KR20180069064A - 세포내 항원들에 대해 지시된 단일 도메인 항체 - Google Patents
세포내 항원들에 대해 지시된 단일 도메인 항체 Download PDFInfo
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- KR20180069064A KR20180069064A KR1020187015132A KR20187015132A KR20180069064A KR 20180069064 A KR20180069064 A KR 20180069064A KR 1020187015132 A KR1020187015132 A KR 1020187015132A KR 20187015132 A KR20187015132 A KR 20187015132A KR 20180069064 A KR20180069064 A KR 20180069064A
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Abstract
본 발명은 외인성 표적화 서열 또는 화학적 조성물을 사용하지 않고 병태 또는 질병을 치료하는 조성물 및 방법들을 제공한다. 본 발명은 병태 또는 질병을 유발하는 표적에 대해 지시되는 단일-도메인 항체 (sdAbs), 이러한 sdAbs를 포함하는 단백질 및 폴리펩티드에 관한 것이다. 본 발명은 또한 이러한 sdAbs, 단백질 및 폴리펩티드를 인코딩하는 핵산, 그리고 sdAbs를 포함하는 조성물을 포함한다. 본 발명은 예방, 치료 또는 진단을 목적으로 하는 이러한 조성물, sdAbs, 및 이러한 sdAbs를 인코딩하는 핵산의 용도를 포함한다.
Description
관련 출원들에 대한 상호 참조
본 출원은 2015년 11월 2일 출원된 미국 가특허 출원 제 62/249,868호에 대한 우선권을 주장하며, 이의 내용은 본 출원에 온전히 참고문헌으로 포함된다.
서열 목록
본 출원은 서류 사본 대신 텍스트 형식의 서열 목록과 함께 출원된다. 서열 목록은 2016년 10월 27일에 생성된, 58 킬로바이트 크기의 “sequence listing.txt”제목의 파일로 제공된다. 전자 형식의 서열 목록에 있는 정보는 본 출원에 온전히 참고문헌으로 포함된다.
배경
보다 대형의 단백질 또는 폴리펩티드에서 단일 항원-결합 단백질로서 또는 항원-결합 도메인으로서의 단일-도메인 항체 (sdAbs)의 사용은 종래의 항체 또는 항체 단편들을 사용하는 것 이상의 수많은 현저한 이점들을 제공한다. sdAbs의 이점들에는 다음이 포함된다: 고 친화성과 고 선택성으로 항원을 결합시킴에 하나의 단일 도메인만이 필요하며; sdAbs는 단일 유전자로부터 발현될 수 있으며 번역-후 변형이 필요없고; sdAbs는 열, pH, 및 프로테아제를 비롯한 변성 조건 및 변성 제제들에 매우 안정하고; sdAbs는 값싸게 제조되고; 그리고 sdAbs는 종래의 항체는 접근할 수 없는 표적 및 에피토프들에 접근할 수 있다.
비정상적인 세포내 또는 막횡단 성분들, 가령, 뉴클레오티드 및 단백질에 의해 유발되는 수많은 질병 또는 병태들, 가령, 바이러스 감염 또는 암이 존재한다. 이러한 질병 또는 병태를 예방 또는 치료하기 위하여 비정상적인 성분들의 제거가 사용될 수 있다. 이러한 질병의 치료에 이용가능한 수많은 약리학적 화합물들이 존재하지만, 이들 화합물들은 비효과적이거나, 전달될 수 없거나 질병에 걸리지 않은 세포들에 대해 독성일 수 있다.
다른 치료들에는 외인성 표적화 서열을 내포하는 치료 단백질 또는 제제들의 사용이 포함되며, 이러한 치료제는 세포막에서 수용체에 의해 인식되므로, 세포막을 경유하여 세포에 진입할 수 있게 된다. 일단 치료제가 세포 내부에 존재하게 되면, 치료제는 질병을 치료하기 위하여 표적 성분과 상호작용 할 수 있다. 그러나, 외인성 표적화 서열의 사용은 이러한 치료제에 의해 표적되는 세포 유형을 제한하여, 치료제의 제조 비용을 높일 수 있다.
전술한 이유로, 세포에 진입하기 위하여 외인성 표적화 서열들 또는 화학적 조성물들에 의존하지 않고 신체 내 질병에 걸린 세포들만을 표적화함에 효과적인, 질병 치료 또는 예방용 조성물 및 방법들에 대한 필요성이 존재한다.
본 발명은 단일-도메인 항체 (sdAbs), 단백질 및 sdAbs를 포함하는 폴리펩티드에 관한 것이다. 이들 sdAbs는 병태 또는 질병을 유발하는 표적들에 대해 지시된다. 본 발명은 또한 이러한 sdAbs, 단백질 및 폴리펩티드를 인코딩하는 핵산, 그리고 sdAbs를 포함하는 조성물을 포함한다. 본 발명은 예방, 치료 또는 진단을 목적으로 하는, 이러한 조성물, sdAbs, 단백질 또는 폴리펩티드의 용도를 포함한다. 본 발명은 또한 본 발명의 sdAbs에 대해 지시되는 단클론 항체의 용도를 포함한다.
요약
본 발명은 병태 또는 질병을 치료 또는 예방하기 위해 사용되는 sdAbs에 관련된다. 한 구체예는 항-제1형 인간 면역결핍 바이러스 (HIV-1) 역전사효소 단일 도메인 항체 (sdAb)에 관련된다. 한 양상에서, 항-HIV-1 역전사효소 sdAb는 서열 번호:27에 제시된 아미노산 서열을 포함한다. 본 발명은 또한 필요로 하는 대상체에게 유효량의 항-HIV-1 역전사효소 sdAb를 투여함에 의한, 대상체에서 항-HIV-1 역전사효소 sdAb를 사용한 질병의 치료, 질병 발달의 예방, 또는 질병 재발의 예방 방법을 포함한다. 대상체는 포유동물, 가령, 인간일 수 있다. 항-HIV-1 역전사효소 sdAb는 하나 또는 그 이상의 화합물들, 가령, 예를 들면, 프로테아제 억제제와 조합하여 투여될 수 있다. 필요로 하는 대상체에 대한 유효량의 항-HIV-1 역전사효소 sdAb의 투여는 정맥내 투여, 근육내 투여, 경구 투여, 직장 투여, 장관 투여, 비장관 투여, 안구내 투여, 피하 투여, 경피 투여에 의하거나, 점안액으로 투여되거나, 코 스프레이로 투여되거나, 흡입 또는 분무에 의해 투여되거나, 국소 투여되거나, 삽입가능한 (implantable) 약물로서 투여될 수 있다.
또다른 구체예에서, 본 발명은 서열 번호:27에 제시된 아미노산 서열을 가지는 단리된 폴리펩티드에 관련된다. 또다른 구체예에서, 본 발명은 서열 번호:27의 폴리펩티드에 대해 지시되는 항체를 포함한다.
본 발명은 다음 단계들을 포함하는, 대상체의 샘플에서 항-HIV-1 역전사효소 sdAb의 수준을 측정하는 방법을 포함하는 것을 또한 고려한다: a) 서열 번호:27에 제시된 아미노산 서열을 포함하는 폴리펩티드의 하나 또는 그 이상의 도메인들에 대하여 지시되는 마우스 단클론 항체를 생성하는 단계; b) 대상체로부터 샘플을 얻는 단계; c) 대상체에서 sdAb의 양을 결정하기 위하여 마우스 단클론 항체 및 샘플을 이용하여 정량 면역분석을 수행하고; 그리하여 대상체에서 sdAb의 양을 측정하는 단계. 한 양상에서, 정량적 면역분석은 효소-결합 면역흡착 검사 (ELISA), 특이적 피분석물 표지 및 재포획 검사 (specific analyte labeling and recapture assay, SALRA), 액체 크로마토그래피, 질량 분광법, 형광-활성 세포 분류법, 또는 이의 조합을 포함한다.
본 발명의 또다른 구체예는 항-에볼라 VP24 sdAb에 관련된다. 한 양상에서, 항-에볼라 VP 24 sdAb는 서열 번호:55에 제시된 아미노산 서열을 포함한다. 본 발명은 또한 필요로 하는 대상체에게 유효량의 항-에볼라 VP24 sdAb를 투여함에 의한, 대상체에서 항-에볼라 VP24 sdAb를 사용한 질병의 치료, 질병 발달의 예방, 또는 질병 재발의 예방 방법을 포함한다. 대상체는 포유동물, 가령, 인간일 수 있다. 항-에볼라 VP24 sdAb는 하나 또는 그 이상의 화합물들, 가령, 예를 들면, 프로테아제 억제제와 조합하여 투여될 수 있다. 필요로 하는 대상체에 대한 유효량의 항-에볼라 VP24 sdAb의 투여는 정맥내 투여, 근육내 투여, 경구 투여, 직장 투여, 장관 투여, 비장관 투여, 안구내 투여, 피하 투여, 경피 투여에 의하거나, 점안액으로 투여되거나, 코 스프레이로 투여되거나, 흡입 또는 분무에 의해 투여되거나, 국소 투여되거나, 삽입가능한 약물로서 투여될 수 있다.
