggctcctac ttctgcagag gcctcgtggg cagcaagaac 540
gtgtccagcg agacagtgaa catcaccatc acccagggcc tggccgtgtc taccatcagc 600
agctttttcc cacccggctt ttgggtgctg gtggtcgtgg gcggagtgct ggcttgttat 660
tctctgctgg tcaccgtggc cttcatcatc ttttgggtcc gactgaagat ccaggtccga 720
aaggccgcca tcaccagcta cgagaagtct gatggcgtgt acaccggcct gagcaccaga 780
aaccaggaaa cctacgagac actgaagcac gagaagcccc cccag 825
<210> 36
<211> 275
<212> PRT
<213> Artificial Sequence
<220>
<223> CD16aV CAR with ECD - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(275)
<223> CD16aV CAR with ECD - CD28 TM - FceRIg domains
<400> 36
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Phe Trp
195 200 205
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
210 215 220
Thr Val Ala Phe Ile Ile Phe Trp Val Arg Leu Lys Ile Gln Val Arg
225 230 235 240
Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly
245 250 255
Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys
260 265 270
Pro Pro Gln
275
<210> 37
<211> 1017
<212> DNA
<213> Artificial Sequence
<220>
<223> CD16aV CAR with ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(1017)
<223> CD16aV CAR with ECD - CD8 - CD28 TM - FceRIg domains
<400> 37
atgtggcagc tgctgctgcc tacagctctc ctgctgctgg tgtccgccgg catgagaacc 60
gaggatctgc ctaaggccgt ggtgttcctg gaaccccagt ggtacagagt gctggaaaag 120
gacagcgtga ccctgaagtg ccagggcgcc tacagccccg aggacaatag cacccagtgg 180
ttccacaacg agagcctgat cagcagccag gccagcagct acttcatcga cgccgccacc 240
gtggacgaca gcggcgagta tagatgccag accaacctga gcaccctgag cgaccccgtg 300
cagctggaag tgcacatcgg atggctgctg ctgcaggccc ccagatgggt gttcaaagaa 360
gaggacccca tccacctgag atgccactct tggaagaaca ccgccctgca caaagtgacc 420
tacctgcaga acggcaaggg cagaaagtac ttccaccaca acagcgactt ctacatcccc 480
aaggccaccc tgaaggactc cggctcctac ttctgcagag gcctcgtggg cagcaagaac 540
gtgtccagcg agacagtgaa catcaccatc acccagggcc tggccgtgtc taccatcagc 600
agctttttcc cacccggcct gagcaacagc atcatgtact tcagccactt cgtgcctgtg 660
ttcctgcctg ccaagcctac aacaacacca gcccctagac ctccaacccc tgcccctaca 720
attgcctctc agcctctgtc tctgaggccc gaagcttgta gacctgctgc tggcggagct 780
gtgcacacca gaggactgga tttcgcctgc ttttgggtgc tggtggtcgt gggcggagtg 840
ctggcttgtt attctctgct ggtcaccgtg gccttcatca tcttttgggt ccgactgaag 900
atccaggtcc gaaaggccgc catcaccagc tacgagaagt ctgatggcgt gtacaccggc 960
ctgagcacca gaaaccagga aacctacgag acactgaagc acgagaagcc cccccag 1017
<210> 38
<211> 339
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD16aV ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(339)
<223> CAR comprising ECD - CD8 - CD28 TM - FceRIg domains
<400> 38
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Leu Ser
195 200 205
Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu Pro Ala
210 215 220
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
225 230 235 240
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
245 250 255
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Phe Trp
260 265 270
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
275 280 285
Thr Val Ala Phe Ile Ile Phe Trp Val Arg Leu Lys Ile Gln Val Arg
290 295 300
Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly
305 310 315 320
Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys
325 330 335
Pro Pro Gln
<210> 39
<211> 999
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD16b ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(998)
<223> CAR comprising CD16b ECD - CD8 - CD28 TM - FceRIg domains
<400> 39
atgtggcagc tgctcctccc aactgctctg ctacttctag tttcagctgg catgcggact 60
gaagatctcc caaaggctgt ggtgttcctg gagcctcaat ggtacagcgt gcttgagaag 120
gacagtgtga ctctgaagtg ccagggagcc tactcccctg aggacaattc cacacagtgg 180
tttcacaatg agaacctcat ctcaagccag gcctcgagct acttcattga cgctgccaca 240
gtcaacgaca gtggagagta caggtgccag acaaacctct ccaccctcag tgacccggtg 300
cagctagaag tccatatcgg ctggctgttg ctccaggccc ctcggtgggt gttcaaggag 360
gaagacccta ttcacctgag gtgtcacagc tggaagaaca ctgctctgca taaggtcaca 420
tatttacaga atggcaaaga caggaagtat tttcatcata attctgactt ccacattcca 480
aaagccacac tcaaagatag cggctcctac ttctgcaggg ggcttgttgg gagtaaaaat 540
gtgtcttcag agactgtgaa catcaccatc actcaaggtt tggcagtgtc aaccatctca 600
ctgagcaaca gcatcatgta cttcagccac ttcgtgcctg tgttcctgcc tgccaagcct 660
acaacaacac cagcccctag acctccaacc cctgccccta caattgcctc tcagcctctg 720
tctctgaggc ccgaagcttg tagacctgct gctggcggag ctgtgcacac cagaggactg 780
gatttcgcct gcttttgggt gctggtggtc gtgggcggag tgctggcttg ttattctctg 840
ctggtcaccg tggccttcat catcttttgg gtccgactga agatccaggt ccgaaaggcc 900
gccatcacca gctacgagaa gtctgatggc gtgtacaccg gcctgagcac cagaaaccag 960
gaaacctacg agacactgaa gcacgagaag cccccccag 999
<210> 40
<211> 333
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD16b ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(333)
<223> CAR comprising CD16b ECD - CD8 - CD28 TM - FceRIg domains
<400> 40
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Ser Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Asn Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Leu Ser Asn Ser Ile Met Tyr Phe
195 200 205
Ser His Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro
210 215 220
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
225 230 235 240
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
245 250 255
Thr Arg Gly Leu Asp Phe Ala Cys Phe Trp Val Leu Val Val Val Gly
260 265 270
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
275 280 285
Phe Trp Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser
290 295 300
Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln
305 310 315 320
Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
325 330
<210> 41
<211> 807
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD16b ECD - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(807)
<223> CAR comprising CD16b ECD - CD28 TM - FceRIg domians
<400> 41
atgtggcagc tgctcctccc aactgctctg ctacttctag tttcagctgg catgcggact 60
gaagatctcc caaaggctgt ggtgttcctg gagcctcaat ggtacagcgt gcttgagaag 120
gacagtgtga ctctgaagtg ccagggagcc tactcccctg aggacaattc cacacagtgg 180
tttcacaatg agaacctcat ctcaagccag gcctcgagct acttcattga cgctgccaca 240
gtcaacgaca gtggagagta caggtgccag acaaacctct ccaccctcag tgacccggtg 300
cagctagaag tccatatcgg ctggctgttg ctccaggccc ctcggtgggt gttcaaggag 360
gaagacccta ttcacctgag gtgtcacagc tggaagaaca ctgctctgca taaggtcaca 420
tatttacaga atggcaaaga caggaagtat tttcatcata attctgactt ccacattcca 480
aaagccacac tcaaagatag cggctcctac ttctgcaggg ggcttgttgg gagtaaaaat 540
gtgtcttcag agactgtgaa catcaccatc actcaaggtt tggcagtgtc aaccatctca 600
ttttgggtgc tggtggtcgt gggcggagtg ctggcttgtt attctctgct ggtcaccgtg 660
gccttcatca tcttttgggt ccgactgaag atccaggtcc gaaaggccgc catcaccagc 720
tacgagaagt ctgatggcgt gtacaccggc ctgagcacca gaaaccagga aacctacgag 780
acactgaagc acgagaagcc cccccag 807
<210> 42
<211> 269
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD16b ECD - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(269)
<223> CAR comprising CD16b ECD - CD28 TM - FceRIg domains
<400> 42
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Ser Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Asn Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Phe Trp Val Leu Val Val Val Gly
195 200 205
