KR20200020708A - 형질전환 대식세포, 키메라 항원 수용체, 및 관련 방법 - Google Patents
형질전환 대식세포, 키메라 항원 수용체, 및 관련 방법 Download PDFInfo
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Abstract
본 명세서에는 키메라 수용체가 기재된다. 키메라 수용체는 세포질 도메인; 막관통 도메인; 및 세포외 도메인을 포함한다. 실시 형태에서, 세포질 도메인은 활성화될 때 대식세포를 분극시키는 수용체의 세포질 부분을 포함한다. 추가의 실시 형태에서, 세포질 부분을 포함하는 야생형 단백질은 키메라 수용체의 세포외 도메인을 포함하지 않는다. 실시 형태에서, 키메라 수용체의 세포외 도메인에 대한 리간드의 결합은 키메라 수용체의 세포내 부분을 활성화시킨다. 키메라 수용체의 세포내 부분의 활성화는 대식세포를 M1 또는 M2 대식세포로 분극시킬 수 있다.
Description
본 발명은 일반적으로 생명공학에 관한 것이다. 더욱 구체적으로, 본 발명은 키메라 항원 수용체, 키메라 항원 수용체를 암호화하는 핵산, 키메라 항원 수용체 및/또는 암호화하는 핵산을 보유하는 대식세포, 및 관련 방법에 관한 것이다.
암은 조절되지 않는 세포 성장 및 사멸, 게놈 불안정성 및 돌연변이, 종양-촉진 염증, 혈관신생의 유도, 면역계 회피, 대사 경로의 탈조절, 불멸 세포 복제, 및 전이성 조직 침범을 포함하는 질환의 군으로 이루어진다[1]. 암은 심장 질환에 이어서 미국내 사망의 두번째 주요 원인이다[2]. 매년 160만 건 초과의 신규 암 사례가 진단될 것으로 전망되며, 580,000명 초과의 미국인이 사망할 것으로 예상되고(일당 약 1600 건의 암 사망), 이는 모든 미국인 사망 중 거의 1/4을 차지한다[2,3].
면역계는 암의 발생 및 진행에서 중요한 역할을 한다. 종양 부위로의 면역 세포 침윤은 악성종양 진행 및 전이에 악영향을 줄 수 있다[4, 5]. 종양 부위로의 대식세포의 침윤은 소정의 유방암 사례에서 종괴의 50% 초과를 차지하는 것으로 나타났으며, 이는 대식세포가 종양 진행에서 유의적인 역할을 갖는다는 것을 시사한다[6-8].
대식세포는 골수 계통으로부터 유래된 세포이며, 선천성 면역계에 속한다. 이들은 조직 내로 이동하는 혈액 단핵구로부터 유래된다. 이들의 주요 기능 중 하나는 미생물을 식균하고 세포 잔해를 제거하는 것이다. 이들은 또한 염증의 개시 및 해소 둘 모두에서 중요한 역할을 한다[9, 10]. 더욱이, 대식세포는 주위 미세환경으로부터 받는 자극의 유형에 따라 전염증성 내지 항염증성 범위의 상이한 반응을 나타낼 수 있다[11]. 극도의 대식세포 반응과 상관관계가 있는 2개의 주요 대식세포 표현형, M1 및 M2가 제안되었다.
M1 전염증성 대식세포는 지질다당류(LPS), IFN-γ, Il-1β, TNF-α, 및 Toll-유사 수용체 결합과 같은 소정의 분자와의 접촉시에 활성화된다. M1 대식세포는 감염과 싸우기 위해 배치된 면역계의 강력한 무장을 구성한다. 이들은 병원체의 직접(병원체 패턴 인식 수용체) 또는 간접(Fc 수용체, 보체 수용체) 인식할 수 있다. 이들은 또한 병원체를 죽이는 것을 돕기 위한 수단으로서 반응성 산소 종(ROS)을 생성하는 능력으로 무장되어 있다. 또한, M1 대식세포는 다른 유형의 면역 세포를 유인하고 면역 반응을 통합/조정하는 전염증성 사이토카인 및 케모카인을 분비한다. M1 활성화는 IFN-g, TNFa, GM-CSF, LPS, 및 다른 toll-유사 수용체(TLR) 리간드에 의해 유도된다.
대조적으로, 대안적으로 활성화된 대식세포로도 알려진 M2 항염증성 대식세포는 IL-4, IL-13, 및 IL-10과 같은 항염증성 분자에 의해 활성화된다[12, 13]. M2 대식세포는 면역조절, 조직 복구, 및 혈관신생 특성을 나타내며, 이는 이들이 염증 부위에 조절 T 세포를 동원하는 것을 가능하게 한다. M2 대식세포는 균일한 집단을 구성하지 않으며, 종종 M2a, M2b, 및 M2c 카테고리로 더 하위분류된다. 3개의 하위집단 모두의 공통 분모는 IL-12의 낮은 생성을 동반하는 높은 IL-10 생성이다. 이들의 특징 중 하나는 L-아르기닌을 고갈시킴으로써 T 세포 반응을 억제하고 그의 기질의 iNOS를 박탈하는 효소 아르기나제-1의 생성이다.
대식세포가 세포 미세환경에서 경험하는 다양한 신호로 인해 대식세포 분극의 생체내 분자 메커니즘은 잘 특성화되지 않는다[10, 14]. 최근에, 개체발생, 임신, 및 병리학적 조건, 예컨대 알러지, 만성 염증, 및 암과 같은 생리학적 조건 하에 생체내 대식세포 분극을 확인하는 데 있어서 진보가 이루어졌다. 그러나, 시험관내 대식세포 분극은 가변적이며 대식세포는 사이토카인의 도움으로 어느 하나의 표현형으로 왕복하여 분극될 수 있다는 것을 본 발명자들은 알고 있다[15, 16]. 인터페론 감마(IFN-γ) 및 IL-4는 각각 M1 및 M2 표현형으로 대식세포를 분극시킬 수 있는 2개의 사이토카인이다[15].
대식세포의 존재는 종양 진행 및 성장에 중요하며, 예후를 결정하는 것에 관여한다[17, 18]. 대식세포는 전염증성 및 항염증 특성 둘 모두를 나타낼 수 있기 때문에, 종양 진행 및 전이에서 이들의 분극 및 기능을 이해하는 것이 중요하다.
대식세포 분극
종양 미세환경은 대식세포 분극에 영향을 줄 수 있다. 분극 과정은 IL-10, 글루코코르티코이드 호르몬, 아포토시스 세포, 및 선천성 면역 세포 기능을 방해할 수 있는 면역 복합체의 적대적인 환경으로 인해 다양하고 복잡할 수 있다[11, 19]. 분극의 메커니즘은 여전히 명확하지 않지만, 본 발명자들은 이들이 전사 조절에 관여한다는 것을 알고 있다. 예를 들어, LPS 또는 IFN-γ에 노출된 대식세포는 M1 표현형을 향하여 분극되는 반면, IL-4 또는 IL-13에 노출된 대식세포는 M2 표현형을 향하여 분극될 것이다. LPS 또는 IFN-γ는 Trif 및 MyD88 경로를 유도하는 대식세포의 표면 상의 Toll-유사 수용체 4(TLR4)와 상호작용하여, 전사 인자 IRF3, AP-1, 및 NFκB의 활성화를 유도할 수 있고, 따라서 TNF 유전자, 인터페론 유전자, CXCL10, NOS2, IL-12 등을 활성화시키며, 이는 전염증성 M1 대식세포 반응에 필요하다[20]. 유사하게, IL-4 및 IL-13은 IL-4R에 결합하여, 항염증성 반응(M2 반응)과 관련된 유전자인, CCL17, ARG1, IRF4, IL-10, SOCS3 등의 발현을 조절하는 Jak/Stat6 경로를 활성화시킨다.
대식세포 분극의 추가의 메커니즘은 마이크로 RNA(miRNA) 미세조정(micromanagement)을 포함한다. miRNA는 22개 뉴클레오티드 길이의 작은 비-코딩 RNA이며, 이는 mRNA 분해의 속도에 이들이 영향을 미치므로 전사 후 유전자 발현을 조절한다. 몇몇 miRNA, 특히 miRNA-155, miRNA-125, miRNA-378(M1 분극), 및 miRNA let-7c, miRNA-9, miRNA-21, miRNA-146, miRNA147, miRNA-187(M2 분극)은 분극된 대식세포에서 고도로 발현되는 것으로 나타났다[21].
대식세포 분극은 복잡한 과정이며, 대식세포는 미세환경 자극에 따라 거동하고 상이한 반응을 도출한다. 따라서, 대식세포 분극은 M1 및 M2 표현형이 스펙트럼의 극단인 연속 활성화 상태에 의해 더 양호하게 표현된다. 최근에, 대식세포 활성화 및 대식세포 분극의 정의/설명에 대한 많은 논란이 있었다. 머레이(Murray) 등에 의해 간행된 최근 논문에서, 이들은 대식세포 활성화, 분극, 활성화제, 및 마커의 공통 정의/설명에 대해 고려되어야 하는 표준 세트를 기재한다. 이 간행물은 활성화된/분극된 대식세포의 정의 및 특성화에 매우 필요하였다[22].
M1 표현형
M1 전염증성 대식세포 또는 고전적으로 활성화된 대식세포는 공격적이며, 고도로 식작용성이고, 많은 양의 반응성 산소 및 질소 종을 생성하며, 이에 의해 Th1 반응을 촉진한다[11]. M1 대식세포는 높은 수준의 2 가지 중요한 염증성 사이토카인, IL-12 및 IL-23을 분비한다. IL-12는 Th17 세포의 활성화 및 클론 확장을 유도하며, 이는 염증에 기여하는 많은 양의 IL-17을 분비한다[23]. 이들 특징은 M1 대식세포가 전이를 제어하고, 종양 성장을 억제하고, 미생물 감염을 제어하는 것을 가능하게 한다[24]. 더욱이, 종양 부위로의 M1 대식세포의 침윤 및 동원은 고형 종양을 가진 환자에서 더 양호한 예후 및 더 높은 전체 생존율과 상관관계가 있다[17, 18, 25-28].
M1 표현형으로의 대식세포의 분극은 IFN-γ, TNF-α, IL-1β, 및 LPS와 같은 염증성 신호뿐만 아니라 전사 인자 및 miRNA에 의해 시험관내에서 조절된다[29, 30]. 고전적으로 활성화된 대식세포는 CXCL9, CXCL10(IP-10으로도 알려짐), IFN 조절 인자-1을 표적화하는 STAT1 전사 인자, 및 사이토카인 신호전달의 억제제-1의 유도를 개시한다[31]. 사이토킨 신호전달-1 단백질은 사이토카인 수용체의 다운스트림에서 기능하며, 사이토카인 신호전달을 약화시키기 위한 음성 피드백 루프(negative feedback loop)에 참여한다. 종양 미세환경에서, 노치(Notch) 신호전달은 M1 대식세포의 분극에서 중요한 역할을 하며, 이는 그것이 전사인자 RBP-J가 고전적인 활성화를 조절하는 것을 가능하게 하기 때문이다. 노치 신호전달이 결핍된 대식세포는 다른 외인성 유도제에 관계없이 M2 표현형을 발현한다[32]. 하나의 중요한 miRNA인 miRNA-155는 대식세포가 M2로부터 M1로 전환될 때 상향조절되며; miRNA-155를 과발현하는 M1 대식세포는 일반적으로 더욱 공격적이고 종양 감소와 관련된다[33]. 더욱이, miRNA-342-5p는 마우스에서 Akt1을 표적화함으로써 대식세포에서 더 큰 염증성 반응을 조장하는 것으로 밝혀졌다. 이 miRNA는 또한 Nos2 및 IL-6의 상향조절을 촉진하며, 이들 둘 모두는 대식세포에 대한 염증성 신호로서 작용한다[34]. miRNA-125 및 miRNA-378과 같은 다른 miRNA는 또한 대식세포(M1)의 고전적인 활성화 경로에 관여하는 것으로 나타났다[35].
고전적으로 활성화된 대식세포는 암 세포의 인식 및 파괴에서 중요한 역할을 하는 것으로 생각되며, 이는 그들의 존재가 보통 양호한 예후를 나타내기 때문이다. 인식 후, 악성 세포는 접촉-의존성 식세포작용 및 세포독성(즉, TNF-α와 같은 사이토카인 방출)을 포함하는 몇몇 메커니즘을 통해 M1 대식세포에 의해 파괴될 수 있다[24]. 그러나, 종양 미세환경 또는 조직-상주 세포와 같은 환경 신호는 M1 대식세포를 M2 대식세포로 분극시킬 수 있다. 쥐과 대식세포의 생체내 연구는 대식세포가 이들의 사이토카인 및 표면 마커 발현에 있어서 가변적이고 암의 존재 하에 대식세포를 M1 표현형으로 재분극시키는 것이 면역계가 종양을 거부하는 것을 도울 수 있음을 나타냈다[19].
M2 표현형
M2 대식세포는 항염증성이며 혈관신생 및 조직 복구의 과정을 돕는다. 이들은 포착제 수용체를 발현하고 많은 양의 IL-10 및 다른 항염증성 사이토카인을 생성한다[33, 36]. M2 대식세포에 의한 IL-10의 발현은 Th2 반응을 촉진한다. Th2 세포는 결과적으로 IL-3 및 IL-4의 생성을 상향조절한다. IL-3은 다른 사이토카인, 예를 들어 에리트로포이에틴(EPO), 과립구 대식세포 콜로니-자극 인자(GM-CSF), 및 IL-6과 함께, 골수 계통(과립구, 단핵구, 및 수지상 세포) 내의 모든 세포의 증식을 자극한다. IL-4는, 세포외 기질의 생성에 기여하므로 치유 과정에서 중요한 사이토카인이다[23]. M2 대식세포는 혈관이 악성 세포에 영양분을 공급하여 이들의 성장을 촉진하는 것을 가능하게 함으로써 종양 진행을 도울 수 있는 기능을 나타낸다. 대부분의 고형 종양에서 대식세포(M2인 것으로 생각됨)의 존재는 치료 성공 및 더 긴 생존율과 부정적인 상관관계가 있다[37]. 추가로, M2 대식세포의 존재는 유방암에서 전이 잠재력에 관련이 있다. 린(Lin) 및 동료들은 마우스에서 유방 종양 부위로의 대식세포의 초기 동원이 혈관신생 및 악성종양 발생률을 증가시킨다는 것을 발견하였다[38]. 종양 미세환경은 대식세포가 M2 표현형을 유지하는 것을 돕는 것으로 생각된다[23, 39]. 아디포넥틴 및 IL-10과 같은 종양 미세환경에 존재하는 항염증성 신호는 M2 반응을 향상시킬 수 있다[41].
종양-관련 대식세포(TAM)
종양 미세환경에 노출된 세포는 상이하게 거동한다. 예를 들어, 고형 종양의 주변부에서 발견되는 종양-관련 대식세포는 종양 성장 및 전이를 촉진하는 데 도움을 주는 것으로 생각되며, M2-유사 표현형을 갖는다[42]. 종양-관련 대식세포는 조직 상주 대식세포 또는 골수 유래의 동원된 대식세포(단핵구로부터 대식세포로 분화되고 조직 내로 이동하는 대식세포)일 수 있다. 코르테즈-레타모조(Cortez-Retamozo)에 의한 연구는 비장 내의 많은 수의 TAM 전구체가 종양 스트로마로 이동한다는 것을 발견하였으며, 이 기관을 또한 TAM 저장소로서 제시한다[43]. 비장에서 발견되는 TAM 전구체는 이들의 CCR2 케모카인 수용체를 통해 이동을 개시하는 것으로 밝혀졌다[43]. 최근의 연구들은 종양 주변부에 대식세포를 유인하는 주요 인자로서 CSF-1을 발견하였고, 암 세포에 의한 CSF-1 생성은 더 낮은 생존율을 예측하며 그것이 전반적인 불량한 예후를 나타낸다는 것을 발견하였다[44-46]. 다른 사이토카인, 예컨대 TNF-α 및 IL-6은 또한 종양 주변부로의 대식세포의 축적/동원에 관련이 있다[45].
종양 경계 주위에 동원된 대식세포는 종양에서 활성화되는 "혈관신생 스위치"에 의해 조절되는 것으로 생각된다. 혈관신생 스위치는 종양이 고밀도 혈관 네트워크를 발달시키는 과정으로서 정의되며, 이는 잠재적으로 종양이 전이성이 되는 것을 가능하게 하고 악성 전이를 위해 필요하다. 유방암 마우스 모델에서, 대식세포의 존재가 완전한 혈관신생 스위치에 필요하다는 것이 관찰되었다. 종양 주위의 대식세포 성숙, 이동, 및 축적이 지연되었을 때, 혈관신생 스위치가 또한 지연되었으며, 이는 혈관신생 스위치가 대식세포의 부재 하에서는 일어나지 않고, 악성종양 진행을 위해 대식세포 존재가 필요함을 시사한다[47]. 더욱이, 종양 스트로마 세포는 종양 주변에 대식세포를 동원할 CSF1, CCL2, CCL3, CCL5, 및 태반 성장 인자와 같은 케모카인을 생성한다. 이들 케모카인은 대식세포가 혈관신생 스위치를 활성화시키기 위한 환경을 제공하며, 여기서 대식세포는 높은 수준의 IL-10, TGF-β, ARG-1, 및 낮은 수준의 IL-12, TNF-α, 및 IL-6을 생성할 것이다. 이들 사이토카인의 발현 수준은 대식세포가 면역 회피를 조절함을 시사한다. 대식세포가 저산소 종양 환경에 유인되고, 저산소-유도성 인자-1α(HIF-1α) 및 HIF-2α를 생성함으로써 반응할 것이며, 이는 혈관신생과 관련된 유전자의 전사를 조절한다는 것에 유의하는 것이 중요하다. 혈관신생 스위치 중에, 대식세포는 또한 VEGF(NF-κB 경로에 의해 자극됨)를 분비할 수 있으며, 이는 혈관 성숙 및 혈관 투과성을 촉진할 것이다[48].
종양-관련 대식세포는 IkB 키나제 β 및 NF-kB 신호전달 캐스케이드를 통해 매개되는 IL-1R 및 MyD88과 같은 악성 세포로부터 분극 신호를 받음으로써 이들의 M2-유사 표현형을 유지할 수 있는 것으로 생각된다. TAM에서의 NF-kB의 억제는 고전적인 활성화를 촉진한다[40]. 더욱이, 다른 연구는 p50 NF-kB 서브유닛이 M1 대식세포의 억제, 및 염증 촉진 종양 성장의 감소에 관여하였음을 시사하였다. 사카니(Saccani) 등에 의해 생성된 p50 NF-κB 녹-아웃 마우스는 M1 공격성이 p50 NF-kB 녹아웃시에 복원되어 종양 생존을 감소시킨다는 것을 시사하였다[49].
종괴는 많은 수의 M2-유사 대식세포를 함유하기 때문에, TAM은 암 치료를 위한 표적으로서 사용될 수 있다. TAM의 수를 감소시키거나 이들을 M1 표현형을 향해 분극시키는 것은 암 세포를 파괴하고 종양 성장을 손상시키는 것을 도울 수 있다[50-52]. 루오(Luo) 및 동료들은 잠재적 종양 표적(potential tumor target)인 것으로 생각되는 TAM에서 상향조절되는 시스테인 프로테아제 및 스트레스 단백질인 레구마인에 대한 백신을 사용하였다[52]. 레구마인에 대한 백신을 마우스에 투여하였을 때, 혈관신생을 제어하는 유전자가 하향조절되고 종양 성장이 중단되었다[52].
대사 및 활성화 경로
종양 세포에 존재하는 대사 변화는 암을 생성하는 동일한 유전자 돌연변이에 의해 제어된다[53]. 이들 대사 변화의 결과로서, 암 세포는 대식세포의 분극을 변형시키고 종양 성장을 촉진할 수 있는 신호를 생성할 수 있다[54, 55].
M1 및 M2 대식세포는 이들의 유사하지 않은 거동을 반영하는 별개의 대사 패턴을 나타낸다[56]. M1 표현형은 해당작용 증가시키고 산화성 펜토스 포스페이트 경로를 향해 글루코스 대사를 편향시킴으로써, 산소 소모를 감소시키고 결과적으로 많은 양의 라디칼 산소 및 질소 종뿐만 아니라 염증성 사이토카인, 예컨대 TNF-α, IL-12, 및 IL-6을 생성한다[56, 57]. M2 표현형은 지방산 흡수 및 산화를 증가시키며, 이는 전반적인 세포 산화환원 전위를 증가시키면서 펜토스 포스페이트 경로를 향한 플럭스를 감소시키고, 결과적으로 포착제 수용체 및 면역조절 사이토카인, 예컨대 IL-10 및 TGF-β를 상향조절한다[56].
다중의 대사 경로가 대식세포 분극에서 중요한 역할을 한다. Akt1 및 Akt2와 같은 단백질 키나제는 암 세포가 생존하고, 증식하고, 중간 대사(intermediary metabolism)를 사용하는 것을 가능하게 함으로써 대식세포 분극을 변경한다[58]. 다른 단백질 키나제는 해당작용을 증가시키고 산소 소모를 감소시킴으로써 글루코스 대사를 통해 대식세포 분극을 유도할 수 있다[57, 59]. 슈(Shu) 및 동료들은 PET 스캔 및 글루코스 유사체를 사용하여 생체 내에서 대식세포 대사 및 면역 반응을 최초로 가시화하였다[60].
L-아르기닌 대사는 또한 대식세포에서 사이토카인 발현에 중요한 별개의 이동을 나타내며, TAM-종양 세포 상호작용을 변경하는 별개의 대사 경로를 예시한다[61]. 고전적으로 활성화된(M1) 대식세포는 유도성 산화질소 합성효소(iNOS)를 선호한다. iNOS 경로는 세포독성 산화질소(NO)를 생성하고, 결과적으로 항종양 거동을 나타낸다. 대안적으로 활성화된(M2) 대식세포는 아르기나제 경로를 선호하고 우레움 및 1-오르니틴을 생성하는 것으로 나타났으며, 이는 진행성 종양 세포 성장에 기여한다[61, 62].
대사 경로의 직접적인 조작은 대식세포 분극을 변경할 수 있다. 글루코스 대사에서 역할을 하는 탄수화물 키나제-유사 단백질(CARKL) 단백질은 대식세포 사이토카인 특징을 변경하기 위해 사용되어 왔다[56, 57]. CARKL이 RNAi에 의해 녹 다운될 때, 대식세포는 M1-유사 대사 경로를 채택하는 경향이 있다(대사는 해당작용을 향해 편향되었고 산소 소모가 감소됨). CARKL이 과발현될 때, 대식세포는 M2-유사 대사(감소된 해당작용 플럭스 및 더 많은 산소 소모)를 채택한다(56]. 대식세포가 LPS/TLR4 결합을 통해 M1-유사 대사 상태를 채택할 때, CARKL 수준은 감소하며, NFκB 경로에 의해 제어되는 유전자는 활성화되고(TNF-α, IL-12, 및 IL-6), NADH:NAD+ 및 GSH:GSSSG 복합체의 증가하는 농도로 인해 세포 산화환원 전위가 증가한다. M2-유사 대사 상태 중에, 대식세포는 CARKL 및 STAT6/IL-4(IL-10 및 TGF-β)에 의해 조절되는 유전자를 상향조절한다.
비만 또한 대식세포 분극에 영향을 줄 수 있다. 비만은 만성 염증의 상태, IL4/STAT6 경로를 유도하여 NKT 세포를 활성화시키는 환경과 관련되며, 이는 대식세포를 M2 반응을 향해 유도한다. 후기-단계 식이-유도 비만 중에, 대식세포는 지방 조직으로 이동하며, 여기서 면역 세포는 지방 조직 내의 TH1 또는 TH2 사이토카인 발현의 수준을 변경하여 M2 표현형 바이어스 및 가능하게는 증가된 인슐린 민감성을 야기한다[63].
TAM에서 대사 경로를 표적화함으로써 M1 표현형 바이어스는 종양 성장 및 전이를 감소시키는 대안적인 수단을 제공할 수 있다.
암에 대한 대식세포 면역요법 접근법
암 면역요법의 역할은 암 세포를 인식하고, 거부하고, 파괴하기 위해 면역계를 자극하는 것이다. 단핵구/대식세포를 이용한 암 면역요법은 대식세포를 전염증성 반응(M1)을 향하여 분극시키고, 따라서 대식세포 및 다른 면역 세포가 종양을 파괴하는 것을 가능하게 하는 것이 목적이다. 많은 사이토카인 및 박테리아 화합물이 시험관 내에서 이를 달성할 수 있지만, 전형적으로 부작용이 생체내에서 너무 심각하다. 핵심은 최소 또는 용이하게 관리되는 환자 부작용을 갖는 화합물을 찾는 것이다. 단핵구/대식세포를 사용하는 면역요법이 지난 수십년간 사용되어 왔으며, 새로운 접근법이 매년 개발되고 있다[64, 65]. 초기 면역요법은 더 양호한 암 요법을 위한 양호한 기초를 확립하였으며 면역요법으로 치료한 환자에서 생존율을 증가시켰다[66].
암 면역요법에 대한 일부 접근법은 종양 부위의 인식 및 표적화된 파괴를 가능하게 하는, 활성화된 대식세포 및 다른 면역 세포를 종양 부위로 동원하는 사이토카인 또는 케모카인의 사용을 포함한다[67, 68]. IFN-α 및 IFN-β는 세포 분화 및 아포토시스를 유도함으로써 종양 진행을 억제하는 것으로 나타났다[69]. 또한, IFN 치료는 항증식성이며 세포 주기에서 S기 시간을 증가시킬 수 있다[70, 71]. 장(Zhang) 및 동료들은 인간 전립선암 세포를 표적화하기 위해 IFN-β 유전자 요법을 사용하여 누드 마우스에서 연구를 수행하였다. 이들의 결과는 아데노바이러스 전달 IFN-β 유전자 요법이 대식세포에 관여하며 성장 및 전이를 억제하는 것을 돕는다는 것을 나타낸다[72].
대식세포 억제 인자(MIF)는 암 면역요법에서 사용될 수 있는 다른 사이토카인이다. MIF는 보통 고형 종양에서 발견되고 불량한 예후를 나타낸다. MIF는 공격적 대식세포 기능을 억제하고, M2 표현형을 향하여 대식세포를 유도하며, 이는 종양 성장 및 진행을 도울 수 있다. 심슨(Simpson), 템플턴(Templeton), 및 크로스(Cross)(2012)는, M2 표현형을 발현하는 골수 세포의 억제성 집단으로 대식세포 전구체인 골수 세포가 분화되는 것을 MIF가 유도함을 발견하였다[73]. MIF를 표적화함으로써, 이들은 대식세포의 이러한 억제성 집단을 고갈시켜, 이들의 성장을 억제하고, 따라서 종양 성장 및 전이를 제어할 수 있었다[73].
케모카인 수용체 유형 2, CCR2는 염증성 부위로의 단핵구의 동원에 결정적이며, 그것은 종양 부위로의 대식세포의 동원, 혈관신생, 및 전이를 방지하기 위한 표적인 것으로 나타났다. 샌포드(Sanford) 및 동료들(2013)은 췌장 마우스 모델에서 신규한 CCR2 억제제(PF-04136309)를 연구하였으며, 이는 CCR2 억제제가 종양 부위로의 단핵구/대식세포 동원을 고갈시키고, 종양 성장 및 전이를 감소시키고, 항종양 면역을 증가시켰음을 입증한다[74]. 슈몰(Schmall) 등의 다른 최근의 연구는, 10개의 상이한 인간 폐암과 공동 배양된 대식세포가 CCR2 발현을 상향조절하였음을 나타냈다. 더욱이, 이들은 CCR2 길항제로 처리한 폐 마우스 모델에서 종양 성장 및 전이가 감소되었음을 나타냈다[75].
다른 연구에서는 종양으로부터 M2 대식세포를 고갈시키고 혈관신생을 중단시키기 위해 약물을 전달하는 리포좀이 사용되었다. 높은 수준의 IL-1β를 발현하는 암 세포는 더 빨리 성장하고 생체 내에서 더 많은 혈관신생을 유도한다. 키무라(Kimura) 및 동료들은 IL-1β를 발현하는 종양 세포에 노출된 대식세포가 더 높은 수준의 혈관신생 인자 및 케모카인, 예컨대 혈관 내피 성장 인자 A(VEG-A), IL-8, 단핵구 화학유인제 단백질 1 등을 생성하여, 종양 성장 및 혈관신생을 촉진함을 발견하였다[76]. 클로드로네이트 리포좀을 사용하여 대식세포를 고갈시킬 때, 이들은 더 적은 IL-1β-생성 종양 세포를 발견하였다. 이들은 또한 암 세포에서 NF-κB 및 AP-1 전사 인자를 억제함으로써 종양 성장 및 혈관신생이 감소되었음을 발견하였다. 이들 발견은 종양 부위를 둘러싸는 대식세포가 종양 성장 및 혈관신생을 촉진하는 데 관여할 수 있음을 시사할 수 있다[76].
메티오닌 엔케팔린(MENK)과 같은 화합물은 생체내 및 시험관내에서 항종양 특성을 갖는다. MENK는 CD64, MHC-II, 및 산화질소(M1 마커)의 생성을 상향조절하면서 CD206 및 아르기나제-1(M2 마커)을 하향조절함으로써 M2 대식세포를 M1 대식세포로 분극시키는 능력을 갖는다. MENK는 또한 TNF-α를 상향조절하고 IL-10을 하향조절할 수 있다[77].