또다른 구체예에서, 본 발명은 서열 번호:55에 제시된 아미노산 서열을 가지는 단리된 폴리펩티드에 관련된다. 또다른 구체예에서, 본 발명은 서열 번호:55의 폴리펩티드에 대해 지시되는 항체를 포함한다.
본 발명은 다음 단계들을 포함하는, 대상체의 샘플에서 항-에볼라 VP24 sdAb의 수준을 측정하는 방법을 포함하는 것을 또한 고려한다: a) 서열 번호:55에 제시된 아미노산 서열을 포함하는 폴리펩티드의 하나 또는 그 이상의 도메인들에 대하여 지시되는 마우스 단클론 항체를 생성하는 단계; b) 대상체로부터 샘플을 얻는 단계; c) 대상체에서 sdAb의 양을 결정하기 위하여 마우스 단클론 항체 및 샘플을 이용하여 정량 면역분석을 수행하고; 그리하여 대상체에서 sdAb의 양을 측정하는 단계. 한 양상에서, 정량적 면역분석은 ELISA, SALRA, 액체 크로마토그래피, 질량 분광법, 형광-활성 세포 분류법, 또는 이의 조합을 포함한다.
또한 본 발명의 또다른 구체예는 항-아라키도네이트 12-리폭시게나아제 (ALOX12) sdAb에 관한 것이다. 한 양상에서, 항-ALOX12 sdAb는 서열 번호:49, 서열 번호:50, 서열 번호:51, 또는 서열 번호:52에 제시된 아미노산 서열을 포함한다. 본 발명은 또한 필요로 하는 대상체에게 유효량의 항-ALOX12 sdAb를 투여함에 의한, 대상체에서 항-ALOX12 sdAb를 사용한 질병의 치료, 질병 발달의 예방, 또는 질병 재발의 예방 방법을 포함한다. 대상체는 포유동물, 가령, 인간일 수 있다. 항-ALOX12 sdAb는 하나 또는 그 이상의 화합물들과 조합하여 투여될 수 있다. 필요로 하는 대상체에 대한 유효량의 항-ALOX12 sdAb의 투여는 정맥내 투여, 근육내 투여, 경구 투여, 직장 투여, 장관 투여, 비장관 투여, 안구내 투여, 피하 투여, 경피 투여에 의하거나, 점안액으로 투여되거나, 코 스프레이로 투여되거나, 흡입 또는 분무에 의해 투여되거나, 국소 투여되거나, 삽입가능한 약물로서 투여될 수 있다.
또다른 구체예에서, 본 발명은 서열 번호:49, 서열 번호:50, 서열 번호:51, 또는 서열 번호:52에 제시된 아미노산 서열을 가지는 단리된 폴리펩티드에 관련된다. 또다른 구체예에서, 본 발명은 서열 번호:49, 서열 번호:50, 서열 번호:51, 또는 서열 번호:52의 폴리펩티드에 대해 지시되는 항체를 포함한다.
본 발명은 다음 단계들을 포함하는, 대상체의 샘플에서 항-HIV-1 역전사효소 sdAb의 수준을 측정하는 방법을 포함하는 것을 또한 고려한다: a) 서열 번호:27에 제시된 아미노산 서열을 포함하는 폴리펩티드의 하나 또는 그 이상의 도메인들에 대하여 지시되는 마우스 단클론 항체를 생성하는 단계; b) 대상체로부터 샘플을 얻는 단계; c) 대상체에서 sdAb의 양을 결정하기 위하여 마우스 단클론 항체 및 샘플을 이용하여 정량 면역분석을 수행하고; 그리하여 대상체에서 sdAb의 양을 측정하는 단계. 한 양상에서, 정량적 면역분석은 ELISA, SALRA, 액체 크로마토그래피, 질량 분광법, 형광-활성 세포 분류법, 또는 이의 조합을 포함한다.
도면
본 발명의 이러한 그리고 다른 특징들, 양상들 그리고 이점들은 하기 상세한 설명, 첨부된 청구범위, 그리고 첨부된 다음과 같은 도면들과 관련하여 보다 잘 이해될 것이다:
도 1 및 2는 HIV1-9 항-HIV-1 RT sdAb (서열 번호:27)을 사용한 ELISA 결과를 도시한다;
도 3 및 4는 HIV1-9 항-HIV-1 RT sdAb (서열 번호:27)의 연속 희석물을 사용한 ELISA 결과를 도시한다;
도 5 내지 8은 VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)를 사용한 ELISA 결과를 도시한다; 그리고
도 9 및 10은 VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)의 연속 희석물을 사용한 ELISA 결과를 보여준다.
본 발명의 이러한 그리고 다른 특징들, 양상들 그리고 이점들은 하기 상세한 설명, 첨부된 청구범위, 그리고 첨부된 다음과 같은 도면들과 관련하여 보다 잘 이해될 것이다:
도 1 및 2는 HIV1-9 항-HIV-1 RT sdAb (서열 번호:27)을 사용한 ELISA 결과를 도시한다;
도 3 및 4는 HIV1-9 항-HIV-1 RT sdAb (서열 번호:27)의 연속 희석물을 사용한 ELISA 결과를 도시한다;
도 5 내지 8은 VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)를 사용한 ELISA 결과를 도시한다; 그리고
도 9 및 10은 VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)의 연속 희석물을 사용한 ELISA 결과를 보여준다.
설명
본 명세서에서 사용되는 하기 용어 및 이의 변화형들은 이러한 용어가 사용되는 내용이 명확하게 상이한 의미를 의도하는 것이 아닌 한 하기 제공되는 의미를 가진다.
본 출원에서 사용되는 용어 “하나 (a, an)”그리고 “그것 (the)" 그리고 유사한 지칭어들은 해당 내용에서 이들의 용도가 다른 것을 의미하는 것이 아닌 한 단수 및 복수 모두를 포괄하는 것으로 해석되어야 한다.
용어 “항원 결정인자”는 항원-결합 분자에 의해 그리고 더욱 특히 항원-결합 분자의 항원-결합 부위에 의해 인식되는 항원 상의 에피토프 (가령, 본 발명의 sdAb 또는 폴리펩티드)를 지칭한다. 용어 “항원 결정인자” 및 “에피토프”는 또한 호환적으로 사용될 수 있다. 특이적 항원 결정인자, 에피토프, 항원 또는 단백질에 결합할 수 있는, 이들에 대한 친화성을 가지는 및/또는 특이성을 가지는 아미노산 서열은 항원 결정인자, 에피토프, 항원 또는 단백질에 '대항하는' 것 또는 '대해 지시되는 것'이라 말한다.
본 출원에서 사용되는 용어 “포함하다” 및 이 용어의 변화형, 가령, "포함하는" 및 "포함하며"는 다른 첨가제들, 성분들, 정수들 또는 단계들을 제외시키고자 하는 것이 아니다.
본 출원에 기재된 sdAbs, 폴리펩티드 및 단백질은 소위 “보존적” 아미노산 치환을 내포할 수 있음이 고려되며, 이 치환은 일반적으로 하나의 아미노산 잔기가 유사한 화학적 구조의 또다른 아미노산 잔기로 치환되는 아미노산 치환으로서 기술될 수 있으며 폴리펩티드의 기능, 활성 또는 다른 생물학적 특성에 거의 또는 본질적으로 전혀 영향을 미치지 않는다. 보존적 아미노산 치환은 해당 기술 분야에 널리 공지이다. 보존적 치환은 다음 그룹들 (a)-(e)에 속하는 하나의 아미노산이 동일한 그룹에 속하는 또다른 아미노산으로 치환되는 치환이다: (a) 소형 지방족, 비극성 또는 약간의 극성 잔기들: Ala, Ser, Thr, Pro 및 Gly; (b) 극성, 음으로 하전된 잔기 및 이의 (하전되지 않은) 아미드: Asp, Asn, Glu 및 Gln; (c) 극성, 양으로 하전된 잔기: His, Arg 및 Lys; (d) 대형 지방족, 비극성 잔기: Met, Leu, Ile, Val 및 Cys; 그리고 (e) 방향족 잔기: Phe, Tyr 및 Trp. 다른 보존적 치환은 다음이 포함된다: Ala이 Gly으로 또는 Ser으로; Arg이 Lys으로; Asn이 Gln으로 또는 His으로; Asp이 Glu으로; Cys이 Ser으로; Gln이 Asn으로; Glu이 Asp으로; Gly이 Ala으로 또는 Pro으로; His이 Asn으로 또는 Gln으로; Ile이 Leu으로 또는 Val으로; Leu이 Ile으로 또는 Val으로; Lys이 Arg으로, Gln으로 또는 Glu으로; Met이 Leu으로, Tyr으로 또는 Ile으로; Phe이 Met으로, Leu으로 또는 Tyr으로; Ser이 Thr으로; Thr이 Ser으로; Trp이 Tyr으로; Tyr이 Trp으로; 및/또는 Phe이 Val으로, Ile으로 또는 Leu으로.