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
210 215 220
Phe Trp Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser
225 230 235 240
Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln
245 250 255
Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
260 265
<210> 43
<211> 1056
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64a ECD - CD64 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(1056)
<223> CAR comprising CD64a ECD - CD64 TM - FceRIg domains
<400> 43
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggtagacacc 60
acaaaggcag tgatcacttt gcagcctcca tgggtcagcg tgttccaaga ggaaaccgta 120
accttgcact gtgaggtgct ccatctgcct gggagcagct ctacacagtg gtttctcaat 180
ggcacagcca ctcagacctc gacccccagc tacagaatca cctctgccag tgtcaatgac 240
agtggtgaat acaggtgcca gagaggtctc tcagggcgaa gtgaccccat acagctggaa 300
atccacagag gctggctact actgcaggtc tccagcagag tcttcacgga aggagaacct 360
ctggccttga ggtgtcatgc gtggaaggat aagctggtgt acaatgtgct ttactatcga 420
aatggcaaag cctttaagtt tttccactgg aattctaacc tcaccattct gaaaaccaac 480
ataagtcaca atggcaccta ccattgctca ggcatgggaa agcatcgcta cacatcagca 540
ggaatatctg tcactgtgaa agagctattt ccagctccag tgctgaatgc atctgtgaca 600
tccccactcc tggaggggaa tctggtcacc ctgagctgtg aaacaaagtt gctcttgcag 660
aggcctggtt tgcagcttta cttctccttc tacatgggca gcaagaccct gcgaggcagg 720
aacacatcct ctgaatacca aatactaact gctagaagag aagactctgg gttatactgg 780
tgcgaggctg ccacagagga tggaaatgtc cttaagcgca gccctgagtt ggagcttcaa 840
gtgcttggcc tccagttacc aactcctgtc tggtttcatg tccttttcta tctggcagtg 900
ggaataatgt ttttagtgaa cactgttctc tggctgaaga tccaggtccg aaaggccgcc 960
atcaccagct acgagaagtc tgatggcgtg tacaccggcc tgagcaccag aaaccaggaa 1020
acctacgaga cactgaagca cgagaagccc ccccag 1056
<210> 44
<211> 352
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64a ECD - CD64 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(352)
<223> CAR comprising CD64a ECD - CD64 TM - FceRIg domains
<400> 44
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val
20 25 30
Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His
35 40 45
Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr
50 55 60
Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp
65 70 75 80
Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro
85 90 95
Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser
100 105 110
Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp
115 120 125
Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala
130 135 140
Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn
145 150 155 160
Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg
165 170 175
Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala
180 185 190
Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu
195 200 205
Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu
210 215 220
Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg
225 230 235 240
Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser
245 250 255
Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys
260 265 270
Arg Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr
275 280 285
Pro Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe
290 295 300
Leu Val Asn Thr Val Leu Trp Leu Lys Ile Gln Val Arg Lys Ala Ala
305 310 315 320
Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr
325 330 335
Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
340 345 350
<210> 45
<211> 1086
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64a ECD - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(1086)
<223> CAR comprising CD64a ECD - CD28 TM - FceRIg domains
<400> 45
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggtagacacc 60
acaaaggcag tgatcacttt gcagcctcca tgggtcagcg tgttccaaga ggaaaccgta 120
accttgcact gtgaggtgct ccatctgcct gggagcagct ctacacagtg gtttctcaat 180
ggcacagcca ctcagacctc gacccccagc tacagaatca cctctgccag tgtcaatgac 240
agtggtgaat acaggtgcca gagaggtctc tcagggcgaa gtgaccccat acagctggaa 300
atccacagag gctggctact actgcaggtc tccagcagag tcttcacgga aggagaacct 360
ctggccttga ggtgtcatgc gtggaaggat aagctggtgt acaatgtgct ttactatcga 420
aatggcaaag cctttaagtt tttccactgg aattctaacc tcaccattct gaaaaccaac 480
ataagtcaca atggcaccta ccattgctca ggcatgggaa agcatcgcta cacatcagca 540
ggaatatctg tcactgtgaa agagctattt ccagctccag tgctgaatgc atctgtgaca 600
tccccactcc tggaggggaa tctggtcacc ctgagctgtg aaacaaagtt gctcttgcag 660
aggcctggtt tgcagcttta cttctccttc tacatgggca gcaagaccct gcgaggcagg 720
aacacatcct ctgaatacca aatactaact gctagaagag aagactctgg gttatactgg 780
tgcgaggctg ccacagagga tggaaatgtc cttaagcgca gccctgagtt ggagcttcaa 840
gtgcttggcc tccagttacc aactcctgtc tggtttcatt tttgggtgct ggtggtcgtg 900
ggcggagtgc tggcttgtta ttctctgctg gtcaccgtgg ccttcatcat cttttgggtc 960
cgactgaaga tccaggtccg aaaggccgcc atcaccagct acgagaagtc tgatggcgtg 1020
tacaccggcc tgagcaccag aaaccaggaa acctacgaga cactgaagca cgagaagccc 1080
ccccag 1086
<210> 46
<211> 362
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64a ECD - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(362)
<223> CAR comprising CD64a ECD - CD28 TM - FceRIg domains
<400> 46
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val
20 25 30
Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His
35 40 45
Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr
50 55 60
Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp
65 70 75 80
Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro
85 90 95
Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser
100 105 110
Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp
115 120 125
Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala
130 135 140
Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn
145 150 155 160
Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg
165 170 175
Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala
180 185 190
Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu
195 200 205
Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu
210 215 220
Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg
225 230 235 240
Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser
245 250 255
Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys
260 265 270
Arg Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr
275 280 285
Pro Val Trp Phe His Phe Trp Val Leu Val Val Val Gly Gly Val Leu
290 295 300
Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
305 310 315 320
Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys
325 330 335
Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr
340 345 350
Glu Thr Leu Lys His Glu Lys Pro Pro Gln
355 360
<210> 47
<211> 1278
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64a ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(1278)
<223> CAR comprising CD64a ECD - CD8 - CD28 TM - FceRIg domains
<400> 47
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggtagacacc 60
acaaaggcag tgatcacttt gcagcctcca tgggtcagcg tgttccaaga ggaaaccgta 120
accttgcact gtgaggtgct ccatctgcct gggagcagct ctacacagtg gtttctcaat 180
ggcacagcca ctcagacctc gacccccagc tacagaatca cctctgccag tgtcaatgac 240
agtggtgaat acaggtgcca gagaggtctc tcagggcgaa gtgaccccat acagctggaa 300
atccacagag gctggctact actgcaggtc tccagcagag tcttcacgga aggagaacct 360