최근의 연구는 M2 대식세포의 잠재적인 억제제로서 비스포스포네이트에 집중하였다. 비스포스포네이트는 전이성 유방암 환자를 치료하기 위해 통상적으로 사용되어 골 재흡수(bone resorption)와 같은 골격 합병증을 방지한다[78]. 비스포스포네이트가 단기간 동안 체내에 머무르는 동안, 비스포스포네이트는 하이드록시아파타이트에 대한 그의 높은 친화도로 인해 대식세포와 동일한 부류의 세포인 파골세포를 표적화할 수 있다. 일단 비스포스포네이트가 골에 결합하면, 골 매트릭스는 세포내 이입에 의해 비스포스포네이트를 내재화한다. 일단 세포질 내에 있으면, 비스포스포네이트는 인테그린 신호전달 및 엔도솜 수송을 방지하는 이벤트인 단백질 프레닐화를 억제함으로써, 세포를 아포토시스로 진행시킬 수 있다[69]. 최근까지, 비스포스포네이트가 종양-관련 대식세포를 표적화할 수 있는지 여부가 알려지지 않았지만, 주난카(Junankar) 등에 의한 최근의 연구에서는 대식세포가 종양을 둘러싸는 상피 세포에서 발생하지 않는 사건인 음세포작용 및 식세포작용에 의해 질소-함유 비스포스포네이트 화합물을 흡수하는 것으로 나타냈다[79]. 비스포스포네이트를 사용하여 TAM을 아포토시스로 진행하게 하는 것은 혈관신생 및 전이를 감소시킬 수 있을 것이다.
암 면역요법에 대한 추가의 접근법은 면역 반응을 도출할 수 있는 생체재료의 사용을 포함한다. 양이온성 중합체는, 일단 물에 용해되면, 그의 반응성으로 인해 면역요법에 사용된다. 첸(Chen) 등은 PEI, 폴리라이신, 양이온성 덱스트란, 및 양이온성 젤라틴을 포함하는 양이온성 중합체를 사용하여 강력한 Th1 면역 반응을 생성하였다[77]. 이들은 또한 M1 대식세포를 대표하는 CD4+ 세포의 증식 및 IL-12의 분비를 유도할 수 있었다[77]. 황(Huang) 및 동료들은 또한 TLR4를 표적화함으로써 항종양 반응을 생성하기 위해 생체재료를 사용하여 TAM을 촉발하였다[80]. 이 연구는 TAM이 M1 표현형으로 분극되고 IL-12를 발현할 수 있음을 발견하였다. 이들은 이들 양이온성 분자가 마우스에서 직접적인 종양살해 활성을 가지며 종양 감소를 나타낸다는 것을 발견하였다[80].
TLR4
Toll-유사 수용체 4는 TLR4 유전자에 의해 암호화되는 인간에서의 단백질이다. TLR 4는 그램 음성 박테리아 상에서 지질다당류(LPS)를 검출하고, 따라서 위험의 인식 및 선천성 면역계의 활성화에서 필수 역할을 한다(도 7). 그것은 LY96(MD-2) 및 CD14와 협동하여, 대식세포가 LPS에 의해 유도될 때 신호 전달을 매개한다. TLR4의 세포질 도메인은 이들이 LPS의 존재를 검출할 때 M1 대식세포의 활성화를 담당한다. 이는 CAR이 그의 표적 단백질에 결합할 때 단핵구/대식세포의 활성화를 유도하기 위해 MOTO-CAR(즉, 키메라 수용체)에 커플링될 수용체의 기능부이다.
어댑터 단백질 MyD88 및 TIRAP는 TLR4의 Toll/인터류킨-1 수용체(IL-1R)(TIR) 도메인과의 직접적인 상호작용을 통한 몇몇 경로, 그리고 가능하게는 모든 경로의 활성화에 기여한다. 그러나, 특정 서브세트의 경로의 활성화를 위해 필요한 추가의 어댑터가 존재할 수 있으며, 이는 표적 유전자의 차등적인 조절에 기여할 수 있다.
티미딘 키나제
인간 티미딘 키나제 1(TK1)은 종양에서 그의 과발현과 관련하여 주로 연구된 잘 알려진 뉴클레오티드 구제 경로 효소이다. TK1이 초기에 암 환자의 혈청에서의 그의 발현(sTK)에 의해 대중화된 이후로, 그의 진단 및 예후 잠재력이 광범위하게 연구되었다. 예를 들어, 몇몇 연구들은 많은 상이한 암 환자에서 더 진행된 종양을 나타내는 TK1의 더 높은 수준과 함께 sTK1이 단계-유사 방식으로 상승한다는 것을 입증하였다[81].
다른 연구는 TK1의 예후 잠재력을 조사하였다. 한 가지 이러한 연구는 원발성 유방 종양 내의 TK1 수준이 재발을 예측하기 위해 사용될 수 있음을 입증한다. 다른 흥미로운 TK1 예후 연구는, 환자가 치료에 반응할 때 sTK1 수준의 유의적인 감소를 나타내는 반면에, 치료에 반응하는 것으로 보이지 않는 환자에서는 sTK1 수준이 계속 상승함을 나타낸다. sTK1 수준이 재발 전에 상승하기 시작하고, 일부 경우에는 "임상 증상의 시작 전 1 내지 6 개월에" sTK1 수준이 재발을 예측할 수 있다고 언급된 것이 또한 알려져 있다. 몇몇 다른 연구는 암의 진단 및 예후 지표로서 TK1의 풍부한 잠재력을 확인한다[82].
TK1의 진단 및 예후 잠재력이 잘 확립되었지만, TK1의 치료 잠재력은 비교적 분명하지 않은 채 남아 있다. HSV-TK가 유전자 요법에 사용되었고 PET 영상화가 증식성 암 세포를 확인하기 위해 TK1을 이용하는 것이 사실이지만, TK1 면역요법의 가능성을 언급하는 연구는 거의 없다. 아마도 이는 주로 TK1이 알려진 세포액 단백질이기 때문이다. TK1은 암 세포에서뿐만 아니라 다중의 종양 유형의 표면 막 상에서 발현되며, 따라서 종양 면역요법을 위한 매우 실행가능한 표적임이 최근에 발견되었다.
본 명세서에는 키메라 수용체가 기재된다. 키메라 수용체는 세포질 도메인; 막관통 도메인; 및 세포외 도메인을 포함한다. 실시 형태에서, 세포질 도메인은 활성화될 때 대식세포를 분극시키는 수용체의 세포질 부분을 포함한다. 추가의 실시 형태에서, 세포질 부분을 포함하는 야생형 단백질은 키메라 수용체의 세포외 도메인을 포함하지 않는다(예를 들어, 도 21 참조). 실시 형태에서, 키메라 수용체의 세포외 도메인에 대한 리간드의 결합은 키메라 수용체의 세포내 부분을 활성화시킨다(예를 들어, 도 22 참조). 키메라 수용체의 세포내 부분의 활성화는 대식세포를 M1 또는 M2 대식세포로 분극시킬 수 있다(예를 들어, 도 23 및 도 24a 및 도 25 참조).
소정의 실시 형태에서, 세포외 도메인은 리간드에 특이적으로 결합하는 항체 또는 이의 단편을 포함할 수 있다. 실시 형태에서, 키메라 수용체는 링커를 함유할 수 있다. 실시 형태에서, 키메라 수용체는 힌지 영역을 함유할 수 있다.
추가의 실시 형태는 키메라 수용체 또는 키메라 수용체를 암호화하는 핵산을 포함하는 세포를 포함한다.
실시 형태는 키메라 수용체를 포함하는 대식세포를 키메라 수용체의 세포외 도메인에 대한 리간드와 접촉시키는 단계; 리간드를 키메라 수용체의 세포외 도메인에 결합시키는 단계에 의해 대식세포를 분극시키는 방법을 포함한다. 키메라 수용체의 세포외 도메인에 대한 리간드의 결합은 세포질 부분을 활성화시키고, 세포질 부분의 활성화는 대식세포를 분극시킨다.
본 발명의 이들 및 다른 태양은 본 명세서에 포함된 교시 내용을 고려하여 당업자에게 명백할 것이다.
도 1a는 키메라 수용체 TK1-MOTO1 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 1b는 TK1-MOTO1의 서열(서열 번호 35)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 313은 TLR4 막관통 도메인이며, 아미노산 314 내지 496은 TLR4 세포액 도메인이다.
도 2a는 키메라 수용체 TK1-MOTO2 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 2b는 TK1-MOTO2의 서열(서열 번호 36)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 295는 LRR 짧은 힌지이며, 아미노산 296 내지 318은 TLR4 막관통 도메인이고, 아미노산 319 내지 500은 TLR4 세포액 도메인이다.
도 3a는 키메라 수용체 TK1-MOTO3 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 3b는 TK1-MOTO3의 서열(서열 번호 37)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 345는 LRR 긴 힌지이며, 아미노산 346 내지 368은 TLR4 막관통 도메인이고, 아미노산 269 내지 501은 TLR4 세포액 도메인이다.
도 4a는 키메라 수용체 TK1-MOTO4 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 4b는 TK1-MOTO4의 서열(서열 번호 38)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 302은 IgG4 짧은 힌지이며, 아미노산 303 내지 325는 TLR4 막관통 도메인이고, 아미노산 326-508은 TLR4 세포액 도메인이다.
도 5a는 키메라 수용체 TK1-MOTO5 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 5b는 TK1-MOTO5의 서열(서열 번호 39)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 409는 IgG 119 아미노산 중간 힌지이며, 아미노산 410 내지 432는 TLR4 막관통 도메인이고, 아미노산 433 내지 615는 TLR4 세포액 도메인이다.
도 6a는 키메라 수용체 TK1-MOTO6 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 6b는 TK1-MOTO6의 서열(서열 번호 40)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 518은 IgG4 긴 힌지이며, 아미노산 519 내지 541은 TLR4 막관통 도메인이고, 아미노산 542 내지 724는 TLR4 세포액 도메인이다.
도 7a는 키메라 수용체 TK1-MOTO7 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 7b는 TK1-MOTO7의 서열(서열 번호 41)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 C339S 및 C356S로 돌연변이화된 CD8 힌지이며, 아미노산 359 내지 381은 TLR4 막관통 도메인이고, 아미노산 382 내지 564는 TLR4 세포액 도메인이다.
도 8a는 키메라 수용체 TK1-MOTO8 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 8b는 TK1-MOTO8의 서열(서열 번호 42)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 CD8 힌지의 일부이며, 아미노산 359 내지 381은 TLR4 막관통 도메인이고, 아미노산 382 내지 564는 TLR4 세포액 도메인이다.
도 9a는 키메라 수용체 TK1-MO-FCGRA-CAR-1 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 9b는 TK1-MO-FCGRA-CAR-1의 서열(서열 번호 43)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 311은 FCGR3A 막관통 도메인이며, 아미노산 312 내지 336은 FCGR3A 세포액 도메인이고, 아미노산 337 내지 378은 FCER1G 세포액 도메인이다.
도 10a는 키메라 수용체 TK1-MO-FCGRA-CAR-2 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 10b는 TK1-MO-FCGRA-CAR-2의 서열(서열 번호 44)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 C339S 및 C356S로 돌연변이화된 CD8 힌지이며, 아미노산 359 내지 379는 FCGR3A 막관통 도메인이고, 아미노산 380 내지 404는 FCGR3A 세포액 도메인이며, 아미노산 405 내지 446은 FCER1G 세포액 도메인이다.
도 11a는 키메라 수용체 TK1-MO-FCGRA-CAR-3 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 11b는 TK1-MO-FCGRA-CAR-3의 서열(서열 번호 45)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 CD8 힌지의 일부이며, 아미노산 359 내지 379는 FCGR3A 막관통 도메인이고, 아미노산 380 내지 404는 FCGR3A 세포액 도메인이며, 아미노산 405 내지 446은 FCER1G 세포액 도메인이다.
도 12a는 키메라 수용체 TK1-MO-FCGRA-CAR-4 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 12b는 TK1-MO-FCGRA-CAR-4의 서열(서열 번호 46)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 303은 IgG4 짧은 힌지이며, 아미노산 304 내지 324는 FCGR3A 막관통 도메인이고, 아미노산 325 내지 349는 FCGR3A 세포액 도메인이며, 아미노산 350 내지 391은 FCER1G 세포액 도메인이다.
도 13a는 키메라 수용체 TK1-MO-FCGRA-CAR-5 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 13b는 TK1-MO-FCGRA-CAR-5의 서열(서열 번호 47)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 409는 IgG4 119 아미노산 힌지이며, 아미노산 410 내지 430은 FCGR3A 막관통 도메인이고, 아미노산 431 내지 455는 FCGR3A 세포액 도메인이며, 아미노산 456 내지 497은 FCER1G 세포액 도메인이다.
도 14a는 키메라 수용체 TK1-MO-FCGRA-CAR-6 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 14b는 TK1-MO-FCGRA-CAR-6의 서열(서열 번호 48)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 519는 IgG4 긴 힌지이며, 아미노산 520 내지 540은 FCGR3A 막관통 도메인이고, 아미노산 541 내지 565는 FCGR3A 세포액 도메인이며, 아미노산 566 내지 607은 FCER1G 세포액 도메인이다.
도 15a는 키메라 수용체 TK1-MO-FCG2A-CAR-1 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 15b는 TK1-MO-FCG2A-CAR-1의 서열(서열 번호 49)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 312는 FCGR2A 막관통 도메인이며, 아미노산 313 내지 390은 FCGR2A 세포액 도메인이다.
도 16a는 키메라 수용체 TK1-MO-FCG2A-CAR-2 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 16b는 TK1-MO-FCG2A-CAR-2의 서열(서열 번호 50)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 C339S 및 C356S로 돌연변이화된 CD8 힌지이며, 아미노산 359 내지 380은 FCGR2A 막관통 도메인이고, 아미노산 381 내지 458은 FCGR2A 세포액 도메인이다.
도 17a는 키메라 수용체 TK1-MO-FCG2A-CAR-3 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 17b는 TK1-MO-FCG2A-CAR-3의 서열(서열 번호 51)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 CD8 힌지의 일부이며, 아미노산 359 내지 380은 FCGR2A 막관통 도메인이고, 아미노산 381 내지 458은 FCGR2A 세포액 도메인이다.
도 18a는 키메라 수용체 TK1-MO-FCG2A-CAR-4 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 18b는 TK1-MO-FCG2A-CAR-4의 서열(서열 번호 52)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 303은 IgG4 짧은 힌지이며, 아미노산 304 내지 325는 FCGR2A 막관통 도메인이고, 아미노산 326 내지 403은 FCGR2A 세포액 도메인이다.
도 19a는 키메라 수용체 TK1-MO-FCG2A-CAR-5 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 19b는 TK1-MO-FCG2A-CAR-5의 서열(서열 번호 53)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 409는 IgG4 119 아미노산 힌지이며, 아미노산 410 내지 431은 FCGR2A 막관통 도메인이고, 아미노산 432 내지 509는 FCGR2A 세포액 도메인이다.
도 20a는 키메라 수용체 TK1-MO-FCG2A-CAR-6 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 20b는 TK1-MO-FCG2A-CAR-6의 서열(서열 번호 54)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 519는 IgG4 긴 힌지이며, 아미노산 520 내지 541은 FCGR2A 막관통 도메인이고, 아미노산 542 내지 619는 FCGR2A 세포액 도메인이다.
도 21은 키메라 수용체를 예시하는 개략도이다.
도 22는 키메라 수용체를 발현하는 대식세포를 나타내는 개략도이다. 도시된 바와 같이, 키메라 수용체는 toll 유사 수용체의 세포액 도메인, 막관통 도메인, 및 리간드에 특이적인 ScFv를 포함한다. 화살표는 ScFv가 리간드에 결합시에 대식세포를 분극시키는 신호전달을 도시한다.
도 23은 키메라 수용체를 구축하기 위해 이용될 수 있는 상이한 대식세포 수용체를 나타내는 개략도이다.
도 24a 내지 도 24c. 도 24a는 세포 활성화를 유발하는 Fc 감마 수용체 III 신호전달 캐스케이드를 나타내는 개략도이다. 도 24b는 칼슘 플럭스 및 증식의 억제를 유발하는 Fc 감마 수용체 III 신호전달 캐스케이드를 나타내는 개략도이다. 도 24c는 아포토시스를 유발하는 Fc 감마 수용체 III 신호전달 캐스케이드를 나타내는 개략도이다.
도 25는 Toll 유사 수용체 신호전달 캐스케이드를 예시하는 개략도이다.
도 26은 발현된 항체 단편이 관심 리간드에 결합하는 것을 확인하는 유세포 분석법을 예시하는 그래프를 나타낸다.
도 27은 키메라 수용체로 형질도입된 후 대식세포에서의 표현형 변화를 나타내는 2개의 영상을 나타낸다.
도 28은 단핵구에서 키메라 수용체의 발현을 확인하는 2개의 영상을 나타낸다.
도 29는 dTomato의 발현을 입증하는 형광 활성화 세포 분류의 3개의 산란 플롯을 나타낸다. 최좌측 플롯은 단지 0.58%의 세포가 dTomato의 발현을 나타낼 형광을 나타내는 대조군을 나타낸다. 우측 2개의 플롯은 형질도입 후 27.1%의 형질도입 효율을 나타낸다.
도 30은 키메라 수용체로 형질도입된 대식세포에서 염료(Alexa 647)의 보유, 및 CD80, CD163, CD206, 및 CD14의 발현을 입증하는 형광 활성화 세포 분류의 6개의 산란 플롯을 나타낸다.
도 31은 키메라 수용체로 형질도입된 대식세포에서 CD80, CD163, CD206, 및 CD14의 상대적인 발현 수준을 입증하는 히스토그램을 나타낸다.
도 32는 폐암 세포주(NCI-H460)에서 세포 사멸을 검출하고, 공격하고, 유도하는 키메라 수용체를 발현하는 형질도입된 대식세포의 6개의 영상을 나타낸다.
도 2a는 키메라 수용체 TK1-MOTO2 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 2b는 TK1-MOTO2의 서열(서열 번호 36)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 295는 LRR 짧은 힌지이며, 아미노산 296 내지 318은 TLR4 막관통 도메인이고, 아미노산 319 내지 500은 TLR4 세포액 도메인이다.
도 3a는 키메라 수용체 TK1-MOTO3 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 3b는 TK1-MOTO3의 서열(서열 번호 37)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 345는 LRR 긴 힌지이며, 아미노산 346 내지 368은 TLR4 막관통 도메인이고, 아미노산 269 내지 501은 TLR4 세포액 도메인이다.
도 4a는 키메라 수용체 TK1-MOTO4 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 4b는 TK1-MOTO4의 서열(서열 번호 38)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 302은 IgG4 짧은 힌지이며, 아미노산 303 내지 325는 TLR4 막관통 도메인이고, 아미노산 326-508은 TLR4 세포액 도메인이다.
도 5a는 키메라 수용체 TK1-MOTO5 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 5b는 TK1-MOTO5의 서열(서열 번호 39)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 409는 IgG 119 아미노산 중간 힌지이며, 아미노산 410 내지 432는 TLR4 막관통 도메인이고, 아미노산 433 내지 615는 TLR4 세포액 도메인이다.
도 6a는 키메라 수용체 TK1-MOTO6 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 6b는 TK1-MOTO6의 서열(서열 번호 40)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 518은 IgG4 긴 힌지이며, 아미노산 519 내지 541은 TLR4 막관통 도메인이고, 아미노산 542 내지 724는 TLR4 세포액 도메인이다.
도 7a는 키메라 수용체 TK1-MOTO7 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 7b는 TK1-MOTO7의 서열(서열 번호 41)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 C339S 및 C356S로 돌연변이화된 CD8 힌지이며, 아미노산 359 내지 381은 TLR4 막관통 도메인이고, 아미노산 382 내지 564는 TLR4 세포액 도메인이다.
도 8a는 키메라 수용체 TK1-MOTO8 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 8b는 TK1-MOTO8의 서열(서열 번호 42)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 CD8 힌지의 일부이며, 아미노산 359 내지 381은 TLR4 막관통 도메인이고, 아미노산 382 내지 564는 TLR4 세포액 도메인이다.
도 9a는 키메라 수용체 TK1-MO-FCGRA-CAR-1 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 9b는 TK1-MO-FCGRA-CAR-1의 서열(서열 번호 43)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 311은 FCGR3A 막관통 도메인이며, 아미노산 312 내지 336은 FCGR3A 세포액 도메인이고, 아미노산 337 내지 378은 FCER1G 세포액 도메인이다.
도 10a는 키메라 수용체 TK1-MO-FCGRA-CAR-2 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 10b는 TK1-MO-FCGRA-CAR-2의 서열(서열 번호 44)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 C339S 및 C356S로 돌연변이화된 CD8 힌지이며, 아미노산 359 내지 379는 FCGR3A 막관통 도메인이고, 아미노산 380 내지 404는 FCGR3A 세포액 도메인이며, 아미노산 405 내지 446은 FCER1G 세포액 도메인이다.
도 11a는 키메라 수용체 TK1-MO-FCGRA-CAR-3 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 11b는 TK1-MO-FCGRA-CAR-3의 서열(서열 번호 45)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 CD8 힌지의 일부이며, 아미노산 359 내지 379는 FCGR3A 막관통 도메인이고, 아미노산 380 내지 404는 FCGR3A 세포액 도메인이며, 아미노산 405 내지 446은 FCER1G 세포액 도메인이다.
도 12a는 키메라 수용체 TK1-MO-FCGRA-CAR-4 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 12b는 TK1-MO-FCGRA-CAR-4의 서열(서열 번호 46)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 303은 IgG4 짧은 힌지이며, 아미노산 304 내지 324는 FCGR3A 막관통 도메인이고, 아미노산 325 내지 349는 FCGR3A 세포액 도메인이며, 아미노산 350 내지 391은 FCER1G 세포액 도메인이다.
도 13a는 키메라 수용체 TK1-MO-FCGRA-CAR-5 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 13b는 TK1-MO-FCGRA-CAR-5의 서열(서열 번호 47)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 409는 IgG4 119 아미노산 힌지이며, 아미노산 410 내지 430은 FCGR3A 막관통 도메인이고, 아미노산 431 내지 455는 FCGR3A 세포액 도메인이며, 아미노산 456 내지 497은 FCER1G 세포액 도메인이다.
도 14a는 키메라 수용체 TK1-MO-FCGRA-CAR-6 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 14b는 TK1-MO-FCGRA-CAR-6의 서열(서열 번호 48)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 519는 IgG4 긴 힌지이며, 아미노산 520 내지 540은 FCGR3A 막관통 도메인이고, 아미노산 541 내지 565는 FCGR3A 세포액 도메인이며, 아미노산 566 내지 607은 FCER1G 세포액 도메인이다.
도 15a는 키메라 수용체 TK1-MO-FCG2A-CAR-1 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 15b는 TK1-MO-FCG2A-CAR-1의 서열(서열 번호 49)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 312는 FCGR2A 막관통 도메인이며, 아미노산 313 내지 390은 FCGR2A 세포액 도메인이다.
도 16a는 키메라 수용체 TK1-MO-FCG2A-CAR-2 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 16b는 TK1-MO-FCG2A-CAR-2의 서열(서열 번호 50)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 C339S 및 C356S로 돌연변이화된 CD8 힌지이며, 아미노산 359 내지 380은 FCGR2A 막관통 도메인이고, 아미노산 381 내지 458은 FCGR2A 세포액 도메인이다.
도 17a는 키메라 수용체 TK1-MO-FCG2A-CAR-3 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 17b는 TK1-MO-FCG2A-CAR-3의 서열(서열 번호 51)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 358은 CD8 힌지의 일부이며, 아미노산 359 내지 380은 FCGR2A 막관통 도메인이고, 아미노산 381 내지 458은 FCGR2A 세포액 도메인이다.
도 18a는 키메라 수용체 TK1-MO-FCG2A-CAR-4 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 18b는 TK1-MO-FCG2A-CAR-4의 서열(서열 번호 52)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 303은 IgG4 짧은 힌지이며, 아미노산 304 내지 325는 FCGR2A 막관통 도메인이고, 아미노산 326 내지 403은 FCGR2A 세포액 도메인이다.
도 19a는 키메라 수용체 TK1-MO-FCG2A-CAR-5 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 19b는 TK1-MO-FCG2A-CAR-5의 서열(서열 번호 53)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 409는 IgG4 119 아미노산 힌지이며, 아미노산 410 내지 431은 FCGR2A 막관통 도메인이고, 아미노산 432 내지 509는 FCGR2A 세포액 도메인이다.
도 20a는 키메라 수용체 TK1-MO-FCG2A-CAR-6 내의 요소의 순서의 블록 다이어그램을 도시한다. 도 20b는 TK1-MO-FCG2A-CAR-6의 서열(서열 번호 54)을 도시한다. 아미노산 1 내지 18은 신호 펩티드(SP)이고, 아미노산 19 내지 275는 항-TK1 ScFv이며, 아미노산 276 내지 290은 GS 링커이고, 아미노산 291 내지 519는 IgG4 긴 힌지이며, 아미노산 520 내지 541은 FCGR2A 막관통 도메인이고, 아미노산 542 내지 619는 FCGR2A 세포액 도메인이다.
도 21은 키메라 수용체를 예시하는 개략도이다.
도 22는 키메라 수용체를 발현하는 대식세포를 나타내는 개략도이다. 도시된 바와 같이, 키메라 수용체는 toll 유사 수용체의 세포액 도메인, 막관통 도메인, 및 리간드에 특이적인 ScFv를 포함한다. 화살표는 ScFv가 리간드에 결합시에 대식세포를 분극시키는 신호전달을 도시한다.
도 23은 키메라 수용체를 구축하기 위해 이용될 수 있는 상이한 대식세포 수용체를 나타내는 개략도이다.
도 24a 내지 도 24c. 도 24a는 세포 활성화를 유발하는 Fc 감마 수용체 III 신호전달 캐스케이드를 나타내는 개략도이다. 도 24b는 칼슘 플럭스 및 증식의 억제를 유발하는 Fc 감마 수용체 III 신호전달 캐스케이드를 나타내는 개략도이다. 도 24c는 아포토시스를 유발하는 Fc 감마 수용체 III 신호전달 캐스케이드를 나타내는 개략도이다.
도 25는 Toll 유사 수용체 신호전달 캐스케이드를 예시하는 개략도이다.
도 26은 발현된 항체 단편이 관심 리간드에 결합하는 것을 확인하는 유세포 분석법을 예시하는 그래프를 나타낸다.
도 27은 키메라 수용체로 형질도입된 후 대식세포에서의 표현형 변화를 나타내는 2개의 영상을 나타낸다.
도 28은 단핵구에서 키메라 수용체의 발현을 확인하는 2개의 영상을 나타낸다.
도 29는 dTomato의 발현을 입증하는 형광 활성화 세포 분류의 3개의 산란 플롯을 나타낸다. 최좌측 플롯은 단지 0.58%의 세포가 dTomato의 발현을 나타낼 형광을 나타내는 대조군을 나타낸다. 우측 2개의 플롯은 형질도입 후 27.1%의 형질도입 효율을 나타낸다.
도 30은 키메라 수용체로 형질도입된 대식세포에서 염료(Alexa 647)의 보유, 및 CD80, CD163, CD206, 및 CD14의 발현을 입증하는 형광 활성화 세포 분류의 6개의 산란 플롯을 나타낸다.
도 31은 키메라 수용체로 형질도입된 대식세포에서 CD80, CD163, CD206, 및 CD14의 상대적인 발현 수준을 입증하는 히스토그램을 나타낸다.
도 32는 폐암 세포주(NCI-H460)에서 세포 사멸을 검출하고, 공격하고, 유도하는 키메라 수용체를 발현하는 형질도입된 대식세포의 6개의 영상을 나타낸다.
본 명세서에는 키메라 수용체가 기재된다. 키메라 수용체는 세포질 도메인; 막관통 도메인; 및 세포외 도메인을 포함한다. 실시 형태에서, 세포질 도메인은 활성화될 때 대식세포를 분극시키는 수용체의 세포질 부분을 포함한다. 추가의 실시 형태에서, 세포질 부분을 포함하는 야생형 단백질은 키메라 수용체의 세포외 도메인을 포함하지 않는다. 실시 형태에서, 키메라 수용체의 세포외 도메인에 대한 리간드의 결합은 키메라 수용체의 세포내 부분을 활성화시킨다. 키메라 수용체의 세포내 부분의 활성화는 대식세포를 M1 또는 M2 대식세포로 분극시킬 수 있다.
소정의 실시 형태에서, 키메라 수용체의 세포질 부분은 toll-유사 수용체, 골수 분화 1차 반응 단백질(MYD88)(서열 번호 19), toll-유사 수용체 3(TLR3)(서열 번호 1), toll-유사 수용체 4(TLR4)(서열 번호 3), toll-유사 수용체 7(TLR7)(서열 번호 7), toll-유사 수용체 8(TLR8)(서열 번호 9), toll-유사 수용체 9(TLR9)(서열 번호 11), 미엘린 및 림프구 단백질(MAL)(서열 번호 21), 인터류킨-1 수용체-관련 키나제 1(IRAK1)(서열 번호 23), 저친화도 면역글로불린 감마 Fc 영역 수용체 III-A(FCGR3A)(서열 번호 15), 저친화도 면역글로불린 감마 Fc 영역 수용체 II-a(FCGR2A)(서열 번호 13), 고친화도 면역글로불린 엡실론 수용체 서브유닛 감마(FCER1G)(서열 번호 19)로부터의 세포질 도메인, 또는 전술한 것 중 어느 하나의 세포질 도메인에 대해 90% 이상의 서열 동일성을 갖는 서열을 포함할 수 있다. 소정의 실시 형태에서, 세포질 부분은 toll-유사 수용체, FCGR3A, IL-1 수용체, 또는 IFN-감마 수용체로부터의 세포질 도메인이 아니다. 실시 형태에서, 세포액 부분은 활성화될 때 대식세포의 분극을 유발할 임의의 폴리펩티드일 수 있다.