본 출원에서 사용되는 “도메인”은 일반적으로 하나의 항체 사슬의 구형 영역, 그리고 특히, 중쇄 항체의 구형 영역, 또는 본질적으로 이러한 구형 영역을 구성하는 폴리펩티드를 지칭한다.
sdAb의 아미노산 서열 및 구조는 전형적으로 4개의 프레임워크 영역들 또는 “FRs”로 이루어지는데, 이들은 각각 “프레임워크 영역 1”또는 “FR1”로서; “프레임워크 영역 2”또는 “FR2”로서; “프레임워크 영역 3”또는 “FR3”으로서; 그리고 “프레임워크 영역 4”또는 “FR4”로서 지칭된다. 프레임워크 영역들은 3개의 상보성 결정 영역 또는 “CDRs”에 의해 불연속되는데, 이들은 각각 “상보성 결정 영역 1”또는 “CDR1”로서; “상보성 결정 영역 2”또는 “CDR2”로서; 그리고 “상보성 결정 영역 3”또는 “CDR3”으로서 지칭된다.
본 출원에서 사용되는 용어 “인간화 sdAb”는 자연 발생 VHH 서열의 아미노산 서열 내 하나 또는 그 이상의 아미노산 잔기들이 인간으로부터 얻은 종래의 4-사슬 항체의 VH 도메인에 해당하는 위치에서 발견되는 하나 또는 그 이상의 아미노산 잔기들로 치환되어 있는 sdAb를 의미한다. 이는 해당 기술 분야에 널리 공지된 방법에 의해 수행될 수 있다. 예를 들면, sdAbs의 FRs는 인간 가변 FRs로 치환될 수 있다.
본 출원에서 사용되는, “단리된” 핵산 또는 아미노산은 이것이 일반적으로 결합되어 있는 최소한 하나의 다른 성분, 가령, 그 원료 또는 배지, 또다른 핵산, 또다른 단백질/폴리펩티드, 또 다른 생물학적 성분 또는 거대분자 또는 오염물질, 불순물 또는 미량의 성분으로부터 분리되었다.
용어 “포유동물”은 포유류에 속하는 개체로 정의되며, 제한없이, 인간, 가축 및 농장 동물들, 및 동물원, 경기, 및 애완 동물들, 가령, 소, 말, 양, 개 및 고양이가 포함된다.
본 출원에서 사용되는, “약학적으로 허용가능한 담체”는 약학적 투여와 양립가능한 임의의 그리고 모든 용매들, 분산 매질, 코팅, 항균 및 항진균 제제들, 등장성 및 흡수 지연 제제들 등을 포함하는 것으로 한다. 적합한 담체들이 해당 분야에서 표준 참고 문헌인 Remington's Pharmaceutical Sciences의 최신판에 기재되어 있다. 이러한 담체들 또는 희석제들의 바람직한 예들에는, 물, 식염수, 링거 용액, 덱스트로스 용액, PBS (인산염-완충 식염수), 및 5% 인간 혈청 알부민이 포함되나, 이에 제한되는 것은 아니다. 리포좀, 양이온성 지질 및 비-수성 비히클, 가령, 고정유가 또한 사용될 수 있다. 약학적 활성 물질을 위한 이러한 매질 및 제제들의 사용은 해당 기술 분야에 널리 공지이다. 임의의 종래의 매질 또는 제제가 상기 정의된 치료제와 양립불가능한 한 이를 제외하고, 본 발명의 조성물에서 이의 사용이 고려된다.
“정량적 면역분석”은 항체를 사용하여 샘플에 존재하는 항원의 양윽 측정하는 임의의 수단들을 지칭한다. 정량적 면역분석을 수행하는 방법은 효소-결합 면역흡착 검사 (ELISA), 특이적 피분석물 표지 및 재포획 검사 (SALRA), 액체 크로마토그래피, 질량 분광법, 형광-활성 세포 분류법, 등을 포함하나 이에 제한되는 것은 아니다.
용어 “용액”은 용매 및 용질을 포함하는 조성물을 지칭하며, 진 용액 및 현탁액을 포함한다. 용액의 예들에는 액체에 용해된 고체, 액체 또는 기체 그리고 액체에 현탁된 미립자 또는 마이셀이 포함된다.
용어 “특이성”은 특정 항원-결합 분자 또는 항원-결합 단백질 분자가 결합할 수 있는 상이한 유형들의 항원 또는 항원 결정인자들의 수를 지칭한다. 항원-결합 단백질의 특이성은 친화성 및/또는 결합력(avidity)에 기초하여 결정될 수 있다. 항원-결합 단백질과 항원의 해리에 대한 평형 상수(KD)로 나타내어지는 친화성은, 항원-결합 단백질 상의 항원-결합 부위와 항원 결정인자 간 결합 강도에 관한 측정치이며: KD 값이 작을 수록, 항원 결정인자와 항원-결합 분자 간의 결합 강도는 강해진다(택일적으로, 친화성은 또한 1/KD인 친화성 상수 (KA)로 표현될 수도 있다). 해당 기술 분야의 숙련된 기술자에게 자명하게 되는 바와 같이, 친화성은 특정 관심 항원에 따라 결정될 수 있다. 결합력은 항원-결합 분자와 항원 간 결합 강도의 측정치이다. 결합력은 항원-결합 분자 상의 항원 결합 부위와 항원 결정인자 간 친화성 그리고 항원-결합 분자 상에 존재하는 관련 결합 부위들의 수 모두에 관계된다. 항원-결합 단백질의 항원 또는 항원 결정인자에 대한 특이적 결합은 임의의 공지된 방식, 가령, 예를 들면, Scatchard 분석 및/또는 경쟁적 결합 분석, 가령, 방사면역측정법 (RIA), 효소 면역분석법 (EIA) 및 샌드위치 경쟁 분석법에 의해 결정될 수 있다.
본 출원에서 사용되는 용어 “재조합”은 본 발명의 sdAbs를 제조하기 위하여 사용되는 유전 공학 방법들 (예를 들면, 클로닝, 및 증폭)의 사용을 지칭한다.
“단일 도메인 항체,” “sdAb” 또는 “VHH”는 일반적으로 3개의 상보성 결정 영역에 의해 불연속되는 4개의 프레임워크 영역들로 구성된 아미노산 서열을 포함하는 폴리펩티드 또는 단백질로 정의될 수 있다. 이는 FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4로 나타내어진다. 본 발명의 sdAb는 또한 sdAb 아미노산 서열을 포함하는 폴리펩티드 또는 단백질을 포함한다. 전형적으로, sdAbs는 낙타과, 가령, 라마에서 생성되지만, 해당 기술 분야에 널리 공지된 기법들을 사용하여 합성적으로 생성될 수도 있다. 본 출원에서 사용되는 바와 같이, 천연 중쇄 항체에 존재하는 가변 도메인들은“VH 도메인”으로 지칭되는 종래의 4-사슬 항체에 존재하는 중쇄 가변 도메인과 그리고 “도메인”으로 지칭되는 종래의 4-사슬 항체에 존재하는 경쇄 사슬 가변 도메인과 구별하기 위하여 “도메인”으로도 지칭될 것이다. “VHH”및 “sdAb”는 본 출원에서 호환적으로 사용된다. sdAb 또는 폴리펩티드의 아미노산 잔기들의 넘버링은 Kabat 등에 의해 제공되는 VH 도메인들에 대한 일반적인 넘버링에 따른다. ("Sequence of proteins of immunological interest,”US Public Health Services, NIH Bethesda, MD, Publication No. 91). 이 넘버링에 따르면, sdAb의 FR1은 위치 1-30의 아미노산 잔기들을 포함하고, sdAb의 CDR1은 위치 31-36의 아미노산 잔기들을 포함하고 , sdAb의 FR2는 위치 36-49의 아미노산을 포함하고, sdAb의 CDR2는 위치 50-65의 아미노산 잔기들을 포함하고, sdAb의 FR3은 위치 66-94의 아미노산 잔기들을 포함하고, sdAb의 CDR3은 위치 95-102의 아미노산 잔기들을 포함하고, sdAb의 FR4는 위치 103-113의 아미노산 잔기들을 포함한다.
용어 “합성”은 시험관내 화학적 또는 효소적 합성에 의한 제조를 지칭한다.
본 출원에서 사용되는 용어 “표적”은 sdAb에 의해 인식되는 임의의 성분, 항원, 또는 모이어티를 지칭한다. 용어 “세포내 표적”은 세포 내 존재하는 임의의 성분, 항원, 또는 모이어티를 지칭한다. “막횡단 표적”은 세포막 내 위치하는 성분, 항원, 또는 모이어티이다. “세포외 표적”은 세포 밖에 위치하는 성분, 항원, 또는 모이어티를 지칭한다.
본 출원에서 사용되는 "치료 조성물”은 치료 효과를 가지도록 의도되는 물질, 가령, 약학적 조성물, 유전 물질, 생물제제, 및 다른 물질들을 의미한다. 유전 물질은 직접적인 또는 간접적인 유전적 치료 효과를 가지도록 의도된 물질들, 가령, 유전적 벡터, 유전적 조절 요소, 유전적 구조 요소, DNA, RNA 등을 포함한다. 생물제제는 치료 효과를 가지도록 의도된, 생물인 물질 또는 생물로부터 유도된 물질을 포함한다.