ctggccttga ggtgtcatgc gtggaaggat aagctggtgt acaatgtgct ttactatcga 420
aatggcaaag cctttaagtt tttccactgg aattctaacc tcaccattct gaaaaccaac 480
ataagtcaca atggcaccta ccattgctca ggcatgggaa agcatcgcta cacatcagca 540
ggaatatctg tcactgtgaa agagctattt ccagctccag tgctgaatgc atctgtgaca 600
tccccactcc tggaggggaa tctggtcacc ctgagctgtg aaacaaagtt gctcttgcag 660
aggcctggtt tgcagcttta cttctccttc tacatgggca gcaagaccct gcgaggcagg 720
aacacatcct ctgaatacca aatactaact gctagaagag aagactctgg gttatactgg 780
tgcgaggctg ccacagagga tggaaatgtc cttaagcgca gccctgagtt ggagcttcaa 840
gtgcttggcc tccagttacc aactcctgtc tggtttcatc tgagcaacag catcatgtac 900
ttcagccact tcgtgcctgt gttcctgcct gccaagccta caacaacacc agcccctaga 960
cctccaaccc ctgcccctac aattgcctct cagcctctgt ctctgaggcc cgaagcttgt 1020
agacctgctg ctggcggagc tgtgcacacc agaggactgg atttcgcctg cttttgggtg 1080
ctggtggtcg tgggcggagt gctggcttgt tattctctgc tggtcaccgt ggccttcatc 1140
atcttttggg tccgactgaa gatccaggtc cgaaaggccg ccatcaccag ctacgagaag 1200
tctgatggcg tgtacaccgg cctgagcacc agaaaccagg aaacctacga gacactgaag 1260
cacgagaagc ccccccag 1278
<210> 48
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64a ECD - CD8 - CD28 TM - FceRIg domains
<400> 48
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val
20 25 30
Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His
35 40 45
Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr
50 55 60
Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp
65 70 75 80
Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro
85 90 95
Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser
100 105 110
Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp
115 120 125
Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala
130 135 140
Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn
145 150 155 160
Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg
165 170 175
Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala
180 185 190
Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu
195 200 205
Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu
210 215 220
Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg
225 230 235 240
Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser
245 250 255
Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys
260 265 270
Arg Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr
275 280 285
Pro Val Trp Phe His Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe
290 295 300
Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg
305 310 315 320
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
325 330 335
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
340 345 350
Leu Asp Phe Ala Cys Phe Trp Val Leu Val Val Val Gly Gly Val Leu
355 360 365
Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
370 375 380
Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys
385 390 395 400
Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr
405 410 415
Glu Thr Leu Lys His Glu Lys Pro Pro Gln
420 425
<210> 49
<211> 780
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64b ECD - CD64 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(780)
<223> CAR comprising CD64b ECD - CD64 TM - FceRIg domains
<400> 49
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca 60
aaggcagtga tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc 120
ttgcactgtg aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc 180
acagccactc agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt 240
ggtgaataca ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc 300
cacagaggct ggctactact gcaggtctcc agcagagtct tcatggaagg agaacctctg 360
gccttgaggt gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat 420
ggcaaagcct ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata 480
agtcacaatg gcacctacca ttgctcaggc atgggaaagc atcgctacac atcagcagga 540
atatcacaat acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatgtcctt 600
ttctatctgg cagtgggaat aatgttttta gtgaacactg ttctctgggt gacaatactg 660
aagatccagg tccgaaaggc cgccatcacc agctacgaga agtctgatgg cgtgtacacc 720
ggcctgagca ccagaaacca ggaaacctac gagacactga agcacgagaa gcccccccag 780
780
<210> 50
<211> 260
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64b ECD - CD64 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(260)
<223> CAR comprising CD64b ECD - CD64 TM - FceRIg domains
<400> 50
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Met Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met
195 200 205
Phe Leu Val Asn Thr Val Leu Trp Val Thr Ile Leu Lys Ile Gln Val
210 215 220
Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr
225 230 235 240
Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu
245 250 255
Lys Pro Pro Gln
260
<210> 51
<211> 801
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64b ECD - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(801)
<223> CAR comprising CD64b ECD - CD28 TM - FceRIg domains
<400> 51
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca 60
aaggcagtga tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc 120
ttgcactgtg aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc 180
acagccactc agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt 240
ggtgaataca ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc 300
cacagaggct ggctactact gcaggtctcc agcagagtct tcatggaagg agaacctctg 360
gccttgaggt gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat 420
ggcaaagcct ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata 480
agtcacaatg gcacctacca ttgctcaggc atgggaaagc atcgctacac atcagcagga 540
atatcacaat acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatttttgg 600
gtgctggtgg tcgtgggcgg agtgctggct tgttattctc tgctggtcac cgtggccttc 660
atcatctttt gggtccgact gaagatccag gtccgaaagg ccgccatcac cagctacgag 720
aagtctgatg gcgtgtacac cggcctgagc accagaaacc aggaaaccta cgagacactg 780
aagcacgaga agccccccca g 801
<210> 52
<211> 267
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64b ECD - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(267)
<223> CAR comprising CD64b ECD - CD28 TM - FceRIg domains
<400> 52
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Met Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Phe Trp Val Leu Val Val Val Gly Gly Val
195 200 205
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
210 215 220
Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu
225 230 235 240
Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr
245 250 255
Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
260 265
<210> 53
<211> 993
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64b ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(993)
<223> CAR comprising CD64b ECD - CD8 - CD28 TM - FceRIg domains
<400> 53
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca 60
aaggcagtga tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc 120
ttgcactgtg aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc 180
acagccactc agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt 240
ggtgaataca ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc 300
cacagaggct ggctactact gcaggtctcc agcagagtct tcatggaagg agaacctctg 360
gccttgaggt gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat 420
