KR20200031143A - 국소 조성물 및 용도 - Google Patents
국소 조성물 및 용도 Download PDFInfo
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- KR20200031143A KR20200031143A KR1020207004757A KR20207004757A KR20200031143A KR 20200031143 A KR20200031143 A KR 20200031143A KR 1020207004757 A KR1020207004757 A KR 1020207004757A KR 20207004757 A KR20207004757 A KR 20207004757A KR 20200031143 A KR20200031143 A KR 20200031143A
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Abstract
본 발명은 보툴리눔 신경독 (BoNT) 과 같은 치료 펩티드에 융합된 하나 이상의 징크 핑거 모티프를 포함하는 키메라 폴리펩티드를 제공한다. 징크 핑거 모티프는 BoNT의 C-말단 측에 위치할 수 있고 키메라 폴리펩티드는 임의로 2 개 이상의 이러한 징크 핑거 모티프를 포함할 수 있다. 개시된 키메라 폴리펩티드는 대상에게 경피적으로 효과적으로 전달될 수 있는 것으로 나타났다.
Description
보툴리눔 신경독 (BoNT) 은 박테리아 클로스트리디움 보툴리눔 (Clostridium botulinum) 및 관련 종에 의해 생성된 자연 발생 신경독이다. BoNT, A, B, C1, D, E, F 및 G 의 7 가지 알려진 혈청형이 있다. BoNT 는 단일 폴리펩티드 사슬로서 박테리아로부터 방출된 후, 단일 디술피드 결합을 통해 연결된, 100 kDa 중쇄 및 50 kDa 경쇄로 자가-절단된다. 중쇄는 보툴리눔 독소를 전-시냅스 신경 말단으로 향하게 하고 경쇄의 세포질 내로의 내재화를 매개한다. 보툴리눔의 경쇄는 SNARE (가용성 N-에틸말레이미드-민감성 융합 부착 단백질 수용체) 복합 단백질을 특이적으로 절단하는 메탈로프로테아제이다.
SNARE 는 포유류 세포에서 60 개 초과의 구성원으로 이루어진 큰 단백질 슈퍼 패밀리이다. 코어 SNARE 복합체는 시냅토브레빈 (소낭-연관 막 단백질, VAMP 라고도 함) 및 신택신-1 각각으로부터의 하나의 헬릭스 및 시냅토소말-연관 단백질 25 (SNAP-25) 로부터의 2 개의 헬렉스를 포함하는, 4-α-헬릭스 번들이다. 이들 SNARE 단백질로부터의 4 개의 헬릭스는 서로를 감아서 코일화-코일 4 차 구조를 조립한다. 신택신-1 은 SNAP-25 의 N-말단 헬릭스에 결합하는 반면, 시냅토브레빈 헬릭스는 SNAP-25 의 C-말단 헬릭스에 결합한다. SNARE 복합체의 주요 역할은 소낭 융합, 예를 들어 뉴런에서 시냅스 소낭과 전-시냅스 막의 융합을 매개하는 것이다.
BoNT 는 3 개의 코어 SNARE 단백질 중 하나, 시냅토브레빈, 신택신-1 또는 SNAP-25 를 특이적으로 절단한다. 이들 3 가지 단백질 중 어느 하나의 불활성화는 코어 SNARE 복합체의 형성 또는 코어 SNARE 복합체와 SNARE 슈퍼복합체 내의 다른 성분과의 상호작용을 방해할 것이다. SNARE 슈퍼복합체의 기능 차단은 세포막과 소낭의 융합을 방지하여, 축삭 말단으로부터 신경전달물질 아세틸콜린의 방출을 막아 근육 마비를 초래한다.
BoNT 는 지구에서 가장 강력한 자연 발생 독소로, 50 ng 정도의 물질로 인간에게 보톨리눔독소증을 유발한다. 자연적으로, BoNT 는 야생 동물 및 가축을 주로 감염시키며 무척추 동물을 통해 유포된다. 독소의 기원에 따르면, 인간 보톨리눔독소증은, 음식-유발 보톨리눔독소증, 유아 보톨리눔독소증, 흡입 보톨리눔독소증, 의원성 보톨리눔독소증 (BoNT 의 과도한 임상 복용으로 인해 야기됨) 및 상처 보톨리눔독소증 (주로 약물 주사로 인해 야기됨), 5 개 계열로 분류된다. 첫번째 두가지가 가장 흔히 보이는 인간 보톨리눔독소증이다.
BoNT 의 치료적 용도는 Alan B. Scott 에 의해 1960 년대 후반에 처음 제안되었으며 1977 년 사시가 있는 어린이에게 실시되었다. BoNT 의 특별한 특이성은 신경 말단의 과잉활동성을 특징으로 하는 인간 질병에 효과적인 작용제로 만든다. BoNT 의 치료적 용도의 가장 큰 비율은 신경학적 장애, 예컨대 근긴장이상, 경련, 반측안면 경련, 다한증 (과다한 발한) 및 과다침분비 (과다한 타액) 이다. BoNT 의 또 다른 중요한 용도는 비뇨기과 장애, 예컨대 배뇨근 괄약근 협동장애, 특발성 배뇨근 과활동성, 신경성 배뇨근 과활동성, 요정체, 항문 균열 및 양성 전립선 비대증을 치료하는 것이다. 드물게 보이지만, BoNT 는 위장관학적 및 이비인후과적 장애를 치료하는 데 사용될 수 있다. BoNTA 는 65 세 이하의 성인 환자에서 중등도 내지 중증의 미간 주름의 치료를 위해 2002 년에 미국 식품의약국 (FDA) 의 승인을 받았다. 2005 년부터, BoNTA 는 가장 널리 사용되는 비침습적, 의사-보조 화장품 시술이 되었다. 전체 환자 만족도는 80% 를 넘지만, 주사가능한 BoNTA 는 통증, 바늘 자국, 압통, 출혈 및 멍과 같은 많은 단점에 직면한다. 특히, 눈가의 잔주름 또는 외안각 부위에 BoNTA 를 주사하는 것은 얇은 피부 및 표면 혈관으로 인한 높은 멍의 위험과 연관될 수 있다. 일부 치료의 경우, 최대 효과를 얻으려면 여러 번 주사해야한다.
본 발명은, 하나의 구현예에서, (a) 보툴리눔 독소 (BoNT) 경쇄 및 (b) BoNT 경쇄의 C-말단에 위치하는 또는, BoNT 경쇄의 C-말단에 위치하거나 디술피드 결합을 통해 BoNT 경쇄에 결합된 BoNT 중쇄에 대해 C-말단에 위치하는 제 1 징크 핑거 모티프를 포함하는 키메라 폴리펩티드를 제공한다. 일부 구현예에서, 키메라 폴리펩티드는 2000 개 초과의 아미노산 잔기를 포함하지 않는다.
일부 구현예에서, BoNT 경쇄 및 제 1 징크 핑거 모티프는 동일한 펩티드 사슬 상에 있다. 일부 구현예에서, BoNT 경쇄 및 제 1 징크 핑거 모티프는 상이한 펩티드 사슬 상에 있다.
일부 구현예에서, 키메라 폴리펩티드는 BoNT 경쇄의 N-말단에 위치한 제 2 징크 핑거 모티프를 추가로 포함한다. 일부 구현예에서, 제 1 징크 핑거 모티프 및 제 2 징크 핑거 모티프 중 적어도 하나는 적어도 추가의 징크 핑거 모티프에 연결된다. 일부 구현예에서, 징크 핑거 모티프 중 적어도 하나는 Cys2-His2 징크 핑거 모티프이다. 일부 구현예에서, 징크 핑거 모티프는 징크 핑거 모티프에서 알파-헬릭스 단편의 잔기 -1, 2, 3 또는 6 에서 적어도 알라닌을 함유한다.
하나의 예시적인 구현예에서, (a) 보툴리눔 독소 (BoNT) 경쇄 및 BoNT 경쇄의 N-말단에 위치한 3 개의 징크 핑거 모티프를 포함하는 제 1 사슬, 및 (b) BoNT 중쇄 및 BoNT 중쇄에 대한 C-말단에 위치된 3 개의 징크 핑거 모티프를 포함하는 제 2 사슬 (여기서 BoNT 경쇄는 디술피드 결합을 통해 BoNT 경쇄에 결합됨) 을 포함하는, 2-사슬 폴리펩티드가 제공된다. 유사하게, 하나의 구현예에서, N-말단에서 C-말단까지, 3 개의 징크 핑거 모티프, 보툴리눔 독소 (BoNT) 경쇄, BoNT 중쇄 및 3 개 이상의 징크 핑거 모티프를 포함하는, 키메라 폴리펩티드가 제공된다.
일부 구현예에서, 징크 핑거 모티프 중 적어도 하나는 SEQ ID NO: 1 및 5 내지 7 로 이루어진 군으로부터 선택된 아미노산 서열을 포함한다. 일부 구현예에서, 징크 핑거 모티프는 SEQ ID NO: 1 의 아미노산 서열을 포함한다. 일부 구현예에서, 제 1 징크 핑거는 BoNT 경쇄 또는 BoNT 중쇄의 C-말단으로부터 200 개 아미노산 잔기 이하로 떨어져 있다.
일부 구현예에서, BoNT 는 BoNT A, B, C, D, E, F, G 또는 그와 적어도 90% 서열 동일성을 갖는 변이체로부터 선택된다. 일부 구현예에서, BoNT 는 BoNT A1-A10, B1-B8, E1-E9 및 F1-F7 의 서브타입으로부터 선택된다. 일부 구현예에서, BoNT는 BoNT A이다. 일부 구현예에서, BoNT 경쇄는 SEQ ID NO: 8 의 아미노산 서열 또는 SEQ ID NO: 8 과 적어도 90% 서열 동일성을 갖는 아미노산 서열을 포함한다. 일부 구현예에서, BoNT 중쇄는 SEQ ID NO: 9 의 아미노산 서열 또는 SEQ ID NO: 9 와 적어도 90% 서열 동일성을 갖는 아미노산 서열을 포함한다.
일부 구현예에서, 키메라 폴리펩티드는 SEQ ID NO: 10 내지 17 로 이루어진 군으로부터 선택된 아미노산 서열을 포함하는 단일-사슬 폴리펩티드, 또는 아미노산 서열로부터 프로세싱된 2-사슬 폴리펩티드를 포함한다.
하나의 구현예에서, 보툴리눔 독소 (BoNT) 경쇄 및 적어도 징크 핑거 모티프를 포함하는 키메라 폴리펩티드가 또한 제공된다. 일부 구현예에서, 키메라성 폴리펩티드는 2000 개 초과의 아미노산 잔기를 포함하지 않는다. 일부 구현예에서, 징크 핑거 모티프는 C-말단에 위치하고 BoNT 경쇄로부터 200 개 아미노산 잔기 이하로 떨어져 있다.
본 발명의 또다른 구현예는 치료 펩티드 및 치료 펩티드의 C-말단에 위치된 징크 핑거 모티프를 적어도 포함하는 키메라 폴리펩티드를 제공하며, 여기서 징크 핑거 모티프의 N-말단은 치료 펩티드의 C-말단으로부터 100 개 아미노산 잔기 이하로 떨어져 있다. 일부 구현예에서, 치료 펩티드는 표피 성장 인자 (EGF) 및 슈퍼옥시드 디스뮤타제 (SOD) 로 이루어진 군으로부터 선택된다.
의약의 제조를 위한 용도 및 치료 방법도 또한 제공된다. 일부 구현예에서, 본 발명의 키메라 BoNT 폴리펩티드를 포함하는 제형을 국소적으로 적용하는 것을 포함하는, BoNT 경쇄를 포유동물 대상체에게 투여하는 방법이 제공된다. 일부 구현예에서, 투여는 대안적으로 근육내일 수 있다.
일부 구현예에서, 국소 적용은 피부 또는 눈, 귀, 코, 입, 입술, 요도 개구, 항문 또는 혀의 점막 상에 대한 것이다. 일부 구현예에서, 국소 적용은 붕괴된 피부의 각질층 상에 대한 것이다. 일부 구현예에서, 붕괴는 제형을 전달하기 위해 사용되는 바늘 또는 미세바늘로 수행된다. 일부 구현예에서, 국소 적용은 대상체의 얼굴 또는 목의 피부 상에 대한 것이다. 일부 구현예에서, 제형은 크림, 젤 또는 스프레이를 포함한다.
일부 구현예에서, 대상체는 안면 주름, 근긴장이상, 경련, 반측안면 경련, 다한증 또는 과다침분비의 치료를 필요로 한다.
본 발명의 키메라 폴리펩티드를 인코딩하는 폴리뉴클레오티드, 폴리뉴클레오티드 및/또는 폴리펩티드를 포함하는 세포 및 폴리펩티드를 포함하는 제형이 또한 특정 구현예에서 제공된다.
도 1 은 실시예에서 시험된 다양한 BoNTA 융합 단백질의 구조를 예시한다.
도 2 는 패널 A 및 B 와 함께, E. 콜라이 (E. coli) 에서 발현된 BoNTA-CPP 재조합 융합 단백질의 정제 결과를 보여준다. (A) TAT 및 Pep-1 은 단백질 발현 및 정제의 양호한 수율을 제공하지 않았다. (B) BoNTA-ZFP (Protein ID: 6) 는 우수한 단백질 발현 및 정제 수율을 제공하였다.
도 3 은 세포-침투 BoNTA 단백질의 시험관 내 활성의 SNAPtide 검정법 결과를 보여준다. 양성 대조군은 시판되는 재조합 BoNTA 경쇄 (BoNTA-LC, R&D Systems) 이다. Mock 은 SNAPtide 단독 반응이다.
도 4 는 세포-침투 BoNTA 단백질로 처리된 인간 진피 섬유아세포의 세포 용해의 SNAPtide 검정법 결과를 보여준다. 음성 대조군은 시판되는 재조합 BoNTA-LC (R&D Systems) 이다.
도 5 는 세포-침투 BoNTA 단백질의 생체 내 효과의 대표 이미지를 제시한다.
도 6 은 세포-침투 BoNTA 단백질로 처리된 마우스의 발가락 외전 (digit abduction) 의 산점도를 제시한다. A, 0.9% NaCl 식염수 용액을 처리함. B, BOTOX 를 주사함. C, 미세바늘로 전처리한 후 BOTOX 를 처리함. D, 미세바늘로 전처리한 후 세포-침투 BoNTA-ZFP (Protein ID 6) 를 처리함. E, 미세바늘 전처리 없이 세포-침투 BoNTA-ZFP (Protein ID 6) 를 처리함.
도 7 은 곤충 세포에서 BoNTA-ZFP (Protein ID 6) 의 발현을 보여준다. M, 단백질 마커. T, 총 세포 용리물. S, 가용성 분획. +, 로딩 대조군.
도 8 은 BoNTA-ZFP 의 근육 마비 활성을 분석하기 위한 트레드밀 연구의 시험 결과를 제시한다.
도 9 는 BoNTA-ZFP 의 근육 마비 활성을 분석하기 위한 빔 밸런스 연구의 시험 결과를 제시한다.
도 10 은 BoNTA-ZFP 의 근육 마비 활성을 분석하기 위한 발자국 연구의 시험 결과를 제시한다.
도 2 는 패널 A 및 B 와 함께, E. 콜라이 (E. coli) 에서 발현된 BoNTA-CPP 재조합 융합 단백질의 정제 결과를 보여준다. (A) TAT 및 Pep-1 은 단백질 발현 및 정제의 양호한 수율을 제공하지 않았다. (B) BoNTA-ZFP (Protein ID: 6) 는 우수한 단백질 발현 및 정제 수율을 제공하였다.
도 3 은 세포-침투 BoNTA 단백질의 시험관 내 활성의 SNAPtide 검정법 결과를 보여준다. 양성 대조군은 시판되는 재조합 BoNTA 경쇄 (BoNTA-LC, R&D Systems) 이다. Mock 은 SNAPtide 단독 반응이다.
도 4 는 세포-침투 BoNTA 단백질로 처리된 인간 진피 섬유아세포의 세포 용해의 SNAPtide 검정법 결과를 보여준다. 음성 대조군은 시판되는 재조합 BoNTA-LC (R&D Systems) 이다.
도 5 는 세포-침투 BoNTA 단백질의 생체 내 효과의 대표 이미지를 제시한다.
도 6 은 세포-침투 BoNTA 단백질로 처리된 마우스의 발가락 외전 (digit abduction) 의 산점도를 제시한다. A, 0.9% NaCl 식염수 용액을 처리함. B, BOTOX 를 주사함. C, 미세바늘로 전처리한 후 BOTOX 를 처리함. D, 미세바늘로 전처리한 후 세포-침투 BoNTA-ZFP (Protein ID 6) 를 처리함. E, 미세바늘 전처리 없이 세포-침투 BoNTA-ZFP (Protein ID 6) 를 처리함.
