KR102139844B1 - 암 표적화 치료용 알부민-결합 아르기닌 데이미나제를 포함하는 약제학적 조성물 - Google Patents
암 표적화 치료용 알부민-결합 아르기닌 데이미나제를 포함하는 약제학적 조성물 Download PDFInfo
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- KR102139844B1 KR102139844B1 KR1020157027321A KR20157027321A KR102139844B1 KR 102139844 B1 KR102139844 B1 KR 102139844B1 KR 1020157027321 A KR1020157027321 A KR 1020157027321A KR 20157027321 A KR20157027321 A KR 20157027321A KR 102139844 B1 KR102139844 B1 KR 102139844B1
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Abstract
본 발명은 암 또는 다른 아르기닌-의존성 질병을 치료하기 위한 알부민-결합 아르기닌 데이미나제 융합 단백질(AAD)을 함유하는 약제학적 조성물을 제공한다. AAD 융합 단백질은 조 단백질의 가용성 및 불용성 분획 둘 다로부터 정제될 수 있으며, 이는 사람 혈청 알부민(HSA)에 결합하고 암 세포에서 아르기닌의 효율적인 고갈을 위한 보다 긴 반감기와 함께 이의 높은 활성을 갖는다. 본 발명에서 야생형 ADI 및 AAD의 특이 활성은 각각 8.4 및 9.2U/mg(생리학적 pH 7.4에서)이다. 본 발명에 사용된 AAD는 다양한 암(예를 들면, 췌장암, 백혈병, 두경부암, 결장직장암, 폐암, 유방암, 간암, 간암, 비인강암, 식도암, 전립샘 암, 위암 및 뇌암)의 치료시 및 아르기닌-의존성 질병을 치유하는데 사용될 수 있다. 조성물은 단독으로 또는 적어도 하나의 화학치료제와 함께 사용되어 암 치료 및/또는 전이를 억제하는데 있어서 상승 효과를 제공할 수 있다.
Description
관련 출원에 대한 교차-참조
본 출원은 2013년 3월 6일자로 출원된 미국 가특허원 일련 번호 제61/773,214호 및 2014년 3월 5일자로 출원된 미국 비-가특허원 일련 번호 제14/197,236호로부터의 이익을 청구하며, 이의 기재내용은, 이의 전문이 참조로 본원에 포함된다.
기술 분야
본 발명은 유전적으로 변형되어 고 활성 및 장기간의 생체내 반감기를 갖는 물질을 생성하는 알부민-결합 아르기닌 데이미나제(AAD) 융합 단백질을 기술한다. 본 발명은 상이한 AAD 융합 단백질을 생성하기 위해 가공되는 DNA 및 단백질에 대한 설계를 추가로 기술한다. AAD 융합 단백질은 조 단백질의 가용성 분획 및 불용성 분획(봉입체)으로부터 분리되어 정제될 수 있다. 본 발명은 또한 사람 및 다른 동물에서 암 표적화 치료 및 아르기닌-의존성 질병을 치유하기 위한 알부민-결합 아르기닌 데이미나제-함유 약제학적 조성물에 관한 것이다.
발명의 배경
전세계 인구에서 췌장 암, 결장 암, 간 암, 흑색종 및 경부 암의 발생은 증가하고 있다. 이들 질병에 대한 효과적인 치료가 급격하게 요구되고 있다. 백혈병, 흑색종, 췌장, 결장, 신장 세포 암종, 폐, 전립샘, 유방, 뇌, 경부 및 간 암을 포함하는 많은 유형의 암에서, 암 세포는 아르기니노석시네이트 신테타제(ASS)의 발현을 결여하므로 아르기닌에 대한 영양요구성이어서, 이들 암이 아르기닌 고갈 치료요법에 대한 탁월한 표적이 되도록 한다.
아르기닌은 사람 및 다른 포유동물에 대한 반-필수적인 아미노산이다. 이는 우레아 주기 효소 아르기니노석시네이트 신타제(ASS) 및 아르기니노석시네이트 리아제(ASL)에 의해 촉매된 2 단계 공정을 통해 시트룰린으로부터 합성될 수 있다. 아르기닌은 효소 아르기나제에 의해 오르니틴으로 대사될 수 있으며, 오르니틴은 미토콘드리아에서 오르니틴 카바모일트랜스퍼라제(OTC)에 의해 시트룰린으로 전환될 수 있다. 시트룰린은 다시 아르기닌을 합성하는데 이용될 수 있다. 정상 세포는 일반적으로 ASS 및 ASL의 풍부한 촉매 활성으로 인하여 성장을 위한 아르기닌의 외인성 공급을 필요로 하지 않는다. 대조적으로, 많은 유형의 암은 ASS를 발현하지 않으므로 아르기닌에 대해 영양요구성이다. 이들의 성장은 혈액 순환으로부터 유일하게 수득된 아르기닌에 의존적이다. 따라서, 아르기닌-분해 효소를 사용함에 의한 순환하는 아르기닌의 표적화는 ASS-음성 종양 성장을 억제하기 위한 실행가능한 전략이다[참조: Feun et al., Curr. Pharm. Des. 14: 1049-1057 (2008); Kuo et al., Oncotarget. 1 :246-251 (2010)]
아르기닌은 아르기나제, 아르기닌 데카복실라제, 및 아르기닌 데이미나제(ADI)에 의해 분해될 수 있다. 이들 중에서, 아르기닌 데이미나제(ADI)는 아르기닌에 대해 최대 친화성(낮은 Km 값)을 갖는 것으로 여겨진다. ADI는 아르기닌을 우레아 주기의 대사산물인, 시트룰린 및 암모니아로 전환시킨다. 불행하게도, ADI는 원핵세포, 예를 들면, 마이코플라스마 아종(Mycoplasma sp.)에서만 발견될 수 있다. 원핵세포로부터 ADI의 분리 및 정제와 관련된 일부 문제가 존재한다. 슈도모나스 푸디타(Pseudomonas pudita)로부터 분리된 ADI는 중성 pH에서 이의 낮은 효소 활성으로 인하여 생체내에서 효능을 나타내지 못한다. 에스케리키아 콜라이(Escherichia coli)로부터 생산된 ADI는 효소적으로 불활성이며 후속적인 생산 비용을 유발하는 다수의 변성 및 복원 공정을 후속적으로 필요로 한다.
천연의 ADI는 미생물에서 발견되므로, 이는 항원성이고 환자에서 순환으로부터 신속하게 정화된다. ADI의 천연 형태는 사람 순환내로 주사시 면역원성이며 반감기가 짧고(~4 시간) 중화 항체를 유발한다[참조: Ensor et al., Cancer Res. 62:5443-5450 (2002); Izzo et al, J. Clin. Oncol. 22: 1815-1822 (2004)]. 이들 단점은 페길화에 의해 제거될 수 있다. 다양한 형태의 페길화된 ADI 중에서, PEG(분자량 20,000)에 석신이미딜 석시네이트를 통해 결합된 ADI(ADI-PEG 20)는 효율적인 제형인 것으로 밝혀졌다. 그러나, 페길화 후 ADI의 활성은 50%의 정도로 크게 감소한다[참조: Ensor et al, Cancer Res. 62:5443-5450 (2002)]. 페길화된 ADI를 생성하기 위한 앞서의 시도는 동종이 아닌 물질을 생성하며(단백질 표면 Lys 잔기 상의 PEG의 무작위적인 부착으로 인하여) 또한 제조 공정 동안에 특성화하고 품질 조절을 수행하기가 어렵다. 또한, PEG는 매우 비싸고, 생산 비용이 크게 증가한다. 페길화된 ADI를 생체내에서 정맥내 주사한 후, 유리된 PEG의 누출 또는 탈착이 관찰되며 ADI(PEG 부재)는 면역원성 문제를 유발할 수 있다. 따라서, 개선된 암-치료 조성물, 특히, 활성 및 생체내 반감기가 향상된 개선된 암-치료 조성물에 대한 요구가 존재한다.
발명의 요약
본 발명에서, 알부민-결합 아르기닌 데이미나제(AAD) 융합 단백질은 이의 활성 및 혈장 반감기를 증가시켜 암 세포내에서 아르기닌을 효율적으로 고갈시킨다. 천연의 ADI는 미생물에서 발견될 수 있으며 항원성이고 환자내 순환으로부터 신속하게 정화된다. 본 발명은 1개 또는 2개의 알부민-결합 단백질과의 상이한 AAD 융합 단백질을 작제하여 고 활성과 함께 보다 긴 생체내 반감기(1회 주사 후 적어도 5일의 아르기닌 고갈)를 유지한다. 본 발명에서, AAD 융합 단백질 생성물내 알부민 결합 단백질은 이의 특이적인 효소 활성에 영향을 미치는 것으로 여겨지지 않지만 대신 순환하는 반감기를 증가시키는 것으로 여겨진다. 본 발명에서 야생형 ADI 및 AAD 융합 단백질의 특이 활성은 각각 8.4 및 9.2U/mg(생리학적 pH 7.4에서)이다.
이의 광범위한 의미에서, 본 발명은 아르기닌 데이미나제를 포함하는 제2의 부위에 융합됨으로써 알부민-결합 아르기닌 데이미나제 융합 단백질을 형성함으로써 알부민-결합 아르기닌 데이미나제 융합 단백질이 아르기닌 데이미나제의 활성을 보유하고 또한 혈청 알부민에 결합할 수 있는 알부민-결합 도메인, 알부민-결합 펩타이드 또는 알부민-결합 단백질(들)로부터 선택된 1개 또는 2개의 성분을 포함하는 제1의 부위를 포함하는 알부민-결합 아르기닌 데이미나제 융합 단백질을 제공한다.
본 발명은 또한 사람 및 다른 동물에서 표적화된 암 치료를 위한 알부민-결합 아르기닌 데이미나제(AAD) 융합 단백질-함유 약제학적 조성물에 관한 것이다. 본 발명의 제1 국면은 암 세포에 대해 고 친화성을 지닌 변형된 AAD 융합 단백질을 작제하는 것이다. 본 발명의 제2 국면은 조 단백질의 가용성 및 불용성 분획 둘 다로부터 고 순도를 지닌 AAD 융합 단백질을 정제하는 것이다. 본 발명의 제3 국면은 순환시 알부민에 보다 잘 결합할 수 있도록 AAD 융합 단백질의 반감기를 연장시키는 것이다. 본 발명의 제4 국면은 상기 조성물을 다양한 종양, 암 또는, 종양 또는 암과 관련된 질병 또는 다른 아르기닌-의존성 질병으로 고생하는 이를 필요로 하는 피검자에게 투여함으로써 암을 치료하기 위한 본 발명의 AAD-함유 약제학적 조성물의 사용 방법을 제공하는 것이다.
본 발명의 AAD 융합 단백질은 알부민-결합 단백질 및 ADI로의 분리를 피하기 위해 변형시킴으로써 이것이 보다 안정하게 되고 순환시 보다 긴 반감기를 가지도록 한다. ADI는 AAD 융합 생성물 속에서 알부민-결합 도메인/펩타이드/단백질에 융합하여 혈장 반감기를 연장시키고 융합 생성물의 면역원성을 감소시킨다. 알부민 결합 도메인(ABD)은 혈액 속에서 알부민에 결합하는 펩타이드이다. 상이하거나 증진된 사람 혈청 알부민(HSA) 친화도를 나타내는 ABD의 상이한 변이체가 존재한다. ABD의 상이한 변이체를 작제하여 ADI에 융합시킬 수 있다. 천연적으로 존재하는 ADI와는 달리, 이러한 보다 긴 반감기 특성은 암 세포, 암 줄기 세포 및/또는 암 후대 세포에서 아르기닌의 고갈을 효율적으로 촉진시킨다.
AAD 융합 단백질을 함유하는 약제학적 조성물은 정맥(i.v.) 주사(의약의 신속히 작용하는 용량용) 및 근육내(i.m.) 주사(의약이 상당한 신속-작용 및 장기-지속 용량용)용으로 사용될 수 있다. 본 발명에서 AAD 융합 단백질의 적용은 췌장 암, 백혈병, 두경부암(head and neck cancer), 결장직장암, 폐암, 유방암, 전립샘암, 경부암, 간암, 비인강암, 식도암 및 뇌암과 같은 다양한 암의 치료에 사용될 수 있다. 본 발명은 AAD 융합 단백질, 암을 치료하는 방법, 암 조직의 전이를 치료하고/하거나 억제하는 방법, 및 아르기닌-의존성 질병을 치유하는 방법에 관한 것이다.
본 발명의 방법은 또한 화학치료학적 약물 및/또는 방사선치료요법과 본 발명의 AAD 융합 단백질의 조합물을 사용하여 암 치료시 상승 효과를 제공함을 포함한다.
도면의 간단한 설명
도 1은 3차원 구조에서 1개 또는 2개의 알부민-결합 도메인/펩타이드/단백질(들)과의 상이한 AAD 융합 단백질의 작제를 위한 설계 시도를 나타낸다. 1개 또는 2개의 알부민-결합 도메인/펩타이드/단백질(들)을 ADI에 융합시켜 AAD 융합 단백질을 형성할 수 있다. 알부민-결합 도메인/펩타이드/단백질의 위치는 ADI 활성 부위로부터 멀다.
알부민-결합 도메인/펩타이드/단백질을 ADI의 N-말단 또는/및 C-말단에 융합시킬 수 있다. 당해 도에서 구조는 마이코플라스마 아르기니니(Mycoplasma arginini) ADI 구조(단백질 데이타 뱅크: 1LXY)를 기본으로 한다. (A) 천연의 ADI; (B) 2개의 ABD 또는 ABDl과의 AAD 융합 단백질; (C) N-말단에서 하나의 ABD 또는 ABDl과의 AAD 융합 단백질; (D) C-말단에서 하나의 ABD 또는 ABDl과의 AAD 융합 단백질.
도 2는 마이코플라스마 아르기니니(서열 번호 23), 락토코쿠스 락티스(Lactococcus lactis) (서열 번호 24), 바실러스 세레우스(Bacillus cereus)(서열 번호 25) 및 바실러스 리체니포르미스(Bacillus licheniformis)(서열 번호 26)을 포함하는 일부 세균 종에서 ADI에 대한 서열 정렬을 나타낸다.
도 3은 마이코플라스마 아르기니니로부터 기원한 상이한 AAD 융합 단백질(A 내지 E) 및 바실러스 세레우스로부터 기원한 AAD 융합 단백질(F)에 대한 설계 및 아미노산 서열을 나타낸다.
도 4는 다음의 도식 하에서 인테인-융합 단백질 및 발현된 단백질 연결(CBD, 키틴 결합 도메인)의 사용에 의한 2개의 구현예 (A) 및 (B)에서 AAD 융합 단백질의 생성을 나타낸다; (C) C-말단 융합체; (D) N-말단 융합체; (E) 인테인-매개된 단백질 연결.
도 5는 AAD 융합 단백질을 생산하기 위해 작제된 발현 벡터의 플라스미드 지도를 나타낸다.
도 6은 His-ABD-폴리N-ADI의 (A) 유전자 지도, (B) 뉴클레오타이드 서열(서열 번호 44) 및 (C) 아미노산 서열(서열 번호 40)을 나타낸다. (ADI: 마이코플라스마 아르기니니 ADI)
도 7은 His-ABD-폴리N-bcADI의 (A) 유전자 지도, (B) 뉴클레오타이드 서열(서열 번호 45) 및 (C) 아미노산 서열(서열 번호 41)을 나타낸다(bcADI, 바실러스 세레우스(Bacillus cereus) ADI)
도 8은 AAD 융합 단백질의 발현 및 정제를 나타낸다: (A) AAD는 20℃에 노출되는 경우 ~90% 가용성이고(레인 2 및 3) 37℃에 노출되는 경우 ~90% 불용성(봉입체)이다(레인 4 및 5); (B) 나트륨 도데실 설페이트 폴리아크릴아미드 겔 전기영동(SDS-PAGE) 겔에서 정제된 AAD 융합 단백질: 레인 1, 정제된 AAD 융합 단백질(52.8 kDa); 레인 2, 분자량 마커.
도 9는 AAD 융합 단백질이 아르기닌을 효율적으로 고갈시키며 사람 흑색종(A375), 사람 결장암(HCT116), 및 사람 췌장암(패널 I)을 포함하는, 시험관내 조직 배양 연구에서 다양한 유형의 사람 암 세포주의 성장을 억제함을 나타낸다.
도 10은 AAD 융합 단백질의 알부민 결합 결과를 나타낸다: (A) 첨가된 AAD 융합 단백질(아미노산 서열은 서열 번호 36에 나타낸다; 도 3a)의 양이 증가하는 경우 HSA+AAD 복합체의 양에 있어서의 증가를 나타내는 비-변성의 천연 폴리아크릴아미드 겔(12%). 사람 혈청 알부민(HSA)의 몰 비: 레인 3 내지 6에서 AAD는 각각 1 :1, 1:2, 1:5, 및 1:15이다. 레인 1 및 2는 6 및 30 pmole 각각에서 HSA 및 AAD를 나타낸다; (B) AAD 융합 단백질(서열 번호 40; 도 3e)을 기본으로 한 다른 실험에서, 1:8의 알부민:AAD 비가 존재하는 모든 알부민을 결합시키는데 충분하다(레인 5).