추가의 실시 형태에서, 세포외 도메인에 결합하는 리간드의 예는 티미딘 키나제(TK1), 하이포잔틴-구아닌 포스포리보실트랜스페라제(HPRT), 수용체 티로신 키나제-유사 오르펀 수용체 1(ROR1), 뮤신-16(MUC-16), 상피세포 성장 인자 수용체 vIII(EGFRvIII), 메소텔린, 인간 상피세포 성장 인자 수용체 2(HER2), 암종배아 항원(CEA), B-세포 성숙 항원(BCMA), 글리피칸 3(GPC3), 섬유아세포 활성화 단백질(FAP), 에리트로포이에틴-생성 간세포 암종 A2(EphA2), 자연 살해 군 2D(NKG2D) 리간드, 다이시알로강글리오사이드 2(GD2), CD19, CD20, CD30, CD33, CD123, CD133, CD138, 및 CD171일 수 있으나 이로 제한되지 않는다. 소정의 실시 형태에서, 리간드는 TK1 또는 HPRT가 아니다.
키메라 수용체의 세포외 도메인을 생성하도록 조정될 수 있는 항체는 당업계에 잘 알려져 있으며 구매가능하다. 구매가능한 항체의 예는 항-HGPRT, 클론 13H11.1(EMD Millipore), 항-ROR1(ab135669)(Abcam), 항-MUC1[EP1024Y](ab45167)(Abcam), 항-MUC16[X75](ab1107)(Abcam), 항-EGFRvIII[L8A4](Absolute antibody), 항-메소텔린[EPR2685(2)](ab134109)(Abcam), HER2[3B5](ab16901)(Abcam), 항-CEA(LS-C84299-1000)(LifeSpan BioSciences), 항-BCMA(ab5972)(Abcam), 항-글리피칸 3[9C2](ab129381)(Abcam), 항-FAP(ab53066)(Abcam), 항-EphA2[RM-0051-8F21](ab73254)(Abcam), 항-GD2(LS-C546315)(LifeSpan BioSciences), 항-CD19[2E2B6B10](ab31947)(Abcam), 항-CD20[EP459Y](ab78237)(Abcam), 항-CD30[EPR4102](ab134080)(Abcam), 항-CD33[SP266](ab199432)(Abcam), 항-CD123(ab53698)(Abcam), 항-CD133(BioLegend), 항-CD123(1A3H4) ab181789(Abcam), 및 항-CD171(L1.1)(Invitrogen antibodies)을 포함하지만 이로 제한되지 않는다. 알려진 항체로부터 ScFv와 같은 항체 단편을 생성하기 위한 기술은 당업계에서 통상적이다. 추가로, 이러한 단편을 암호화하는 서열을 생성하고 키메라 단백질을 암호화하는 폴리뉴클레오티드의 일부로서 이들을 재조합적으로 포함하는 것 또한 당업계에서 통상적이다.
소정의 실시 형태에서, 세포외 도메인은 리간드에 특이적으로 결합하는 항체 또는 그의 단편을 포함할 수 있다. 항체 및 이의 단편의 예는 IgA, IgD, IgE, IgG, IgM, Fab 단편, F(ab′)2 단편, 1가 항체, ScFv 단편, scRv-Fc 단편, IgNAR, hcIgG, VhH 항체, 나노바디, 및 알파바디(alphabody)를 포함하지만 이로 제한되지 않는다. 추가의 실시 형태에서, 세포외 도메인은 이량체화 도메인, 수용체, 결합 포켓 등을 포함하지만 이로 제한되지 않는 리간드의 특이적 결합을 가능하게 하는 임의의 아미노산 서열을 포함할 수 있다.
실시 형태에서, 키메라 수용체는 링커를 함유할 수 있다. 제한 없이, 링커는 키메라 수용체의 세포외 도메인과 막관통 도메인 사이에 위치할 수 있다. 제한없이, 링커는 G 링커, GS 링커, G4S 링커, EAAAK 링커, PAPAP 링커, 또는 (Ala-Pro)n 링커일 수 있다. 링커의 다른 예는 당업계에 잘 알려져 있다.
실시 형태에서, 키메라 수용체는 힌지 영역을 함유할 수 있다. 제한 없이, 힌지 영역은 키메라 수용체의 세포외 도메인과 막관통 도메인 사이에 위치할 수 있다. 추가의 실시 형태에서, 힌지 영역은 링커와 막관통 도메인 사이에 위치할 수 있다. 제한 없이, 링커는 류신 풍부 반복(LRR), 또는 toll-유사 수용체, IgG, IgG4, CD8m, 또는 FcγIIIa-hing으로부터의 힌지 영역일 수 있다. 실시 형태에서, 힌지 영역 내의 시스테인은 세린으로 대체될 수 있다. 힌지 영역의 다른 예는 본 기술 분야에 잘 알려져 있다.
본 명세서에 기재된 키메라 수용체는 서열 번호 1, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 및 25 내지 34 중 하나 이상, 이들 중 임의의 것의 단편, 및/또는 서열 번호 1, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 및 25 내지 34 중 하나 이상 또는 이들의 단편에 대해 90% 이상의 서열 동일성을 갖는 폴리펩티드를 포함할 수 있다. 키메라 수용체의 예는 서열 번호 35 내지 54 또는 이들의 상동체 또는 단편을 포함하지만 이로 제한되지 않는다. 다른 실시 형태에서, 폴리펩티드는 서열 번호 35 내지 54 중 하나 이상에 대해 90% 이상의 서열 동일성을 갖는 폴리펩티드로 이루어진 군으로부터 선택된 아미노산 서열을 포함한다.
실시 형태는 상기 기재된 바와 같은 키메라 수용체를 암호화하는 핵산 서열을 포함하는 핵산 서열을 포함한다. 이러한 핵산의 예는 서열 번호 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 및 24 중 하나 이상, 이들 중 임의의 것의 단편, 및/또는 서열 번호 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 및 24 중 하나 이상 또는 이들의 단편에 대해 90% 이상의 서열 동일성을 갖는 핵산을 포함할 수 있다. 추가의 예는 서열 번호 24 내지 54 중 하나 이상 및 이들 중 임의의 것의 단편을 암호화하는 핵산을 포함한다.
실시 형태에서, 키메라 수용체는 글리코실화, 페길화, 및/또는 달리 번역 후 변형될 수 있다. 추가로, 핵산 서열은 벡터의 일부일 수 있다. 예로서, 벡터는 플라스미드, 파지, 코스미드, 인공 염색체, 바이러스 벡터, AAV 벡터, 아데노바이러스 벡터, 또는 렌티바이러스 벡터일 수 있다. 소정의 실시 형태에서, 키메라 수용체를 암호화하는 핵산은 프로모터 및/또는 다른 조절 서열(예를 들어, 인핸서, 사일런서, 인슐레이터, 유전자좌 제어 영역, 시스-작용 요소 등)에 작동가능하게 연결될 수 있다.
추가의 실시 형태는 키메라 수용체 또는 키메라 수용체를 암호화하는 핵산을 포함하는 세포를 포함한다. 이러한 세포의 비제한적인 예는 골수 세포, 골수 전구 세포, 단핵구, 호중구, 호염기구, 호산구, 거핵구, T 세포, B 세포, 자연 살해 세포, 백혈구, 림프구, 수지상 세포, 및 대식세포를 포함한다.
실시 형태는 키메라 수용체를 포함하는 대식세포를 키메라 수용체의 세포외 도메인에 대한 리간드와 접촉시키는 단계; 리간드를 키메라 수용체의 세포외 도메인에 결합시키는 단계에 의해 대식세포를 분극시키는 방법을 포함한다. 키메라 수용체의 세포외 도메인에 대한 리간드의 결합은 세포질 부분을 활성화시키고, 세포질 부분의 활성화는 대식세포를 분극시킨다.
뉴클레오티드, 폴리뉴클레오티드, 또는 핵산 서열은 단량체성 및 이량체성(소위, 탠덤(tandem)으로) 형태의 이중 가닥 또는 단일 가닥 DNA 또는 RNA 및 DNA 또는 RNA의 전사 산물 둘 모두를 의미하는 것으로 본 발명에 따라 이해될 것이다.
본 발명의 태양은, 예를 들어 이온 교환 크로마토그래피와 같은 분리 방법으로부터 시작하여, 분자 크기에 기초한 배제에 의해, 또는 친화도, 또는 대안적으로 상이한 용매 중의 용해도에 기초한 분획화 기술에 의해, 또는 증폭, 클로닝, 및 서브클로닝과 같은 유전 공학 방법으로부터 시작하여, 단리하거나, 정제하거나, 부분적으로 정제하는 것이 가능한 뉴클레오티드 서열과 관련되며, 서열은 벡터에 의해 운반되는 것이 가능하다.
뉴클레오티드 서열 단편은 임의의 뉴클레오티드 단편을 지정하는 것으로 이해될 것이며, 비제한적인 예로서, 그것이 기원하는 서열의 적어도 8, 12, 20, 25, 50, 75, 100, 200, 300, 400, 500, 1000개 또는 그 이상의 연속 뉴클레오티드의 길이를 포함할 수 있다.
뉴클레오티드 서열의 특이적 단편은, 상응하는 야생형 서열과의 정렬 및 비교 후에, 하나 이상이 더 적은 뉴클레오티드 또는 염기를 갖는 임의의 뉴클레오티드 단편을 지정하는 것으로 이해될 것이다.
본 명세서에 사용되는 바와 같은 상동성 뉴클레오티드 서열은 적어도 약 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 또는 99.7% 이상의 뉴클레오티드 서열의 염기와의 백분율 동일성을 갖는 뉴클레오티드 서열을 의미하는 것으로 이해되며, 이 백분율은 전적으로 통계적이고 2개의 뉴클레오티드 서열 사이의 차이를 이들의 길이 전체에 걸쳐 무작위로 분배하는 것이 가능하다.
본 발명의 의미에서 특이적 상동성 뉴클레오티드 서열은 상기 정의된 것과 같은 특이적 단편의 하나 이상의 서열을 갖는 상동성 서열을 의미하는 것으로 이해된다. "특이적" 상동성 서열은, 예를 들어 게놈 서열 또는 게놈 서열의 변이체를 대표하는 그의 단편의 서열에 상응하는 서열을 포함할 수 있다. 따라서, 이들 특이적 상동성 서열은 서열 내의 돌연변이에 연결된 변이에 상응할 수 있으며, 특히 하나 이상의 뉴클레오티드의 절단, 치환, 결실, 및/또는 부가에 상응한다. 상동성 서열은 마찬가지로 유전자 코드의 축퇴성(degeneracy)에 연결된 변이에 상응할 수 있다.
용어 "서열 상동성의 정도 또는 백분율"은 본 출원에 정의된 바와 같이 "최적 정렬 후 2개의 서열 사이의 서열 동일성의 정도 또는 백분율"을 지칭한다.
하기 기재된 바와 같이 최대 상응도를 위해 정렬될 때 2개의 서열 내의 아미노산 또는 뉴클레오티드 잔기의 서열이 동일하다면 2개의 뉴클레오티드 서열은 "동일한" 것으로 언급된다. 2개(또는 그 이상)의 펩티드 또는 폴리뉴클레오티드 사이의 서열 비교는 전형적으로, 서열 유사성의 국소 영역을 확인하고 비교하기 위해 세그먼트 또는 "비교 윈도우"에 걸쳐 2개의 최적으로 정렬된 서열의 서열을 비교함으로써 수행된다. 비교를 위한 서열의 최적 정렬은 문헌[Smith and Waterman, Ad. App. Math 2: 482(1981)]의 국소 상동성 알고리즘에 의해, 문헌[Neddleman and Wunsch, J. Mol. Biol. 48: 443(1970)]의 상동성 정렬 알고리즘에 의해, 문헌[Pearson and Lipman, Proc. Natl. Acad. Sci. (U.S.A.) 85: 2444(1988)]의 유사성 검색 방법에 의해, 이들 알고리즘의 전산화 구현(위스콘신주 매디슨 575 사이언스 Dr. 소재의 Genetics Computer Group(GCG)의, Wisconsin Genetics Software Package 내의 GAP, BESTFIT, FASTA, 및 TFASTA)에 의해, 또는 시각적 검사에 의해 수행될 수 있다.
"서열 동일성의 백분율"(또는 동일성의 정도)은 비교 윈도우에 걸쳐 2개의 최적으로 정렬된 서열을 비교함으로써 결정되며, 여기서 비교 윈도우 내의 펩티드 또는 폴리뉴클레오티드 서열의 부분은 2개의 서열의 최적 정렬을 위한 기준 서열(부가 또는 결실을 포함하지 않음)과 비교하여 부가 또는 결실(즉, 갭)을 포함할 수 있다. 동일한 아미노산 잔기 또는 핵산 염기가 둘 모두의 서열에서 나타나는 위치의 수를 결정하여 일치하는 위치의 수를 산출하고, 일치하는 위치의 수를 비교 윈도우 내의 위치의 총 수로 나누고, 그 결과에 100을 곱하여 서열 동일성의 백분율을 산출함으로써 백분율을 계산한다.
상기 주어진 서열 동일성의 정의는 당업자에 의해 사용될 정의이다. 정의 그 자체는 임의의 알고리즘의 도움을 필요로 하지 않으며, 알고리즘은 서열 동일성의 계산보다는 단지 서열의 최적 정렬을 달성하는 데 도움이 된다.
상기 주어진 정의로부터, 2개의 비교되는 서열 사이의 서열 동일성에 대해 잘 정의된 단 하나의 값이 존재하며, 이 값은 최상의 또는 최적의 정렬에 대해 얻어진 값에 상응한다는 결론에 도달한다.
2개의 서열 사이의 동일성을 비교하고 결정하기 위해 본 발명자들이 관용적으로 사용하고 당업자가 일반적으로 사용하며 웹 사이트 worldwideweb.ncbi.nlm.nih.gov/gorf/bl2.html에서 입수가능한 소프트웨어인, BLAST N 또는 BLAST P "BLAST 2 서열"에서, 비교할 서열 길이에 의존하는 갭 코스트는 소프트웨어에 의해 직접 선택된다(즉, 치환 매트릭스 BLOSUM-62의 경우에 85 초과의 길이에 대해 11.2).
본 명세서에 사용되는 바와 같은 서열의 상보적 뉴클레오티드 서열은, 그의 뉴클레오티드가 서열의 것들에 상보적이고 그의 배향이 역전된(안티센스 서열) 임의의 DNA를 의미하는 것으로 이해된다.
본 명세서에 사용되는 바와 같은 뉴클레오티드 서열을 갖는 엄격성 조건 하에서의 혼성화는, 이들이 상보적 DNA의 2개의 단편 사이의 혼성화의 유지를 가능하게 하는 방식으로 선택된 온도 및 이온 강도의 조건 하에서의 혼성화를 의미하는 것으로 이해된다.
예시로서, 상기 기재된 뉴클레오티드 단편을 정의하는 목적을 갖는 혼성화 단계의 높은 엄격성의 조건은 유리하게는 하기와 같다.
SSC 완충제, 0.15 M NaCl 및 0.05 M Na 시트레이트에 상응하는 1 × SSC의 존재 하에 65℃의 우선적인 온도에서 혼성화가 실행된다. 예를 들어, 세척 단계는 하기와 같을 수 있다: 주위 온도에서 2 × SSC, 이어서 65℃에서 2 × SSC, 0.5% SDS로 2회 세척; 65℃에서 각각 10분 동안; 2 × 0.5 × SSC, 0.5% SDS.
예를 들어, 2 × SSC 완충제의 존재 하에 42℃의 온도를 사용하는 중간 엄격성 조건, 또는 더 낮은 엄격성 조건, 예를 들어 2 × SSC 완충제의 존재 하에 37℃의 온도는, 각각 2개의 서열 사이의 혼성화에 대해 전반적으로 덜 유의적인 상보성을 필요로 한다.
문헌[Sambrook et al., 1989]의 교시내용에 따라, 대략 350개 염기의 크기를 갖는 폴리뉴클레오티드에 대해 상기 기재된 엄격한 혼성화 조건은 더 크거나 더 작은 크기의 올리고뉴클레오티드에 대해 당업자에 의해 조정될 것이다.
본 명세서에 기재된 뉴클레오티드 서열 중에는 상동성 서열을 얻는 것을 가능하게 하는 방법에서 프라이머 또는 프로브로서 사용될 수 있는 것들이 있으며, 중합효소 연쇄 반응(PCR), 핵산 클로닝, 및 서열분석과 같은 이들 방법은 당업자에게 잘 알려져 있다.
뉴클레오티드 서열 중에는 특이적 핵산, 이들의 단편 중 하나, 또는 하기 정의된 것과 같은 이들의 변이체 중 하나의 존재를 결정하는 것을 가능하게 하는 방법에서 프라이머 또는 프로브로서 사용될 수 있는 것들이 있다. 실시 형태에서, 뉴클레오티드 서열은 막관통 도메인, 세포액 도메인, 또는 이들의 일부를 암호화하는 서열 번호 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 및 24의 단편을 포함할 수 있다. 추가의 단편은 서열 번호 26 내지 34 중 하나 이상을 암호화하는 뉴클레오티드와 같은 링커, 힌지, 또는 이들의 단편을 암호화하는 뉴클레오티드 서열을 포함할 수 있다. 추가의 단편은 서열 번호 35 내지 54 중 하나 이상을 암호화하는 뉴클레오티드 서열의 단편을 포함할 수 있다.
뉴클레오티드 서열 단편은, 예를 들어 PCR과 같은 특이적 증폭에 의해, 또는 뉴클레오티드 서열을 적절한 제한 효소로 분해한 후에 얻어질 수 있으며, 이들 방법은 특히 문헌[Sambrook et al., 1989]의 연구에 기재되어 있다. 또한, 이러한 단편은 GenScript®와 같은 회사로부터 입수가능한 유전자 합성 표준 기술에 의해 얻어질 수 있다. 이러한 대표적인 단편은 당업자에게 잘 알려진 방법에 따라 화학적 합성에 의해 마찬가지로 얻어질 수 있다.
변형된 뉴클레오티드 서열은 당업자에게 잘 알려진 기술에 따라 돌연변이유발에 의해 얻어지고 야생형 서열에 대한 변형, 예를 들어, 특히 폴리펩티드의 발현율의 변경 또는 복제 주기의 조절을 유발하는 폴리펩티드 발현의 조절 서열 및/또는 프로모터 서열의 돌연변이를 함유하는 임의의 뉴클레오티드 서열을 의미하는 것으로 이해될 것이다.
변형된 뉴클레오티드 서열은 마찬가지로, 하기 정의된 것과 같은 변형된 폴리펩티드를 코딩하는 임의의 뉴클레오티드 서열을 의미하는 것으로 이해될 것이다.
서열 번호 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 및 24로부터 선택된 뉴클레오티드 서열 또는 이들의 단편 중 하나를 포함하는, 키메라 수용체를 암호화하는 뉴클레오티드 서열이 개시된다. 이러한 단편은 특정 도메인, 예컨대 막관통 도메인 또는 세포액 도메인 또는 이들의 부분을 암호화할 수 있다. 키메라 수용체를 암호화하는 추가의 뉴클레오티드 서열은 서열 번호 26 내지 34 중 하나 이상을 암호화하는 뉴클레오티드와 같은 링커, 힌지, 또는 이들의 단편을 암호화하는 뉴클레오티드 서열을 포함할 수 있다. 키메라 수용체를 암호화하는 뉴클레오티드 서열은 서열 번호 35 내지 54 중 하나 이상 또는 이들의 단편을 암호화하는 뉴클레오티드 서열을 추가로 포함할 수 있다.
실시 형태는 마찬가지로 a) 서열번호 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 및 24의 뉴클레오티드 서열 중 하나 이상, 서열 번호 25 내지 54 중 하나 이상을 암호화하는 뉴클레오티드 서열, 또는 이들의 단편 중 하나; b) a)에서 정의된 것과 같은 서열의 특이적 단편의 뉴클레오티드 서열; c) a) 또는 b)에서 정의된 것과 같은 서열과 80% 이상의 동일성을 갖는 상동성 뉴클레오티드 서열; d) 상보적 뉴클레오티드 서열 또는 a), b), 또는 c)에서 정의된 것과 같은 서열에 상응하는 RNA의 서열; 및 e) a), b), c), 또는 d)에서 정의된 것과 같은 서열에 의해 변형된 뉴클레오티드 서열로부터 선택된 뉴클레오티드 서열을 포함함을 특징으로 하는 뉴클레오티드 서열에 관한 것이다.
뉴클레오티드 서열 중에는 서열 번호 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 및 24의 뉴클레오티드 서열, 서열 번호 25 내지 54 중 하나 이상을 암호화하는 뉴클레오티드 서열, 또는 이들의 단편 및 서열 번호 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 및 24의 서열 중 하나 이상, 서열 번호 25 내지 54 중 하나 이상을 암호화하는 뉴클레오티드 서열, 또는 이들의 단편과 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 또는 99.7% 이상의 동일성의 상동성을 갖는 임의의 뉴클레오티드 서열이 있다. 상동성 서열은, 예를 들어 야생형 서열에 상응하는 서열을 포함할 수 있다. 동일한 방식으로, 이들 특이적 상동성 서열은 야생형 서열 내의 돌연변이에 연결된 변이에 상응할 수 있으며, 특히 하나 이상의 뉴클레오티드의 절단, 치환, 결실, 및/또는 부가에 상응한다. 당업자에게 명백한 바와 같이, 이러한 상동체는 표준 기술 및 BLAST와 같은 공개적으로 입수가능한 컴퓨터 프로그램을 사용하여 용이하게 생성되고 확인된다. 이와 같이, 상기 언급된 각각의 상동체는 본 명세서에 기술되고 완전히 기재된 것으로 간주되어야 한다.
실시 형태는 본 명세서에 기재된 뉴클레오티드 서열, 또는 이의 단편에 의해 코딩되는 키메라 수용체를 포함하며, 그의 서열은 단편에 의해 표현된다. 서열 번호 35 내지 54의 서열 중 하나 이상의 서열의 3개의 가능한 해독 프레임 중 하나에 따라 코딩될 수 있는 폴리펩티드에 상응하는 아미노산 서열.
실시 형태는 마찬가지로 서열 번호 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 및 25 내지 54의 아미노산 서열 중 하나 이상으로부터 선택되는 폴리펩티드, 또는 이들의 단편 중 하나를 포함함을 특징으로 하는 키메라 수용체에 관한 것이다.
폴리펩티드 중에는, 실시 형태에 따라, 서열 번호 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 및 25 내지 54의 아미노산 서열의 폴리펩티드, 또는 이들의 단편 또는 서열 번호 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 및 25 내지 54의 서열 중 하나 이상 또는 이들의 단편과 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 또는 99.7% 이상의 동일성의 상동성을 갖는 임의의 다른 폴리펩티드가 있다. 당업자에게 명백한 바와 같이, 이러한 상동체는 표준 기술 및 BLAST와 같은 공개적으로 입수가능한 컴퓨터 프로그램을 사용하여 용이하게 생성되고 확인된다. 이와 같이, 상기 언급된 각각의 상동체는 본 명세서에 기술되고 완전히 기재된 것으로 간주되어야 한다.
실시 형태는 또한, a) 아미노산 서열의 폴리펩티드의 5개 이상의 아미노산의 특이적 단편; b) a)에서 정의된 것과 같은 폴리펩티드와 상동성인 폴리펩티드; c) a) 또는 b)에서 정의된 것과 같은 폴리펩티드의 특이적 생물학적 활성 단편; 및 d) a), b), 또는 c)에서 정의된 것과 같은 폴리펩티드에 의해 변형된 폴리펩티드로부터 선택된 폴리펩티드를 포함함을 특징으로 하는 폴리펩티드에 관한 것이다.
본 명세서에서, 용어 폴리펩티드, 펩티드, 및 단백질은 상호교환가능하다.
실시 형태에서, 키메라 수용체는 글리코실화, 페길화, 및/또는 달리 번역 후 변형될 수 있다. 추가의 실시 형태에서, 글리코실화, 페길화, 및/또는 다른 번역 후 변형은 생체내 또는 시험관내에서 일어날 수 있고/있거나 화학적 기술을 사용하여 수행할 수 있다. 추가의 실시 형태에서, 임의의 글리코실화, 페길화, 및/또는 다른 번역 후 변형은 N-연결 또는 O-연결될 수 있다.
실시 형태에서, 세포외 도메인이 리간드에 의해 결합될 때 신호가 전달되어 대식세포를 분극시키도록, 키메라 수용체 중 어느 하나는 효소적으로 또는 기능적으로 활성일 수 있다.
본 명세서에 사용되는 바와 같이, "분극된 대식세포"는 M1 또는 M2 대식세포 표현형과 상관관계가 있는 대식세포이다. M1 분극된 대식세포는 IL-12 및 IL-23을 분비한다. M1으로 분극된 대식세포의 결정은 표준 사이토카인 검정을 사용하여 IL-12 및/또는 IL-23의 발현을 측정하고 그 발현을 새롭게 분화된 비분극된 대식세포에 의한 발현에 비교함으로써 수행할 수 있다. 대안적으로, 세포가 CD14+, CD80+, CD206+, 및 CDCD163-인지를 결정함으로써 결정이 이루어질 수 있다. M2 분극된 대식세포는 IL-10을 분비한다. M2로 분극된 대식세포의 결정은 표준 사이토카인 검정을 사용하여 IL-10의 발현을 측정하고 그 발현을 새롭게 분화된 비분극된 대식세포에 의한 발현에 비교함으로써 수행할 수 있다. 대안적으로, 세포가 CD14+, CD80-, CD206+, 및 CDCD163+인지를 결정함으로써 결정이 이루어질 수 있다.
본 발명의 태양은 유전자 재조합에 의해, 또는 대안적으로 화학적 합성에 의해 얻어지는 키메라 수용체에 관한 것이며, 따라서 이들은 하기 기재될 바와 같이 비천연 아미노산을 함유할 수 있다.
실시 형태에 따른 "폴리펩티드 단편"은 5 개 이상의 연속적 아미노산, 바람직하게는 10개의 연속적 아미노산 또는 15개의 연속적 아미노산을 함유하는 폴리펩티드를 지정하는 것으로 이해된다.
본 명세서에서, 특이적 폴리펩티드 단편은 특정 단편 뉴클레오티드 서열에 의해 코딩되는 연속적 폴리펩티드 단편을 지정하는 것으로 이해된다.
"상동성 폴리펩티드"는 천연 폴리펩티드에 대하여, 특히 하나 이상의 아미노산의 결실, 부가, 또는 치환, 절단, 연장, 키메라 융합, 및/또는 돌연변이와 같은 소정의 변형을 갖는 폴리펩티드를 지정하는 것으로 이해될 것이다. 상동성 폴리펩티드 중에서, 그의 아미노산 서열이 본 명세서에 기재된 폴리펩티드의 아미노산의 서열과 80% 또는 90% 이상의 상동성을 갖는 것들이 바람직하다.
"특이적 상동성 폴리펩티드"는 상기 정의된 것과 같고 본 명세서에 기재된 폴리펩티드의 특이적 단편을 갖는 상동성 폴리펩티드를 지정하는 것으로 이해될 것이다.
치환의 경우, 하나 이상의 연속적 또는 비연속적 아미노산이 "등가의" 아미노산에 의해 대체된다. 본 명세서에서 표현 "등가의" 아미노산은 상응하는 펩티드의 생물학적 활성을 본질적으로 변형시키지 않는 염기 구조의 아미노산 중 하나에 의해 치환될 수 있는 임의의 아미노산을 지정하는 것을 지향하며, 이들은 하기에 의해 정의될 것이다. 당업자에게 명백한 바와 같이, 이러한 치환은 표준 분자 생물학 기술 및 BLAST와 같은 공개적으로 입수가능한 컴퓨터 프로그램을 사용하여 용이하게 생성되고 확인된다. 이와 같이, 상기 언급된 각각의 치환은 본 명세서에 기술되고 완전히 기재된 것으로 간주되어야 한다.
이들 등가의 아미노산은 이들이 치환하는 아미노산과의 이들의 구조적 상동성, 또는 실행될 수 있는 상이한 폴리펩티드들 사이의 생물학적 활성의 비교 시험의 결과에 따라 결정할 수 있다.
비제한적인 예로서, 상응하는 변형된 폴리펩티드의 생물학적 활성의 광범위한 변형을 유발하지 않으면서 실행될 수 있는 치환의 가능성, 예를 들어, 발린 또는 아이소류신에 의한 류신의 대체, 글루탐산에 의한 아스파르트산의 대체, 아스파라긴에 의한 글루타민의 대체, 리신에 의한 아르기닌의 대체 등이 언급될 것이며, 동일한 조건 하에 역 치환을 당연히 구상할 수 있다.
추가의 실시 형태에서, 치환은 유사한 확인된 효소 활성을 갖는 다른 단백질 중에서 보존되지 않은 아미노산에서의 치환으로 제한된다. 예를 들어, 당업자는 유사한 유기체 내의 동일한 기능의 단백질을 정렬하고, 그 기능의 단백질 중에서 어느 아미노산이 일반적으로 보존되는지를 결정할 수 있다. 이러한 정렬을 생성하기 위해 사용될 수 있는 프로그램의 일례는 NCBI에 의해 제공되는 데이터베이스와 함께, wordlwideweb.charite.de/bioinf/strap/이다.
따라서, 일 실시 형태에 따라, 치환 또는 돌연변이는 그 기능의 단백질 중에서 일반적으로 보존되는 위치에서 이루어질 수 있다. 추가의 실시 형태에서, 핵산 서열은 이들이 코딩하는 아미노산이 변화하지 않도록 돌연변이화되거나 치환되고/되거나(축퇴된 치환 및/돌연변이) 임의의 유발되는 아미노산 치환 또는 돌연변이가 그 기능의 단백질 중에서 일반적으로 보존되는 위치에서 이루어지도록 돌연변이화되거나 치환될 수 있다.
