KR20190117603A - 신규 vegfr-2 표적화 면역요법상 접근법 - Google Patents
신규 vegfr-2 표적화 면역요법상 접근법 Download PDFInfo
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Abstract
본 발명은 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이다. 본 발명은 또한 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이기도 한데, 다만 이 암은 교모세포종, 유암종, 신장암, 구체적으로 신세포암종, 갑상선암, 폐암, 구체적으로 비소세포 폐암(NSCLC), 유방암, 난소암, 전립선암, 위장관암, 구체적으로 결장직장암, 더욱 구체적으로 결장암, 그리고 피부암, 구체적으로 흑색종으로 이루어진 군으로부터 선택된다. 본 발명은 또한 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, VEGF 수용체 단백질 발현 암세포 적어도 하나를 포함하는 환자를 대상으로 하는 암 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이기도 하다.
Description
본 발명은 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라(Salmonella) 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이다. 본 발명은 또한 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이기도 한데, 다만 이 암은 교모세포종, 유암종, 신장암, 구체적으로 신세포암종, 갑상선암, 폐암, 구체적으로 비소세포 폐암(NSCLC), 유방암, 난소암, 전립선암, 위장관암, 구체적으로 결장직장암, 더욱 구체적으로 결장암, 그리고 피부암, 구체적으로 흑색종으로 이루어진 군으로부터 선택된다. 본 발명은 또한 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, VEGF 수용체 단백질 발현 암세포 적어도 하나를 포함하는 환자를 대상으로 하는 암 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이기도 하다.
혈관신생은 고형 종양 성장 및 전이를 초래하는 주요 요인이다. 혈관내피성장인자수용체(VEGFR) 2(KDR 또는 Flk-1으로도 공지됨)는 혈관내피성장인자(VEGFR)에 대한 고친화성 수용체로서, 증식, 이동 및 혈관생성을 포함하여 모든 주요 내피 기능에 연루되어 있는 것으로 보아 고형 종양의 혈관신생에 대한 주요 매개체인 것으로 생각된다. 종양 신생혈관계의 내부는, VEGFR-2를 과발현하고 혈류를 통해 용이하게 접근 가능한 내피 세포들이 감싸고 있다. 이러한 세포의 유전적 안정성과, 하나당 수백개의 종양 세포를 지지하는 내피 세포의 능력은, 이 내피 세포를 항암 치료법, 즉 항체, 티로신 키나아제 억제제 또는 백신을 통한 항암 치료법의 주된 표적이 되게끔 해준다(Augustin, Trends Pharmacol Sci 1998,19:216-222). 현재까지 VEGF/VEGFR2 신호전달 경로는 다수 항혈관신생의 치료적 접근법에서 표적화되어 왔다. 종양 신생혈관계를 특이적으로 표적화하는 화합물, 예컨대 베바시주맙 및 기타의 것, 예를 들어 소분자, 예컨대 수니티닙 및 액시티닙은 다양한 종양의 적응증에서 효능을 보였다(Powles et al., Br J Cancer 2011,104(5):741-5); Rini et al., Lancet 2011, 378:1931-1939).
WO 2014/005683에는, VEGF 수용체 단백질을 암호화하는 재조합 DNA 분자를 포함하는 살모넬라 약독화 돌연변이 균주로서, 암 면역요법, 구체적으로 췌장암 치료에 사용하기 위한 살모넬라 약독화 돌연변이 균주가 개시되어 있다.
WO 2016/202459에는, VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암 치료법, 즉 추가의 함암제 적어도 하나를 투여하는 단계를 추가로 포함하는 암 치료법에 사용하기 위한 살모넬라 약독화 균주가 개시되어 있다.
WO 2013/09189에는, 갈락토스 에피머라아제 활성이 결여되었고, 재조합 DNA 분자를 보유하고 있는 약독화 돌연변이 살모넬라 타이피(Salmonella typhi) 균주를 생육하기 위한 방법이 개시되어 있다.
VEGF 수용체는 오랫동안 악성종양 혈관계, 즉 종양 기질(tumor stroma)에만 제한되어 발현되는 것으로 추정되어 왔다. 그러나 최근의 발현 분석은 종양 세포 자체에 혈관내피성장인자수용체, 구체적으로 VEGFR-2가 발현됨을 규명하였다. 종양 특이적 VEGF 수용체 발현은 다양한 기원의 암세포에서 관찰되었다. 이 점은, VEGF가 신생혈관생성을 촉진하는 이외에 종양발생에 있어서 추가의 영향을 줄 수 있음을 나타낸다.
VEGF 수용체를 표적화하는, 신규의 안전하고 효율적인 암 면역요법상 접근법을 제공하는 것이 본 발명의 목적이다. 이러한 신규의 치료적 접근법은 암 환자를 위한 치료 선택권을 개선한다는 주요 이점을 제공할 것이다.
최근의 발현 분석은, 다양한 기원의 암세포에 혈관내피성장인자수용체, 구체적으로 VEGFR-2가 종양 특이적으로 발현됨을 규명하였다. 그러나 종양 특이적 VEGF 수용체 발현의 생물학적 역할은 아직 불분명한 실정이다. 교모세포종에 대한 VEGFR-2 발현의 영향력에 관한 가용 데이터는 논란이 많다. 그러나 Kessler외 다수는, 신경교종 세포 내 VEGFR-2의 발현은 신경교종 세포의 증식을 유도하고, 다양한 화학요법에 대한 신경교종 세포의 내성을 증가시킨다고 보고하였으며(Oncotarget, 2015), Lu외 다수는, VEGF가 VEGFR-2를 통하여 종양 세포 침습을 직접적이면서 음성적으로 조절한다는 것을 발견하였다(Cancer Cell, 2012).
본 발명은, VEGF 수용체를 표적화하는 살모넬라 기반 DNA 백신은, 오로지 종양 혈관계에서 VEGFR 수용체 발현만을 보이는 종양보다는 (선택적으로는 종양 혈관계에서의 VEGF 수용체 발현에 더하여) 종양 특이적 VEGF 수용체 발현을 보이는 종양에 특히 효율적이라는 놀라운 발견에 바탕을 두고 있다. 본 발명의 내용 중 "종양 특이적 VEGF 수용체 발현"이란 용어는, 종양 혈관계에서가 아닌 종양 세포 자체에서의 VEGF 수용체 발현을 지칭한다.
그러므로 제1 양태에서, 본 발명은 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이다.
제2 양태에서, 본 발명은 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것인데, 다만 이 암은 교모세포종, 유암종, 신장암, 구체적으로 신세포암종, 갑상선암, 폐암, 구체적으로 비소세포 폐암(NSCLC), 유방암, 난소암, 전립선암, 위장관암, 구체적으로 결장직장암, 더욱 구체적으로 결장암, 그리고 피부암, 구체적으로 흑색종으로 이루어진 군으로부터 선택된다.
제3 양태에서, 본 발명은 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, VEGF 수용체 단백질 발현 암세포 적어도 하나를 포함하는 환자를 대상으로 하는 암 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이다.
특정 구현예들에서, 살모넬라의 약독화 균주는 살모넬라 엔테리카(Salmonella enterica) 종이다. 구체적으로 살모넬라 약독화 균주는 살모넬라 타이피 Ty21a이다.
특정 구현예들에서, 발현 카세트는 진핵생물 발현 카세트이다. 구체적으로 발현 카세트는 CMV 프로모터를 포함한다.
특정 구현예들에서, VEGF 수용체 단백질은 VEGFR-2, 구체적으로 인간 VEGFR-2이다. 구체적으로 VEGF 수용체 단백질은 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2 및 이것과 적어도 80%의 서열 동일성을 공유하는 단백질로 이루어진 군으로부터 선택된다. 구체적으로 VEGF 수용체 단백질은 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가진다.
특정 구현예들에서, DNA 분자는 카나마이신 항생제 내성 유전자, pMB1 ori 및 CMV 프로모터를 포함한다. 이러한 특정 구현예들에서, DNA 분자는 서열 번호 2에서 발견되는 바와 같은 DNA 서열을 포함한다.
특정 구현예들에서, 암 면역요법은 화학요법, 방사선요법 또는 생물학적 암 치료법이 동반된다. 이러한 특정 구현예들에서, 살모넬라 약독화 균주는 화학요법 또는 방사선요법 치료 또는 생물학적 암 치료법이 수행되기 전, 수행되는 도중 또는 수행된 후에 투여되거나, 화학요법 또는 방사선요법 치료 또는 생물학적 암 치료법이 수행되기 전 및 수행되는 도중에 투여된다.
특정 구현예들에서, 생물학적 암 치료법은, 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가의 DNA 백신 적어도 하나를 투여하는 것을 포함한다. 이러한 특정 구현예들에서, 상기 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가의 DNA 백신 적어도 하나는 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가의 발현 카세트를 포함하는 추가의 DNA 분자 복사체 적어도 하나를 포함하는, 살모넬라의 추가 약독화 균주 적어도 하나로부터 선택된다. 구체적으로 상기 살모넬라의 추가 약독화 균주 적어도 하나는 추가의 진핵생물 발현 카세트를 포함하는 살모넬라 타이피 Ty21a이다.
특정 구현예들에서, 상기 추가의 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 항원은 인간 빌름 종양 단백질(Wilms' Tumor Protein; WT1), 인간 메소텔린(MSLN), CEA 및 CMV pp65로 이루어진 군으로부터 선택된다. 구체적으로 상기 추가의 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 항원은, 서열 번호 3에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 빌름 종양 단백질(WT1) 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 4에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 메소텔린(MSLN) 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 5에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 CEA 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 6에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 7에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 그리고 서열 번호 8에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질로 이루어진 군으로부터 선택된다. 구체적으로 인간 빌름 종양 단백질(WT1)은 서열 번호 3에서 발견되는 바와 같은 아미노산 서열을 가지고, 인간 메소텔린(MSLN)은 서열 번호 4에서 발견되는 바와 같은 아미노산 서열을 가지며, 인간 CEA는 서열 번호 5에서 발견되는 바와 같은 아미노산 서열을 가지고, CMV pp65는 서열 번호 6, 서열 번호 7 또는 서열 번호 8에서 발견되는 바와 같은 아미노산 서열을 가진다. 특정 구현예들에서, 상기 추가의 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 기질 항원은 인간 섬유아세포 활성화 단백질(FAP)로 이루어진 군으로부터 선택된다.
특정 구현예들에서, 살모넬라 약독화 균주는 경구 투여된다.
특정 구현예들에서, 살모넬라 약독화 균주의 단일 용량은 약 105 내지 약 1011, 구체적으로 약 106 내지 약 1010, 더욱 구체적으로 약 106 내지 약 109, 더욱 구체적으로 약 106 내지 약 108, 가장 구체적으로 약 106 내지 약 107의 콜로니 형성 단위(Colony Forming Unit; CFU)를 포함한다.
특정 구현예들에서, 살모넬라 약독화 균주는, 환자에서 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2의 발현 패턴 및/또는 이에 대한 전면역 반응을 평가하는 단계를 포함하는 개별맞춤 암 면역요법에 사용하기 위한 것이다.
제1 양태에서, 본 발명은 VEGF 수용체 단백질, 구체적으로 VEGFR-2를 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질, 구체적으로 VEGFR-2 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이다.
본 발명의 내용 중 "VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암"이란 용어는, 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2를 mRNA 및/또는 단백질 수준으로 발현하는 암세포의 존재에 의해 특징지어지는 암의 적응증을 지칭한다. 특정 구현예들에서, 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2의 mRNA 및/또는 단백질 수준 발현은, 동일 조직 유형의 비암성 세포에서와 비교되게 증가한다. 예를 들어 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2의 발현은 동일 환자의 동일 조직 유형 비암성 세포에서와 비교되게 증가할 수 있다. 다른 구현예들에서, 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2의 발현은, 건강한 대상체 대표 집단의 동일 조직 비암성 세포에서의 평균 발현과 비교되게 증가할 수 있다. VEGF 수용체 단백질 발현에 의해 특징지어지는 암의 적응증으로서는 무엇보다도 교모세포종, 유암종, 신장암, 구체적으로 신세포암종, 췌장암, 갑상선암, 폐암, 구체적으로 비소세포 폐암(NSCLC), 유방암, 난소암, 전립선암, 위장관암, 구체적으로 결장직장암, 더욱 구체적으로 결장암, 그리고 피부암, 구체적으로 흑색종을 포함한다.