본 출원에서 사용되는, 어구 “치료적 유효량” 및 “예방적 유효량”은 질병 또는 질병의 명시적인 증상의 치료, 예방 또는 관리에 치료적 이점을 제공하는 양을 지칭한다. 치료적 유효량은 질병, 질병의 증상, 또는 질병에 대한 소인을 회복, 치유, 완화, 경감, 변화, 구제, 개선, 향상, 또는 영향을 줄 목적으로 질병 또는 병태, 질병의 증상, 또는 질병에 대한 소인을 치료할 수 있다. 치료적으로 유효한 구체적인 양은 통상의 의사에 의해 용이하게 결정될 수 있으며, 해당 분야에 공지된 요인들, 가령, 예컨대, 질병 유형, 환자 병력 및 연령, 질병 단계, 및 다른 치료적 제제들의 투여에 따라 달라질 수 있다.
본 발명은 바이러스 및 세포내 성분들에 대해 지시되는 단일-도메인 항체 (sdAbs), 뿐만 아니라 sdAbs를 포함하는 단백질 및 폴리펩티드 그리고 이러한 단백질 및 폴리펩티드를 인코딩하는 뉴클레오티드에 관한 것이다. 본 발명은 또한 세포간, 세포횡단 (transcellular) 및 세포외 표적들 또는 항원들에 대해 지시되는 sdAbs에 관한 것일 수 있다. 본 발명은 또한 이러한 sdAbs, 단백질 및 폴리펩티드를 인코딩하는 핵산, 그리고 sdAbs를 포함하는 조성물을 포함한다. 본 발명은 예방, 치료 또는 진단을 목적으로 하는, 이러한 조성물, sdAbs, 단백질 또는 폴리펩티드의 용도를 포함한다.
SdAbs는 기능적 항원-결합 도메인 또는 단백질로서 sdAbs를 사용하기에 매우 이롭게 하는 많은 독특한 구조적 특징들 및 기능적 성질들을 가진다. SdAbs는 경쇄 가변 도메인의 부재시 항원에 기능적으로 결합하여, 단일의, 비교적 작은, 기능적 항원-결합 구조 단위, 도메인 또는 단백질로서 기능할 수 있다. 이러한 점은 sdAbs를, 그 자체로 항원-결합 단백질 또는 도메인으로서 기능하지 않지만, 항원을 결합시키기 위해 종래의 항체 단편들, 가령, 항원-결합 단편들 (Fab) 또는 단일 사슬 가변 단편들 (ScFv)과 조합될 필요가 있는 종래의 항체의 도메인들과 구별시킨다.
SdAbs는 해당 기술 분야에 널리 공지된 방법들을 사용하여 얻을 수 있다. 예를 들면, sdAbs를 얻은 하나의 방법은 (a) 카멜리드를 하나 또는 그 이상의 항원들로 면역화시키는 단계, (b) 면역화시킨 카멜리드로부터 말초 림프구를 단리하여, 전체 RNA를 얻고 이에 상응하는 상보적 DNAs (cDNAs)를 합성하는 단계, (c) VHH 도메인을 인코딩하는 cDNA 단편들의 라이브러리를 작제하는 단계, (d) PCR을 사용하여 단계 (c)에서 얻은 VHH 도메인-인코딩 cDNAs를 전령 RNA (mRNA)로 전사시키고, 이 mRNA를 리보솜 디스플레이 형식으로 전환시키고, 리보솜 디스플레이에 의하여 VHH 도메인을 선택하는 단계, 그리고 (e) VHH 도메인을 적합한 벡터에서 발현시키는 단계 그리고, 선택적으로 발현된 VHH 도메인을 정제하는 단계를 포함한다.
본 발명의 sdAbs를 얻는 또 다른 방법은 핵산을 합성하는 기법들을 사용하여 sdAb를 인코딩하는 핵산을 제조한 후, 이 핵산을 생체내 또는 시험관내 발현시킴에 의한 것이다. 추가적으로, 본 발명의 sdAb, 폴리펩티드 및 단백질은 단백질, 폴리펩티드 또는 다른 아미노산 서열들을 제조하기 위한 합성 또는 반-합성 기법들을 사용하여 제조될 수 있다.
본 발명의 sdAbs는 일반적으로 표적의 모든 천연 또는 합성 유사체, 변이체, 돌연변이체, 대립유전자, 부분들 및 단편들에, 또는 적어도 본 발명의 sdAbs가 야생형 표적에서 결합되는 항원 결정인자 또는 에피토프와 본질적으로 동일한 하나 또는 그 이상의 항원 결정인자 또는 에피토프를 내포하는 표적의 유사체, 변이체, 돌연변이체, 대립유전자, 부분들 및 단편들에 결합할 것이다. 본 발명의 sdAbs는, 본 발명의 sdAbs가 야생형 표적에 결합하는 친화성 및 특이성과 동일하거나, 또는 이보다 높거나 또는 이보다 낮은 친화성 및/또는 특이성으로 이러한 유사체, 변이체, 돌연변이체, 대립유전자, 부분들 및 단편들에 결합할 수 있다. 본 발명의 범위내에서, 본 발명의 sdAbs는 또한 표적의 일부 유사체, 변이체, 돌연변이체, 대립유전자, 부분들 및 단편들에는 결합하지만 다른 것들에는 결합하지 않는 것으로 고려된다. 또한, 본 발명의 sdAb는 인간화될 수 있고, 일가 또는 다가, 및/또는 다중특이적일 수 있다. 추가적으로, 본 발명의 sdAbs는 표적 단백질의 인산화 형태 뿐만 아니라의 비인산화 형태에 결합할 수 있다. sdAbs는 그 외 다른 분자들, 가령, 알부민 또는 다른 거대분자들에 결합할 수 있다.
또한, 본 발명의 범위내에서, sdAbs는 다가이다, 즉, sdAb는 표적의 둘 이상의 상이한 에피토프들에 대해 지시되는 둘 이상의 단백질 또는 폴리펩티드를 가질 수 있다. 이러한 다가 sdAb에서, 단백질 또는 폴리펩티드는, 예를 들면, 동일한 에피토프, 실질적으로 균등한 에피토프, 또는 상이한 에피토프에 대해 지시될 수 있다. 상이한 에피토프들은 동일한 표적 상에 위치될 수 있으며, 또는 둘 이상의 상이한 표적들 상에 위치될 수 있다.
또한 본 발명의 하나 또는 그 이상의 sdAbs의 서열은 하나 또는 그 이상의 링커 서열들과 연결되거나 결합될 수 있는 것으로 생각된다. 링커는, 예를 들면, 세린, 글리신 및 알라닌의 조합을 내포하는 단백질 서열일 수 있다.
또한 본 발명의 sdAbs의 부분, 단편, 유사체, 돌연변이체, 변이체, 대립유전자 및;또는 유도체를 사용하는 것은, 이들이 기재된 용도에 적합한 한, 본 발명의 범위에 속한다.
본 발명의 sdAbs는 주로 치료 및/또는 진단 용도를 위한 것이기 때문에, 이들은 포유동물, 바람직하게는 인간, 표적들에 대해 지시된다. 그러나, 본 출원에 기재된 sdAbs는 다른 종들로부터의 표적들, 예를 들면, 하나 또는 그 이상의 다른 종들의 영장류 또는 다른 동물들 (예를 들면, 마우스, 래트, 토끼, 돼지 또는 개)로부터의 표적들과, 그리고 특히, 이러한 표적들과 연관된 질병과 관련된 질병 및 장애에 관한 동물 모델에서 교차-반응성일 수 있다.
또 다른 양상에서, 본 발명은 본 발명의 sdAb를 인코딩하는 핵산에 관한 것이다. 이러한 핵산은, 예를 들면, 유전자 작제물의 형태일 수 있다.
또 다른 양상에서, 본 발명은 본 발명의 sdAb를 발현시키는 또는 발현시킬 수 있는, 및/또는 본 발명의 sdAb를 인코딩하는 핵산을 내포하는, 숙주 또는 숙주 세포에 관한 것이다. sdAbs의 서열들은 임의의 유기체의 유전체 내부에 삽입하기 위해 사용되어 유전자 변형된 유기체 (GMO)를 생성할 수 있다. 예들에는, 식물, 박테리아, 바이러스, 및 동물들이 포함되나 이에 제한되는 것은 아니다.
본 발명은 또한 sdAbs, sdAbs를 인코딩하는 핵산, 이러한 sdAbs를 발현시키는 또는 발현시킬 수 있는 숙주 세포, 본 발명의 sdAbs를 내포하는 생성물 및 조성물을 제조 또는 생성하는 방법에 관한 것이다.