ggcaaagcct ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata 480
agtcacaatg gcacctacca ttgctcaggc atgggaaagc atcgctacac atcagcagga 540
atatcacaat acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatctgagc 600
aacagcatca tgtacttcag ccacttcgtg cctgtgttcc tgcctgccaa gcctacaaca 660
acaccagccc ctagacctcc aacccctgcc cctacaattg cctctcagcc tctgtctctg 720
aggcccgaag cttgtagacc tgctgctggc ggagctgtgc acaccagagg actggatttc 780
gcctgctttt gggtgctggt ggtcgtgggc ggagtgctgg cttgttattc tctgctggtc 840
accgtggcct tcatcatctt ttgggtccga ctgaagatcc aggtccgaaa ggccgccatc 900
accagctacg agaagtctga tggcgtgtac accggcctga gcaccagaaa ccaggaaacc 960
tacgagacac tgaagcacga gaagcccccc cag 993
<210> 54
<211> 331
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64b ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(331)
<223> CAR comprising CD64b ECD - CD8 - CD28 TM - FceRIg domains
<400> 54
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Met Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Leu Ser Asn Ser Ile Met Tyr Phe Ser His
195 200 205
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
210 215 220
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
225 230 235 240
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
245 250 255
Gly Leu Asp Phe Ala Cys Phe Trp Val Leu Val Val Val Gly Gly Val
260 265 270
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
275 280 285
Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu
290 295 300
Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr
305 310 315 320
Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
325 330
<210> 55
<211> 771
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64c ECD - CD64 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(771)
<223> CAR comprising CD64c ECD - CD64 TM - FceRIg domains
<400> 55
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca 60
aaggcagtga tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc 120
ttgcactgtg aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc 180
acagccactc agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt 240
ggtgaataca ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc 300
cacagaggct ggccactact gcaggtctcc agcagagtct tcacggaagg agaacctctg 360
gccttgaggt gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat 420
ggcaaagcct ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata 480
agtcacaatg gcacctacca ttgctcaggc aagggaaagc atcactacac atcagcagga 540
atatcacaat acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatgtcctt 600
ttctatctgg cagtgggaat aatgttttta gtgaacactg ttctctggct gaagatccag 660
gtccgaaagg ccgccatcac cagctacgag aagtctgatg gcgtgtacac cggcctgagc 720
accagaaacc aggaaaccta cgagacactg aagcacgaga agccccccca g 771
<210> 56
<211> 257
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64c ECD - CD64 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(257)
<223> CAR comprising CD64c ECD - CD64 TM - FceRIg domains
<400> 56
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Pro Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Lys Gly Lys His His Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met
195 200 205
Phe Leu Val Asn Thr Val Leu Trp Leu Lys Ile Gln Val Arg Lys Ala
210 215 220
Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser
225 230 235 240
Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro
245 250 255
Gln
<210> 57
<211> 801
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD64c ECD - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(801)
<223> CAR comprising CD64c ECD - CD28 TM - FceRIg domains
<400> 57
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca 60
aaggcagtga tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc 120
ttgcactgtg aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc 180
acagccactc agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt 240
ggtgaataca ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc 300
cacagaggct ggccactact gcaggtctcc agcagagtct tcacggaagg agaacctctg 360
gccttgaggt gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat 420
ggcaaagcct ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata 480
agtcacaatg gcacctacca ttgctcaggc aagggaaagc atcactacac atcagcagga 540
atatcacaat acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatttttgg 600
gtgctggtgg tcgtgggcgg agtgctggct tgttattctc tgctggtcac cgtggccttc 660
atcatctttt gggtccgact gaagatccag gtccgaaagg ccgccatcac cagctacgag 720
aagtctgatg gcgtgtacac cggcctgagc accagaaacc aggaaaccta cgagacactg 780
aagcacgaga agccccccca g 801
<210> 58
<211> 267
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64c ECD - CD28 TM - FceRIg domains
<400> 58
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Pro Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Lys Gly Lys His His Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Phe Trp Val Leu Val Val Val Gly Gly Val
195 200 205
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
210 215 220
Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu
225 230 235 240
Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr
245 250 255
Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
260 265
<210> 59
<211> 993
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprsing CD64c ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(993)
<223> CAR comprising CD64c ECD - CD8 - CD28 TM - FceRIg domains
<400> 59
atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca 60
aaggcagtga tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc 120
ttgcactgtg aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc 180
acagccactc agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt 240
ggtgaataca ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc 300
cacagaggct ggccactact gcaggtctcc agcagagtct tcacggaagg agaacctctg 360
gccttgaggt gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat 420
ggcaaagcct ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata 480
agtcacaatg gcacctacca ttgctcaggc aagggaaagc atcactacac atcagcagga 540
atatcacaat acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatctgagc 600
aacagcatca tgtacttcag ccacttcgtg cctgtgttcc tgcctgccaa gcctacaaca 660
acaccagccc ctagacctcc aacccctgcc cctacaattg cctctcagcc tctgtctctg 720
aggcccgaag cttgtagacc tgctgctggc ggagctgtgc acaccagagg actggatttc 780
gcctgctttt gggtgctggt ggtcgtgggc ggagtgctgg cttgttattc tctgctggtc 840
accgtggcct tcatcatctt ttgggtccga ctgaagatcc aggtccgaaa ggccgccatc 900
accagctacg agaagtctga tggcgtgtac accggcctga gcaccagaaa ccaggaaacc 960
tacgagacac tgaagcacga gaagcccccc cag 993
<210> 60
<211> 331
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD64c ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(331)
<223> CAR comprising CD64c ECD - CD8 - CD28 TM - FceRIg domains
<400> 60
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Pro Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Lys Gly Lys His His Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro
180 185 190
Thr Pro Val Trp Phe His Leu Ser Asn Ser Ile Met Tyr Phe Ser His
195 200 205
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
210 215 220
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
225 230 235 240
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