그러므로 제2 양태에서, 본 발명은 VEGF 수용체 단백질, 구체적으로 VEGFR-2를 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포, 구체적으로 VEGFR-2 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이되, 다만 상기 암은 교모세포종, 유암종, 신장암, 구체적으로 신세포암종, 갑상선암, 폐암, 구체적으로 비소세포 폐암(NSCLC), 유방암, 난소암, 전립선암, 위장관암, 구체적으로 결장직장암, 더욱 구체적으로 결장암, 그리고 피부암, 구체적으로 흑색종으로 이루어진 군으로부터 선택된다.
VEGFR-2 표적화 면역요법에 특히 유력한 효능을 보일 적응증 하나는 교모세포종이다. 교모세포종은 매우 왕성한 종양 혈관화를 보인다. 게다가 VEGFR-2는 종양의 혈관계와 종양 세포 둘 다에서 표적화될 수 있다. 교모세포종 환자의 약 20% 내지 약 50%는 종양 특이적 VEGFR-2 발현을 보이는데, 이는 특히 침습 초기에 관찰된다. 더욱이 VEGFR-2 발현은 신경교종 유사 줄기 세포에서 관찰되었다. 지금까지 교모세포종에 대한 치료 선택권은 만족스럽지 못한 단계였다. 예를 들어 VEGF를 표적화하는 모노클로날 항체 아바스틴은 오로지 무진행성 생존에서만 이득을 보였을뿐, 전반적인 생존에는 그렇지 못하였다.
제3 양태에서, 본 발명은 VEGF 수용체 단백질, 구체적으로 VEGFR-2를 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 환자, 즉 VEGF 수용체 단백질 발현 암세포 적어도 하나, 구체적으로 VEGFR-2 발현 암세포 적어도 하나를 포함하는 환자를 대상으로 한 암 면역요법에 사용하기 위한 살모넬라 약독화 균주에 관한 것이다.
본 발명의 특정 구현예들에서, 환자는 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암이 발병하였거나 또는 VEGF 수용체 단백질 발현 암세포 적어도 하나를 가지는 것으로 확정되었다. 첫 번째 단계에서, 환자의 종양 특이적 VEGF 수용체 단백질 발현, 예컨대 VEGFR-2의 종양 특이적 발현은 mRNA 또는 단백질 수준에서, 바람직하게는 시험관 내에서 평가될 수 있다. 이러한 목적으로 종양 조직 시료(예컨대 생검편)는, 예를 들어 면역조직화학적 염색에 의해 염색될 수 있거나, 또는 현장 잡종화의 대상이 될 수 있다. 종양 특이적 항원 발현의 평가를 위한 방법은 당 분야에 널리 공지되어 있다.
본 발명에 따르면 약독화 살모넬라 균주는 VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 재조합 DNA 분자를 표적 세포에 운반하기 위한, 이 같은 재조합 DNA 분자의 세균 운반체로서의 역할을 한다. 이와 같이 이종 항원, 예컨대 VEGF 수용체 단백질을 암호화하는 DNA 분자를 포함하는 운반 벡터는 DNA 백신이라 칭하여진다. 따라서 "~를 암호화하는 DNA 백신"및 "~를 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주"란 용어들은 본원에서 호환되어 사용된다.
본 발명의 내용중 "백신"이란 용어는 투여시 대상체에서 면역 반응을 유도할 수 있는 제제를 지칭한다. 백신은, 바람직하게 질환을 예방, 완화 또는 치료할 수 있다.
본 발명에 따른 약독화 살모넬라 생균주는 VEGF 수용체 단백질을 암호화하는 재조합 DNA 분자를 안정적으로 운반한다. 이는, 이러한 재조합 DNA 분자의 경구 운반을 위한 비이클로서 사용될 수 있다.
유전자 면역화는 종래의 백신화에 비해 유리할 수 있다. 표적 DNA는 상당한 기간 동안 검출될 수 있으므로, 항원의 데포(depot)로서의 역할을 할 수 있다. 몇몇 플라스미드 내 서열 모티프, 예컨대 GpC 섬(GpC island)은 면역자극성으로서, LPS 및 기타 세균 성분으로 말미암은 면역자극에 의해 촉진되는 아주반트(adjuvant)로서의 기능을 수행할 수 있다.
약독화 살모넬라 생 벡터는 자신만의 면역조정 인자, 예컨대 리포다당체(LPS)를 현장에서 생성하는데, 이 점은 다른 투여형, 예컨대 마이크로캡슐에 비한 이점을 이룰 수 있다. 게다가 본 발명에 따른 점막 백신(mucosal vaccine)은 유리한 것으로 입증된 림프내 작용 방식을 가진다. 본 발명에 따른 약독화 백신이 섭취되면, 소장의 페이에르판(Peyer's patch) 내 대식세포와 기타 세포에는 변형된 세균이 침입하게 된다. 이러한 세균은 이들 식세포에 의해 흡수된다. 세균의 약독화 돌연변이로 말미암아, 에스. 타이피 Ty21 균주인 세균은 이러한 식세포 내에서 지속적으로 존재할 수 없게 되고, 이 시점에서 사멸하게 된다. 그 다음 재조합 DNA 분자는 방출되고, 이 재조합 DNA 분자는 특이적인 운반계 또는 엔도좀 누출(endosomal leakage)에 의해 식세포인 면역세포의 세포기질로 이동하게 된다. 마지막으로 재조합 DNA 분자는 핵에 도입되고, 여기에서 이 재조합 DNA 분자는 전사되는 결과, 식세포 세포기질 내 다량의 VEGF 수용체 단백질 발현이 유도된다. 감염된 세포는 VEGF 수용체 단백질 항원을 보유한 채 세포자살을 진행하게 되고, 소장의 면역계에 의해 흡수 및 처리된다. 이 과정에서 세균 감염의 위험 신호는 강력한 아주반트로서 사용되는데, 그 결과 강력한 표적 항원 특이적 CD8+T 세포 및 항체 반응이 전신 및 점막 구획 둘 다의 수준으로 유도된다. 면역 반응은 백신화 이후 약 10일 정도에 최고에 이르게 된다. 항 운반체 반응은 일어나지 않는데, 이로 말미암아 동일한 백신으로 수 회에 걸쳐 면역증강이 달성될 수 있다.
본 발명의 내용중 "약독화된"이란 용어는 어떤 세균 균주의 균독성이 약독화 돌연변이를 가지지 않는 모 세균 균주의 균독성에 비해 감소한 경우를 지칭한다. 약독화 세균 균주는, 바람직하게 균독성은 상실하였지만, 방어적 면역성을 유도하는 능력은 보유하고 있다. 약독화는 균독성, 조절 및 대사 유전자를 포함하는 다양한 유전자의 결실에 의해 달성될 수 있다. 약독화 세균은 자연에서 발견될 수 있거나, 예를 들어 새 배지 또는 세포 배양액에의 적응에 의해 실험실에서 인공적으로 제조될 수 있거나, 또는 재조합 DNA 기술에 의해 제조될 수 있다. 본 발명에 따른 살모넬라 약독화 균주 약 1011 CFU의 투여는, 바람직하게 대상체의 5% 미만, 더욱 바람직하게는 1% 미만, 가장 바람직하게는 1‰ 미만에서 살모넬라증을 유발시킨다.
본 발명의 내용 중 "~를 포함하다" 또는 "~를 포함하는"이란 용어는 "~를 포함하되, 이에 한정되는 것은 아니다(또는 아닌)"을 의미한다. 이 용어는 제약을 두지 않는 것으로서, 진술된 특징, 요소, 정수, 단계 또는 성분 임의의 것이 존재함을 명시하되, 다만 기타의 특징, 요소, 정수, 단계, 성분 또는 이의 군을 배제하도록 의도되는 것은 아니다. 그러므로 "~를 포함하는"이란 용어는 더욱 제한적인 용어들, 즉 "~으로 이루어진" 및 "본질적으로 ~으로 이루어진"을 포함한다. 일 구현예에서, 본 출원 전반과, 구체적으로 특허청구의범위 내에 사용된 " ~를 포함하는"이란 용어는, "~으로 이루어진"이란 용어로 대체될 수 있다.
VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자는 적합하게 재조합 DNA 분자, 즉 조작된 DNA 구조체, 바람직하게는 상이한 기원의 DNA 조각들로 이루어진 조작된 DNA 구조체이다. 이 DNA 분자는 선형 핵산일 수 있거나, 바람직하게는 VEGF 수용체 단백질을 암호화하는 개방 해독틀을 발현 벡터 플라스미드에 삽입함으로써 제조된 환형 DNA 플라스미드일 수 있다.
본 발명의 내용중 "발현 카세트"란 용어는, 발현을 제어하는 조절 서열의 제어 하에 있는 개방 해독틀(ORF) 적어도 하나 포함하는 핵산 단위를 지칭한다. 발현 카세트는, 바람직하게 이에 포함된 개방 해독틀로서, 항원, 예컨대 VEGF 수용체 단백질을 암호화하는 개방 해독틀의 전사를 표적 세포 내에서 매개할 수 있다. 발현 카세트는 통상 프로모터, 개방 해독틀 적어도 하나와, 전사 종결 신호를 포함한다.
특정 구현예들에서, 살모넬라의 약독화 균주는 살모넬라 엔테리카 종의 균주이다. 살모넬라 엔테리카의 약독화된 유도체는 이종 항원을 포유동물 면역계에 전달함에 있어서 매력적인 비이클인데, 그 이유는 이 에스. 엔테리카 균주는 면역화의 점막 경로, 즉 경구 또는 비강 경로를 통해 잠재적으로 전달될 수 있어서, 비경구 투여에 비해 간편함과 안전성이라는 이점을 제공하기 때문이다. 이뿐만 아니라 살모넬라 균주는 전신 및 점막 구획 둘 다의 수준에서 강력한 체액성 면역 반응 및 세포성 면역 반응을 유도한다. 회분의 제조 비용은 낮고, 생균 백신은 매우 안정적이다. 약독화는 균독성, 조절 및 대사 유전자를 포함한 다양한 유전자의 결실에 의해 달성될 수 있다.
aro 돌연변이에 의해 약독화된 몇몇 살모넬라 타이피뮤리움 균주는 동물 모델에 있어 이종 항원의 안전하고도 유효한 전달 비이클인 것으로 확인되었다.
특정 구현예들에서, 살모넬라의 약독화 균주와, 살모넬라의 추가 약독화 균주 적어도 하나는 살모넬라 타이피 Ty21a이다. 에스. 타이피 Ty21a의 약독화 생 균주는 Vivotif®라고도 공지된 Typhoral L®(Berna Biotech Ltd. 제품, Crucell Company, Switzerland)의 활성 성분이다. 이는 현재 승인을 받은 유일한 장티푸스 경구 생 백신이다. 이 백신은 광범위하게 시험되어 왔으며, 그 결과 환자 독성뿐만 아니라 제3자에의 감염에 대해서 안전한 것으로 입증되었다(Wahdan et al., J. Infectious Diseases 1982, 145:292-295). 이 백신은 40개국을 초과하는 국가에서 승인받았으며, 장티푸스에 대한 예방적 백신으로서 수천 명의 어린이를 포함하는 수백만명의 개체에 사용되어 왔다. 이 백신은 비할데 없는 안전에 관한 실적을 보유하고 있다. 에스. 타이피 Ty21a가 혈류를 통해 전신으로 침투할 수 있음을 말해주는 가용 데이터는 존재하지 않는다. 그러므로 약독화 살모넬라 타이피 Ty21a 생 백신 균주는 안전성과 널리 관용되는 특성을 보이면서, 소장 내 면역계의 특이적 표적화를 달성할 수 있다. Typhoral L®의 마케팅허가번호(Marketing Authorization number)는 PL 15747/0001(1996년 12월 16일)이다. 백신의 1회 용량은 적어도 2x109의 생존 에스. 타이피 Ty21a 콜로니 형성 단위 및 적어도 5x109의 비생존 에스. 타이피 Ty21a 세포이다.