도 11은 마우스에서 혈장 아르기닌 수준에 있어서 AAD 융합 단백질의 투여량 반응을 나타내는 그래프이다. 100㎍의 AAD의 투여량은 적어도 5일 동안 혈장 아르기닌을 고갈시키는데 충분하다.
도 1은 3차원 구조에서 1개 또는 2개의 알부민-결합 도메인/펩타이드/단백질(들)과의 상이한 AAD 융합 단백질의 작제를 위한 설계 시도를 나타낸다. 1개 또는 2개의 알부민-결합 도메인/펩타이드/단백질(들)을 ADI에 융합시켜 AAD 융합 단백질을 형성할 수 있다. 알부민-결합 도메인/펩타이드/단백질의 위치는 ADI 활성 부위로부터 멀다.
알부민-결합 도메인/펩타이드/단백질을 ADI의 N-말단 또는/및 C-말단에 융합시킬 수 있다. 당해 도에서 구조는 마이코플라스마 아르기니니(Mycoplasma arginini) ADI 구조(단백질 데이타 뱅크: 1LXY)를 기본으로 한다. (A) 천연의 ADI; (B) 2개의 ABD 또는 ABDl과의 AAD 융합 단백질; (C) N-말단에서 하나의 ABD 또는 ABDl과의 AAD 융합 단백질; (D) C-말단에서 하나의 ABD 또는 ABDl과의 AAD 융합 단백질.
도 2는 마이코플라스마 아르기니니(서열 번호 23), 락토코쿠스 락티스(Lactococcus lactis) (서열 번호 24), 바실러스 세레우스(Bacillus cereus)(서열 번호 25) 및 바실러스 리체니포르미스(Bacillus licheniformis)(서열 번호 26)을 포함하는 일부 세균 종에서 ADI에 대한 서열 정렬을 나타낸다.
도 3은 마이코플라스마 아르기니니로부터 기원한 상이한 AAD 융합 단백질(A 내지 E) 및 바실러스 세레우스로부터 기원한 AAD 융합 단백질(F)에 대한 설계 및 아미노산 서열을 나타낸다.
도 4는 다음의 도식 하에서 인테인-융합 단백질 및 발현된 단백질 연결(CBD, 키틴 결합 도메인)의 사용에 의한 2개의 구현예 (A) 및 (B)에서 AAD 융합 단백질의 생성을 나타낸다; (C) C-말단 융합체; (D) N-말단 융합체; (E) 인테인-매개된 단백질 연결.
도 5는 AAD 융합 단백질을 생산하기 위해 작제된 발현 벡터의 플라스미드 지도를 나타낸다.
도 6은 His-ABD-폴리N-ADI의 (A) 유전자 지도, (B) 뉴클레오타이드 서열(서열 번호 44) 및 (C) 아미노산 서열(서열 번호 40)을 나타낸다. (ADI: 마이코플라스마 아르기니니 ADI)
도 7은 His-ABD-폴리N-bcADI의 (A) 유전자 지도, (B) 뉴클레오타이드 서열(서열 번호 45) 및 (C) 아미노산 서열(서열 번호 41)을 나타낸다(bcADI, 바실러스 세레우스(Bacillus cereus) ADI)
도 8은 AAD 융합 단백질의 발현 및 정제를 나타낸다: (A) AAD는 20℃에 노출되는 경우 ~90% 가용성이고(레인 2 및 3) 37℃에 노출되는 경우 ~90% 불용성(봉입체)이다(레인 4 및 5); (B) 나트륨 도데실 설페이트 폴리아크릴아미드 겔 전기영동(SDS-PAGE) 겔에서 정제된 AAD 융합 단백질: 레인 1, 정제된 AAD 융합 단백질(52.8 kDa); 레인 2, 분자량 마커.
도 9는 AAD 융합 단백질이 아르기닌을 효율적으로 고갈시키며 사람 흑색종(A375), 사람 결장암(HCT116), 및 사람 췌장암(패널 I)을 포함하는, 시험관내 조직 배양 연구에서 다양한 유형의 사람 암 세포주의 성장을 억제함을 나타낸다.
도 10은 AAD 융합 단백질의 알부민 결합 결과를 나타낸다: (A) 첨가된 AAD 융합 단백질(아미노산 서열은 서열 번호 36에 나타낸다; 도 3a)의 양이 증가하는 경우 HSA+AAD 복합체의 양에 있어서의 증가를 나타내는 비-변성의 천연 폴리아크릴아미드 겔(12%). 사람 혈청 알부민(HSA)의 몰 비: 레인 3 내지 6에서 AAD는 각각 1 :1, 1:2, 1:5, 및 1:15이다. 레인 1 및 2는 6 및 30 pmole 각각에서 HSA 및 AAD를 나타낸다; (B) AAD 융합 단백질(서열 번호 40; 도 3e)을 기본으로 한 다른 실험에서, 1:8의 알부민:AAD 비가 존재하는 모든 알부민을 결합시키는데 충분하다(레인 5).
도 11은 마우스에서 혈장 아르기닌 수준에 있어서 AAD 융합 단백질의 투여량 반응을 나타내는 그래프이다. 100㎍의 AAD의 투여량은 적어도 5일 동안 혈장 아르기닌을 고갈시키는데 충분하다.
정의
용어 "암 줄기 세포"는 생체내에서 종양 성장을 개시하고 지속시킬 수 있는 신생물 클론내 생물학적으로 명백한 세포를 말한다(즉,암-개시 세포).
발명의 상세한 설명
아르기닌은 사람 및 다른 포유동물용의 반-필수 아미노산이다. 이는 우레아 주기 효소 아르기니노석시네이트 신타제(ASS) 및 아르기니노석시네이트 리아제(ASL)에 의해 촉매된 2 단계 공정을 통한 시트룰린으로부터 합성될 수 있다. 아르기닌은 효소 아르기나제에 의해 오르니틴으로 대사될 수 있으며, 오르니틴은 미토콘드리아내에서 오르니틴 카르바모일트랜스퍼라제(OTC)에 의해 시트룰린으로 전환될 수 있다. 시트룰린은 다시 아르기닌을 합성하는데 이용될 수 있다. 정상 세포는 전형적으로 ASS 및 ASL의 풍부한 촉매 활성으로 인하여 성장을 위해 아르기닌의 외인성 공급을 필요로 하지 않는다. 대조적으로, 많은 유형의 암이 ASS를 발현하지 않으므로 아르기닌에 대해 영양요구성이다. 이들의 성장은 순환으로부터 아르기닌에 의존적이다. 따라서, 아르기닌-분해 효소를 사용함으로써 순환하는 아르기닌을 표적화하는 것은 ASS-음성 종양 성장을 억제하는 용이한 전략이다.
아르기닌은 아르기닌 데이미나제(ADI)에 의해 분해될 수 있다. ADI는 아르기닌을 우레아 주기의 대사산물인, 시트룰린 및 암모니아로 전환시킨다. 불행하게도, ADI는 원핵세포, 예를 들면, 마이코플라스마 아종에서만 발견될 수 있다. 원핵세포로부터 아르기닌 데이미나제의 분리 및 정제와 관련된 많은 문제들이 존재한다. 슈도모나스 푸디타로부터 분리된 ADI는 중성 pH에서 이의 낮은 효소 활성으로 인하여 생체내에서 효능을 나타내지 못하였다. 에스케리키아 콜라이로부터 생산된 ADI는 효소적으로 불활성이며 후속적인 생산 비용을 상승시키는 다중 변성 및 복원 공정을 필요로 한다. ADI의 천연 형태의 혈장 반감기는 사람 순환내로 주사시 짧다(~4시간)[참조: Ensor et al, Cancer Res. 62:5443-5450 (2002); Izzo et al, J. Clin. Oncol. 22: 1815-1822 (2004)]. 이들 단점은 페길화에 의해 부분적으로 제거된다. 다양한 형태의 페길화된 ADI 중에서, PEG(분자량 20,000)에 석신이미딜 석시네이트를 통해 결합된 ADI(ADI-PEG 20)는 효율적인 제형임이 밝혀졌다. 그러나, 페길화 후 ADI의 활성은 크게 감소한다(~50% 까지)[참조: Ensor et al, Cancer Res. 62:5443-5450 (2002); Wang et al, Bioconjug. Chem. 17: 1447-1459 (2006)]. 또한, 석신이미딜 석시네이트 PEG 링커는 단백질로부터 용이하게 가수분해되고 탈착되어 체내에서 짧은 사용 기간 후 면역원성 문제를 유발한다. 따라서, 개선된 암-치료 조성물, 특히, 활성이 향상된 개선된 암-치료 조성물에 대한 요구가 존재한다.
피. 푸디타(P. pudita)로부터 분리된 ADI는 중성 pH에서 효소 활성을 거의 지니지 않았고 실험 동물의 순환으로부터 신속하게 정화되었으므로 생체내에서 효능을 나타내는데 실패하였다. 마이코플라스마 아르기니니로부터 기원한 ADI는 예를 들면, 문헌[참조: Takaku et al, Int. J. Cancer, 51 :244-249 (1992), 및 미국 특허 제5,474,928호]에 기술되어 있다. 그러나, 이러한 이종 단백질의 치료학적 용도와 관련된 문제는 이의 항원성이다. 마이코플라스마 아르기니니로부터의 ADI의 시아누릭 클로라이드 연결 그룹을 통해, 폴리에틸렌 글리콜(PEG)을 사용한 화학적 변형은 문헌[참조: Takaku et al, Jpn. J. Cancer Res., 84: 1195-1200 (1993)]에 기술되어 있다. 그러나, 변형된 단백질은 시아누릭 클로라이드 연결 그룹으로부터 시아나이드의 방출로 인하여 대사시 독성이었다. 대조적으로, ADI-PEG20의 경우에서조차, PEG 링커는 단백질로부터 용이하게 가수분해되어 탈착됨으로써 체내에서 짧은 기간의 사용 후 면역원성 문제를 유발할 수 있다. 따라서, 비-필수 아미노산을 분해하고 선행 기술과 관련된 문제를 가지지 않는 조성물에 대한 필요성이 존재한다.
흑색종, 췌장, 결장, 백혈병, 유방, 전립샘, 신장 세포 암종 및 간암을 포함하는 많은 유형의 암에서, 암 세포는 아르기니노석시네이트 신타제(ASS)의 발현을 결여하므로 아르기닌에 대해 영양요구성이어서, 이들을 아르기닌 고갈 치료요법에 대한 탁월한 표적이 되도록 한다. 본 발명에서, 알부민-결합 아르기닌 데이미나제 (AAD) 융합 단백질은 암 세포에서 아르기닌의 효율적인 고갈에 대한 긴 반감기와 함께 고 활성을 갖는다.
ADI에 대한 단량체의 크기는 45 kDa의 정도이며 이는 이량체로서 존재한다(90 kDa의 정도)[참조: Das et al, Structure. 12:657-667 (2004)]. AAD 융합 단백질의 작제를 위한 설계는 도 1에 나타나 있다. 링커(들)의 존재 또는 부재하에 1개 또는 2개의 알부민-결합 도메인/펩타이드/단백질(들), 서열 번호 46 내지 49는 ADI에 융합되어 AAD 융합 단백질을 형성한다. 1개 또는 2개의 특수한 알부민-결합 도메인/펩타이드/단백질(들)의 선택이 표적화될 암 조직의 유형, 바람직한 크기 및 생성되는 융합 단백질의 반감기, 및 도메인 또는 전체 단백질의 선택 여부에 의존하여 이루질 수 있으므로 가치가 있다. 또한, 선택된 알부민-결합 물질은 동일하거나 상이할 수 있다. 즉, 단백질 및 펩타이드는, 생성되는 분자가 ADI의 활성을 보유하고 또한 융합 단백질의 하나의 일부의 기능이 융합 단백질의 다른 일부에 의해 방해되지 않으면서 혈청 알부민에 결합할 수 있는 한, 2개의 단백질, 2개의 도메인, 도메인 및 단백질에 융합될 수 있다. 알부민-결합 도메인/펩타이드/단백질의 위치는 활성 부위로부터 멀다. 알부민-결합 도메인/펩타이드/단백질은 ADI의 N-말단 또는/및 C-말단에 융합될 수 있다. 상이하거나 개선된 사람 혈청 알부민(HSA) 친화성을 나타내는 ABD의 상이한 변이체가 존재한다. ABD의 상이한 변이체를 작제하여 ADI에 융합시킬 수 있다. ADI를 지닌 일부 미생물(예를 들면, 슈도모나스 아종)은 이들의 잠재적인 병원성 및 발열원성으로 인하여, 사용될 수 없다. ADI의 공급원은 상이한 미생물, 예를 들면, 마이코플라스마[예를 들면, 마이코플라스마 아르기니니, 마이코플라스마 아르트리티디스(Mycoplasma arthritidis), 마이코플라스마 호미니스(Mycoplasma hominis)], 락토코쿠스(Lactococcus)[예를 들면, 락토코쿠스 락티스(Lactococcus lactis)], 슈도모나스[예를 들면, 슈도모나스 플레코글로씨키다(Pseudomonas plecoglossicida), 슈도모나스 푸티다(Pseudomonas putida), 슈도모나스 아에루기노사(Pseudomonas aeruginosa)], 스트렙토코쿠스(Steptococcus)[예를 들면, 스트렙토코쿠스 피로게네스(Streptococcus pyogenes), 스트렙토코쿠스 뉴모니아(Streptococcus pneumonia), 스트렙토코쿠스 뉴모니아에(Streptococcus pneumoniae)], 에스케리키아, 마이코박테리움(Mycobacterium)[예를 들면, 마이코박테리움 투베르쿨로시스(Mycobacterium tuberculosis)] 및 바실러스[예를 들면, 바실러스 리케니포르미스(Bacillus licheniformis), 바실러스 세레우스(Bacillus cereus)]로부터 기원할 수 있으나, 이에 한정되지 않는다. ADI는 마이코플라스마 아르기니니, 락토코쿠스 락티스, 바실러스 리케니포르미스, 바실러스 세레우스(Bacillus cereus), 또는 이의 어떠한 조합으로부터 클로닝되는 것이 바람직하다. 서열 번호(서열 번호 23 내지 35)를 지닌 이들의 아미노산 서열 및 도 2에서 아미노산 서열 중의 일부에 대한 서열 정렬은 본원 및 또한 문헌[참조: Das et al, Structure. 12:657-667 (2004); Wang et al, Bioconjug. Chem. 17: 1447-1459 (2006); Ni et al, Appl. Microbiol. Biotechnol. 90: 193-201 (2011)]에 개재되어 있다.
(A) 천연의 마이코플라스마 아르기니니 ADI 단백질(서열 번호 23), (B) 마이코플라스마 아르기니니 ADI로부터 기원한 상이한 AAD 융합 단백질(서열 번호 36 내지 40) 및 (C) 바실러스 세레우스 ADI로부터 기원한 AAD 융합 단백질(서열 번호 41)에 대한 설계 및 아미노산 서열은 도 3에 나타나 있다. 상이한 AAD 융합 단백질이 성공적으로 작제되어 있다. 링커는 이들 구현에에서 AAD 융합 단백질내 알부민-결합 단백질과 ADI 사이에 삽입된다.
다른 한편, 신규한 AAD 융합 단백질은 또한 인테인-융합 단백질의 사용 및 발현된 단백질 연결에 의해 생성된다(도 4). 신규한 AAD 융합 단백질은 (1) N-말단 시스테인 잔기를 지닌 ADI를 ABD의 C-말단에서 반응성 티오에스테르와 반응시키거나, (2) N-말단 시스테인 잔기를 지닌 ABD를 ADI의 C-말단에서 반응성 티오에스테르와 반응시킴으로써 ADI 및 ABD가 공유결합에 의해 연결되도록 함으로써 형성될 수 있다. 도 4e에서, N-말단 시스테인 잔기를 지닌 ADI는 ABD의 C-말단에서 반응성 티오에스테르와 반응한다. ABD의 C-말단에서 티오에스테르 태그, 및 ADI의 N-말단에서 α-시스테인은 단백질 연결을 촉진시키는데 요구된다. 이들 단편은 pTWINl 벡터(제조원: New England Biolabs)를 사용하여 제조업자의 매뉴얼에 따라 생산된다. 특히, ABD-인테인-CBD 융합 단백질을 암호화하는 유전자를 합성하여 이를 이. 콜라이내에서 발현시키기 위한 T7 프로모터의 조절하에 벡터내로 클로닝한다(도 4c). 생산된 ABD-인테인-CBD 융합 단백질은 컬럼내에서 키틴에 결합한다. ABD-인테인-CBD의 아미노산 서열(서열 번호 42)은 도 4a에 나타낸다. 티올-유도성 절단 및 컬럼으로부터의 용출 후, 이의 C-말단에서 반응성 티오에스테르를 지닌 ABD를 수득한다(도 4c). 다른 한편, CBD-인테인-ADI 융합 단백질을 암호화하는 유전자를 합성하여 이. 콜라이내에서 발현시키기 위한 T7 프로모터의 조절하에 벡터내로 클로닝한다(도 4d). 생산된 CBD-인테인-ADI 융합 단백질은 컬럼에서 키틴에 결합한다. CBD-인테인-ADI의 아미노산 서열(서열 번호 43)은 도 4b에 나타낸다. pH 7 및 25℃에서 분해, 및 컬럼으로부터 용출 후, 이의 N-말단에 α-시스테인을 지닌 ADI를 수득한다(도 4d). 최종적으로, AAD 융합 단백질은 도 4e에 나타낸 바와 같이 단백질 연결 반응에 의해 생산된다.