245 250 255
Gly Leu Asp Phe Ala Cys Phe Trp Val Leu Val Val Val Gly Gly Val
260 265 270
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
275 280 285
Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu
290 295 300
Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr
305 310 315 320
Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
325 330
<210> 61
<211> 840
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD32a ECD - CD32a TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(840)
<223> CAR comprising CD32a ECD - CD32a TM - FceRIg domains
<400> 61
atgactatgg agacccaaat gtctcagaat gtatgtccca gaaacctgtg gctgcttcaa 60
ccattgacag ttttgctgct gctggcttct gcagacagtc aagctgctcc cccaaaggct 120
gtgctgaaac ttgagccccc gtggatcaac gtgctccagg aggactctgt gactctgaca 180
tgccaggggg ctcgcagccc tgagagcgac tccattcagt ggttccacaa tgggaatctc 240
attcccaccc acacgcagcc cagctacagg ttcaaggcca acaacaatga cagcggggag 300
tacacgtgcc agactggcca gaccagcctc agcgaccctg tgcatctgac tgtgctttcc 360
gaatggctgg tgctccagac ccctcacctg gagttccagg agggagaaac catcatgctg 420
aggtgccaca gctggaagga caagcctctg gtcaaggtca cattcttcca gaatggaaaa 480
tcccagaaat tctcccattt ggatcccacc ttctccatcc cacaagcaaa ccacagtcac 540
agtggtgatt accactgcac aggaaacata ggctacacgc tgttctcatc caagcctgtg 600
accatcactg tccaagtgcc cagcatgggc agctcttcac caatggggat cattgtggct 660
gtggtcattg cgactgctgt agcagccatt gttgctgctg tagtggcctt gatctacctg 720
aagatccagg tccgaaaggc cgccatcacc agctacgaga agtctgatgg cgtgtacacc 780
ggcctgagca ccagaaacca ggaaacctac gagacactga agcacgagaa gcccccccag 840
840
<210> 62
<211> 280
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD32a ECD - CD32a TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(280)
<223> CAR comprising CD32a ECD - CD32a TM - FceRIg domains
<400> 62
Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu
1 5 10 15
Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp
20 25 30
Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp
35 40 45
Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala
50 55 60
Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu
65 70 75 80
Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn
85 90 95
Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp
100 105 110
Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro
115 120 125
His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser
130 135 140
Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys
145 150 155 160
Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala
165 170 175
Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr
180 185 190
Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro Ser
195 200 205
Met Gly Ser Ser Ser Pro Met Gly Ile Ile Val Ala Val Val Ile Ala
210 215 220
Thr Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr Leu
225 230 235 240
Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp
245 250 255
Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr
260 265 270
Leu Lys His Glu Lys Pro Pro Gln
275 280
<210> 63
<211> 849
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprsing CD32a ECD - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(849)
<223> CAR comprising CD32a ECD - CD28 TM - FceRIg domains
<400> 63
atgactatgg agacccaaat gtctcagaat gtatgtccca gaaacctgtg gctgcttcaa 60
ccattgacag ttttgctgct gctggcttct gcagacagtc aagctgctcc cccaaaggct 120
gtgctgaaac ttgagccccc gtggatcaac gtgctccagg aggactctgt gactctgaca 180
tgccaggggg ctcgcagccc tgagagcgac tccattcagt ggttccacaa tgggaatctc 240
attcccaccc acacgcagcc cagctacagg ttcaaggcca acaacaatga cagcggggag 300
tacacgtgcc agactggcca gaccagcctc agcgaccctg tgcatctgac tgtgctttcc 360
gaatggctgg tgctccagac ccctcacctg gagttccagg agggagaaac catcatgctg 420
aggtgccaca gctggaagga caagcctctg gtcaaggtca cattcttcca gaatggaaaa 480
tcccagaaat tctcccattt ggatcccacc ttctccatcc cacaagcaaa ccacagtcac 540
agtggtgatt accactgcac aggaaacata ggctacacgc tgttctcatc caagcctgtg 600
accatcactg tccaagtgcc cagcatgggc agctcttcac cattttgggt gctggtggtc 660
gtgggcggag tgctggcttg ttattctctg ctggtcaccg tggccttcat catcttttgg 720
gtccgactga agatccaggt ccgaaaggcc gccatcacca gctacgagaa gtctgatggc 780
gtgtacaccg gcctgagcac cagaaaccag gaaacctacg agacactgaa gcacgagaag 840
cccccccag 849
<210> 64
<211> 283
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD32a ECD - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(283)
<223> CAR comprising CD32a ECD - CD28 TM - FceRIg domains
<400> 64
Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu
1 5 10 15
Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp
20 25 30
Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp
35 40 45
Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala
50 55 60
Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu
65 70 75 80
Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn
85 90 95
Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp
100 105 110
Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro
115 120 125
His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser
130 135 140
Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys
145 150 155 160
Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala
165 170 175
Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr
180 185 190
Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro Ser
195 200 205
Met Gly Ser Ser Ser Pro Phe Trp Val Leu Val Val Val Gly Gly Val
210 215 220
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
225 230 235 240
Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu
245 250 255
Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr
260 265 270
Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
275 280
<210> 65
<211> 1041
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD32a ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(1041)
<223> CAR comprising CD32a ECD - CD8 - CD28 TM - FceRIg domains
<400> 65
atgactatgg agacccaaat gtctcagaat gtatgtccca gaaacctgtg gctgcttcaa 60
ccattgacag ttttgctgct gctggcttct gcagacagtc aagctgctcc cccaaaggct 120
gtgctgaaac ttgagccccc gtggatcaac gtgctccagg aggactctgt gactctgaca 180
tgccaggggg ctcgcagccc tgagagcgac tccattcagt ggttccacaa tgggaatctc 240
attcccaccc acacgcagcc cagctacagg ttcaaggcca acaacaatga cagcggggag 300
tacacgtgcc agactggcca gaccagcctc agcgaccctg tgcatctgac tgtgctttcc 360
gaatggctgg tgctccagac ccctcacctg gagttccagg agggagaaac catcatgctg 420
aggtgccaca gctggaagga caagcctctg gtcaaggtca cattcttcca gaatggaaaa 480
tcccagaaat tctcccattt ggatcccacc ttctccatcc cacaagcaaa ccacagtcac 540
agtggtgatt accactgcac aggaaacata ggctacacgc tgttctcatc caagcctgtg 600
accatcactg tccaagtgcc cagcatgggc agctcttcac cactgagcaa cagcatcatg 660
tacttcagcc acttcgtgcc tgtgttcctg cctgccaagc ctacaacaac accagcccct 720
agacctccaa cccctgcccc tacaattgcc tctcagcctc tgtctctgag gcccgaagct 780
tgtagacctg ctgctggcgg agctgtgcac accagaggac tggatttcgc ctgcttttgg 840
gtgctggtgg tcgtgggcgg agtgctggct tgttattctc tgctggtcac cgtggccttc 900
atcatctttt gggtccgact gaagatccag gtccgaaagg ccgccatcac cagctacgag 960
aagtctgatg gcgtgtacac cggcctgagc accagaaacc aggaaaccta cgagacactg 1020
aagcacgaga agccccccca g 1041
<210> 66
<211> 347
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD32a ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(347)