이처럼 널리 관용되는, 장티푸스에 대한 경구용 생 백신은 야생형 균독성 세균 분리주 에스. 타이피 Ty2의 화학적 돌연변이에 의해 유도된 것으로서, galE 유전자에 기능 상실 돌연변이가 발생하여 갈락토스 대사 불능이 초래된 것이다. 약독화된 세균 균주는 또한 설페이트를 설파이드로 환원할 수 없는데, 이 점은 야생형 살모넬라 타이피 Ty2 균주와 구별되는 점이다. 살모넬라 타이피 Ty21a 균주의 혈청학적 특징들에 관하여, 이 살모넬라 타이피 Ty21a 균주는 세균 외막 다당체인 O9-항원을 함유하지만, 살모넬라 타이피뮤리움의 특징을 나타내는 성분인 05-항원은 함유하지 않는다. 이러한 혈청학적 특징은 회분 방출에 대한 동일성 시험 패널에서 각각의 시험을 포함하는 것에 관한 근거를 뒷받침해준다.
특정 구현예들에서, 발현 카세트는 진핵생물 발현 카세트이다. 구체적으로 발현 카세트는 CMV 프로모터를 포함한다. 본 발명의 내용중 "진핵생물 발현 카세트"란 용어는, 진핵생물 세포 내 개방 해독틀의 발현을 허용하는 발현 카세트를 지칭한다. 적당한 면역 반응을 유도하는데 필요한 이종 항원의 양은 세균에 독성일 수 있어서, 세포 사멸, 과 약독화(over-attenuation) 또는 이종 항원 발현의 비발생을 초래할 수 있음이 확인되었다. 세균 벡터에서는 발현되지 않고, 오로지 표적 세포내에서만 발현되는 진핵생물 발현 카세트가 사용되면, 이러한 독성의 문제는 극복될 수 있으며, 이때 발현된 단백질은 통상 진핵생물 당화 패턴을 보인다.
진핵생물 발현 카세트는 진핵생물 세포 내 개방 해독틀의 발현을 제어할 수 있는 조절 서열, 바람직하게는 프로모터와 폴리아데닐화 신호를 포함한다. 본 발명의 살모넬라 약독화 균주에 의해 포함된 재조합 DNA 분자 내에 포함된 프로모터 및 폴리아데닐화 신호는, 바람직하게 면역화될 대상체의 세포 내에서 기능을 발휘하는 것으로 선택된다. 적합한 프로모터, 특히 인간용 DNA 백신의 제조에 적합한 프로모터의 예로서는 거대세포바이러스(CMV) 유래 프로모터, 예컨대 CMV 강력 급속 초기 프로모터, 유인원 바이러스 40(SV40) 유래 프로모터, 마우스 유암바이러스(MMTV) 유래 프로모터, 인간 면역결핍증바이러스(HIV) 유래 프로모터, 예컨대 HIV 긴말단반복부(LTR) 프로모터, 몰로니(Moloney) 바이러스 유래 프로모터, 엡스타인 바 바이러스(Epstein Barr Virus; EBV) 유래 프로모터 및 루 육종 바이러스(Rous Sarcoma Virus; RSV) 유래 프로모터, CMV 초기 인핸서 요소, 프로모터, 닭 베타-액틴 유전자의 제1 엑손 및 제1 인트론, 그리고 토끼 베타 글로빈 유전자의 스플라이싱(splicing) 수용체로 이루어진 합성 CAG 프로모터, 그리고 인간 유전자, 예컨대 인간 액틴, 인간 미오신, 인간 헤모글로빈, 인간 근육 크레아틴 및 인간 메탈로티오네인 유래 프로모터를 포함하나, 이에 한정되는 것은 아니다. 특정 구현예에서, 진핵생물 발현 카세트는 CMV 프로모터를 함유한다. 본 발명의 내용중 "CMV 프로모터"란 용어는 강력 급속 초기 거대세포바이러스 프로모터를 지칭한다.
특히 인간용 DNA 백신 제조에 적합한 폴리아데닐화 신호의 예들로서는 소 성장 호르몬(BGH) 폴리아데닐화 부위, SV40 폴리아데닐화 신호 및 LTR 폴리아데닐화 신호를 포함하나, 이에 한정되는 것은 아니다. 특정 구현예에서, 본 발명의 살모넬라 약독화 균주에 의해 포함된 재조합 DNA 분자에 포함된 진핵생물 발현 카세트는 BGH 폴리아데닐화 부위를 포함한다.
프로모터 및 폴리아데닐화 신호와 같이 VEGF 수용체 단백질의 발현에 필요한 조절 요소에 더하여, 다른 요소들도 또한 재조합 DNA 분자에 포함될 수 있다. 이러한 추가 요소들로서는 인핸서를 포함한다. 인핸서는, 예를 들어 인간 액틴, 인간 미오신, 인간 헤모글로빈, 인간 근육 크레아틴의 인핸서와, 바이러스 인핸서, 예컨대 CMV, RSV 및 EBV 유래 인핸서일 수 있다.
조절 서열과 코돈은 일반적으로 종에 의존적이어서, 단백질 발현량을 최대화하기 위해 조절 서열과 코돈은, 바람직하게 면역화될 종에서 유효한 것으로 선택된다. 당 업자는 주어진 대상체 종에서 기능을 발휘하는 재조합 DNA 분자를 제조할 수 있다.
특정 구현예들에서, VEGF 수용체 단백질은 VEGFR-2, 구체적으로 인간 VEGFR-2이다. 특히 VEGF 수용체 단백질은 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2 및 이것과 적어도 80%의 서열 동일성을 공유하는 단백질로 이루어진 군으로부터 선택된다. 특히 VEGF 수용체 단백질은 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가진다.
본 발명의 내용중 "약" 또는 "대략적으로"란 용어는, 주어진 값 또는 범위의 80% 내지 120% 이내, 대안적으로는 90% 내지 110% 이내, 예컨대 95% 내지 105% 이내에 해당하는 경우를 의미한다.
본 발명의 내용중 "주어진 단백질, 예컨대 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2와 적어도 약 80%의 서열 동일성을 공유하는 단백질"이란 용어는, 이 기준 단백질, 예컨대 서열 번호 1의 아미노산 서열을 가지는 VEGFR-2의 아미노산 서열을 암호화하는 아미노산 서열에 있어서 상이할 수 있는 단백질을 지칭한다. 단백질은 자연 기원의 것, 예컨대 야생형 단백질이 돌연변이된 것, 예컨대 야생형 VEGFR-2가 돌연변이된 것, 또는 상이한 종의 상동체 또는 조작된 단백질, 예컨대 조작된 VEGFR-2일 수 있다. 코돈의 선호도는 종들간에 상이한 것으로 공지되어 있다. 그러므로 이종 단백질이 표적 세포 내에서 발현될 때, 핵산 서열을 표적 세포의 코돈 선호도에 적응시키는 것이 필요할 수 있거나, 적어도 도움이 될 수 있다. 주어진 단백질의 유도체를 디자인 및 구성하기 위한 방법은 임의의 당 업자에게 널리 공지되어 있다.
주어진 단백질, 예컨대 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2와 적어도 약 80%의 서열 동일성을 공유하는 단백질은 기준 단백질, 예컨대 서열 번호 1의 아미노산 서열을 가지는 VEGFR-2에 비하여 하나 이상의 아미노산의 추가, 결실 및/또는 치환을 포함하는 돌연변이 하나 이상을 함유할 수 있다. 본 발명의 교시내용에 따르면, 상기 결실, 부가 및/또는 치한된 아미노산은 연속 아미노산일 수 있거나, 또는 기준 단백질, 예컨대 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2와 적어도 약 80%의 서열 동일성을 공유하는 단백질의 아미노산 서열의 전체 길이에 걸쳐 배치될 수 있다. 본 발명의 교시내용에 따르면, 기준 단백질과의 아미노산 서열 동일성이 적어도 약 80%이고 돌연변이된 단백질이 면역원성인 한, 임의의 수만큼의 아미노산이 부가, 결실 및/또는 치환될 수 있다. 바람직하게 주어진 기준 단백질, 예컨대 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2와 적어도 약 80%의 서열 동일성을 공유하는 단백질의 면역원성은, ELISA에 의해 측정되는 바에 따르면, 상기 기준 단백질, 예컨대 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2의 면역원성에 비하여 50% 미만, 40% 미만, 30% 미만, 20% 미만, 10% 미만, 5% 미만 또는 1% 미만 감소한다. 단백질 상동체를 디자인 및 구성하기 위한 방법과, 이러한 상동체를 대상으로 이 상동체의 면역원으로서의 잠재성에 대해 시험하기 위한 방법은 임의의 당 업자에게 널리 공지되어 있다. 특정 구현예들에서, 기준 단백질, 예컨대 서열 번호 1의 아미노산 서열을 가지는 VEGFR-2와의 아미노산 서열 동일성은 적어도 약 80%, 적어도 약 85%, 적어도 약 90%, 또는 가장 구체적으로는 적어도 약 95%이다. 모 단백질과, 모 단백질 서열과는 달리 결실, 부가 및/또는 치환을 가지는 모 단백질 유도체의 비교를 포함하여 서열 동일성을 확정하기 위한 방법과 이를 위한 알고리즘은 당 업자인 실무자에게 널리 공지되어 있다. DNA 수준에서, 주어진 기준 단백질, 예컨대 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2와 적어도 약 80%의 서열 동일성을 공유하는 단백질을 암호화하는 핵산 서열은, 유전자 코드의 축퇴성으로 말미암아 더 큰 정도로 상이할 수 있다.
특정 구현예들에서, DNA 분자는 카나마이신 항생제 내성 유전자, pMB1 ori 및 CMV 프로모터를 포함한다. 특정 구현예들에서, 재조합 DNA 분자는 시판중인 pVAX1TM 발현 플라스미드(Invitrogen, San Diego, California)로부터 유래한다. 이 발현 벡터는, 고 복사체 pUC 복제 기원을 pBR322의 저 복사체 pMB1 복제 기원으로 치환함으로써 변형된 것이다. 저 복사체 변형은 대사 부담(metabolic burden)을 줄이고 구조체를 더욱 안정적으로 만들기 위해 이루어졌다. 제조된 발현 벡터의 백본(backbone)은 pVAX10으로 명명되었다.
특정 구현예들에서, DNA 분자는 서열 번호 2(벡터 백본 pVAX10)에서 발견되는 바와 같은 DNA 서열을 포함한다.
서열 번호 1의 아미노산 서열을 가지는 인간 VEGFR-2를 암호화하는 ORF가 NheI/XhoI를 통해 발현 박터 백본에 삽입되면, 발현 벡터 pVAX10.VR2-1이 수득된다(WO 2013/091898). 발현 플라스미드 pVAX10.VR2-1은 도 9에 도식적으로 묘사되어 있다. 발현 플라스미드 pVAX10.VR2-1을 보유하는 살모넬라 약독화 균주 Ty21a를 포함하는 DNA 백신은 VXM01로 명명된다(WO 2013/091898).
특정 구현예들에서, 암의 면역요법은 화학요법, 방사선요법 또는 생물학적 암 치료법이 동반된다. 이러한 특정 구현예들에서, 살모넬라의 약독화 균주는 화학요법 또는 방사선요법 치료 또는 생물학적 암 치료법 수행 이전, 도중 또는 이후에 투여되거나, 또는 화학요법 또는 방사선요법 치료 또는 생물학적 암 치료법 수행 이전 및 도중에 투여된다. 암 치유를 위해서는 암 줄기 세포의 완전한 제거가 필수적일 수 있다. 최대의 효능을 보기 위해서 상이한 치료적 접근법들의 병행이 유리할 수 있다.
본 발명의 내용중, "생물학적 암 치료법"이란 용어는, 바이러스를 비롯한 생 유기체, 이 생 유기체로부터 유래하는 물질, 또는 이러한 물질의 실험실 제조의 것을 사용하는 것을 수반하는 암 치료법을 지칭한다. 암에 대한 몇몇 생물학적 치료법은 체내 면역계를 자극하여 암세포에 대해 작동을 하도록 만드는 것을 목표로 한다(소위 생물학적 암 면역요법). 암의 생물학적 치료 접근법은 종양 항원과 종양 기질 항원의 전달, 예를 들어 살모넬라 기반 DNA 백신, 구체적으로 에스. 타이피 Ty21a 기반 DNA 백신에 의한 종양 항원 및 종양 기질 항원의 전달, 치료적 항체의 약물로서의 전달, 면역자극 시토카인의 투여, 그리고 면역 세포, 예컨대 조작된 T 세포의 투여를 포함한다. 치료적 항체는 종양 항원 또는 종양 기질 항원을 표적화하는 항체를 포함한다.