특이적 상동성 폴리펩티드는 마찬가지로 상기 정의된 것과 같은 특이적 상동성 뉴클레오티드 서열에 의해 코딩되는 폴리펩티드에 상응하며, 따라서 돌연변이화되거나 야생형 서열에 존재할 수 있는 변이체에 상응하고 특히 하나 이상의 아미노산 잔기의 절단, 치환, 결실, 및/또는 부가에 상응하는 폴리펩티드를 본 정의 내에 포함한다.
본 명세서에 사용되는 바와 같이, "폴리펩티드의 특이적 생물학적 활성 단편"은 특히 본 명세서에 기재된 폴리펩티드의 특징 중 하나 이상을 갖는, 상기 정의된 것과 같은 특이적 폴리펩티드 단편을 지정하는 것으로 이해될 것이다. 소정의 실시 형태에서, 펩티드는 활성화될 때 대식세포를 분극시키는 키메라 항원 수용체로서 거동할 수 있다.
본 명세서에 사용되는 바와 같이 폴리펩티드의 "변형된 폴리펩티드"는 야생형 서열에 대하여 하나 이상의 변형을 갖는, 하기 기재될 화학적 합성 또는 유전자 재조합에 의해 얻어지는 폴리펩티드를 지정하는 것으로 이해된다. 이들 변형은 특이성 및/또는 활성의 기원에 있는, 또는 본 명세서에 기재된 폴리펩티드의 구조적 입체배좌, 국재화, 및 막 삽입의 능력의 기원에 있는 아미노산에 관련될 수 있거나 그렇지 않을 수 있다. 따라서, 등가이거나, 증가되거나, 활성이 감소된 폴리펩티드, 및 등가이거나, 더 좁거나, 더 넓은 특이성의 폴리펩티드를 생성하는 것이 가능할 것이다. 변형된 폴리펩티드 중에서, 최대 5개 이상의 아미노산이 변형되거나, N-말단 또는 C-말단 단부에서 절단되거나, 심지어 결실되거나 부가될 수 있는 폴리펩티드를 언급할 필요가 있다.
진핵 또는 원핵 세포에 대한 조절을 입증하는 것을 가능하게 하는 방법이 당업자에게 잘 알려져 있다. 예를 들어 벡터를 통해 조절을 위해 변형된 폴리펩티드를 코딩하는 뉴클레오티드 서열을 사용하는 것이 가능할 것임이 마찬가지로 잘 이해되며 하기 기재되어 있다.
전술한 변형된 폴리펩티드는 조합 화학(combinatorial chemistry)을 사용함으로써 얻어질 수 있으며, 여기서 이들을 모델, 세포 배양물, 또는 미생물 상에서 시험하기 전에 폴리펩티드의 부분을 체계적으로 변동시켜, 예를 들어 가장 활성이거나 추구하는 특성을 가진 화합물을 선택하는 것이 가능하다.
마찬가지로 화학적 합성은 비천연 아미노산 또는 비펩티드 결합을 사용할 수 있는 이점을 갖는다.
따라서, 폴리펩티드의 수명의 지속기간을 개선하기 위하여, 예를 들어 D 형태의 비천연 아미노산, 또는 아미노산 유사체, 특히 예를 들어 황-함유 형태를 사용하는 것이 관심의 대상이 될 수 있다.
마지막으로, 폴리펩티드의 구조, 그의 특이적이거나 변형된 상동성 형태를 폴리펩티드 유형 또는 기타의 화학적 구조 내로 통합하는 것이 가능할 것이다. 따라서, N-말단 및 C-말단 단부에 프로테아제에 의해 인식되지 않는 화합물을 제공하는 것이 관심의 대상이 될 수 있다.
폴리펩티드를 코딩하는 뉴클레오티드 서열이 마찬가지로 본 명세서에 개시된다.
실시 형태는 마찬가지로, 본 명세서에 기재된 뉴클레오티드 서열로부터 서열이 선택됨을 특징으로 하는, 프라이머 또는 프로브로서 이용될 수 있는 뉴클레오티드 서열에 관한 것이다.
마찬가지로 다양한 실시 형태가, 천연 폴리펩티드로부터의 정제, 유전적 재조합, 또는 당업자에게 잘 알려지고 특히 하기 기재된 것과 같은 절차에 의한 화학적 합성에 의해 얻어질 수 있는, 뉴클레오티드 서열에 의해 코딩되는 키메라 수용체를 포함하는 특이적 폴리펩티드에 관한 것임이 잘 이해된다. 동일한 방식으로, 뉴클레오티드 서열에 의해 코딩되는 특이적 폴리펩티드에 대해 지향된 표지되거나 표지되지 않은 단클론 또는 다클론 항체가 또한 본 발명에 의해 포함된다.
실시 형태는 추가로 핵산 서열의 검출 및/또는 증폭을 위한 프라이머 또는 프로브로서의 뉴클레오티드 서열의 용도에 관한 것이다.
따라서, 실시 형태에 따른 뉴클레오티드 서열은, 특히 PCR 기술(중합효소 연쇄 반응)(문헌[Erlich, 1989]; 문헌[Innis et al., 1990]; 문헌[Rolfs et al., 1991]; 및 문헌[White et al., 1997])에 의해 뉴클레오티드 서열을 증폭하기 위해 사용될 수 있다.
이들 올리고데옥시리보뉴클레오티드 또는 올리고리보뉴클레오티드 프라이머는 유리하게는 길이가 8개 이상의 뉴클레오티드, 바람직하게는 12개 이상의 뉴클레오티드, 더욱 더 바람직하게는 20개 이상의 뉴클레오티드이다.
PCR에 대한 대안으로서 표적 핵산의 다른 증폭 기술이 유리하게 사용될 수 있다.
본 명세서에 기재된 뉴클레오티드 서열, 특히 프라이머는, 표적 핵산의 증폭의 하기와 같은 다른 절차에 마찬가지로 사용될 수 있다: 문헌[Kwoh et al., 1989]에 의해 기재된 TAS 기술(전사-기반 증폭 시스템); 문헌[Guatelli et al., 1990]에 의해 기재된 3SR 기술(자가-유지 서열 복제); 문헌[Kievitis et al., 1991]에 의해 기재된 NASBA 기술(핵산 서열 기반 증폭); SDA 기술(가닥 치환 증폭)(문헌[Walker et al., 1992]); TMA 기술(전사 매개 증폭).
키메라 수용체를 포함하는 폴리뉴클레오티드는 또한 프로브로서 작용하여 핵산의 증폭 또는 변형의 하기와 같은 기술에 사용될 수 있다: 문헌[Landegren et al., 1988]에 의해 기재되고 문헌[Barany et al., 1991]에 의해 개선된, 열안정성 리가제를 사용하는 LCR 기술(리가제 연쇄 반응); 문헌[Segev, 1992]에 의해 기재된 RCR 기술(복구 연쇄 반응); 문헌[Duck et al., 1990]에 의해 기재된 CPR 기술(주기순환 프로브 반응); 문헌[Miele et al., 1983]에 의해 기재되고 특히 문헌[Chu et al., 1986], 문헌[Lizardi et al., 1988], 이어서 문헌[Burg et al.]뿐만 아니라 문헌[Stone et al., 1996]에 의해 개선된, Q-베타 복제효소를 이용하는 증폭 기술.
검출될 표적 폴리뉴클레오티드가 아마도 RNA, 예를 들어 mRNA 인 경우, 하나 이상의 프라이머의 도움으로 증폭 반응을 사용하기 전에, 또는 하나 이상의 프로브의 도움으로 검출 절차를 사용하기 전에, 생물학적 샘플에 함유된 RNA로부터 cDNA를 얻기 위하여 역전사효소 유형의 효소를 사용하는 것이 가능할 것이다. 따라서, 얻어진 cDNA는 증폭 또는 검출 절차에 사용되는 프라이머(들) 또는 프로브(들)에 대한 표적으로서 작용할 것이다.
검출 프로브는 그것이 표적 서열 또는 표적 서열로부터 생성된 앰플리콘과 혼성화되는 방식으로 선택될 것이다. 서열로서, 이러한 프로브는 유리하게는 12개 이상의 뉴클레오티드, 특히 20개 이상의 뉴클레오티드, 바람직하게는 100개 이상의 뉴클레오티드의 서열을 가질 것이다.
실시 형태는 또한, 방사성 화합물 또는 비방사성 화합물로 표지됨을 특징으로 하는, 프로브 또는 프라이머로서 이용할 수 있는 뉴클레오티드 서열을 포함한다.
표지되지 않은 뉴클레오티드 서열은 프로브 또는 프라이머로서 직접 사용될 수 있지만, 다수의 응용에 이용될 수 있는 프로브를 얻기 위해 서열은 일반적으로 방사성 동위원소(32P, 35S, 3H, 125I) 또는 비방사성 분자(바이오틴, 아세틸아미노플루오렌, 디곡시게닌, 5-브로모데옥시우리딘, 플루오레세인)로 표지된다.
뉴클레오티드 서열의 비방사성 표지화의 예는, 예를 들어 프랑스 특허 제78.10975호 또는 문헌[Urdea et al.] 또는 문헌[Sanchez-Pescador et al., 1988]에 기재되어 있다.
후자의 경우에, 특허 FR-2 422 956 및 FR-2 518 755에 기재된 표지화 방법 중 하나를 사용하는 것이 또한 가능할 것이다.
혼성화 기술은 다양한 방식으로 실행될 수 있다(문헌[Matthews et al., 1988]). 가장 일반적인 방법은 지지체(예컨대 니트로셀룰로스, 나일론, 폴리스티렌) 상에 세포의 핵산 추출물을 고정하는 단계, 및 고정된 표적 핵산을 프로브와 함께 잘 정의된 조건 하에 인큐베이션하는 단계로 이루어진다. 혼성화 후, 과량의 프로브를 제거하고, 형성된 혼성체 분자를 적절한 방법(프로브에 연결된 방사능, 형광, 또는 효소 활성의 측정)에 의해 검출한다.
다양한 실시 형태는 마찬가지로, 공유적으로 또는 비공유적으로 지지체 상에 고정됨을 특징으로 하는, 본 명세서에 기재된 뉴클레오티드 서열 또는 폴리펩티드 서열을 포함한다.
뉴클레오티드 서열을 사용하는 다른 유리한 모드에 따라, 후자는 지지체 상에 고정된 상태로 사용될 수 있고, 따라서 특이적 혼성화에 의해, 시험할 생물학적 샘플로부터 얻어진 표적 핵산을 포획하는 작용을 할 수 있다. 필요한 경우, 고체 지지체를 샘플로부터 분리하고, 이어서 포획 프로브와 표적 핵산 사이에 형성된 혼성화 복합체를 용이하게 검출가능한 요소로 표지된 제2 프로브, 소위 검출 프로브의 도움으로 검출한다.
다른 태양은, 본 명세서에 기재된 뉴클레오티드 서열을 함유함을 특징으로 하는, 서열의 클로닝 및/또는 발현을 위한 벡터이다.
결정된 숙주 세포에서 뉴클레오티드 서열의 통합, 발현, 및/또는 분비를 가능하게 하는 요소를 함유함을 특징으로 하는 벡터가 마찬가지로 제공된다.
이어서, 벡터는 프로모터, 번역의 개시 및 종결 신호뿐만 아니라 적절한 전사 조절 영역을 함유할 수 있다. 그것은 숙주 세포 내에 안정하게 유지될 수 있고, 임의로 번역된 단백질의 분비를 명시하는 특정 신호를 가질 수 있다. 이들 상이한 요소들은 사용되는 숙주 세포의 기능으로서 선택될 수 있다. 이 목적을 위해, 본 명세서에 기재된 뉴클레오티드 서열은 선택된 숙주 내의 자율 복제 벡터, 또는 선택된 숙주의 통합된 벡터 내로 삽입될 수 있다.
이러한 벡터는 당업자에 의해 현재 사용되는 방법에 따라 제조될 것이며, 이로부터 생성되는 클론을, 예를 들어 인산칼슘 침전, 리포펙션(lipofection), 전기천공(electroporation), 및 열 충격과 같은 표준 방법에 의해 적절한 숙주 내로 도입하는 것이 가능할 것이다.
따라서 벡터는, 예를 들어 플라스미드 또는 바이러스 기원의 벡터이다. 본 명세서에 기재된 폴리펩티드의 발현을 위한 벡터의 예는 플라스미드, 파지, 코스미드, 인공 염색체, 바이러스 벡터, AAV 벡터, 바큘로바이러스 벡터, 아데노바이러스 벡터, 렌티바이러스 벡터, 레트로바이러스 벡터, 키메라 바이러스 벡터, 및 키메라 아데노비리대, 예컨대 AD5/F35 이다.
이들 벡터는 본 명세서에 기재된 뉴클레오티드 서열을 클로닝하거나 발현하기 위하여 숙주 세포를 형질변환시키는 데 유용하다.
실시 형태는 마찬가지로 벡터에 의해 형질변환된 숙주 세포를 포함한다.
이들 세포는 상기 정의된 것과 같은 벡터 내로 삽입된 뉴클레오티드 서열을 숙주 세포 내로의 도입한 후에 형질감염된 뉴클레오티드 서열의 복제 및/또는 발현을 가능하게 하는 조건 하에 세포를 배양함으로써 얻을 수 있다.
숙주 세포는, 예를 들어 박테리아 세포(문헌[Olins and Lee, 1993]), 그러나 마찬가지로 효모 세포(문헌[Buckholz, 1993])뿐만 아니라, 식물 세포, 예컨대 아라비돕시스 종(Arabidopsis sp.), 및 동물 세포, 특히 포유류 세포(문헌[Edwards and Aruffo, 1993]), 예를 들어, HEK 293 세포, HEK 293T 세포, 중국 햄스터 난소(CHO) 세포, 골수 세포, 골수 전구 세포, 단핵구, 호중구, 호염기구, 호산구, 거핵구, T 세포, B 세포, 자연 살해 세포, 백혈구, 림프구, 수지상 세포, 및 대식세포, 그러나 마찬가지로 바큘로바이러스를 사용하는 절차를 사용하는 것이 가능한 곤충의 세포, 예를 들어 sf9 곤충 세포(문헌[Luckow, 1993])의 배양물과 같은 원핵 또는 진핵 시스템으로부터 선택될 수 있다.
실시 형태는 마찬가지로 형질변환된 세포 중 하나를 포함하는 유기체에 관한 것이다.
핵산 또는 핵산의 일부 중 하나 이상을 발현하는 형질전환 유기체를 얻는 것은, 예를 들어, 래트, 마우스, 또는 토끼에서 당업자에게 잘 알려진 방법에 따라, 예컨대 바이러스 또는 비바이러스 형질감염에 의해 실행될 수 있다. 전신발현 성질(ubiquitous nature)의, 또는 하나의 유형의 조직에 대해 선택적인 강력한 프로모터의 제어 하에 유전자의 다중 사본의 형질감염에 의해 하나 이상의 유전자를 발현하는 형질전환 유기체를 얻을 수 있다. 배아 세포주에서의 상동성 재조합, 이들 세포주의 배아로의 전달, 생식 계통의 수준에서 영향을 받은 키메라의 선택, 및 키메라의 성장에 의해 형질전환 유기체를 얻는 것이 마찬가지로 가능할 것이다.
형질변환된 세포뿐만 아니라 형질전환 유기체는 재조합 폴리펩티드의 제조를 위한 절차에서 이용될 수 있다.
발현 벡터에 의해 형질변환된 세포를 사용하거나 형질전환 유기체를 사용하는 유전자 조작에 의해 비교적 많은 양으로 재조합 폴리펩티드를 생산하는 것이 현재 가능하다.
벡터 및/또는 벡터에 의해 형질변환된 세포 및/또는 형질변환된 세포 중 하나를 포함하는 형질전환 유기체를 사용함을 특징으로 하는, 재조합 형태의 키메라 수용체와 같은 폴리펩티드의 제조 절차는 그 자체가 본 발명에 포함된다.
본 명세서에 사용되는 바와 같이, "형질변환" 및 "형질변환된"은, 원핵생물이든 진핵생물이든, 세포 내로의 핵산의 도입에 관한 것이다. 추가로, 본 명세서에 사용되는 바와 같이, "형질변환" 및 "형질변환된"은 성장 제어 또는 성장 탈조절에 관한 것일 필요가 없다.
재조합 형태의 키메라 수용체와 같은 폴리펩티드의 제조 절차 중에는, 키메라 수용체를 암호화하는 것들과 같은 뉴클레오티드 서열을 함유하는, 벡터, 및/또는 벡터에 의해 형질변환된 세포, 및/또는 형질변환된 세포 중 하나를 포함하는 형질전환 유기체를 사용하는 제조 절차가 있다.
따라서 변이체는, 본 명세서에 사용되는 바와 같이, "담체" 단백질(키메라 단백질)에 융합된 재조합 폴리펩티드를 생성하는 단계로 이루어질 수 있다. 이 시스템의 이점은 그것이 재조합 산물의 안정화 및/또는 단백질 분해의 감소, 시험관내 탈변성 과정에서 용해도의 증가 및/또는 융합 파트너가 특이적 리간드에 대한 친화도를 가질 때 정제의 단순화를 가능하게 할 수 있다는 것이다.
더욱 구체적으로, 실시 형태는 하기 단계를 포함하는 폴리펩티드의 제조 절차에 관한 것이다: a) 뉴클레오티드 서열의 재조합 폴리펩티드의 발현을 가능하게 하는 조건 하에 형질변환된 세포를 배양하는 단계; b)필요한 경우, 재조합 폴리펩티드를 회수하는 단계.
키메라 수용체와 같은 폴리펩티드의 제조 절차가 형질전환 유기체를 사용하는 경우, 재조합 폴리펩티드는 이어서 유기체로부터 추출되거나 정위치에 남겨질 수 있다.
실시 형태는 또한 이전에 기재된 것과 같은 절차에 의해 얻어질 수 있는 폴리펩티드에 관한 것이다.
실시 형태는 또한 폴리펩티드의 아미노산의 서열을 사용함을 특징으로 하는, 합성 폴리펩티드의 제조 절차를 포함한다.
본 발명은 마찬가지로, 절차에 의해 얻어진 키메라 수용체와 같은 합성 폴리펩티드에 관한 것이다.
키메라 수용체와 같은 폴리펩티드는 펩티드 합성 분야에서 통상적인 기술에 의해 마찬가지로 제조될 수 있다. 이 합성은 균질한 용액 또는 고체상 내에서 실행될 수 있다.
예를 들어, 문헌[Houben-Weyl, 1974]에 의해 기재된 균질한 용액 내의 합성 기술을 사용할 수 있다.
이 합성 방법은 연속적인 아미노산을 필요한 순서로 2개씩 연속적으로 축합하는 단계, 또는 이전에 형성되고 몇몇 아미노산을 이미 함유하는 단편 및 아미노산을 적절한 순서로, 또는 대안적으로 이 방식으로 이전에 제조된 몇몇 단편을 축합하는 단계로 이루어지며, 펩티드 합성에서 잘 알려진 방법에 따라, 특히 카르복실 기능의 활성화 후에, 펩티드 결합의 형성에 정상적으로 관여해야 하는, 하나의 아민 기능 및 다른 하나의 카르복실 또는 그 반대의 경우를 제외하고는, 이들 아미노산 또는 단편이 지닌 모든 반응성 기능을 미리 보호하는 것이 필요할 것임이 이해된다.
메리필드(Merrifield)에 의해 기재된 기술을 또한 사용할 수 있다.
메리필드 절차에 따라 펩티드 사슬을 제조하기 위해서는, 매우 다공성인 중합체성 수지를 사용하며, 그 위에는 사슬의 제1 C-말단 아미노산이 고정된다. 이 아미노산은 그의 카르복실 기를 통해 수지 상에 고정되고, 그의 아민 기능은 보호된다. 따라서, 이미 형성되고 수지에 부착된 펩티드 사슬의 부분의 매번 미리 탈보호되는 아미노 기 상에, 펩티드 사슬을 형성할 아미노산이 차례로 고정된다. 원하는 펩티드 사슬의 전체가 형성되었을 때, 펩티드 사슬을 형성하는 상이한 아미노산의 보호기가 제거되고, 펩티드는 산의 도움으로 수지로부터 탈착된다.
이들 혼성체 분자는 부분적으로, 가능하게는 면역원성 부분, 특히 디프테리아 독소, 파상풍 독소, B 형 간염 바이러스의 표면 항원(특허 FR 79 21811), 회색질척수염 바이러스의 VP1 항원, 또는 임의의 다른 바이러스 또는 박테리아 독소 또는 항원의 에피토프와 관련된 폴리펩티드 담체 분자 또는 이들의 단편으로 형성될 수 있다.
키메라 수용체를 포함하는 폴리펩티드, 하기 기재된 항체, 및 전술한 것들 중 임의의 것을 암호화하는 뉴클레오티드 서열은 대식세포의 분극을 위한 절차에 유리하게 사용될 수 있다.
실시 형태에서, 키메라 수용체를 암호화하는 핵산 서열은 세포에 제공된다. 이어서, 세포는 암호화된 키메라 수용체를 발현할 수 있다. 발현된 키메라 수용체는 세포의 표면 상에 또는 세포질 내에 존재할 수 있다. 특정 실시 형태에서, 키메라 수용체를 발현하는 세포는 대식세포이다. 대식세포 발현된 키메라 수용체는 리간드에 결합할 수 있고, 리간드의 결합은 이전에 기재된 바와 같이 대식세포의 분극을 유도하도록 키메라 수용체를 활성화시킬 수 있다.
실시 형태에서, 키메라 수용체를 암호화하는 핵산 서열이 제공된 세포를 대상으로부터 단리할 수 있다. 세포에 핵산이 제공된 후, 예를 들어 주사 또는 수혈에 의해, 세포를 그것이 얻어진 대상에 복귀시킬 수 있다. 다른 실시 형태에서, 핵산이 제공된 세포는 공여자에 의해 제공될 수 있다. 공여자 세포에 핵산이 제공된 후, 이어서 세포를 공여자 이외의 개체에 제공할 수 있다. 공여자 세포의 예는 대상으로부터의 1차 세포 및 세포주로부터의 세포를 포함하지만 이로 제한되지 않는다.
다른 실시 형태에서, 키메라 수용체는 세포 내로 직접 도입될 수 있다. 미세주입, 전기천공, 막 융합, 및 단백질 형질도입 도메인의 사용이 포함되지만 이로 제한되지 않는, 세포 내로 단백질을 도입하는 임의의 방법이 사용될 수 있다. 세포에 키메라 수용체가 제공된 후, 예를 들어 주사 또는 수혈에 의해, 세포를 그것이 얻어진 대상에 복귀시킬 수 있다. 다른 실시 형태에서, 키메라 수용체가 제공된 세포는 공여자에 의해 제공된다. 공여자 세포에 핵산이 제공된 후, 이어서 세포를 공여자 이외의 개체에 제공할 수 있다. 공여자 세포의 예는 대상으로부터의 1차 세포 및 세포주로부터의 세포를 포함하지만 이로 제한되지 않는다.
실시 형태는 마찬가지로 효소, 형광, 또는 방사성 유형과 같은 적절한 표지의 도움으로 표지된 키메라 수용체와 같은 폴리펩티드에 관한 것이다.
폴리펩티드는 단클론 또는 다클론 항체를 제조하는 것을 가능하게 하며, 이는 폴리펩티드를 특이적으로 인식함을 특징으로 한다. 문헌[Kohler and Milstein, 1975]에 의해 기재된 기술에 따라 하이브리도마로부터 단클론 항체를 제조하는 것이 유리하게 가능할 것이다. 예를 들어, 면역 반응의 보조제와 연계하여 폴리펩티드 또는 DNA로 동물, 특히 마우스를 면역화하는 단계, 및 이어서 항원으로서 작용한 폴리펩티드가 이전에 고정된 친화도 컬럼 상에서 면역화된 동물의 혈청 내에 함유된 특이적 항체를 정제하는 단계에 의해 다클론 항체를 제조하는 것이 가능할 것이다. 다클론 항체는 또한, 폴리펩티드가 이전에 고정된 친화도 컬럼 상에서의, 키메라 수용체에 의해 면역학적으로 챌린지된 동물의 혈청 내에 함유된 항체, 또는 이의 폴리펩티드 또는 단편의 정제에 의해 제조될 수 있다.
또한, IgA, IgD, IgE, IgG, IgM, Fab 단편, F(ab′)2 단편, 1 가 항체, scFv 단편, scRv-Fc 단편, IgNAR, hcIgG, VhH 항체, 나노바디, 및 알파바디를 포함하지만 이로 제한되지 않는 다른 형태의 결합 분자를 제조하기 위해 항체를 사용할 수 있다.
마찬가지로, 실시 형태는 본 명세서에 기재된 폴리펩티드 또는 폴리펩티드 및/또는 키메라 수용체의 리간드를 특이적으로 인식할 수 있음을 특징으로 하는, 단클론 또는 다클론 항체 또는 이들의 단편, 또는 키메라 항체, 또는 이들의 단편에 관한 것이다.
효소, 형광, 또는 방사성 유형의 표지화와 같은, 핵 프로브에 대해 이전에 기재된 것과 동일한 방식으로 항체를 표지하는 것이 마찬가지로 가능할 것이다. 또한, 이러한 항체 및/또는 이들의 단편을 키메라 수용체의 일부로서 포함하는 것이 가능할 것이다. 비제한적인 예로서, 이러한 항체 또는 이의 단편은 키메라 수용체의 세포외 도메인의 일부를 구성할 수 있다.
실시 형태는 추가로, 하기 단계를 포함함을 특징으로 하는, 샘플 내의 키메라 수용체의 검출 및/또는 확인을 위한 절차에 관한 것이다: a) 샘플을 단클론 또는 다클론과 접촉시키는 단계(가능하게는 생물학적 샘플 내에 존재하는 키메라 수용체와 항체 사이의 면역학적 반응을 가능하게 하는 조건 하에); b) 가능하게는 형성된 항원-항체 복합체의 입증.
실시 형태는 하기 예시적인 실시예에서 추가로 상세히 기재된다. 실시예는 단지 선택된 실시 형태만을 나타낼 수 있지만, 하기 실시예는 예시적이며 제한적이지 않음이 이해되어야 한다.
실시예
실시예 1: 특이적 리간드에 대한 ScFv 단편의 단리
인간 TK1에 특이적인 항체를 발현하는 단클론 항체 하이브리도마 세포(CB1)로부터 cDNA를 정제하였다. 단리된 cDNA를 사용하여, 중합효소 연쇄 반응(PCR)을 통해 CB1 가변 영역의 중쇄 및 경쇄를 증폭하였다. 중쇄 및 경쇄로부터의 서열은 NCBI Blast를 사용하여 확인하였다. CB1 중쇄 및 경쇄를 부위 중첩 연장(SOE) PCR을 통해 함께 융합시켜, G4S 링커를 사용하여 단쇄 단편 가변(scFv)을 형성하였다. 단백질 발현을 최대화하기 위하여 IDT(https://www.idtdna.com/CodonOpt)에 의해 제공된 코돈 최적화 도구를 사용하여 효모 및 인간에 대해 G4S 링커를 코돈 최적화하였다. 제한 효소를 사용하여 CB1 scFv를 절단해내고 pMP71 CAR 벡터 내로 삽입하였다.
TK-1 및 HPRT-특이적 인간 scFv 단편을 효모 항체 라이브러리로부터 단리하였다. TK-1 및 HPRT 단백질을 단리하고, His-태깅하고, 정제하였다. TK-1 및 HPRT 단백질을 항-His 바이오티닐화 항체로 표지하고, 라이브러리에 첨가하여 TK-1 및 HPRT-특이적 항체 클론을 선택하였다. TK-1 및 HPRT 항체 클론을 스트렙타비딘 또는 항-바이오틴 마이크로비드로 교대로 염색하고, 자기 컬럼을 사용하여 농축시켰다. 분류 및 선택의 추가의 2개 라운드를 수행하여 TK-1 및 HPRT 특이적 항체를 단리하였다. 최종 선택을 위해, 가능한 TK-1 및 HPRT 항체 클론 및 이들 각각의 단백질을 형광-접합된 항-HA 또는 항-c-myc 항체로 교대로 표지함으로써 형광-활성화 세포 분류(FACS)에 의해 분류하여 TK-1 및 HPRT 특이적 항체를 단리하였다. 키메라 수용체 작제를 위해 고친화도 클론을 선택하였다. 파지 디스플레이 또는 다른 재조합 방법을 사용함으로써 다른 동물로부터의 다른 인간 항체 또는 인간화 항체를 선택하거나 TK-1 또는 HPRT 특이성이 되도록 변경할 수 있었다.
이어서, 선택된 scFv 클론을 인간 IgG1 불변 도메인과 조합하여, scFv의 결합 특이성을 확인하기 위하여 웨스턴 블롯 또는 ELISA와 같은 응용에 사용하기 위한 항체를 생성하였다. 항체 작제물을 pPNL9 효모 분비 벡터 내로 삽입하고, YVH10 효모를 작제물로 형질변환시키고, 항체를 생성하도록 유도하였다. E. 콜라이(E. coli) 또는 포유류 시스템과 같은 다른 발현 시스템이 또한 항체를 분비하기 위해 사용될 수 있었다.
단백질-특이적 항체 단편의 단리 및 특성화.
도 26을 참조하면, 105개의 효모를 형광 태그 APC로 표지된 2.5 ug의 관심 단백질과 함께 인큐베이션하였다. 더 높은 좌측(적색) 피크는 관심 단백질에 결합하지 않은 효모 집단(음성 대조군)을 나타낸다. 좌측의 더 낮은 좌측(청색) 피크는 그의 표면 단백질을 발현하지 않는 효모를 예시하는 반면, 우측의 높은(청색) 피크는 발현된 항체 단편의 관심 단백질에 대한 결합을 나타낸다.