본 발명은 또한 본 출원에 기재된 sdAbs, sdAbs를 인코딩하는 핵산, 숙주 세포, 생성물 및 조성물의 응용 및 용도에 관한 것이다. 이러한 생성물 또는 조성물은, 예를 들면, 질병의 치료 또는 예방을 위한 약학적 조성물, 또는 진단용 생성물 또는 조성물일 수 있다. sdAbs는 sdAbs의 혈청 및 조직 수준을 측정하기 위하여 다양한 검사, 예를 들면 ELISA 검사 및 질량 분광법 검사에서 사용될 수 있다.
또 다른 양상에서, 질병을 치료 또는 예방하기 위해 본 발명의 하나 또는 그 이상의 sdAbs를 인코딩하는 핵산이 유기체의 유전체 내부에 삽입될 수 있다.
본 발명은 일반적으로 예방적, 치료적 및/또는 진단 목적으로 사용될 수 있는 sdAbs, 뿐만 아니라 하나 또는 그 이상의 이러한 sdAbs를 포함하는 또는 이들로 본질적으로 구성되는 단백질 또는 폴리펩티드에 관한 것이다.
본 발명에 상세히 기재된 방법 및 조성물은 본 출원에 기재된 질병을 치료하기 위해 사용될 수 있으며, 본 출원에 기재되거나 그 외 해당 분야의 숙련된 기술자에게 공지된 임의의 용량 및/또는 제형으로, 뿐만 아니라 본 출원에 기재되거나 그 외 해당 분야의 숙련된 기술자에게 공지된 임의의 투여 경로로 사용될 수 있다.
본 발명의 sdAbs는 바이러스에 의해 또는 비정상적인 세포 단백질에 의해 유발된 질병의 치료 및 예방을 위해 사용될 수 있다. 본 발명의 sdAbs는 또한 질병의 치료 및 예방을 위해 사용될 수 있다. 본 발명의 sdAbs는 세포내 분자의 과발현이 있는 경우 질병을 표적하기 위해 사용될 수 있다. 이 항체들은 또한 감염된 세포들에서 세포내 바이러스 단백질을 표적함으로써 바이러스 감염을 치료하기 위해 사용될 수 있다. 바이러스 단백질, 가령, 예를 들면, HIV-1 역전사효소의 생성을 차단하는 것은 바이러스 생활-주기를 차단할 수 있다.
본 발명의 sdAbs는 또한 표적 세포내 바이러스 단백질, 가령, 에볼라 VP24를 표적하여, 숙주의 항-바이러스 면역 반응을 정지시키는 에볼라의 능력을 차단시킬 수 있다.
본 발명의 sdAbs는 하나 또는 그 이상의 화합물들과 함께 사용될 수 있다. 예를 들면, 본 발명의 sdAb는 JAK/STAT 억제제, 가령, 예를 들면, 커큐민, 레스베라트롤, 쿠쿠르비타신 A, B, E, I, Q, 플라보피리돌, 데옥시테트란고마이신, 사이클로펜텐온 유도체, N-아실호모세린 락톤, 인디루빈 유도체, 메이소인디고, 티르포스틴, 백금-내포 화합물들 (예컨대, IS3-295), 펩티드모방체, 안티센스 올리고뉴클레오티드, S3I-201, 포스포티로신 트리펩티드 유도체, HIV 프로테아제 억제제 (예컨대, 넬피나비르, 인디나비르, 사퀴나비르, & 리토르나비르), JSI-124, XpYL, Ac-pYLPQTV-NH2, ISS 610, CJ-1383, 피리메타민, 메트포르민, 아티프리모드, S3I-M2001, STX-0119; N-[2-(1,3,4-옥사디아졸릴)]-4 퀴놀린카르복스아미드 유도체, S3I-1757, LY5; 5,8-디옥소-6(피리딘-3-일아미노)-5,8,-디하이드로-나프탈렌-1-설폰아미드, 위타신스틴 (withacinstin), 스타틱 (Stattic), STA-21, LLL-3, LLL12, XZH-5, SF-1066, SF-1087, 17o, 크립토탄시논, FLL32, FLL62, C188-9, BP-1108 및 BP-1075, 갈리엘라락톤, JQ1, 5, 15 DPP, WP1066, 니클로사미드, SD1008, 니푸록사지드, 크립토탄시논, BBI 퀴논, 및 룩솔리티닙 포스페이트와 함께 사용될 수 있다. 상기 하나 또는 그 이상의 화합물들은 치료 반응을 증가시켜 본 발명의 sdAbs의 유효성을 증대시킬 수 있다. 또한, sdAbs의 유효성은 sdAbs를 펩티드, 펩티드모방체, 및 다른 약물들, 가령, 예를 들면, 시메티딘, 아토르바스타틴, 셀레콕시브, 메트포르민, 및 시메티딘 (그러나 이에 제한되는 것은 아님)과 조합함으로써 증가될 수 있다.
본 발명의 하나 또는 그 이상의 sdAbs, 또는 본 발명의 sdAbs는 다른 sdAbs와 조합될 있는 것으로 생각된다.
본 발명의 특정 sdAbs는 sdAb 상의 단백질 서열을 추가로 표적화 할 필요 없이, 그리고 세포 표면 수용체에 결합하여 세포막을 경유하도록 sdAb를 지시하는 외인성 화합물들의 도움 없이 세포막을 경유하여 세포에 진입할 수 있는 것으로 생각된다.
세포막을 경유한 후, 이들 sdAbs는 표적 막횡단 또는 세포내 분자 또는 항원들을 표적할 수 있다. 이들 표적들은, 예를 들면, 단백질, 탄수화물, 지질, 핵산, 돌연변이된 단백질, 바이러스 단백질, 및 프리온일 수 있다. sdAb 표적은 효소, 세포의 구조적 단백질, 세포막 분자의 세포내 부분, 소기관의 막 내부의 분자들, 임의의 유형의 RNA 분자, DNA 또는 염색체의 임의의 영역, 메틸화 또는 비메틸화 핵산, 세포의 합성 메커니즘에서 부분적으로 조립된 분자, 2차 신호전달자 분자, 및 세포 신호전달 메커니즘 내 분자로서 기능할 수 있다. 표적들은 세포질, 핵, 소기관, 및 세포막 내 분자들 모두를 포함할 수 있다. 세포막 내 분비 또는 배치될 분자들은 세포에서 나가기 전 세포질 내에서 표적화될 수 있다.
sdAb 표적들은 인간, 동물, 식물, 진균, 기생충, 원생생물, 박테리아, 바이러스, 프리온, 원핵세포, 및 진핵세포 안에 존재할 수 있다. 본 발명의 sdAbs에 의해 표적화될 수 있는 세포간 및 세포내 신호전달 분자 및 단백질 그룹들의 일부 예들은 다음과 같다: 종양유전자 생성물s, 호르몬, 사이토킨, 성장 인자, 신경전달물질, 키나아제 (티로신 키나아제, 세린 키나아제, 및 트레오닌 키나아제 포함), 인산분해효소, 유비퀴틴, 사이클릭 뉴클레오티드, 사이클라아제 (아데닐릴 및 구아닐릴), G 단백질, 포스포디에스테라아제, GTPase 수퍼패밀리, 면역글로불린 (항체, Fab 단편들, 결합제, sdAbs), 면역글로불린 수퍼패밀리, 이노시톨 포스페이트 지질, 스테로이드 수용체, 칼모듈린, CD 그룹 (예컨대, CD4, CD8, CD28, 등), 전사 인자, TGF-베타, TNF-알파 및 베타, TNF 리간드 수퍼패밀리, 노치(notch) 수용체 신호전달 분자, 헤지호그 수용체 신호전달분자, Wnt 수용체 신호전달분자, 톨-유사 수용체 신호전달분자, 카스파제, 액틴, 미오신, 미오스타틴, 12-리폭시게나아제, 15-리폭시게나아제, 리폭시게나아제 수퍼패밀리, 역전사효소, 바이러스 및 이의 단백질, 아밀로이드 단백질, 콜라겐, G 단백질 결합 수용체, 돌연변이된 정상 단백질, 프리온, Ras, Raf, Myc, Src, BCR/ABL, MEK, Erk, Mos, Tpl2, MLK3, TAK, DLK, MKK, p38, MAPK, MEKK, ASK, SAPK, JNK, BMK, MAP, JAK, PI3K, 사이클로옥시게나아제, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, Myc, p53, BRAF, NRAS, KRAS, HRAS 및 케모카인.
HIV는 인간에서 후천성 면역결핍 증후군 (AIDS)을 유발하는 레트로바이러스이다. AIDS는 감염된 개체의 면역계의 진행성 기능상실을 유발하여, 삶을 위협하는 기회 감염 및 암의 발달을 가져온다. HIV 감염 후 평균 생존 시간은 치료 없이 9 내지 11인 것으로 추정된다.