특정 구현예들에서, 생물학적 암 치료법은 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가의 DNA 백신 적어도 하나(발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라의 추가 약독화 균주 적어도 하나)를 투여하는 것을 포함한다. 이러한 특정 구현예들에서, 종양 항원 및/또는 종양 기질 항원을 암호화하는 상기 추가 DNA 백신 적어도 하나는, 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가의 발현 카세트를 포함하는 추가의 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라의 추가 약독화 균주 적어도 하나로부터 선택된다. 구체적으로 상기 살모넬라의 추가 약독화 균주 적어도 하나는 추가의 진핵생물 발현 카세트를 포함하는 살모넬라 타이피 Ty21a이다.
특정 구현예들에서, 상기 추가 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 항원은 인간 빌름 종양 단백질(WT1), 인간 메소텔린(MSLN), 인간 CEA 및 CMV pp65로 이루어진 군으로부터 선택된다. 구체적으로 상기 추가 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 항원은 서열 번호 3에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 빌름 종양 단백질(WT1) 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 4에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 메소텔린(MSLN) 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 5에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 CEA 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 6에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 7에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 8에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질로 이루어진 군으로부터 선택된다. 구체적으로 인간 빌름 종양 단백질(WT1)은 서열 번호 3에서 발견되는 바와 같은 아미노산 서열을 가지고, 인간 메소텔린(MSLN)은 서열 번호 4에서 발견되는 바와 같은 아미노산 서열을 가지며, 인간 CEA는 서열 번호 5에서 발견되는 바와 같은 아미노산 서열을 가지고, CMV pp65는 서열 번호 6, 서열 번호 7 또는 서열 번호 8에서 발견되는 바와 같은 아미노산 서열을 가진다. 특정 구현예들에서, 상기 추가 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 기질 항원은 인간 섬유아세포 활성화 단백질(FAP)로 이루어진 군으로부터 선택된다.
특정 구현예들에서, VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주는 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가 DNA 백신 적어도 하나보다 먼저, 아니면 이와 동시에 투여된다.
본 발명의 내용중 "~와 동시에"란 용어는, VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주와, 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가 DNA 백신 적어도 하나의 투여가 동일한 날에, 더욱 구체적으로는 어느 하나가 투여되고나서 12시간 이내에, 더욱 구체적으로는 어느 하나가 투여되고나서 2시간 이내에 이루어짐을 의미한다.
특정 구현예들에서, VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주와, 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가 DNA 백신 적어도 하나의 투여는 8 연속주 이내에, 더욱 구체적으로는 3 내지 6 연속주 이내에 이루어진다. VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주와, 종양 항원 또는 종양 기질 항원을 암호화하는 추가 DNA 백신 적어도 하나는 동일한 경로 또는 상이한 경로들을 통해 투여될 수 있다. 예를 들어 구체적으로 만일 추가 DNA 백신 적어도 하나가 살모넬라의 추가 약독화 균주라면, 이는 경구 투여될 수 있다.
살모넬라의 추가 약독화 균주의 단일 용량은 약 105 내지 약 1011, 구체적으로 약 106 내지 약 1010, 더욱 구체적으로 약 106 내지 약 109, 더욱 구체적으로 약 106 내지 약 108, 가장 구체적으로 약 106 내지 약 107의 콜로니 형성 단위(CFU)를 포함할 수 있다.
본 발명의 살모넬라 약독화 돌연변이 균주와 함께 사용될 수 있는 화학요법 제제는, 예를 들어 겜시타빈, 아미포스틴(에티올), 카바지탁셀, 카보플라틴, 옥살리플라틴, 시스플라틴, 카페시타빈, 다카바진(DTIC), 닥티노마이신, 도세탁셀, 메클로레타민, 스트렙토조신, 사이클로포스파미드, 니머스틴 (ACNU), 카머스틴(BCNU), 로머스틴(CCNU), 독소루비신(아드리아마이신), 독소루비신 리포(독실), 폴리닌산, 겜시타빈(겜자), 도노루비신, 도노루비신 리포(도녹솜), 에피루비신, 프로카바진, 케토코나졸, 미토마이신, 시타라빈, 에토포시드, 메토트렉세이트, 5-플루오로우라실(5-FU), 빈블라스틴, 빈크리스틴, 블레오마이신, 파클리탁셀(탁솔), 도세탁셀(탁소텔), 퍼메트렉시드, 알데스루킨, 아스파라기나아제, 부설판, 카보플라틴, 클라드리빈, 캄프토테신, CPT-11, 10-하이드록시-7-에틸-캄프토테신(SN38), 다카바진, 플록수리딘, 플루다라빈, 하이드록시우레아, 이포스파미드, 이다루비신, 메스나, 인터페론 알파, 인터페론 베타, 이리노테칸, 미토잔트론, 토포테칸, 루프롤리드, 메게스트롤, 멜파란, 머캅토퓨린, 옥살리플라틴, 플리카마이신, 미토탄, 페가스파르가아제, 펜토스타틴, 피포브로만, 플리카마이신, 스트렙토조신, 타목시펜, 테니포시드, 테스토락톤, 티오구아닌, 티오테파, 우라실 머스타드, 비노렐빈, 클로람부실, 테모졸로미드 및 이것들의 조합일 수 있다.
본 발명에 따라서 가장 바람직한 화학요법 제제는 카바지탁셀, 카보플라틴, 옥살리플라틴, 시스플라틴, 사이클로포스파미드, 도세탁셀, 에토포시드, 겜시타빈, 독소루비신, 로머스틴, 파클리탁셀(탁솔), 이리노테칸, 빈크리스틴, 빈블라스틴, 비노렐빈, 폴리닌산, 5-플루오로우라실, 블레오마이신 및 테모졸로미드이고, 특히 겜시타빈이다.
특정 구현예들에서, 암의 면역요법은 화학요법과 방사선요법의 병행이 동반된다. 이러한 특정 구현예들에서, 화학요법은 테모졸로미드의 투여를 포함한다.
특정 구현예들에서, 살모넬라의 약독화 균주는 경구 투여된다. 경구 투여는 비경구 투여보다 더 간단하고, 더 안전하며, 더 편하다. 그러나 VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주는 또한 기타 임의의 적합한 경로에 의해 투여될 수 있음을 주목하여야 한다. 바람직하게 치료적 유효량이 대상체에 투여되는데, 이 용량은 구체적인 적용예, 악성종양의 유형, 대상체의 체중, 나이, 성별 및 건강 상태, 투여 및 제제화 방식 등에 따라 달라진다. 투여는 필요에 따라서 단일 회 또는 다수 회 이루어질 수 있다.
VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주는 용액, 현탁액, 동결건조물 또는 장용외피 캡슐의 형태, 또는 기타 임의의 적합한 형태로 제공될 수 있다. 통상적으로 살모넬라의 약독화 균주는 음용 용액으로 제제화된다. 이 구현예는 환자의 순응성 개선이라는 이점을 제공한다. 바람직하게 음용 용액은 위산을 적어도 어느 정도까지 중화시키는 수단, 즉 위액의 pH를 pH 7에 가깝게 만드는 수단을 포함한다. 바람직하게 음용 용액은 VEGF 수용체 단백질을 암호화하는 살모넬라 약독화 균주를 포함하는 완충 현탁액이다. 특정 구현예에서, 완충 현탁액은 살모넬라 약독화 균주를 적합한 완충제, 바람직하게는 탄산수소나트륨 2.6 g, L-아스코르브산 1.7 g, 락토스 일수화물 0.2 g 및 음용수 100 ml를 함유하는 완충제에 현탁함으로써 수득된다.
VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주는 놀랍게도 비교적 저용량에서도 유효하다. VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주의 효능은 특히 암 특이적 VEGF 수용체 단백질 발현을 동반하는 암에서 크다. 생균 백신의 저용량 투여는 배출 위험을 최소화하고, 이로 말미암아 제3자에의 전염 위험도 최소화한다.
특정 구현예들에서, VEGF 수용체 단백질을 암호화하는 살모넬라 약독화 균주, 구체적으로 인간 VEGFR-2를 암호화하는 살모넬라 타이피 Ty21a의 단일 용량은 약 105 내지 약 1011, 구체적으로 약 106 내지 약 1010, 더욱 구체적으로 약 106 내지 약 109, 더욱 구체적으로 약 106 내지 약 108, 가장 구체적으로 약 106 내지 약 107의 콜로니 형성 단위(CFU)를 포함한다.
본 내용중, "약" 또는 "대략적으로"란 용어는, 주어진 값이나 범위의 3 팩터(factor) 이내, 대안적으로는 2 팩터 이내, 예컨대 1.5 팩터 이내를 의미한다.
특정 구현예들에서, 살모넬라의 약독화 균주는, 환자에서 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2의 발현 패턴 및/또는 이에 대한 전면역 반응을 평가하는 단계를 포함하는, 개별맞춤 암 면역요법에 사용하기 위한 것이다. 대안적으로 살모넬라 약독화 균주는, 구체적으로 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2의 발현 패턴 및/또는 이에 대한 전면역 반응을 평가함으로써, VEGF 수용체 단백질(예컨대 VEGFR-2) 발현 암세포에 의해 특징지어지는 암이 발병하였거나, 적어도 하나의 VEGF 수용체 단백질(예컨대 VEGFR-2) 발현 암세포를 보유하는 것으로 확인된 환자를 대상으로 하는 암 면역요법에 사용하기 위한 것이다. 환자의 VEGF 수용체 단백질 발현 및/또는 환자의 VEGF 수용체 단백질에 대한 전염증 반응은 첫 번째 단계에서, 예를 들어 동반 진단(companion diagnostic)에 의해 평가될 수 있다. 표적 유전자, 예컨대 VEGFR-2를 mRNA 수준 또는 단백질 수준 중 어느 하나의 수준에서 평가하기 위한 방법은 임의의 당 업자에게 널리 공지되어 있다. 예를 들어 면역조직화학적 염색, 유세포분석 방법 또는 RNA 서열결정, 또는 표지화를 이용하는 대안적 방법이 종양 내 표적 발현의 수준을 동정하는데 사용될 수 있다. 이와 유사하게, 주어진 단백질, 예컨대 VEGFR-2에 대한 환자의 전염증 반응을 평가하기 위한 방법도 임의의 당 업자에게 널리 공지되어 있다. 이전부터 환자에 존재하던 VEGFR-2 특이적 T 세포 풀(pool)은, 예컨대 ELISpot 또는 다량체 FACS 분석에 의해 검출될 수 있다. 종양 특이적 VEGFR-2의 다량 발현 및/또는 VEGFR-2에 대한 전면역 반응의 발생은, VEGFR-2를 암호화하는 살모넬라 약독화 균주를 사용하는 치료에 환자가 특히 유리하게 반응하게 될 소인에 대한 예후적 지표이다.
항생제나 소염제를 사용하는 치료를 포함시킬지 여부는, 발생 가능한 부작용의 발생에 의존적인 것이 유리할 수 있다.
히스타민, 루코트리엔 또는 시토카인에 의해 매개되는 과민증 반응을 닮은 부작용이 일어나면, 발열, 아나필락시스, 혈압 불안정, 기관지경련 및 호흡곤란에 대한 치료 선택권이 적용될 수 있다. 원치않는 T 세포 유래 자기 공격의 경우 치료 선택권은, 줄기 세포 이식 이후에 적용되는 급성 및 만성 이식편 대 숙주병의 표준적 치료 계획으로부터 유래한다. 사이클로스포린과 글루코코르티코이드가 치료 선택권으로서 제안된다.
전신 살모넬라 타이피 Ty21a형 감염의 경우와는 달리, 적당한 항생제 치료법, 예를 들어 시프로플록사신 또는 오플록사신을 포함하는 플루오로퀴놀론 치료법이 권장된다. 위장관의 세균 감염은 각각의 제제, 예컨대 리팍시민으로 치료될 것이다.