문헌[Structural Consensus among Antibodies Defines the Antigen 5 Binding Site, PLoS Comput. Biol. 8(2): e1002388. doi:10.1371/journal.pcbi.1002388, Kunik V, Ashkenazi S, Ofran Y (2012)]. 문헌[Paratome: An online tool for systematic identification of antigen binding regions in antibodies based on sequence or structure, Nucleic Acids Res. 2012 Jul; 40 (Web Server issue):W521-4. doi: 10.1093/nar/gks480. Epub 2012 Jun 6].
실시예 2: 키메라 수용체의 생성
키메라 수용체 벡터의 작제:
과정의 제1 단계는 합성 키메라 수용체 유전자에 대한 뉴클레오티드 서열의 설계 및 적절한 렌티바이러스 벡터의 선택이다. Genious 소프트웨어 버전 9.1.6에서 모든 벡터 설계를 실행하였다. 서열은 Uniprot 및 인간 단백질 참조 데이터 베이스(Human Protein Reference Data base) 및 또한 NCBI로부터 검색된다.
재조합 DNA 기술과 유전자 합성의 조합으로 벡터를 합성한다.
인간화 항체 효모 디스플레이 라이브러리 또는 파지 디스플레이 라이브러리로 단쇄 가변 단편에 대한 서열을 생성한다. TK1, HPRT, ROR1, MUC-16, EGFRvIII, 메소텔린, HER2, CEA, BCMA, GPC3, FAP, EphA2, NKG2D 리간드, GD2, CD19, CD20, CD30, CD33, CD123, CD133, CD138, 및 CD171 각각에 대해 특이적인 ScFv를 암호화하는 핵산. 키메라 수용체를 암호화하는 핵산의 모든 가능한 조합은 a), b), c), d), 및 e) 각각 중 하나 이상을 가지며, 여기서 a), b), c), d) 및 e)는 하기와 같다:
a) TK1, HPRT, ROR1, MUC-16, EGFRvIII, 메소텔린, HER2, CEA, BCMA, GPC3, FAP, EphA2, NKG2D 리간드, GD2, CD19, CD20, CD30, CD33, CD123, CD133, CD138, 및 CD171에 대해 특이적인 ScFv;
b) GS 링커 또는 GS 링커 없음;
c) LRR 5 아미노산 짧은 힌지, LRR 긴 힌지, IgG4 짧은 힌지, IgG 119 아미노산 중간 힌지, 및 IgG4 긴 힌지, CD8 힌지, 시스테인이 세린으로 전환된 CD8 힌지, 및 힌지 없음으로부터 선택된 힌지 영역;
d) MYD88, TLR3, TLR4, TLR7, TLR8, TLR9, MAL, IRAK1, FCGR2A, FCGR3A, 및 FCER1G의 막관통 도메인으로부터 선택된 막관통 도메인; 및
e) MYD88, TLR3, TLR4, TLR7, TLR8, TLR9, MAL, IRAK1, FCGR2A, FCGR3A, 및 FCER1G의 세포액 도메인으로부터 선택된 세포액 도메인.
재조합 DNA 기술과 유전자 합성의 조합으로 키메라 수용체를 암호화하는 전술한 핵산을 합성한다.
렌티바이러스-매개 유전자 전달을 통해 통합된 유전자 전달 방법으로 대식세포를 유전자 변형하여 키메라 수용체를 암호화하는 핵산을 제공한다. Addgene으로부터의 제3 세대 렌티바이러스 시스템을 사용하여 본 발명자들의 렌티바이러스 벡터를 패키징한다. pHIV-dTomato(#21374) 및 pUltra-chilli(#48687)는 유전자 전달 플라스미드이다. pCMV-VSV-G(#8454), pMDLg/pRRE(#12251), pRSV-Rev(#12253), pHCMV-AmphoEnv(#15799)는 패키징 플라스미드이다. 최대 50% 형질도입의 효율을 얻는 인간 림프구의 렌티바이러스 매개 유전자 전달이 이전에 표준화되어 있다. 인산칼슘 방법(SIGMA CAPHOS)으로 HEK293T 세포를 형질감염시킨다. 형질감염당 각각의 패키징 플라스미드 약 10 ㎍ 및 키메라 수용체를 암호화하는 벡터 20 ug을 사용한다. 48 내지 36시간 후에, 바이러스 입자를 수확하고 멸균 여과한다. HT1080 및 U937 세포를 감염시키는 바이러스 역가를 결정한다.
적색 형광 단백질을 검출하는 유세포 분석법에 의해 분석을 수행한다. 바이러스 역가측정 후에 레트로넥틴 플레이트(Clonetech, T100B) 및 스핀 감염 방법을 사용하여 인간 단핵구를 형질도입한다.
렌티바이러스 형질도입 전에, 인간 단핵구 단리 키트 II(MACS130-091-153)를 사용하는 음성 선택 및 자기 분류에 의해 전체 PBMNC로부터 단핵구를 단리한다. 단핵구 단리 후에 세포를 2개의 Nunclon 6-웰 플레이트(Thermo, 145380)에 분할하며, 각각의 벡터에 대해 각각의 웰에 1.5X106개의 세포를 접종한다. 하나의 플레이트는 즉시 형질도입된 반면, 두번째 플레이트는 단핵구의 M1 대식세포로의 생체외 분화에 사용된다. 배지 M1-대식세포 생성 배지 DFX(Promocell, C-28055)를 사용하여 M1 대식세포를 생성한다. 7일 후에, 대식세포를 형질도입하고, 제9일에 LPS(500X)(Affimetryx, 00-4976-03) 및 IFN-γ(Promokine, C-60724)로 활성화한다. 형질도입 효율을 유세포 분석법에 의해 분석한다. FACS Aria 세포 분류기를 사용하여 세포 분류에 의해 형질도입된 세포를 분리한다. 세포 분류 후에 형질도입된 단핵구는 분화 전 2일 동안 생체외 배양되는 반면, 분화된 대식세포는 1개월 지속될 수 있다.
실시예 3: 키메라 수용체를 통한 대식세포의 분극
실시예 2에서 제조된 형질도입된 대식세포를 TK1, HPRT, ROR1, MUC-16, EGFRvIII, 메소텔린, HER2, CEA, BCMA, GPC3, FAP, EphA2, NKG2D 접합된 리간드, GD2, CD19, CD20, CD30, CD33, CD123, CD133, CD138, 및 CD171에 개별적으로 노출시키고, 표준 사이토카인 검정을 사용하여 IL-12 및 IL-23의 분비를 모니터링하거나 RNA 생성을 측정함으로써 M1 표현형으로의 분극에 대해 시험하였다. 키메라 수용체를 보유하는 대식세포는 특정 키메라 수용체에 대해 특이적인 리간드에 노출될 때 M1 표현형으로 분극되며, IL-12 및/또는 IL-23의 증가된 분비에 의해 결정된다. 특이적 키메라 수용체에 대한 특이적 리간드 이외의 리간드는 IL-12 및/또는 IL-21의 증가를 나타내지 않는다.
실시예 4: 단핵구-유래 대식세포의 생성 및 형질도입
7일의 분화 후에, 단핵구-유래 대식세포는 표현형 변화를 겪었다. 이들 변화를 형질도입된 세포와 비-형질도입된 세포 사이에서 비교하였다. 도 27에서 관찰될 수 있는 바와 같이, 형질도입된 세포는 M1 또는 고전적으로 활성화된 대식세포와 유사한 더 공격적인 표현형을 갖는다. 도 27은 분화의 제8일에 비-형질도입된 단핵구-유래 대식세포 및 형질도입된 단핵구-유래 대식세포의 영상을 나타낸다. 이 시점에서 인터페론 감마 및 LPS를 첨가하지 않았다. 키메라 수용체로 형질도입된 대식세포의 표현형은 비-형질도입된 대식세포와 상이하다는 것을 관찰할 수 있다. 형질도입된 세포는 대식세포 활성화를 나타내는 전통적으로 활성화된 표현형 또는 M1-유사 표현형을 나타냈다. 변경된 표현형은 형질도입 과정과 새로운 합성 수용체의 발현의 조합된 효과일 수 있다.
도 28은 형질도입 후 48 내지 72시간에 dTomato의 발현에 의해 확인된 바와 같은 키메라 수용체를 암호화하는 작제물의 삽입 및 발현의 확인을 제공한다. 이는 인간 단핵구-유래 대식세포의 성공적인 형질도입을 입증한다.
실시예 5: 형질도입 효율
분화의 제10일 후에, 형질도입 효율을 평가하고 키메라 수용체를 발현하는 대식세포를 세포 분류하였다. 대식세포에서는 렌티바이러스 형질도입이 어렵다. 그러나, EF1-α 프로모터를 갖는 HIV-1 기반 시스템을 사용하여 거의 30%의 대식세포 형질도입이 달성되었다. 대식세포 분화의 초기 단계에서 세포의 형질도입은 상이한 형질도입 효율을 나타냈다. 분화의 초기 단계에서의 단핵구 또는 대식세포는 형질도입이 더 용이하다. 키메라 아데노바이러스 AD5/F35에 의한 아데노바이러스 형질도입이 대식세포 형질도입을 위한 다른 대안으로서 등장했다. 도 29는 FACSAria 시스템을 사용하여 세포 분류되는 형질도입된 대식세포의 결과를 나타낸다. 대식세포 형질도입의 약 30%가 렌티바이러스 접근법을 사용하여 달성되었다. 최좌측 플롯은 단지 0.58%의 세포가 dTomato의 발현을 나타낼 형광을 나타내는 대조군을 나타낸다. 우측 2개의 플롯은 형질도입 후 27.1%의 형질도입 효율을 나타낸다.
실시예 6: 형질도입된 대식세포의 면역표현형분석
키메라 수용체의 발현을 위한 벡터로 형질도입된 대식세포의 면역표현형분석을 수행하여 형질도입된 세포의 활성화 상태를 확인하였다. TLR-4의 세포외 도메인의 변형은 그의 신호전달 도메인의 상시 활성화(constant activation)를 유도할 수 있다는 것이 보고되었다(문헌[Gay et al., 2014]). TLR-4 신호전달의 상시 활성화는 대식세포 활성화 또는 M1 표현형을 유발할 수 있었다. TLR-4를 기반으로 하는, 사용된 작제물이 TLR-4로부터 취해진 TIR 도메인을 통한 신호전달의 상시 활성화를 촉발할 수 있는지는 알려지지 않았다. 그러나, 형질도입 과정 후에, 표현형의 변화 및 대식세포에서의 세포 표면 마커의 발현의 변화가 관찰되었다. 이는 렌티바이러스 형질도입 및 키메라 수용체 단백질의 발현의 조합으로 인한 것일 가능성이 있다. CD14, CD80, D206의 발현 및 CD163의 낮은 발현은 M1 표현형을 향한 대식세포 분극의 지표였다. 이들 세포 표면 마커의 발현이 형질도입된 세포에서 관찰되었다. 도 30은 키메라 수용체로 형질도입된 대식세포에서 염료(Alexa 647)의 보유, 및 CD80, CD163, CD206, 및 CD14의 발현을 입증하는 형광 활성화 세포 분류의 6개의 산란 플롯을 나타낸다.
도 31은 키메라 수용체를 발현하기 위한 벡터로 형질도입된 대식세포에서 M1 세포 표면 마커의 상대적인 발현 수준의 히스토그램을 나타낸다.
실시예 7: TK1 표적화 키메라 수용체 형질도입된 대식세포의 NCI-H460 세포에 대한 시험관내 독성.
TK1 표적화 키메라 수용체 형질도입된 대식세포의 종양살해 활성을 NCI-H460-GFP 세포에 대하여 시험하였다. 사용된 E:T 비는 1:10이었다. 공초점 현미경으로 분석을 수행하였다. 12시간의 기간 동안 5분마다 형광의 검출을 수행하였다. TK1 표적화 키메라 수용체 형질도입된 대식세포가 H460-GFP 세포를 향하여 이동하여 이들을 공격한다는 것을 시간 경과 중에 관찰하였다. 시냅시스 후에, 표적 세포에서 특이적 세포 사멸이 유도된다. 도 32의 영상에 의해 입증되는 바와 같이, TK1 표적화 키메라 수용체 형질도입된 대식세포는 TK1을 발현하는 폐암 세포주에서 세포 사멸을 검출하고, 공격하고, 유도할 수 있다. GFP를 발현하도록 NCI-H460 세포를 변형하였다. TK1 표적화 키메라 수용체 형질도입된 대식세포의 종양살해 활성을 표적 세포 내의 형광의 손실로서 공초점 현미경으로 검출하였다.
본 발명은 본 발명의 사상 및 범주 내에서 추가로 변형될 수 있다. 따라서, 본 출원은 그의 일반적인 원리를 사용하여 본 발명의 임의의 변동, 용도, 또는 개조를 포함하도록 의도된다. 추가로, 본 출원은 본 발명으로부터의 이러한 이탈을 본 발명이 속하는 기술 분야에서 공지되거나 관용적인 실시의 범위 내에 있는 것으로서 포함하도록 의도되며, 이는 첨부된 청구범위 및 이들의 법적 등가물의 한계 내에 있다.
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<110> O'Neill, Kim
<120> TRANSGENIC MACROPHAGES, CHIMERIC ANTIGEN RECEPTORS, AND
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Val Gln Lys Glu Arg Ile Gly Ala Phe Arg His Lys Leu Gln Val Ala
885 890 895
Leu Gly Ser Lys Asn Ser Val His
900
<210> 2
<211> 2715
<212> DNA
<213> Homo sapiens
<400> 2
atgagacaga ctttgccttg tatctacttt tgggggggcc ttttgccctt tgggatgctg 60
tgtgcatcct ccaccaccaa gtgcactgtt agccatgaag ttgctgactg cagccacctg 120
aagttgactc aggtacccga tgatctaccc acaaacataa cagtgttgaa ccttacccat 180
aatcaactca gaagattacc agccgccaac ttcacaaggt atagccagct aactagcttg 240
gatgtaggat ttaacaccat ctcaaaactg gagccagaat tgtgccagaa acttcccatg 300
ttaaaagttt tgaacctcca gcacaatgag ctatctcaac tttctgataa aacctttgcc 360
ttctgcacga atttgactga actccatctc atgtccaact caatccagaa aattaaaaat 420
aatccctttg tcaagcagaa gaatttaatc acattagatc tgtctcataa tggcttgtca 480
tctacaaaat taggaactca ggttcagctg gaaaatctcc aagagcttct attatcaaac 540
aataaaattc aagcgctaaa aagtgaagaa ctggatatct ttgccaattc atctttaaaa 600
aaattagagt tgtcatcgaa tcaaattaaa gagttttctc cagggtgttt tcacgcaatt 660
ggaagattat ttggcctctt tctgaacaat gtccagctgg gtcccagcct tacagagaag 720
ctatgtttgg aattagcaaa cacaagcatt cggaatctgt ctctgagtaa cagccagctg 780
tccaccacca gcaatacaac tttcttggga ctaaagtgga caaatctcac tatgctcgat 840
ctttcctaca acaacttaaa tgtggttggt aacgattcct ttgcttggct tccacaacta 900
gaatatttct tcctagagta taataatata cagcatttgt tttctcactc tttgcacggg 960
cttttcaatg tgaggtacct gaatttgaaa cggtctttta ctaaacaaag tatttccctt 1020
gcctcactcc ccaagattga tgatttttct tttcagtggc taaaatgttt ggagcacctt 1080
aacatggaag ataatgatat tccaggcata aaaagcaata tgttcacagg attgataaac 1140
ctgaaatact taagtctatc caactccttt acaagtttgc gaactttgac aaatgaaaca 1200
tttgtatcac ttgctcattc tcccttacac atactcaacc taaccaagaa taaaatctca 1260
aaaatagaga gtgatgcttt ctcttggttg ggccacctag aagtacttga cctgggcctt 1320
aatgaaattg ggcaagaact cacaggccag gaatggagag gtctagaaaa tattttcgaa 1380
atctatcttt cctacaacaa gtacctgcag ctgactagga actcctttgc cttggtccca 1440
agccttcaac gactgatgct ccgaagggtg gcccttaaaa atgtggatag ctctccttca 1500
ccattccagc ctcttcgtaa cttgaccatt ctggatctaa gcaacaacaa catagccaac 1560
ataaatgatg acatgttgga gggtcttgag aaactagaaa ttctcgattt gcagcataac 1620
aacttagcac ggctctggaa acacgcaaac cctggtggtc ccatttattt cctaaagggt 1680
ctgtctcacc tccacatcct taacttggag tccaacggct ttgacgagat cccagttgag 1740
gtcttcaagg atttatttga actaaagatc atcgatttag gattgaataa tttaaacaca 1800
cttccagcat ctgtctttaa taatcaggtg tctctaaagt cattgaacct tcagaagaat 1860
ctcataacat ccgttgagaa gaaggttttc gggccagctt tcaggaacct gactgagtta 1920
gatatgcgct ttaatccctt tgattgcacg tgtgaaagta ttgcctggtt tgttaattgg 1980
attaacgaga cccataccaa catccctgag ctgtcaagcc actacctttg caacactcca 2040
cctcactatc atgggttccc agtgagactt tttgatacat catcttgcaa agacagtgcc 2100
ccctttgaac tctttttcat gatcaatacc agtatcctgt tgatttttat ctttattgta 2160
cttctcatcc actttgaggg ctggaggata tctttttatt ggaatgtttc agtacatcga 2220
gttcttggtt tcaaagaaat agacagacag acagaacagt ttgaatatgc agcatatata 2280
attcatgcct ataaagataa ggattgggtc tgggaacatt tctcttcaat ggaaaaggaa 2340
gaccaatctc tcaaattttg tctggaagaa agggactttg aggcgggtgt ttttgaacta 2400
gaagcaattg ttaacagcat caaaagaagc agaaaaatta tttttgttat aacacaccat 2460
ctattaaaag acccattatg caaaagattc aaggtacatc atgcagttca acaagctatt 2520
gaacaaaatc tggattccat tatattggtt ttccttgagg agattccaga ttataaactg 2580
aaccatgcac tctgtttgcg aagaggaatg tttaaatctc actgcatctt gaactggcca 2640
gttcagaaag aacggatagg tgcctttcgt cataaattgc aagtagcact tggatccaaa 2700
aactctgtac attaa 2715
<210> 3
<211> 839
<212> PRT
<213> Homo sapiens
<400> 3
Met Met Ser Ala Ser Arg Leu Ala Gly Thr Leu Ile Pro Ala Met Ala
1 5 10 15
Phe Leu Ser Cys Val Arg Pro Glu Ser Trp Glu Pro Cys Val Glu Val
20 25 30
Val Pro Asn Ile Thr Tyr Gln Cys Met Glu Leu Asn Phe Tyr Lys Ile
35 40 45
Pro Asp Asn Leu Pro Phe Ser Thr Lys Asn Leu Asp Leu Ser Phe Asn
50 55 60
Pro Leu Arg His Leu Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu
65 70 75 80
Gln Val Leu Asp Leu Ser Arg Cys Glu Ile Gln Thr Ile Glu Asp Gly
85 90 95
Ala Tyr Gln Ser Leu Ser His Leu Ser Thr Leu Ile Leu Thr Gly Asn
100 105 110
Pro Ile Gln Ser Leu Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu
115 120 125
Gln Lys Leu Val Ala Val Glu Thr Asn Leu Ala Ser Leu Glu Asn Phe
130 135 140
Pro Ile Gly His Leu Lys Thr Leu Lys Glu Leu Asn Val Ala His Asn
145 150 155 160
Leu Ile Gln Ser Phe Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn
165 170 175
Leu Glu His Leu Asp Leu Ser Ser Asn Lys Ile Gln Ser Ile Tyr Cys
180 185 190
Thr Asp Leu Arg Val Leu His Gln Met Pro Leu Leu Asn Leu Ser Leu
195 200 205
Asp Leu Ser Leu Asn Pro Met Asn Phe Ile Gln Pro Gly Ala Phe Lys
210 215 220
Glu Ile Arg Leu His Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu
225 230 235 240
Asn Val Met Lys Thr Cys Ile Gln Gly Leu Ala Gly Leu Glu Val His
245 250 255
Arg Leu Val Leu Gly Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe
260 265 270
Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn Leu Thr Ile Glu Glu Phe
275 280 285
Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp Asp Ile Ile Asp Leu Phe
290 295 300
Asn Cys Leu Thr Asn Val Ser Ser Phe Ser Leu Val Ser Val Thr Ile
305 310 315 320
Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe Gly Trp Gln His Leu Glu
325 330 335
Leu Val Asn Cys Lys Phe Gly Gln Phe Pro Thr Leu Lys Leu Lys Ser
340 345 350
Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys Gly Gly Asn Ala Phe Ser
355 360 365
Glu Val Asp Leu Pro Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly
370 375 380
Leu Ser Phe Lys Gly Cys Cys Ser Gln Ser Asp Phe Gly Thr Thr Ser
385 390 395 400
Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly Val Ile Thr Met Ser Ser
405 410 415
Asn Phe Leu Gly Leu Glu Gln Leu Glu His Leu Asp Phe Gln His Ser
420 425 430
Asn Leu Lys Gln Met Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn
435 440 445
Leu Ile Tyr Leu Asp Ile Ser His Thr His Thr Arg Val Ala Phe Asn
450 455 460
Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly
465 470 475 480
Asn Ser Phe Gln Glu Asn Phe Leu Pro Asp Ile Phe Thr Glu Leu Arg
485 490 495
Asn Leu Thr Phe Leu Asp Leu Ser Gln Cys Gln Leu Glu Gln Leu Ser
500 505 510
Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu Gln Val Leu Asn Met Ser
515 520 525
His Asn Asn Phe Phe Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn
530 535 540
Ser Leu Gln Val Leu Asp Tyr Ser Leu Asn His Ile Met Thr Ser Lys
545 550 555 560
Lys Gln Glu Leu Gln His Phe Pro Ser Ser Leu Ala Phe Leu Asn Leu
565 570 575
Thr Gln Asn Asp Phe Ala Cys Thr Cys Glu His Gln Ser Phe Leu Gln
580 585 590
Trp Ile Lys Asp Gln Arg Gln Leu Leu Val Glu Val Glu Arg Met Glu
595 600 605
Cys Ala Thr Pro Ser Asp Lys Gln Gly Met Pro Val Leu Ser Leu Asn
610 615 620
Ile Thr Cys Gln Met Asn Lys Thr Ile Ile Gly Val Ser Val Leu Ser
625 630 635 640
Val Leu Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe
645 650 655
His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn
660 665 670
Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val
675 680 685
Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln
690 695 700
Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala
705 710 715 720
Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val
725 730 735
Val Ser Gln His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu
740 745 750
Ile Ala Gln Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe
755 760 765
Ile Val Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu
770 775 780
Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser
785 790 795 800
Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu
805 810 815
Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn
820 825 830
Trp Gln Glu Ala Thr Ser Ile
835
<210> 4
<211> 23
<212> PRT
<213> Homo sapiens
<400> 4
Ile Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala Val
1 5 10 15
Leu Val Tyr Lys Phe Tyr Phe
20
<210> 5
<211> 183
<212> PRT
<213> Homo sapiens
<400> 5
His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn
1 5 10 15
Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val
20 25 30
Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln
35 40 45
Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala
50 55 60
Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val
65 70 75 80
Val Ser Gln His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu
85 90 95
Ile Ala Gln Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe
100 105 110
Ile Val Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu
115 120 125
Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser
130 135 140
Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu
145 150 155 160
Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn
165 170 175
Trp Gln Glu Ala Thr Ser Ile
180
<210> 6
<211> 2520
<212> DNA
<213> Homo sapiens
<400> 6
atgatgtctg cctcgcgcct ggctgggact ctgatcccag ccatggcctt cctctcctgc 60
gtgagaccag aaagctggga gccctgcgtg gaggtggttc ctaatattac ttatcaatgc 120
atggagctga atttctacaa aatccccgac aacctcccct tctcaaccaa gaacctggac 180
ctgagcttta atcccctgag gcatttaggc agctatagct tcttcagttt cccagaactg 240
caggtgctgg atttatccag gtgtgaaatc cagacaattg aagatggggc atatcagagc 300
ctaagccacc tctctacctt aatattgaca ggaaacccca tccagagttt agccctggga 360
gccttttctg gactatcaag tttacagaag ctggtggctg tggagacaaa tctagcatct 420
ctagagaact tccccattgg acatctcaaa actttgaaag aacttaatgt ggctcacaat 480
cttatccaat ctttcaaatt acctgagtat ttttctaatc tgaccaatct agagcacttg 540
gacctttcca gcaacaagat tcaaagtatt tattgcacag acttgcgggt tctacatcaa 600
atgcccctac tcaatctctc tttagacctg tccctgaacc ctatgaactt tatccaacca 660
ggtgcattta aagaaattag gcttcataag ctgactttaa gaaataattt tgatagttta 720
aatgtaatga aaacttgtat tcaaggtctg gctggtttag aagtccatcg tttggttctg 780
ggagaattta gaaatgaagg aaacttggaa aagtttgaca aatctgctct agagggcctg 840
tgcaatttga ccattgaaga attccgatta gcatacttag actactacct cgatgatatt 900
attgacttat ttaattgttt gacaaatgtt tcttcatttt ccctggtgag tgtgactatt 960
gaaagggtaa aagacttttc ttataatttc ggatggcaac atttagaatt agttaactgt 1020
aaatttggac agtttcccac attgaaactc aaatctctca aaaggcttac tttcacttcc 1080
aacaaaggtg ggaatgcttt ttcagaagtt gatctaccaa gccttgagtt tctagatctc 1140
agtagaaatg gcttgagttt caaaggttgc tgttctcaaa gtgattttgg gacaaccagc 1200
ctaaagtatt tagatctgag cttcaatggt gttattacca tgagttcaaa cttcttgggc 1260
ttagaacaac tagaacatct ggatttccag cattccaatt tgaaacaaat gagtgagttt 1320
tcagtattcc tatcactcag aaacctcatt taccttgaca tttctcatac tcacaccaga 1380
gttgctttca atggcatctt caatggcttg tccagtctcg aagtcttgaa aatggctggc 1440
aattctttcc aggaaaactt ccttccagat atcttcacag agctgagaaa cttgaccttc 1500
ctggacctct ctcagtgtca actggagcag ttgtctccaa cagcatttaa ctcactctcc 1560
agtcttcagg tactaaatat gagccacaac aacttctttt cattggatac gtttccttat 1620
aagtgtctga actccctcca ggttcttgat tacagtctca atcacataat gacttccaaa 1680
aaacaggaac tacagcattt tccaagtagt ctagctttct taaatcttac tcagaatgac 1740
tttgcttgta cttgtgaaca ccagagtttc ctgcaatgga tcaaggacca gaggcagctc 1800
ttggtggaag ttgaacgaat ggaatgtgca acaccttcag ataagcaggg catgcctgtg 1860
ctgagtttga atatcacctg tcagatgaat aagaccatca ttggtgtgtc ggtcctcagt 1920
gtgcttgtag tatctgttgt agcagttctg gtctataagt tctattttca cctgatgctt 1980
cttgctggct gcataaagta tggtagaggt gaaaacatct atgatgcctt tgttatctac 2040
tcaagccagg atgaggactg ggtaaggaat gagctagtaa agaatttaga agaaggggtg 2100
cctccatttc agctctgcct tcactacaga gactttattc ccggtgtggc cattgctgcc 2160
aacatcatcc atgaaggttt ccataaaagc cgaaaggtga ttgttgtggt gtcccagcac 2220
ttcatccaga gccgctggtg tatctttgaa tatgagattg ctcagacctg gcagtttctg 2280
agcagtcgtg ctggtatcat cttcattgtc ctgcagaagg tggagaagac cctgctcagg 2340
cagcaggtgg agctgtaccg ccttctcagc aggaacactt acctggagtg ggaggacagt 2400
gtcctggggc ggcacatctt ctggagacga ctcagaaaag ccctgctgga tggtaaatca 2460
tggaatccag aaggaacagt gggtacagga tgcaattggc aggaagcaac atctatctga 2520
2520
<210> 7
<211> 1049
<212> PRT
<213> Homo sapiens
<400> 7
Met Val Phe Pro Met Trp Thr Leu Lys Arg Gln Ile Leu Ile Leu Phe
1 5 10 15
Asn Ile Ile Leu Ile Ser Lys Leu Leu Gly Ala Arg Trp Phe Pro Lys
20 25 30
Thr Leu Pro Cys Asp Val Thr Leu Asp Val Pro Lys Asn His Val Ile
35 40 45
Val Asp Cys Thr Asp Lys His Leu Thr Glu Ile Pro Gly Gly Ile Pro
50 55 60
Thr Asn Thr Thr Asn Leu Thr Leu Thr Ile Asn His Ile Pro Asp Ile
65 70 75 80
Ser Pro Ala Ser Phe His Arg Leu Asp His Leu Val Glu Ile Asp Phe
85 90 95
Arg Cys Asn Cys Val Pro Ile Pro Leu Gly Ser Lys Asn Asn Met Cys
100 105 110
Ile Lys Arg Leu Gln Ile Lys Pro Arg Ser Phe Ser Gly Leu Thr Tyr
115 120 125
Leu Lys Ser Leu Tyr Leu Asp Gly Asn Gln Leu Leu Glu Ile Pro Gln
130 135 140
Gly Leu Pro Pro Ser Leu Gln Leu Leu Ser Leu Glu Ala Asn Asn Ile
145 150 155 160
Phe Ser Ile Arg Lys Glu Asn Leu Thr Glu Leu Ala Asn Ile Glu Ile
165 170 175
Leu Tyr Leu Gly Gln Asn Cys Tyr Tyr Arg Asn Pro Cys Tyr Val Ser
180 185 190
Tyr Ser Ile Glu Lys Asp Ala Phe Leu Asn Leu Thr Lys Leu Lys Val
195 200 205
Leu Ser Leu Lys Asp Asn Asn Val Thr Ala Val Pro Thr Val Leu Pro
210 215 220
Ser Thr Leu Thr Glu Leu Tyr Leu Tyr Asn Asn Met Ile Ala Lys Ile
225 230 235 240
Gln Glu Asp Asp Phe Asn Asn Leu Asn Gln Leu Gln Ile Leu Asp Leu
245 250 255
Ser Gly Asn Cys Pro Arg Cys Tyr Asn Ala Pro Phe Pro Cys Ala Pro
260 265 270
Cys Lys Asn Asn Ser Pro Leu Gln Ile Pro Val Asn Ala Phe Asp Ala
275 280 285
Leu Thr Glu Leu Lys Val Leu Arg Leu His Ser Asn Ser Leu Gln His
290 295 300
Val Pro Pro Arg Trp Phe Lys Asn Ile Asn Lys Leu Gln Glu Leu Asp
305 310 315 320
Leu Ser Gln Asn Phe Leu Ala Lys Glu Ile Gly Asp Ala Lys Phe Leu
325 330 335
His Phe Leu Pro Ser Leu Ile Gln Leu Asp Leu Ser Phe Asn Phe Glu
340 345 350
Leu Gln Val Tyr Arg Ala Ser Met Asn Leu Ser Gln Ala Phe Ser Ser
355 360 365
Leu Lys Ser Leu Lys Ile Leu Arg Ile Arg Gly Tyr Val Phe Lys Glu
370 375 380
Leu Lys Ser Phe Asn Leu Ser Pro Leu His Asn Leu Gln Asn Leu Glu
385 390 395 400
Val Leu Asp Leu Gly Thr Asn Phe Ile Lys Ile Ala Asn Leu Ser Met
405 410 415
Phe Lys Gln Phe Lys Arg Leu Lys Val Ile Asp Leu Ser Val Asn Lys
420 425 430
Ile Ser Pro Ser Gly Asp Ser Ser Glu Val Gly Phe Cys Ser Asn Ala
435 440 445
Arg Thr Ser Val Glu Ser Tyr Glu Pro Gln Val Leu Glu Gln Leu His
450 455 460
Tyr Phe Arg Tyr Asp Lys Tyr Ala Arg Ser Cys Arg Phe Lys Asn Lys
465 470 475 480
Glu Ala Ser Phe Met Ser Val Asn Glu Ser Cys Tyr Lys Tyr Gly Gln
485 490 495
Thr Leu Asp Leu Ser Lys Asn Ser Ile Phe Phe Val Lys Ser Ser Asp
500 505 510
Phe Gln His Leu Ser Phe Leu Lys Cys Leu Asn Leu Ser Gly Asn Leu
515 520 525
Ile Ser Gln Thr Leu Asn Gly Ser Glu Phe Gln Pro Leu Ala Glu Leu
530 535 540
Arg Tyr Leu Asp Phe Ser Asn Asn Arg Leu Asp Leu Leu His Ser Thr
545 550 555 560
Ala Phe Glu Glu Leu His Lys Leu Glu Val Leu Asp Ile Ser Ser Asn
565 570 575
Ser His Tyr Phe Gln Ser Glu Gly Ile Thr His Met Leu Asn Phe Thr
580 585 590
Lys Asn Leu Lys Val Leu Gln Lys Leu Met Met Asn Asp Asn Asp Ile
595 600 605
Ser Ser Ser Thr Ser Arg Thr Met Glu Ser Glu Ser Leu Arg Thr Leu
610 615 620
Glu Phe Arg Gly Asn His Leu Asp Val Leu Trp Arg Glu Gly Asp Asn
625 630 635 640
Arg Tyr Leu Gln Leu Phe Lys Asn Leu Leu Lys Leu Glu Glu Leu Asp
645 650 655
Ile Ser Lys Asn Ser Leu Ser Phe Leu Pro Ser Gly Val Phe Asp Gly
660 665 670
Met Pro Pro Asn Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys
675 680 685
Ser Phe Ser Trp Lys Lys Leu Gln Cys Leu Lys Asn Leu Glu Thr Leu
690 695 700
Asp Leu Ser His Asn Gln Leu Thr Thr Val Pro Glu Arg Leu Ser Asn
705 710 715 720
Cys Ser Arg Ser Leu Lys Asn Leu Ile Leu Lys Asn Asn Gln Ile Arg
725 730 735
Ser Leu Thr Lys Tyr Phe Leu Gln Asp Ala Phe Gln Leu Arg Tyr Leu
740 745 750
Asp Leu Ser Ser Asn Lys Ile Gln Met Ile Gln Lys Thr Ser Phe Pro
755 760 765
Glu Asn Val Leu Asn Asn Leu Lys Met Leu Leu Leu His His Asn Arg
770 775 780
Phe Leu Cys Thr Cys Asp Ala Val Trp Phe Val Trp Trp Val Asn His
785 790 795 800
Thr Glu Val Thr Ile Pro Tyr Leu Ala Thr Asp Val Thr Cys Val Gly
805 810 815
Pro Gly Ala His Lys Gly Gln Ser Val Ile Ser Leu Asp Leu Tyr Thr
820 825 830
Cys Glu Leu Asp Leu Thr Asn Leu Ile Leu Phe Ser Leu Ser Ile Ser
835 840 845
Val Ser Leu Phe Leu Met Val Met Met Thr Ala Ser His Leu Tyr Phe
850 855 860
Trp Asp Val Trp Tyr Ile Tyr His Phe Cys Lys Ala Lys Ile Lys Gly
865 870 875 880
Tyr Gln Arg Leu Ile Ser Pro Asp Cys Cys Tyr Asp Ala Phe Ile Val
885 890 895
Tyr Asp Thr Lys Asp Pro Ala Val Thr Glu Trp Val Leu Ala Glu Leu
900 905 910
Val Ala Lys Leu Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys Leu
915 920 925
Glu Glu Arg Asp Trp Leu Pro Gly Gln Pro Val Leu Glu Asn Leu Ser
930 935 940
Gln Ser Ile Gln Leu Ser Lys Lys Thr Val Phe Val Met Thr Asp Lys
945 950 955 960
Tyr Ala Lys Thr Glu Asn Phe Lys Ile Ala Phe Tyr Leu Ser His Gln
965 970 975
Arg Leu Met Asp Glu Lys Val Asp Val Ile Ile Leu Ile Phe Leu Glu
980 985 990
Lys Pro Phe Gln Lys Ser Lys Phe Leu Gln Leu Arg Lys Arg Leu Cys
995 1000 1005
Gly Ser Ser Val Leu Glu Trp Pro Thr Asn Pro Gln Ala His Pro Tyr
1010 1015 1020
Phe Trp Gln Cys Leu Lys Asn Ala Leu Ala Thr Asp Asn His Val Ala
1025 1030 1035 1040
Tyr Ser Gln Val Phe Lys Glu Thr Val
1045
<210> 8
<211> 3150
<212> DNA
<213> Homo sapiens
<400> 8
atggtgtttc caatgtggac actgaagaga caaattctta tcctttttaa cataatccta 60
atttccaaac tccttggggc tagatggttt cctaaaactc tgccctgtga tgtcactctg 120