HIV는 단일-가닥의, 양성-센스, 외피형 RNA 바이러스로서 전달된다. 표적 세포에 진입시, 바이러스 RNA 유전체는 바이러스 입자 내에에서 바이러스 유전체와 함께 운반되는 바이러스 인코딩된 역전사효소 (RT)에 의해 이중-가닥 DNA로 역전사된다. RT는 RNA-의존성 DNA 중합효소이며 또한 RNaseH 활성을 가진다. 이후 생성된 바이러스 DNA는 숙주 세포 핵 안으로 들어가서 바이러스 인코딩된 인테그라제 및 숙주 보조-인자들에 의해 세포 DNA에 통합되었다. 일단 통합되면, 바이러스는 수 개월 또는 수 년 동안 잠복기가 될 수 있다. 택일적으로, 바이러스는 전사되어, 새로운 RNA 유전체 및 바이러스 단백질을 생성하며, 이들은 새로운 바이러스 입자들로서 패키징되어 방출된다.
2가지 유형의 HIV가 특성화되었다: HIV-1 및 HIV-2. HIV-1은 더욱 맹독성이고, 더욱 감염성이며, 전세계적으로 대다수의 HIV 감염 원인이다. HIV-2는 대부분 서 아프리카에 국한된다.
항-HIV RT sdAbs는 표적 HIV-1 역전사효소를 표적하도록 개발되었다. 항-HIV-1 RT sdAb는 단독으로 또는 다른 레트로바이러스 제제들과의 조합되어 HIV로 감염된 개체들을 성공적으로 치료할 수 있다. 해당 분야에 널리 공지된 방법들을 사용하여, HIV-1 RT의 에피토프에 대해 지시되는 또는 이에 결합할 수 있는 sdAbs를 생성하기 위해 재조합 HIV-1 역전사효소 단백질 (Creative Biomart, Shirley, NY) (서열 번호:1)을 사용하였다.
낙타를 면역화하기 위해 사용된, 재조합 HIV-1 역전사효소 단백질의 단백질 서열 (서열 번호:1)은 PISPIETVPVKLKPGMDGPKVKQWPLT EEKIKALVEICAELEEEGKISRIGPENPYNTPVFAIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSIPLDEDFRKYTAFTIPSTNNETPGTRYQYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIYQYVDDLYVGSDLEIGQHRTKVEELRQHLWRWGFYTPDKKHQKEPPFLWMGYELHPDKWTVQPIVLPEKDSWTVNDIQK 이었다.
면역화시킨 결과로, 수 개의 sdAbs를 얻어 선별하였다. 항-HIV-1 RT sdAbs의 DNA 서열들을 하기에 나열한다:
HIV1-1 (서열 번호:2): 5'-gatgtgcagctggtggagtctgggggaggctcggtgcaggctggagggtc tctgagactctcctgtgcagcctctgtttacagctacaacacaaactgcatgggttggttccgccaggctccagggaaggagcgcgagggggtcgcagttatttatgctgctggtggattaacatactatgccgactccgtgaagggccgattcaccatctcccaggagaatggcaagaatacggtgtacctgacgatgaaccgcctgaaacctgaggacactgccatgtactactgtgcggcaaagcgatggtgtagtagctggaatcgcggtgaggagtataactactggggccaggggacccaggtcaccgtctcctca-3'
HIV1-2 (서열 번호:3): 5'-caggtgcagctggtggagtctgggggaggctcggtgcaggctggaga ctctctgagactctcctgtgcagcctctggaaacactgccagtaggttctccatgggctggttccgccaggctccagggaaggagcgcgagggggtcgcggctatttctgctggtggtaggcttacatactatgccgactccgtgaagggccgattcaccatctcccgagacaacgccaagaacacgctgtatctggacatgaacaacctgaaacctgaggacactgccatgtactactgtgccgcaattagtgaccggatgactggtattcaggctcttgcggctctacccagacttcgcccagaagactacggtaactggggccaggggaccctggtcaccgtctcctca-3'
HIV1-7 (서열 번호:4): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctgga gggtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggaccctggtcaccgtctcctca-3'
HIV1-8 (서열 번호:5): 5'-caggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggccaggggacccaggtcaccgtctcctca-3'
HIV1-6 (서열 번호:6): 5'-caggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccaatatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggccaggggaccctggtcaccgtctcctca-3'
HIV1_28 (서열 번호:7): 5'- aggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggccaggggaccctggtcaccgtctcctca-3'
HIV1-21 (서열 번호:8): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca-3'
HIV1-37 (서열 번호:9): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca-3'
HIV1-3 (서열 번호:10): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcactgtctcctca-3'
HIV1-5 (서열 번호:11): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaggcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctaccattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgctaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca -3'
HIV1-10 (서열 번호:12): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcagcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca-3'
HIV1_29 (서열 번호:13): 5'-gaggtgcagctggtggagtctgggggagactcagtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca -3'
HIV1_32 (서열 번호:14): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca-3'
HIV1-9 (서열 번호:15): 5'-gaggtgcagctggtggagtctgggggaggctcggtgcaggctggagg gtctctgagactctcctgtgcagcctctgtttacagctacaacacaaactgcatgggttggttccgccaggctccagggaaggagcgcgagggggtcgcagttatttatgctgctggtggattaacatactatgccgactccgtgaagggccgattcaccatctcccaggagaatggcaagaacacggtgtacctgacgatgaaccgcctgaaacctgaggacactgccatgtactactgtgcggcaaagcgatggtgtagtagctggaatcgcggtgaggagtataactactggggccaggggacccaggtcactgtctcctca-3'
HIV1-16 (서열 번호:16): 5'-caggtgcagctggtggagtctgggggaggctcggtgcaggctggagg gtctctgagactctcctgtgcagcctctggaaacacctacagtagtagctactgcatgggctggttccgccaggctccagggaaggaccgcgagggggtcgcgcgtattttcactcgaagtggtaccacatactatgccgactccgtgaagggccgattcaccatttcccgtgacaacgccaagaacacggtgtatctgcaaatgaacagcctgaaacctgaagacgctgccatgtactactgtgcggcagcccaggggggtgcctgcatttcgtttacttcgttcgcgaagaatttcgtgtaccggggccaggggaccctggtcactgtctcctca-3'
HIV1-13 (서열 번호:17): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggtcctctgactataactactggggtgaggggaccctggtcaccgtctcctca-3'
HIV1_35 (서열 번호:18): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggtcctctgactataactactggggtgaggggaccctggtcaccgtctcctca-3'
HIV1-11 (서열 번호:19): 5'-caggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcactgtctcctca-3'
HIV1_22 (서열 번호:20): 5'-caggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca-3'
HIV1-4 (서열 번호:21): 5'- catgtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggaccctggtcaccgtctcctca-3'
HIV1_38 (서열 번호:22): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccaactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactatgactactggggtgaggggaccctggtcaccgtctcctca-3'
HIV1_23 (서열 번호:23): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaagcctctggatacacctacaatagtagagtcgatatcagatctatgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatggacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca-3'
HIV1_25 (서열 번호:24): 5'-gaggtgcagctggtggagtctgggggagactcggtgcaggctggagg gtctcttcaactctcctgtaaggcctctggatacacctacaatagtagagtcgatatcagatctgtgggctggttccgccagtatccaggaaaggagcgcgagggggtcgctactattaatattcgtaatagtgtcacatactatgccgactccgtgaagggccgattcaccatctcccaagacaacgccaagaacacggtgtatctgcaaatgaacgccctgaaacctgaggacactgccatgtactactgtgcgttgtcagacagattcgcggcgcaggtacctgccaggtacggaatacggccctctgactataactactggggtgaggggacccaggtcaccgtctcctca-3'
항-HIV-1 RT sdAbs의 아미노산 서열들을 하기에 나타낸다:
HIV1-1 (서열 번호:25): DVQLVESGGGSVQAGGSLRLSCAASVYSYNTNC MGWFRQAPGKEREGVAVIYAAGGLTYYADSVKGRFTISQENGKNTVYLTMNRLKPEDTAMYYCAAKRWCSSWNRGEEYNYWGQGTQVTVSS
HIV1-2 (서열 번호:26): QVQLVESGGGSVQAGDSLRLSCAASGNTASRFSM GWFRQAPGKEREGVAAISAGGRLTYYADSVKGRFTISRDNAKNTLYLDMNNLKPEDTAMYYCAAISDRMTGIQALAALPRLRPEDYGNWGQGTLVTVSS
HIV1-9 (서열 번호:27): EVQLVESGGGSVQAGGSLRLSCAASVYSYNTNCM GWFRQAPGKEREGVAVIYAAGGLTYYADSVKGRFTISQENGKNTVYLTMNRLKPEDTAMYYCAAKRWCSSWNRGEEYNYWGQGTQVTVSS
HIV1-16 (서열 번호:28): QVQLVESGGGSVQAGGSLRLSCAASGNTYSSSY CMGWFRQAPGKDREGVARIFTRSGTTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDAAMYYCAAAQGGACISFTSFAKNFVYRGQGTLVTVSS
HIV1-27 (서열 번호:29): EVQLGESGGGSVQAGGSLRLSCAASVYSYTTNCM GWFRQAPGKEREGVAVIYSAGGLTYYADSVKGRFTISQDNGKNTVYLTMNRLKPEDTAMYYCAAKRWCSSWNRGEEYNYWGQGTQVTVSS
HIV1-30 (서열 번호:30): QVQLVESGGGSVQAGGSLRLSCAASVYSYNTN CMGWFRQAPGKEREGAAVIYAAGGLTYYADSVKGRFTISQENGKNTVYLTMNRLKPEDTAMYYCAAKRWCSSWNRGEEYNYWGQGTQVTVSS
HIV1-21 (서열 번호:31): EVQLVESGGDSVQAGGSLQLSCKASGYTYNSR VDIRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTQVTVSS
HIV1-4 (서열 번호:32): HVQLVESGGDSVQAGGSLQLSCKASGYTYNSR VDIRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTLVTVSS
HIV1-6 (서열 번호:33): QVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGQGTLVTVSS
HIV1-7 (서열 번호:34): EVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTLVTVSS
HIV1-8 (서열 번호:35): QVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGQGTQVTVSS
HIV1-11 (서열 번호:36): QVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTQVTVSS
HIV1-13 (서열 번호:37): EVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRSSDYNYWGEGTLVTVSS
HIV1-23 (서열 번호:38): EVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMDALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTQVTVSS
HIV1-24 (서열 번호:39): HVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPGDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGQGTLVTVSS
HIV1-25 (서열 번호:40): EVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSVGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTQVTVSS
HIV1-31 (서열 번호:41): DVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTQVTVSS
HIV1-38 (서열 번호:42): EVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYANSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYDYWGEGTLVTVSS
HIV1-39 (서열 번호:43): EVQLVESGGDSVQAGGSLQLSCKASGYTYNSRVD IRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPTRYGIRPSDYNYWGQGTQVTVSS
하나 또는 그 이상의 마우스 단클론 항체는 본 발명의 항-HIV-1 RT sdAbs의 하나 또는 그 이상의 도메인에 대해 생성될 수 있다. 마우스 단클론 항체는 해당 기술 분야의 숙련된 기술자에게 공지된 방법에 의해 생성될 수 있는데, 예를 들면, 마우스 단클론 항체는 마우스 하이브리도마에 의해 생성될 수 있다. 마우스 단클론 항체는 진단 검사에 사용될 수 있는데, 예를 들면, 이 항체는 환자의 샘플에 존재하는 항-HIV-1 RT sdAb의 양을 측정하기위하여 면역분석, 가령, ELISA 또는 질량 분광법 검사에서 사용될 수 있다.