VEGF 수용체 단백질을 암호화하는 살모넬라의 약독화 균주는 약학 조성물 중에 함유되어 제공될 수 있다. 약학 조성물은 용액, 현탁액, 장용 외피 캡슐, 동결건조 분말의 형태, 또는 의도로 하는 용도에 적합한 기타 임의의 형태를 가질 수 있다.
약학 조성물은 하나 이상의 약학적으로 허용 가능한 부형제를 추가로 포함할 수 있다.
본 발명의 내용중 "부형제"란 용어는 의약품의 활성 성분과 함께 제제화되는 자연 또는 합성 물질을 지칭한다. 적합한 부형제로서는 점착방지제(antiadherent), 결합제, 코팅, 붕해제, 풍미제, 발색제, 윤활제, 활강제, 흡수제, 보존제 및 감미제를 포함한다.
본 발명의 내용중 "약학적으로 허용 가능한"이란 용어는, 약학 조성물중 분자적 실체 및 기타 성분이 생리학적으로 관용적이어서 포유동물(예컨대 인간)에 투여될 때 통상 뜻밖의 반응을 일으키지 않는 경우를 지칭한다. "약학적으로 허용 가능한"이란 용어는 또한, 연방 규제 당국이나 주 정부에 의해 포유동물, 더욱 구체적으로는 인간에서의 사용에 대해 승인을 받았거나, 또는 미국 약전이나 기타 일반적으로 인식되고 있는 약전에 나열되었음을 의미할 수도 있다.
특정 구현예들에서, 약학 조성물은 음용 용액으로 제공된다. 이 구현예는 환자 순응성의 개선이라는 이점을 제공하고, 신속하고, 실현가능하며, 알맞은 집단 백신화 프로그램을 실현할 수 있다.
구체적으로, 적합한 음용 용액은 위산을 적어도 어느 정도까지 중화시키는 수단, 즉 위액의 pH를 pH 7에 가깝게 만드는 수단을 포함한다. 특정 구현예에서, 이 음용 용액은 본 발명에 따른 살모넬라 약독화 균주를 적합한 완충제, 바람직하게 위산을 적어도 어느 정도까지 중화하는 완충제로서, 바람직하게는 탄산수소나트륨 2.6 g, L-아스코르브산 1.7 g, 락토스 일수화물 0.2 g 및 음용수 100 ml를 함유하는 완충제 중에 현탁함으로써 수득되는 완충 현탁액이다.
특정 구현예들에서, 암의 면역요법은 VEGF 수용체 단백질을 암호화하는 살모넬라 약독화 균주 또는 이를 포함하는 약학 조성물을 단일 회 또는 다수 회 투여하는 것을 포함한다. 투여의 단일 용량은 동일하거나 상이할 수 있다. 구체적으로 암의 면역요법은 VEGF 수용체 단백질을 암호화하는 살모넬라 약독화 균주의 1, 2, 3, 4, 5 또는 6회 투여를 포함하는데, 이때 다수 회 투여는 3 내지 6 연속월 이내에 이루어지는 것이 바람직하다.
도면의 간단한 설명
도 1: 플라스미드 pVAX10.VR2-1에 함유된 VEGFR-2 cDNA에 의해 암호화되는, 인간 VEGFR-2의 아미노산 서열(서열 번호 1).
도 2: 빈 발현벡터 pVAX10에 포함된 핵산 서열(제한 부위 NheI 및 XhoI 사이에 위치하는 다중 클로닝 부위의 일부가 빠진 발현 벡터 pVAX10의 서열)(서열 번호 2).
도 3: 플라스미드 pVAX10.hWT1에 함유된 WT-1 cDNA에 의해 암호화되는, 절단형(아연-핑거(zinc-finger) 도메인이 결실된) 인간 WT-1의 아미노산 서열(서열 번호 3).
도 4: 플라스미드 pVAX10.hMSLN에 함유된 MSLN cDNA에 의해 암호화되는 인간 MSLN의 아미노산 서열(서열 번호 4).
도 5: 플라스미드 pVAX10.hCEA에 함유된 CEA cDNA에 의해 암호화되는 인간 CEA의 아미노산 서열(서열 번호 5).
도 6: 플라스미드 pVAX10.CMVpp65_1에 함유된 CMV pp65 cDNA에 의해 암호화되는 CMV pp65의 아미노산 서열(서열 번호 6).
도 7: 플라스미드 pVAX10.CMVpp65_2에 함유된 CMV pp65 cDNA에 의해 암호화되는 CMV pp65의 아미노산 서열(서열 번호 7).
도 8: 플라스미드 pVAX10.CMVpp65_3에 함유된 CMV pp65 cDNA에 의해 암호화되는 CMV pp65의 아미노산 서열(서열 번호 8).
도 9: pVAX10.VR2-1의 플라스미드 맵(map).
도 10: 환자 2605호의 뇌 MRI 영상.
실시예
실시예
1:
교모세포종이 재발하였으나 수술 치료가 가능한 환자의
VXM01
치료
본 연구의 목표는, VEGFR-2 암호화 DNA 백신 VXM01에 대한 안전성, 관용성, 면역 및 바이오마커 반응을 관찰하는 것이다.
본 연구는 테모졸로미드 화학방사선요법을 포함하여야 하는 표준 치료 적어도 한 가지에 실패한 환자들로서, 교모세포종이 재발하였으나 수술로 치료 가능한 환자들을 대상으로 수행하였다. 대상 환자 모두에게는 이들의 표준 치료법에 추가하여 DNA 백신 VXM01을 투여하였다.
본 연구는 스크리닝 기간, 치료 및 관찰 기간(3개월 이하), 종양 추적관찰기간(3개월 내지 12개월), 그리고 종양 추적관찰기간 중 면역증강치료기간(8주 내지 48주)로 이루어졌다. 연구를 마친 후 2년 이하의 기간 동안 환자들을 대상으로 추적검사를 실시하였다.
치료 및 관찰 과정은, 1, 3, 5 및 7일마다 VXM01 1회 경구 투여와, 이 이후 5±1주 경과시 재수술을 포함하였다. 면역증강치료기간중 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 및 48주차, 즉 4주에 1회 행하여지는 면역증강투여시에 VXM01을 경구 투여하였다.
VXM01 단일 용량만큼, 즉 106 및 107 콜로니 형성 단위(CFU)/ml만큼을 경구 투여하였다.
9명의 교모세포종 환자들 중 5명은 해당 질환의 유리한 경과를 보였다.
환자 2605호:
환자 2605호는 WHO IV 등급인 재발성 교모세포종 여성 환자(55세)이다. 본 환자가 앞서 받은 암 치료로서는 교모세포종 1차 수술과 1차 화학방사선요법 치료(Gy 60 → 테모졸로미드 75 mg/m2)를 포함한하였다.
본 환자를 VXM01(용량 106 CFU)로 치료하였다. 우선 1, 3, 5 및 7 연구일에 VXM01을 투여하여 총 4회 투여함으로써 VXM01 치료를 개시하였으며, 이후 35일에 정례적인 수술을 한 이후에도 VXM01 치료를 계속하였는데, 이때 8주차를 시작으로 4주마다 한 번씩 면역증강투여가 이루어졌다. 10주차에는 VXM01 투여 이외에 로머스틴/에토포시드 화학요법을 개시하였다.
스크리닝을 위한 외래 방문시 종양의 기준 표적 병변은 25 x 10 mm였다. 종양 크키의 변화를 이하 표 1에 요약하였다:
기준일, 35일, 12주, 20주 및 76주차에서의 각각의 MRI 영상들을 도 10에 제시하였다.
종양 크기는 10 연구일과 정례의 수술일(35일) 사이에 28 x 13 mm로부터 25 x 12 mm로 감소하는 경향을 보였다. RANO 기준에 따르면, 이는 안정 병변(stable disease; SD)으로서 평가되었다. 12주차, 즉 정례의 재수술일(35일) 이후 7주 경과시 RANO 기준에 따른 평가 결과는, 새로운 비 표적 병변의 발생으로 말미암아 진행 병변(progressive disease; PD)이었다. 수술 후 12주차에 행하여진 MRI 보고에 따르면 가시적"표적 병변"은 없었다. VXM01 투여 이외에 로머스틴/에토포시드 화학요법을 개시하였다. 20주차(즉 재수술 후 15주 경과시)에 종양은 RANO 기준에 따라 안정 병변(SD)으로 평가되었다. 36주차에 로머스틴/에토포시드 화학요법을 중단하고, 환자를 VXM01으로 계속 치료하였으며(4주마다 한 번씩), 본 출원을 출원할 때까지 치료를 중단하지 않았다.
카르노프스키 지수(Karnofsky Index)는 스크리닝시 100%였다가 12주차에는 90%였다.
연구전에 수집한 원발성 종양 시료의 면역조직화학적 염색 결과, 이 환자의 종양은 VEGFR-2를 발현하였다는 것이 밝혀졌다. VXM01로 치료하고 난 후인 35일에 재발성 종양 시료 중 종양 세포는 VEGFR-2를 발현하는 것으로 확인되지 않았다.
종양 조직의 면역조직화학적 분석에 있어서, CD8+ T 세포는 VXM01 치료후 원발성 종양에서에 비해 재발성 종양에서 2.3 팩터만큼 증가하였다.