gatgttccaa agaaccatgt gatcgtggac tgcacagaca agcatttgac agaaattcct 180
ggaggtattc ccacgaacac cacgaacctc accctcacca ttaaccacat accagacatc 240
tccccagcgt cctttcacag actggaccat ctggtagaga tcgatttcag atgcaactgt 300
gtacctattc cactggggtc aaaaaacaac atgtgcatca agaggctgca gattaaaccc 360
agaagcttta gtggactcac ttatttaaaa tccctttacc tggatggaaa ccagctacta 420
gagataccgc agggcctccc gcctagctta cagcttctca gccttgaggc caacaacatc 480
ttttccatca gaaaagagaa tctaacagaa ctggccaaca tagaaatact ctacctgggc 540
caaaactgtt attatcgaaa tccttgttat gtttcatatt caatagagaa agatgccttc 600
ctaaacttga caaagttaaa agtgctctcc ctgaaagata acaatgtcac agccgtccct 660
actgttttgc catctacttt aacagaacta tatctctaca acaacatgat tgcaaaaatc 720
caagaagatg attttaataa cctcaaccaa ttacaaattc ttgacctaag tggaaattgc 780
cctcgttgtt ataatgcccc atttccttgt gcgccgtgta aaaataattc tcccctacag 840
atccctgtaa atgcttttga tgcgctgaca gaattaaaag ttttacgtct acacagtaac 900
tctcttcagc atgtgccccc aagatggttt aagaacatca acaaactcca ggaactggat 960
ctgtcccaaa acttcttggc caaagaaatt ggggatgcta aatttctgca ttttctcccc 1020
agcctcatcc aattggatct gtctttcaat tttgaacttc aggtctatcg tgcatctatg 1080
aatctatcac aagcattttc ttcactgaaa agcctgaaaa ttctgcggat cagaggatat 1140
gtctttaaag agttgaaaag ctttaacctc tcgccattac ataatcttca aaatcttgaa 1200
gttcttgatc ttggcactaa ctttataaaa attgctaacc tcagcatgtt taaacaattt 1260
aaaagactga aagtcataga tctttcagtg aataaaatat caccttcagg agattcaagt 1320
gaagttggct tctgctcaaa tgccagaact tctgtagaaa gttatgaacc ccaggtcctg 1380
gaacaattac attatttcag atatgataag tatgcaagga gttgcagatt caaaaacaaa 1440
gaggcttctt tcatgtctgt taatgaaagc tgctacaagt atgggcagac cttggatcta 1500
agtaaaaata gtatattttt tgtcaagtcc tctgattttc agcatctttc tttcctcaaa 1560
tgcctgaatc tgtcaggaaa tctcattagc caaactctta atggcagtga attccaacct 1620
ttagcagagc tgagatattt ggacttctcc aacaaccggc ttgatttact ccattcaaca 1680
gcatttgaag agcttcacaa actggaagtt ctggatataa gcagtaatag ccattatttt 1740
caatcagaag gaattactca tatgctaaac tttaccaaga acctaaaggt tctgcagaaa 1800
ctgatgatga acgacaatga catctcttcc tccaccagca ggaccatgga gagtgagtct 1860
cttagaactc tggaattcag aggaaatcac ttagatgttt tatggagaga aggtgataac 1920
agatacttac aattattcaa gaatctgcta aaattagagg aattagacat ctctaaaaat 1980
tccctaagtt tcttgccttc tggagttttt gatggtatgc ctccaaatct aaagaatctc 2040
tctttggcca aaaatgggct caaatctttc agttggaaga aactccagtg tctaaagaac 2100
ctggaaactt tggacctcag ccacaaccaa ctgaccactg tccctgagag attatccaac 2160
tgttccagaa gcctcaagaa tctgattctt aagaataatc aaatcaggag tctgacgaag 2220
tattttctac aagatgcctt ccagttgcga tatctggatc tcagctcaaa taaaatccag 2280
atgatccaaa agaccagctt cccagaaaat gtcctcaaca atctgaagat gttgcttttg 2340
catcataatc ggtttctgtg cacctgtgat gctgtgtggt ttgtctggtg ggttaaccat 2400
acggaggtga ctattcctta cctggccaca gatgtgactt gtgtggggcc aggagcacac 2460
aagggccaaa gtgtgatctc cctggatctg tacacctgtg agttagatct gactaacctg 2520
attctgttct cactttccat atctgtatct ctctttctca tggtgatgat gacagcaagt 2580
cacctctatt tctgggatgt gtggtatatt taccatttct gtaaggccaa gataaagggg 2640
tatcagcgtc taatatcacc agactgttgc tatgatgctt ttattgtgta tgacactaaa 2700
gacccagctg tgaccgagtg ggttttggct gagctggtgg ccaaactgga agacccaaga 2760
gagaaacatt ttaatttatg tctcgaggaa agggactggt taccagggca gccagttctg 2820
gaaaaccttt cccagagcat acagcttagc aaaaagacag tgtttgtgat gacagacaag 2880
tatgcaaaga ctgaaaattt taagatagca ttttacttgt cccatcagag gctcatggat 2940
gaaaaagttg atgtgattat cttgatattt cttgagaagc cctttcagaa gtccaagttc 3000
ctccagctcc ggaaaaggct ctgtgggagt tctgtccttg agtggccaac aaacccgcaa 3060
gctcacccat acttctggca gtgtctaaag aacgccctgg ccacagacaa tcatgtggcc 3120
tatagtcagg tgttcaagga aacggtctag 3150
<210> 9
<211> 1041
<212> PRT
<213> Homo sapiens
<400> 9
Met Glu Asn Met Phe Leu Gln Ser Ser Met Leu Thr Cys Ile Phe Leu
1 5 10 15
Leu Ile Ser Gly Ser Cys Glu Leu Cys Ala Glu Glu Asn Phe Ser Arg
20 25 30
Ser Tyr Pro Cys Asp Glu Lys Lys Gln Asn Asp Ser Val Ile Ala Glu
35 40 45
Cys Ser Asn Arg Arg Leu Gln Glu Val Pro Gln Thr Val Gly Lys Tyr
50 55 60
Val Thr Glu Leu Asp Leu Ser Asp Asn Phe Ile Thr His Ile Thr Asn
65 70 75 80
Glu Ser Phe Gln Gly Leu Gln Asn Leu Thr Lys Ile Asn Leu Asn His
85 90 95
Asn Pro Asn Val Gln His Gln Asn Gly Asn Pro Gly Ile Gln Ser Asn
100 105 110
Gly Leu Asn Ile Thr Asp Gly Ala Phe Leu Asn Leu Lys Asn Leu Arg
115 120 125
Glu Leu Leu Leu Glu Asp Asn Gln Leu Pro Gln Ile Pro Ser Gly Leu
130 135 140
Pro Glu Ser Leu Thr Glu Leu Ser Leu Ile Gln Asn Asn Ile Tyr Asn
145 150 155 160
Ile Thr Lys Glu Gly Ile Ser Arg Leu Ile Asn Leu Lys Asn Leu Tyr
165 170 175
Leu Ala Trp Asn Cys Tyr Phe Asn Lys Val Cys Glu Lys Thr Asn Ile
180 185 190
Glu Asp Gly Val Phe Glu Thr Leu Thr Asn Leu Glu Leu Leu Ser Leu
195 200 205
Ser Phe Asn Ser Leu Ser His Val Pro Pro Lys Leu Pro Ser Ser Leu
210 215 220
Arg Lys Leu Phe Leu Ser Asn Thr Gln Ile Lys Tyr Ile Ser Glu Glu
225 230 235 240
Asp Phe Lys Gly Leu Ile Asn Leu Thr Leu Leu Asp Leu Ser Gly Asn
245 250 255
Cys Pro Arg Cys Phe Asn Ala Pro Phe Pro Cys Val Pro Cys Asp Gly
260 265 270
Gly Ala Ser Ile Asn Ile Asp Arg Phe Ala Phe Gln Asn Leu Thr Gln
275 280 285
Leu Arg Tyr Leu Asn Leu Ser Ser Thr Ser Leu Arg Lys Ile Asn Ala
290 295 300
Ala Trp Phe Lys Asn Met Pro His Leu Lys Val Leu Asp Leu Glu Phe
305 310 315 320
Asn Tyr Leu Val Gly Glu Ile Ala Ser Gly Ala Phe Leu Thr Met Leu
325 330 335
Pro Arg Leu Glu Ile Leu Asp Leu Ser Phe Asn Tyr Ile Lys Gly Ser
340 345 350
Tyr Pro Gln His Ile Asn Ile Ser Arg Asn Phe Ser Lys Leu Leu Ser
355 360 365
Leu Arg Ala Leu His Leu Arg Gly Tyr Val Phe Gln Glu Leu Arg Glu
370 375 380
Asp Asp Phe Gln Pro Leu Met Gln Leu Pro Asn Leu Ser Thr Ile Asn
385 390 395 400
Leu Gly Ile Asn Phe Ile Lys Gln Ile Asp Phe Lys Leu Phe Gln Asn
405 410 415
Phe Ser Asn Leu Glu Ile Ile Tyr Leu Ser Glu Asn Arg Ile Ser Pro
420 425 430
Leu Val Lys Asp Thr Arg Gln Ser Tyr Ala Asn Ser Ser Ser Phe Gln
435 440 445
Arg His Ile Arg Lys Arg Arg Ser Thr Asp Phe Glu Phe Asp Pro His
450 455 460
Ser Asn Phe Tyr His Phe Thr Arg Pro Leu Ile Lys Pro Gln Cys Ala
465 470 475 480
Ala Tyr Gly Lys Ala Leu Asp Leu Ser Leu Asn Ser Ile Phe Phe Ile
485 490 495
Gly Pro Asn Gln Phe Glu Asn Leu Pro Asp Ile Ala Cys Leu Asn Leu
500 505 510
Ser Ala Asn Ser Asn Ala Gln Val Leu Ser Gly Thr Glu Phe Ser Ala
515 520 525
Ile Pro His Val Lys Tyr Leu Asp Leu Thr Asn Asn Arg Leu Asp Phe
530 535 540
Asp Asn Ala Ser Ala Leu Thr Glu Leu Ser Asp Leu Glu Val Leu Asp
545 550 555 560
Leu Ser Tyr Asn Ser His Tyr Phe Arg Ile Ala Gly Val Thr His His
565 570 575
Leu Glu Phe Ile Gln Asn Phe Thr Asn Leu Lys Val Leu Asn Leu Ser
580 585 590
His Asn Asn Ile Tyr Thr Leu Thr Asp Lys Tyr Asn Leu Glu Ser Lys
595 600 605
Ser Leu Val Glu Leu Val Phe Ser Gly Asn Arg Leu Asp Ile Leu Trp
610 615 620
Asn Asp Asp Asp Asn Arg Tyr Ile Ser Ile Phe Lys Gly Leu Lys Asn
625 630 635 640
Leu Thr Arg Leu Asp Leu Ser Leu Asn Arg Leu Lys His Ile Pro Asn
645 650 655
Glu Ala Phe Leu Asn Leu Pro Ala Ser Leu Thr Glu Leu His Ile Asn
660 665 670
Asp Asn Met Leu Lys Phe Phe Asn Trp Thr Leu Leu Gln Gln Phe Pro
675 680 685
Arg Leu Glu Leu Leu Asp Leu Arg Gly Asn Lys Leu Leu Phe Leu Thr
690 695 700
Asp Ser Leu Ser Asp Phe Thr Ser Ser Leu Arg Thr Leu Leu Leu Ser
705 710 715 720
His Asn Arg Ile Ser His Leu Pro Ser Gly Phe Leu Ser Glu Val Ser
725 730 735
Ser Leu Lys His Leu Asp Leu Ser Ser Asn Leu Leu Lys Thr Ile Asn
740 745 750
Lys Ser Ala Leu Glu Thr Lys Thr Thr Thr Lys Leu Ser Met Leu Glu
755 760 765
Leu His Gly Asn Pro Phe Glu Cys Thr Cys Asp Ile Gly Asp Phe Arg
770 775 780
Arg Trp Met Asp Glu His Leu Asn Val Lys Ile Pro Arg Leu Val Asp
785 790 795 800
Val Ile Cys Ala Ser Pro Gly Asp Gln Arg Gly Lys Ser Ile Val Ser
805 810 815
Leu Glu Leu Thr Thr Cys Val Ser Asp Val Thr Ala Val Ile Leu Phe
820 825 830
Phe Phe Thr Phe Phe Ile Thr Thr Met Val Met Leu Ala Ala Leu Ala
835 840 845
His His Leu Phe Tyr Trp Asp Val Trp Phe Ile Tyr Asn Val Cys Leu
850 855 860
Ala Lys Val Lys Gly Tyr Arg Ser Leu Ser Thr Ser Gln Thr Phe Tyr
865 870 875 880
Asp Ala Tyr Ile Ser Tyr Asp Thr Lys Asp Ala Ser Val Thr Asp Trp
885 890 895
Val Ile Asn Glu Leu Arg Tyr His Leu Glu Glu Ser Arg Asp Lys Asn
900 905 910
Val Leu Leu Cys Leu Glu Glu Arg Asp Trp Asp Pro Gly Leu Ala Ile
915 920 925
Ile Asp Asn Leu Met Gln Ser Ile Asn Gln Ser Lys Lys Thr Val Phe
930 935 940
Val Leu Thr Lys Lys Tyr Ala Lys Ser Trp Asn Phe Lys Thr Ala Phe
945 950 955 960
Tyr Leu Ala Leu Gln Arg Leu Met Asp Glu Asn Met Asp Val Ile Ile
965 970 975
Phe Ile Leu Leu Glu Pro Val Leu Gln His Ser Gln Tyr Leu Arg Leu
980 985 990
Arg Gln Arg Ile Cys Lys Ser Ser Ile Leu Gln Trp Pro Asp Asn Pro
995 1000 1005
Lys Ala Glu Gly Leu Phe Trp Gln Thr Leu Arg Asn Val Val Leu Thr
1010 1015 1020
Glu Asn Asp Ser Arg Tyr Asn Asn Met Tyr Val Asp Ser Ile Lys Gln
1025 1030 1035 1040
Tyr
<210> 10
<211> 3126
<212> DNA
<213> Homo sapiens
<400> 10
atggaaaaca tgttccttca gtcgtcaatg ctgacctgca ttttcctgct aatatctggt 60
tcctgtgagt tatgcgccga agaaaatttt tctagaagct atccttgtga tgagaaaaag 120
caaaatgact cagttattgc agagtgcagc aatcgtcgac tacaggaagt tccccaaacg 180
gtgggcaaat atgtgacaga actagacctg tctgataatt tcatcacaca cataacgaat 240
gaatcatttc aagggctgca aaatctcact aaaataaatc taaaccacaa ccccaatgta 300
cagcaccaga acggaaatcc cggtatacaa tcaaatggct tgaatatcac agacggggca 360
ttcctcaacc taaaaaacct aagggagtta ctgcttgaag acaaccagtt accccaaata 420
ccctctggtt tgccagagtc tttgacagaa cttagtctaa ttcaaaacaa tatatacaac 480
ataactaaag agggcatttc aagacttata aacttgaaaa atctctattt ggcctggaac 540
tgctatttta acaaagtttg cgagaaaact aacatagaag atggagtatt tgaaacgctg 600
acaaatttgg agttgctatc actatctttc aattctcttt cacacgtgcc acccaaactg 660
ccaagctccc tacgcaaact ttttctgagc aacacccaga tcaaatacat tagtgaagaa 720
gatttcaagg gattgataaa tttaacatta ctagatttaa gcgggaactg tccgaggtgc 780
ttcaatgccc catttccatg cgtgccttgt gatggtggtg cttcaattaa tatagatcgt 840
tttgcttttc aaaacttgac ccaacttcga tacctaaacc tctctagcac ttccctcagg 900
aagattaatg ctgcctggtt taaaaatatg cctcatctga aggtgctgga tcttgaattc 960
aactatttag tgggagaaat agcctctggg gcatttttaa cgatgctgcc ccgcttagaa 1020
atacttgact tgtcttttaa ctatataaag gggagttatc cacagcatat taatatttcc 1080
agaaacttct ctaaactttt gtctctacgg gcattgcatt taagaggtta tgtgttccag 1140
gaactcagag aagatgattt ccagcccctg atgcagcttc caaacttatc gactatcaac 1200
ttgggtatta attttattaa gcaaatcgat ttcaaacttt tccaaaattt ctccaatctg 1260
gaaattattt acttgtcaga aaacagaata tcaccgttgg taaaagatac ccggcagagt 1320
tatgcaaata gttcctcttt tcaacgtcat atccggaaac gacgctcaac agattttgag 1380
tttgacccac attcgaactt ttatcatttc acccgtcctt taataaagcc acaatgtgct 1440
gcttatggaa aagccttaga tttaagcctc aacagtattt tcttcattgg gccaaaccaa 1500
tttgaaaatc ttcctgacat tgcctgttta aatctgtctg caaatagcaa tgctcaagtg 1560
ttaagtggaa ctgaattttc agccattcct catgtcaaat atttggattt gacaaacaat 1620
agactagact ttgataatgc tagtgctctt actgaattgt ccgacttgga agttctagat 1680
ctcagctata attcacacta tttcagaata gcaggcgtaa cacatcatct agaatttatt 1740
caaaatttca caaatctaaa agttttaaac ttgagccaca acaacattta tactttaaca 1800
gataagtata acctggaaag caagtccctg gtagaattag ttttcagtgg caatcgcctt 1860
gacattttgt ggaatgatga tgacaacagg tatatctcca ttttcaaagg tctcaagaat 1920
ctgacacgtc tggatttatc ccttaatagg ctgaagcaca tcccaaatga agcattcctt 1980
aatttgccag cgagtctcac tgaactacat ataaatgata atatgttaaa gttttttaac 2040
tggacattac tccagcagtt tcctcgtctc gagttgcttg acttacgtgg aaacaaacta 2100
ctctttttaa ctgatagcct atctgacttt acatcttccc ttcggacact gctgctgagt 2160
cataacagga tttcccacct accctctggc tttctttctg aagtcagtag tctgaagcac 2220
ctcgatttaa gttccaatct gctaaaaaca atcaacaaat ccgcacttga aactaagacc 2280
accaccaaat tatctatgtt ggaactacac ggaaacccct ttgaatgcac ctgtgacatt 2340
ggagatttcc gaagatggat ggatgaacat ctgaatgtca aaattcccag actggtagat 2400
gtcatttgtg ccagtcctgg ggatcaaaga gggaagagta ttgtgagtct ggagctaaca 2460
acttgtgttt cagatgtcac tgcagtgata ttatttttct tcacgttctt tatcaccacc 2520
atggttatgt tggctgccct ggctcaccat ttgttttact gggatgtttg gtttatatat 2580
aatgtgtgtt tagctaaggt aaaaggctac aggtctcttt ccacatccca aactttctat 2640
gatgcttaca tttcttatga caccaaagat gcctctgtta ctgactgggt gataaatgag 2700
ctgcgctacc accttgaaga gagccgagac aaaaacgttc tcctttgtct agaggagagg 2760
gattgggacc cgggattggc catcatcgac aacctcatgc agagcatcaa ccaaagcaag 2820
aaaacagtat ttgttttaac caaaaaatat gcaaaaagct ggaactttaa aacagctttt 2880
tacttggctt tgcagaggct aatggatgag aacatggatg tgattatatt tatcctgctg 2940
gagccagtgt tacagcattc tcagtatttg aggctacggc agcggatctg taagagctcc 3000
atcctccagt ggcctgacaa cccgaaggca gaaggcttgt tttggcaaac tctgagaaat 3060
gtggtcttga ctgaaaatga ttcacggtat aacaatatgt atgtcgattc cattaagcaa 3120
tactaa 3126
<210> 11
<211> 1032
<212> PRT
<213> Homo sapiens
<400> 11
Met Gly Phe Cys Arg Ser Ala Leu His Pro Leu Ser Leu Leu Val Gln
1 5 10 15
Ala Ile Met Leu Ala Met Thr Leu Ala Leu Gly Thr Leu Pro Ala Phe
20 25 30
Leu Pro Cys Glu Leu Gln Pro His Gly Leu Val Asn Cys Asn Trp Leu
35 40 45
Phe Leu Lys Ser Val Pro His Phe Ser Met Ala Ala Pro Arg Gly Asn
50 55 60
Val Thr Ser Leu Ser Leu Ser Ser Asn Arg Ile His His Leu His Asp
65 70 75 80
Ser Asp Phe Ala His Leu Pro Ser Leu Arg His Leu Asn Leu Lys Trp
85 90 95
Asn Cys Pro Pro Val Gly Leu Ser Pro Met His Phe Pro Cys His Met
100 105 110
Thr Ile Glu Pro Ser Thr Phe Leu Ala Val Pro Thr Leu Glu Glu Leu
115 120 125
Asn Leu Ser Tyr Asn Asn Ile Met Thr Val Pro Ala Leu Pro Lys Ser
130 135 140
Leu Ile Ser Leu Ser Leu Ser His Thr Asn Ile Leu Met Leu Asp Ser
145 150 155 160
Ala Ser Leu Ala Gly Leu His Ala Leu Arg Phe Leu Phe Met Asp Gly
165 170 175
Asn Cys Tyr Tyr Lys Asn Pro Cys Arg Gln Ala Leu Glu Val Ala Pro
180 185 190
Gly Ala Leu Leu Gly Leu Gly Asn Leu Thr His Leu Ser Leu Lys Tyr
195 200 205
Asn Asn Leu Thr Val Val Pro Arg Asn Leu Pro Ser Ser Leu Glu Tyr
210 215 220
Leu Leu Leu Ser Tyr Asn Arg Ile Val Lys Leu Ala Pro Glu Asp Leu
225 230 235 240
Ala Asn Leu Thr Ala Leu Arg Val Leu Asp Val Gly Gly Asn Cys Arg
245 250 255
Arg Cys Asp His Ala Pro Asn Pro Cys Met Glu Cys Pro Arg His Phe
260 265 270
Pro Gln Leu His Pro Asp Thr Phe Ser His Leu Ser Arg Leu Glu Gly
275 280 285
Leu Val Leu Lys Asp Ser Ser Leu Ser Trp Leu Asn Ala Ser Trp Phe
290 295 300
Arg Gly Leu Gly Asn Leu Arg Val Leu Asp Leu Ser Glu Asn Phe Leu
305 310 315 320
Tyr Lys Cys Ile Thr Lys Thr Lys Ala Phe Gln Gly Leu Thr Gln Leu
325 330 335
Arg Lys Leu Asn Leu Ser Phe Asn Tyr Gln Lys Arg Val Ser Phe Ala
340 345 350
His Leu Ser Leu Ala Pro Ser Phe Gly Ser Leu Val Ala Leu Lys Glu
355 360 365
Leu Asp Met His Gly Ile Phe Phe Arg Ser Leu Asp Glu Thr Thr Leu
370 375 380
Arg Pro Leu Ala Arg Leu Pro Met Leu Gln Thr Leu Arg Leu Gln Met
385 390 395 400
Asn Phe Ile Asn Gln Ala Gln Leu Gly Ile Phe Arg Ala Phe Pro Gly
405 410 415
Leu Arg Tyr Val Asp Leu Ser Asp Asn Arg Ile Ser Gly Ala Ser Glu
420 425 430
Leu Thr Ala Thr Met Gly Glu Ala Asp Gly Gly Glu Lys Val Trp Leu
435 440 445
Gln Pro Gly Asp Leu Ala Pro Ala Pro Val Asp Thr Pro Ser Ser Glu
450 455 460
Asp Phe Arg Pro Asn Cys Ser Thr Leu Asn Phe Thr Leu Asp Leu Ser
465 470 475 480
Arg Asn Asn Leu Val Thr Val Gln Pro Glu Met Phe Ala Gln Leu Ser
485 490 495
His Leu Gln Cys Leu Arg Leu Ser His Asn Cys Ile Ser Gln Ala Val
500 505 510
Asn Gly Ser Gln Phe Leu Pro Leu Thr Gly Leu Gln Val Leu Asp Leu
515 520 525
Ser His Asn Lys Leu Asp Leu Tyr His Glu His Ser Phe Thr Glu Leu
530 535 540
Pro Arg Leu Glu Ala Leu Asp Leu Ser Tyr Asn Ser Gln Pro Phe Gly
545 550 555 560
Met Gln Gly Val Gly His Asn Phe Ser Phe Val Ala His Leu Arg Thr
565 570 575
Leu Arg His Leu Ser Leu Ala His Asn Asn Ile His Ser Gln Val Ser
580 585 590
Gln Gln Leu Cys Ser Thr Ser Leu Arg Ala Leu Asp Phe Ser Gly Asn
595 600 605
Ala Leu Gly His Met Trp Ala Glu Gly Asp Leu Tyr Leu His Phe Phe
610 615 620
Gln Gly Leu Ser Gly Leu Ile Trp Leu Asp Leu Ser Gln Asn Arg Leu
625 630 635 640
His Thr Leu Leu Pro Gln Thr Leu Arg Asn Leu Pro Lys Ser Leu Gln
645 650 655
Val Leu Arg Leu Arg Asp Asn Tyr Leu Ala Phe Phe Lys Trp Trp Ser
660 665 670
Leu His Phe Leu Pro Lys Leu Glu Val Leu Asp Leu Ala Gly Asn Gln
675 680 685
Leu Lys Ala Leu Thr Asn Gly Ser Leu Pro Ala Gly Thr Arg Leu Arg
690 695 700
Arg Leu Asp Val Ser Cys Asn Ser Ile Ser Phe Val Ala Pro Gly Phe
705 710 715 720
Phe Ser Lys Ala Lys Glu Leu Arg Glu Leu Asn Leu Ser Ala Asn Ala
725 730 735
Leu Lys Thr Val Asp His Ser Trp Phe Gly Pro Leu Ala Ser Ala Leu
740 745 750
Gln Ile Leu Asp Val Ser Ala Asn Pro Leu His Cys Ala Cys Gly Ala
755 760 765
Ala Phe Met Asp Phe Leu Leu Glu Val Gln Ala Ala Val Pro Gly Leu
770 775 780
Pro Ser Arg Val Lys Cys Gly Ser Pro Gly Gln Leu Gln Gly Leu Ser
785 790 795 800
Ile Phe Ala Gln Asp Leu Arg Leu Cys Leu Asp Glu Ala Leu Ser Trp
805 810 815
Asp Cys Phe Ala Leu Ser Leu Leu Ala Val Ala Leu Gly Leu Gly Val
820 825 830
Pro Met Leu His His Leu Cys Gly Trp Asp Leu Trp Tyr Cys Phe His
835 840 845
Leu Cys Leu Ala Trp Leu Pro Trp Arg Gly Arg Gln Ser Gly Arg Asp
850 855 860
Glu Asp Ala Leu Pro Tyr Asp Ala Phe Val Val Phe Asp Lys Thr Gln
865 870 875 880
Ser Ala Val Ala Asp Trp Val Tyr Asn Glu Leu Arg Gly Gln Leu Glu
885 890 895
Glu Cys Arg Gly Arg Trp Ala Leu Arg Leu Cys Leu Glu Glu Arg Asp
900 905 910
Trp Leu Pro Gly Lys Thr Leu Phe Glu Asn Leu Trp Ala Ser Val Tyr
915 920 925
Gly Ser Arg Lys Thr Leu Phe Val Leu Ala His Thr Asp Arg Val Ser
930 935 940
Gly Leu Leu Arg Ala Ser Phe Leu Leu Ala Gln Gln Arg Leu Leu Glu
945 950 955 960
Asp Arg Lys Asp Val Val Val Leu Val Ile Leu Ser Pro Asp Gly Arg
965 970 975
Arg Ser Arg Tyr Val Arg Leu Arg Gln Arg Leu Cys Arg Gln Ser Val
980 985 990
Leu Leu Trp Pro His Gln Pro Ser Gly Gln Arg Ser Phe Trp Ala Gln
995 1000 1005
Leu Gly Met Ala Leu Thr Arg Asp Asn His His Phe Tyr Asn Arg Asn
1010 1015 1020
Phe Cys Gln Gly Pro Thr Ala Glu
1025 1030
<210> 12
<211> 3099
<212> DNA
<213> Homo sapiens
<400> 12
atgggtttct gccgcagcgc cctgcacccg ctgtctctcc tggtgcaggc catcatgctg 60
gccatgaccc tggccctggg taccttgcct gccttcctac cctgtgagct ccagccccac 120
ggcctggtga actgcaactg gctgttcctg aagtctgtgc cccacttctc catggcagca 180
ccccgtggca atgtcaccag cctttccttg tcctccaacc gcatccacca cctccatgat 240
tctgactttg cccacctgcc cagcctgcgg catctcaacc tcaagtggaa ctgcccgccg 300
gttggcctca gccccatgca cttcccctgc cacatgacca tcgagcccag caccttcttg 360
gctgtgccca ccctggaaga gctaaacctg agctacaaca acatcatgac tgtgcctgcg 420
ctgcccaaat ccctcatatc cctgtccctc agccatacca acatcctgat gctagactct 480
gccagcctcg ccggcctgca tgccctgcgc ttcctattca tggacggcaa ctgttattac 540
aagaacccct gcaggcaggc actggaggtg gccccgggtg ccctccttgg cctgggcaac 600
ctcacccacc tgtcactcaa gtacaacaac ctcactgtgg tgccccgcaa cctgccttcc 660
agcctggagt atctgctgtt gtcctacaac cgcatcgtca aactggcgcc tgaggacctg 720
gccaatctga ccgccctgcg tgtgctcgat gtgggcggaa attgccgccg ctgcgaccac 780
gctcccaacc cctgcatgga gtgccctcgt cacttccccc agctacatcc cgataccttc 840
agccacctga gccgtcttga aggcctggtg ttgaaggaca gttctctctc ctggctgaat 900
gccagttggt tccgtgggct gggaaacctc cgagtgctgg acctgagtga gaacttcctc 960
tacaaatgca tcactaaaac caaggccttc cagggcctaa cacagctgcg caagcttaac 1020
ctgtccttca attaccaaaa gagggtgtcc tttgcccacc tgtctctggc cccttccttc 1080
gggagcctgg tcgccctgaa ggagctggac atgcacggca tcttcttccg ctcactcgat 1140
gagaccacgc tccggccact ggcccgcctg cccatgctcc agactctgcg tctgcagatg 1200
aacttcatca accaggccca gctcggcatc ttcagggcct tccctggcct gcgctacgtg 1260
gacctgtcgg acaaccgcat cagcggagct tcggagctga cagccaccat gggggaggca 1320
gatggagggg agaaggtctg gctgcagcct ggggaccttg ctccggcccc agtggacact 1380
cccagctctg aagacttcag gcccaactgc agcaccctca acttcacctt ggatctgtca 1440
cggaacaacc tggtgaccgt gcagccggag atgtttgccc agctctcgca cctgcagtgc 1500
ctgcgcctga gccacaactg catctcgcag gcagtcaatg gctcccagtt cctgccgctg 1560
accggtctgc aggtgctaga cctgtcccac aataagctgg acctctacca cgagcactca 1620
ttcacggagc taccgcgact ggaggccctg gacctcagct acaacagcca gccctttggc 1680
atgcagggcg tgggccacaa cttcagcttc gtggctcacc tgcgcaccct gcgccacctc 1740
agcctggccc acaacaacat ccacagccaa gtgtcccagc agctctgcag tacgtcgctg 1800
cgggccctgg acttcagcgg caatgcactg ggccatatgt gggccgaggg agacctctat 1860
ctgcacttct tccaaggcct gagcggtttg atctggctgg acttgtccca gaaccgcctg 1920
cacaccctcc tgccccaaac cctgcgcaac ctccccaaga gcctacaggt gctgcgtctc 1980
cgtgacaatt acctggcctt ctttaagtgg tggagcctcc acttcctgcc caaactggaa 2040
gtcctcgacc tggcaggaaa ccagctgaag gccctgacca atggcagcct gcctgctggc 2100
acccggctcc ggaggctgga tgtcagctgc aacagcatca gcttcgtggc ccccggcttc 2160
ttttccaagg ccaaggagct gcgagagctc aaccttagcg ccaacgccct caagacagtg 2220
gaccactcct ggtttgggcc cctggcgagt gccctgcaaa tactagatgt aagcgccaac 2280
cctctgcact gcgcctgtgg ggcggccttt atggacttcc tgctggaggt gcaggctgcc 2340
gtgcccggtc tgcccagccg ggtgaagtgt ggcagtccgg gccagctcca gggcctcagc 2400
atctttgcac aggacctgcg cctctgcctg gatgaggccc tctcctggga ctgtttcgcc 2460
ctctcgctgc tggctgtggc tctgggcctg ggtgtgccca tgctgcatca cctctgtggc 2520
tgggacctct ggtactgctt ccacctgtgc ctggcctggc ttccctggcg ggggcggcaa 2580
agtgggcgag atgaggatgc cctgccctac gatgccttcg tggtcttcga caaaacgcag 2640
agcgcagtgg cagactgggt gtacaacgag cttcgggggc agctggagga gtgccgtggg 2700
cgctgggcac tccgcctgtg cctggaggaa cgcgactggc tgcctggcaa aaccctcttt 2760
gagaacctgt gggcctcggt ctatggcagc cgcaagacgc tgtttgtgct ggcccacacg 2820
gaccgggtca gtggtctctt gcgcgccagc ttcctgctgg cccagcagcg cctgctggag 2880
gaccgcaagg acgtcgtggt gctggtgatc ctgagccctg acggccgccg ctcccgctac 2940
gtgcggctgc gccagcgcct ctgccgccag agtgtcctcc tctggcccca ccagcccagt 3000
ggtcagcgca gcttctgggc ccagctgggc atggccctga ccagggacaa ccaccacttc 3060
tataaccgga acttctgcca gggacccacg gccgaatag 3099
<210> 13
<211> 317
<212> PRT
<213> Homo sapiens
<400> 13
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 Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro
35 40 45
Trp Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly
50 55 60
Ala Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn
65 70 75 80
Leu Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn
85 90 95
Asn Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser
100 105 110
Asp Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr
115 120 125
Pro His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His
130 135 140
Ser Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly
145 150 155 160
Lys Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln
165 170 175
Ala Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly
180 185 190
Tyr Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro
195 200 205
Ser Met Gly Ser Ser Ser Pro Met Gly Ile Ile Val Ala Val Val Ile
210 215 220
Ala Thr Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr
225 230 235 240
Cys Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala
245 250 255
Ala Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg
260 265 270
Gln Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr
275 280 285
Met Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr
290 295 300
Leu Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn
305 310 315
<210> 14
<211> 954
<212> DNA
<213> Homo sapiens
<400> 14
atgactatgg agacccaaat gtctcagaat gtatgtccca gaaacctgtg gctgcttcaa 60
ccattgacag ttttgctgct gctggcttct gcagacagtc aagctgcagc tcccccaaag 120
gctgtgctga aacttgagcc cccgtggatc aacgtgctcc aggaggactc tgtgactctg 180
acatgccagg gggctcgcag ccctgagagc gactccattc agtggttcca caatgggaat 240
ctcattccca cccacacgca gcccagctac aggttcaagg ccaacaacaa tgacagcggg 300
gagtacacgt gccagactgg ccagaccagc ctcagcgacc ctgtgcatct gactgtgctt 360