도 7 은 곤충 세포에서 BoNTA-ZFP (Protein ID 6) 의 발현을 보여준다. M, 단백질 마커. T, 총 세포 용리물. S, 가용성 분획. +, 로딩 대조군.
도 8 은 BoNTA-ZFP 의 근육 마비 활성을 분석하기 위한 트레드밀 연구의 시험 결과를 제시한다.
도 9 는 BoNTA-ZFP 의 근육 마비 활성을 분석하기 위한 빔 밸런스 연구의 시험 결과를 제시한다.
도 10 은 BoNTA-ZFP 의 근육 마비 활성을 분석하기 위한 발자국 연구의 시험 결과를 제시한다.
정의
단수형 실체라는 용어는 그 실체의 하나 이상을 지칭하고; 예를 들어, "항체" 는 하나 이상의 항체를 나타내는 것으로 이해됨을 명시한다. 이와 같이, 용어 "하나", "하나 이상" 및 "적어도 하나" 는 본 명세서에서 상호교환적으로 사용될 수 있다.
본원에서 사용되는 용어 "폴리펩티드" 는 단수형 "폴리펩티드" 와 복수형 "폴리펩티드들" 을 포함하는 것으로 의도되며, 아미드 결합 (펩티드 결합이라고도 알려짐) 을 통해 선형적으로 연결된 단량체 (아미노산) 로 구성된 분자를 의미한다. 용어 "폴리펩티드" 는 둘 이상의 아미노산의 임의 사슬 또는 사슬들을 의미하고, 생성물의 특별한 길이를 의미하지 않는다. 따라서, 펩티드, 디펩티드, 트리펩티드, 올리고펩티드, "단백질", "아미노산 사슬", 또는 둘 이상의 아미노산의 사슬 또는 사슬들을 언급하기 위해 사용된 임의의 다른 용어는 "폴리펩티드" 의 정의 내에 포함되고, 용어 "폴리펩티드" 가 임의의 이들 용어 대신에 또는 그와 호환되게 사용될 수 있다. 용어 "폴리펩티드" 는 또한 제한없이 글리코실화, 아세틸화, 인산화, 아미드화, 기지의 보호/차단 기에 의한 유도체화, 단백질가수분해 절단, 또는 비천연 발생 아미노산에 의한 변형을 포함하는, 폴리펩티드의 발현후 변형의 생성물을 의미하고자 한다. 폴리펩티드는 천연 생물학적 공급원으로부터 유래될 수 있거나 또는 재조합 기술로 제조될 수 있지만, 반드시 지정된 핵산 서열로부터 번역되지는 않는다. 이것은 화학 합성을 포함하여 임의의 방식으로 생성될 수 있다.
세포, 핵산, 예컨대 DNA 또는 RNA 와 관련하여 본원에 사용되는 용어 "단리된" 은 거대분자의 천연 공급원에 존재하는, 다른 DNA 또는 RNA 로부터 각각 분리된 분자를 지칭한다. 본원에 사용되는 용어 "단리된"은 또한 재조합 DNA 기술에 의해 생성시 세포 물질, 바이러스 재료, 또는 배양 배지가 실질적으로 없는 핵산 또는 펩티드, 또는 화학적으로 합성시 화학적 전구체 또는 다른 화학물을 의미한다. 또한, "단리된 핵산"은 단편으로서 천연발생되지 않고 자연 상태에서 존재하지 않는 핵산 단편을 포함한다는 것을 의미한다. 용어 "단리된" 은 또한 다른 세포 단백질 또는 조직으로부터 단리된 세포 또는 폴리펩티드를 지칭하기 위해 본원에서 사용된다. 단리된 폴리펩티드는 정제된 폴리펩티드 및 재조합 폴리펩티드 둘 다를 포함하는 것을 의미한다.
본원에 사용되는 용어 "재조합" 은 폴리펩티드 또는 폴리뉴클레오티드에 관한 것으로 자연적으로 존재하지 않는 폴리펩티드 또는 폴리뉴클레오티드의 형태를 의도하며, 이의 비-제한적인 예는 통상 함께 발생하지 않을 폴리뉴클레오티드 또는 폴리펩티드를 조합함으로써 생성될 수 있다.
"상동성" 또는 "동일성" 또는 "유사성" 은 2 개의 펩티드 사이 또는 2 개의 핵산 분자 사이의 서열 유사성을 지칭한다. 상동성은 비교의 목적을 위해 정렬될 수 있는 각 서열 내 위치를 비교하여 결정될 수 있다. 비교된 서열에서의 위치가 동일한 염기 또는 아미노산으로 채워진 경우라면, 분자는 그 위치에서 상동성이다. 서열간 상동성 정도는 서열에 의해 공유되는 일치되거나 또는 상동성인 위치의 개수의 함수이다. "비관련" 또는 "비-상동성" 서열은 본 발명의 서열 중 하나와, 40% 미만의 동일성, 또는 바람직하게는 25% 미만의 동일성을 공유한다.
폴리뉴클레오티드 또는 폴리뉴클레오티드 영역 (또는 폴리펩티드 또는 폴리펩티드 영역) 이 또 다른 서열에 대해 "서열 동일성" 의 특정 백분율 (예를 들어, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% 또는 99%) 을 갖는 것은 정렬시, 염기 (또는 아미노산) 의 백분율이 2 개 서열의 비교에서 동일한 것을 의미한다.
용어 "등가 핵산 또는 폴리뉴클레오티드" 는 핵산의 뉴클레오티드 서열 또는 이의 상보체와 특정한 정도의 상동성, 또는 서열 동일성을 갖는 뉴클레오티드 서열을 갖는 핵산을 지칭한다. 이중 가닥 핵산의 상동체는 그와 또는 이의 상보체와 특정한 정도의 상동성을 갖는 뉴클레오티드 서열을 갖는 핵산을 포함하는 것으로 의도된다. 하나의 측면에서, 핵산의 상동체는 핵산 또는 이의 상보체에 하이브리드화할 수 있다. 마찬가지로, "등가 폴리펩티드" 는 참조 폴리펩티드의 아미노산 서열과 특정한 정도의 상동성, 또는 서열 동일성을 갖는 폴리펩티드를 지칭한다. 일부 측면에서, 서열 동일성은 적어도 약 70%, 75%, 80%, 85%, 90%, 95%, 98%, 또는 99% 이다. 일부 측면에서, 등가 폴리펩티드 또는 폴리뉴클레오티드는 참조 폴리펩티드 또는 폴리뉴클레오티드와 비교하여 1, 2, 3, 4 또는 5 개의 부가, 결실, 치환 및 이들의 조합을 갖는다. 일부 측면에서, 등가 서열은 참조 서열의 활성 (예, 에피토프-결합) 또는 구조 (예, 염-브릿지) 를 유지한다.
하이브리드화 반응은 상이한 "엄격성" 의 조건 하에서 수행될 수 있다. 일반적으로, 낮은 엄격도 하이브리드화 반응은 약 10 x SSC 또는 동등한 이온 강도/온도의 용액 중의 약 40℃ 에서 수행된다. 적당한 엄격도 하이브리드화는 전형적으로 약 6 x SSC 중의 약 50℃ 에서 수행되고, 높은 엄격도 하이브리드화 반응은 일반적으로 약 1 x SSC 중의 약 60℃ 에서 수행된다. 하이브리드화 반응은 또한 당업자에게 공지된 "생리학적 조건" 하에서 수행될 수 있다. 생리학적 조건의 비-제한적인 예는 일반적으로 세포에서 발견되는 온도, 이온 강도, pH 및 Mg2+ 의 농도이다.
폴리뉴클레오티드는 4 개의 뉴클레오티드 염기: 아데닌 (A); 시토신 (C); 구아닌 (G); 티민 (T); 및 폴리뉴클레오티드가 RNA 인 경우에는 티민에 대한 우라실 (U) 의 특정 서열로 구성된다. 따라서, 용어 "폴리뉴클레오티드 서열" 은 폴리뉴클레오티드 분자의 알파벳 표시이다. 이 알파벳 표시는 중앙 처리 장치가 있는 컴퓨터의 데이터베이스에 입력될 수 있으며 기능 유전체학 및 상동성 검색과 같은 생물정보학 어플리케이션에 사용된다. 용어 "다형성" 은 하나 초과의 형태의 유전자 또는 이의 일부의 공존을 지칭한다. 적어도 2 개의 상이한 형태, 즉 2 개의 상이한 뉴클레오티드 서열이 존재하는 유전자의 일부를 "유전자의 다형성 영역" 이라 한다. 다형성 영역은 단일 뉴클레오티드일 수 있으며, 그 동일성은 상이한 대립유전자에서 상이하다.
용어 "폴리뉴클레오티드" 및 "올리고뉴클레오티드" 는 상호교환적으로 사용되며, 데옥시리보뉴클레오티드 또는 리보뉴클레오티드, 또는 이의 유사체인, 임의 길이의 뉴클레오티드의 중합체 형태를 말한다. 폴리뉴클레오티드는 임의의 3 차원 구조를 가질 수 있으며, 기지의 또는 미지의 임의의 기능을 수행할 수 있다. 다음은 폴리뉴클레오티드의 비-제한적인 예이다: 유전자 또는 유전자 단편 (예를 들어, 프로브, 프라이머, EST 또는 SAGE 태그), 엑손, 인트론, 메신저 RNA (mRNA), 전달 RNA (tRNA), 리보솜 RNA (rRNA), 리보자임, cDNA, dsRNA, siRNA, miRNA, 재조합 폴리뉴클레오티드, 분지형 폴리뉴클레오티드, 플라스미드, 벡터, 임의 서열의 단리된 DNA, 임의 서열의 단리된 RNA, 핵산 프로브 및 프라이머. 폴리뉴클레오티드는 개질된 뉴클레오티드, 예컨대 메틸화 뉴클레오티드 및 뉴클레오티드 유사체를 포함할 수 있다. 뉴클레오티드 구조에 대한 변형이 존재한다면, 폴리뉴클레오티드의 조립 전에 또는 후에 부여될 수 있다. 뉴클레오티드의 서열은 비-뉴클레오티드 성분에 의해 중단될 수 있다. 폴리뉴클레오티드는 중합 후에, 예를 들어, 표지화 성분과의 콘쥬게이션에 의해 추가로 변형될 수 있다. 이 용어는 또한 이중- 및 단일-가닥 분자 모두에 대해 언급된다. 달리 명시되거나 요구되지 않는 한, 폴리뉴클레오티드인 본 발명의 임의의 구현예는 이중-가닥 형태와 이중-가닥 형태를 구성하는 것으로 알려져 있거나 예측된 각각의 2 개의 상보적인 단일-가닥 형태 모두를 포함한다.
용어 "인코딩" 은 폴리뉴클레오티드에 적용되면 본래 상태로 또는 당업자에게 잘 알려진 방법에 의해 조작될 때 폴리펩티드를 "인코딩" 하는 폴리뉴클레오티드를 지칭하며, 이는 또는 폴리펩티드 및/또는 이의 단편에 대한 mRNA 를 생성하도록 전사 및/또는 번역될 수 있다. 안티센스 가닥은 이러한 핵산의 상보체이며, 인코딩 서열이 이로부터 추론될 수 있다.
본원에 사용되는 용어 "디술피드 결합" 은 2 개의 황 원자 사이에 형성된 공유 결합을 포함한다. 아미노산 시스테인은 디술피드 결합을 형성하거나 제 2 티올 기와 가교될 수 있는 티올기를 포함한다.
본원에 사용되는 용어 "치료하다" 또는 "치료" 는 치료적 치료 및 예방적 또는 방지적 조치 둘 다를 지칭하며, 여기서 목적은 바람직하지 않은 주름과 같은 바람직하지 않은 생리학적 변화 또는 장애를 예방하거나 늦추는 (줄이는) 것이다. 유익하거나 바람직한 임상 결과에는 감지 여부에 관계 없이, 증상 완화, 질환 정도의 감소, 질환 상태의 안정화 (즉, 악화하지 않음), 질환 진행의 지연 또는 둔화, 질환 상태의 경감 또는 완화, 및 차도 (부분적이든 전체적이든) 를 포함하나 이에 제한되지 않는다. "치료" 는 또한 치료를 받지 않는 경우의 예상 생존과 비교하여 생존 연장을 의미할 수 있다. 치료를 필요로 하는 환자는 이미 상태 또는 장애가 있는 환자 및 상태 또는 장애가 있는 경향이 있는 환자 또는 상태 또는 장애가 예방되어야 하는 환자를 포함한다.
"대상체" 또는 "개체" 또는 "동물" 또는 "환자" 또는 "포유동물" 은 진단, 예후 또는 치료가 바람직한 임의의 대상체, 특히 포유동물 대상체를 의미한다. 포유동물 대상체는 인간, 가축, 농장 동물 및 동물원, 스포츠, 또는 애완 동물, 예컨대 개, 고양이, 기니아 피그, 토끼, 래트, 마우스, 말, 소, 젖소 등을 포함한다.
본원에 사용되는 "치료를 필요로 하는 환자에게" 또는 "치료를 필요로 하는 대상체" 와 같은 구절은 예를 들어, 검출, 진단 절차 및/또는 치료를 위해, 사용된 본 발명의 항체 또는 조성물의 투여로부터 이익을 얻을 수 있는 포유동물 대상체와 같은 대상체를 포함한다.
징크 핑거 모티프를 갖는 키메라 폴리펩티드
시장에는 BoNT 단백질의 경피 전달에 대한 요구가 있다. 단백질의 경피 전달은, 특히 피부를 가로지르는 것이 본질적으로 어렵다. 피부는 표피와 진피로 알려진, 두 층의 세포로 구성된다. 피부의 최상층인 표피는 기저 및 분화된 각질형성세포로 구성된 중층 편평 상피이다. 각질형성세포는 표피의 주요 세포 유형이다. 기저층의 각질형성세포는 유사분열을 통해 증식하고 다수의 세포 분화 단계를 거쳐 무핵 세포가 된다. 무핵 또는 분화된 각질형성세포는 케라틴 단백질 및 지질을 분비하는, 고도로 조직화된 조직 구조이며, 이는 병원체와 같은 침입 물질에 대한 보호 장벽을 제공한다.
경피 BoNT 조성물 개발에는 성공하지 못했다. 그러나, 본 발명은 BoNT 폴리펩티드의 하나 이상의 징크 핑거 모티프 (또는 징크 핑거 단백질 도메인, 또는 ZFP) 에 대한 융합이 BoNT 가 피부를 투과할 수 있게 함을 보여준다. 징크 핑거 단백질은 자연 발생 전사 인자이며 표적화된 게놈 유전자좌를 인지하도록 재프로그램될 수 있다. 징크 핑거 뉴클레아제-N-말단 ZFP 도메인 및 C-말단 Fok I 엔도뉴클레아제 도메인을 함유하는 키메라 단백질-은 본질적으로 세포-침투성인 것으로 나타났다. 일부 ZFP 는 Cys2-His2 ZFP 도메인을 포함한다. Cys2-His2 ZFP 는 ββα 구성을 가진 대략 30 개의 아미노산으로 이루어진다.
이 발견은 적어도 다음과 같은 이유로 놀랍고 예상치 못했다. 첫째, 동물의 피부를 가로질러 큰 단백질을 효율적으로 전달하는 능력은 그 자체로 놀라운 일이며 예기치 않은 일고; 특히, ZFP 의 세포-침투 활성은 에너지-의존적인 것으로 알려져 있는데, 이는 죽은 각질세포에 의해 형성되는 피부의 최외층인 각질층에서, 있더라도, 매우 제한적인 효율이 예상됨을 의미하며, 이것은 심지어 물리적 또는 화학적 수단에 의해 파괴되더라도, 여전히 전형적인 생물학적 분자에 대한 극복할 수 없는 장벽을 구성한다.
둘째, ZFP 는 징크-의존성 메탈로프로테아제이고, 이것은 또한 보툴리눔 독소의 활성이 프로테아제 억제제 및 아연 킬레이터에 의해 억제될 수 있기 때문에 아연을 필요로 하는 것으로 알려져 있다. ZFP 와 BoNT 둘 다 아연 이온의 혼입을 필요로 하기 때문에, 융합 단백질에 ZFP 와 BoNT 둘 다의 존재는 그들 사이에 간섭을 야기하여, 활성 감소 또는 심지어 비활성화를 초래할 것으로 의심되었다.
이러한 맥락에서, 본 발명자는 BoNT 의 C-말단 방향에서 ZFP 를 융합시키는 것이 그러한 간섭을 피하거나 감소시킬 수 있다고 생각했다. 추가로 또는 대안적으로, 이분형 (bipartite) (탠덤) ZFP 의 사용은 ZFP 의 활성이 유지되도록 보장할 수 있다.
셋째, 실험예에서 입증된 바와 같이, BoNT-ZFP 융합 단백질은 박테리아 세포로부터 대량으로 발현되는데, BoNT 가 2 개의 일반적으로 조사되는 세포 침투 펩티드인 TAT 또는 Pep-1 과 융합될 때보다 훨씬 더 크다. 이 효과에 대한 제안은 없었으므로, 이것은 또한 예상치 못했다.