SEQUENCE LISTING
<110> Vaximm AG
<120> Novel VEGFR-2 targeting immunotherapy approach
<130> 113255P855PC
<150> EP17156718.3
<151> 2017-02-17
<160> 8
<170> BiSSAP 1.3.6
<210> 1
<211> 1356
<212> PRT
<213> Homo sapiens
<400> 1
Met Gln Ser Lys Val Leu Leu Ala Val Ala Leu Trp Leu Cys Val Glu
1 5 10 15
Thr Arg Ala Ala Ser Val Gly Leu Pro Ser Val Ser Leu Asp Leu Pro
20 25 30
Arg Leu Ser Ile Gln Lys Asp Ile Leu Thr Ile Lys Ala Asn Thr Thr
35 40 45
Leu Gln Ile Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro
50 55 60
Asn Asn Gln Ser Gly Ser Glu Gln Arg Val Glu Val Thr Glu Cys Ser
65 70 75 80
Asp Gly Leu Phe Cys Lys Thr Leu Thr Ile Pro Lys Val Ile Gly Asn
85 90 95
Asp Thr Gly Ala Tyr Lys Cys Phe Tyr Arg Glu Thr Asp Leu Ala Ser
100 105 110
Val Ile Tyr Val Tyr Val Gln Asp Tyr Arg Ser Pro Phe Ile Ala Ser
115 120 125
Val Ser Asp Gln His Gly Val Val Tyr Ile Thr Glu Asn Lys Asn Lys
130 135 140
Thr Val Val Ile Pro Cys Leu Gly Ser Ile Ser Asn Leu Asn Val Ser
145 150 155 160
Leu Cys Ala Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly Asn Arg
165 170 175
Ile Ser Trp Asp Ser Lys Lys Gly Phe Thr Ile Pro Ser Tyr Met Ile
180 185 190
Ser Tyr Ala Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp Glu Ser
195 200 205
Tyr Gln Ser Ile Met Tyr Ile Val Val Val Val Gly Tyr Arg Ile Tyr
210 215 220
Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu
225 230 235 240
Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile
245 250 255
Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu
260 265 270
Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe
275 280 285
Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu
290 295 300
Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr
305 310 315 320
Phe Val Arg Val His Glu Lys Pro Phe Val Ala Phe Gly Ser Gly Met
325 330 335
Glu Ser Leu Val Glu Ala Thr Val Gly Glu Arg Val Arg Ile Pro Ala
340 345 350
Lys Tyr Leu Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr Lys Asn Gly
355 360 365
Ile Pro Leu Glu Ser Asn His Thr Ile Lys Ala Gly His Val Leu Thr
370 375 380
Ile Met Glu Val Ser Glu Arg Asp Thr Gly Asn Tyr Thr Val Ile Leu
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Thr Asn Pro Ile Ser Lys Glu Lys Gln Ser His Val Val Ser Leu Val
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Val Tyr Val Pro Pro Gln Ile Gly Glu Lys Ser Leu Ile Ser Pro Val
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Asp Ser Tyr Gln Tyr Gly Thr Thr Gln Thr Leu Thr Cys Thr Val Tyr
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Ala Ile Pro Pro Pro His His Ile His Trp Tyr Trp Gln Leu Glu Glu
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Glu Cys Ala Asn Glu Pro Ser Gln Ala Val Ser Val Thr Asn Pro Tyr
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Pro Cys Glu Glu Trp Arg Ser Val Glu Asp Phe Gln Gly Gly Asn Lys
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Ile Glu Val Asn Lys Asn Gln Phe Ala Leu Ile Glu Gly Lys Asn Lys
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Thr Val Ser Thr Leu Val Ile Gln Ala Ala Asn Val Ser Ala Leu Tyr
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Lys Cys Glu Ala Val Asn Lys Val Gly Arg Gly Glu Arg Val Ile Ser
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Phe His Val Thr Arg Gly Pro Glu Ile Thr Leu Gln Pro Asp Met Gln
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Pro Thr Glu Gln Glu Ser Val Ser Leu Trp Cys Thr Ala Asp Arg Ser
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Thr Phe Glu Asn Leu Thr Trp Tyr Lys Leu Gly Pro Gln Pro Leu Pro
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Ile His Val Gly Glu Leu Pro Thr Pro Val Cys Lys Asn Leu Asp Thr
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Leu Trp Lys Leu Asn Ala Thr Met Phe Ser Asn Ser Thr Asn Asp Ile
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Leu Ile Met Glu Leu Lys Asn Ala Ser Leu Gln Asp Gln Gly Asp Tyr
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Val Cys Leu Ala Gln Asp Arg Lys Thr Lys Lys Arg His Cys Val Val
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Arg Gln Leu Thr Val Leu Glu Arg Val Ala Pro Thr Ile Thr Gly Asn
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Leu Glu Asn Gln Thr Thr Ser Ile Gly Glu Ser Ile Glu Val Ser Cys
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Thr Ala Ser Gly Asn Pro Pro Pro Gln Ile Met Trp Phe Lys Asp Asn
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Glu Thr Leu Val Glu Asp Ser Gly Ile Val Leu Lys Asp Gly Asn Arg
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Asn Leu Thr Ile Arg Arg Val Arg Lys Glu Asp Glu Gly Leu Tyr Thr
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Ile Ile Glu Gly Ala Gln Glu Lys Thr Asn Leu Glu Ile Ile Ile Leu
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Val Gly Thr Ala Val Ile Ala Met Phe Phe Trp Leu Leu Leu Val Ile
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Ile Leu Arg Thr Val Lys Arg Ala Asn Gly Gly Glu Leu Lys Thr Gly
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Tyr Leu Ser Ile Val Met Asp Pro Asp Glu Leu Pro Leu Asp Glu His
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Cys Glu Arg Leu Pro Tyr Asp Ala Ser Lys Trp Glu Phe Pro Arg Asp
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Arg Leu Lys Leu Gly Lys Pro Leu Gly Arg Gly Ala Phe Gly Gln Val
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Ile Glu Ala Asp Ala Phe Gly Ile Asp Lys Thr Ala Thr Cys Arg Thr
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Val Ala Val Lys Met Leu Lys Glu Gly Ala Thr His Ser Glu His Arg
865 870 875 880
Ala Leu Met Ser Glu Leu Lys Ile Leu Ile His Ile Gly His His Leu
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Asn Val Val Asn Leu Leu Gly Ala Cys Thr Lys Pro Gly Gly Pro Leu
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Met Val Ile Val Glu Phe Cys Lys Phe Gly Asn Leu Ser Thr Tyr Leu
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Arg Ser Lys Arg Asn Glu Phe Val Pro Tyr Lys Thr Lys Gly Ala Arg
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Phe Arg Gln Gly Lys Asp Tyr Val Gly Ala Ile Pro Val Asp Leu Lys
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Arg Arg Leu Asp Ser Ile Thr Ser Ser Gln Ser Ser Ala Ser Ser Gly
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Phe Val Glu Glu Lys Ser Leu Ser Asp Val Glu Glu Glu Glu Ala Pro
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Glu Asp Leu Tyr Lys Asp Phe Leu Thr Leu Glu His Leu Ile Cys Tyr
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Ser Phe Gln Val Ala Lys Gly Met Glu Phe Leu Ala Ser Arg Lys Cys
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Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Ser Glu Lys Asn
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Val Val Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile Tyr Lys Asp
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Pro Asp Tyr Val Arg Lys Gly Asp Ala Arg Leu Pro Leu Lys Trp Met
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Ala Pro Glu Thr Ile Phe Asp Arg Val Tyr Thr Ile Gln Ser Asp Val
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Trp Ser Phe Gly Val Leu Leu Trp Glu Ile Phe Ser Leu Gly Ala Ser
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Pro Tyr Pro Gly Val Lys Ile Asp Glu Glu Phe Cys Arg Arg Leu Lys
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Glu Gly Thr Arg Met Arg Ala Pro Asp Tyr Thr Thr Pro Glu Met Tyr
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Gln Thr Met Leu Asp Cys Trp His Gly Glu Pro Ser Gln Arg Pro Thr
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Phe Ser Glu Leu Val Glu His Leu Gly Asn Leu Leu Gln Ala Asn Ala
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Gln Gln Asp Gly Lys Asp Tyr Ile Val Leu Pro Ile Ser Glu Thr Leu
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Ser Met Glu Glu Asp Ser Gly Leu Ser Leu Pro Thr Ser Pro Val Ser
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Ser Phe Gly Gly Met Val Pro Ser Lys Ser Arg Glu Ser Val Ala Ser
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Pro Asp Ser Gly Thr Thr Leu Ser Ser Pro Pro Val
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<210> 2
<211> 3500
<212> DNA
<213> artificial sequence
<220>
<223> expression plasmid
<400> 2
tgggcttttg ctggcctttt gctcacatgt tcttgactct tcgcgatgta cgggccagat 60
atacgcgttg acattgatta ttgactagtt attaatagta atcaattacg gggtcattag 120
ttcatagccc atatatggag ttccgcgtta cataacttac ggtaaatggc ccgcctggct 180
gaccgcccaa cgacccccgc ccattgacgt caataatgac gtatgttccc atagtaacgc 240
caatagggac tttccattga cgtcaatggg tggactattt acggtaaact gcccacttgg 300
cagtacatca agtgtatcat atgccaagta cgccccctat tgacgtcaat gacggtaaat 360
ggcccgcctg gcattatgcc cagtacatga ccttatggga ctttcctact tggcagtaca 420
tctacgtatt agtcatcgct attaccatgg tgatgcggtt ttggcagtac atcaatgggc 480
gtggatagcg gtttgactca cggggatttc caagtctcca ccccattgac gtcaatggga 540
gtttgttttg gcaccaaaat caacgggact ttccaaaatg tcgtaacaac tccgccccat 600
tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta tataagcaga gctctctggc 660
taactagaga acccactgct tactggctta tcgaaattaa tacgactcac tatagggaga 720
cccaagctgg ctagcctcga gtctagaggg cccgtttaaa cccgctgatc agcctcgact 780
gtgccttcta gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg 840
gaaggtgcca ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg 900
agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg 960
gaagacaata gcaggcatgc tggggatgcg gtgggctcta tggcttctac tgggcggttt 1020
tatggacagc aagcgaaccg gaattgccag ctggggcgcc ctctggtaag gttgggaagc 1080
cctgcaaagt aaactggatg gctttctcgc cgccaaggat ctgatggcgc aggggatcaa 1140
gctctgatca agagacagga tgaggatcgt ttcgcatgat tgaacaagat ggattgcacg 1200
caggttctcc ggccgcttgg gtggagaggc tattcggcta tgactgggca caacagacaa 1260
tcggctgctc tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg gttctttttg 1320
tcaagaccga cctgtccggt gccctgaatg aactgcaaga cgaggcagcg cggctatcgt 1380
ggctggccac gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact gaagcgggaa 1440
gggactggct gctattgggc gaagtgccgg ggcaggatct cctgtcatct caccttgctc 1500
ctgccgagaa agtatccatc atggctgatg caatgcggcg gctgcatacg cttgatccgg 1560
ctacctgccc attcgaccac caagcgaaac atcgcatcga gcgagcacgt actcggatgg 1620
aagccggtct tgtcgatcag gatgatctgg acgaagagca tcaggggctc gcgccagccg 1680
aactgttcgc caggctcaag gcgagcatgc ccgacggcga ggatctcgtc gtgacccatg 1740
gcgatgcctg cttgccgaat atcatggtgg aaaatggccg cttttctgga ttcatcgact 1800
gtggccggct gggtgtggcg gaccgctatc aggacatagc gttggctacc cgtgatattg 1860
ctgaagagct tggcggcgaa tgggctgacc gcttcctcgt gctttacggt atcgccgctc 1920
ccgattcgca gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga attattaacg 1980
cttacaattt cctgatgcgg tattttctcc ttacgcatct gtgcggtatt tcacaccgca 2040
tacaggtggc acttttcggg gaaatgtgcg cggaacccct atttgtttat ttttctaaat 2100
acattcaaat atgtatccgc tcatgagaca ataaccctga taaatgcttc aataatagca 2160
cgtgctaaaa cttcattttt aatttaaaag gatctaggtg aagatccttt ttgataatct 2220
catgaccaaa atcccttaac gtgagttttc gttccactga gcgtcagacc cccatcagtg 2280
accaaacagg aaaaaaccgc ccttaacatg gcccgcttta tcagaagcca gacattaacg 2340