SdAbs는 또한 재조합 아라키도네이트 12-리폭시게나아제 (ALOX12)에 대해 생성되었다. ALOX12는 또한 혈소판-형 12-리폭시게나아제, 아라키도네이트 산소 12-산화환원효소, 델타12-리폭시게나아제, 12델타-리폭시게나아제, C-12 리폭시게나아제, 류코트리엔 A4 합성효소, 및 LTA4 합성효소로서 공지되어 있다. ALOX12는 아라키돈산 대사에 참여하는 리폭시게나아제-형 효소이다. ALOX12는 식이-유도 및/또는 유전자-유도 당뇨병, 지방 세포/조직 기능이상, 및 비만의 발달 및 합병증의 원인이었다. ALOX12는 또한 혈관 수축, 확장, 압력, 재형성 (remodeling), 및 혈관형성을 조절하는 것으로 생각되어 왔다. ALOX12의 억제는 혈관 형성의 발달을 저해하므로 ALOX12는 죽상경화증, 지방간염, 및 다른 관절염 및 암 질병을 촉진시키는 신생혈관증식을 감소시키기 위한 표적이 된다. 상승된 양의 ALOX12는 알츠하이머 질병의 발달에 원인이 될 수 있다.
본 발명은 ALOX12 단백질에 대해 지시되는 sdAbs, 단백질, 및 폴리펩티드를 제공한다.
본 발명의 항-ALOX12 sdAbs 및 폴리펩티드는 ALOX12와 연관된 및/또는 ALOX12에 의해 매개된 질병 및 장애, 가령, 당뇨병, 지방 세포 기능이상, 비만, 죽상경화증, 지방간염, 관절염 및 암의 예방 및/또는 치료에 사용될 수 있는 것으로 생각된다.
재조합 인간 ALOX12 단백질을 사용하여 ALOX12의 에피토프에 대해 지시되는 또는 ALOX12의 에피토프에 결합될 수 있는 sdAbs를 생성하였다. 항-ALOX12 sdAbs를 생성하기 위해, 재조합 인간 ALOX12를 대장균에서 발현시켜 표적 항원으로서 사용하였다.
낙타의 면역화를 위해 사용된 재조합 ALOX12 단백질 서열 (서열 번호:44)은 다음과 같았다:
MGRYRIRVATGAWLFSGSYNRVQLWLVGTRGEAELELQLRPARGEEEEFDHDVAEDLGLLQFVRLRKHHWLVDDAWFCDRITVQGPGACAEVAFPCYRWVQGEDILSLPEGTARLPGDNALDMFQKHREKELKDRQQIYCWATWKEGLPLTIAADRKDDLPPNMRFHEEKRLDFEWTLKAGALEMALKRVYTLLSSWNCLEDFDQIFWGQKSALAEKVRQCWQDDELFSYQFLNGANPMLLRRSTSLPSRLVLPSGMEELQAQLEKELQNGSLFEADFILLDGIPANVIRGEKQYLAAPLVMLKMEPNGKLQPMVIQIQPPNPSSPTPTLFLPSDPPLAWLLAKSWVRNSDFQLHEIQYHLLNTHLVAEVIAVATMRCLPGLHPIFKFLIPHIRYTMEINTRARTQLISDGGIFDKAVSTGGGGHVQLLRRAAAQLTYCSLCPPDDLADRGLLGLPGALYAHDALRLWEIIARYVEGIVHLFYQRDDIVKGDPELQAWCREITEVGLCQAQDRGFPVSFQSQSQLCHFLTMCVFTCTAQHAAINQGQLDWYAWVPNAPCTMRMPPPTTKEDVTMATVMGSLPDVRQACLQMAISWHLSRRQPDMVPLGHHKEKYFSGPKPKAVLNQFRTDLEKLEKEITARNEQLDWPYEYLKPSCIENSVTI
면역화시킨 결과로, 수 개의 sdAbs를 얻어 선별하였다. sdAbs의 DNA 서열들을 하기에 나열한다:
ALOX_21 (서열 번호:45): 5'-gaggtgcagctggtggagtctgggggaggttcggtgcagg ctggagggtctctgaggatctcctgtacagcctctggattcacttttgatgacactgacatgggctggtaccgccagactctaggaaatgggtgcgagttggtttctcagattagtaatgatggtagtacattctatagagattccgtgaagggccgattcaccatctcctgggaccgcgtcaacaacacggtgtatctgcaaatgagcgccctgagacctgaggacacggccatgtattactgcaatatcaacgggtgtaggagaccctcgtacaatcttcacttgaacgcatggggccaggggacacaggtcaccgtctcctca-3'
ALOX_41 (서열 번호:46): 5'-caggtgcagctggtggagtctgggggaggctcggtgcagg ctggagggtctctgacactgtcctgtgtagcctctggatacggctacagtgccacgtgcatgggctggttccgccaggctccagggaaggagcgcgagggggtcgcgtctatttcaccttatggtgttagaaccttctatgccgactccgcgaaaggccgattcaccgtctcccgagacaacgccaagaacacgctgtatctgcaaatgaacagcctgaaacctgaggacacgtccgtgtactactgtgcggccggttcgggcgttggtgtttgttcactttcgtatccatacacctactggggccaggggacccaggtcaccgtctcctca-3'
ALOX_43 (서열 번호:47): 5'-caggtgcagctggtggagtctgggggaggctcggtgcgg gctggagagtctctgagactctcctgtgtagcctctagatccatctatgtttggtactgcatgggctggttccgccaggctgcagggaaggagcgcgagggggtcggaagtatgttcgttggtggcggtaggacatattatgacgactccgtcaagggccgattcaccatctcccaagacaaggccaagaacacgctgtatctgcaaatggacaacctggcacctgaagacactgccatgtattactgtgcggctgggcgctgcggtggcaactggctgagaagcaatgctttcgacaaatggggccaggggacactggtcaccgtctcctca-3'
ALOX_46 (서열 번호:48): 5'-gatgtgcagctggtggagtctgggggaggctcggtgcagg ctggagggtctctgagactctcctgtgcagccactggaaacacctacattagccgctgcatgggctggttccgccagcctccagggaaggagcgcgaggtggtcgcacgtatttataccgactctggtaatacatactatcccgacgccgtggagggccgattcaccatctcccaagacaacgccaagaacacgatatatctgcaaatgaacagcctgaaacctgacgacaccgccgtgtactactgtgtgctctcagaggccgtctgtacaaaagaacctggggactttcgttactggggccaggggacccaggtcactgtctcctca-3'
생성된 항-ALOX sdAbs의 단백질 서열들은 다음과 같다:
ALOX_21 (서열 번호:49): EVQLVESGGGSVQAGGSLRISCTAS GFTFDDTDMGWYRQTLGNGCELVSQISNDGSTFYRDSVKGRFTISWDRVNNTVYLQMSALRPEDTAMYYCNINGCRRPSYNLHLNAWGQGTQVTVSS
ALOX_41 (서열 번호:50): QVQLVESGGGSVQAGGSLTLSCVAS GYGYSATCMGWFRQAPGKEREGVASISPYGVRTFYADSAKGRFTVSRDNAKNTLYLQMNSLKPEDTSVYYCAAGSGVGVCSLSYPYTYWGQGTQVTVSS
ALOX_43 (서열 번호:51): QVQLVESGGGSVRAGESLRLSCVAS RSIYVWYCMGWFRQAAGKEREGVGSMFVGGGRTYYDDSVKGRFTISQDKAKNTLYLQMDNLAPEDTAMYYCAAGRCGGNWLRSNAFDKWGQGTLVTVSS
ALOX_46 (서열 번호:52): DVQLVESGGGSVQAGGSLRLSCAAT GNTYISRCMGWFRQPPGKEREVVARIYTDSGNTYYPDAVEGRFTISQDNAKNTIYLQMNSLKPDDTAVYYCVLSEAVCTKEPGDFRYWGQGTQVTVSS
본 발명의 항-ALOX12 sdAbs의 하나 또는 그 이상의 도메인들에 대해 하나 또는 그 이상의 마우스 단클론 항체가 생성될 수 있다. 마우스 단클론 항체는 해당 기술 분야의 숙련된 기술자에게 공지된 방법에 의해 생성될 수 있는데, 예를 들면, 마우스 단클론 항체는 마우스 하이브리도마에 의해 생성될 수 있다. 마우스 단클론 항체는 진단 검사에 사용될 수 있는데, 예를 들면, 이 항체는 환자의 샘플에 존재하는 항-ALOX12 sdAb의 양을 측정하기위하여 면역분석, 가령, ELISA 또는 질량 분광법 검사에서 사용될 수 있다.