마지막으로, 발현된 BoNT-ZFP 융합 단백질은 높은 효소 활성을 나타냈을 뿐만 아니라 (참조, 예, 도 3), 그들은 또한 세포 구성원을 세포내 공간으로 가로지른 후에 그러한 활성을 유지했다 (참조, 예, 도 4). 더 나아가, 생체 내 설정에서 사용되었을 때, 바람직하게는 미세바늘-처리된 동물 피부에, 국소적으로 적용된 BoNTA-ZFP 융합 단백질은 주사된 BoNTA 와 같이 근육 마비를 일으켰다. 이러한 치료 효과가 국소 제형으로 달성될 수 있다는 것은 당업계에 기대되지 않았기 때문에 이것은 또한 놀랍다.
따라서, 본 발명의 하나의 구현예에 따르면, (a) 보툴리눔 독소 (BoNT) 경쇄 및 (b) BoNT 경쇄의 C-말단에 위치한 징크 핑거 모티프를 포함하는 키메라 (또는 융합) 폴리펩티드가 제공된다.
또한, 하나의 구현예에서, (a) 보툴리눔 독소 (BoNT) 경쇄, (b) BoNT 중쇄, 및 (C) BoNT 중쇄의 C-말단에 위치한 징크 핑거 모티프를 포함하는 키메라 (또는 융합) 폴리펩티드가 제공된다. 일부 구현예에서, 경쇄 및 중쇄는 동일한 펩티드 사슬 상에 있다. 일부 구현예에서, 경쇄는 중쇄의 N-말단 측에 있다. 일부 구현예에서, 경쇄는 중쇄의 C-말단 측에 있다. 일부 구현예에서, 경쇄 및 중쇄는 상이한 펩티드 사슬 상에 있고 디술피드 결합과 연결되어 있다.
또한 일부 구현예에서, 보툴리눔 독소 (BoNT) 경쇄 및 적어도 징크 핑거 모티프를 포함하는 키메라 폴리펩티드가 제공된다. 하나의 구현예에서, 키메라 폴리펩티드는 BoNT 중쇄를 추가로 포함한다.
일부 구현예에서, 키메라 폴리펩티드의 총 크기는 5000 개 이하의 아미노산 잔기, 또는 대안적으로 4000 개 이하의 아미노산 잔기, 3000 개 이하의 아미노산 잔기, 2000 개 이하의 아미노산 잔기, 1800 개 이하의 아미노산 잔기, 1600 개 이하의 아미노산 잔기, 1500 개 이하의 아미노산 잔기, 1400 개 이하의 아미노산 잔기, 1300 개 이하의 아미노산 잔기, 1200 개 이하의 아미노산 잔기, 1100 개 이하의 아미노산 잔기, 1000 개 이하의 아미노산 잔기, 900 개 이하의 아미노산 잔기, 800 개 이하의 아미노산 잔기, 700 개 이하의 아미노산 잔기, 600 개 이하의 아미노산 잔기, 500 개 이하의 아미노산 잔기, 450 개 이하의 아미노산 잔기, 400 개 이하의 아미노산 잔기, 350 개 이하의 아미노산 잔기, 300 개 이하의 아미노산 잔기, 250 개 이하 아미노산 잔기, 또는 200 개 이하의 아미노산 잔기이다.
보툴리눔 독소에는 적어도 7 가지 유형이 있고, 타입 A-G 로 불린다. 타입 A 와 B 는 인간에게 질환을 일으킬 수 있으며, 상업적으로 또는 의학적으로도 사용된다. 타입 C-G 는 덜 일반적이다. 보툴리눔 독소 타입 A 와 B 는 다양한 근육 연축과 과활성 근육을 특징으로 하는 질환을 치료하기 위한 의약에 사용된다. 각각의 BoNT 혈청형은 또한 서브타입을 가질 수 있다. 예를 들어, 하기 서브타입이 알려져 있다: BoNT A1-A10, B1-B8, E1-E9, 및 F1-F7.
용어 BoNT 또는 이의 특정 타입 또는 서브타입은 또한 그의 등가 폴리뉴클레오티드, 예컨대 특정 수준 (예를 들어, 적어도 85%, 90%, 95%, 98% 또는 99%) 의 서열 동일성을 갖거나 하나 이상의 아미노산 잔기 부가, 결실 또는 치환으로 변형된 것들을 포함한다. 일부 구현예에서, 치환은 보존적 아미노선 치환이다.
"보존적 아미노산 치환" 은 아미노산 잔기가 유사한 측쇄를 갖는 아미노산 잔기로 대체되는 것이다. 이러한 유사한 측쇄를 갖는 아미노산 잔기의 패밀리는 염기성 측쇄 (예를 들면, 리신, 아르기닌, 히스티딘), 산성 측쇄 (예를 들면, 아스파르트산, 글루탐산), 하전되지 않은 극성 측쇄 (예를 들면, 글리신, 아스파라긴, 글루타민, 세린, 트레오닌, 티로신, 시스테인), 비극성 측쇄 (예를 들면, 알라닌, 발린, 류신, 이소류신, 프롤린, 페닐알라닌, 메티오닌, 트립토판), 베타-가지의 측쇄 (예를 들면, 트레오닌, 발린, 이소류신) 및 방향족 측쇄 (예를 들면, 티로신, 페닐알라닌, 트립토판, 히스티딘) 를 포함하여, 당업계에 정의되어 있다. 따라서, 폴리펩티드에서 비필수 아미노산 잔기는 바람직하게는 동일한 측쇄 패밀리로부터 또다른 아미노산 잔기로 대체된다. 또다른 구현예에서, 아미노산의 스트링은 측쇄 패밀리 구성원의 순서 및/또는 조성이 상이한 구조적으로 유사한 스트링으로 대체될 수 있다.
보존적 아미노산 치환의 비-제한적 예는 하기 표에 제공되며, 0 이상의 유사성 점수는 2 개의 아미노산 사이의 보존적 치환을 나타낸다.
표 1A. 아미노산 유사성 매트릭스
표 1B. 보존적 아미노산 치환
일부 구현예에서, BoNT 펩티드는 천연 BoNT 펩티드로부터의 상기 치환 중 1 개 이하, 2 개 이하 또는 3 개 이하를 포함한다.
BoNT 경쇄의 비-제한적 예는 SEQ ID NO: 8 (BoNT A 경쇄) 및 SEQ ID NO: 8 과 적어도 90% (또는 적어도 95%, 적어도 98% 또는 적어도 99%) 의 서열 동일성을 갖는 아미노 서열을 포함한다. BoNT 중쇄의 비-제한적 예는 SEQ ID NO: 9 (BoNT A 중쇄) 및 SEQ ID NO: 9 과 적어도 90% (또는 적어도 95%, 적어도 98% 또는 적어도 99%) 의 서열 동일성을 갖는 아미노 서열을 포함한다. SEQ ID NO: 8 및 9 의 아미노산 서열은 하기 표 2 에 제공된다.
표 2. 대표적인 BoNT 서열
"징크 핑거 모티프" 는 폴딩을 안정화시키기 위해 하나 이상의 아연 이온의 배위를 특징으로 하는 작은 단백질 구조 모티프이다. 일반적으로, 징크 핑거는 시스테인과 히스티딘 잔기의 조합으로 아연 이온을 배위한다. 이들 잔기의 수 및 순서는 상이한 유형의 징크 핑거 (예, Cys2His2, Cys4, 및 Cys6) 를 분류하기 위해 사용될 수 있다. 또 다른 방법은 폴딩된 도메인에서 단백질 백본의 전체 형태에 기초하여 징크 핑거 단백질을 폴딩 그룹으로 분류한다. 가장 일반적인 징크 핑거의 폴딩 그룹은 Cys2His2 (고전적 징크 핑거), 트레블 클레프 (treble clef), 징크 리본, 개그 너클 (gag knuckle), Zn2/Cys6 및 TAZ2 도메인 유사이다.
Cys2His2 폴딩 그룹은 간단한 ββα 폴딩을 채택하고 하기 아미노산 서열 모티프를 갖는다:
X2-Cys-X2,4-Cys-X12-His-X3,4,5-His.
개별 징크 핑거 도메인은 단백질의 DNA-결합 도메인을 포함하는 2 개, 3 개 또는 그 이상의 핑거와 탠덤 반복으로 발생할 수 있다.
징크 핑거 모티프는 DNA 에 결합하는 능력을 제거하거나 감소시키도록 변형될 수 있다. 예를 들어, 변형된 Cys2His2 는 징크 핑거 모티프에서 알파-헬릭스 단편의 잔기 -1, 2, 3 또는 6 에서 적어도 알라닌을 함유한다. 징크 핑거 모티프의 비-제한적 예는 아래 표 3 에 제시되어 있다. 표 3 의 서열 일부, SEQ ID NO: 1 및 5-7 은 개별 징크 핑거 모티프인 반면, 다른 일부 (징크 핑거 모티프의 탠덤), SEQ ID NO: 2-4 는 다수의 연결된 징크 핑거 모티프를 함유한다. 2 개 이상의 징크 핑거가 탬덤에서 사용될 때, 이들은 서로 바로 옆에 위치하거나 또는 펩티드 링커, 즉 1, 2 또는 3 개의 아미노산 잔기에서 2, 3, 4, 5, 6, 7, 8, 9 또는 10 개의 아미노산 잔기 길이인 짧은 펩티드를 통해 연결될 수 있다. SEQ ID NO: 1 의 변형된 알라닌 잔기는 밑줄로 표시되고 굵게 표시된다.
표 3. 예시 징크 핑거 모티프 (ZFP)
일부 구현예에서, 키메라 폴리펩티드는 BoNT 경쇄의 N-말단 측에 위치한 징크 핑거 모티프를 추가로 포함한다. 일부 구현예에서, 키메라 폴리펩티드는 BoNT 중쇄의 N-말단 측에 징크 핑거 모티프를 추가로 포함한다. 일부 구현예에서, 키메라 폴리펩티드는 2-사슬 폴리펩티드이고 BoNT 경쇄의 C-말단 측에 징크 핑거 모티프 (또는 2 개의 징크 핑거 또는 3 개의 징크 핑거의 탠덤) 를 포함한다. 일부 구현예에서, 키메라 폴리펩티드는 2-사슬 폴리펩티드이고, BoNT 경쇄의 C-말단 측에 징크 핑거 모티프 (또는 2 개의 징크 핑거 또는 3 개의 징크 핑거의 탠덤) 및 BoNT 중쇄의 N-말단 측에 징크 핑거 모티프 (또는 2 개의 징크 핑거 또는 3 개의 징크 핑거의 탠덤) 을 포함한다.
일부 구현예에서, 징크 핑거 모티프 중 적어도 하나는 적어도 하나 또는 두 개 이상의 징크 핑거 모티프에 연결되어 이분형 또는 삼분형 (tripartite) 징크 핑거 모티프 구조 (예를 들어, 탠덤 징크 핑거 모티프) 를 형성한다. 일부 구현예에서, 탠덤 징크 핑거 모티프는 그들 사이에 0, 1, 2, 3, 4 또는 5 개의 아미노산 잔기를 갖는다.
BoNT 경쇄, 중쇄 및 징크 핑거 모티프 사이의 거리는 선호도 및 필요에 따라 조정할 수 있다. 일부 구현예에서, 징크 핑거는 인접 BoNT 경쇄 또는 중쇄의 N- 또는 C-말단으로부터 200 개 아미노산 잔기 이하로 떨어져 있다. 일부 구현예에서, 거리는 0 내지 약 150, 5 내지 100, 10 내지 75, 10 내지 50, 10 내지 40, 10 내지 30, 10 내지 20, 20 내지 150, 20 내지 100, 20 또는 50 또는 50 내지 100 개의 아미노산 잔기이다. 일부 구현예에서, 거리는 스페이서 서열 (예를 들어, 알라닌, 글리신 또는 이들의 조합) 을 삽입함으로써 제공된다.
키메라 폴리펩티드 서열의 비-제한적인 예는 SEQ ID NO: 10 내지 17 에 제공된다 (표 3). 이들 서열 중 일부는 BoNT 경쇄 및 BoNT 중쇄 둘 다를 포함하고, 이들 서열은 절단되지 않은 단일-사슬 버전 및 절단된 2-사슬 버전 둘 모두를 포함한다.
표 4. 대표적인 키메라 폴리펩티드 서열
또한, 본 기술은 제한 없이 상피 성장 인자 (EGF) 및 슈퍼옥시드 디스뮤타제 (SOD) 와 같은 다른 치료 펩티드에도 적용할 수 있는 것으로 고려된다. 따라서, 하나의 구현예에서, 본 발명은 치료 펩티드 및 적어도 징크 핑거 모티프를 포함하는 키메라 폴리펩티드를 제공한다. 일부 구현예에서, 징크 핑거 모티프는 치료 펩티드의 C-말단 측에 위치된다. 일부 구현예에서, 징크 핑거 모티프는 치료 펩티드로부터 100 개 이하의 아미노산 잔기 (또는 90, 80, 70, 60, 50, 40, 30, 20, 10 또는 5 개 이하의 아미노산 잔기) 떨어져 있다. 일부 구현예에서, 징크 핑거 모티프는 또다른 징크 핑거 모티프에 연결되어 이분형 징크 핑거 모티프를 형성한다. 일부 구현예에서, 키메라 폴리펩티드는 치료 펩티드의 N-말단 측 및 C-말단 측 모두에 징크 핑거 모티프 (또는 이분형 하나) 를 포함한다.
일부 구현예에서, 치료 펩티드는 EGF 및 SOD 로부터 선택되며, 이의 예시 서열은 표 5 에 제시되어 있다. 징크 핑거 모티프의 예, 예시 스페이서 서열 및 징크 핑거 모티프와 치료 펩티드 사이의 거리가 또한 본원에 기재되어 있다.
표 5. 대표적인 치료 펩티드 서열
일부 구현예에서, 폴리펩티드는 치료제, 프로드러그, 펩티드, 단백질, 효소, 바이러스, 지질, 생물학적 반응 조절제, 약제 또는 PEG 에 컨쥬게이션될 수 있다. 폴리펩티드는 치료제에 컨쥬게이션되거나 융합될 수 있으며, 치료제에는 방사성 표지, 면역조절제, 호르몬, 효소, 올리고뉴클레오티드, 광활성 치료제 또는 진단제, 세포독성제 (이는 약물 또는 독소일 수 있음), 초음파 강화제, 비-방사성 표지, 이들의 조합 및 당업계에 공지된 다른 이러한 작용제와 같은 검출가능한 표지가 포함될 수 있다.
폴리펩티드는 화학발광 화합물에 커플링함으로써 검출가능하게 표지될 수 있다. 화학발광-태그된 항원-결합 폴리펩티드의 존재는 화학 반응 과정에서 발생하는 발광의 존재를 검출함으로써 결정된다. 특히 유용한 화학발광 표지 화합물의 예는 루미놀, 이소루미놀, 테로마틱 (theromatic) 아크리디늄 에스테르, 이미다졸, 아크리디늄 염 및 옥살레이트 에스테르이다.
폴리펩티드는 또한 다음과 같은 형광 방출 금속, 예컨대 152Eu 또는 란타나이드 계열의 다른 것을 사용하여 검출가능하게 표지될 수 있다. 이들 금속은 디에틸렌트리아민펜트아세트산 (DTPA) 또는 에틸렌디아민테트라아세트산 (EDTA) 과 같은 금속 킬레이트기를 사용하여 항체에 부착될 수 있다.
본 발명은 또한 본 발명의 폴리펩티드, 그의 변이체 또는 유도체를 인코딩하는 단리된 폴리뉴클레오티드 또는 핵산 분자를 제공한다. 본 발명의 폴리뉴클레오티드는 동일한 폴리뉴클레오티드 분자 또는 별도의 폴리뉴클레오티드 분자 상에서 폴리펩티드, 이의 변이체 또는 유도체의 전체 중쇄 및 경쇄를 인코딩할 수 있다. 부가적으로, 본 발명의 폴리뉴클레오티드는 동일한 폴리뉴클레오티드 분자 또는 별도의 폴리뉴클레오티드 분자 상에서 폴리펩티드, 이의 변이체 또는 유도체의 중쇄 및 경쇄의 일부를 인코딩할 수 있다.