cttctggaga aactcaacga gctggacgcg gatgaacagg cagacatctg tgaatcgctt 2400
cacgaccacg ctgatgagct ttaccgcagc tgcctcgcgc gtttcggtga tgacggtgaa 2460
aacctctgac acatgcagct cccggagacg gtcacagctt gtctgtaagc ggatgccggg 2520
agcagacaag cccgtcaggg cgcgtcagcg ggtgttggcg ggtgtcgggg cgcagccatg 2580
acccagtcac gtagcgatag cggagtgtat actggcttaa ctatgcggca tcagagcaga 2640
ttgtactgag agtgcaccat atgcggtgtg aaataccgca cagatgcgta aggagaaaat 2700
accgcatcag gcgctcttcc gcttcctcgc tcactgactc gctgcgctcg gtcgttcggc 2760
tgcggcgagc ggtatcagct cactcaaagg cggtaatacg gttatccaca gaatcagggg 2820
ataacgcagg aaagaacatg tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg 2880
ccgcgttgct ggcgtttttc cataggctcc gcccccctga cgagcatcac aaaaatcgac 2940
gctcaagtca gaggtggcga aacccgacag gactataaag ataccaggcg tttccccctg 3000
gaagctccct cgtgcgctct cctgttccga ccctgccgct taccggatac ctgtccgcct 3060
ttctcccttc gggaagcgtg gcgctttctc atagctcacg ctgtaggtat ctcagttcgg 3120
tgtaggtcgt tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct 3180
gcgccttatc cggtaactat cgtcttgagt ccaacccggt aagacacgac ttatcgccac 3240
tggcagcagc cactggtaac aggattagca gagcgaggta tgtaggcggt gctacagagt 3300
tcttgaagtg gtggcctaac tacggctaca ctagaaggac agtatttggt atctgcgctc 3360
tgctgaagcc agttaccttc ggaaaaagag ttggtagctc ttgatccggc aaacaaacca 3420
ccgctggtag cggtggtttt tttgtttgca agcagcagat tacgcgcaga aaaaaaggat 3480
ctcaagaaga tcctttgatc 3500
<210> 3
<211> 371
<212> PRT
<213> Homo sapiens
<400> 3
Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val Pro
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Ser Leu Gly Gly Gly Gly Gly Cys Ala Leu Pro Val Ser Gly Ala Ala
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Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr
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Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro Pro Pro Pro Pro
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Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro Ser Trp Gly Gly
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Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe Thr Val His Phe
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Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly Pro Phe
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Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln Ala Arg Met Phe
115 120 125
Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser Gln Pro Ala Ile
130 135 140
Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly Thr Pro Ser Tyr
145 150 155 160
Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Asn His Ser Phe
165 170 175
Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln
180 185 190
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser
195 200 205
Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp
210 215 220
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
225 230 235 240
Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala Gly Ser Ser Ser
245 250 255
Ser Val Lys Trp Thr Glu Gly Gln Ser Asn His Ser Thr Gly Tyr Glu
260 265 270
Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln Tyr Arg Ile
275 280 285
His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val Pro
290 295 300
Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu Lys
305 310 315 320
Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys
325 330 335
Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly Glu Lys Pro
340 345 350
Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp
355 360 365
Gln Leu Lys
370
<210> 4
<211> 630
<212> PRT
<213> Homo sapiens
<400> 4
Met Ala Leu Pro Thr Ala Arg Pro Leu Leu Gly Ser Cys Gly Thr Pro
1 5 10 15
Ala Leu Gly Ser Leu Leu Phe Leu Leu Phe Ser Leu Gly Trp Val Gln
20 25 30
Pro Ser Arg Thr Leu Ala Gly Glu Thr Gly Gln Glu Ala Ala Pro Leu
35 40 45
Asp Gly Val Leu Ala Asn Pro Pro Asn Ile Ser Ser Leu Ser Pro Arg
50 55 60
Gln Leu Leu Gly Phe Pro Cys Ala Glu Val Ser Gly Leu Ser Thr Glu
65 70 75 80
Arg Val Arg Glu Leu Ala Val Ala Leu Ala Gln Lys Asn Val Lys Leu
85 90 95
Ser Thr Glu Gln Leu Arg Cys Leu Ala His Arg Leu Ser Glu Pro Pro
100 105 110
Glu Asp Leu Asp Ala Leu Pro Leu Asp Leu Leu Leu Phe Leu Asn Pro
115 120 125
Asp Ala Phe Ser Gly Pro Gln Ala Cys Thr Arg Phe Phe Ser Arg Ile
130 135 140
Thr Lys Ala Asn Val Asp Leu Leu Pro Arg Gly Ala Pro Glu Arg Gln
145 150 155 160
Arg Leu Leu Pro Ala Ala Leu Ala Cys Trp Gly Val Arg Gly Ser Leu
165 170 175
Leu Ser Glu Ala Asp Val Arg Ala Leu Gly Gly Leu Ala Cys Asp Leu
180 185 190
Pro Gly Arg Phe Val Ala Glu Ser Ala Glu Val Leu Leu Pro Arg Leu
195 200 205
Val Ser Cys Pro Gly Pro Leu Asp Gln Asp Gln Gln Glu Ala Ala Arg
210 215 220
Ala Ala Leu Gln Gly Gly Gly Pro Pro Tyr Gly Pro Pro Ser Thr Trp
225 230 235 240
Ser Val Ser Thr Met Asp Ala Leu Arg Gly Leu Leu Pro Val Leu Gly
245 250 255
Gln Pro Ile Ile Arg Ser Ile Pro Gln Gly Ile Val Ala Ala Trp Arg
260 265 270
Gln Arg Ser Ser Arg Asp Pro Ser Trp Arg Gln Pro Glu Arg Thr Ile
275 280 285
Leu Arg Pro Arg Phe Arg Arg Glu Val Glu Lys Thr Ala Cys Pro Ser
290 295 300
Gly Lys Lys Ala Arg Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys Lys
305 310 315 320
Trp Glu Leu Glu Ala Cys Val Asp Ala Ala Leu Leu Ala Thr Gln Met
325 330 335
Asp Arg Val Asn Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val Leu
340 345 350
Lys His Lys Leu Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser Val
355 360 365
Ile Gln His Leu Gly Tyr Leu Phe Leu Lys Met Ser Pro Glu Asp Ile
370 375 380
Arg Lys Trp Asn Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu Glu
385 390 395 400
Val Asn Lys Gly His Glu Met Ser Pro Gln Ala Pro Arg Arg Pro Leu
405 410 415
Pro Gln Val Ala Thr Leu Ile Asp Arg Phe Val Lys Gly Arg Gly Gln
420 425 430
Leu Asp Lys Asp Thr Leu Asp Thr Leu Thr Ala Phe Tyr Pro Gly Tyr
435 440 445
Leu Cys Ser Leu Ser Pro Glu Glu Leu Ser Ser Val Pro Pro Ser Ser
450 455 460
Ile Trp Ala Val Arg Pro Gln Asp Leu Asp Thr Cys Asp Pro Arg Gln
465 470 475 480
Leu Asp Val Leu Tyr Pro Lys Ala Arg Leu Ala Phe Gln Asn Met Asn
485 490 495
Gly Ser Glu Tyr Phe Val Lys Ile Gln Ser Phe Leu Gly Gly Ala Pro
500 505 510
Thr Glu Asp Leu Lys Ala Leu Ser Gln Gln Asn Val Ser Met Asp Leu
515 520 525
Ala Thr Phe Met Lys Leu Arg Thr Asp Ala Val Leu Pro Leu Thr Val
530 535 540
Ala Glu Val Gln Lys Leu Leu Gly Pro His Val Glu Gly Leu Lys Ala
545 550 555 560
Glu Glu Arg His Arg Pro Val Arg Asp Trp Ile Leu Arg Gln Arg Gln
565 570 575
Asp Asp Leu Asp Thr Leu Gly Leu Gly Leu Gln Gly Gly Ile Pro Asn
580 585 590
Gly Tyr Leu Val Leu Asp Leu Ser Met Gln Glu Ala Leu Ser Gly Thr
595 600 605
Pro Cys Leu Leu Gly Pro Gly Pro Val Leu Thr Val Leu Ala Leu Leu
610 615 620
Leu Ala Ser Thr Leu Ala
625 630
<210> 5
<211> 702
<212> PRT
<213> Homo sapiens
<400> 5
Met Glu Ser Pro Ser Ala Pro Pro His Arg Trp Cys Ile Pro Trp Gln
1 5 10 15
Arg Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Leu Val His Asn Leu Pro Gln His Leu Phe Gly
50 55 60
Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Ile
65 70 75 80
Gly Tyr Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Ile Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Ile
100 105 110
Ile Gln Asn Asp Thr Gly Phe Tyr Thr Leu His Val Ile Lys Ser Asp
115 120 125
Leu Val Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu
130 135 140
Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu Asp Lys
145 150 155 160
Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Ala Thr Tyr
165 170 175
Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln
180 185 190
Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr Arg Asn
195 200 205
Asp Thr Ala Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Ala Arg
210 215 220
Arg Ser Asp Ser Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro
225 230 235 240
Thr Ile Ser Pro Leu Asn Thr Ser Tyr Arg Ser Gly Glu Asn Leu Asn
245 250 255
Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe
260 265 270
Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
275 280 285
Ile Thr Val Asn Asn Ser Gly Ser Tyr Thr Cys Gln Ala His Asn Ser
290 295 300
Asp Thr Gly Leu Asn Arg Thr Thr Val Thr Thr Ile Thr Val Tyr Ala
305 310 315 320
Glu Pro Pro Lys Pro Phe Ile Thr Ser Asn Asn Ser Asn Pro Val Glu
325 330 335
Asp Glu Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Ile Gln Asn Thr
340 345 350
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg
355 360 365
Leu Gln Leu Ser Asn Asp Asn Arg Thr Leu Thr Leu Leu Ser Val Thr
370 375 380
Arg Asn Asp Val Gly Pro Tyr Glu Cys Gly Ile Gln Asn Lys Leu Ser
385 390 395 400
Val Asp His Ser Asp Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp
405 410 415
Asp Pro Thr Ile Ser Pro Ser Tyr Thr Tyr Tyr Arg Pro Gly Val Asn
420 425 430
Leu Ser Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser
435 440 445
Trp Leu Ile Asp Gly Asn Ile Gln Gln His Thr Gln Glu Leu Phe Ile
450 455 460
Ser Asn Ile Thr Glu Lys Asn Ser Gly Leu Tyr Thr Cys Gln Ala Asn
465 470 475 480
Asn Ser Ala Ser Gly His Ser Arg Thr Thr Val Lys Thr Ile Thr Val
485 490 495
Ser Ala Glu Leu Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro
500 505 510
Val Glu Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Ala Gln
515 520 525
Asn Thr Thr Tyr Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser
530 535 540
Pro Arg Leu Gln Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn
545 550 555 560
Val Thr Arg Asn Asp Ala Arg Ala Tyr Val Cys Gly Ile Gln Asn Ser
565 570 575
Val Ser Ala Asn Arg Ser Asp Pro Val Thr Leu Asp Val Leu Tyr Gly
580 585 590
Pro Asp Thr Pro Ile Ile Ser Pro Pro Asp Ser Ser Tyr Leu Ser Gly
595 600 605
Ala Asn Leu Asn Leu Ser Cys His Ser Ala Ser Asn Pro Ser Pro Gln
610 615 620
Tyr Ser Trp Arg Ile Asn Gly Ile Pro Gln Gln His Thr Gln Val Leu
625 630 635 640
Phe Ile Ala Lys Ile Thr Pro Asn Asn Asn Gly Thr Tyr Ala Cys Phe
645 650 655
Val Ser Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Ser Ile
660 665 670
Thr Val Ser Ala Ser Gly Thr Ser Pro Gly Leu Ser Ala Gly Ala Thr
675 680 685
Val Gly Ile Met Ile Gly Val Leu Val Gly Val Ala Leu Ile
690 695 700
<210> 6
<211> 561
<212> PRT
<213> Cytomegalovirus
<400> 6
Met Glu Ser Arg Gly Arg Arg Cys Pro Glu Met Ile Ser Val Leu Gly
1 5 10 15
Pro Ile Ser Gly His Val Leu Lys Ala Val Phe Ser Arg Gly Asp Thr
20 25 30
Pro Val Leu Pro His Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val
35 40 45
Arg Val Ser Gln Pro Ser Leu Ile Leu Val Ser Gln Tyr Thr Pro Asp
50 55 60
Ser Thr Pro Cys His Arg Gly Asp Asn Gln Leu Gln Val Gln His Thr
65 70 75 80
Tyr Phe Thr Gly Ser Glu Val Glu Asn Val Ser Val Asn Val His Asn
85 90 95
Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln Glu Pro Met Ser Ile Tyr
100 105 110
Val Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser Ile Asn Val
115 120 125
His His Tyr Pro Ser Ala Ala Glu Arg Lys His Arg His Leu Pro Val
130 135 140
Ala Asp Ala Val Ile His Ala Ser Gly Lys Gln Met Trp Gln Ala Arg
145 150 155 160
Leu Thr Val Ser Gly Leu Ala Trp Thr Arg Gln Gln Asn Gln Trp Lys
165 170 175
Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro Thr Lys Asp
180 185 190
Val Ala Leu Arg His Val Val Cys Ala His Glu Leu Val Cys Ser Met