중요하게도, AAD 융합 단백질은 통상의 방식으로 생산되어 정제될 수 있다. 예를 들면, AAD 융합 단백질은 가용성 분획 및 불용성 분획 둘 다에서 이. 콜라이로부터 성공적으로 발현되어 정제되며, 당해 결과는 도 8에 나타낸다. 또한, 도 8은 나트륨 도데실 설페이트 폴리아크릴아미드 겔 전기영동(SDS-PAGE)에 의해 분석된 정제된 AAD 융합 단백질을 나타낸다. 정제된 AAD 융합 단백질의 크기는 52.8 kDa로서 측정된다.
본 발명의 약제학적 조성물은 암 치료를 위해 종양 세포내에서 아르기닌을 고갈시키는데 고 활성을 지닌 AAD 융합 단백질을 함유한다. 정제된 AAD 융합 단백질의 특이 활성은 야생형 ADI의 것과 유사한 것으로 밝혀져 있다. IC50은 최대 억제 농도의 1/2이며, 즉, 이는 암 세포주의 50% 억제에 요구되는 AAD 융합 단백질의 농도를 나타낸다. IC50은 약물의 효능의 척도이다. 상이한 암 세포주(사람 흑색종, A375 & SK-mel-28; 사람 결장 암종, HCTl16; 사람 췌장 암, PancI; 사람 간 암, Sk-hepl; 사람 경부암, C-33A)에 대한 AAD 융합 단백질(아미노산 서열은 서열 번호 40에 나타낸다; 도 3e)의 IC50은 표 1에 나타낸다. 상이한 암 세포주에서 AAD 융합 단백질의 시험관내 효능은 도 9에 입증되어 있다. AAD 융합 단백질은 사람 흑색종, 사람 결장 암종 및 췌장 암 세포주를 포함하는 많은 세포유형을 사멸시킬 수 있음을 나타낸다.
암 세포주 | AAD의 IC50(㎍/ml) |
A375(사람 흑색종) | 0.104 |
SK-mel-28(사람 흑색종) | 1.92 |
PancI(사람 췌장암) | 1 |
Sk-hep1(사람 간암) | 10 |
C-33A(사람 경부암) | 0.063 |
HCT116(사람 결장 암종) | 1.30 |
알부민 결합 연구를 위해, 본 발명자들은, 가공된 AAD 융합 단백질이 사람 혈청 알부민(HSA)에 결합할 수 있음을 성공적으로 입증하였다. 도 10은, AAD 융합 단백질(아미노산 서열은 서열 번호 40에 나타낸다; 도 3e)은 HSA에 용이하게 결합한다. 1:5 또는 1:15의 몰 비에서, HSA-AAD 복합체의 형성은 도 1의 작제에 따라서 링커 분자 설계를 사용하여 형성시킨다. 혈액 속에서 AAD 융합 단백질의 순환하는 반감기는 비-공유결합성 HSA-AAD 복합체 형성에 의해 증가되는 것으로 예측된다. 따라서, AAD 융합 단백질의 장기-지속되는 버젼(version)이 성공적으로 생성되었다.
본 발명에서 제조된 AAD 융합 단백질-함유 약제학적 조성물과 비교하는 경우 어떠한 시판 제품도 고 효능을 나타내지 않는다. 암 치료에서 사용하기 위해, 본 발명의 AAD 융합 단백질-함유 약제학적 조성물은 종양 조직내에서 아르기닌을 고갈시키기 위한 항암제로서 제공된다. AAD 융합 단백질은 다른 분자 표적화 또는 세포독성제와 함께 사용될 우수한 후보물이다.
실시예
다음의 실시예는 본 발명의 영역을 어떠한 방식으로도 제한할 의도없이 본 발명의 구체적인 구현예를 기술하는 방식으로 제공된다.
하기 실시예 몇몇은 알부민-결합 아르기닌 데이미나제 융합 단백질을 제조하는 방법에 관한 것이다. 클로닝 및 인테인-매개된 단백질 연결을 포함하는 다양한 기술을 사용할 수 있다. 본원에 사용된 것으로서, 용어 "클로닝"은 광범위하게 사용되며 알부민-결합 아르기닌 데이미나제 융합 단백질을 암호화하는 융합 유전자를 작제하고, 융합 유전자를 벡터내로 삽입하며, 당해 벡터를 숙주 유기체내로 삽입하고 알부민-결합 아르기닌 데이미나제 융합 단백질을 포함하는 단백질을 발현시킴을 포함한다. 당해 기술에서 다수의 변형을 본 발명에 의해 고려되는 클로닝내에서 수행할 수 있으며 여전히 이에 속한다.
실시예
1
알부민-결합 도메인/
펩타이드
/단백질(
ABD
)을 암호화하는 유전자의
작제
ABD를 암호화하는 유전자를 2 라운드의 PCR로 작제한다. 제1 라운드에서, PCR 반응 혼합물(25μl의 총 용적)은 다음 물질을 함유한다:
1 x iProof PCR 완충제(제조원: Bio-Rad)
50 μΜ dNTP 혼합물
0.5 단위의 iProof DNA 폴리머라제(제조원: Bio-Rad)
10 nM의 각각의 다음의 올리고
ABD
-F1 전방
프라이머
(forward primer)(서열 번호 01):
5'-CATGATGCGAATTCCTTAGCTGAAGCTAAAGTCTTAGCTAACAGAGAACT-3'
ABD - R2 역방 프라이머 (reverse primer)(서열 번호 02):
5'-TAGTCACTTACTCCATATTTGTCAAGTTCTCTGTTAGCTAAGACTTTAGC-3'
ABD -F3 전방 프라이머(서열 번호 03):
5'-GAACTTGACAAATATGGAGTAAGTGACTATTACAAGAACCTAATCAACAA-3'
ABD - R4 역방 프라이머(서열 번호 04):
5'-TACACCTTCAACAGTTTTGGCATTGTTGATTAGGTTCTTGTAATAGTCAC-3 '
ABD -F5 전방 프라이머(서열 번호 05):
5 '-GCCAAAACTGTTGAAGGTGTAAAAGCACTGATAGATGAAATTTTAGCTGC-3 '
ABD - R6 역방 프라이머(서열 번호 06):
5 '-AGCTACGATAAGCTTAAGGTAATGCAGCTAAAATTTCATCTATCAGTG-3'
다음의 PCR 프로그램이 사용된다:
98℃ 30s; 20주기의 {98℃ 10s, 50℃ 20s, 72℃ 20s}
제2 라운드의 PCR에서, PCR 혼합물(50μl의 총 용적)은 다음의 물질을 함유한다:
1x iProof PCR 완충액(Bio-Rad);
50μΜ dNTP 혼합물;
제1 라운드로부터의 DNA 주형(template)으로서 1μl의 PCR 반응제;
1 단위의 iProof DNA 폴리머라제(제조원: Bio-Rad);
200nM의 각각의 다음의 올리고:
ABD -F7 전방 프라이머(서열 번호 07):
5'-CATGATGCGAATTCCTTAGCTGAAGCTAAAGTCTTAGCTAACAGAGAACT-3'
ABD - R8 역방 프라이머(서열 번호 08):
5'-AGCTACGATAAGCTTAAGGTAATGCAGCTAAAATTTCATCTATCAGTG-3'
다음의 PCR 프로그램이 사용된다:
98℃ 30s; 35 주기의 {98℃ 10s, 60℃ 20s, 72℃ 20s}; 72℃ 5분
ABD의 DNA 서열을 함유하는 PCR 생성물(169 bp)을 수득하고 클로닝 목적을 위해 Qiagen DNA 겔 추출 키트(Gel Extration Kit)로 정제한다.
실시예
2A
AAD 융합 단백질을 암호화하는 융합 유전자의
작제
제1의 PCR에서, PCR 혼합물(50μl의 총 용적)은 다음의 물질을 함유한다:
1 x iProof PCR 완충액(제조원: Bio-Rad);
50μΜ dNTP 혼합물;
25ng의 마이코플라스마 아르기니니 게놈성 DNA;
1 단위의 iProof DNA 폴리머라제(제조원: Bio-Rad);
200nM의 각각의 다음의 올리고:
ADINde-F 전방 프라이머(서열 번호 09):
5' -
ATCGATCGATGTCTGTATTTGACAGTAAATTTAAAGG
-3'
ADIhis-R 역방 프라이머(서열 번호 10):
5'-AGCTAAGGAATTCGCATCATGATGGTGATGGTGGTGGCTACCCCACTTAAC-3'
다음의 PCR 프로그램이 사용된다:
98℃ 1분; 35 주기의 {98℃ 10s, 50℃ 20s, 72℃ 40s}; 72℃ 5분
1280bp 길이의 PCR 생성물을 수득하고 Qiagen DNA 겔 추출 키트로 정제한다. 이후에, 제2의 PCR을 수행한다. PCR 혼합물(50μl의 총 용적)은 다음의 물질을 함유한다:
1x iProof PCR 완충액(제조원: Bio-Rad);
50μΜ dNTP 혼합물;
10ng의 1280bp PCR 생성물;
10ng의 169bp PCR 생성물;
1 단위의 iProof DNA 폴리머라제(제조원: Bio-Rad);
200nM의 각각의 다음의 올리고:
ADINde-F 전방 프라이머(서열 번호 11):
5'-ATCGATCGATGTCTGTATTTGACAGTAAATTTAAAGG-3'
ABD-RIO 역방 프라이머(서열 번호 12):
5'-AGCTACGATAAGCTTAAGGTAATGCAGCTAAAATTTCATCTATCAGTG-3'
다음의 PCR 프로그램이 사용된다:
98℃ 1분; 35 주기의 {98℃ 10s, 50℃ 20s, 72℃ 45s}; 72℃ 5분
1428 bp의 PCR 생성물을 수득하고 Qiagen DNA 겔 추출 키트로 정제한다. 이후에, 이를 제한 효소 Ndel 및 HindIII로 분해하고, 동일한 효소로 예비분해된 플라스미드 pREST A(제조원: Invitrogen)에 연결한다. 이후에, 연결 생성물을 이. 콜라이 BL21(DE3) 세포내로 형질전환시킨다. 작제된 융합 유전자의 서열은 DNA 서열분석에 의해 입증된다.
실시예
2B
His-
ABD
-
폴리
N-
ADI
의
클로닝
His-ABD-폴리N-ADI(서열 번호 40, 도 3e)의 작제는 2 단계의 오우버랩핑 PCR로 수행하며, 마지막 단계에서 수득된 PCR 단편을 벡터 pET3a내에 NdeI과 BamHI 부위 사이에 삽입한다. 유전자 지도, 뉴클레오타이드 서열 및 His-ABD-폴리N-ADI의 아미노산 서열은 도 6에 나타낸다.
His-ABD-폴리N-ADI의 작제시 포함된 프라이머:
hisABDNde-F 전방 프라이머(서열 번호 13):
5'-GGAGATATACATATGCATCATCACCATCACCATGATGAAGCCGTGGATG-3'
ABDnn-Rl 역방 프라이머(서열 번호 14):
5'-TTGTTATTATTGTTGTTACTACCCGAAGGTAATGCAGCTAAAATTTCATC-3'
ABDn-R2 역방 프라이머(서열 번호 15):
5'-AGAACCGCCGCTACCATTGTTATTATTGTTGTTACTACCCGA-3'
ADln-F 전방 프라이머(서열 번호 16):
5'-AATAATAACAATGGTAGCGGCGGTTCTGTATTTGACAGTAAATTTAAAGG-3'
ADIBam-R 역방 프라이머(서열 번호 17):
5'-TAGATCAATGGATCCTTACCACTTAACATCTTTACGTGATAAAG-3'
제1 라운드의 PCR에서, 공지된 농도의 성분을 함유하는 50μl의 반응 용적을 2개의 PCR 튜브에서 제조한다. 각각의 튜브에, dNTP, iProof 완충액(제조원: BIO-RAD), iProof DNA 폴리머라제(제조원: BIO-RAD), 프라이머 및 DNA 주형을 혼합하고 50μl까지 ddH20로 가한다. 반응에 사용된 DNA 주형은 ADI 유전자의 단백질 서열의 변경없이 내부 NdeI 부위 돌연변이의 제거로 마이코플라스마 아르기니니로부터의 ADI의 유전자를 함유하는 pET3a 벡터이다.
2개의 반응 튜브는 (A) 10pmol의 hisABDNde-F(서열 번호 13), 0.5pmol의 ABDnn-Rl(서열 번호 14) 및 10pmol ABDn-R2(서열 번호 15); 및 (B) 10pmol의 ADIn-F(서열 번호 16) 및 10pmol의 ADIBam-R(서열 번호 17) 각각의 프라이머 혼합물을 함유한다.
PCR 프로그램은 50℃(20s) 및 72℃(40s) 각각에서 어닐링(annealing) 및 연장 온도(시간)를 사용한 매뉴얼에서 추천된 단계에 따라 설정한다. 2개의 생성물은 PCR에 의해 237bp 및 1278bp의 크기로 생성되었다. 생성물을 추출하여 다음 라운드의 PCR에 대한 주형으로 적용한다.
제2 라운드의 오우버랩핑 단계에서, 반응 혼합물을, 사용된 주형이 제1 라운드의 PCR 프라이머로부터의 1pmol의 237bp PCR 생성물 및 1pmol의 1278bp PCR 생성물인 것을 제외하고는 제1 라운드와 유사한 방식으로 제조한다. 사용된 프라이머는 10 pmol의 hisABDNde-F(서열 번호 13) 및 10pmol의 ADIBam-R(서열 번호 17)로 변한다.
어닐링 및 연장 온도(시간)은 각각 50℃(20s) 및 72℃(60 s)이다. 크기가 1484 bp인 PCR 생성물이 반응으로부터 생성된다. PCR 생성물을 정제하고 Ndel 및 BamHI로 분해한 후 예비-분해된 pET3a 플라스미드내로 연결한다. 이후에, 연결된 생성물을 재조합체 단백질의 생성을 위한 이. 콜라이 BL21(DE3)내로 형질전환시킨다.
실시예
2C
His-
ABD
-
PolyN
-
bcADI
의
클로닝
His-ABD-PolyN-bcADI(서열 번호 41, 도 3f에서)의 작제는 2 단계의 오우버랩핑 PCR로 수행하며, 마지막 단계로부터 수득한 PCR 단편은 벡터 pET3a내에 NdeI과 BamHI 부위 사이에 삽입한다. His-ABD-PolyN-bcADI의 유전자 지도, 뉴클레오타이드 서열 및 아미노산 서열은 도 7에 나타낸다.
His-ABD-PolyN-bcADI의 작제시 포함된 프라이머:
hisABDNde-F2 전방 프라이머(서열 번호 18):
5'-GGAGATATACATATGCATCATCACCATCACCATGATGAAGCCGTGGATG-3'
bcABDnn-Rl 역방 프라이머(서열 번호 19):
5'-TTGTTATTATTGTTGTTACTACCCGAAGGTAATGCAGCTAAAATTTCATC-3'
bcABDn-R2 역방 프라이머(서열 번호 20):
5'-TTTACCGCCGCTACCATTGTTATTATTGTTGTTACTACCCGA-3'
bcADln-F 전방 프라이머(서열 번호 21):
5'-AATAATAACAATGGTAGCGGCGGTAAACATCCGATACATGTTACTTCAGA-3'
bcADIBam-R 역방 프라이머(서열 번호 22):
5'-TAGATCAATGGATCCCTAAATATCTTTACGAACAATTGGCATAC-3'
제1 라운드의 PCR에서, 공지된 농도의 성분을 함유하는 50μl의 반응 용적을 2개의 PCR 튜브에서 제조한다. 각각의 튜브에, dNTP, iProof 완충액(제조원: BIO-RAD), iProof DNA 폴리머라제(제조원: BIO-RAD), 프라이머 및 DNA 주형을 혼합하고 50μl까지 ddH20로 가한다. 반응에 사용된 DNA 주형은 ADI 유전자의 단백질 서열의 변경없이 내부 NdeI 부위 돌연변이의 제거로 바실러스 세레우스로부터의 ADI의 유전자를 함유하는 pET3a 벡터이다.