융합 폴리펩티드 또는 그의 도메인을 인코딩하는 폴리뉴클레오티드는 "발현 벡터" 내에 삽입될 수 있다. 용어 "발현 벡터" 는 본 발명의 폴리펩티드를 인코딩하는 폴리뉴클레오티드를 함유하도록 조작될 수 있는 플라스미드, 바이러스 또는 당업계에 공지된 다른 비히클과 같은 유전자 구축물을 지칭한다. 이러한 발현 벡터는 전형적으로, 숙주 세포에서 삽입된 유전자 서열의 전사를 촉진하는 프로모터 서열을 함유하는 플라스미드이다. 발현 벡터는 전형적으로, 복제 기원, 및 프로모터 뿐만 아니라 형질전환된 세포의 표현형 선별을 허용하는 유전자 (예를 들어, 항생제 내성 유전자) 를 함유한다. 유도성 및 구성성 프로모터를 포함하는 다양한 프로모터가 본 발명에 이용될 수 있다. 전형적으로, 발현 벡터는 숙주 세포와 상용성인 종으로부터 유래된 레플리콘 부위 및 제어 서열을 함유한다.
폴리뉴클레오티드로의 숙주 세포의 형질전환 또는 트랜스펙션은 당업자에게 널리 공지된 통상적인 기술을 사용하여 수행될 수 있다. 예를 들어, 숙주 세포가 E. 콜라이인 경우, DNA 흡수가 가능한 적격 세포는 당업계에 공지된 CaCl2, MgCl2 또는 RbCl 방법을 사용하여 제조될 수 있다. 대안적으로, 전기천공법 또는 미세주사와 같은 물리적 수단이 사용될 수 있다. 전기천공법은 고전압 전기 임펄스에 의해 폴리뉴클레오티드를 세포 내로 전달할 수 있게 한다. 또한, 폴리뉴클레오티드는 당업계에 공지된 방법을 사용하여 원형질체 융합에 의해 숙주 세포 내로 도입될 수 있다. 전기천공법 및 리포펙션과 같은 진핵생물 세포를 형질전환시키는 적합한 방법이 또한 공지되어 있다.
본 발명에 포함되는 "숙주 세포" 는 본 발명의 폴리뉴클레오티드가 융합 폴리펩티드 또는 이의 기능성 도메인을 발현시키기 위해 사용될 수 있는 임의의 세포이다. 이 용어는 또한 숙주 세포의 임의의 자손을 포함한다. 유용한 숙주 세포는 박테리아 세포 (예를 들어, 클로스트리디움 보툴리눔 (Clostridium botulinum)), 진균 세포 (예를 들어, 효모 세포), 곤충 세포 (예를 들어, 스포도프테라 (Spodoptera)), 식물 세포 및 동물 세포를 포함한다. 본 발명의 융합 폴리펩티드는 원핵생물에서 융합 폴리펩티드를 인코딩하는 폴리뉴클레오티드의 발현에 의해 생성될 수 있다. 이들은 제한 없이, 미생물, 예컨대 본 발명의 융합 폴리펩티드를 인코딩하는 재조합 박테리오파지 DNA, 플라스미드 DNA, 또는 코스미드 DNA 발현 벡터로 형질전환된 박테리아를 포함한다. 숙주 세포 내로의 구축물의 도입은 인산 칼슘 트랜스펙션, DEAE-덱스트란 매개 트랜스펙션, 또는 전기천공에 의해 수행될 수 있다.
구축물은 BoNT 단백질이 자연적으로 생성되는 클로스트리디움 보툴리눔 (Clostridium botulinum) 에서 발현될 수 있다. 본 발명의 놀라운 발견은 BoNT 경쇄 및/또는 중쇄를 함유하는 키메라 단백질이 곤충 세포 (예를 들어, 스포도프테라 프루지페르다 (Spodoptera frugiperda) Sf9) 에서 효율적으로 생성될 수 있다. 따라서, 하나의 구현예에서, 숙주 세포는 곤충 세포, 예컨대 나비목 세포, 밤나방과 세포, 스포도프테라 (Spodoptera) 세포, 및 스포도프테라 프루지페르다 (Spodoptera frugiperda) 세포일 수 있다.
재조합 단백질의 장기간, 고수율 생산을 위해, 안정한 발현이 전형적으로 사용된다. 바이러스 복제 기원을 함유하는 발현 벡터를 사용하는 대신에, 숙주 세포는 적절한 발현 제어 요소 (예를 들어, 프로모터, 인핸서, 서열, 전사 종결자, 폴리아데닐화 부위, 및 등) 및 선별가능한 마커에 의해 제어되는 본 발명의 융합 폴리펩티드를 인코딩하는 cDNA 로 형질전환될 수 있다. 선별가능한 마커는 선별적 살해제에 대한 내성을 부여하고 이종성 폴리뉴클레오티드의 안정적인 통합시 내성 세포의 성장을 허용한다. 이러한 내성 세포는 성장하여 포사이 (foci) 를 형성하고, 차례로 클로닝되어 세포주로 확장될 수 있다.
치료 방법 및 용도
본원에 기재된 바와 같이, 본 발명의 징크 핑거 모티프-함유 키메라 (융합) 폴리펩티드는 경피적으로 효과적으로 전달될 수 있다. 따라서, 융합 치료 단백질에 따라, 키메라 폴리펩티드는 치료 용도를 갖는다.
선택적으로 BoNT 중쇄와 함께, BoNT 경쇄를 포함하는 키메라 폴리펩티드는 광범위한 미용 및 치료 적용을 갖는다. 미용 적용의 경우, 이러한 키메라 폴리펩티드는 주름을 치료하고 입의 모서리 또는 윗입술의 라인을 조정하는데 유용할 수 있다. 치료제에서, 키메라 폴리펩티드는 신경학적 장애, 예컨대 근긴장이상, 경련, 반측안면 경련, 다한증 (과다한 발한), 과다침분비 (과다한 타액) 를 치료하는데 유용할 수 있다. 키메라 폴리펩티드는 비뇨기과 장애, 예컨대 배뇨근 괄약근 협동장애, 특발성 배뇨근 과활동성, 신경성 배뇨근 과활동성, 요정체, 항문 균열, 양성 전립선 비대증에 대해 사용될 수 있다.
또다른 추가의 징후는 위장관적, 이비인후과적 장애 또는 다른 의학적 상태이다. 일부 구현예에서, 키메라 폴리펩티드는 안면 주름, 근긴장이상, 경련, 반측안면 경련, 다한증 또는 과다침분비의 치료에 사용된다.
또다른 예에서, EGF 를 포함하는 키메라 폴리펩티드는 당뇨병성 족부 궤양 또는 일반적으로 상처 치유와 같은 상태를 치료하는데 사용될 수 있다. 또 다른 예에서, SOD 펩티드를 포함하는 키메라 폴리펩티드는 피부에 대한 자유 라디칼 손상을 감소시키기 위해, 예를 들어 유방암에 대한 방사선 후 섬유증을 감소시키기 위해 사용될 수 있다.
키메라 폴리펩티드의 국소 적용은 대상체의 피부 위치, 예컨대 피부 또는 눈, 귀, 코, 입, 입술, 요도 개구, 항문 또는 혀의 점막에서 수행될 수 있다. 위치의 특정 예는 제한 없이, 얼굴, 목, 머리, 다리, 어깨, 등, 손바닥, 발, 사타구니, 겨드랑이, 팔꿈치, 팔, 무릎, 엉덩이, 몸통 및 골반을 포함한다. 마찬가지로, 키메라 폴리펩티드는 또한 이 위치에서 근육 내 투여될 수 있다.
따라서, 일부 구현예에서, 징크 핑거 모티프 및 치료 펩티드를 포함하는 키메라 폴리펩티드를 함유하는 제형을 포유동물 대상체에게 국소적으로 또는 근육내로 적용하는 것을 포함하는, 치료 펩티드 (예를 들어, BoNT, EGF 또는 SOD) 를 포유동물 대상체에게 투여하는 방법이 제공된다.
국소 적용이 피부의 각질층에 대한 것일 때, 일부 구현예에서, 각질층은 바람직하게는 붕괴된다. 각질층의 붕괴는 실험예에 예시된 바와 같이 미세바늘과 같은 바늘로 수행될 수 있다. 대안적으로, 적용은 근육내일 수 있다.
임의의 특정 환자를 위한 특정한 투여량 및 치료법은, 이용되는 특정 폴리펩티드, 이의 변이체 또는 유도체, 환자의 연령, 체중, 일반적인 건강, 성별 및 식이, 투여 시간, 배출 속도, 약물 조합, 및 치료하고자 하는 특정 질환의 중증도를 비롯한, 다양한 인자에 따라 달라질 것이다. 의료 간병인에 의한 이러한 인자의 판단은 당업자에게 있다. 양은 또한 치료될 개별 환자, 투여 경로, 제형의 유형, 사용되는 화합물의 특성, 질환의 중증도 및 원하는 효과에 따라 달라질 것이다. 사용되는 양은 당업계에 공지된 약리학적 및 약동학적 원리에 의해 결정될 수 있다.
조성물
본 발명은 약학 조성물을 제공한다. 이러한 조성물은 유효량의 키메라 폴리펩티드 및 허용가능한 담체를 포함한다.
특별한 구체예에서, 용어 "약학적으로 허용가능한" 은 미국 약전 또는 동물, 더욱 특히 인간에서 사용에 대해 다른 일반적으로 인정되는 약전에 열거되거나 또는 연방 정부 또는 주정부의 규제 기관이 승인한 것을 의미한다. 또한, "약학적으로 허용가능한 담체" 는 일반적으로 무독성 고체, 반고체 또는 액체 충전제, 희석제, 캡슐화 물질 또는 임의의 유형의 제형 보조제일 것이다.
용어 "담체" 는 치료제와 투여되는 희석제, 보강제, 부형제 또는 비히클을 의미한다. 이러한 약학 담체는 멸균된 액체, 예컨대 물 및 석유, 동물, 식물 또는 합성 기원의 것을 포함하는 오일, 예컨대 땅콩유, 대두유, 미네랄유, 참깨유 등일 수 있다. 물은 약학 조성물이 정맥내로 투여될 때 바람직한 담체이다. 염수 및 수성 덱스트로오스 및 글리세롤 용액은 또한 특히 주사가능한 용액을 위한 액체 담체로서 사용될 수 있다. 적합한 약학 부형제는 전분, 글루코오스, 락토오스, 수크로오스, 젤라틴, 맥아, 쌀, 밀가루, 분필, 실리카 겔, 소듐 스테아레이트, 글리세롤 모노스테아레이트, 탈크, 염화나트륨, 건조 탈지유, 글리세롤, 프로필렌, 글리콜, 물, 에탄올 등을 포함한다. 바람직하다면, 조성물은 또한 소량의 습윤제 또는 유화제, 또는 pH 완충제, 예컨대 아세테이트, 시트레이트 또는 포스페이트를 함유할 수도 있다. 항균제, 예컨대 벤질 알코올 또는 메틸 파라벤; 항산화제, 예컨대 아스코르브산 또는 나트륨 비술파이트; 킬레이트제, 예컨대 에틸렌디아민테트라아세트산; 및 긴장성 조절제, 예컨대 염화나트륨 또는 덱스트로스가 또한 고려된다. 이들 조성물은 젤, 크림, 스프레이, 용액, 현탁제, 에멀션, 정제, 알약, 캡슐, 분말, 지속-방출형 제형 등의 형태를 취할 수 있다. 상기 조성물은 통상의 결합제 및 담체, 예컨대 트리글리세리드와 함께, 좌제로서 제형화될 수 있다.
특정 구현예에서 키메라 폴리펩티드, 또는 이의 조성물 또는 제형, 및 키메라 폴리펩티드, 조성물 또는 제형을 사용하기 위한 지침을 포함하는 키트 및 패키지가 또한 제공된다. 일부 구현예에서, 키트 또는 패키지는 키메라 폴리펩티드, 조성물 또는 제형을 전달하기 위한 바늘 또는 미세바늘을 추가로 포함한다. 상기 언급한 바와 같이, 미세바늘은 피부의 각질층을 붕괴시켜 전달을 개선하는데 유용할 수 있다.
동물 시험 방법
현재 the rat Digit Abduction Score (DAS) 검정법은 BoNT-유도 골격근 마비를 평가하기 위한 주요 생리학적 모델이다. 이 검정법은 완전히 객관적이지 않으며 오류가 발생하기 쉽다. 일부 구현예에서, 본 발명은 동물에서 BoNT-유도 골격근 마비를 정량적으로 측정하기 위한 새로운 방법을 기술한다.
하나의 예에서, 시험제를 받기 전 또는 후에 동물을 트레드밀에 둔다. 트레드밀이 시작될 때, 동물이 신체적으로 30 분의 최대 러닝 타임을 가질 수 있는 한 동물을 강제로 움직인다. 움직임의 지속기간, 거리 또는 시간은 시험제의 영향을 정량적으로 반영할 수 있다 (시험제를 제공하지 않은 동물과 같은 적합한 대조군과 함께).
또다른 예에서, 동물은 동물이 다른 끝쪽으로 걸어가도록 지시되는 밸런스 빔 상에 배치된다. 균형 유지 능력이 감소된 근육 마비는 동물이 밸런스 빔을 가로지르는 데 걸리는 시간에 의해 반영될 것이다.
또 다른 예에서, 동물의 발자국이, 서 있거나 걷는 동안 (예를 들어, 트레드밀 상에서) 측정된다. 발자국의 크기는 또한 마비 정도의 정량적 측정일 수 있다.
실시예
실시예 1. 에스케리챠 콜라이 (
Escherichia coli
) 로부터의 BoNTA-CPP 융합 단백질의 발현 및 정제
이 실험은 BoNTA-CPP (세포 침투 펩티드) 융합 단백질이 E. 콜라이 세포로부터 발현 및 정제될 수 있음을 입증한다.
방법
단백질 발현
상이한 BoNTA 구축물을 함유하는 pET28b 벡터 (Protein ID: 1~8; 도. 1) 를 BL21(DE3) E. 콜라이 세포 내로 형질전환시켰다. 이들 구축물의 서열은 SEQ ID NO: 10-17 에 제공된다. His6: 히스티딘 태크; BoNTA-LC: BoNT A 경쇄; BoNTA-HC: BoNT A 중쇄; ZFP2: 탠덤 징크 핑거 펩티드 (SEQ ID NO: 1); TAT: 전사 펩티드의 전사촉진제; Pep-1: pep-1 펩티드. TAT 및 Pep-1 은 공지된 세포 침투 펩티드 (CPP) 이다.
아가 플레이트에서 단일 콜로니를 채취하고, 50 ㎍/mL 카나마이신 및 90 μM ZnCl2 이 보충된 10 mL 리소겐 브로쓰 (LB) 배지에서 37℃ 에서 밤새 성장시켰다. 다음날, 10 mL 의 스타터 배양물을 50 ㎍/mL 카나마이신 및 90 μM ZnCl2 이 보충된 1 리터 LB 배지에 접종시키고, 0.8 의 OD600 으로 성장시켰다. 단백질 발현은 0.1 mM 이소프로필-β-D-티오갈락토피라노시드 (IPTG) 로 25℃ 에서 4 시간 동안 유도되었다. 세포 펠렛을 5,000 rpm 에서 10 분 동안 원심분리하여 수확하였다.
단백질 정제
2 리터 배양물로부터의 세포 펠렛 (대략 30 그램) 을 200 mL BoNTA 용리 완충액 (20 mM HEPES, pH 7.0, 500 mM NaCl, 0.01% Triton X-100, 1x 프로테아제 칵테일 (Roche) 및 10% 글리세롤) 에 재현탁시키고, 얼음 위에서 3 회 초음파처리하였다. 용리된 세포를 4℃ 에서 1 시간 동안 25,000 g 에서 원심분리하고 상청액을 새로운 튜브로 옮겼다. 이 상청액에 1 mL (정치된 부피) 평형화된 Ni-NTA 수지 (Qiagen) 를 첨가하였다. His6 태그를 포함하는 BoNTA 단백질을 회전시키면서 수지와 30 분 동안 결합하도록 두었다. 수지를 컬럼으로 옮기고 관류액을 버렸다. 수지를 50 mL BoNTA 세척 완충액 (20 mM HEPES, pH 7.0, 500 mM NaCl 및 10% 글리세롤, 20 mM 이미다졸) 로 세척한 다음 50 mL BoNTA 용리 완충액 (20 mM HEPES, pH 7.0, 500 mM NaCl 및 10% 글리세롤, 300 mM 이미다졸) 으로 용리시켰다. 이어서, 용리 분획을 농축한 다음, 시작 완충액 (20 mM TrisHCl, pH 8.5) 및 종료 완충액 (20 mM TrisHCl, pH 8.5, 1 M NaCl) 을 사용하여 이온 교환에 의해 추가로 정제하였다. 최적 순도를 갖는 분획을 재조합하고, 스핀 농축에 의해 농축시키고, 10% 글리세롤을 보충한 후, 추가 적용을 위해 -80℃ 에서 저장하였다.
결과 및 데이터 분석
1-단계 친화성 정제는 오직 적당한 순도의 단백질을 산출하였다. 2-단계 이온 교환 후, 순도가 크게 향상되었다. 전체 수율은 배양물 리터 당 0.1 mg 으로 추정되었으며 최종 생성물의 순도는 90% 였다 (도. 2 패널 A-B). 놀랍게도, ZFP 와의 융합 단백질은 세포 침투 펩티드와의 융합보다 높은 단백질 발현 및 정제 수율을 갖는다 (TAT 및 Pep-1, 도. 2, 패널 A).