195 200 205
Glu Asn Thr Arg Ala Thr Lys Met Gln Val Ile Gly Asp Gln Tyr Val
210 215 220
Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp Val Pro Ser Gly Lys Leu
225 230 235 240
Phe Met His Val Thr Leu Gly Ser Asp Val Glu Glu Asp Leu Thr Met
245 250 255
Thr Arg Asn Pro Gln Pro Phe Met Arg Pro His Glu Arg Asn Gly Phe
260 265 270
Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys Pro Gly Lys Ile Ser
275 280 285
His Ile Met Leu Asp Val Ala Phe Thr Ser His Glu His Phe Gly Leu
290 295 300
Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser Ile Ser Gly Asn Leu Leu
305 310 315 320
Met Asn Gly Gln Gln Ile Phe Leu Glu Val Gln Ala Ile Arg Glu Thr
325 330 335
Val Glu Leu Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe Phe Phe Asp
340 345 350
Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln Tyr Ser Glu His Pro Thr
355 360 365
Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys Leu Glu Tyr Arg His Thr
370 375 380
Trp Asp Arg His Asp Glu Gly Ala Ala Gln Gly Asp Asp Asp Val Trp
385 390 395 400
Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu Val Thr Thr Glu Arg Lys
405 410 415
Thr Pro Arg Val Thr Gly Gly Gly Ala Met Ala Gly Ala Ser Thr Ser
420 425 430
Ala Gly Arg Lys Arg Lys Ser Ala Ser Ser Ala Thr Ala Cys Thr Ala
435 440 445
Gly Val Met Thr Arg Gly Arg Leu Lys Ala Glu Ser Thr Val Ala Pro
450 455 460
Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn Glu Ile His Asn Pro Ala
465 470 475 480
Val Phe Thr Trp Pro Pro Trp Gln Ala Gly Ile Leu Ala Arg Asn Leu
485 490 495
Val Pro Met Val Ala Thr Val Gln Gly Gln Asn Leu Lys Tyr Gln Glu
500 505 510
Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg Ile Phe Ala Glu Leu Glu
515 520 525
Gly Val Trp Gln Pro Ala Ala Gln Pro Lys Arg Arg Arg His Arg Gln
530 535 540
Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser Thr Pro Lys Lys His Arg
545 550 555 560
Gly
<210> 7
<211> 561
<212> PRT
<213> artificial sequence
<220>
<223> mutated CMV pp65
<400> 7
Met Glu Ser Arg Gly Arg Arg Cys Pro Glu Met Ile Ser Val Leu Gly
1 5 10 15
Pro Ile Ser Gly His Val Leu Lys Ala Val Phe Ser Arg Gly Asp Thr
20 25 30
Pro Val Leu Pro His Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val
35 40 45
Arg Val Ser Gln Pro Ser Leu Ile Leu Val Ser Gln Tyr Thr Pro Asp
50 55 60
Ser Thr Pro Cys His Arg Gly Asp Asn Gln Leu Gln Val Gln His Thr
65 70 75 80
Tyr Phe Thr Gly Ser Glu Val Glu Asn Val Ser Val Asn Val His Asn
85 90 95
Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln Glu Pro Met Ser Ile Tyr
100 105 110
Val Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser Ile Asn Val
115 120 125
His His Tyr Pro Ser Ala Ala Glu Arg Lys His Arg His Leu Pro Val
130 135 140
Ala Asp Ala Val Ile His Ala Ser Gly Lys Gln Met Trp Gln Ala Arg
145 150 155 160
Leu Thr Val Ser Gly Leu Ala Trp Thr Arg Gln Gln Asn Gln Trp Lys
165 170 175
Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro Thr Lys Asp
180 185 190
Val Ala Leu Arg His Val Val Cys Ala His Glu Leu Val Cys Ser Met
195 200 205
Glu Asn Thr Arg Ala Thr Lys Met Gln Val Ile Gly Asp Gln Tyr Val
210 215 220
Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp Val Pro Ser Gly Lys Leu
225 230 235 240
Phe Met His Val Thr Leu Gly Ser Asp Val Glu Glu Asp Leu Thr Met
245 250 255
Thr Arg Asn Pro Gln Pro Phe Met Arg Pro His Glu Arg Asn Gly Phe
260 265 270
Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys Pro Gly Lys Ile Ser
275 280 285
His Ile Met Leu Asp Val Ala Phe Thr Ser His Glu His Phe Gly Leu
290 295 300
Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser Ile Ser Gly Asn Leu Leu
305 310 315 320
Met Asn Gly Gln Gln Ile Phe Leu Glu Val Gln Ala Ile Arg Glu Thr
325 330 335
Val Glu Leu Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe Phe Phe Asp
340 345 350
Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln Tyr Ser Glu His Pro Thr
355 360 365
Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys Leu Glu Tyr Arg His Thr
370 375 380
Trp Asp Arg His Asp Glu Gly Ala Ala Gln Gly Asp Asp Asp Val Trp
385 390 395 400
Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu Val Thr Thr Glu Arg Lys
405 410 415
Thr Pro Arg Val Thr Gly Gly Gly Ala Met Ala Gly Ala Ser Thr Ser
420 425 430
Ala Gly Arg Asn Arg Lys Ser Ala Ser Ser Ala Thr Ala Cys Thr Ala
435 440 445
Gly Val Met Thr Arg Gly Arg Leu Lys Ala Glu Ser Thr Val Ala Pro
450 455 460
Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn Glu Ile His Asn Pro Ala
465 470 475 480
Val Phe Thr Trp Pro Pro Trp Gln Ala Gly Ile Leu Ala Arg Asn Leu
485 490 495
Val Pro Met Val Ala Thr Val Gln Gly Gln Asn Leu Lys Tyr Gln Glu
500 505 510
Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg Ile Phe Ala Glu Leu Glu
515 520 525
Gly Val Trp Gln Pro Ala Ala Gln Pro Lys Arg Arg Arg His Arg Gln
530 535 540
Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser Thr Pro Lys Lys His Arg
545 550 555 560
Gly
<210> 8
<211> 536
<212> PRT
<213> artificial sequence
<220>
<223> mutated CMV pp65
<400> 8
Met Glu Ser Arg Gly Arg Arg Cys Pro Glu Met Ile Ser Val Leu Gly
1 5 10 15
Pro Ile Ser Gly His Val Leu Lys Ala Val Phe Ser Arg Gly Asp Thr
20 25 30
Pro Val Leu Pro His Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val
35 40 45
Arg Val Ser Gln Pro Ser Leu Ile Leu Val Ser Gln Tyr Thr Pro Asp
50 55 60
Ser Thr Pro Cys His Arg Gly Asp Asn Gln Leu Gln Val Gln His Thr
65 70 75 80
Tyr Phe Thr Gly Ser Glu Val Glu Asn Val Ser Val Asn Val His Asn
85 90 95
Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln Glu Pro Met Ser Ile Tyr
100 105 110
Val Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser Ile Asn Val
115 120 125
His His Tyr Pro Ser Ala Ala Glu Arg Lys His Arg His Leu Pro Val
130 135 140
Ala Asp Ala Val Ile His Ala Ser Gly Lys Gln Met Trp Gln Ala Arg
145 150 155 160
Leu Thr Val Ser Gly Leu Ala Trp Thr Arg Gln Gln Asn Gln Trp Lys
165 170 175
Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro Thr Lys Asp
180 185 190
Val Ala Leu Arg His Val Val Cys Ala His Glu Leu Val Cys Ser Met
195 200 205
Glu Asn Thr Arg Ala Thr Lys Met Gln Val Ile Gly Asp Gln Tyr Val
210 215 220
Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp Val Pro Ser Gly Lys Leu
225 230 235 240
Phe Met His Val Thr Leu Gly Ser Asp Val Glu Glu Asp Leu Thr Met
245 250 255
Thr Arg Asn Pro Gln Pro Phe Met Arg Pro His Glu Arg Asn Gly Phe
260 265 270
Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys Pro Gly Lys Ile Ser
275 280 285
His Ile Met Leu Asp Val Ala Phe Thr Ser His Glu His Phe Gly Leu
290 295 300
Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser Ile Ser Gly Asn Leu Leu
305 310 315 320
Met Asn Gly Gln Gln Ile Phe Leu Glu Val Gln Ala Ile Arg Glu Thr
325 330 335
Val Glu Leu Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe Phe Phe Asp
340 345 350
Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln Tyr Ser Glu His Pro Thr
355 360 365
Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys Leu Glu Tyr Arg His Thr
370 375 380
Trp Asp Arg His Asp Glu Gly Ala Ala Gln Gly Asp Asp Asp Val Trp
385 390 395 400
Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu Val Thr Thr Glu Arg Lys
405 410 415
Thr Pro Arg Val Thr Gly Gly Gly Ala Met Ala Gly Ala Ser Thr Ser
420 425 430
Ala Gly Arg Asn Arg Lys Ser Ala Ser Ser Ala Thr Ala Cys Thr Ala
435 440 445
Gly Val Met Thr Arg Gly Arg Leu Lys Ala Glu Ser Thr Val Ala Pro
450 455 460
Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn Glu Ile His Asn Pro Ala
465 470 475 480
Val Phe Thr Trp Pro Pro Trp Gln Ala Gly Ile Leu Ala Arg Asn Leu
485 490 495
Val Pro Met Val Ala Thr Val Gln Gly Gln Asn Leu Lys Tyr Gln Glu
500 505 510
Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg Ile Phe Ala Glu Leu Glu
515 520 525
Gly Val Trp Gln Pro Ala Ala Gln
530 535
Claims (15)
- VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항에 있어서, 상기 암은 교모세포종, 유암종, 신장암, 구체적으로 신세포암종, 갑상선암, 폐암, 구체적으로 비소세포 폐암(NSCLC), 유방암, 난소암, 전립선암, 위장관암, 구체적으로 결장직장암, 더욱 구체적으로 결장암, 그리고 피부암, 구체적으로 흑색종으로 이루어진 군으로부터 선택되는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- VEGF 수용체 단백질을 암호화하는 발현 카세트를 포함하는 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라 약독화 균주로서, VEGF 수용체 단백질 발현 암세포 적어도 하나를 포함하는 환자를 대상으로 하는 암 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 살모넬라 약독화 균주는 살모넬라 엔테리카 종이고, 구체적으로 상기 살모넬라 약독화 균주는 살모넬라 타이피 Ty21a인, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 상기 발현 카세트는 진핵생물 발현 카세트이고, 구체적으로 상기 발현 카세트는 CMV 프로모터를 포함하는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제5항 중 어느 한 항에 있어서, 상기 VEGF 수용체 단백질은 VEGFR-2이고, 구체적으로 상기 VEGF 수용체 단백질은 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는 VEGFR-2 및 이것과 적어도 80%의 서열 동일성을 공유하는 단백질로 이루어진 군으로부터 선택되며, 구체적으로 상기 VEGF 수용체 단백질은 서열 번호 1에서 발견되는 바와 같은 아미노산 서열을 가지는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제6항 중 어느 한 항에 있어서, 상기 DNA 분자는 카나마이신 항생제 내성 유전자, pMB1 ori 및 CMV 프로모터를 포함하고, 구체적으로 상기 DNA 분자는 서열 번호 2에서 발견되는 바와 같은 DNA 서열을 포함하는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제7항 중 어느 한 항에 있어서, 상기 암 면역요법은 화학요법, 방사선요법 또는 생물학적 암 치료법이 동반되고, 구체적으로 상기 살모넬라 약독화 균주는 화학요법 또는 방사선요법 치료 또는 생물학적 암 치료법이 수행되기 전, 수행되는 도중 또는 수행된 후에 투여되거나, 화학요법 또는 방사선요법 치료 또는 생물학적 암 치료법이 수행되기 전 및 수행되는 도중에 투여되는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제8항에 있어서, 상기 생물학적 암 치료법은, 구체적으로 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가의 발현 카세트를 포함하는 추가의 DNA 분자 복사체 적어도 하나를 포함하는 살모넬라의 추가 약독화 균주 적어도 하나로부터 선택되는, 종양 항원 및/또는 종양 기질 항원을 암호화하는 추가의 DNA 백신 적어도 하나를 투여하는 것을 포함하고, 구체적으로 상기 살모넬라의 추가 약독화 균주 적어도 하나는 추가의 진핵생물 발현 카세트를 포함하는 살모넬라 타이피 Ty21a인, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제9항에 있어서, 상기 추가의 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 항원은 인간 빌름 종양 단백질(WT1), 인간 메소텔린(MSLN), 인간 CEA 및 CMV pp65로 이루어진 군으로부터 선택되는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제10항에 있어서, 상기 종양 항원은 서열 번호 3에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 빌름 종양 단백질(WT1) 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 4에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 메소텔린(MSLN) 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 5에서 발견되는 바와 같은 아미노산 서열을 가지는 인간 CEA 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 6에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 서열 번호 7에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질, 그리고 서열 번호 8에서 발견되는 바와 같은 아미노산 서열을 가지는 CMV pp65 및 이것과 적어도 약 80%의 서열 동일성을 공유하는 단백질로 이루어진 군으로부터 선택되는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제9항에 있어서, 상기 추가의 DNA 백신 적어도 하나에 의해 암호화되는 상기 종양 기질 항원은 인간 섬유아세포 활성화 단백질(FAP)인, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제12항 중 어느 한 항에 있어서, 상기 살모넬라 약독화 균주는 경구 투여되는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제13항 중 어느 한 항에 있어서, 상기 살모넬라 약독화 균주의 단일 용량은 약 105 내지 약 1011, 구체적으로 약 106 내지 약 1010, 더욱 구체적으로 약 106 내지 약 109, 더욱 구체적으로 약 106 내지 약 108, 가장 구체적으로 약 106 내지 약 107의 콜로니 형성 단위(CFU)를 포함하는, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 살모넬라 약독화 균주는 환자에서 적어도 하나의 VEGF 수용체 단백질, 구체적으로 VEGFR-2의 발현 패턴 및/또는 이에 대한 전면역 반응을 평가하는 단계를 포함하는 개별맞춤 암 면역요법에 사용하기 위한 것인, 암, 즉 VEGF 수용체 단백질 발현 암세포에 의해 특징지어지는 암의 면역요법에 사용하기 위한 살모넬라 약독화 균주.
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