2개의 반응 튜브는 (A) 10pmol의 hisABDNde-F(서열 번호 18), 0.5pmol의 bcABDnn-Rl(서열 번호 19) 및 10pmol bcABDn-R2(서열 번호 20); 및 (B) 10pmol의 bcADIn-F(서열 번호 21) 및 10pmol의 bcADIBam-R(서열 번호 22) 각각의 프라이머 혼합물을 함유한다. PCR 프로그램은 50℃(20s) 및 72℃(40s) 각각에서 어닐링 및 연장 온도(시간)를 사용한 매뉴얼에서 추천된 단계에 따라 설정한다. 2개의 생성물은 PCR에 의해 237bp 및 1278bp의 크기로 생성되었다. 생성물을 추출하여 다음 라운드의 PCR에 대한 주형으로 적용한다.
제2 라운드의 오우버랩핑 단계에서, 반응 혼합물을, 사용된 주형이 제1 라운드의 PCR 프라이머로부터의 1pmol의 237bp PCR 생성물 및 1pmol의 1250bp PCR 생성물의 혼합물인 것을 제외하고는 제1 라운드와 유사한 방식으로 제조한다. 사용된 프라이머는 10 pmol의 hisABDNde-F2(서열 번호 18) 및 10pmol의 bcADIBam-R(서열 번호 22)로 변한다.
어닐링 및 연장 온도(시간)는 각각 50℃(20s) 및 72℃(60 s)이다. 크기가 1512 bp인 PCR 생성물이 반응으로부터 생성된다. PCR 생성물을 정제하고 Ndel 및 BamHI로 분해한 후 예비-분해된 pET3a 플라스미드내로 연결한다. 이후에, 연결된 생성물을 재조합체 단백질의 생성을 위한 이. 콜라이 BL21(DE3)내로 형질전환시킨다.
실시예 3
AAD 융합 단백질의 발현 및 정제
종균 배양물을 제조하기 위해, AAD 융합 단백질(도 5)을 암호화하는 균주 이. 콜라이 BL21(DE3)을 5ml의 2xTY 배지 속에서, 30℃로, 250rpm에서 밤새 배양한다. 밤샌 종균 배양물(2.5 ml)을 250ml의 2xTY에, 37℃, 250 rpm에서, 2.5시간(OD600 0.6-0.7가 될 때까지) 동안 가한다. OD600이 도달하면, IPTG를 배양물(0.2mM의 최종 농도)에 가한다. 성장을 22시간 이상 동안 20℃에서 지속한 후 세포를 원심분리로 수집하였다. 세포 펠렛을 25ml의 10mM 인산나트륨 완충액, pH 7.4 속에 재현탁한다. 세포를 초음파로 분해한다. 가용성 부위를 원심분리 후 수집한다. 이후에, 융합 단백질(His tag 함유)을 니켈 친화성 크로마토그래피로 정제한다. 표 2는, 배양 온도가 발현 숙주로부터 수득된 AAD 융합 단백질(아미노산 서열은 서열 번호 40에 나타냄; 도 3e)의 용해도에 영향을 미치는 중요한 인자임을 나타낸다.
AAD 융합 단백질의 가용성 분획을 분리하기 위하여, 세포 펠렛을 25ml의 10mM 인산나트륨 완충액, pH 7.4 속에 재현탁시킨다. 세포를 초음파처리로 용해한다. 가용성 부위를 원심분리 후 수집한다. AAD 융합 단백질(His tag 함유)을 이후에 니켈 친화성 크로마토그래피로 정제한다.
AAD 융합 단백질의 불용성 분획을 분리하기 위하여, 세포 펠렛을 25ml의 20mM 트리스-HCl, pH 7.4, 1% 트리톤 X-100 속에 재현탁한다. 세포를 초음파처리로 용해한다. 불용성 부위(봉입체)를 원심분리로 수집한다. 단백질은 10ml의 20mM 트리스-HCl, pH 7.4, 6M 구아니딘 HCl 속에 재현탁시켜 펼치고(unfolding), 가용성이 될 때까지 와동시킨다. 단백질을, 펼쳐진 단백질 용액 점적(drop)을 100ml의 20mM 인산나트륨 완충액, pH 7.4의 신속한 교반 용액내로 적가식으로 가하여 펼친다. 불용성 물질을 원심분리로 제거한다. 단백질의 염석(salting out)을, 고체 황산암모늄 분말을 상층액에 가하여 수행함으로써 70% 포화도를 달성한다. 불용성 부위를 원심분리로 수집하고 이를 10ml의 20mM 인산나트륨 완충액 속에 재현탁시킨다. 이후에, AAD 융합 단백질(His tag 함유)을 니켈 친화성 크로마토그래피로 정제한다.
AAD | 1 | 2 | 3 |
배양 온도(℃) | 30 | 20 | 37 |
수율(mg)/250ml의 배양물 | ~0.66 | ~12.0 | ~7.0 |
용해도 | 50% 가용성 | 90% 가용성 | 90% 봉입체 |
A375 세포에서 IC50(㎍/ml) | 0.10 | 0.68 | 0.23 |
실시예
4
AAD 융합 단백질에 대한 효소 활성 검정 및 효소 역학야생형 ADI 및 본 발명의 AAD 융합 단백질에 대한 효소 활성을 측정하기 위하여, 시트룰린 검출을 위한 디아세틸 모노옥심(DAM)-티오세미카바지드(TSC) 검정을 사용한다. 반응은 하기 나타낸다.
당해 검정을, 시료를 산성 염화철 용액과 DAM-TSC 용액을 혼합하여 제조한, 색상 시약에 가하여 수행한다. 요약하면, 효소를 20mM 아르기닌, 10mM 인산나트륨 pH 7.4로 5분 동안 37℃에서 항온처리한다. 반응 혼합물을 100℃에서 5분 동안 가열하여 색상이 발색되도록 하고 540nm(광 경로 = 1cm)에서 판독한다. 표준 곡선을 다양한 농도의 시트룰린을 사용하여 작제한다. ADI 천연 효소 1 단위는 검정 조건하에 37℃에서 분당 1μmol의 아르기닌을 1μmol의 시트룰린으로 전환시키는 양의 효소 활성이다. 본 발명에서 야생형 ADI 및 AAD 융합 단백질의 특이 활성은 각각 8.4 및 9.2U/mg(pH 7.4에서, 생리학적 pH)이다. 상이한 pH 범위(pH 5.5 내지 9.5)에서 야생형 ADI 및 AAD 융합 단백질에 대한 특이 활성을 또한 측정하며, 최적 pH는 6.5이다. 따라서, 결과는, AAD 융합 단백질이 알부민-결합 단백질과의 융합물이 ADI의 효소 활성에 영향을 미치지 않으므로, 아르기닌을 효율적으로 고갈시킴을 나타낸다.
미카엘리스 상수(Michaelis constant) Km은, 반응 속도가 최대의 1/2인 기질 농도이며, 효소에 대한 기질의 친화성의 역수이다. 작은 Km은 기질에 대한 고 친화성을 나타내며, 이는, 당해 속도가 최대 반응 속도에 보다 신속하게 도달할 것임을 의미한다. 효소 역학 또는 Km 값의 측정을 위해, 야생형 ADI 및 AAD 융합 단백질의 활성을 상이한 농도의 기질 아르기닌(2000μΜ, 1000μΜ, 500μΜ, 250μΜ, 125μΜ, 62.5μΜ) 하에서 pH 7.4에서 측정한다. 도 3e(서열 번호 40, ADI 단백질은 마이코플라스마 아르기니니로부터 기원한다)에 나타낸 AAD 융합 단백질 및 도 3f(서열 번호 41, ADI 단백질은 바실러스 세레우스로부터 기원한다)에 나타낸 AAD 융합 단백질의 측정된 Km 값은 각각 0.0041mM 및 0.132mM이다. 당해 결과는, ABD에 대한 융합이 아르기닌에 대한 상이한 AAD 융합 단백질의 결합 친화성에 영향을 미치지 않았음을 제안한다.
실시예
5
암 세포주에서 AAD 융합 단백질의 세포 증식 검정 및
시험관내
효능
배양 배지 DMEM을 사용하여 사람 흑색종 A375 & SK-mel-28, 사람 췌장암 PancI 및 사람 경부암 C-33A 세포주를 성장시킨다. EMEM 배지를 사용하여 SK-hep 1 간세포 및 C-33A 경부암 세포주를 배양한다. 100μl의 배양 배지 중 암 세포(2-5 X 103)를 96-웰 플레이트에 종균배양하고 24시간 동안 항온처리한다. 배양 배지를 상이한 농도의 AAD 융합 단백질을 함유하는 배지로 교체한다. 플레이트를 추가로 3일 동안 37℃에서 95% 공기/5% C02의 대기 속에서 항온처리한다. MTT 검정을 수행하여 제조업자의 지시사항에 따라 배양물 속에서 생존 세포의 수를 평가한다. 세포 성장의 50% 억제를 달성하는데 요구되는 효소의 양을 IC50로 정의한다.
표 1 및 도 9에 나타낸 바와 같이, 당해 결과는, AAD 융합 단백질이 아르기닌을 효율적으로 고갈시키며 시험관내 조직 배양 연구에서 다양한 유형의 사람 암 세포주의 성장을 억제함을 나타낸다. 예를 들면, 사람 흑색종, 사람 결장 암종, 사람 췌장암, 사람 간암 및 사람 경부암은 AAD 융합 단백질에 의해 모두 용이하게 억제되므로, 이들 모두는 낮은 값의 IC50을 갖는다(참조: 표 1). 예측된 바와 같이, AAD 융합 단백질은 아르기닌-의존성(예를 들면, ASS-음성 암)인 모든 암 유형을 억제할 수 있다.
실시예
6
AAD 융합 단백질의
생체내
반감기 측정
Balb/c 마우스(5 내지 7주령)을 당해 연구에 사용하여 이들이 실험 전 1주일 동안 익숙해지도록 한다. 마우스(n=3)를 4개 그룹으로 나누고 100μl의 PBS 중 0, 100, 500 또는 1000μl의 AAD 융합 단백질(서열 번호 40, 도 3e)을 각각 복강내 주사한다. 각각의 마우스의 혈액을 0h 및 1 내지 7일째에 수집한다. 혈청을 원심분리 후 수득한다. 이후에, 혈청을 탈단백질화시키고 아르기닌에 대해 아미노산 분석기로 분석한다.
도 11에 나타낸 바와 같이, AAD 융합 단백질(서열 번호 40, 도 3e)은, 심지어 최저 용량인 100μg에서도, 혈장 아르기닌을 1, 3 및 5일째에 효율적으로 고갈시키며, 이는, AAD가 적어도 5일 동안 생체내에서 아르기닌을 효율적으로 고갈시킬 수 있음을 제안한다. 아르기닌 수준은 모든 처리 그룹에서 6 및 7일째에 점진적으로 정상으로 돌아온다.
실시예
7
암 세포
이종이식체에서
AAD 융합 단백질의
생체내
효능
누드(Nude) balb/c 마우스(5 내지 7주령)을 당해 연구에 사용하며 이들을 실험 전 1주 동안 적응하도록 한다. 마우스에게 100μl의 신선한 배양 배지 중 2xl06개의 암 세포를 피하 접종한다. 10이 후, 마우스를 대조군 및 처리 그룹으로 무작위로 분리한다. 대조군 그룹에게 100μl의 PBS를 제공하고 처리 그룹에게 100μl의 AAD 융합 단백질을 매주 복강내 제공한다. 종양 크기는 캘리퍼(caliper)로 측정하고 종양 용적을 식: (길이 x 너비2)/2를 사용하여 계산한다. 혈액 채취(blood draw)를 아르기닌의 혈장 측정을 위한 각각의 처리 후 5일째에 수득한다.
<110> Vision Global Holdings Ltd.