이 예는 BoNTA-CPP 융합 단백질이 E. 콜라이로부터 재조합 단백질로서 발현되고 친화성 정제에 이은 이온 교환에 의해 정제될 수 있다는 것을 보여준다.
실시예 2. BoNTA-CPP 융합 단백질에 의한 보툴리눔 기질의 절단
이 실험은 발현된 BoNTA-CPP 융합 단백질이 BoNT 기질 SNAP-25 에 대해 활성이었음을 입증한다.
SNAPtide
TM
검정법을 이용한 보툴리눔 활성 시험
SNAPtide (Millipore, Cat. No. 567333-200NMOL) 를 반응 완충액 (20 mM, pH 7.4, 0.25 mM ZnCl2, 5 mM DTT, 0.05% Tween-20) 을 사용하여 5 μM 로 희석하였다. 재조합 BoNTA-ZFP 융합 단백질 (200 nM; Protein ID: 1 ~ 8) 각각을 SNAPtide 를 함유하는 반응 완충액에 첨가하였다. 반응물을 37℃ 에서 40 분 동안 인큐베이션하였다. 여기 파장 320 nm 및 방출 파장 420 nm 의 플레이트 판독기를 사용하여 형광을 기록하였다. SNAPtide 는 BoNTA 의 세포내 기질인 SNAP-25 로부터 유래된 짧은 펩티드였다. SNAPtide 는 BoNTA 의 절단 부위 및 형광단 및 소광제 그룹을 모두 함유하였다. 펩티드의 절단은 형광단을 유리시키고 형광을 활성화시킨다. 반응 양성 대조군은 R&D Systems (Cat. No. 4489-ZN-010) 으로부터 구매한 시판되는 재조합 BoNTA 경쇄 (BoNTA-LC) 단백질이었다. 모든 데이터는 3 회 반복으로 수행되었다.
결과 및 데이터 분석
도 3 의 데이터는 평균 ± 표준 편차로 표시되며 원-테일 스튜던트 (one-tailed Student) 시험에 의해 분석되었다. 상용 BoNTA-LC 를 포함한 모든 시험된 샘플은SNAPtide 대조군보다 상당히 (p<0.05) 높은 신호를 갖는다. 도. 3 에 제시된 바와 같이, ZFP 의 단일-말단 및 이분형 융합 모두 SNAP-25 로부터 유래된 펩티드 기질 상에서 BoNTA 의 활성을 유지하였다.
실시예 3. BoNTA-ZFP 융합 단백질의 세포 투과 활성 검정법
이 실험은 선택된 BoNTA-ZFP 융합 단백질이 인간 피부 섬유아세포 (hDF) 에 효과적으로 침투할 수 있음을 입증한다.
재조합 BoNTA-ZFP 융합 단백질을 사용한 hDF 세포의 형질도입
hDF 세포를 폴리-리신으로 미리 코팅된 6-웰 플레이트에 시딩하였다. 시딩 후 24 시간에, 세포를 포스페이트 완충 식염수 (PBS) 로 3 회 세척하였다. BoNTA-ZFP 단백질 (Protein ID 5 및 6) 및 대조군 단백질 (R&D BoNTA-LC, R&D Systems 사의 BoNTA 의 시판 이용가능한 경쇄) 를 DMEM 무-혈청 배지로 희석하였다. 세포를 37℃ 에서 2 시간 동안 BoNTA-ZFP 단백질 (0.15 μM) 및 BoNTA-LC (0.5 μM) 로 처리하였다. 이어서, 세포를 0.5 mg/mL 헤파린이 보충된 PBS 로 3 회 세척하여 표면-결합 단백질을 제거한 다음 트립신 처리에 의해 수확하였다. 수집된 세포를 초음파처리에 의해 용리시키고 BoNTA 활성을 상기 기재된 바와 같이 검정하였다.
결과 및 데이터 분석
도 4 에 제시된 데이터는 평균 ± 표준 편차로 표시되며 원-테일 스튜던트 (one-tailed Student) 시험에 의해 분석되었다. BoNTA-ZFP 단백질 (Protein ID 5 및 6) 로 처리된 hDF 세포는 대조군보다 상당히 높은 신호를 갖는 (p<0.05), 명백한 BoNTA 활성을 나타냈다. 이것은 BoNTA-ZFP 단백질이 세포를 효과적으로 침투할 수 있음을 입증한다.
실시예 4. 마우스에서 BoNTA-ZFP 단백질의 생체 내 활성
이 실험은 온전한 또는 미세바늘로 처리된 마우스 피부에 적용될 때 BoNTA-ZFP 융합 단백질이 발가락 외전을 특징으로 하는 근육 마비를 유발할 수 있음을 입증한다.
발가락 외전 (Digit abduction) 실험
대략 36 g 의 체중을 가진 15 마리의 C57 암컷 마우스를 무작위로 5 개의 그룹으로 나누었다 (n = 3). 모든 마우스에서, 왼쪽 다리를 대조군으로 처리하지 않고 오른쪽 다리를 상이한 약물로 처리하였다. 처리 전에 마우스를 마취시켰다. 모의 그룹 (A) 에서, 마우스에 저장 완충제 (20 mM HEPES, pH 7.0, 300 mM NaCl 및 10% 글리세롤) 를 투여하였다. BOTOX (Allergan) 주사 그룹 (B) 에서, 지시된 바와 같이 BOTOX 를 0.9% NaCl 식염수로 재구성하고 5 ㎕ 의 45 U/mL 용액을 오른쪽 다리에 주사하였다. 그룹 C 에서, 마우스 다리 및 발은 미세바늘 롤러 (RoHS MR20, 0.2 mm, 하우스 사용) 로 전-처리된 후, 60 ㎕ 의 45 U/mL BOTOX 를 국소 적용하였다. 그룹 D 에서, 마우스 다리 및 발은 미세바늘 롤러 (RoHS MR20, 0.2 mm, 하우스 사용) 로 전-처리된 후, 저장 완충제 (20 mM HEPES, pH 7.0, 300 mM NaCl 및 10% 글리세롤) 중의 0.05 mg/mL BoNTA-ZFP 단백질 (Protein ID 6) 60 ㎕ 로 국소 적용하였다. 그룹 E 에서, 저장 완충제 (20 mM HEPES, pH 7.0, 300 mM NaCl 및 10% 글리세롤) 중의 0.05 mg/mL BoNTA-ZFP 단백질 60 ㎕ 을 국소 적용하였다. 다리와 발에 3 번 롤링하여 미세바늘 롤러 처리를 적용하였다. 국소 적용시, 다리 및 발을 물질로 균일하게 펴고 마사지한 다음 공기 건조시켜, 모든 용액이 투여될 때까지 여러 번 반복하였다. 0 일에 마우스가 깨어난 후 발가락 외전을 기록한 후, 다음 4 일 동안 매일 기록하였다.
결과 및 데이터 분석
미세바늘 전처리를 갖는 주사가능한 BOTOX 및 BoNTA-ZFP 둘 다, 대조군 A 보다 상당히 높은 점수로 (p <0.05; 스튜던트 t 검정), 주목할만한 발가락 외전을 나타냈다 (도. 5). BoNTA-ZFP 를 직접 적용하면 효과가 최소화되었다. 3 명의 독립적인 연구자들에 의해 맹검 방식으로 발가락 외전 점수 (DAS) 를 평가하였다. DAS 는 제 2 일에 피크 값에 도달했다 (도. 6). 따라서 이 예는 마우스 피부에 적용될 때 세포-침투성 BoNTA-ZFP 가 SNAP-25 절단의 생체 내 활성의 지표인, 근육 마비를 유발할 수 있음을 보여준다.
실시예 5. 곤충 세포에서의 발현
이 실험은 BoNTA-ZFP 융합 단백질이 높은 수율로 곤충 세포에서 발현될 수 있음을 입증한다. 천연 BoNT 가 박테리아 클로스트리디움 보툴리눔 (원핵생물) 에서 생산된다는 것을 고려하면, 곤충 세포 (진핵생물) 로부터 BoNTA 의 대량 생산은 정말 놀랍다.
방법
Protein ID 6 (SEQ ID NO:15) 을 함유하는 pFastBac 벡터를 배큘로바이러스 (BV) 에 패키지하였다. 재조합 Protein ID 6 단백질을 함유하는 BV 를 사용하여 스포도프테라 프루지페르다 Sf9 곤충 세포를 감염시켰다. 세포 생존율이 60% 미만이 되면 세포를 수확한다. 대략 1 mL 의 배양물을 원심분리하여 세포를 수집하였다. 이들 세포를 1 mL PBS 완충액에 재현탁시키고 초음파처리하였다. 대략 10 ㎕ 의 세포 용리액을 SDS-PAGE 상에 분석하였다. 항-His 항체를 사용하여 단백질을 검출하고 이미지화하였다.
결과 및 데이터 분석
가용성 BoNTA-ZF 는 총 단백질의 거의 100% 이다 (도. 7). 단백질의 양은 로딩 대조군 (5 ㎍ 단백질) 과 비교하여 1 ㎍ 인 것으로 정량화되었다 (도. 7). 따라서, 발현 수율은 배양물 리터 당 100 mg 인 것으로 계산된다.
실시예 6. 근육내 주사는 근육 마비를 야기한다
방법
다양한 용량의 BoNTA-ZFP 를 해밀턴 주사기를 사용하여 우측 비복근 근육에 근육 내 주사하였다. 근육 마비를 실시예 4 에 기재된 바와 같이 모니터링하였다.
결과 및 데이터 분석
1 또는 3 ng 의 BoNTA-ZFP (Protein ID 6) 의 근육내 주사는 명백한 발가락 외전을 유발하였다. 모든 마우스에 대해 4 점에 도달하였다 (그룹 당 n = 3).
실시예 7. 트레드밀 시험
이 예는 작용제의 근육-마비 활성을 측정하는 방법을 시험한다. 자발적인 달리기 연구와 비교하여, 이 방법은 세포-투과 BoNTA-ZFP 의 근육-마비 활성을 객관적으로 반영할 수 있다.
방법
BoNTA-ZFP 를 실시예 4 에 기재된 바와 같이 CJ57 암컷 마우스에 국소적으로 적용하였다. 마우스는 각도와 속도에 대해 다음과 같은 순서로 설정되었다: 0°/5 m/min, 3°/8 m/min, 6°/11 m/min, 9°/14 m/min, 12°/17 m/min, 12°/20 m/min. 마우스를 각 단계에서 5 분 동안 유지시켰다. 총 거리를 계산하였다.
결과 및 데이터 분석
Botox 주사 또는 국소 BoNTA-ZFP 로 처리된 마우스는 완충 식염수와 비교하여 트레드밀 연구에서 감소된 운동 능력을 나타냈다 (도. 8).
실시예 8. 빔 밸런스 시험
이 예는 작용제의 근육-마비 활성을 측정하는 또다른 방법을 시험한다.
방법
BoNTA-ZFP 를 실시예 4 에 기재된 바와 같이 CJ57 암컷 마우스에 국소적으로 적용하였다. 마우스를 빔 밸런스 연구에 적용하였다. 마우스가 빔을 통과하는 시간을 계수하였다.
결과 및 데이터 분석
Botox 주사 또는 국소 BoNTA-ZFP 로 처리된 마우스는 완충 식염수와 비교하여 빔 밸런스 연구에서 감소된 운동 능력을 나타냈다 (도. 9).
실시예 9. 발자국 시험
이 예는 작용제의 근육-마비 활성을 측정하는 또 다른 방법을 시험한다.
방법
BoNTA-ZFP 를 실시예 4 에 기재된 바와 같이 CJ57 암컷 마우스에 국소적으로 적용하였다. 마우스를 발자국 분석 연구에 적용하였다. 발자국 폭을 기록하였다.
결과 및 데이터 분석
Botox 주사 또는 국소 BoNTA-ZFP 로 처리된 마우스는 완충 식염수와 비교하여 발자국 분석에서 감소된 접촉 면적을 나타냈다 (도. 10).
실시예 8-10 은 시험제의 근육-마비 활성을 측정하기 위한 이들 시험의 유효성 및 정량적 특성을 입증한다.
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본 발명은 본 발명의 개별 양상의 단일 예시로서 의도된 설명된 특정 구현예에 의해 범위가 제한되지 않으며, 기능적으로 동등한 임의의 조성물 또는 방법은 본 발명의 범위 내에 있다. 다양한 변형들 및 변경들이 본 발명의 취지 또는 범위로부터 벗어남 없이 본 발명의 방법 및 조성물에 대해 행해질 수 있음이 당업자에게 자명할 것이다. 따라서, 본 발명은 첨부된 청구 범위 및 그 균등물의 범위 내에 있는 본 발명의 변형 및 변경을 포함하는 것으로 의도된다.
본 명세서에 언급된 모든 공개물 및 특허 출원은 각각의 개별적 공개물 또는 특허 출원이 본원에 참조로 포함되는 것으로 구체적이고 개별적으로 표시되는 것과 동일한 정도로 본원에 참조로 포함된다.