tccgaatggc tggtgctcca gacccctcac ctggagttcc aggagggaga aaccatcatg 420
ctgaggtgcc acagctggaa ggacaagcct ctggtcaagg tcacattctt ccagaatgga 480
aaatcccaga aattctccca tttggatccc accttctcca tcccacaagc aaaccacagt 540
cacagtggtg attaccactg cacaggaaac ataggctaca cgctgttctc atccaagcct 600
gtgaccatca ctgtccaagt gcccagcatg ggcagctctt caccaatggg gatcattgtg 660
gctgtggtca ttgcgactgc tgtagcagcc attgttgctg ctgtagtggc cttgatctac 720
tgcaggaaaa agcggatttc agccaattcc actgatcctg tgaaggctgc ccaatttgag 780
ccacctggac gtcaaatgat tgccatcaga aagagacaac ttgaagaaac caacaatgac 840
tatgaaacag ctgacggcgg ctacatgact ctgaacccca gggcacctac tgacgatgat 900
aaaaacatct acctgactct tcctcccaac gaccatgtca acagtaataa ctaa 954
<210> 15
<211> 254
<212> PRT
<213> Homo sapiens
<400> 15
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 Phe
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> 16
<211> 765
<212> DNA
<213> Homo sapiens
<400> 16
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> 17
<211> 86
<212> PRT
<213> Homo sapiens
<400> 17
Met Ile Pro Ala Val Val Leu Leu Leu Leu Leu Leu Val Glu Gln Ala
1 5 10 15
Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Ile Leu
20 25 30
Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile
35 40 45
Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val
50 55 60
Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys
65 70 75 80
His Glu Lys Pro Pro Gln
85
<210> 18
<211> 261
<212> DNA
<213> Homo sapiens
<400> 18
atgattccag cagtggtctt gctcttactc cttttggttg aacaagcagc ggccctggga 60
gagcctcagc tctgctatat cctggatgcc atcctgtttc tgtatggaat tgtcctcacc 120
ctcctctact gtcgactgaa gatccaagtg cgaaaggcag ctataaccag ctatgagaaa 180
tcagatggtg tttacacggg cctgagcacc aggaaccagg agacttacga gactctgaag 240
catgagaaac caccacagta g 261
<210> 19
<211> 296
<212> PRT
<213> Homo sapiens
<400> 19
Met Ala Ala Gly Gly Pro Gly Ala Gly Ser Ala Ala Pro Val Ser Ser
1 5 10 15
Thr Ser Ser Leu Pro Leu Ala Ala Leu Asn Met Arg Val Arg Arg Arg
20 25 30
Leu Ser Leu Phe Leu Asn Val Arg Thr Gln Val Ala Ala Asp Trp Thr
35 40 45
Ala Leu Ala Glu Glu Met Asp Phe Glu Tyr Leu Glu Ile Arg Gln Leu
50 55 60
Glu Thr Gln Ala Asp Pro Thr Gly Arg Leu Leu Asp Ala Trp Gln Gly
65 70 75 80
Arg Pro Gly Ala Ser Val Gly Arg Leu Leu Glu Leu Leu Thr Lys Leu
85 90 95
Gly Arg Asp Asp Val Leu Leu Glu Leu Gly Pro Ser Ile Glu Glu Asp
100 105 110
Cys Gln Lys Tyr Ile Leu Lys Gln Gln Gln Glu Glu Ala Glu Lys Pro
115 120 125
Leu Gln Val Ala Ala Val Asp Ser Ser Val Pro Arg Thr Ala Glu Leu
130 135 140
Ala Gly Ile Thr Thr Leu Asp Asp Pro Leu Gly His Met Pro Glu Arg
145 150 155 160
Phe Asp Ala Phe Ile Cys Tyr Cys Pro Ser Asp Ile Gln Phe Val Gln
165 170 175
Glu Met Ile Arg Gln Leu Glu Gln Thr Asn Tyr Arg Leu Lys Leu Cys
180 185 190
Val Ser Asp Arg Asp Val Leu Pro Gly Thr Cys Val Trp Ser Ile Ala
195 200 205
Ser Glu Leu Ile Glu Lys Arg Cys Arg Arg Met Val Val Val Val Ser
210 215 220
Asp Asp Tyr Leu Gln Ser Lys Glu Cys Asp Phe Gln Thr Lys Phe Ala
225 230 235 240
Leu Ser Leu Ser Pro Gly Ala His Gln Lys Arg Leu Ile Pro Ile Lys
245 250 255
Tyr Lys Ala Met Lys Lys Glu Phe Pro Ser Ile Leu Arg Phe Ile Thr
260 265 270
Val Cys Asp Tyr Thr Asn Pro Cys Thr Lys Ser Trp Phe Trp Thr Arg
275 280 285
Leu Ala Lys Ala Leu Ser Leu Pro
290 295
<210> 20
<211> 954
<212> DNA
<213> Homo sapiens
<400> 20
atgcgacccg accgcgctga ggctccagga ccgcccgcca tggctgcagg aggtcccggc 60
gcggggtctg cggccccggt ctcctccaca tcctcccttc ccctggctgc tctcaacatg 120
cgagtgcggc gccgcctgtc tctgttcttg aacgtgcgga cacaggtggc ggccgactgg 180
accgcgctgg cggaggagat ggactttgag tacttggaga tccggcaact ggagacacaa 240
gcggacccca ctggcaggct gctggacgcc tggcagggac gccctggcgc ctctgtaggc 300
cgactgctcg agctgcttac caagctgggc cgcgacgacg tgctgctgga gctgggaccc 360
agcattgagg aggattgcca aaagtatatc ttgaagcagc agcaggagga ggctgagaag 420
cctttacagg tggccgctgt agacagcagt gtcccacgga cagcagagct ggcgggcatc 480
accacacttg atgaccccct ggggcatatg cctgagcgtt tcgatgcctt catctgctat 540
tgccccagcg acatccagtt tgtgcaggag atgatccggc aactggaaca gacaaactat 600
cgactgaagt tgtgtgtgtc tgaccgcgat gtcctgcctg gcacctgtgt ctggtctatt 660
gctagtgagc tcatcgaaaa gaggttggct agaaggccac ggggtgggtg ccgccggatg 720
gtggtggttg tctctgatga ttacctgcag agcaaggaat gtgacttcca gaccaaattt 780
gcactcagcc tctctccagg tgcccatcag aagcgactga tccccatcaa gtacaaggca 840
atgaagaaag agttccccag catcctgagg ttcatcactg tctgcgacta caccaacccc 900
tgcaccaaat cttggttctg gactcgcctt gccaaggcct tgtccctgcc ctga 954
<210> 21
<211> 153
<212> PRT
<213> Homo sapiens
<400> 21
Met Ala Pro Ala Ala Ala Thr Gly Gly Ser Thr Leu Pro Ser Gly Phe
1 5 10 15
Ser Val Phe Thr Thr Leu Pro Asp Leu Leu Phe Ile Phe Glu Phe Ile
20 25 30
Phe Gly Gly Leu Val Trp Ile Leu Val Ala Ser Ser Leu Val Pro Trp
35 40 45
Pro Leu Val Gln Gly Trp Val Met Phe Val Ser Val Phe Cys Phe Val
50 55 60
Ala Thr Thr Thr Leu Ile Ile Leu Tyr Ile Ile Gly Ala His Gly Gly
65 70 75 80
Glu Thr Ser Trp Val Thr Leu Asp Ala Ala Tyr His Cys Thr Ala Ala
85 90 95
Leu Phe Tyr Leu Ser Ala Ser Val Leu Glu Ala Leu Ala Thr Ile Thr
100 105 110
Met Gln Asp Gly Phe Thr Tyr Arg His Tyr His Glu Asn Ile Ala Ala
115 120 125
Val Val Phe Ser Tyr Ile Ala Thr Leu Leu Tyr Val Val His Ala Val
130 135 140
Phe Ser Leu Ile Arg Trp Lys Ser Ser
145 150
<210> 22
<211> 462
<212> DNA
<213> Homo sapiens
<400> 22
atggcccccg cagcggcgac ggggggcagc accctgccca gtggcttctc ggtcttcacc 60
accttgcccg acttgctctt catctttgag tttatcttcg ggggcctggt gtggatcctg 120
gtggcctcct ccctggtgcc ctggcccctg gtccagggct gggtgatgtt cgtgtctgtg 180
ttctgcttcg tggccaccac caccttgatc atcctgtaca taattggagc ccacggtgga 240
gagacttcct gggtcacctt ggacgcagcc taccactgca ccgctgccct cttttacctc 300
agcgcctcag tcctggaggc cctggccacc atcacgatgc aagacggctt cacctacagg 360
cactaccatg aaaacattgc tgccgtggtg ttctcctaca tagccactct gctctacgtg 420
gtccatgcgg tgttctcttt aatcagatgg aagtcttcat aa 462
<210> 23
<211> 712
<212> PRT
<213> Homo sapiens
<400> 23
Met Ala Gly Gly Pro Gly Pro Gly Glu Pro Ala Ala Pro Gly Ala Gln
1 5 10 15
His Phe Leu Tyr Glu Val Pro Pro Trp Val Met Cys Arg Phe Tyr Lys
20 25 30
Val Met Asp Ala Leu Glu Pro Ala Asp Trp Cys Gln Phe Ala Ala Leu
35 40 45
Ile Val Arg Asp Gln Thr Glu Leu Arg Leu Cys Glu Arg Ser Gly Gln
50 55 60
Arg Thr Ala Ser Val Leu Trp Pro Trp Ile Asn Arg Asn Ala Arg Val
65 70 75 80
Ala Asp Leu Val His Ile Leu Thr His Leu Gln Leu Leu Arg Ala Arg
85 90 95
Asp Ile Ile Thr Ala Trp His Pro Pro Ala Pro Leu Pro Ser Pro Gly
100 105 110
Thr Thr Ala Pro Arg Pro Ser Ser Ile Pro Ala Pro Ala Glu Ala Glu
115 120 125
Ala Trp Ser Pro Arg Lys Leu Pro Ser Ser Ala Ser Thr Phe Leu Ser
130 135 140
Pro Ala Phe Pro Gly Ser Gln Thr His Ser Gly Pro Glu Leu Gly Leu
145 150 155 160
Val Pro Ser Pro Ala Ser Leu Trp Pro Pro Pro Pro Ser Pro Ala Pro
165 170 175
Ser Ser Thr Lys Pro Gly Pro Glu Ser Ser Val Ser Leu Leu Gln Gly
180 185 190
Ala Arg Pro Phe Pro Phe Cys Trp Pro Leu Cys Glu Ile Ser Arg Gly
195 200 205
Thr His Asn Phe Ser Glu Glu Leu Lys Ile Gly Glu Gly Gly Phe Gly
210 215 220
Cys Val Tyr Arg Ala Val Met Arg Asn Thr Val Tyr Ala Val Lys Arg
225 230 235 240
Leu Lys Glu Asn Ala Asp Leu Glu Trp Thr Ala Val Lys Gln Ser Phe
245 250 255
Leu Thr Glu Val Glu Gln Leu Ser Arg Phe Arg His Pro Asn Ile Val
260 265 270
Asp Phe Ala Gly Tyr Cys Ala Gln Asn Gly Phe Tyr Cys Leu Val Tyr
275 280 285
Gly Phe Leu Pro Asn Gly Ser Leu Glu Asp Arg Leu His Cys Gln Thr
290 295 300
Gln Ala Cys Pro Pro Leu Ser Trp Pro Gln Arg Leu Asp Ile Leu Leu
305 310 315 320
Gly Thr Ala Arg Ala Ile Gln Phe Leu His Gln Asp Ser Pro Ser Leu
325 330 335
Ile His Gly Asp Ile Lys Ser Ser Asn Val Leu Leu Asp Glu Arg Leu
340 345 350
Thr Pro Lys Leu Gly Asp Phe Gly Leu Ala Arg Phe Ser Arg Phe Ala
355 360 365
Gly Ser Ser Pro Ser Gln Ser Ser Met Val Ala Arg Thr Gln Thr Val
370 375 380
Arg Gly Thr Leu Ala Tyr Leu Pro Glu Glu Tyr Ile Lys Thr Gly Arg
385 390 395 400
Leu Ala Val Asp Thr Asp Thr Phe Ser Phe Gly Val Val Val Leu Glu
405 410 415
Thr Leu Ala Gly Gln Arg Ala Val Lys Thr His Gly Ala Arg Thr Lys
420 425 430
Tyr Leu Lys Asp Leu Val Glu Glu Glu Ala Glu Glu Ala Gly Val Ala
435 440 445
Leu Arg Ser Thr Gln Ser Thr Leu Gln Ala Gly Leu Ala Ala Asp Ala
450 455 460
Trp Ala Ala Pro Ile Ala Met Gln Ile Tyr Lys Lys His Leu Asp Pro
465 470 475 480
Arg Pro Gly Pro Cys Pro Pro Glu Leu Gly Leu Gly Leu Gly Gln Leu
485 490 495
Ala Cys Cys Cys Leu His Arg Arg Ala Lys Arg Arg Pro Pro Met Thr
500 505 510
Gln Val Tyr Glu Arg Leu Glu Lys Leu Gln Ala Val Val Ala Gly Val
515 520 525
Pro Gly His Ser Glu Ala Ala Ser Cys Ile Pro Pro Ser Pro Gln Glu
530 535 540
Asn Ser Tyr Val Ser Ser Thr Gly Arg Ala His Ser Gly Ala Ala Pro
545 550 555 560
Trp Gln Pro Leu Ala Ala Pro Ser Gly Ala Ser Ala Gln Ala Ala Glu
565 570 575
Gln Leu Gln Arg Gly Pro Asn Gln Pro Val Glu Ser Asp Glu Ser Leu
580 585 590
Gly Gly Leu Ser Ala Ala Leu Arg Ser Trp His Leu Thr Pro Ser Cys
595 600 605
Pro Leu Asp Pro Ala Pro Leu Arg Glu Ala Gly Cys Pro Gln Gly Asp
610 615 620
Thr Ala Gly Glu Ser Ser Trp Gly Ser Gly Pro Gly Ser Arg Pro Thr
625 630 635 640
Ala Val Glu Gly Leu Ala Leu Gly Ser Ser Ala Ser Ser Ser Ser Glu
645 650 655
Pro Pro Gln Ile Ile Ile Asn Pro Ala Arg Gln Lys Met Val Gln Lys
660 665 670
Leu Ala Leu Tyr Glu Asp Gly Ala Leu Asp Ser Leu Gln Leu Leu Ser
675 680 685
Ser Ser Ser Leu Pro Gly Leu Gly Leu Glu Gln Asp Arg Gln Gly Pro
690 695 700
Glu Glu Ser Asp Glu Phe Gln Ser
705 710
<210> 24
<211> 2139
<212> DNA
<213> Homo sapiens
<400> 24
atggccgggg ggccgggccc gggggagccc gcagcccccg gcgcccagca cttcttgtac 60
gaggtgccgc cctgggtcat gtgccgcttc tacaaagtga tggacgccct ggagcccgcc 120
gactggtgcc agttcgccgc cctgatcgtg cgcgaccaga ccgagctgcg gctgtgcgag 180
cgctccgggc agcgcacggc cagcgtcctg tggccctgga tcaaccgcaa cgcccgtgtg 240
gccgacctcg tgcacatcct cacgcacctg cagctgctcc gtgcgcggga catcatcaca 300
gcctggcacc ctcccgcccc gcttccgtcc ccaggcacca ctgccccgag gcccagcagc 360
atccctgcac ccgccgaggc cgaggcctgg agcccccgga agttgccatc ctcagcctcc 420
accttcctct ccccagcttt tccaggctcc cagacccatt cagggcctga gctcggcctg 480
gtcccaagcc ctgcttccct gtggcctcca ccgccatctc cagccccttc ttctaccaag 540
ccaggcccag agagctcagt gtccctcctg cagggagccc gcccctttcc gttttgctgg 600
cccctctgtg agatttcccg gggcacccac aacttctcgg aggagctcaa gatcggggag 660
ggtggctttg ggtgcgtgta ccgggcggtg atgaggaaca cggtgtatgc tgtgaagagg 720
ctgaaggaga acgctgacct ggagtggact gcagtgaagc agagcttcct gaccgaggtg 780
gagcagctgt ccaggtttcg tcacccaaac attgtggact ttgctggcta ctgtgctcag 840
aacggcttct actgcctggt gtacggcttc ctgcccaacg gctccctgga ggaccgtctc 900
cactgccaga cccaggcctg cccacctctc tcctggcctc agcgactgga catccttctg 960
ggtacagccc gggcaattca gtttctacat caggacagcc ccagcctcat ccatggagac 1020
atcaagagtt ccaacgtcct tctggatgag aggctgacac ccaagctggg agactttggc 1080
ctggcccggt tcagccgctt tgccgggtcc agccccagcc agagcagcat ggtggcccgg 1140
acacagacag tgcggggcac cctggcctac ctgcccgagg agtacatcaa gacgggaagg 1200
ctggctgtgg acacggacac cttcagcttt ggggtggtag tgctagagac cttggctggt 1260
cagagggctg tgaagacgca cggtgccagg accaagtatc tgaaagacct ggtggaagag 1320
gaggctgagg aggctggagt ggctttgaga agcacccaga gcacactgca agcaggtctg 1380
gctgcagatg cctgggctgc tcccatcgcc atgcagatct acaagaagca cctggacccc 1440
aggcccgggc cctgcccacc tgagctgggc ctgggcctgg gccagctggc ctgctgctgc 1500
ctgcaccgcc gggccaaaag gaggcctcct atgacccagg tgtacgagag gctagagaag 1560
ctgcaggcag tggtggcggg ggtgcccggg cattcggagg ccgccagctg catcccccct 1620
tccccgcagg agaactccta cgtgtccagc actggcagag cccacagtgg ggctgctcca 1680
tggcagcccc tggcagcgcc atcaggagcc agtgcccagg cagcagagca gctgcagaga 1740
ggccccaacc agcccgtgga gagtgacgag agcctaggcg gcctctctgc tgccctgcgc 1800
tcctggcact tgactccaag ctgccctctg gacccagcac ccctcaggga ggccggctgt 1860
cctcaggggg acacggcagg agaatcgagc tgggggagtg gcccaggatc ccggcccaca 1920
gccgtggaag gactggccct tggcagctct gcatcatcgt cgtcagagcc accgcagatt 1980
atcatcaacc ctgcccgaca gaagatggtc cagaagctgg ccctgtacga ggatggggcc 2040
ctggacagcc tgcagctgct gtcgtccagc tccctcccag gcttgggcct ggaacaggac 2100
aggcaggggc ccgaagaaag tgatgaattt cagagctga 2139
<210> 25
<211> 257
<212> PRT
<213> Artificial Sequence
<220>
<223> ScFv fragment
<400> 25
Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser
1 5 10 15
Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser
20 25 30
Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys
35 40 45
Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile Ser Arg
65 70 75 80
Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser
85 90 95
Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Ala
115 120 125
Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser Gly Ala
130 135 140
Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr Ala Ser
145 150 155 160
Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln Arg Pro
165 170 175
Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn Gly Asn
180 185 190
Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr Thr Asp
195 200 205
Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr Ser Glu
210 215 220
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His Trp Tyr
225 230 235 240
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Val Asp
245 250 255
Leu
<210> 26
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Short hinge linker
<400> 26
Met Asn Lys Thr Ile
1 5
<210> 27
<211> 55
<212> PRT
<213> Artificial Sequence
<220>
<223> Long hinge linker
<400> 27
Asn Asp Phe Ala Cys Thr Cys Glu His Gln Ser Phe Leu Gln Trp Ile
1 5 10 15
Lys Asp Gln Arg Gln Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala
20 25 30
Thr Pro Ser Asp Lys Gln Gly Met Pro Val Leu Ser Leu Asn Ile Thr
35 40 45
Cys Gln Met Asn Lys Thr Ile
50 55
<210> 28
<211> 327
<212> PRT
<213> Homo sapiens
<400> 28
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 29
<211> 12
<212> PRT
<213> Homo sapiens
<400> 29
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 30
<211> 119
<212> PRT
<213> Homo sapiens
<400> 30
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gln Pro Arg
1 5 10 15
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
20 25 30
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
35 40 45
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
50 55 60
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
65 70 75 80
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
85 90 95
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
100 105 110
Leu Ser Leu Ser Leu Gly Lys
115
<210> 31
<211> 228
<212> PRT
<213> Homo sapiens
<400> 31
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Pro Val
1 5 10 15
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr
65 70 75 80
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
180 185 190
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Leu Gly Lys
225
<210> 32
<211> 235
<212> PRT
<213> Homo sapiens
<400> 32
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Ser Gln Phe Arg Val Ser Pro Leu Asp Arg Thr
20 25 30
Trp Asn Leu Gly Glu Thr Val Glu Leu Lys Cys Gln Val Leu Leu Ser
35 40 45
Asn Pro Thr Ser Gly Cys Ser Trp Leu Phe Gln Pro Arg Gly Ala Ala
50 55 60
Ala Ser Pro Thr Phe Leu Leu Tyr Leu Ser Gln Asn Lys Pro Lys Ala
65 70 75 80
Ala Glu Gly Leu Asp Thr Gln Arg Phe Ser Gly Lys Arg Leu Gly Asp
85 90 95
Thr Phe Val Leu Thr Leu Ser Asp Phe Arg Arg Glu Asn Glu Gly Tyr
100 105 110
Tyr Phe Cys Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe
115 120 125
Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg
130 135 140
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
145 150 155 160
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
165 170 175
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
180 185 190
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His
195 200 205
Arg Asn Arg Arg Arg Val Cys Lys Cys Pro Arg Pro Val Val Lys Ser
210 215 220
Gly Asp Lys Pro Ser Leu Ser Ala Arg Tyr Val
225 230 235
<210> 33
<211> 68
<212> PRT
<213> Artificial Sequence
<220>
<223> Mutated CD8 hinge
<400> 33
Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val
1 5 10 15
Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
20 25 30
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
35 40 45
Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
50 55 60
Ala Ser Asp Ile
65
<210> 34
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> GS linker
<400> 34
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 35
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1-ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS-Linker
<220>
<221> MISC_FEATURE
<222> (291)..(313)
<223> TLR4-Transmembrane domain
<220>
<221> MISC_FEATURE
<222> (314)..(496)
<223> TLR4-Cytosolic domain
<400> 35
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ile Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val
290 295 300
Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly
305 310 315 320
Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp Ala Phe Val Ile
325 330 335
Tyr Ser Ser Gln Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn
340 345 350
Leu Glu Glu Gly Val Pro Pro Phe Gln Leu Cys Leu His Tyr Arg Asp
355 360 365
Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile His Glu Gly Phe
370 375 380
His Lys Ser Arg Lys Val Ile Val Val Val Ser Gln His Phe Ile Gln
385 390 395 400
Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala Gln Thr Trp Gln Phe
405 410 415
Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu Gln Lys Val Glu
420 425 430
Lys Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr Arg Leu Leu Ser Arg
435 440 445
Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His Ile Phe
450 455 460
Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro
465 470 475 480
Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu Ala Thr Ser Ile
485 490 495
<210> 36
<211> 500
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1-ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS-Linker
<220>
<221> MISC_FEATURE
<222> (291)..(295)
<223> LRR Short Hinge
<220>
<221> MISC_FEATURE
<222> (296)..(318)
<223> TLR4 transmembrane domain
<220>
<221> MISC_FEATURE
<222> (319)..(500)
<223> TLR4 cytosolic domain
<400> 36
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Met Asn Lys Thr Ile Ile Gly Val Ser Val Leu Ser Val Leu
290 295 300
Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu
305 310 315 320
Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr
325 330 335
Asp Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val Arg Asn
340 345 350
Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln Leu Cys
355 360 365
Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile
370 375 380
Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val Val Ser
385 390 395 400
Gln His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala
405 410 415
Gln Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val
420 425 430
Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr
435 440 445
Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu
450 455 460
Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly
465 470 475 480
Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln
485 490 495
Glu Ala Thr Ser
500
<210> 37
<211> 551
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Singal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1-ScFv
<220>
<221> MISC_FEATURE
<222> (269)..(551)
<223> TLR4 cytosolic domain
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS-Linker
<220>
<221> MISC_FEATURE
<222> (291)..(345)
<223> LRR long hinge
<220>
<221> MISC_FEATURE
<222> (346)..(368)
<223> TLR4 transmembrane domain
<400> 37
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Asn Asp Phe Ala Cys Thr Cys Glu His Gln Ser Phe Leu Gln
290 295 300
Trp Ile Lys Asp Gln Arg Gln Leu Leu Val Glu Val Glu Arg Met Glu
305 310 315 320
Cys Ala Thr Pro Ser Asp Lys Gln Gly Met Pro Val Leu Ser Leu Asn
325 330 335
Ile Thr Cys Gln Met Asn Lys Thr Ile Ile Gly Val Ser Val Leu Ser
340 345 350
Val Leu Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe
355 360 365
His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn
370 375 380
Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val
385 390 395 400
Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln
405 410 415
Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala
420 425 430
Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val
435 440 445
Val Ser Gln His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu
450 455 460
Ile Ala Gln Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe
465 470 475 480
Ile Val Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu
485 490 495
Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser
500 505 510
Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu
515 520 525
Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn
530 535 540
Trp Gln Glu Ala Thr Ser Ile
545 550
<210> 38
<211> 508
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(302)
<223> IgG4 short hinge
<220>
<221> MISC_FEATURE
<222> (303)..(325)
<223> TLR4 transmembrane domain
<220>
<221> MISC_FEATURE
<222> (326)..(508)
<223> TLR4 cytosolic domain
<400> 38
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ile Gly
290 295 300
Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala Val Leu Val
305 310 315 320
Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr
325 330 335
Gly Arg Gly Glu Asn Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gln
340 345 350
Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly
355 360 365
Val Pro Pro Phe Gln Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly
370 375 380
Val Ala Ile Ala Ala Asn Ile Ile His Glu Gly Phe His Lys Ser Arg
385 390 395 400
Lys Val Ile Val Val Val Ser Gln His Phe Ile Gln Ser Arg Trp Cys
405 410 415
Ile Phe Glu Tyr Glu Ile Ala Gln Thr Trp Gln Phe Leu Ser Ser Arg
420 425 430
Ala Gly Ile Ile Phe Ile Val Leu Gln Lys Val Glu Lys Thr Leu Leu
435 440 445
Arg Gln Gln Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu
450 455 460
Glu Trp Glu Asp Ser Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu
465 470 475 480
Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val
485 490 495
Gly Thr Gly Cys Asn Trp Gln Glu Ala Thr Ser Ile
500 505
<210> 39
<211> 615
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(409)
<223> IgG4 medium hinge
<220>
<221> MISC_FEATURE
<222> (410)..(432)
<223> TLR4 transmembrane domain
<220>
<221> MISC_FEATURE
<222> (433)..(615)
<223> TLR4 cytosolic domain
<400> 39
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gln
290 295 300
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
305 310 315 320
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
325 330 335
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
340 345 350
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
355 360 365
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Gly Val Ser Val Leu Ser
405 410 415
Val Leu Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe
420 425 430
His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn
435 440 445
Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val
450 455 460
Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln
465 470 475 480
Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala
485 490 495
Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val