WONG, Bing Lou
<120> PHARMACEUTICAL COMPOSITION COMPRISING ALBUMIN-BINDING ARGININE
DEIMINASE FOR CANCER TARGETING TREATMENT
<130> P6890US01
<140> PCT/US14/020943
<141> 2014-03-06
<150> US 61/773,214
<151> 2013-03-06
<150> US 14/197,236
<151> 2014-03-05
<160> 53
<170> PatentIn version 3.5
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<223> ABD-F3 forward primer
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agaaccgccg ctaccattgt tattattgtt gttactaccc ga 42
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aataataaca atggtagcgg cggttctgta tttgacagta aatttaaagg 50
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<220>
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tagatcaatg gatccttacc acttaacatc tttacgtgat aaag 44
<210> 18
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<212> DNA
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<220>
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ggagatatac atatgcatca tcaccatcac catgatgaag ccgtggatg 49
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Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu
1 5 10 15
Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile
20 25 30
Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile
35 40 45
Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu
50 55 60
Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Ile Asp Leu Val Ala
65 70 75 80
Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu
85 90 95
Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Val
100 105 110
Val Val Arg Asn Phe Leu Lys Ala Lys Lys Thr Ser Arg Glu Leu Val
115 120 125
Glu Ile Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala
130 135 140
Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg
145 150 155 160
Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg
165 170 175
Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser
180 185 190
Asn His Pro Lys Leu Ile Asn Thr Pro Trp Tyr Tyr Asp Pro Ser Leu
195 200 205
Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr
210 215 220
Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val Thr Leu
225 230 235 240
Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile
245 250 255
Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr
260 265 270
Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala
275 280 285
Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala
290 295 300
Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Gln
305 310 315 320
Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Glu Gly
325 330 335
Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn
340 345 350
Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu
355 360 365
Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe
370 375 380
His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser
385 390 395 400
Met Pro Leu Ser Arg Lys Asp Val Lys Trp
405 410
<210> 24
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Met Asn Asn Gly Ile Asn Val Asn Ser Glu Ile Gly Lys Leu Lys Ser
1 5 10 15
Val Leu Leu His Arg Pro Gly Ala Glu Val Glu Asn Ile Thr Pro Asp
20 25 30
Thr Met Lys Gln Leu Leu Phe Asp Asp Ile Pro Tyr Leu Lys Ile Ala
35 40 45
Gln Lys Glu His Asp Phe Phe Ala Gln Thr Leu Arg Asp Asn Gly Ala
50 55 60
Glu Thr Val Tyr Ile Glu Asn Leu Ala Thr Glu Val Phe Glu Lys Ser
65 70 75 80
Ser Glu Thr Lys Glu Glu Phe Leu Ser His Leu Leu His Glu Ala Gly
85 90 95
Tyr Arg Pro Gly Arg Thr Tyr Asp Gly Leu Thr Glu Tyr Leu Thr Ser
100 105 110
Met Pro Thr Lys Asp Met Val Glu Lys Val Tyr Ala Gly Val Arg Lys
115 120 125
Asn Glu Leu Asp Ile Lys Arg Thr Ala Leu Ser Asp Met Ala Gly Ser
130 135 140
Asp Ala Glu Asn Tyr Phe Tyr Leu Asn Pro Leu Pro Asn Ala Tyr Phe
145 150 155 160
Thr Arg Asp Pro Gln Ala Ser Met Gly Val Gly Met Thr Ile Asn Lys
165 170 175
Met Thr Phe Pro Ala Arg Gln Pro Glu Ser Leu Ile Thr Glu Tyr Val
180 185 190
Met Ala Asn His Pro Arg Phe Lys Asp Thr Pro Ile Trp Arg Asp Arg
195 200 205
Asn His Thr Thr Arg Ile Glu Gly Gly Asp Glu Leu Ile Leu Asn Lys
210 215 220
Thr Thr Val Ala Ile Gly Val Ser Glu Arg Thr Ser Ser Lys Thr Ile
225 230 235 240
Gln Asn Leu Ala Lys Glu Leu Phe Ala Asn Pro Leu Ser Thr Phe Asp
245 250 255
Thr Val Leu Ala Val Glu Ile Pro His Asn His Ala Met Met His Leu
260 265 270
Asp Thr Val Phe Thr Met Ile Asn His Asp Gln Phe Thr Val Phe Pro
275 280 285
Gly Ile Met Asp Gly Ala Gly Asn Ile Asn Val Phe Ile Leu Arg Pro
290 295 300
Gly Gln Asp Gly Glu Val Glu Ile Glu His Leu Thr Asp Leu Lys Ala
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Ala Leu Lys Lys Val Leu Asn Leu Ser Glu Leu Asp Leu Ile Glu Cys
325 330 335
Gly Ala Gly Asp Pro Ile Ala Ala Pro Arg Glu Gln Trp Asn Asp Gly
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Ser Asn Thr Leu Ala Ile Ala Pro Gly Glu Ile Val Thr Tyr Asp Arg
355 360 365
Asn Tyr Val Thr Val Glu Leu Leu Lys Glu His Gly Ile Lys Val His
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Glu Ile Leu Ser Ser Glu Leu Gly Arg Gly Arg Gly Gly Ala Arg Cys
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Met Ser Gln Pro Leu Trp Arg Glu Asp Leu
405 410
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Met Lys His Pro Ile His Val Thr Ser Glu Ile Gly Glu Leu Gln Thr
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Val Leu Leu Lys Arg Pro Gly Lys Glu Val Glu Asn Leu Thr Pro Asp
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Tyr Leu Gln Gln Leu Leu Phe Asp Asp Ile Pro Tyr Leu Pro Ile Ile
35 40 45
Gln Lys Glu His Asp Tyr Phe Ala Gln Thr Leu Arg Asn Arg Gly Val
50 55 60
Glu Val Leu Tyr Leu Glu Lys Leu Ala Ala Glu Ala Leu Val Asp Lys
65 70 75 80
Lys Leu Arg Glu Glu Phe Val Asp Arg Ile Leu Lys Glu Gly Gln Ala
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Asp Val Asn Val Ala His Gln Thr Leu Lys Glu Tyr Leu Leu Ser Phe
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Ser Asn Glu Glu Leu Ile Gln Lys Ile Met Gly Gly Val Arg Lys Asn
115 120 125
Glu Ile Glu Thr Ser Lys Lys Thr His Leu Tyr Glu Leu Met Glu Asp
130 135 140
His Tyr Pro Phe Tyr Leu Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg
145 150 155 160
Asp Pro Ala Ala Ser Val Gly Asp Gly Leu Thr Ile Asn Lys Met Arg
165 170 175
Glu Pro Ala Arg Arg Arg Glu Ser Leu Phe Met Glu Tyr Ile Ile Lys
180 185 190
Tyr His Pro Arg Phe Ala Lys His Asn Val Pro Ile Trp Leu Asp Arg
195 200 205
Asp Tyr Lys Phe Pro Ile Glu Gly Gly Asp Glu Leu Ile Leu Asn Glu
210 215 220
Glu Thr Ile Ala Ile Gly Val Ser Ala Arg Thr Ser Ala Lys Ala Ile
225 230 235 240
Glu Arg Leu Ala Lys Asn Leu Phe Ser Arg Gln Asn Lys Ile Lys Lys
245 250 255
Val Leu Ala Ile Glu Ile Pro Lys Cys Arg Ala Phe Met His Leu Asp
260 265 270
Thr Val Phe Thr Met Val Asp Tyr Asp Lys Phe Thr Ile His Pro Ala
275 280 285
Ile Gln Gly Pro Lys Gly Asn Met Asn Ile Tyr Ile Leu Glu Lys Gly
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Ala Asp Glu Glu Thr Leu Lys Ile Thr His Arg Thr Ser Leu Met Glu
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Ala Leu Lys Glu Val Leu Asp Leu Ser Glu Leu Val Leu Ile Pro Cys
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Gly Gly Gly Asp Val Ile Ala Ser Ala Arg Glu Gln Trp Asn Asp Gly
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Ser Asn Thr Leu Ala Ile Ala Pro Gly Val Val Val Thr Tyr Asp Arg
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Asn Tyr Val Ser Asn Thr Leu Leu Arg Glu His Gly Ile Glu Val Ile
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Glu Val Leu Ser Ser Glu Leu Ser Arg Gly Arg Gly Gly Pro Arg Cys
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Met Ser Met Pro Ile Val Arg Lys Asp Ile
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<213> Bacillus licheniformis
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Met Ile Met Thr Thr Pro Ile His Val Tyr Ser Glu Ile Gly Pro Leu
1 5 10 15
Lys Thr Val Met Leu Lys Arg Pro Gly Arg Glu Leu Glu Asn Leu Thr
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Pro Glu Tyr Leu Glu Arg Leu Leu Phe Asp Asp Ile Pro Phe Leu Pro
35 40 45
Ala Val Gln Lys Glu His Asp Gln Phe Ala Glu Thr Leu Lys Gln Gln
50 55 60
Gly Ala Glu Val Leu Tyr Leu Glu Lys Leu Thr Ala Glu Ala Leu Asp
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Asp Ala Leu Val Arg Glu Gln Phe Ile Asp Glu Leu Leu Thr Glu Ser
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Lys Ala Asp Ile Asn Gly Ala Tyr Asp Arg Leu Lys Glu Phe Leu Leu
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Thr Phe Asp Ala Asp Ser Met Val Glu Gln Val Met Ser Gly Ile Arg
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Lys Asn Glu Leu Glu Arg Glu Lys Lys Ser His Leu His Glu Leu Met
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Glu Asp His Tyr Pro Phe Tyr Leu Asp Pro Met Pro Asn Leu Tyr Phe
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Thr Arg Asp Pro Ala Ala Ala Ile Gly Ser Gly Leu Thr Ile Asn Lys
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Met Lys Glu Pro Ala Arg Arg Arg Glu Ser Leu Phe Met Arg Tyr Ile
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Ile Asn His His Pro Arg Phe Lys Gly His Glu Ile Pro Val Trp Leu
195 200 205
Asp Arg Asp Phe Lys Phe Asn Ile Glu Gly Gly Asp Glu Leu Val Leu
210 215 220
Asn Glu Glu Thr Val Ala Ile Gly Val Ser Glu Arg Thr Thr Ala Gln
225 230 235 240
Ala Ile Glu Arg Leu Val Arg Asn Leu Phe Gln Arg Gln Ser Arg Ile
245 250 255
Arg Arg Val Leu Ala Val Glu Ile Pro Lys Ser Arg Ala Phe Met His
260 265 270
Leu Asp Thr Val Phe Thr Met Val Asp Arg Asp Gln Phe Thr Ile His
275 280 285
Pro Ala Ile Gln Gly Pro Glu Gly Asp Met Arg Ile Phe Val Leu Glu
290 295 300
Arg Gly Lys Thr Ala Asp Glu Ile His Thr Thr Glu Glu His Asn Leu
305 310 315 320
Pro Glu Val Leu Lys Arg Thr Leu Gly Leu Ser Asp Val Asn Leu Ile
325 330 335
Phe Cys Gly Gly Gly Asp Glu Ile Ala Ser Ala Arg Glu Gln Trp Asn
340 345 350
Asp Gly Ser Asn Thr Leu Ala Ile Ala Pro Gly Val Val Val Thr Tyr
355 360 365
Asp Arg Asn Tyr Ile Ser Asn Glu Cys Leu Arg Glu Gln Gly Ile Lys
370 375 380
Val Ile Glu Ile Pro Ser Gly Glu Leu Ser Arg Gly Arg Gly Gly Pro
385 390 395 400
Arg Cys Met Ser Met Pro Leu Tyr Arg Glu Asp Val Lys
405 410
<210> 27
<211> 409
<212> PRT
<213> Mycoplasma arthritidis
<400> 27
Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu
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Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Lys Glu Ile
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Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile
35 40 45
Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Glu Phe Val Ala Glu
50 55 60
Leu Lys Lys Arg Gly Ile Asn Val Val Glu Leu Val Asp Leu Ile Val
65 70 75 80
Glu Thr Tyr Asp Leu Ala Ser Lys Glu Ala Lys Glu Lys Leu Leu Glu
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Glu Phe Leu Asp Asp Ser Val Pro Val Leu Ser Asp Glu His Arg Ala
100 105 110
Ala Val Lys Lys Phe Leu Gln Ser Gln Lys Ser Thr Arg Ser Leu Val
115 120 125
Glu Tyr Met Ile Ala Gly Ile Thr Lys His Asp Leu Lys Ile Glu Ser
130 135 140
Asp Leu Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg
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Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg
165 170 175
Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser
180 185 190
Asn His Pro Lys Leu Val Asn Thr Pro Trp Tyr Tyr Asp Pro Ala Glu
195 200 205
Gly Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr
210 215 220
Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Ile Thr Leu
225 230 235 240
Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile
245 250 255
Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr
260 265 270
Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala
275 280 285
Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Asp
290 295 300
Ala Pro Gln Pro Val Asp Asn Gly Leu Pro Leu Glu Asp Leu Leu Lys
305 310 315 320
Ser Ile Ile Gly Lys Lys Pro Thr Leu Ile Pro Ile Ala Gly Ala Gly
325 330 335
Ala Ser Gln Ile Asp Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn
340 345 350
Tyr Leu Ala Val Ala Pro Gly Ile Val Ile Gly Tyr Ala Arg Asn Glu
355 360 365
Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Thr Val Leu Pro Phe
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Arg Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser
385 390 395 400
Met Pro Leu Ser Arg Lys Asp Val Lys
405
<210> 28
<211> 409
<212> PRT
<213> Mycoplasma hominis
<400> 28
Met Ser Val Phe Asp Ser Lys Phe Asn Gly Ile His Val Tyr Ser Glu
1 5 10 15
Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Arg Glu Ile
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Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile
35 40 45
Leu Glu Ser His Asp Ala Arg Lys Glu His Gln Ser Phe Val Lys Ile
50 55 60
Met Lys Asp Arg Gly Ile Asn Val Val Glu Leu Thr Asp Leu Val Ala
65 70 75 80
Glu Thr Tyr Asp Leu Ala Ser Lys Ala Ala Lys Glu Glu Phe Ile Glu
85 90 95
Thr Phe Leu Glu Glu Thr Val Pro Val Leu Thr Glu Ala Asn Lys Lys
100 105 110
Ala Val Arg Ala Phe Leu Leu Ser Lys Pro Thr His Glu Met Val Glu
115 120 125
Phe Met Met Ser Gly Ile Thr Lys Tyr Glu Leu Gly Val Glu Ser Glu
130 135 140
Asn Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp
145 150 155 160
Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Phe Met Arg Tyr
165 170 175
Ile Val Arg Arg Arg Glu Thr Leu Phe Ala Arg Phe Val Phe Arg Asn
180 185 190
His Pro Lys Leu Val Lys Thr Pro Trp Tyr Tyr Asp Pro Ala Met Lys
195 200 205
Met Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Glu Thr Leu
210 215 220
Val Val Gly Val Ser Glu Arg Thr Asp Leu Asp Thr Ile Thr Leu Leu
225 230 235 240
Ala Lys Asn Ile Lys Ala Asn Lys Glu Val Glu Phe Lys Arg Ile Val
245 250 255
Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr Trp
260 265 270
Leu Thr Met Leu Asp Lys Asn Lys Phe Leu Tyr Ser Pro Ile Ala Asn
275 280 285
Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala Glu
290 295 300
Pro Gln Pro Gln Leu Asn Gly Leu Pro Leu Asp Lys Leu Leu Ala Ser
305 310 315 320
Ile Ile Asn Lys Glu Pro Val Leu Ile Pro Ile Gly Gly Ala Gly Ala
325 330 335
Thr Glu Met Glu Ile Ala Arg Glu Thr Asn Phe Asp Gly Thr Asn Tyr
340 345 350
Leu Ala Ile Lys Pro Gly Leu Val Ile Gly Tyr Asp Arg Asn Glu Lys