<110> ShanghaiTech University
<120> TOPICAL COMPOSITIONS AND USES
<130> 49BD-258138-WO2
<150> PCT/CN2017/093810
<151> 2017-07-21
<160> 19
<170> PatentIn version 3.5
<210> 1
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<213> Artificial Sequence
<220>
<223> Synthetic
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Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly
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<213> Artificial Sequence
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Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser
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Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr
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Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val
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Ala His Gln Arg Thr His Thr Gly
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<212> PRT
<213> Artificial Sequence
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Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser
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Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr
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Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val
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Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu
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Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg
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Thr His Thr Gly
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Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser
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Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr
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Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val
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Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu
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Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg
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Thr His Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser
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Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly
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Arg Ile Pro Leu Ser Cys Thr Ile Cys Arg Lys Arg Lys Val Lys Cys
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Asp Lys Leu Arg Pro His Cys Gln Gln Cys Thr Lys Thr Gly Val Ala
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His Leu Cys His Tyr Met
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<211> 17
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<213> Artificial Sequence
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Thr Cys Tyr Asn Cys Gly Gln Thr Gly His Leu Ser Arg Glu Cys Pro
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Ser
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Arg Arg Cys Asn Cys Met Ala Thr Arg His Pro Leu Phe Glu Val Ala
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Pro Asn Cys Leu Asn Cys Gly Lys Ile Ile Cys Glu Lys Glu Gly Leu
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Gln Pro Cys Ser Tyr Cys Gly Gln Glu Leu Leu Ser Pro Lys Asp Lys
35 40 45
Gln Glu Ile Ile
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<210> 8
<211> 425
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<213> Artificial Sequence
<220>
<223> Synthetic
<400> 8
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
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Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
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Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
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Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe
420 425
<210> 9
<211> 871
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 9
Tyr Lys Leu Leu Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser
1 5 10 15
Leu Asp Lys Gly Tyr Asn Lys Ala Leu Asn Asp Leu Cys Ile Lys Val
20 25 30
Asn Asn Trp Asp Leu Phe Phe Ser Pro Ser Glu Asp Asn Phe Thr Asn
35 40 45
Asp Leu Asn Lys Gly Glu Glu Ile Thr Ser Asp Thr Asn Ile Glu Ala
50 55 60
Ala Glu Glu Asn Ile Ser Leu Asp Leu Ile Gln Gln Tyr Tyr Leu Thr
65 70 75 80
Phe Asn Phe Asp Asn Glu Pro Glu Asn Ile Ser Ile Glu Asn Leu Ser
85 90 95
Ser Asp Ile Ile Gly Gln Leu Glu Leu Met Pro Asn Ile Glu Arg Phe
100 105 110
Pro Asn Gly Lys Lys Tyr Glu Leu Asp Lys Tyr Thr Met Phe His Tyr
115 120 125
Leu Arg Ala Gln Glu Phe Glu His Gly Lys Ser Arg Ile Ala Leu Thr
130 135 140
Asn Ser Val Asn Glu Ala Leu Leu Asn Pro Ser Arg Val Tyr Thr Phe
145 150 155 160
Phe Ser Ser Asp Tyr Val Lys Lys Val Asn Lys Ala Thr Glu Ala Ala
165 170 175
Met Phe Leu Gly Trp Val Glu Gln Leu Val Tyr Asp Phe Thr Asp Glu
180 185 190
Thr Ser Glu Val Ser Thr Thr Asp Lys Ile Ala Asp Ile Thr Ile Ile
195 200 205
Ile Pro Tyr Ile Gly Pro Ala Leu Asn Ile Gly Asn Met Leu Tyr Lys
210 215 220
Asp Asp Phe Val Gly Ala Leu Ile Phe Ser Gly Ala Val Ile Leu Leu
225 230 235 240
Glu Phe Ile Pro Glu Ile Ala Ile Pro Val Leu Gly Thr Phe Ala Leu
245 250 255
Val Ser Tyr Ile Ala Asn Lys Val Leu Thr Val Gln Thr Ile Asp Asn
260 265 270
Ala Leu Ser Lys Arg Asn Glu Lys Trp Asp Glu Val Tyr Lys Tyr Ile
275 280 285
Val Thr Asn Trp Leu Ala Lys Val Asn Thr Gln Ile Asp Leu Ile Arg
290 295 300
Lys Lys Met Lys Glu Ala Leu Glu Asn Gln Ala Glu Ala Thr Lys Ala
305 310 315 320
Ile Ile Asn Tyr Gln Tyr Asn Gln Tyr Thr Glu Glu Glu Lys Asn Asn
325 330 335
Ile Asn Phe Asn Ile Asp Asp Leu Ser Ser Lys Leu Asn Glu Ser Ile
340 345 350
Asn Lys Ala Met Ile Asn Ile Asn Lys Phe Leu Asn Gln Cys Ser Val
355 360 365
Ser Tyr Leu Met Asn Ser Met Ile Pro Tyr Gly Val Lys Arg Leu Glu
370 375 380
Asp Phe Asp Ala Ser Leu Lys Asp Ala Leu Leu Lys Tyr Ile Tyr Asp
385 390 395 400
Asn Arg Gly Thr Leu Ile Gly Gln Val Asp Arg Leu Lys Asp Lys Val
405 410 415
Asn Asn Thr Leu Ser Thr Asp Ile Pro Phe Gln Leu Ser Lys Tyr Val
420 425 430
Asp Asn Gln Arg Leu Leu Ser Thr Phe Thr Glu Tyr Ile Lys Asn Ile
435 440 445
Ile Asn Thr Ser Ile Leu Asn Leu Arg Tyr Glu Ser Asn His Leu Ile
450 455 460
Asp Leu Ser Arg Tyr Ala Ser Lys Ile Asn Ile Gly Ser Lys Val Asn
465 470 475 480
Phe Asp Pro Ile Asp Lys Asn Gln Ile Gln Leu Phe Asn Leu Glu Ser
485 490 495
Ser Lys Ile Glu Val Ile Leu Lys Asn Ala Ile Val Tyr Asn Ser Met
500 505 510
Tyr Glu Asn Phe Ser Thr Ser Phe Trp Ile Arg Ile Pro Lys Tyr Phe
515 520 525
Asn Ser Ile Ser Leu Asn Asn Glu Tyr Thr Ile Ile Asn Cys Met Glu
530 535 540
Asn Asn Ser Gly Trp Lys Val Ser Leu Asn Tyr Gly Glu Ile Ile Trp
545 550 555 560
Thr Leu Gln Asp Thr Gln Glu Ile Lys Gln Arg Val Val Phe Lys Tyr
565 570 575
Ser Gln Met Ile Asn Ile Ser Asp Tyr Ile Asn Arg Trp Ile Phe Val
580 585 590
Thr Ile Thr Asn Asn Arg Leu Asn Asn Ser Lys Ile Tyr Ile Asn Gly
595 600 605
Arg Leu Ile Asp Gln Lys Pro Ile Ser Asn Leu Gly Asn Ile His Ala
610 615 620
Ser Asn Asn Ile Met Phe Lys Leu Asp Gly Cys Arg Asp Thr His Arg
625 630 635 640
Tyr Ile Trp Ile Lys Tyr Phe Asn Leu Phe Asp Lys Glu Leu Asn Glu
645 650 655
Lys Glu Ile Lys Asp Leu Tyr Asp Asn Gln Ser Asn Ser Gly Ile Leu
660 665 670
Lys Asp Phe Trp Gly Asp Tyr Leu Gln Tyr Asp Lys Pro Tyr Tyr Met
675 680 685
Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val Asp Val Asn Asn Val Gly
690 695 700
Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro Arg Gly Ser Val Met Thr
705 710 715 720
Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr Arg Gly Thr Lys Phe Ile
725 730 735
Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp Asn Ile Val Arg Asn Asn
740 745 750
Asp Arg Val Tyr Ile Asn Val Val Val Lys Asn Lys Glu Tyr Arg Leu
755 760 765
Ala Thr Asn Ala Ser Gln Ala Gly Val Glu Lys Ile Leu Ser Ala Leu
770 775 780
Glu Ile Pro Asp Val Gly Asn Leu Ser Gln Val Val Val Met Lys Ser
785 790 795 800
Lys Asn Asp Gln Gly Ile Thr Asn Lys Cys Lys Met Asn Leu Gln Asp
805 810 815
Asn Asn Gly Asn Asp Ile Gly Phe Ile Gly Phe His Gln Phe Asn Asn
820 825 830
Ile Ala Lys Leu Val Ala Ser Asn Trp Tyr Asn Arg Gln Ile Glu Arg
835 840 845
Ser Ser Arg Thr Leu Gly Cys Ser Trp Glu Phe Ile Pro Val Asp Asp
850 855 860
Gly Trp Gly Glu Arg Pro Leu
865 870
<210> 10
<211> 1312
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 10
Met His His His His His His Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10 15
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
20 25 30
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro
35 40 45
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
50 55 60
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
65 70 75 80
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
85 90 95
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
100 105 110
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
115 120 125
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
130 135 140
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
145 150 155 160
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
165 170 175
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
180 185 190
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
195 200 205
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
210 215 220
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
225 230 235 240
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
245 250 255
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
260 265 270
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
275 280 285
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
290 295 300
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
305 310 315 320
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
325 330 335
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
340 345 350
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
355 360 365
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
370 375 380
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
385 390 395 400
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
405 410 415
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
420 425 430
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
435 440 445
Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys
450 455 460
Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe
465 470 475 480
Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu
485 490 495
Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu
500 505 510
Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro
515 520 525
Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu
530 535 540
Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu
545 550 555 560
Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu
565 570 575
His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu
580 585 590
Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys
595 600 605
Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu
610 615 620
Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr
625 630 635 640
Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala
645 650 655
Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu
660 665 670
Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala
675 680 685
Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys
690 695 700
Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu
705 710 715 720
Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys
725 730 735
Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu
740 745 750
Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn
755 760 765
Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp
770 775 780
Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile
785 790 795 800
Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met
805 810 815
Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys
820 825 830
Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly
835 840 845
Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp
850 855 860
Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser
865 870 875 880
Thr Phe Thr Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn
885 890 895
Leu Arg Tyr Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser
900 905 910
Lys Ile Asn Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn
915 920 925
Gln Ile Gln Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu
930 935 940
Lys Asn Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser
945 950 955 960
Phe Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn
965 970 975
Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val
980 985 990
Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu
995 1000 1005
Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser
1010 1015 1020
Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu
1025 1030 1035 1040
Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln Lys Pro
1045 1050 1055
Ile Ser Asn Leu Gly Asn Ile His Ala Ser Asn Asn Ile Met Phe Lys
1060 1065 1070
Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile Trp Ile Lys Tyr Phe
1075 1080 1085
Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu Ile Lys Asp Leu Tyr
1090 1095 1100
Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys Asp Phe Trp Gly Asp Tyr
1105 1110 1115 1120
Leu Gln Tyr Asp Lys Pro Tyr Tyr Met Leu Asn Leu Tyr Asp Pro Asn
1125 1130 1135
Lys Tyr Val Asp Val Asn Asn Val Gly Ile Arg Gly Tyr Met Tyr Leu
1140 1145 1150
Lys Gly Pro Arg Gly Ser Val Met Thr Thr Asn Ile Tyr Leu Asn Ser
1155 1160 1165
Ser Leu Tyr Arg Gly Thr Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly
1170 1175 1180
Asn Lys Asp Asn Ile Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val
1185 1190 1195 1200
Val Val Lys Asn Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala
1205 1210 1215
Gly Val Glu Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn
1220 1225 1230
Leu Ser Gln Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr
1235 1240 1245
Asn Lys Cys Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly
1250 1255 1260
Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala Ser
1265 1270 1275 1280
Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu Gly Cys
1285 1290 1295
Ser Trp Glu Phe Ile Pro Val Asp Asp Gly Trp Gly Glu Arg Pro Leu
1300 1305 1310
<210> 11
<211> 534
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 11
Met His His His His His His Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10 15
Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser
20 25 30
Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr
35 40 45
Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val
50 55 60
Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu
65 70 75 80
Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg
85 90 95
Thr His Thr Gly Gly Gly Ser Gly Gly Ser Gly Gly Ser Met Pro Phe
100 105 110
Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly Val Asp Ile
115 120 125
Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro Val Lys Ala
130 135 140
Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg Asp Thr Phe
145 150 155 160
Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu Ala Lys Gln
165 170 175
Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr Asp Asn Glu
180 185 190
Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu Arg Ile Tyr
195 200 205
Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val Arg Gly Ile
210 215 220
Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys Val Ile Asp
225 230 235 240
Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr Arg Ser Glu
245 250 255
Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile Ile Gln Phe
260 265 270
Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr Arg Asn Gly
275 280 285
Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe Thr Phe Gly
290 295 300
Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu Gly Ala Gly
305 310 315 320
Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu Leu Ile His
325 330 335
Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn Arg Val Phe
340 345 350
Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu Glu Val Ser
355 360 365
Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys Phe Ile Asp
370 375 380
Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn Lys Phe Lys
385 390 395 400
Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val Gly Thr Thr
405 410 415
Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys Tyr Leu Leu
420 425 430
Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu Lys Phe Asp
435 440 445
Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp Asn Phe Val
450 455 460
Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn Phe Asp Lys
465 470 475 480
Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr Thr Ile Tyr
485 490 495
Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn Phe Asn Gly
500 505 510
Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu Lys Asn Phe
515 520 525
Thr Gly Leu Phe Glu Phe
530
<210> 12
<211> 1405
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 12
Met His His His His His His Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10 15
Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser
20 25 30
Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr
35 40 45
Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val
50 55 60
Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu
65 70 75 80
Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg
85 90 95
Thr His Thr Gly Gly Gly Ser Gly Gly Ser Gly Gly Ser Met Pro Phe
100 105 110
Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly Val Asp Ile
115 120 125
Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro Val Lys Ala
130 135 140
Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg Asp Thr Phe
145 150 155 160
Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu Ala Lys Gln
165 170 175
Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr Asp Asn Glu
180 185 190
Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu Arg Ile Tyr
195 200 205
Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val Arg Gly Ile
210 215 220
Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys Val Ile Asp
225 230 235 240
Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr Arg Ser Glu
245 250 255
Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile Ile Gln Phe
260 265 270
Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr Arg Asn Gly
275 280 285
Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe Thr Phe Gly
290 295 300
Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu Gly Ala Gly
305 310 315 320
Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu Leu Ile His
325 330 335
Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn Arg Val Phe
340 345 350
Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu Glu Val Ser
355 360 365
Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys Phe Ile Asp
370 375 380
Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn Lys Phe Lys
385 390 395 400
Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val Gly Thr Thr
405 410 415
Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys Tyr Leu Leu
420 425 430
Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu Lys Phe Asp
435 440 445
Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp Asn Phe Val
450 455 460
Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn Phe Asp Lys
465 470 475 480
Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr Thr Ile Tyr
485 490 495
Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn Phe Asn Gly
500 505 510
Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu Lys Asn Phe
515 520 525
Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg Gly Ile Ile
530 535 540
Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys Ala Leu Asn
545 550 555 560
Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe Ser Pro Ser
565 570 575
Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu Ile Thr Ser
580 585 590
Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu Asp Leu Ile
595 600 605
Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro Glu Asn Ile
610 615 620
Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu Glu Leu Met
625 630 635 640
Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu Leu Asp Lys
645 650 655
Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu His Gly Lys
660 665 670
Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu Leu Asn Pro
675 680 685
Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys Lys Val Asn
690 695 700
Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu Gln Leu Val
705 710 715 720
Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr Asp Lys Ile
725 730 735
Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala Leu Asn Ile
740 745 750
Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu Ile Phe Ser
755 760 765
Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala Ile Pro Val
770 775 780
Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys Val Leu Thr
785 790 795 800
Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu Lys Trp Asp
805 810 815
Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys Val Asn Thr
820 825 830
Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu Glu Asn Gln
835 840 845
Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn Gln Tyr Thr
850 855 860
Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp Leu Ser Ser
865 870 875 880
Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile Asn Lys Phe
885 890 895
Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met Ile Pro Tyr
900 905 910
Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys Asp Ala Leu
915 920 925
Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly Gln Val Asp
930 935 940
Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp Ile Pro Phe
945 950 955 960
Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser Thr Phe Thr
965 970 975
Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn Leu Arg Tyr
980 985 990
Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser Lys Ile Asn
995 1000 1005
Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn Gln Ile Gln
1010 1015 1020
Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu Lys Asn Ala
1025 1030 1035 1040
Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser Phe Trp Ile
1045 1050 1055
Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn Glu Tyr Thr
1060 1065 1070
Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val Ser Leu Asn
1075 1080 1085
Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu Ile Lys Gln
1090 1095 1100
Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser Asp Tyr Ile
1105 1110 1115 1120
Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu Asn Asn Ser
1125 1130 1135
Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln Lys Pro Ile Ser Asn
1140 1145 1150
Leu Gly Asn Ile His Ala Ser Asn Asn Ile Met Phe Lys Leu Asp Gly
1155 1160 1165
Cys Arg Asp Thr His Arg Tyr Ile Trp Ile Lys Tyr Phe Asn Leu Phe
1170 1175 1180
Asp Lys Glu Leu Asn Glu Lys Glu Ile Lys Asp Leu Tyr Asp Asn Gln
1185 1190 1195 1200
Ser Asn Ser Gly Ile Leu Lys Asp Phe Trp Gly Asp Tyr Leu Gln Tyr
1205 1210 1215
Asp Lys Pro Tyr Tyr Met Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val
1220 1225 1230
Asp Val Asn Asn Val Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro
1235 1240 1245
Arg Gly Ser Val Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr
1250 1255 1260
Arg Gly Thr Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp
1265 1270 1275 1280
Asn Ile Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val Val Lys
1285 1290 1295
Asn Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val Glu
1300 1305 1310
Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser Gln
1315 1320 1325
Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn Lys Cys
1330 1335 1340
Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly Phe Ile Gly
1345 1350 1355 1360
Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala Ser Asn Trp Tyr
1365 1370 1375
Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu Gly Cys Ser Trp Glu
1380 1385 1390
Phe Ile Pro Val Asp Asp Gly Trp Gly Glu Arg Pro Leu
1395 1400 1405
<210> 13
<211> 533
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 13
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Gly Gly Ser Gly Gly Ser Gly
420 425 430
Gly Ser Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser
435 440 445
Ala Ser Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys
450 455 460
Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala
465 470 475 480
Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr Lys Cys
485 490 495
Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His
500 505 510
Gln Arg Thr His Thr Gly Gly Gly Ser Gly Gly Ser Gly Gly Ser His
515 520 525
His His His His His
530
<210> 14
<211> 1404
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 14
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys
435 440 445
Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe
450 455 460
Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu
465 470 475 480
Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu
485 490 495
Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro
500 505 510
Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu
515 520 525
Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu
530 535 540
Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu
545 550 555 560
His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu
565 570 575
Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys
580 585 590
Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu
595 600 605
Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr
610 615 620
Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala
625 630 635 640
Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu
645 650 655
Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala
660 665 670
Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys
675 680 685
Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu
690 695 700
Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys
705 710 715 720
Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu
725 730 735
Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn
740 745 750
Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp
755 760 765
Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile
770 775 780
Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met
785 790 795 800
Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys
805 810 815
Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly
820 825 830
Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp
835 840 845
Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser
850 855 860
Thr Phe Thr Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn
865 870 875 880
Leu Arg Tyr Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser
885 890 895
Lys Ile Asn Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn
900 905 910
Gln Ile Gln Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu
915 920 925
Lys Asn Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser
930 935 940
Phe Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn
945 950 955 960
Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val
965 970 975
Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu
980 985 990
Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser
995 1000 1005
Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu
1010 1015 1020
Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln Lys Pro
1025 1030 1035 1040
Ile Ser Asn Leu Gly Asn Ile His Ala Ser Asn Asn Ile Met Phe Lys
1045 1050 1055
Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile Trp Ile Lys Tyr Phe
1060 1065 1070
Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu Ile Lys Asp Leu Tyr
1075 1080 1085
Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys Asp Phe Trp Gly Asp Tyr
1090 1095 1100
Leu Gln Tyr Asp Lys Pro Tyr Tyr Met Leu Asn Leu Tyr Asp Pro Asn
1105 1110 1115 1120
Lys Tyr Val Asp Val Asn Asn Val Gly Ile Arg Gly Tyr Met Tyr Leu
1125 1130 1135
Lys Gly Pro Arg Gly Ser Val Met Thr Thr Asn Ile Tyr Leu Asn Ser
1140 1145 1150
Ser Leu Tyr Arg Gly Thr Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly
1155 1160 1165
Asn Lys Asp Asn Ile Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val
1170 1175 1180
Val Val Lys Asn Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala
1185 1190 1195 1200
Gly Val Glu Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn
1205 1210 1215
Leu Ser Gln Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr
1220 1225 1230
Asn Lys Cys Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly
1235 1240 1245
Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala Ser
1250 1255 1260
Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu Gly Cys
1265 1270 1275 1280
Ser Trp Glu Phe Ile Pro Val Asp Asp Gly Trp Gly Glu Arg Pro Leu
1285 1290 1295
Gly Gly Ser Gly Gly Ser Gly Gly Ser Glu Lys Pro Tyr Lys Cys Pro
1300 1305 1310
Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln
1315 1320 1325
Arg Thr His Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys
1330 1335 1340
Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg Thr His Thr
1345 1350 1355 1360
Gly Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala
1365 1370 1375
Ser Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Gly Gly Ser
1380 1385 1390
Gly Gly Ser Gly Gly Ser His His His His His His
1395 1400
<210> 15
<211> 1498
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 15
Met His His His His His His Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10 15
Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser
20 25 30
Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr
35 40 45
Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val
50 55 60
Ala His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu
65 70 75 80
Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg
85 90 95
Thr His Thr Gly Gly Gly Ser Gly Gly Ser Gly Gly Ser Met Pro Phe
100 105 110
Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly Val Asp Ile
115 120 125
Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro Val Lys Ala
130 135 140
Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg Asp Thr Phe
145 150 155 160
Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu Ala Lys Gln
165 170 175
Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr Asp Asn Glu
180 185 190
Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu Arg Ile Tyr
195 200 205
Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val Arg Gly Ile
210 215 220
Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys Val Ile Asp
225 230 235 240
Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr Arg Ser Glu
245 250 255
Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile Ile Gln Phe
260 265 270
Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr Arg Asn Gly
275 280 285
Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe Thr Phe Gly
290 295 300
Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu Gly Ala Gly
305 310 315 320
Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu Leu Ile His
325 330 335
Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn Arg Val Phe
340 345 350
Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu Glu Val Ser
355 360 365
Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys Phe Ile Asp
370 375 380
Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn Lys Phe Lys
385 390 395 400
Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val Gly Thr Thr
405 410 415
Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys Tyr Leu Leu
420 425 430
Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu Lys Phe Asp
435 440 445
Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp Asn Phe Val
450 455 460
Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn Phe Asp Lys
465 470 475 480
Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr Thr Ile Tyr
485 490 495
Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn Phe Asn Gly
500 505 510
Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu Lys Asn Phe
515 520 525
Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg Gly Ile Ile
530 535 540
Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys Ala Leu Asn
545 550 555 560
Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe Ser Pro Ser
565 570 575
Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu Ile Thr Ser
580 585 590
Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu Asp Leu Ile
595 600 605
Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro Glu Asn Ile
610 615 620
Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu Glu Leu Met
625 630 635 640
Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu Leu Asp Lys
645 650 655
Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu His Gly Lys
660 665 670
Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu Leu Asn Pro
675 680 685
Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys Lys Val Asn
690 695 700
Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu Gln Leu Val
705 710 715 720
Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr Asp Lys Ile
725 730 735
Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala Leu Asn Ile
740 745 750
Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu Ile Phe Ser
755 760 765
Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala Ile Pro Val
770 775 780
Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys Val Leu Thr
785 790 795 800
Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu Lys Trp Asp
805 810 815
Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys Val Asn Thr
820 825 830
Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu Glu Asn Gln
835 840 845
Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn Gln Tyr Thr
850 855 860
Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp Leu Ser Ser
865 870 875 880
Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile Asn Lys Phe
885 890 895
Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met Ile Pro Tyr
900 905 910
Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys Asp Ala Leu
915 920 925
Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly Gln Val Asp
930 935 940
Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp Ile Pro Phe
945 950 955 960
Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser Thr Phe Thr
965 970 975
Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn Leu Arg Tyr
980 985 990
Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser Lys Ile Asn
995 1000 1005
Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn Gln Ile Gln
1010 1015 1020
Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu Lys Asn Ala
1025 1030 1035 1040
Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser Phe Trp Ile
1045 1050 1055
Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn Glu Tyr Thr
1060 1065 1070
Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val Ser Leu Asn
1075 1080 1085
Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu Ile Lys Gln
1090 1095 1100
Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser Asp Tyr Ile
1105 1110 1115 1120
Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu Asn Asn Ser
1125 1130 1135
Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln Lys Pro Ile Ser Asn
1140 1145 1150
Leu Gly Asn Ile His Ala Ser Asn Asn Ile Met Phe Lys Leu Asp Gly
1155 1160 1165
Cys Arg Asp Thr His Arg Tyr Ile Trp Ile Lys Tyr Phe Asn Leu Phe
1170 1175 1180
Asp Lys Glu Leu Asn Glu Lys Glu Ile Lys Asp Leu Tyr Asp Asn Gln
1185 1190 1195 1200
Ser Asn Ser Gly Ile Leu Lys Asp Phe Trp Gly Asp Tyr Leu Gln Tyr
1205 1210 1215
Asp Lys Pro Tyr Tyr Met Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val
1220 1225 1230
Asp Val Asn Asn Val Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro
1235 1240 1245
Arg Gly Ser Val Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr
1250 1255 1260
Arg Gly Thr Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp
1265 1270 1275 1280
Asn Ile Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val Val Lys
1285 1290 1295
Asn Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val Glu
1300 1305 1310
Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser Gln
1315 1320 1325
Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn Lys Cys
1330 1335 1340
Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly Phe Ile Gly
1345 1350 1355 1360
Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala Ser Asn Trp Tyr
1365 1370 1375
Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu Gly Cys Ser Trp Glu
1380 1385 1390
Phe Ile Pro Val Asp Asp Gly Trp Gly Glu Arg Pro Leu Gly Gly Ser
1395 1400 1405
Gly Gly Ser Gly Gly Ser Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly
1410 1415 1420
Lys Ser Phe Ser Ala Ser Ala Ala Leu Val Ala His Gln Arg Thr His
1425 1430 1435 1440
Thr Gly Glu Lys Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser
1445 1450 1455
Ala Ser Ala Ala Leu Val Ala His Gln Arg Thr His Thr Gly Glu Lys
1460 1465 1470
Pro Tyr Lys Cys Pro Glu Cys Gly Lys Ser Phe Ser Ala Ser Ala Ala
1475 1480 1485
Leu Val Ala His Gln Arg Thr His Thr Gly
1490 1495
<210> 16
<211> 1333
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 16
Met His His His His His His Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10 15
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Gln Gly Gly Ser Gly
20 25 30
Gly Ser Gly Gly Ser Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys
35 40 45
Asp Pro Val Asn Gly Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Val
50 55 60
Gly Gln Met Gln Pro Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp
65 70 75 80
Val Ile Pro Glu Arg Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu
85 90 95
Asn Pro Pro Pro Glu Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser
100 105 110
Thr Tyr Leu Ser Thr Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val
115 120 125
Thr Lys Leu Phe Glu Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu
130 135 140
Leu Thr Ser Ile Val Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile
145 150 155 160
Asp Thr Glu Leu Lys Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln
165 170 175
Pro Asp Gly Ser Tyr Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly
180 185 190
Pro Ser Ala Asp Ile Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu
195 200 205
Val Leu Asn Leu Thr Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg
210 215 220
Phe Ser Pro Asp Phe Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp
225 230 235 240
Thr Asn Pro Leu Leu Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val
245 250 255
Thr Leu Ala His Glu Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile
260 265 270
Ala Ile Asn Pro Asn Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr
275 280 285
Glu Met Ser Gly Leu Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly
290 295 300
Gly His Asp Ala Lys Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg
305 310 315 320
Leu Tyr Tyr Tyr Asn Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys
325 330 335
Ala Lys Ser Ile Val Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn
340 345 350
Val Phe Lys Glu Lys Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe
355 360 365
Ser Val Asp Lys Leu Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu
370 375 380
Ile Tyr Thr Glu Asp Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg
385 390 395 400
Lys Thr Tyr Leu Asn Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val
405 410 415
Pro Lys Val Asn Tyr Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr
420 425 430
Asn Leu Ala Ala Asn Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met
435 440 445
Asn Phe Thr Lys Leu Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys
450 455 460
Leu Leu Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp
465 470 475 480
Lys Gly Tyr Asn Lys Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn
485 490 495
Trp Asp Leu Phe Phe Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu
500 505 510
Asn Lys Gly Glu Glu Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu
515 520 525
Glu Asn Ile Ser Leu Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn
530 535 540
Phe Asp Asn Glu Pro Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp
545 550 555 560
Ile Ile Gly Gln Leu Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn
565 570 575
Gly Lys Lys Tyr Glu Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg
580 585 590
Ala Gln Glu Phe Glu His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser
595 600 605
Val Asn Glu Ala Leu Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser
610 615 620
Ser Asp Tyr Val Lys Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe
625 630 635 640
Leu Gly Trp Val Glu Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser
645 650 655
Glu Val Ser Thr Thr Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro
660 665 670
Tyr Ile Gly Pro Ala Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp
675 680 685
Phe Val Gly Ala Leu Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe
690 695 700
Ile Pro Glu Ile Ala Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser
705 710 715 720
Tyr Ile Ala Asn Lys Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu
725 730 735
Ser Lys Arg Asn Glu Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr
740 745 750
Asn Trp Leu Ala Lys Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys
755 760 765
Met Lys Glu Ala Leu Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile
770 775 780
Asn Tyr Gln Tyr Asn Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn
785 790 795 800
Phe Asn Ile Asp Asp Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys
805 810 815
Ala Met Ile Asn Ile Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr
820 825 830
Leu Met Asn Ser Met Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe
835 840 845
Asp Ala Ser Leu Lys Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg
850 855 860
Gly Thr Leu Ile Gly Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn
865 870 875 880
Thr Leu Ser Thr Asp Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn
885 890 895
Gln Arg Leu Leu Ser Thr Phe Thr Glu Tyr Ile Lys Asn Ile Ile Asn
900 905 910
Thr Ser Ile Leu Asn Leu Arg Tyr Glu Ser Asn His Leu Ile Asp Leu
915 920 925
Ser Arg Tyr Ala Ser Lys Ile Asn Ile Gly Ser Lys Val Asn Phe Asp
930 935 940
Pro Ile Asp Lys Asn Gln Ile Gln Leu Phe Asn Leu Glu Ser Ser Lys
945 950 955 960
Ile Glu Val Ile Leu Lys Asn Ala Ile Val Tyr Asn Ser Met Tyr Glu
965 970 975
Asn Phe Ser Thr Ser Phe Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser
980 985 990
Ile Ser Leu Asn Asn Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn
995 1000 1005
Ser Gly Trp Lys Val Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu
1010 1015 1020
Gln Asp Thr Gln Glu Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln
1025 1030 1035 1040
Met Ile Asn Ile Ser Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile
1045 1050 1055
Thr Asn Asn Arg Leu Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu
1060 1065 1070
Ile Asp Gln Lys Pro Ile Ser Asn Leu Gly Asn Ile His Ala Ser Asn
1075 1080 1085
Asn Ile Met Phe Lys Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile
1090 1095 1100
Trp Ile Lys Tyr Phe Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu
1105 1110 1115 1120
Ile Lys Asp Leu Tyr Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys Asp
1125 1130 1135
Phe Trp Gly Asp Tyr Leu Gln Tyr Asp Lys Pro Tyr Tyr Met Leu Asn
1140 1145 1150
Leu Tyr Asp Pro Asn Lys Tyr Val Asp Val Asn Asn Val Gly Ile Arg
1155 1160 1165
Gly Tyr Met Tyr Leu Lys Gly Pro Arg Gly Ser Val Met Thr Thr Asn
1170 1175 1180
Ile Tyr Leu Asn Ser Ser Leu Tyr Arg Gly Thr Lys Phe Ile Ile Lys
1185 1190 1195 1200
Lys Tyr Ala Ser Gly Asn Lys Asp Asn Ile Val Arg Asn Asn Asp Arg
1205 1210 1215
Val Tyr Ile Asn Val Val Val Lys Asn Lys Glu Tyr Arg Leu Ala Thr
1220 1225 1230
Asn Ala Ser Gln Ala Gly Val Glu Lys Ile Leu Ser Ala Leu Glu Ile
1235 1240 1245
Pro Asp Val Gly Asn Leu Ser Gln Val Val Val Met Lys Ser Lys Asn
1250 1255 1260
Asp Gln Gly Ile Thr Asn Lys Cys Lys Met Asn Leu Gln Asp Asn Asn
1265 1270 1275 1280
Gly Asn Asp Ile Gly Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala
1285 1290 1295
Lys Leu Val Ala Ser Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser
1300 1305 1310
Arg Thr Leu Gly Cys Ser Trp Glu Phe Ile Pro Val Asp Asp Gly Trp
1315 1320 1325
Gly Glu Arg Pro Leu
1330
<210> 17
<211> 1342
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 17
Met His His His His His His Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10 15
Lys Glu Thr Trp Trp Glu Thr Trp Trp Thr Glu Trp Ser Gln Pro Lys
20 25 30
Lys Lys Arg Lys Val Gly Gly Ser Gly Gly Ser Gly Gly Ser Met Pro
35 40 45
Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly Val Asp
50 55 60
Ile Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro Val Lys
65 70 75 80
Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg Asp Thr
85 90 95
Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu Ala Lys
100 105 110
Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr Asp Asn
115 120 125
Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu Arg Ile
130 135 140
Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val Arg Gly
145 150 155 160
Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys Val Ile
165 170 175
Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr Arg Ser
180 185 190
Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile Ile Gln
195 200 205
Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr Arg Asn
210 215 220
Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe Thr Phe
225 230 235 240
Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu Gly Ala
245 250 255
Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu Leu Ile
260 265 270
His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn Arg Val
275 280 285
Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu Glu Val
290 295 300
Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys Phe Ile
305 310 315 320
Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn Lys Phe
325 330 335
Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val Gly Thr
340 345 350
Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys Tyr Leu
355 360 365
Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu Lys Phe
370 375 380
Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp Asn Phe
385 390 395 400
Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn Phe Asp
405 410 415
Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr Thr Ile
420 425 430
Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn Phe Asn
435 440 445
Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu Lys Asn
450 455 460
Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg Gly Ile
465 470 475 480
Ile Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys Ala Leu
485 490 495
Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe Ser Pro
500 505 510
Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu Ile Thr
515 520 525
Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu Asp Leu
530 535 540
Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro Glu Asn
545 550 555 560
Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu Glu Leu
565 570 575
Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu Leu Asp
580 585 590
Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu His Gly
595 600 605
Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu Leu Asn
610 615 620
Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys Lys Val
625 630 635 640
Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu Gln Leu
645 650 655
Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr Asp Lys
660 665 670
Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala Leu Asn
675 680 685
Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu Ile Phe
690 695 700
Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala Ile Pro
705 710 715 720
Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys Val Leu
725 730 735
Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu Lys Trp
740 745 750
Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys Val Asn
755 760 765
Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu Glu Asn
770 775 780
Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn Gln Tyr
785 790 795 800
Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp Leu Ser
805 810 815
Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile Asn Lys
820 825 830
Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met Ile Pro
835 840 845
Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys Asp Ala
850 855 860
Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly Gln Val
865 870 875 880
Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp Ile Pro
885 890 895
Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser Thr Phe
900 905 910
Thr Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn Leu Arg
915 920 925
Tyr Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser Lys Ile
930 935 940
Asn Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn Gln Ile
945 950 955 960
Gln Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu Lys Asn
965 970 975
Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser Phe Trp
980 985 990
Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn Glu Tyr
995 1000 1005
Thr Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val Ser Leu
1010 1015 1020
Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu Ile Lys
1025 1030 1035 1040
Gln Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser Asp Tyr
1045 1050 1055
Ile Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu Asn Asn
1060 1065 1070
Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln Lys Pro Ile Ser
1075 1080 1085
Asn Leu Gly Asn Ile His Ala Ser Asn Asn Ile Met Phe Lys Leu Asp
1090 1095 1100
Gly Cys Arg Asp Thr His Arg Tyr Ile Trp Ile Lys Tyr Phe Asn Leu
1105 1110 1115 1120
Phe Asp Lys Glu Leu Asn Glu Lys Glu Ile Lys Asp Leu Tyr Asp Asn
1125 1130 1135
Gln Ser Asn Ser Gly Ile Leu Lys Asp Phe Trp Gly Asp Tyr Leu Gln
1140 1145 1150
Tyr Asp Lys Pro Tyr Tyr Met Leu Asn Leu Tyr Asp Pro Asn Lys Tyr
1155 1160 1165
Val Asp Val Asn Asn Val Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly
1170 1175 1180
Pro Arg Gly Ser Val Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu
1185 1190 1195 1200
Tyr Arg Gly Thr Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys
1205 1210 1215
Asp Asn Ile Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val Val
1220 1225 1230
Lys Asn Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val
1235 1240 1245
Glu Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser
1250 1255 1260
Gln Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn Lys
1265 1270 1275 1280
Cys Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly Phe Ile
1285 1290 1295
Gly Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala Ser Asn Trp
1300 1305 1310
Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu Gly Cys Ser Trp
1315 1320 1325
Glu Phe Ile Pro Val Asp Asp Gly Trp Gly Glu Arg Pro Leu
1330 1335 1340
<210> 18
<211> 622
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 18
Leu Glu Glu Lys Lys Val Cys Gln Gly Thr Ser Asn Lys Leu Thr Gln
1 5 10 15
Leu Gly Thr Phe Glu Asp His Phe Leu Ser Leu Gln Arg Met Phe Asn
20 25 30
Asn Cys Glu Val Val Leu Gly Asn Leu Glu Ile Thr Tyr Val Gln Arg
35 40 45
Asn Tyr Asp Leu Ser Phe Leu Lys Thr Ile Gln Glu Val Ala Gly Tyr
50 55 60
Val Leu Ile Ala Leu Asn Thr Val Glu Arg Ile Pro Leu Glu Asn Leu
65 70 75 80
Gln Ile Ile Arg Gly Asn Met Tyr Tyr Glu Asn Ser Tyr Ala Leu Ala
85 90 95
Val Leu Ser Asn Tyr Asp Ala Asn Lys Thr Gly Leu Lys Glu Leu Pro
100 105 110
Met Arg Asn Leu Gln Glu Ile Leu His Gly Ala Val Arg Phe Ser Asn
115 120 125
Asn Pro Ala Leu Cys Asn Val Glu Ser Ile Gln Trp Arg Asp Ile Val
130 135 140
Ser Ser Asp Phe Leu Ser Asn Met Ser Met Asp Phe Gln Asn His Leu
145 150 155 160
Gly Ser Cys Gln Lys Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp
165 170 175
Gly Ala Gly Glu Glu Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala
180 185 190
Gln Gln Cys Ser Gly Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys
195 200 205
His Asn Gln Cys Ala Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys
210 215 220
Leu Val Cys Arg Lys Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys
225 230 235 240
Pro Pro Leu Met Leu Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn
245 250 255
Pro Glu Gly Lys Tyr Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro
260 265 270
Arg Asn Tyr Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly
275 280 285
Ala Asp Ser Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys
290 295 300
Cys Glu Gly Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu
305 310 315 320
Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys
325 330 335
Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe
340 345 350
Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu
355 360 365
Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln
370 375 380
Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu
385 390 395 400
Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val
405 410 415
Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile
420 425 430
Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala
435 440 445
Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr
450 455 460
Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln
465 470 475 480
Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro
485 490 495
Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val
500 505 510
Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn
515 520 525
Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn
530 535 540
Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His
545 550 555 560
Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met
565 570 575
Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val
580 585 590
Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly
595 600 605
Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile
610 615 620
<210> 19
<211> 199
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 19
Met Lys His Ser Leu Pro Asp Leu Pro Tyr Asp Tyr Gly Ala Leu Glu
1 5 10 15
Pro His Ile Asn Ala Gln Ile Met Gln Leu His His Ser Lys His His
20 25 30
Ala Ala Tyr Val Asn Asn Leu Asn Val Thr Glu Glu Lys Tyr Gln Glu
35 40 45
Ala Leu Ala Lys Gly Asp Val Thr Ala Gln Ile Ala Leu Gln Pro Ala
50 55 60
Leu Lys Phe Asn Gly Gly Gly His Ile Asn His Ser Ile Phe Trp Thr
65 70 75 80
Asn Leu Ser Pro Asn Gly Gly Gly Glu Pro Lys Gly Glu Leu Leu Glu
85 90 95
Ala Ile Lys Arg Asp Phe Gly Ser Phe Asp Lys Phe Lys Glu Lys Leu
100 105 110
Thr Ala Ala Ser Val Gly Val Gln Gly Ser Gly Trp Gly Trp Leu Gly
115 120 125
Phe Asn Lys Glu Arg Gly His Leu Gln Ile Ala Ala Cys Pro Asn Gln
130 135 140
Asp Pro Leu Gln Gly Thr Thr Gly Leu Ile Pro Leu Leu Gly Ile Asp
145 150 155 160
Val Trp Glu His Ala Tyr Tyr Leu Gln Tyr Lys Asn Val Arg Pro Asp
165 170 175
Tyr Leu Lys Ala Ile Trp Asn Val Ile Asn Trp Glu Asn Val Thr Glu
180 185 190
Arg Tyr Met Ala Cys Lys Lys
195
Claims (42)
- (a) 보툴리눔 독소 (BoNT) 경쇄 및 (b) BoNT 경쇄의 C-말단에 위치하는 또는, BoNT 경쇄의 C-말단에 위치하거나 디술피드 결합을 통해 BoNT 경쇄에 결합된 BoNT 중쇄에 대해 C-말단에 위치하는 제 1 징크 핑거 모티프를 포함하는 키메라 폴리펩티드.