500 505 510
Val Ser Gln His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu
515 520 525
Ile Ala Gln Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe
530 535 540
Ile Val Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu
545 550 555 560
Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser
565 570 575
Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu
580 585 590
Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn
595 600 605
Trp Gln Glu Ala Thr Ser Ile
610 615
<210> 40
<211> 724
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(518)
<223> IgG4 long hinge
<220>
<221> MISC_FEATURE
<222> (519)..(541)
<223> TLR4 transmembrane domain
<220>
<221> MISC_FEATURE
<222> (542)..(724)
<223> TLR4 cytosolic domain
<400> 40
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
290 295 300
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
305 310 315 320
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
325 330 335
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
340 345 350
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln
355 360 365
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
370 375 380
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
385 390 395 400
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
405 410 415
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
420 425 430
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
435 440 445
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
450 455 460
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
465 470 475 480
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
485 490 495
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
500 505 510
Ser Leu Ser Leu Gly Lys Ile Gly Val Ser Val Leu Ser Val Leu Val
515 520 525
Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met
530 535 540
Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp
545 550 555 560
Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val Arg Asn Glu
565 570 575
Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln Leu Cys Leu
580 585 590
His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile
595 600 605
His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val Val Ser Gln
610 615 620
His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala Gln
625 630 635 640
Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu
645 650 655
Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr Arg
660 665 670
Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly
675 680 685
Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys
690 695 700
Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu
705 710 715 720
Ala Thr Ser Ile
<210> 41
<211> 564
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linkder
<220>
<221> MISC_FEATURE
<222> (291)..(358)
<223> Mutated CD8 hinge
<220>
<221> MISC_FEATURE
<222> (359)..(381)
<223> TLR4 transmembrane domain
<220>
<221> MISC_FEATURE
<222> (382)..(564)
<223> TLR4 cytosolic domain
<400> 41
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val
290 295 300
Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
305 310 315 320
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
325 330 335
Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
340 345 350
Asp Phe Ala Ser Asp Ile Ile Gly Val Ser Val Leu Ser Val Leu Val
355 360 365
Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met
370 375 380
Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp
385 390 395 400
Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val Arg Asn Glu
405 410 415
Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln Leu Cys Leu
420 425 430
His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile
435 440 445
His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val Val Ser Gln
450 455 460
His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala Gln
465 470 475 480
Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu
485 490 495
Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr Arg
500 505 510
Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly
515 520 525
Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys
530 535 540
Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu
545 550 555 560
Ala Thr Ser Ile
<210> 42
<211> 564
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Sginal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(358)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (359)..(381)
<223> TLR4 transmembrane domain
<220>
<221> MISC_FEATURE
<222> (382)..(564)
<223> TLR4 cytosolic domain
<400> 42
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val
290 295 300
Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
305 310 315 320
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
325 330 335
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
340 345 350
Asp Phe Ala Cys Asp Ile Ile Gly Val Ser Val Leu Ser Val Leu Val
355 360 365
Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met
370 375 380
Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp
385 390 395 400
Ala Phe Val Ile Tyr Ser Ser Gln Asp Glu Asp Trp Val Arg Asn Glu
405 410 415
Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln Leu Cys Leu
420 425 430
His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile
435 440 445
His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val Val Ser Gln
450 455 460
His Phe Ile Gln Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala Gln
465 470 475 480
Thr Trp Gln Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu
485 490 495
Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr Arg
500 505 510
Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly
515 520 525
Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys
530 535 540
Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu
545 550 555 560
Ala Thr Ser Ile
<210> 43
<211> 378
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(311)
<223> FCGR3A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (312)..(336)
<223> FCGR3A cytosolic domain
<220>
<221> MISC_FEATURE
<222> (337)..(378)
<223> FCER1G cytosolic domain
<400> 43
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp
290 295 300
Thr Gly Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg
305 310 315 320
Asp Trp Lys Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys
325 330 335
Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys
340 345 350
Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr
355 360 365
Glu Thr Leu Lys His Glu Lys Pro Pro Gln
370 375
<210> 44
<211> 446
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(358)
<223> Modified CD8a linker
<220>
<221> MISC_FEATURE
<222> (359)..(379)
<223> FCGR3A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (380)..(404)
<223> FCGR3A cytosolic domain
<220>
<221> MISC_FEATURE
<222> (405)..(446)
<223> FCER1G cytosolic domain
<400> 44
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val
290 295 300
Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
305 310 315 320
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
325 330 335
Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
340 345 350
Asp Phe Ala Ser Asp Ile Val Ser Phe Cys Leu Val Met Val Leu Leu
355 360 365
Phe Ala Val Asp Thr Gly Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg
370 375 380
Ser Ser Thr Arg Asp Trp Lys Asp His Lys Phe Lys Trp Arg Lys Asp
385 390 395 400
Pro Gln Asp Lys Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr
405 410 415
Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn
420 425 430
Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
435 440 445
<210> 45
<211> 446
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(358)
<223> Portion of CD8 hinge
<220>
<221> MISC_FEATURE
<222> (359)..(379)
<223> FCGR3A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (380)..(404)
<223> FCGR3A cytosolic domain
<220>
<221> MISC_FEATURE
<222> (405)..(446)
<223> FCER1G cytosolic domain
<400> 45
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val
290 295 300
Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
305 310 315 320
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
325 330 335
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
340 345 350
Asp Phe Ala Cys Asp Ile Val Ser Phe Cys Leu Val Met Val Leu Leu
355 360 365
Phe Ala Val Asp Thr Gly Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg
370 375 380
Ser Ser Thr Arg Asp Trp Lys Asp His Lys Phe Lys Trp Arg Lys Asp
385 390 395 400
Pro Gln Asp Lys Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Thr
405 410 415
Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg Asn
420 425 430
Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
435 440 445
<210> 46
<211> 391
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(303)
<223> IgG4 short hinge
<220>
<221> MISC_FEATURE
<222> (304)..(324)
<223> FCGR3A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (325)..(349)
<223> FCGR3A cytosolic domain
<220>
<221> MISC_FEATURE
<222> (350)..(391)
<223> FCER1G cytosolic domain
<400> 46
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ile Val
290 295 300
Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly Leu
305 310 315 320
Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp Lys
325 330 335
Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys Arg Leu Lys
340 345 350
Ile Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly
355 360 365
Val Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu
370 375 380
Lys His Glu Lys Pro Pro Gln
385 390
<210> 47
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linkder
<220>
<221> MISC_FEATURE
<222> (291)..(409)
<223> IgG4 119 aa hinge
<220>
<221> MISC_FEATURE
<222> (410)..(430)
<223> FCGR3A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (431)..(455)
<223> FCGR3A cytosolic domain
<220>
<221> MISC_FEATURE
<222> (456)..(497)
<223> FCER1G cytosolic domain
<400> 47
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gln
290 295 300
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
305 310 315 320
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
325 330 335
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
340 345 350
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
355 360 365
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Ser Leu Ser Leu Ser Leu Gly Lys Val Ser Phe Cys Leu Val Met
405 410 415
Val Leu Leu Phe Ala Val Asp Thr Gly Leu Tyr Phe Ser Val Lys Thr
420 425 430
Asn Ile Arg Ser Ser Thr Arg Asp Trp Lys Asp His Lys Phe Lys Trp
435 440 445
Arg Lys Asp Pro Gln Asp Lys Arg Leu Lys Ile Gln Val Arg Lys Ala
450 455 460
Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser
465 470 475 480
Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro
485 490 495
Gln
<210> 48
<211> 607
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric angtigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(519)
<223> IgG4 long hinge
<220>
<221> MISC_FEATURE
<222> (520)..(540)
<223> FCGR3A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (541)..(565)
<223> FCGR3A cytosolic domain
<220>
<221> MISC_FEATURE
<222> (566)..(607)
<223> FCER1G cytosolic domain
<400> 48
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
290 295 300
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
305 310 315 320
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
325 330 335
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
340 345 350
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln
355 360 365
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
370 375 380
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
385 390 395 400
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
405 410 415
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
420 425 430
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
435 440 445
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
450 455 460
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
465 470 475 480
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
485 490 495
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
500 505 510
Ser Leu Ser Leu Gly Lys Ile Val Ser Phe Cys Leu Val Met Val Leu
515 520 525
Leu Phe Ala Val Asp Thr Gly Leu Tyr Phe Ser Val Lys Thr Asn Ile
530 535 540
Arg Ser Ser Thr Arg Asp Trp Lys Asp His Lys Phe Lys Trp Arg Lys
545 550 555 560
Asp Pro Gln Asp Lys Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile
565 570 575
Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr Arg
580 585 590
Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
595 600 605
<210> 49
<211> 390
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(312)
<223> FCGR2A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (313)..(390)
<223> FCGR2A cytosolic domain
<400> 49
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ile Ile Val Ala Val Val Ile Ala Thr Ala Val Ala Ala Ile
290 295 300
Val Ala Ala Val Val Ala Leu Ile Tyr Cys Arg Lys Lys Arg Ile Ser
305 310 315 320
Ala Asn Ser Thr Asp Pro Val Lys Ala Ala Gln Phe Glu Pro Pro Gly
325 330 335
Arg Gln Met Ile Ala Ile Arg Lys Arg Gln Leu Glu Glu Thr Asn Asn
340 345 350
Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met Thr Leu Asn Pro Arg Ala
355 360 365
Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu Thr Leu Pro Pro Asn Asp
370 375 380
His Val Asn Ser Asn Asn
385 390
<210> 50
<211> 458
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(358)
<223> Modified CD8a hinge
<220>
<221> MISC_FEATURE
<222> (359)..(380)
<223> FCGR2A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (381)..(458)
<223> FCGR2A cytosolic domain
<400> 50
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val
290 295 300
Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
305 310 315 320
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
325 330 335
Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
340 345 350
Asp Phe Ala Ser Asp Ile Ile Ile Val Ala Val Val Ile Ala Thr Ala
355 360 365
Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr Cys Arg Lys
370 375 380
Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala Gln Phe
385 390 395 400
Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln Leu Glu
405 410 415
Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met Thr Leu
420 425 430
Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu Thr Leu
435 440 445
Pro Pro Asn Asp His Val Asn Ser Asn Asn
450 455
<210> 51
<211> 458
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(358)
<223> Portion of CD8a linker
<220>
<221> MISC_FEATURE
<222> (359)..(380)
<223> FCGR2A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (381)..(458)
<223> FCGR2A cytosolic domain
<400> 51
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val
290 295 300
Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
305 310 315 320
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
325 330 335
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
340 345 350
Asp Phe Ala Cys Asp Ile Ile Ile Val Ala Val Val Ile Ala Thr Ala
355 360 365
Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr Cys Arg Lys
370 375 380
Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala Gln Phe
385 390 395 400
Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln Leu Glu
405 410 415
Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met Thr Leu
420 425 430
Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu Thr Leu
435 440 445
Pro Pro Asn Asp His Val Asn Ser Asn Asn
450 455
<210> 52
<211> 403
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(303)
<223> IgG4 short hinge
<220>
<221> MISC_FEATURE
<222> (304)..(325)
<223> FCGR2A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (326)..(403)
<223> FCGR2A cytosolic domain
<400> 52
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ile Ile
290 295 300
Ile Val Ala Val Val Ile Ala Thr Ala Val Ala Ala Ile Val Ala Ala
305 310 315 320
Val Val Ala Leu Ile Tyr Cys Arg Lys Lys Arg Ile Ser Ala Asn Ser
325 330 335
Thr Asp Pro Val Lys Ala Ala Gln Phe Glu Pro Pro Gly Arg Gln Met
340 345 350
Ile Ala Ile Arg Lys Arg Gln Leu Glu Glu Thr Asn Asn Asp Tyr Glu
355 360 365
Thr Ala Asp Gly Gly Tyr Met Thr Leu Asn Pro Arg Ala Pro Thr Asp
370 375 380
Asp Asp Lys Asn Ile Tyr Leu Thr Leu Pro Pro Asn Asp His Val Asn
385 390 395 400
Ser Asn Asn
<210> 53
<211> 509
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK1 ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(409)
<223> IgG4 119 aa hinge
<220>
<221> MISC_FEATURE
<222> (410)..(431)
<223> FCGR2A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (432)..(509)
<223> FCGR2A cytosolic domain
<400> 53
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gln
290 295 300
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
305 310 315 320
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
325 330 335
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
340 345 350
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
355 360 365
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Ile Val Ala Val Val Ile
405 410 415
Ala Thr Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr
420 425 430
Cys Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala
435 440 445
Ala Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg
450 455 460
Gln Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr
465 470 475 480
Met Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr
485 490 495
Leu Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn
500 505
<210> 54
<211> 619
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimeric antigen receptor
<220>
<221> SIGNAL
<222> (1)..(18)
<223> Signal peptide
<220>
<221> MISC_FEATURE
<222> (19)..(275)
<223> TK! ScFv
<220>
<221> MISC_FEATURE
<222> (276)..(290)
<223> GS linker
<220>
<221> MISC_FEATURE
<222> (291)..(519)
<223> IgG4 long hinge
<220>
<221> MISC_FEATURE
<222> (520)..(541)
<223> FCGR2A transmembrane domain
<220>
<221> MISC_FEATURE
<222> (542)..(619)
<223> FCGR2A cytosolic domain
<400> 54
Met Asp Phe Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Phe Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Met Ala Val Val Thr Gly Val Asn Ser Glu Val Gln Leu Gln Gln Ser
145 150 155 160
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys Gln
180 185 190
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
195 200 205
Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
210 215 220
Thr Asp Thr Ser Phe Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr
225 230 235 240
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Gly Tyr Gly His
245 250 255
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
260 265 270
Val Asp Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
275 280 285
Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
290 295 300
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
305 310 315 320
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
325 330 335
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
340 345 350
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln
355 360 365
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
370 375 380
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
385 390 395 400
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
405 410 415
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
420 425 430
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
435 440 445
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
450 455 460
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
465 470 475 480
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
485 490 495
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
500 505 510
Ser Leu Ser Leu Gly Lys Ile Ile Ile Val Ala Val Val Ile Ala Thr
515 520 525
Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr Cys Arg
530 535 540
Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala Gln
545 550 555 560
Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln Leu
565 570 575
Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met Thr
580 585 590
Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu Thr
595 600 605
Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn
610 615
Claims (21)
- 세포질 도메인;
막관통 도메인; 및
세포외 도메인을 포함하며;
여기서 세포질 도메인은 활성화될 때 대식세포를 분극시키는 수용체의 세포질 부분을 포함하고;
여기서 세포질 부분을 포함하는 야생형 단백질은 세포외 도메인을 포함하지 않는 키메라 수용체. - 제1항에 있어서, 세포외 도메인에 대한 리간드의 결합이 세포질 부분을 활성화시키는 키메라 수용체.
- 제1항에 있어서, 세포질 부분이 활성화되는 경우에 그것이 대식세포를 M1 대식세포로 분극시키는 키메라 수용체.
- 제1항에 있어서, 세포질 부분이 활성화되는 경우에 그것이 대식세포를 M2 대식세포로 분극시키는 키메라 수용체.
- 제1항에 있어서, 세포질 부분이 toll-유사 수용체, 골수 분화 1차 반응 단백질(MYD88), toll-유사 수용체 3(TLR3), toll-유사 수용체 4(TLR4), toll-유사 수용체 7(TLR7), toll-유사 수용체 8(TLR8), toll-유사 수용체 9(TLR9), 미엘린 및 림프구 단백질(MAL), 인터류킨-1 수용체-관련 키나제 1(IRAK1), 저친화도 면역글로불린 감마 Fc 영역 수용체 III-A(FCGR3A), 저친화도 면역글로불린 감마 Fc 영역 수용체 II-a(FCGR2A), 및 고친화도 면역글로불린 엡실론 수용체 서브유닛 감마(FCER1G)로부터의 세포질 도메인을 포함하는 키메라 수용체.
- 제2항에 있어서, 리간드가 티미딘 키나제(TK1), 하이포잔틴-구아닌 포스포리보실트랜스페라제(HPRT), 수용체 티로신 키나제-유사 오르펀 수용체 1(ROR1), 뮤신-16(MUC-16), 상피세포 성장 인자 수용체 vIII(EGFRvIII), 메소텔린, 인간 상피세포 성장 인자 수용체 2(HER2), 암종배아 항원(CEA), B-세포 성숙 항원(BCMA), 글리피칸 3(GPC3), 섬유아세포 활성화 단백질(FAP), 에리트로포이에틴-생성 간세포 암종 A2(EphA2), 자연 살해 군 2D(NKG2D) 리간드, 다이시알로강글리오사이드 2(GD2), CD19, CD20, CD30, CD33, CD123, CD133, CD138, 및 CD171로 이루어진 군으로부터 선택되는 키메라 수용체.
- 제1항에 있어서, 세포외 도메인이 티미딘 키나제(TK1), 하이포잔틴-구아닌 포스포리보실트랜스페라제(HPRT), 수용체 티로신 키나제-유사 오르펀 수용체 1(ROR1), 뮤신-16(MUC-16), 상피세포 성장 인자 수용체 vIII(EGFRvIII), 메소텔린, 인간 상피세포 성장 인자 수용체 2(HER2), 암종배아 항원(CEA), B-세포 성숙 항원(BCMA), 글리피칸 3(GPC3), 섬유아세포 활성화 단백질(FAP), 에리트로포이에틴-생성 간세포 암종 A2(EphA2), 자연 살해 군 2D(NKG2D) 리간드, 다이시알로강글리오사이드 2(GD2), CD19, CD20, CD30, CD33, CD123, CD133, CD138, 및 CD171로 이루어진 군으로부터 선택된 리간드에 특이적인 항체 또는 이의 단편인 키메라 수용체.
- 제7항에 있어서, 항체 또는 이의 단편이 ScFv 단편인 키메라 수용체.
- 제1항에 있어서, 막관통 도메인과 세포외 도메인 사이에 링커를 추가로 포함하는 키메라 수용체.
- 제9항에 있어서, 링커가 GS 링커인 키메라 수용체.
- 제1항에 있어서, 막관통 도메인과 세포외 도메인 사이에 힌지 영역을 추가로 포함하는 키메라 수용체.
- 제9항에 있어서, 막관통 도메인과 링커 사이에 힌지 영역을 추가로 포함하는 키메라 수용체.
- 제1항의 키메라 수용체를 암호화하는 폴리뉴클레오티드를 포함하는 핵산.
- 제13항에 있어서, 폴리뉴클레오티드에 작동가능하게 연결된 프로모터를 추가로 포함하는 핵산.
- 제13항의 핵산을 포함하는 벡터.
- 제15항에 있어서, 렌티바이러스 벡터인 벡터.
- 제1항의 키메라 수용체를 포함하는 세포.
- 제15항에 있어서, 단핵구 또는 대식세포인 세포.
- 제13항의 핵산을 포함하는 세포.
- 제19항에 있어서, 단핵구 또는 대식세포인 세포.
- 제1항의 키메라 수용체를 포함하는 대식세포를 키메라 수용체의 세포외 도메인에 대한 리간드와 접촉시키는 단계; 및
리간드를 키메라 수용체의 세포외 도메인에 결합시키는 단계를 포함하며;
여기서 키메라 수용체의 세포외 도메인에 대한 리간드의 결합은 세포질 부분을 활성화시키고;
여기서 세포질 부분의 활성화는 대식세포를 분극시키는, 대식세포를 분극시키는 방법.
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| US11352439B2 (en) | 2015-08-13 | 2022-06-07 | Kim Leslie O'Neill | Macrophage CAR (MOTO-CAR) in immunotherapy |
| CN110036033B (zh) | 2016-09-27 | 2023-12-08 | 森罗治疗公司 | 嵌合吞噬受体分子 |
| US10415017B2 (en) | 2017-05-17 | 2019-09-17 | Thunder Biotech, Inc. | Transgenic macrophages, chimeric antigen receptors, and associated methods |
| CN109336980B (zh) * | 2017-07-27 | 2022-04-12 | 上海细胞治疗研究院 | 一种靶向Muc1的嵌合抗原受体修饰T细胞及其用途 |
| KR20200100598A (ko) | 2017-09-26 | 2020-08-26 | 세로 테라퓨틱스, 인코포레이티드 | 키메라 포식작용 수용체 분자 및 사용 방법 |
| CN114651003A (zh) | 2019-09-10 | 2022-06-21 | 黑曜石疗法公司 | 用于可调调节的ca2-il15融合蛋白 |
| CN113980138B (zh) * | 2021-08-11 | 2023-08-11 | 卡瑞济(北京)生命科技有限公司 | EphA2嵌合抗原受体以及其用途 |
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