355 360 365
Thr Asn Ala Ala Leu Lys Ala Ala Gly Ile Thr Val Leu Pro Phe His
370 375 380
Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser Met
385 390 395 400
Pro Leu Ser Arg Lys Asp Val Lys Trp
405
<210> 29
<211> 411
<212> PRT
<213> Streptococcus pyogenes
<400> 29
Met Thr Ala Gln Thr Pro Ile His Val Tyr Ser Glu Ile Gly Lys Leu
1 5 10 15
Lys Lys Val Leu Leu His Arg Pro Gly Lys Glu Ile Glu Asn Leu Met
20 25 30
Pro Asp Tyr Leu Glu Arg Leu Leu Phe Asp Asp Ile Pro Phe Leu Glu
35 40 45
Asp Ala Gln Lys Glu His Asp Ala Phe Ala Gln Ala Leu Arg Asp Glu
50 55 60
Gly Ile Glu Val Leu Tyr Leu Glu Thr Leu Ala Ala Glu Ser Leu Val
65 70 75 80
Thr Pro Glu Ile Arg Glu Ala Phe Ile Asp Glu Tyr Leu Ser Glu Ala
85 90 95
Asn Ile Arg Gly Arg Ala Thr Lys Lys Ala Ile Arg Glu Leu Leu Met
100 105 110
Ala Ile Glu Asp Asn Gln Glu Leu Ile Glu Lys Thr Met Ala Gly Val
115 120 125
Gln Lys Ser Glu Leu Pro Glu Ile Pro Ala Ser Glu Lys Gly Leu Thr
130 135 140
Asp Leu Val Glu Ser Ser Tyr Pro Phe Ala Ile Asp Pro Met Pro Asn
145 150 155 160
Leu Tyr Phe Thr Arg Asp Pro Phe Ala Thr Ile Gly Thr Gly Val Ser
165 170 175
Leu Asn His Met Phe Ser Glu Thr Arg Asn Arg Glu Thr Leu Tyr Gly
180 185 190
Lys Tyr Ile Phe Thr His His Pro Ile Tyr Gly Gly Gly Lys Val Pro
195 200 205
Met Val Tyr Asp Arg Asn Glu Thr Thr Arg Ile Glu Gly Gly Asp Glu
210 215 220
Leu Val Leu Ser Lys Asp Val Leu Ala Val Gly Ile Ser Gln Arg Thr
225 230 235 240
Asp Ala Ala Ser Ile Glu Lys Leu Leu Val Asn Ile Phe Lys Gln Asn
245 250 255
Leu Gly Phe Lys Lys Val Leu Ala Phe Glu Phe Ala Asn Asn Arg Lys
260 265 270
Phe Met His Leu Asp Thr Val Phe Thr Met Val Asp Tyr Asp Lys Phe
275 280 285
Thr Ile His Pro Glu Ile Glu Gly Asp Leu Arg Val Tyr Ser Val Thr
290 295 300
Tyr Asp Asn Glu Glu Leu His Ile Val Glu Glu Lys Gly Asp Leu Ala
305 310 315 320
Asp Leu Leu Ala Ala Asn Leu Gly Val Glu Lys Val Asp Leu Ile Arg
325 330 335
Cys Gly Gly Asp Asn Leu Val Ala Ala Gly Arg Glu Gln Trp Asn Asp
340 345 350
Gly Ser Asn Thr Leu Thr Ile Ala Pro Gly Val Val Val Val Tyr Asn
355 360 365
Arg Asn Thr Ile Thr Asn Ala Ile Leu Glu Ser Lys Gly Leu Lys Leu
370 375 380
Ile Lys Ile His Gly Ser Glu Leu Val Arg Gly Arg Gly Gly Pro Arg
385 390 395 400
Cys Met Ser Met Pro Phe Glu Arg Glu Asp Ile
405 410
<210> 30
<211> 409
<212> PRT
<213> Streptococcus pneumonia
<400> 30
Met Ser Ser His Pro Ile Gln Val Phe Ser Glu Ile Gly Lys Leu Lys
1 5 10 15
Lys Val Met Leu His Arg Pro Gly Lys Glu Leu Glu Asn Leu Leu Pro
20 25 30
Asp Tyr Leu Glu Arg Leu Leu Phe Asp Asp Ile Pro Phe Leu Glu Asp
35 40 45
Ala Gln Lys Glu His Asp Ala Phe Ala Gln Ala Leu Arg Asp Glu Gly
50 55 60
Ile Glu Val Leu Tyr Leu Glu Gln Leu Ala Ala Glu Ser Leu Thr Ser
65 70 75 80
Pro Glu Ile Arg Asp Gln Phe Ile Glu Glu Tyr Leu Asp Glu Ala Asn
85 90 95
Ile Arg Asp Arg Gln Thr Lys Val Ala Ile Arg Glu Leu Leu His Gly
100 105 110
Ile Lys Asp Asn Gln Glu Leu Val Glu Lys Thr Met Ala Gly Ile Gln
115 120 125
Lys Val Glu Leu Pro Glu Ile Pro Asp Glu Ala Lys Asp Leu Thr Asp
130 135 140
Leu Val Glu Ser Asp Tyr Pro Phe Ala Ile Asp Pro Met Pro Asn Leu
145 150 155 160
Tyr Phe Thr Arg Asp Pro Phe Ala Thr Ile Gly Asn Ala Val Ser Leu
165 170 175
Asn His Met Phe Ala Asp Thr Arg Asn Arg Glu Thr Leu Tyr Gly Lys
180 185 190
Tyr Ile Phe Lys Tyr His Pro Ile Tyr Gly Gly Lys Val Asp Leu Val
195 200 205
Tyr Asn Arg Glu Glu Asp Thr Arg Ile Glu Gly Gly Asp Glu Leu Val
210 215 220
Leu Ser Lys Asp Val Leu Ala Val Gly Ile Ser Gln Arg Thr Asp Ala
225 230 235 240
Ala Ser Ile Glu Lys Leu Leu Val Asn Ile Phe Lys Lys Asn Val Gly
245 250 255
Phe Lys Lys Val Leu Ala Phe Glu Phe Ala Asn Asn Arg Lys Phe Met
260 265 270
His Leu Asp Thr Val Phe Thr Met Val Asp Tyr Asp Lys Phe Thr Ile
275 280 285
His Pro Glu Ile Glu Gly Asp Leu His Val Tyr Ser Val Thr Tyr Glu
290 295 300
Asn Glu Lys Leu Lys Ile Val Glu Glu Lys Gly Asp Leu Ala Glu Leu
305 310 315 320
Leu Ala Gln Asn Leu Gly Val Glu Lys Val His Leu Ile Arg Cys Gly
325 330 335
Gly Gly Asn Ile Val Ala Ala Ala Arg Glu Gln Trp Asn Asp Gly Ser
340 345 350
Asn Thr Leu Thr Ile Ala Pro Gly Val Val Val Val Tyr Asp Arg Asn
355 360 365
Thr Val Thr Asn Lys Ile Leu Glu Glu Tyr Gly Leu Arg Leu Ile Lys
370 375 380
Ile Arg Gly Ser Glu Leu Val Arg Gly Arg Gly Gly Pro Arg Cys Met
385 390 395 400
Ser Met Pro Phe Glu Arg Glu Glu Val
405
<210> 31
<211> 402
<212> PRT
<213> Mycobacterium tuberculosis
<400> 31
Met Gly Val Glu Leu Gly Ser Asn Ser Glu Val Gly Ala Leu Arg Val
1 5 10 15
Val Ile Leu His Arg Pro Gly Ala Glu Leu Arg Arg Leu Thr Pro Arg
20 25 30
Asn Thr Asp Gln Leu Leu Phe Asp Gly Leu Pro Trp Val Ser Arg Ala
35 40 45
Gln Asp Glu His Asp Glu Phe Ala Glu Leu Leu Ala Ser Arg Gly Ala
50 55 60
Glu Val Leu Leu Leu Ser Asp Leu Leu Thr Glu Ala Leu His His Ser
65 70 75 80
Gly Ala Ala Arg Met Gln Gly Ile Ala Ala Ala Val Asp Ala Pro Arg
85 90 95
Leu Gly Leu Pro Leu Ala Gln Glu Leu Ser Ala Tyr Leu Arg Ser Leu
100 105 110
Asp Pro Gly Arg Leu Ala His Val Leu Thr Ala Gly Met Thr Phe Asn
115 120 125
Glu Leu Pro Ser Asp Thr Arg Thr Asp Val Ser Leu Val Leu Arg Met
130 135 140
His His Gly Gly Asp Phe Val Ile Glu Pro Leu Pro Asn Leu Val Phe
145 150 155 160
Thr Arg Asp Ser Ser Ile Trp Ile Gly Pro Arg Val Val Ile Pro Ser
165 170 175
Leu Ala Leu Arg Ala Arg Val Arg Glu Ala Ser Leu Thr Asp Leu Ile
180 185 190
Tyr Ala His His Pro Arg Phe Thr Gly Val Arg Arg Ala Tyr Glu Ser
195 200 205
Arg Thr Ala Pro Val Glu Gly Gly Asp Val Leu Leu Leu Ala Pro Gly
210 215 220
Val Val Ala Val Gly Val Gly Glu Arg Thr Thr Pro Ala Gly Ala Glu
225 230 235 240
Ala Leu Ala Arg Ser Leu Phe Asp Asp Asp Leu Ala His Thr Val Leu
245 250 255
Ala Val Pro Ile Ala Gln Gln Arg Ala Gln Met His Leu Asp Thr Val
260 265 270
Cys Thr Met Val Asp Thr Asp Thr Met Val Met Tyr Ala Asn Val Val
275 280 285
Asp Thr Leu Glu Ala Phe Thr Ile Gln Arg Thr Pro Asp Gly Val Thr
290 295 300
Ile Gly Asp Ala Ala Pro Phe Ala Glu Ala Ala Ala Lys Ala Met Gly
305 310 315 320
Ile Asp Lys Leu Arg Val Ile His Thr Gly Met Asp Pro Val Val Ala
325 330 335
Glu Arg Glu Gln Trp Asp Asp Gly Asn Asn Thr Leu Ala Leu Ala Pro
340 345 350
Gly Val Val Val Ala Tyr Glu Arg Asn Val Gln Thr Asn Ala Arg Leu
355 360 365
Gln Asp Ala Gly Ile Glu Val Leu Thr Ile Ala Gly Ser Glu Leu Gly
370 375 380
Thr Gly Arg Gly Gly Pro Arg Cys Met Ser Cys Pro Ala Ala Arg Asp
385 390 395 400
Pro Leu
<210> 32
<211> 417
<212> PRT
<213> Pseudomonas plecoglossicida
<400> 32
Met Ser Thr Glu Lys Gln Lys Tyr Gly Val His Ser Glu Ala Gly Lys
1 5 10 15
Leu Arg Lys Val Met Val Cys Ser Pro Gly Leu Ala His Lys Arg Leu
20 25 30
Thr Pro Ser Asn Cys Asp Glu Leu Leu Phe Asp Asp Val Ile Trp Val
35 40 45
Asp Gln Ala Lys Arg Asp His Phe Asp Phe Val Thr Lys Met Arg Glu
50 55 60
Arg Gly Val Asp Val Leu Glu Met His Asn Leu Leu Thr Asp Ile Val
65 70 75 80
Gln Asp Lys Asn Ala Leu Lys Trp Ile Leu Asp Arg Lys Leu Thr Asp
85 90 95
Asp Thr Val Gly Val Gly Leu Lys Asn Glu Val Arg Ser Trp Leu Glu
100 105 110
Gly Gln Asp Pro Arg His Leu Ala Glu Phe Leu Ile Gly Gly Val Ala
115 120 125
Gly Gln Asp Leu Pro Gln Ser Glu Gly Ala Asp Val Val Lys Met Tyr
130 135 140
Asn Asp Tyr Leu Gly His Ser Ser Phe Ile Leu Pro Pro Leu Pro Asn
145 150 155 160
Thr Gln Phe Thr Arg Asp Thr Thr Cys Trp Ile Tyr Gly Gly Val Thr
165 170 175
Leu Asn Pro Met Tyr Trp Pro Ala Arg Arg Gln Glu Thr Leu Leu Thr
180 185 190
Thr Ala Ile Tyr Lys Phe His Lys Glu Phe Thr Asn Ala Glu Phe Glu
195 200 205
Val Trp Tyr Gly Asp Pro Asp Lys Glu His Gly Ser Ser Thr Leu Glu
210 215 220
Gly Gly Asp Val Met Pro Ile Gly Lys Gly Ile Val Leu Ile Gly Met
225 230 235 240
Gly Glu Arg Thr Ser Arg Gln Ala Ile Gly Gln Leu Ala Arg Asn Leu
245 250 255
Phe Glu Lys Gly Ala Ala Thr Glu Val Ile Val Ala Gly Leu Pro Lys
260 265 270
Ser Arg Ala Ala Met His Leu Asp Thr Val Phe Ser Phe Cys Asp Arg
275 280 285
Asp Leu Val Thr Val Phe Pro Glu Val Val Asn Glu Ile Val Pro Phe
290 295 300
Ile Ile Arg Pro Asp Glu Lys Lys Pro Tyr Gly Met Asp Val Arg Arg
305 310 315 320
Ile Asn Lys Ser Phe Ile Glu Val Val Gly Glu Gln Leu Gly Val Lys
325 330 335
Leu Arg Val Val Glu Thr Gly Gly Asn Ser Phe Ala Ala Glu Arg Glu
340 345 350
Gln Trp Asp Asp Gly Asn Asn Val Val Ala Ile Glu Pro Gly Val Val
355 360 365
Ile Gly Tyr Asp Arg Asn Thr Tyr Thr Asn Thr Leu Leu Arg Lys Ala
370 375 380
Gly Ile Glu Val Ile Thr Ile Ser Ala Gly Glu Leu Gly Arg Gly Arg
385 390 395 400
Gly Gly Gly His Cys Met Thr Cys Pro Ile Val Arg Asp Pro Ile Asp
405 410 415
Tyr
<210> 33
<211> 420
<212> PRT
<213> Pseudomonas putida
<400> 33
Met Ser Ala Glu Lys Gln Lys Tyr Gly Val His Ser Glu Ala Gly Lys
1 5 10 15
Leu Arg Lys Val Met Val Cys Ser Pro Gly Leu Ala His Lys Arg Leu
20 25 30
Thr Pro Ser Asn Cys Asp Glu Leu Leu Phe Asp Asp Val Ile Trp Val
35 40 45
Asp Gln Ala Lys Arg Asp His Phe Asp Phe Val Thr Lys Met Arg Glu
50 55 60
Arg Gly Val Asp Val Leu Glu Met His Asn Leu Leu Thr Asp Ile Val
65 70 75 80
Gln Gln Pro Glu Ala Leu Lys Trp Ile Leu Asp Arg Lys Ile Thr Ser
85 90 95
Asp Thr Val Gly Val Gly Leu Thr Asn Glu Val Arg Ser Trp Leu Glu
100 105 110
Gly Leu Glu Pro Arg His Leu Ala Glu Phe Leu Ile Gly Gly Val Ala
115 120 125
Gly Gln Asp Leu Pro Val Ser Glu Gly Ala Glu Val Ile Lys Met Tyr
130 135 140
Asn Lys Tyr Leu Gly His Ser Ser Phe Ile Leu Pro Pro Leu Pro Asn
145 150 155 160
Thr Gln Phe Thr Arg Asp Thr Thr Cys Trp Ile Tyr Gly Gly Val Thr
165 170 175
Leu Asn Pro Met Tyr Trp Pro Ala Arg Arg Gln Glu Thr Leu Leu Thr
180 185 190
Thr Ala Ile Tyr Lys Phe His Lys Glu Phe Thr Gly Ala Asp Phe Gln
195 200 205
Val Trp Tyr Gly Asp Pro Asp Lys Asp His Gly Asn Ala Thr Leu Glu
210 215 220
Gly Gly Asp Val Met Pro Val Gly Lys Gly Ile Val Leu Ile Gly Met
225 230 235 240
Gly Glu Arg Thr Ser Arg His Ala Ile Gly Gln Leu Ala Gln Asn Leu
245 250 255
Phe Glu Lys Gly Ala Ala Glu Lys Ile Ile Val Ala Gly Leu Pro Lys
260 265 270
Ser Arg Ala Ala Met His Leu Asp Thr Val Phe Ser Phe Cys Asp Arg
275 280 285
Asp Leu Val Thr Val Phe Pro Glu Val Val Lys Glu Ile Lys Pro Phe
290 295 300
Ile Ile Thr Pro Asp Ser Ser Lys Pro Tyr Gly Met Asn Ile Ala Pro
305 310 315 320
Gln Asp Ala Ser Phe Leu Glu Val Val Ser Glu Gln Leu Leu Gly Lys
325 330 335
Lys Asp Lys Leu Arg Val Val Glu Thr Gly Gly Asn Ser Phe Ala Ala
340 345 350
Glu Arg Glu Gln Trp Asp Asp Gly Asn Asn Val Val Ala Leu Glu Pro
355 360 365
Gly Val Val Ile Gly Tyr Asp Arg Asn Thr Tyr Thr Asn Thr Leu Leu
370 375 380
Arg Lys Ala Gly Ile Glu Val Ile Thr Ile Ser Ala Gly Glu Leu Gly
385 390 395 400
Arg Gly Arg Gly Gly Gly His Cys Met Thr Cys Pro Ile Val Arg Asp
405 410 415
Pro Ile Asp Tyr
420
<210> 34
<211> 418
<212> PRT
<213> Pseudomonas aeruginosa
<400> 34
Met Ser Thr Glu Lys Thr Lys Leu Gly Val His Ser Glu Ala Gly Lys
1 5 10 15
Leu Arg Lys Val Met Val Cys Ser Pro Gly Leu Ala His Gln Arg Leu
20 25 30
Thr Pro Ser Asn Cys Asp Glu Leu Leu Phe Asp Asp Val Ile Trp Val
35 40 45
Asn Gln Ala Lys Arg Asp His Phe Asp Phe Val Thr Lys Met Arg Glu
50 55 60
Arg Gly Ile Asp Val Leu Glu Met His Asn Leu Leu Thr Glu Thr Ile
65 70 75 80
Gln Asn Pro Glu Ala Leu Lys Trp Ile Leu Asp Arg Lys Ile Thr Ala
85 90 95
Asp Ser Val Gly Leu Gly Leu Thr Ser Glu Leu Arg Ser Trp Leu Glu
100 105 110
Ser Leu Glu Pro Arg Lys Leu Ala Glu Tyr Leu Ile Gly Gly Val Ala
115 120 125
Ala Asp Asp Leu Pro Ala Ser Glu Gly Ala Asn Ile Leu Lys Met Tyr
130 135 140
Arg Glu Tyr Leu Gly His Ser Ser Phe Leu Leu Pro Pro Leu Pro Asn
145 150 155 160
Thr Gln Phe Thr Arg Asp Thr Thr Cys Trp Ile Tyr Gly Gly Val Thr
165 170 175
Leu Asn Pro Met Tyr Trp Pro Ala Arg Arg Gln Glu Thr Leu Leu Thr
180 185 190
Thr Ala Ile Tyr Lys Phe His Pro Glu Phe Ala Asn Ala Glu Phe Glu
195 200 205
Ile Trp Tyr Gly Asp Pro Asp Lys Asp His Gly Ser Ser Thr Leu Glu
210 215 220
Gly Gly Asp Val Met Pro Ile Gly Asn Gly Val Val Leu Ile Gly Met
225 230 235 240
Gly Glu Arg Ser Ser Arg Gln Ala Ile Gly Gln Val Ala Gln Ser Leu
245 250 255
Phe Ala Lys Gly Ala Ala Glu Arg Val Ile Val Ala Gly Leu Pro Lys
260 265 270
Ser Arg Ala Ala Met His Leu Asp Thr Val Phe Ser Phe Cys Asp Arg
275 280 285
Asp Leu Val Thr Val Phe Pro Glu Val Val Lys Glu Ile Val Pro Phe
290 295 300
Ser Leu Arg Pro Asp Pro Ser Ser Pro Tyr Gly Met Asn Ile Arg Arg
305 310 315 320
Glu Glu Lys Thr Phe Leu Glu Val Val Ala Glu Ser Leu Gly Leu Lys
325 330 335
Lys Leu Arg Val Val Glu Thr Gly Gly Asn Ser Phe Ala Ala Glu Arg
340 345 350
Glu Gln Trp Asp Asp Gly Asn Asn Val Val Cys Leu Glu Pro Gly Val
355 360 365
Val Val Gly Tyr Asp Arg Asn Thr Tyr Thr Asn Thr Leu Leu Arg Lys
370 375 380
Ala Gly Val Glu Val Ile Thr Ile Ser Ala Ser Glu Leu Gly Arg Gly
385 390 395 400
Arg Gly Gly Gly His Cys Met Thr Cys Pro Ile Val Arg Asp Pro Ile
405 410 415
Asp Tyr
<210> 35
<211> 409
<212> PRT
<213> Streptococcus pneumoniae
<400> 35
Met Ser Ser His Pro Ile Gln Val Phe Ser Glu Ile Gly Lys Leu Lys
1 5 10 15
Lys Val Met Leu His Arg Pro Gly Lys Glu Leu Glu Asn Leu Leu Pro
20 25 30
Asp Tyr Leu Glu Arg Leu Leu Phe Asp Asp Ile Pro Phe Leu Glu Asp
35 40 45
Ala Gln Lys Glu His Asp Ala Phe Ala Gln Ala Leu Arg Asp Glu Gly
50 55 60
Ile Glu Val Leu Tyr Leu Glu Gln Leu Ala Ala Glu Ser Leu Thr Ser
65 70 75 80
Pro Glu Ile Arg Asp Gln Phe Ile Glu Glu Tyr Leu Asp Glu Ala Asn
85 90 95
Ile Arg Asp Arg Gln Thr Lys Val Ala Ile Arg Glu Leu Leu His Gly
100 105 110
Ile Lys Asp Asn Gln Glu Leu Val Glu Lys Thr Met Ala Gly Ile Gln
115 120 125
Lys Val Glu Leu Pro Glu Ile Pro Asp Glu Ala Lys Asp Leu Thr Asp
130 135 140
Leu Val Glu Ser Asp Tyr Pro Phe Ala Ile Asp Pro Met Pro Asn Leu
145 150 155 160
Tyr Phe Thr Arg Asp Pro Phe Ala Thr Ile Gly Asn Ala Val Ser Leu
165 170 175
Asn His Met Phe Ala Asp Thr Arg Asn Arg Glu Thr Leu Tyr Gly Lys
180 185 190
Tyr Ile Phe Lys Tyr His Pro Ile Tyr Gly Gly Lys Val Asp Leu Val
195 200 205
Tyr Asn Arg Glu Glu Asp Thr Arg Ile Glu Gly Gly Asp Glu Leu Val
210 215 220
Leu Ser Lys Asp Val Leu Ala Val Gly Ile Ser Gln Arg Thr Asp Ala
225 230 235 240
Ala Ser Ile Glu Lys Leu Leu Val Asn Ile Phe Lys Lys Asn Val Gly
245 250 255
Phe Lys Lys Val Leu Ala Phe Glu Phe Ala Asn Asn Arg Lys Phe Met
260 265 270
His Leu Asp Thr Val Phe Thr Met Val Asp Tyr Asp Lys Phe Thr Ile
275 280 285
His Pro Glu Ile Glu Gly Asp Leu His Val Tyr Ser Val Thr Tyr Glu
290 295 300