- 제 1 항에 있어서, 키메라 폴리펩티드가 2000 개 초과의 아미노산 잔기를 포함하지 않는 키메라 폴리펩티드.
- 제 1 항 또는 제 2 항에 있어서, BoNT 경쇄 및 제 1 징크 핑거 모티프가 동일한 펩티드 사슬 상에 있는 키메라 폴리펩티드.
- 제 1 항 또는 제 2 항에 있어서, BoNT 경쇄 및 제 1 징크 핑거 모티프가 상이한 펩티드 사슬 상에 있는 키메라 폴리펩티드.
- 제 1 항 내지 제 4 항 중 어느 한 항에 있어서, BoNT 경쇄 또는 BoNT 중쇄의 C-말단에 위치한 징크 핑거 모티프를 하나 더 포함하는 키메라 폴리펩티드.
- 제 1 항 내지 제 5 항 중 어느 한 항에 있어서, BoNT 경쇄 또는 BoNT 중쇄의 C-말단에 위치한 징크 핑거 모티프를 2 개 더 포함하는 키메라 폴리펩티드.
- 제 5 항 또는 제 6 항에 있어서, 징크 핑거 모티프가 직접 또는 펩티드 링커를 통해 연결되는 키메라 폴리펩티드.
- 제 1 항 내지 제 7 항 중 어느 한 항에 있어서, BoNT 경쇄의 N-말단에 위치한 제 2 징크 핑거 모티프를 추가로 포함하는 키메라 폴리펩티드.
- 제 8 항에 있어서, BoNT 경쇄의 N-말단에 위치한 징크 핑거 모티프를 하나 또는 2 개 더 추가로 포함하는 키메라 폴리펩티드.
- 제 1 항 내지 제 9 항 중 어느 한 항에 있어서, 징크 핑거 모티프 중 적어도 하나가 Cys2-His2 징크 핑거 모티프인 키메라 폴리펩티드.
- 제 10 항에 있어서, 징크 핑거 모티프가 징크 핑거 모티프에서 알파-헬릭스 단편의 잔기 -1, 2, 3 또는 6 에서 적어도 알라닌을 함유하는 키메라 폴리펩티드.
- 제 1 항 내지 제 11 항 중 어느 한 항에 있어서, 징크 핑거 모티프 중 적어도 하나가 SEQ ID NO: 1 및 5 내지 7 로 이루어진 군으로부터 선택된 아미노산 서열을 포함하는 키메라 폴리펩티드.
- 제 12 항에 있어서, 징크 핑거 모티프가 SEQ ID NO:1 의 아미노산 서열을 포함하는 키메라 폴리펩티드.
- 제 1 항 내지 제 13 항 중 어느 한 항에 있어서, 제 1 징크 핑거가 BoNT 경쇄 또는 BoNT 중쇄의 C-말단으로부터 200 개 아미노산 잔기 이하로 떨어져 있는 키메라 폴리펩티드.
- (a) 보툴리눔 독소 (BoNT) 경쇄 및 BoNT 경쇄의 N-말단에 위치한 3 개의 징크 핑거 모티프를 포함하는 제 1 사슬, 및 (b) BoNT 중쇄 및 BoNT 중쇄에 대한 C-말단에 위치된 3 개의 징크 핑거 모티프를 포함하는 제 2 사슬 (여기서 BoNT 경쇄는 디술피드 결합을 통해 BoNT 경쇄에 결합됨) 을 포함하는, 2-사슬 폴리펩티드.
- N-말단에서 C-말단까지, 3 개의 징크 핑거 모티프, 보툴리눔 독소 (BoNT) 경쇄, BoNT 중쇄 및 징크 핑거 모티프 3 개 더를 포함하는, 키메라 폴리펩티드.
- 제 1 항 내지 제 16 항 중 어느 한 항에 있어서, BoNT 가 BoNT A, B, C, D, E, F, 또는 G 또는 그와 적어도 90% 서열 동일성을 갖는 변이체로부터 선택되는 키메라 폴리펩티드.
- 제 17 항에 있어서, BoNT 가 BoNT A1-A10, B1-B8, E1-E9 및 F1-F7 의 서브타입으로부터 선택되는 키메라 폴리펩티드.
- 제 17 항에 있어서, BoNT 가 BoNT A 인 키메라 폴리펩티드.
- 제 1 항 내지 제 19 항 중 어느 한 항에 있어서, BoNT 경쇄가 SEQ ID NO: 8 의 아미노산 서열 또는 SEQ ID NO: 8 과 적어도 90% 서열 동일성을 갖는 아미노산 서열을 포함하는 키메라 폴리펩티드.
- 제 1 항 내지 제 20 항 중 어느 한 항에 있어서, BoNT 중쇄가 SEQ ID NO: 9 의 아미노산 서열 또는 SEQ ID NO: 9 와 적어도 90% 서열 동일성을 갖는 아미노산 서열을 포함하는 키메라 폴리펩티드.
- 제 1 항 내지 제 21 항 중 어느 한 항에 있어서, SEQ ID NO: 10 내지 17 로 이루어진 군으로부터 선택된 아미노산 서열을 포함하는 단일-사슬 폴리펩티드, 또는 아미노산 서열로부터 프로세싱된 2-사슬 폴리펩티드를 포함하는 키메라 폴리펩티드.
- 보툴리눔 독소 (BoNT) 경쇄 및 적어도 징크 핑거 모티프를 포함하는 키메라 폴리펩티드.
- 제 23 항에 있어서, 징크 핑거 모티프가 C-말단에 위치하고 BoNT 경쇄로부터 200 개 아미노산 잔기 이하로 떨어져 있는 키메라 폴리펩티드.
- 치료 펩티드 및 치료 펩티드의 C-말단에 위치된 징크 핑거 모티프를 적어도 포함하는 키메라 폴리펩티드로서, 여기서 징크 핑거 모티프의 N-말단은 치료 펩티드의 C-말단으로부터 100 개 아미노산 잔기 이하로 떨어져 있는 키메라 폴리펩티드.
- 제 25 항에 있어서, 치료 펩티드가 표피 성장 인자 (EGF) 및 슈퍼옥시드 디스뮤타제 (SOD) 로 이루어진 군으로부터 선택되는 키메라 폴리펩티드.
- 제 1 항 내지 제 24 항 중 어느 한 항의 키메라 폴리펩티드를 포함하는 제형을 국소적으로 또는 근육내로 적용하는 것을 포함하는, BoNT 경쇄의 포유동물에 대한 투여 방법.
- 제 27 항에 있어서, 국소 적용이 피부 또는 눈, 귀, 코, 입, 입술, 요도 개구, 항문 또는 혀의 점막 상에 대한 것인 투여 방법.
- 제 27 항에 있어서, 국소 적용이 붕괴된 피부의 각질층 상에 대한 것인 투여 방법.
- 제 29 항에 있어서, 붕괴가 제형을 전달하기 위해 사용되는 바늘 또는 미세바늘로 수행되는 투여 방법.
- 제 27 항 내지 제 30 항 중 어느 한 항에 있어서, 국소 적용이 포유동물의 얼굴 또는 목의 피부 상에 대한 것인 투여 방법.
- 제 27 항 내지 제 30 항 중 어느 한 항에 있어서, 제형이 크림, 젤 또는 스프레이를 포함하는 투여 방법.
- 제 27 항 내지 제 30 항 중 어느 한 항에 있어서, 포유동물이 안면 주름, 근긴장이상, 경련, 반측안면 경련, 다한증 또는 과다침분비의 치료를 필요로 하는 투여 방법.
- 제 1 항 내지 제 26 항 중 어느 한 항의 키메라 폴리펩티드를 인코딩하는 폴리뉴클레오티드.
- 제 34 항의 폴리뉴클레오티드를 포함하는 세포.
- 제 35 항에 있어서, 세포가 박테리아 세포인 세포.
- 제 36 항에 있어서, 박테리아 세포가 클로스트리디움 보툴리눔 (Clostridium botulinum) 세포인 세포.
- 제 35 항에 있어서, 세포가 곤충 세포인 세포.
- 제 38 항에 있어서, 곤충 세포가 스포도프테라 (Spodoptera) 세포인 세포.
- 폴리뉴클레오티드에 의해 인코딩된 단백질을 발현시키는 조건 하에서 제 35 항 내지 제 39 항 중 어느 한 항의 세포를 배양하는 단계를 포함하는, 단백질의 제조 방법.
- 제 1 항 내지 제 26 항 중 어느 한 항의 키메라 폴리펩티드 및 약학적으로 적합한 담체를 포함하는 제형.
- 근육의 마비에 대한 작용제 활성의 시험 방법으로서, 작용제를 시험 동물에 투여하고, 시험 동물을 트레드밀 또는 밸런스 빔에 놓고, 이동 거리, 발자국 크기, 또는 밸런스 빔을 횡단하는 시간을 측정하는 단계를 포함하며, 여기서 이동 거리, 발자국 크기, 또는 밸런스 빔을 횡단하는 시간은 대조군과 비교하여 근육 마비에 대한 작용제의 활성을 반영하는 시험 방법.
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| WO2023277432A1 (ko) * | 2021-06-28 | 2023-01-05 | (주)메디톡스 | 재조합 보툴리눔 독소 타입 a 경쇄, 재조합 보툴리눔 독소 및 이의 조성물, 용도 및 방법 |
| WO2023277433A1 (ko) * | 2021-06-28 | 2023-01-05 | (주)메디톡스 | 재조합 보툴리눔 독소 타입 a 경쇄, 재조합 보툴리눔 독소 및 이의 조성물, 용도 및 방법 |
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| TW201718627A (zh) * | 2015-06-11 | 2017-06-01 | 梅茲製藥有限兩合公司 | 重組梭菌神經毒素及其使用與形成方法、包括其之醫藥組合物及對應其之前驅物、編碼前驅物之核酸序列及其獲得方法與前驅物之形成方法、載體與包括核酸序列之重組宿主細胞 |
| US20220135629A1 (en) * | 2020-10-30 | 2022-05-05 | Shanghaitech University | Zinc Finger Protein-Superoxide Dismutase Fusion Protein With Cell Membrane Penetrating Property |
| CN112625140A (zh) * | 2020-12-22 | 2021-04-09 | 北京致力生科科技有限公司 | 一种pep-1-g4s-kgf2融合蛋白及其编码基因和应用 |
| WO2022228443A1 (en) * | 2021-04-26 | 2022-11-03 | Shanghaitech University | Intramuscular compositions of botulinum neurotoxins |
| CN115819526A (zh) * | 2022-12-02 | 2023-03-21 | 海雅美生物技术(珠海)有限公司 | 一种重组肉毒杆菌神经毒素及其制备方法和应用 |
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| CN1470520A (zh) * | 2002-07-26 | 2004-01-28 | 上海博德基因开发有限公司 | 一种多肽——锌指蛋白40和编码这种多肽的多核苷酸 |
| ES2691498T3 (es) * | 2004-03-03 | 2018-11-27 | Revance Therapeutics, Inc. | Aplicación tópica y liberación transdérmica de toxinas botulínicas |
| US20060014712A1 (en) * | 2004-05-30 | 2006-01-19 | Cemines, Inc. | Controlled delivery of therapeutic compounds |
| JP2006320221A (ja) | 2005-05-17 | 2006-11-30 | Keio Gijuku | 運動機能障害評価方法とその利用方法、及びその方法に使用するための運動機能評価装置 |
| US20110111056A1 (en) | 2009-06-03 | 2011-05-12 | Dicerna Pharmaceuticals, Inc. | Peptide dicer substrate agents and methods for their specific inhibition of gene expression |
| EP3156412B1 (en) * | 2014-05-29 | 2020-01-08 | Procell Therapeutics Inc. | Novel cell penetrating peptide, conjugate thereof with botulinum toxin, and use thereof |
| US20170198307A1 (en) | 2014-06-06 | 2017-07-13 | President And Fellows Of Harvard College | Methods for targeted modification of genomic dna |
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Cited By (2)
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| WO2023277432A1 (ko) * | 2021-06-28 | 2023-01-05 | (주)메디톡스 | 재조합 보툴리눔 독소 타입 a 경쇄, 재조합 보툴리눔 독소 및 이의 조성물, 용도 및 방법 |
| WO2023277433A1 (ko) * | 2021-06-28 | 2023-01-05 | (주)메디톡스 | 재조합 보툴리눔 독소 타입 a 경쇄, 재조합 보툴리눔 독소 및 이의 조성물, 용도 및 방법 |
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| US11773145B2 (en) | 2023-10-03 |
| CN110944677A (zh) | 2020-03-31 |
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