<223> CAR comprising CD32a ECD - CD8 - CD28 TM - FceRIg
<400> 66
Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu
1 5 10 15
Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp
20 25 30
Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp
35 40 45
Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala
50 55 60
Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu
65 70 75 80
Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn
85 90 95
Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp
100 105 110
Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro
115 120 125
His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser
130 135 140
Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys
145 150 155 160
Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala
165 170 175
Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr
180 185 190
Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro Ser
195 200 205
Met Gly Ser Ser Ser Pro Leu Ser Asn Ser Ile Met Tyr Phe Ser His
210 215 220
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
225 230 235 240
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
245 250 255
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
260 265 270
Gly Leu Asp Phe Ala Cys Phe Trp Val Leu Val Val Val Gly Gly Val
275 280 285
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
290 295 300
Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu
305 310 315 320
Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr
325 330 335
Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
340 345
<210> 67
<211> 861
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD32b ECD - CD32b TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(861)
<223> CAR comprising CD32b ECD - CD32b TM - FceRIg domains
<400> 67
atgggaatcc tgtcattctt acctgtcctt gccactgaga gtgactgggc tgactgcaag 60
tccccccagc cttggggtca tatgcttctg tggacagctg tgctattcct ggctcctgtt 120
gctgggacac ctgcagctcc cccaaaggct gtgctgaaac tcgagcccca gtggatcaac 180
gtgctccagg aggactctgt gactctgaca tgccggggga ctcacagccc tgagagcgac 240
tccattcagt ggttccacaa tgggaatctc attcccaccc acacgcagcc cagctacagg 300
ttcaaggcca acaacaatga cagcggggag tacacgtgcc agactggcca gaccagcctc 360
agcgaccctg tgcatctgac tgtgctttct gagtggctgg tgctccagac ccctcacctg 420
gagttccagg agggagaaac catcgtgctg aggtgccaca gctggaagga caagcctctg 480
gtcaaggtca cattcttcca gaatggaaaa tccaagaaat tttcccgttc ggatcccaac 540
ttctccatcc cacaagcaaa ccacagtcac agtggtgatt accactgcac aggaaacata 600
ggctacacgc tgtactcatc caagcctgtg accatcactg tccaagctcc cagctcttca 660
ccgatgggga tcattgtggc tgtggtcact gggattgctg tagcggccat tgttgctgct 720
gtagtggcct tgatctacct gaagatccag gtccgaaagg ccgccatcac cagctacgag 780
aagtctgatg gcgtgtacac cggcctgagc accagaaacc aggaaaccta cgagacactg 840
aagcacgaga agccccccca g 861
<210> 68
<211> 287
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprsing CD32b ECD - CD32b TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(287)
<223> CAR comprising CD32b ECD - CD32b TM - FceRIg domains
<400> 68
Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp
1 5 10 15
Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr
20 25 30
Ala Val Leu Phe Leu Ala Pro Val Ala Gly Thr Pro Ala Ala Pro Pro
35 40 45
Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu
50 55 60
Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp
65 70 75 80
Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln
85 90 95
Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr
100 105 110
Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val
115 120 125
Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu
130 135 140
Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu
145 150 155 160
Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg
165 170 175
Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly
180 185 190
Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys
195 200 205
Pro Val Thr Ile Thr Val Gln Ala Pro Ser Ser Ser Pro Met Gly Ile
210 215 220
Ile Val Ala Val Val Thr Gly Ile Ala Val Ala Ala Ile Val Ala Ala
225 230 235 240
Val Val Ala Leu Ile Tyr Leu Lys Ile Gln Val Arg Lys Ala Ala Ile
245 250 255
Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg
260 265 270
Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
275 280 285
<210> 69
<211> 858
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD32b ECD - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(858)
<223> CAR comprising CD32b ECD - CD28 TM - FceRIg
<400> 69
atgggaatcc tgtcattctt acctgtcctt gccactgaga gtgactgggc tgactgcaag 60
tccccccagc cttggggtca tatgcttctg tggacagctg tgctattcct ggctcctgtt 120
gctgggacac ctgcagctcc cccaaaggct gtgctgaaac tcgagcccca gtggatcaac 180
gtgctccagg aggactctgt gactctgaca tgccggggga ctcacagccc tgagagcgac 240
tccattcagt ggttccacaa tgggaatctc attcccaccc acacgcagcc cagctacagg 300
ttcaaggcca acaacaatga cagcggggag tacacgtgcc agactggcca gaccagcctc 360
agcgaccctg tgcatctgac tgtgctttct gagtggctgg tgctccagac ccctcacctg 420
gagttccagg agggagaaac catcgtgctg aggtgccaca gctggaagga caagcctctg 480
gtcaaggtca cattcttcca gaatggaaaa tccaagaaat tttcccgttc ggatcccaac 540
ttctccatcc cacaagcaaa ccacagtcac agtggtgatt accactgcac aggaaacata 600
ggctacacgc tgtactcatc caagcctgtg accatcactg tccaagctcc cttttgggtg 660
ctggtggtcg tgggcggagt gctggcttgt tattctctgc tggtcaccgt ggccttcatc 720
atcttttggg tccgactgaa gatccaggtc cgaaaggccg ccatcaccag ctacgagaag 780
tctgatggcg tgtacaccgg cctgagcacc agaaaccagg aaacctacga gacactgaag 840
cacgagaagc ccccccag 858
<210> 70
<211> 286
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD32b ECD - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(286)
<223> CAR comprising CD32b ECD - CD28 TM - FceRIg domains
<400> 70
Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp
1 5 10 15
Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr
20 25 30
Ala Val Leu Phe Leu Ala Pro Val Ala Gly Thr Pro Ala Ala Pro Pro
35 40 45
Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu
50 55 60
Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp
65 70 75 80
Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln
85 90 95
Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr
100 105 110
Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val
115 120 125
Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu
130 135 140
Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu
145 150 155 160
Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg
165 170 175
Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly
180 185 190
Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys
195 200 205
Pro Val Thr Ile Thr Val Gln Ala Pro Phe Trp Val Leu Val Val Val
210 215 220
Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile
225 230 235 240
Ile Phe Trp Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr
245 250 255
Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn
260 265 270
Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
275 280 285
<210> 71
<211> 1050
<212> DNA
<213> Artificial Sequence
<220>
<223> CAR comprising CD32b ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> misc_feature
<222> (1)..(1050)
<223> CAR comprising CD32b ECD - CD8 - CD28 TM - FceRIg domains