Asn Glu Lys Leu Lys Ile Val Glu Glu Lys Gly Asp Leu Ala Glu Leu
305 310 315 320
Leu Ala Gln Asn Leu Gly Val Glu Lys Val His Leu Ile Arg Cys Gly
325 330 335
Gly Gly Asn Ile Val Ala Ala Ala Arg Glu Gln Trp Asn Asp Gly Ser
340 345 350
Asn Thr Leu Thr Ile Ala Pro Gly Val Val Val Val Tyr Asp Arg Asn
355 360 365
Thr Val Thr Asn Lys Ile Leu Glu Glu Tyr Gly Leu Arg Leu Ile Lys
370 375 380
Ile Arg Gly Ser Glu Leu Val Arg Gly Arg Gly Gly Pro Arg Cys Met
385 390 395 400
Ser Met Pro Phe Glu Arg Glu Glu Val
405
<210> 36
<211> 467
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD1: high affinity albumin binding domain
<400> 36
Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu
1 5 10 15
Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile
20 25 30
Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile
35 40 45
Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu
50 55 60
Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Ile Asp Leu Val Ala
65 70 75 80
Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu
85 90 95
Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Val
100 105 110
Val Val Arg Asn Phe Leu Lys Ala Lys Lys Thr Ser Arg Glu Leu Val
115 120 125
Glu Ile Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala
130 135 140
Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg
145 150 155 160
Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg
165 170 175
Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser
180 185 190
Asn His Pro Lys Leu Ile Asn Thr Pro Trp Tyr Tyr Asp Pro Ser Leu
195 200 205
Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr
210 215 220
Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val Thr Leu
225 230 235 240
Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile
245 250 255
Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr
260 265 270
Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala
275 280 285
Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala
290 295 300
Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Gln
305 310 315 320
Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Glu Gly
325 330 335
Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn
340 345 350
Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu
355 360 365
Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe
370 375 380
His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser
385 390 395 400
Met Pro Leu Ser Arg Lys Asp Val Lys Trp Gly Ser His His His His
405 410 415
His His Ala Asn Ser Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu
420 425 430
Leu Asp Lys Tyr Gly Val Ser Asp Phe Tyr Lys Arg Leu Ile Asn Lys
435 440 445
Ala Lys Thr Val Glu Gly Val Glu Ala Leu Lys Leu His Ile Leu Ala
450 455 460
Ala Leu Pro
465
<210> 37
<211> 467
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD: albumin binding domain
<400> 37
Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu
1 5 10 15
Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile
20 25 30
Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile
35 40 45
Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu
50 55 60
Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Ile Asp Leu Val Ala
65 70 75 80
Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu
85 90 95
Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Val
100 105 110
Val Val Arg Asn Phe Leu Lys Ala Lys Lys Thr Ser Arg Glu Leu Val
115 120 125
Glu Ile Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala
130 135 140
Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg
145 150 155 160
Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg
165 170 175
Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser
180 185 190
Asn His Pro Lys Leu Ile Asn Thr Pro Trp Tyr Tyr Asp Pro Ser Leu
195 200 205
Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr
210 215 220
Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val Thr Leu
225 230 235 240
Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile
245 250 255
Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr
260 265 270
Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala
275 280 285
Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala
290 295 300
Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Gln
305 310 315 320
Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Glu Gly
325 330 335
Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn
340 345 350
Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu
355 360 365
Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe
370 375 380
His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser
385 390 395 400
Met Pro Leu Ser Arg Lys Asp Val Lys Trp Ala Gln His Asp Glu Ala
405 410 415
Val Asp Ala Asn Ser Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu
420 425 430
Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr Lys Asn Leu Ile Asn Asn
435 440 445
Ala Lys Thr Val Glu Gly Val Lys Ala Leu Ile Asp Glu Ile Leu Ala
450 455 460
Ala Leu Pro
465
<210> 38
<211> 473
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD: albumin binding domain
<400> 38
Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu
1 5 10 15
Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile
20 25 30
Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile
35 40 45
Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu
50 55 60
Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Ile Asp Leu Val Ala
65 70 75 80
Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu
85 90 95
Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Val
100 105 110
Val Val Arg Asn Phe Leu Lys Ala Lys Lys Thr Ser Arg Glu Leu Val
115 120 125
Glu Ile Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala
130 135 140
Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg
145 150 155 160
Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg
165 170 175
Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser
180 185 190
Asn His Pro Lys Leu Ile Asn Thr Pro Trp Tyr Tyr Asp Pro Ser Leu
195 200 205
Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr
210 215 220
Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val Thr Leu
225 230 235 240
Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile
245 250 255
Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr
260 265 270
Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala
275 280 285
Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala
290 295 300
Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Gln
305 310 315 320
Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Glu Gly
325 330 335
Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn
340 345 350
Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu
355 360 365
Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe
370 375 380
His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser
385 390 395 400
Met Pro Leu Ser Arg Lys Asp Val Lys Trp His His His His His His
405 410 415
Ala Gln His Asp Glu Ala Val Asp Ala Asn Ser Leu Ala Glu Ala Lys
420 425 430
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
435 440 445
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
450 455 460
Ile Asp Glu Ile Leu Ala Ala Leu Pro
465 470
<210> 39
<211> 473
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD:albumin binding domain
<400> 39
Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu
1 5 10 15
Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile
20 25 30
Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile
35 40 45
Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu
50 55 60
Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Ile Asp Leu Val Ala
65 70 75 80
Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu
85 90 95
Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Val
100 105 110
Val Val Arg Asn Phe Leu Lys Ala Lys Lys Thr Ser Arg Glu Leu Val
115 120 125
Glu Ile Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala
130 135 140
Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg
145 150 155 160
Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg
165 170 175
Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser
180 185 190
Asn His Pro Lys Leu Ile Asn Thr Pro Trp Tyr Tyr Asp Pro Ser Leu
195 200 205
Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr
210 215 220
Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val Thr Leu
225 230 235 240
Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile
245 250 255
Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr
260 265 270
Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala
275 280 285
Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala
290 295 300
Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Gln
305 310 315 320
Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Glu Gly
325 330 335
Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn
340 345 350
Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu
355 360 365
Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe
370 375 380
His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser
385 390 395 400
Met Pro Leu Ser Arg Lys Asp Val Lys Trp Ala Gln His Asp Glu Ala
405 410 415
Val Asp Ala Asn Ser Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu
420 425 430
Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr Lys Asn Leu Ile Asn Asn
435 440 445
Ala Lys Thr Val Glu Gly Val Lys Ala Leu Ile Asp Glu Ile Leu Ala
450 455 460
Ala Leu Pro His His His His His His
465 470
<210> 40
<211> 483
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD: albumin binding domain
<400> 40
Met His His His His His His Asp Glu Ala Val Asp Ala Asn Ser Leu
1 5 10 15
Ala Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val
20 25 30
Ser Asp Tyr Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly
35 40 45
Val Lys Ala Leu Ile Asp Glu Ile Leu Ala Ala Leu Pro Ser Gly Ser
50 55 60
Asn Asn Asn Asn Asn Asn Gly Ser Gly Gly Ser Val Phe Asp Ser Lys
65 70 75 80
Phe Lys Gly Ile His Val Tyr Ser Glu Ile Gly Glu Leu Glu Ser Val
85 90 95
Leu Val His Glu Pro Gly Arg Glu Ile Asp Tyr Ile Thr Pro Ala Arg
100 105 110
Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Glu Ser His Asp Ala Arg
115 120 125
Lys Glu His Lys Gln Phe Val Ala Glu Leu Lys Ala Asn Asp Ile Asn
130 135 140
Val Val Glu Leu Ile Asp Leu Val Ala Glu Thr Tyr Asp Leu Ala Ser
145 150 155 160
Gln Glu Ala Lys Asp Lys Leu Ile Glu Glu Phe Leu Glu Asp Ser Glu
165 170 175
Pro Val Leu Ser Glu Glu His Lys Val Val Val Arg Asn Phe Leu Lys
180 185 190
Ala Lys Lys Thr Ser Arg Glu Leu Val Glu Ile Met Met Ala Gly Ile
195 200 205
Thr Lys Tyr Asp Leu Gly Ile Glu Ala Asp His Glu Leu Ile Val Asp
210 215 220
Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Val Gly
225 230 235 240
Asn Gly Val Thr Ile His Tyr Met Arg Tyr Lys Val Arg Gln Arg Glu
245 250 255
Thr Leu Phe Ser Arg Phe Val Phe Ser Asn His Pro Lys Leu Ile Asn
260 265 270
Thr Pro Trp Tyr Tyr Asp Pro Ser Leu Lys Leu Ser Ile Glu Gly Gly
275 280 285
Asp Val Phe Ile Tyr Asn Asn Asp Thr Leu Val Val Gly Val Ser Glu
290 295 300
Arg Thr Asp Leu Gln Thr Val Thr Leu Leu Ala Lys Asn Ile Val Ala
305 310 315 320
Asn Lys Glu Cys Glu Phe Lys Arg Ile Val Ala Ile Asn Val Pro Lys
325 330 335
Trp Thr Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Leu Asp Lys
340 345 350
Asp Lys Phe Leu Tyr Ser Pro Ile Ala Asn Asp Val Phe Lys Phe Trp
355 360 365
Asp Tyr Asp Leu Val Asn Gly Gly Ala Glu Pro Gln Pro Val Glu Asn
370 375 380
Gly Leu Pro Leu Glu Gly Leu Leu Gln Ser Ile Ile Asn Lys Lys Pro
385 390 395 400
Val Leu Ile Pro Ile Ala Gly Glu Gly Ala Ser Gln Met Glu Ile Glu
405 410 415
Arg Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Ala Ile Arg Pro Gly
420 425 430
Val Val Ile Gly Tyr Ser Arg Asn Glu Lys Thr Asn Ala Ala Leu Glu
435 440 445
Ala Ala Gly Ile Lys Val Leu Pro Phe His Gly Asn Gln Leu Ser Leu
450 455 460
Gly Met Gly Asn Ala Arg Cys Met Ser Met Pro Leu Ser Arg Lys Asp
465 470 475 480
Val Lys Trp
<210> 41
<211> 484
<212> PRT
<213> Artificial Sequence
<220>
<223> His-ABD-PolyN-bcADI
<400> 41
Met Gly His His His His His His Asp Glu Ala Val Asp Ala Asn Ser
1 5 10 15
Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly
20 25 30
Val Ser Asp Tyr Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu
35 40 45
Gly Val Lys Ala Leu Ile Asp Glu Ile Leu Ala Ala Leu Pro Ser Gly
50 55 60
Ser Asn Asn Asn Asn Asn Asn Gly Ser Gly Gly Lys His Pro Ile His
65 70 75 80
Val Thr Ser Glu Ile Gly Glu Leu Gln Thr Val Leu Leu Lys Arg Pro
85 90 95
Gly Lys Glu Val Glu Asn Leu Thr Pro Asp Tyr Leu Gln Gln Leu Leu
100 105 110
Phe Asp Asp Ile Pro Tyr Leu Pro Ile Ile Gln Lys Glu His Asp Tyr
115 120 125
Phe Ala Gln Thr Leu Arg Asn Arg Gly Val Glu Val Leu Tyr Leu Glu
130 135 140
Lys Leu Ala Ala Glu Ala Leu Val Asp Lys Lys Leu Arg Glu Glu Phe
145 150 155 160
Val Asp Arg Ile Leu Lys Glu Gly Gln Ala Asp Val Asn Val Ala His
165 170 175
Gln Thr Leu Lys Glu Tyr Leu Leu Ser Phe Ser Asn Glu Glu Leu Ile
180 185 190
Gln Lys Ile Met Gly Gly Val Arg Lys Asn Glu Ile Glu Thr Ser Lys
195 200 205
Lys Thr His Leu Tyr Glu Leu Met Glu Asp His Tyr Pro Phe Tyr Leu
210 215 220
Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Ala Ala Ser Val
225 230 235 240
Gly Asp Gly Leu Thr Ile Asn Lys Met Arg Glu Pro Ala Arg Arg Arg
245 250 255
Glu Ser Leu Phe Met Glu Tyr Ile Ile Lys Tyr His Pro Arg Phe Ala
260 265 270
Lys His Asn Val Pro Ile Trp Leu Asp Arg Asp Tyr Lys Phe Pro Ile
275 280 285
Glu Gly Gly Asp Glu Leu Ile Leu Asn Glu Glu Thr Ile Ala Ile Gly
290 295 300
Val Ser Ala Arg Thr Ser Ala Lys Ala Ile Glu Arg Leu Ala Lys Asn
305 310 315 320
Leu Phe Ser Arg Gln Asn Lys Ile Lys Lys Val Leu Ala Ile Glu Ile
325 330 335
Pro Lys Cys Arg Ala Phe Met His Leu Asp Thr Val Phe Thr Met Val
340 345 350
Asp Tyr Asp Lys Phe Thr Ile His Pro Ala Ile Gln Gly Pro Lys Gly
355 360 365
Asn Met Asn Ile Tyr Ile Leu Glu Lys Gly Ala Asp Glu Glu Thr Leu
370 375 380
Lys Ile Thr His Arg Thr Ser Leu Met Glu Ala Leu Lys Glu Val Leu
385 390 395 400
Asp Leu Ser Glu Leu Val Leu Ile Pro Cys Gly Gly Gly Asp Val Ile
405 410 415
Ala Ser Ala Arg Glu Gln Trp Asn Asp Gly Ser Asn Thr Leu Ala Ile
420 425 430