<400> 71
atgggaatcc tgtcattctt acctgtcctt gccactgaga gtgactgggc tgactgcaag 60
tccccccagc cttggggtca tatgcttctg tggacagctg tgctattcct ggctcctgtt 120
gctgggacac ctgcagctcc cccaaaggct gtgctgaaac tcgagcccca gtggatcaac 180
gtgctccagg aggactctgt gactctgaca tgccggggga ctcacagccc tgagagcgac 240
tccattcagt ggttccacaa tgggaatctc attcccaccc acacgcagcc cagctacagg 300
ttcaaggcca acaacaatga cagcggggag tacacgtgcc agactggcca gaccagcctc 360
agcgaccctg tgcatctgac tgtgctttct gagtggctgg tgctccagac ccctcacctg 420
gagttccagg agggagaaac catcgtgctg aggtgccaca gctggaagga caagcctctg 480
gtcaaggtca cattcttcca gaatggaaaa tccaagaaat tttcccgttc ggatcccaac 540
ttctccatcc cacaagcaaa ccacagtcac agtggtgatt accactgcac aggaaacata 600
ggctacacgc tgtactcatc caagcctgtg accatcactg tccaagctcc cctgagcaac 660
agcatcatgt acttcagcca cttcgtgcct gtgttcctgc ctgccaagcc tacaacaaca 720
ccagccccta gacctccaac ccctgcccct acaattgcct ctcagcctct gtctctgagg 780
cccgaagctt gtagacctgc tgctggcgga gctgtgcaca ccagaggact ggatttcgcc 840
tgcttttggg tgctggtggt cgtgggcgga gtgctggctt gttattctct gctggtcacc 900
gtggccttca tcatcttttg ggtccgactg aagatccagg tccgaaaggc cgccatcacc 960
agctacgaga agtctgatgg cgtgtacacc ggcctgagca ccagaaacca ggaaacctac 1020
gagacactga agcacgagaa gcccccccag 1050
<210> 72
<211> 350
<212> PRT
<213> Artificial Sequence
<220>
<223> CAR comprising CD32b ECD - CD8 - CD28 TM - FceRIg domains
<220>
<221> MISC_FEATURE
<222> (1)..(350)
<223> CAR comprising CD32b ECD - CD8 - CD28 TM - FceRIg domains
<400> 72
Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp
1 5 10 15
Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr
20 25 30
Ala Val Leu Phe Leu Ala Pro Val Ala Gly Thr Pro Ala Ala Pro Pro
35 40 45
Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu
50 55 60
Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp
65 70 75 80
Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln
85 90 95
Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr
100 105 110
Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val
115 120 125
Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu
130 135 140
Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu
145 150 155 160
Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg
165 170 175
Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly
180 185 190
Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys
195 200 205
Pro Val Thr Ile Thr Val Gln Ala Pro Leu Ser Asn Ser Ile Met Tyr
210 215 220
Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr
225 230 235 240
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
245 250 255
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
260 265 270
His Thr Arg Gly Leu Asp Phe Ala Cys Phe Trp Val Leu Val Val Val
275 280 285
Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile
290 295 300
Ile Phe Trp Val Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr
305 310 315 320
Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn
325 330 335
Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
340 345 350
<210> 73
<211> 69
<212> DNA
<213> Artificial Sequence
<220>
<223> CD16A transmembrane domain
<220>
<221> misc_feature
<222> (1)..(69)
<223> CD16A transmembrane domain
<400> 73
taccaggtgt ccttctgcct cgtgatggtg ctgctgttcg ccgtggacac cggcctgtac 60
ttcagcgtg 69
<210> 74
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> CD16A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (1)..(23)
<223> CD16A transmembrane domain
<400> 74
Tyr Gln Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp
1 5 10 15
Thr Gly Leu Tyr Phe Ser Val
20
<210> 75
<211> 69
<212> DNA
<213> Artificial Sequence
<220>
<223> CD32A transmembrane domain
<220>
<221> misc_feature
<222> (1)..(69)
<223> CD32A transmembrane domain
<400> 75
atcattgtgg ctgtggtcat tgcgactgct gtagcagcca ttgttgctgc tgtagtggcc 60
ttgatctac 69
<210> 76
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> CD32A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (1)..(23)
<223> CD32A transmembrane domain
<400> 76
Ile Ile Val Ala Val Val Ile Ala Thr Ala Val Ala Ala Ile Val Ala
1 5 10 15
Ala Val Val Ala Leu Ile Tyr
20
<210> 77
<211> 87
<212> DNA
<213> Artificial Sequence
<220>
<223> CD32B transmembrane domain
<220>
<221> misc_feature
<222> (1)..(87)
<223> CD32B transmembrane domain
<400> 77
agctcttcac cgatggggat cattgtggct gtggtcactg ggattgctgt agcggccatt 60
gttgctgctg tagtggcctt gatctac 87
<210> 78
<211> 29
<212> PRT
<213> Artificial Sequence
<220>
<223> CD32B transmembrane domain
<220>
<221> MISC_FEATURE
<222> (1)..(29)
<223> CD32B transmembrane domain
<400> 78
Ser Ser Ser Pro Met Gly Ile Ile Val Ala Val Val Thr Gly Ile Ala
1 5 10 15
Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr
20 25
<210> 79
<211> 66
<212> DNA
<213> Artificial Sequence
<220>
<223> CD64A transmembrane domain
<220>
<221> misc_feature
<222> (1)..(66)
<223> CD64A transmembrane domain
<400> 79
gtctggtttc atgtcctttt ctatctggca gtgggaataa tgtttttagt gaacactgtt 60
ctctgg 66
<210> 80
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> CD64A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (1)..(22)
<223> CD64A transmembrane domain
<400> 80
Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu
1 5 10 15
Val Asn Thr Val Leu Trp
20
<210> 81
<211> 75
<212> DNA
<213> Artificial Sequence
<220>
<223> CD64B transmembrane domain
<220>
<221> misc_feature
<222> (1)..(75)
<223> CD64B transmembrane domain
<400> 81
gtctggtttc atgtcctttt ctatctggca gtgggaataa tgtttttagt gaacactgtt 60
ctctgggtga caata 75
<210> 82
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> CD64B transmembrane domain
<220>
<221> MISC_FEATURE
<222> (1)..(25)
<223> CD64B transmembrane domain
<400> 82
Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu
1 5 10 15
Val Asn Thr Val Leu Trp Val Thr Ile
20 25
<210> 83
<211> 66
<212> DNA
<213> Artificial Sequence
<220>
<223> CD64C transmembrane domain
<220>
<221> misc_feature
<222> (1)..(66)
<223> CD64C transmembrane domain
<400> 83
gtctggtttc atgtcctttt ctatctggca gtgggaataa tgtttttagt gaacactgtt 60
ctctgg 66
<210> 84
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> CD64C transmembrane domain
<220>
<221> MISC_FEATURE
<222> (1)..(22)
<223> CD64C transmembrane domain
<400> 84
Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu
1 5 10 15
Val Asn Thr Val Leu Trp
20
Claims (32)
- NK 세포 상에서 발현되는 재조합 키메라 항원 수용체(CAR)로서,
SEQ ID NO:12, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:22, SEQ ID NO:25, SEQ ID NO:28 및 SEQ ID NO:31로 이루어진 군으로부터 선택되는 서열을 갖는 폴리펩타이드의 항체-결합 부분을 갖는 항체 결합 도메인을 포함하고;
상기 항체 결합 도메인은 SEQ ID NO:1을 갖는 FcεRIγ 신호전달 도메인, 선택적인 힌지 부분 및 막관통 부분을 서열에 포함하는 폴리펩타이드에 연결되는, 재조합 키메라 항원 수용체. - 제1항에 있어서, 상기 항체 결합 도메인은 SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:29 및 SEQ ID NO:32로 이루어진 군으로부터 선택되는 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제1항 또는 제2항에 있어서, 상기 선택적인 힌지 부분은 SEQ ID NO:3의 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제1항에 있어서, 상기 막관통 부분은 SEQ ID NO:5, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82 또는 SEQ ID NO:84의 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제1항에 있어서, 적어도 하나의 제 2 신호전달 도메인을 추가로 포함하는, 키메라 항원 수용체.
- 제5항에 있어서, 상기 제 2 신호전달 도메인은 상기 FcεRIγ 신호전달 도메인과 별개인, 키메라 항원 수용체.
- 제6항에 있어서, 상기 제 2 신호전달 도메인은 SEQ ID NO:7, SEQ ID NO:8 및 SEQ ID NO:9로 이루어진 군으로부터 선택되는 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제1항에 있어서, 상기 항체 결합 도메인은 SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:29 및 SEQ ID NO:32로 이루어진 군으로부터 선택되는 펩타이드 서열을 갖고, 상기 신호전달 도메인은 SEQ ID NO:1의 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제8항에 있어서, 상기 선택적인 힌지 부분은 SEQ ID NO:3의 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제8항 또는 제9항에 있어서, 상기 막관통 부분은 SEQ ID NO:5, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82 또는 SEQ ID NO:84의 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제8항에 있어서, 적어도 하나의 추가의 신호전달 도메인을 더 포함하는, 키메라 항원 수용체.
- 제11항에 있어서, 상기 추가의 신호전달 도메인은 SEQ ID NO:1의 펩타이드 서열을 갖는, 키메라 항원 수용체.
- 제8항에 있어서, SEQ ID NO:1의 펩타이드 서열을 갖는 추가의 신호전달 도메인을 더 포함하는, 키메라 항원 수용체.
- 제1항에 있어서, 상기 키메라 항원 수용체는 SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54xx, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70 또는 SEQ ID NO:72의 아미노산 서열을 갖는, 키메라 항원 수용체.
- 제1항에 있어서, 상기 키메라 항원 수용체는 SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69 또는 SEQ ID NO:71의 뉴클레오타이드 서열을 갖는 핵산에 의해 인코딩되는, 키메라 항원 수용체.
- 제1항의 키메라 항원 수용체를 인코딩하는 재조합 핵산.
- 제16항에 있어서, 상기 핵산은 인간 코돈 용법으로 코돈-최적화되는, 재조합 핵산.
- 제16항에 있어서, 시토카인, CD16, 귀소 수용체 또는 TGF-베타 트랩(TGF-beta trap) 중 적어도 하나를 인코딩하는 서열 부분을 추가로 포함하는, 재조합 핵산.
- 제18항에 있어서, 상기 핵산은 키메라 항원 수용체를 인코딩하고,
시토카인, CD16, 귀소 수용체 또는 TGF-베타 트랩 중 적어도 하나를 인코딩하는 서열 부분은 다시스트론성(polycistronic) 핵산으로 구성되는, 재조합 핵산. - 제16항에 있어서, 상기 재조합 핵산은 렌티바이러스 벡터의 일부(part)인, 재조합 핵산.
- 제16항에 있어서, 상기 재조합 핵산은 DNA 벡터의 일부인, 재조합 핵산.
- 제16항의 재조합 핵산으로 형질주입된 NK 세포.
- 제22항에 있어서, 상기 세포는 NK-92 세포, 유전적으로 변형된 NK-92 세포, 또는 자가 NK 세포인, 세포.
- 제1항의 재조합 키메라 항원 수용체를 인코딩하는 재조합 핵산으로 형질주입된 재조합 NK 세포.
- 제24항에 있어서, 상기 NK 세포는 NK-92 세포, 유전적으로 변형된 NK-92 세포, 또는 자가 NK 세포인, 재조합 NK 세포.
- 제14항의 재조합 키메라 항원 수용체를 인코딩하는 재조합 핵산으로 형질주입된 재조합 NK 세포.
- 제26항에 있어서, 상기 NK 세포는 유전적으로 변형된 NK-92 세포 또는 자가 NK 세포인, 재조합 NK 세포.
- 암의 치료를 필요로 하는 환자에서 암을 치료하기 위한 약학적 조성물로서,
상기 환자에게 치료적 유효량으로 투여되기 위한 제22항 내지 제27항 중 어느 한 항의 세포를 포함하는, 약학적 조성물. - 제28항에 있어서, 바이러스 암 백신, 박테리아 암 백신, 효모 암 백신, N-803, 항체, 줄기 세포 이식물 및 종양 표적화된 시토카인으로 이루어진 군으로부터 선택되는 적어도 하나의 추가적인 치료 엔티티(therapeutic entity)와 투여되기 위한, 약학적 조성물.
- 제28항에 있어서, 상기 암은 백혈병(leukemia), 급성 림프구성 백혈병(acute lymphocytic leukemia), 급성 골수구성 백혈병(acute myelocytic leukemia), 만성 백혈병(chronic leukemia), 만성 골수구성 백혈병(만성 과립구성 백혈병, chronic myelocytic leukemia, chronic granulocytic leukemia), 만성 림프구성 백혈병(chronic lymphocytic leukemia), 진성 적혈구증가증(polycythemia vera), 림프종(lymphoma), 호지킨 질환(Hodgkin's disease), 비호지킨 질환(non-Hodgkin's disease), 다발성 골수종(multiple myeloma), 발덴스트롬 마크로글로불린혈증(Waldenstrom's macroglobulinemia), 중쇄 질환(heavy chain disease) 및 고형 종양(solid tumor)으로부터 선택되는, 약학적 조성물.
- 제28항에 있어서,
상기 세포는 상기 환자의 체표면적 m2당 1x108 내지 1x1011개가 환자에게 투여되기 위한, 약학적 조성물. - 암 또는 바이러스 감염의 치료를 위한 제22항 내지 제27항 중 어느 한 항의 세포.
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|---|---|---|---|
| US202063129340P | 2020-12-22 | 2020-12-22 | |
| US63/129,340 | 2020-12-22 | ||
| PCT/US2021/064408 WO2022140284A1 (en) | 2020-12-22 | 2021-12-20 | Fc-receptor car constructs and cells |
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| KR20230123515A true KR20230123515A (ko) | 2023-08-23 |
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| Country | Link |
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| US (1) | US20240042023A1 (ko) |
| EP (1) | EP4267626A1 (ko) |
| JP (1) | JP2024501276A (ko) |
| KR (1) | KR20230123515A (ko) |
| CN (1) | CN116964082A (ko) |
| AU (1) | AU2021409653A1 (ko) |
| CA (1) | CA3205789A1 (ko) |
| WO (1) | WO2022140284A1 (ko) |
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| IL314189A (en) * | 2018-08-01 | 2024-09-01 | Immunitybio Inc | A quadricistronic system containing a receptor or cytokine and a chimeric antigen receptor for genetic modification of immunotherapies |
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2021
- 2021-12-20 WO PCT/US2021/064408 patent/WO2022140284A1/en active Application Filing
- 2021-12-20 EP EP21911989.8A patent/EP4267626A1/en active Pending
- 2021-12-20 JP JP2023538151A patent/JP2024501276A/ja active Pending
- 2021-12-20 CA CA3205789A patent/CA3205789A1/en active Pending
- 2021-12-20 US US18/258,925 patent/US20240042023A1/en active Pending
- 2021-12-20 CN CN202180087463.4A patent/CN116964082A/zh active Pending
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| EP4267626A1 (en) | 2023-11-01 |
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| CA3205789A1 (en) | 2022-06-30 |
| JP2024501276A (ja) | 2024-01-11 |
| WO2022140284A1 (en) | 2022-06-30 |
| AU2021409653A1 (en) | 2023-07-06 |
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