Ala Pro Gly Val Val Val Thr Tyr Asp Arg Asn Tyr Val Ser Asn Thr
435 440 445
Leu Leu Arg Glu His Gly Ile Glu Val Ile Glu Val Leu Ser Ser Glu
450 455 460
Leu Ser Arg Gly Arg Gly Gly Pro Arg Cys Met Ser Met Pro Ile Val
465 470 475 480
Arg Lys Asp Ile
<210> 42
<211> 335
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD-Intein-CBD
<400> 42
Met Ala Gln His Asp Glu Ala Val Asp Ala Asn Ser Leu Ala Glu Ala
1 5 10 15
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
20 25 30
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
35 40 45
Leu Ile Asp Glu Ile Leu Ala Ala Leu Pro Glu Phe Leu Glu Gly Ser
50 55 60
Ser Cys Ile Thr Gly Asp Ala Leu Val Ala Leu Pro Glu Gly Glu Ser
65 70 75 80
Val Arg Ile Ala Asp Ile Val Pro Gly Ala Arg Pro Asn Ser Asp Asn
85 90 95
Ala Ile Asp Leu Lys Val Leu Asp Arg His Gly Asn Pro Val Leu Ala
100 105 110
Asp Arg Leu Phe His Ser Gly Glu His Pro Val Tyr Thr Val Arg Thr
115 120 125
Val Glu Gly Leu Arg Val Thr Gly Thr Ala Asn His Pro Leu Leu Cys
130 135 140
Leu Val Asp Val Ala Gly Val Pro Thr Leu Leu Trp Lys Leu Ile Asp
145 150 155 160
Glu Ile Lys Pro Gly Asp Tyr Ala Val Ile Gln Arg Ser Ala Phe Ser
165 170 175
Val Asp Cys Ala Gly Phe Ala Arg Gly Lys Pro Glu Phe Ala Pro Thr
180 185 190
Thr Tyr Thr Val Gly Val Pro Gly Leu Val Arg Phe Leu Glu Ala His
195 200 205
His Arg Asp Pro Asp Ala Gln Ala Ile Ala Asp Glu Leu Thr Asp Gly
210 215 220
Arg Phe Tyr Tyr Ala Lys Val Ala Ser Val Thr Asp Ala Gly Val Gln
225 230 235 240
Pro Val Tyr Ser Leu Arg Val Asp Thr Ala Asp His Ala Phe Ile Thr
245 250 255
Asn Gly Phe Val Ser His Ala Thr Gly Leu Thr Gly Leu Asn Ser Gly
260 265 270
Leu Thr Thr Asn Pro Gly Val Ser Ala Trp Gln Val Asn Thr Ala Tyr
275 280 285
Thr Ala Gly Gln Leu Val Thr Tyr Asn Gly Lys Thr Tyr Lys Cys Leu
290 295 300
Gln Pro His Thr Ser Leu Ala Gly Trp Glu Pro Ser Asn Val Pro Ala
305 310 315 320
Leu Trp Gln Leu Gln Gly Asp Pro Ile Thr Ile Thr Ile Thr Lys
325 330 335
<210> 43
<211> 636
<212> PRT
<213> Artificial Sequence
<220>
<223> CBD-Intein-ADI
<400> 43
Met Lys Ile Glu Glu Gly Lys Leu Thr Asn Pro Gly Val Ser Ala Trp
1 5 10 15
Gln Val Asn Thr Ala Tyr Thr Ala Gly Gln Leu Val Thr Tyr Asn Gly
20 25 30
Lys Thr Tyr Lys Cys Leu Gln Pro His Thr Ser Leu Ala Gly Trp Glu
35 40 45
Pro Ser Asn Val Pro Ala Leu Trp Gln Leu Gln Asn Asn Gly Asn Asn
50 55 60
Gly Leu Glu Leu Arg Glu Ser Gly Ala Ile Ser Gly Asp Ser Leu Ile
65 70 75 80
Ser Leu Ala Ser Thr Gly Lys Arg Val Ser Ile Lys Asp Leu Leu Asp
85 90 95
Glu Lys Asp Phe Glu Ile Trp Ala Ile Asn Glu Gln Thr Met Lys Leu
100 105 110
Glu Ser Ala Lys Val Ser Arg Val Phe Cys Thr Gly Lys Lys Leu Val
115 120 125
Tyr Ile Leu Lys Thr Arg Leu Gly Arg Thr Ile Lys Ala Thr Ala Asn
130 135 140
His Arg Phe Leu Thr Ile Asp Gly Trp Lys Arg Leu Asp Glu Leu Ser
145 150 155 160
Leu Lys Glu His Ile Ala Leu Pro Arg Lys Leu Glu Ser Ser Ser Leu
165 170 175
Gln Leu Ser Pro Glu Ile Glu Lys Leu Ser Gln Ser Asp Ile Tyr Trp
180 185 190
Asp Ser Ile Val Ser Ile Thr Glu Thr Gly Val Glu Glu Val Phe Asp
195 200 205
Leu Thr Val Pro Gly Pro His Asn Phe Val Ala Asn Asp Ile Ile Val
210 215 220
His Asn Cys Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr
225 230 235 240
Ser Glu Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg
245 250 255
Glu Ile Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser
260 265 270
Ala Ile Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val
275 280 285
Ala Glu Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Ile Asp Leu
290 295 300
Val Ala Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu
305 310 315 320
Ile Glu Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His
325 330 335
Lys Val Val Val Arg Asn Phe Leu Lys Ala Lys Lys Thr Ser Arg Glu
340 345 350
Leu Val Glu Ile Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile
355 360 365
Glu Ala Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe
370 375 380
Thr Arg Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr
385 390 395 400
Met Arg Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val
405 410 415
Phe Ser Asn His Pro Lys Leu Ile Asn Thr Pro Trp Tyr Tyr Asp Pro
420 425 430
Ser Leu Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn
435 440 445
Asp Thr Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val
450 455 460
Thr Leu Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys
465 470 475 480
Arg Ile Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu
485 490 495
Asp Thr Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro
500 505 510
Ile Ala Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly
515 520 525
Gly Ala Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu
530 535 540
Leu Gln Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly
545 550 555 560
Glu Gly Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly
565 570 575
Thr Asn Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg
580 585 590
Asn Glu Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu
595 600 605
Pro Phe His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys
610 615 620
Met Ser Met Pro Leu Ser Arg Lys Asp Val Lys Trp
625 630 635
<210> 44
<211> 1452
<212> DNA
<213> Artificial Sequence
<220>
<223> His-ABD-PolyN-ADI (DNA)
<400> 44
atgcatcatc accatcacca tgatgaagcc gtggatgcga attccttagc tgaagctaaa 60
gtcttagcta acagagaact tgacaaatat ggagtaagtg actattacaa gaacctaatc 120
aacaatgcca aaactgttga aggtgtaaaa gcactgatag atgaaatttt agctgcatta 180
ccttcgggta gtaacaacaa taataacaat ggtagcggcg gttctgtatt tgacagtaaa 240
tttaaaggaa ttcacgttta ttcagaaatt ggtgaattag aatcagttct agttcacgaa 300
ccaggacgcg aaattgacta tattacacca gctagactag atgaattatt attctcagct 360
atcttagaaa gccacgatgc tagaaaagaa cacaaacaat tcgtagcaga attaaaagca 420
aacgacatca atgttgttga attaattgat ttagttgctg aaacatatga tttagcatca 480
caagaagcta aagacaaatt aatcgaagaa tttttagaag actcagaacc agttctatca 540
gaagaacaca aagtagttgt aagaaacttc ttaaaagcta aaaaaacatc aagagaatta 600
gtagaaatca tgatggcagg gatcacaaaa tacgatttag gtatcgaagc agatcacgaa 660
ttaatcgttg acccaatgcc aaacctatac ttcacacgtg acccatttgc atcagtaggt 720
aatggtgtaa caatccacta catgcgttac aaagttagac aacgtgaaac attattctca 780
agatttgtat tctcaaatca ccctaaacta attaacactc catggtacta cgacccttca 840
ctaaaattat caatcgaagg tggggacgta tttatctaca acaatgacac attagtagtt 900
ggtgtttctg aaagaactga cttacaaaca gttactttat tagctaaaaa cattgttgct 960
aataaagaat gtgaattcaa acgtattgtt gcaattaacg ttccaaaatg gacaaactta 1020
atgcacttag acacatggct aacaatgtta gacaaggaca aattcctata ctcaccaatc 1080
gctaatgacg tatttaaatt ctgggattat gacttagtaa acggtggagc agaaccacaa 1140
ccagttgaaa acggattacc tctagaagga ttattacaat caatcattaa caaaaaacca 1200
gttttaattc ctatcgcagg tgaaggtgct tcacaaatgg aaatcgaaag agaaacacac 1260
ttcgatggta caaactactt agcaattaga ccaggtgttg taattggtta ctcacgtaac 1320
gaaaaaacaa acgctgctct agaagctgca ggcattaaag ttcttccatt ccacggtaac 1380
caattatcat taggtatggg taacgctcgt tgtatgtcaa tgcctttatc acgtaaagat 1440
gttaagtggt aa 1452
<210> 45
<211> 1455
<212> DNA
<213> Artificial Sequence
<220>
<223> His-ABD-PolyN-bcADI (DNA)
<400> 45
atgggtcatc atcaccatca ccatgatgaa gccgtggatg cgaacagctt agctgaagct 60
aaagtcttag ctaacagaga acttgacaaa tatggagtaa gtgactatta caagaaccta 120
atcaacaatg ccaaaactgt tgaaggtgta aaagcactga tagatgaaat tttagctgca 180
ttaccttcgg gtagtaacaa caataataac aatggtagcg gcggtaaaca tccgatacat 240
gttacttcag aaattgggga attacaaacg gttttattaa aacgaccggg taaagaagtg 300
gaaaacttga cgccagatta tttgcagcaa ttattatttg acgatattcc atacctacca 360
attattcaaa aagagcatga ttattttgca caaacgttac gcaatcgggg tgttgaagtt 420
ctttatttag aaaaactagc cgctgaggcg ttagtagata aaaaacttcg agaagaattt 480
gttgatcgta ttttaaaaga aggacaggcc gacgtaaatg ttgcacatca aactttaaaa 540
gaatatttac tttccttttc aaatgaagaa ttaattcaaa aaattatggg cggtgtacgg 600
aaaaacgaaa ttgaaacaag taagaagaca catttatatg aattaatgga agatcattat 660
ccgttttact tagatccaat gcctaattta tattttactc gtgatccagc agctagcgtg 720
ggcgatggct taacgataaa taagatgaga gaaccagcgc gtagacgtga atcattattc 780
atggagtaca tcattaaata tcatccaaga tttgcaaaac ataatgtacc aatctggtta 840
gatcgtgatt ataaatttcc aattgaaggt ggcgacgagc taattttaaa tgaagaaaca 900
attgcgattg gagtatctgc tcgtacttca gctaaagcaa ttgaacgttt agcaaaaaat 960
ctctttagcc gacaaaataa aattaagaaa gtgttagcaa tagaaattcc aaaatgccga 1020
gcatttatgc atttagatac agtatttaca atggttgatt atgataagtt tacaattcac 1080
ccagctattc aagggccaaa agggaatatg aatatttata ttttagaaaa aggagcagat 1140
gaggaaactc ttaaaattac acatcgtact tctttaatgg aagcattaaa agaggtatta 1200
gacttaagtg aattagttct tattccatgt ggaggaggag atgtaattgc ttctgctcgt 1260
gaacaatgga atgatggctc gaacacatta gcaatcgcgc caggtgtagt tgttacatat 1320
gatcgcaact atgtatccaa tacgttatta cgggaacacg gtatagaagt gattgaggtg 1380
ctaagttcag aattatctcg tggtcgtggg ggtccacgtt gcatgagtat gccaattgtt 1440
cgtaaagata tttaa 1455
<210> 46
<211> 46
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD without Linker
<400> 46
Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly
1 5 10 15
Val Ser Asp Tyr Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu
20 25 30
Gly Val Lys Ala Leu Ile Asp Glu Ile Leu Ala Ala Leu Pro
35 40 45
<210> 47
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD with Linker
<400> 47
Ala Gln His Asp Glu Ala Val Asp Ala Asn Ser Leu Ala Glu Ala Lys
1 5 10 15
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
20 25 30
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
35 40 45
Ile Asp Glu Ile Leu Ala Ala Leu Pro
50 55
<210> 48
<211> 46
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD1 without Linker
<400> 48
Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly
1 5 10 15
Val Ser Asp Phe Tyr Lys Arg Leu Ile Asn Lys Ala Lys Thr Val Glu
20 25 30
Gly Val Glu Ala Leu Lys Leu His Ile Leu Ala Ala Leu Pro
35 40 45
<210> 49
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<223> ABD1 with Linker
<400> 49
Gly Ser His His His His His His Ala Asn Ser Leu Ala Glu Ala Lys
1 5 10 15
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Phe Tyr
20 25 30
Lys Arg Leu Ile Asn Lys Ala Lys Thr Val Glu Gly Val Glu Ala Leu
35 40 45
Lys Leu His Ile Leu Ala Ala Leu Pro
50 55
<210> 50
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker 1
<400> 50
Gly Ser His His His His His His Ala Asn Ser
1 5 10
<210> 51
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker 2
<400> 51
Ala Gln His Asp Glu Ala Val Asp Ala Asn Ser
1 5 10
<210> 52
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker 3
<400> 52
Asp Glu Ala Val Asp Ala Asn Ser
1 5
<210> 53
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker 5
<400> 53
Gly Ser Gly Gly
1
Claims (30)
- 알부민-결합 아르기닌 데이미나제 융합 단백질이 아르기닌 데이미나제의 활성을 보유하고 또한 혈청 알부민에 결합 가능하도록 알부민-결합 아르기닌 데이미나제 융합 단백질을 형성하기 위해 아르기닌 데이미나제를 포함하는 제2 부위에 융합되는 알부민-결합 도메인, 알부민-결합 펩타이드 또는 알부민-결합 단백질(들)로부터 선택된 1개 또는 2개의 성분을 포함하는 제1 부위를 포함하고, 상기 알부민-결합 아르기닌 데이미나제 융합 단백질은 서열번호 40을 포함하는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 1에 있어서, 상기 제1 부위의 2개의 성분이 동일한, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 1에 있어서, 상기 제1 부위의 2개의 성분이 상이한, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 1에 있어서, 상기 알부민-결합 아르기닌 데이미나제 융합 단백질은 하나 이상의 링커 분자(linker molecule)(들)를 추가로 포함하는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 4에 있어서, 상기 링커 분자가 서열 번호 50, 51, 52, 53, 또는 세린-글리신-세린(SGS) 아미노산 서열로부터 선택된 서열을 포함하는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 1에 있어서, 적어도 하나의 폴리-N 또는 His tag를 더 포함하는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 1에 있어서, 아르기닌 데이미나제가 마이코플라스마(Mycoplasma), 락토코쿠스(Lactococcus), 슈도모나스(Pseudomonas), 스트렙토코쿠스(Steptococcus), 에스케리키아(Escherichia), 마이코박테리움(Mycobacterium) 또는 바실러스(Bacillus) 미생물로부터 생산된 아르기닌 데이미나제로부터 선택되는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 7에 있어서, 상기 아르기닌 데이미나제가 마이코플라스마 아르기니니(Mycoplasma arginini), 락토코쿠스 락티스(Lactococcus lactis), 바실러스 리케니포르미스(Bacillus licheniformis), 바실러스 세레우스(Bacillus cereus), 마이코플라스마 아르트리티디스(Mycoplasma arthritidis), 마이코플라스마 호미니스(Mycoplasma hominis), 스트렙토코쿠스 피오게네스(Streptococcus pyogenes), 스트렙토코쿠스 뉴모니아(Streptococcus pneumonia), 마이코박테리움 투베르쿨로시스(Mycobacterium tuberculosis), 슈도모나스 플레코글로씨키다(Pseudomonas plecoglossicida), 슈도모나스 푸티다(Pseudomonas putida), 슈도모나스 아에루기노사(Pseudomonas putida) 또는 이의 조합으로부터 생산되는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 삭제
- 청구항 1에 있어서, 상기 융합 단백질이 N-말단 시스테인 잔기를 지닌 아르기닌 데이미나제를 알부민-결합 도메인의 C-말단에서 반응성 티오에스테르와 반응시킴으로써 아르기닌 데이미나제 및 알부민-결합 도메인이 공유 결합에 의해 연결되도록 하여 형성되는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 1에 있어서, 상기 융합 단백질이 N-말단 시스테인 잔기를 지닌 알부민-결합 도메인을 아르기닌 데이미나제의 C-말단에서 반응성 티오에스테르와 반응시킴으로써 아르기닌 데이미나제 및 알부민-결합 도메인이 공유 결합에 의해 연결되도록 하여 형성되는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 1에 있어서, 상기 융합 단백질이 서열 번호 42 및 서열 번호 43을 사용하고 N-말단 시스테인 잔기를 지닌 상기 아르기닌 데이미나제를 알부민-결합 도메인의 C-말단에서 반응성 티오에스테르와 반응시킴으로써 상기 아르기닌 데이미나제 및 상기 알부민-결합 도메인이 공유 결합에 의해 연결되도록 하여 형성되는, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 환자에게 임상적 유효량의 융합 단백질을 투여하여 아르기닌의 고갈을 촉진시키는 것을 포함하는, 환자의 암을 치료하기 위한 의약의 제조시 사용되는 청구항 1 내지 청구항 8, 청구항 10 내지 청구항 12 중의 어느 한 항에 따른 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 청구항 13에 있어서, 상기 암이 췌장암, 백혈병, 두경부암, 결장직장암, 폐암, 유방암, 간암, 비인강암, 식도암, 전립샘 암, 위암 또는 뇌암인, 알부민-결합 아르기닌 데이미나제 융합 단백질.
- 알부민-결합 아르기닌 데이미나제 융합 단백질을 암호화하는 융합 유전자를 작제하는 단계, 상기 융합 유전자를 벡터내로 삽입하는 단계, 상기 벡터를 숙주 유기체내로 삽입하는 단계 및 청구항 1의 알부민-결합 아르기닌 데이미나제 융합 단백질을 포함하는 단백질을 발현시키는 단계를 포함하는, 청구항 1의 알부민-결합 아르기닌 데이미나제 융합 단백질의 제조 방법.
- 청구항 15에 있어서, 상기 융합 단백질을 정제하는 단계를 추가로 포함하는, 알부민-결합 아르기닌 데이미나제 융합 단백질의 제조 방법.
- 청구항 16에 있어서, 상기 정제 단계가 크로마토그래피에 의해 수행되는, 알부민-결합 아르기닌 데이미나제 융합 단백질의 제조 방법.
- 청구항 16에 있어서, 상기 정제 단계가 조 단백질의 가용성 분획으로부터 수행되는, 알부민-결합 아르기닌 데이미나제 융합 단백질의 제조 방법.
- 청구항 16에 있어서, 상기 정제 단계가 조 단백질의 불용성 분획으로부터 수행되는, 알부민-결합 아르기닌 데이미나제 융합 단백질의 제조 방법.
- 알부민-결합 도메인, 알부민-결합 펩타이드 또는 알부민-결합 단백질(들)과, 아르기닌 데이미나제를 포함하는 제2 부위 사이의 인테인 매개된 단백질 연결에 의한, 청구항 1의 알부민-결합 아르기닌 데이미나제 융합 단백질의 제조 방법.
- 약제학적으로 허용되는 담체 속에 청구항 1의 알부민-결합 아르기닌 데이미나제 융합 단백질을 포함하는 암을 치료하기 위한 약제학적 조성물.
- 청구항 21에 있어서, pH가 5.5 내지 9.5의 범위인, 암을 치료하기 위한 약제학적 조성물.
- 청구항 21에 있어서, pH가 7.4인, 암을 치료하기 위한 약제학적 조성물.
- 청구항 21에 있어서, pH가 6.5인, 암을 치료하기 위한 약제학적 조성물.
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
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