에볼라 바이러스 질병 (EVD) 및 에볼라 출혈열 (EHF)로도 공지되어 있는 에볼라는, 에볼라바이러스에 의해 유발되는 인감 및 다른 영장류의 바이러스 출혈열이다. 이 질병은 감염된 인간들의 25 내지 90 퍼센트를 증상이 나타난 후 6 내지 16일에 사망시키는 높은 사망위험을 가진다.
에볼라는 감염된 개체의 선천성 면역계의 적절한 기능을 방해한다. 에볼라 단백질은 인터페론 단백질, 가령, 인터페론-알파, 인터페론-베타, 및 인터페론 감마에 대한 반응을 생성하는 세포의 능력을 방해함으로써 바이러스 감염에 대한 면역계의 반응을 약화시켰다. 에볼라의 구조 단백질, VP24 및 VP35는, 이러한 방해에 중요한 역할을 한다. V24 단백질은 숙주 세포의 항바이러스 단백질의 생성을 차단한다. 숙주의 면역 반응을 억제함으로써, 에볼라는 신체 전체에 빠르게 확산된다.
본 출원에 기재된 바와 같이, 항-VP24 sdAbs는 에볼라 VP24 단백질을 표적하기 위해 개발되었다. 항-VP24 sdAb는 단독으로 또는 다른 레트로바이러스 제제들과의 조합되어 에볼라로 감염된 개체들을 성공적으로 치료할 수 있다. 해당 분야에 널리 공지된 방법들을 사용하여, VP24의 에피토프에 대해 지시되는 또는 이에 결합할 수 있는 sdAbs를 생성하기 위해 재조합 VP24 단백질 (서열 번호:53) 을 사용하였다.
낙타의 면역화를 위해 사용된 재조합 VP24 단백질의 단백질 서열 (서열 번호:53)은 다음과 같았다:
AKATGRYNLISPKKDLEKGVVLSDLCNFLVSQTIQGWKVYWAGIEFDVTHKGMALLHRLKTNDFAPAWSMTRNLFPHLFQNPNSTIESPLWALRVILAAGIQDQLIDQSLIEPLAGALGLISDWLLTTNTNHFNMRTQRVKEQLSLKMLSLIRSNILKFINKLDALHVVNYNGLLSSIEI ILEFNSSLAI
면역화시킨 결과, 하나의 항-VP24 sdAb인, VP24_5를 얻었으며 VP24에 대한 결합에 관해 선별하였다. VP24_5의 DNA 서열 (서열 번호: 54)은 다음과 같다:
5'- ATGGGTGAT GTGCAGCTGGTGGAGTCT GGGGGAGAC TCGGTGCGG GCTGGAGGG TCTCTTCAAATGGGTGAT GTGCAGCTG GTGGAGTCT GGGGGAGAC TCGGTGCGGGCTGGAGGGTCTCTTCAA CTCTCCTGT AAAGCCTCT GGATACACC TACAATAGTAGAGTCGATATCAGATCT ATGGGCTGG TTCCGCCAG TATCCAGGA AAGGAGCGCGAGGGGGTCGCTACTATT AATATTCGT AATAGTGTC ACATACTAT GCCGACTCCGTGAAGGGCCGATTCACC ATCTCCCAA GACAACGCC AAGAACACG GTGTATCTGCAAATGAACGCCCTGAAA CCTGAGGAC ACTGCCATG TACTACTGT GCGTTGTCAGACAGATTCGCGGCGCAG GTACCTGCC AGGTACGGA ATACGGCCC TCTGACTAT AACTACTGG GGTGAGGGG ACCCTGGTC ACCGTCTCC TCAAGCTCT GGTCTCGAG-3'
VP24_5 sdAb의 아미노산 서열 (서열 번호:55)을 CDR에 밑줄표시하여, 하기에 나타낸다:
MGDVQLVESGGDSVRAGGSLQLSCKASGYTYNSRVDIRSMGWFRQYPGKEREGVATINIRNSVTYYADSVKGRFTISQDNAKNTVYLQMNALKPEDTAMYYCALSDRFAAQVPARYGIRPSDYNYWGEGTLVTVSSSSGLE
본 발명의 항-VP24 sdAb의 하나 또는 그 이상의 도메인들에 대해 하나 또는 그 이상의 마우스 단클론 항체가 생성될 수 있다. 마우스 단클론 항체는 해당 기술 분야의 숙련된 기술자에게 공지된 방법에 의해 생성될 수 있는데, 예를 들면, 마우스 단클론 항체는 마우스 하이브리도마에 의해 생성될 수 있다. 마우스 단클론 항체는 진단 검사에 사용될 수 있는데, 예를 들면, 이 항체는 환자의 샘플에 존재하는 항-VP24 sdAb의 양을 측정하기위하여 면역분석, 가령, ELISA 또는 질량 분광법 검사에서 사용될 수 있다.
실시예
실시예 1:
SDABS의 생성
SdAbs는 ALOX12 (서열 번호:44), VP24 (서열 번호:53), 및 HIV-1 역전사효소 (서열 번호:1)를 비롯한 여러 단백질로 면역화된 낙타로부터 생성되었다.
표준 기법들을 사용하여, pCDisplay-3M 벡터 (Creative Biogene, Shirley, NY) 및 M13K07 헬퍼 파지 (New England Biolabs, Ipswich, MA)로 파지 디스플레이 라이브러리를 작제하였다. sdAbs의 단일 클론을 ELISA로 확인하고, 표준 방법들을 사용하여 DNA 및 단백질 서열들을 결정하였다.
실시예 2:
HIV1-9 (서열 번호:27) SDAB는 HIV-1 역전사효소 및 에볼라 VP-24에 결합한다
25°°C의 Biacore 3000 (General Electric Company, Fairfield, CT )에서 단백질 결합 실험들을 수행하였다. 검사 완충액은 10 mM HEPES 완충액 (pH 7.4), 150 mM NaCl, 3mM EDTA, 0.05% P20을 함유하였다. 재생 완충액은 10mM 글리신 HCl pH 1.75를 함유하였으며, 고정 완충액은 10 mM 소듐 아세테이트, pH 5.0를 함유하였다. 리간드를 포획함에 사용된 유속은 5ul/분이었다. 동역학 분석에 사용된 유속은 30 ul/분이었다.
단백질 결합 실험에 사용된 리간드는 HIV1-9 (서열 번호:27) 및 STAT3-VHH 14 (서열 번호:56) 이었다. 이 리간드들은 CM5 센서 칩의 유세포 2 및 4 상에서 각각 1200 및 550의 반응 단위 (RU)로 아민 커플링 (EDC/NHS)에 의해 직접 고정화되었다. 유세포 1은 공백으로 두어 바탕 차감에 사용하였다. CM5 칩 상에서 비어있는 부위들은 1M 에탄올 아민으로 차단되었다. 결합 분석을 위해, 피분석물인, rHIV-1 (서열 번호:1)을 센서 칩 위로 흘러가게 하였다. 리간드에 대한 피분석물의 결합을 실시간으로 모니터하였다. 표 1에서 보는 바와 같이, 관찰된 결합 속도 (ka) 및 해리 속도 (kd)로부터 친화성 상수 (KD= kd/ka)를 계산하였다 .
단백질 결합 실험들에 대한 음성 대조군은 항-STAT3 sdAb, VHH14 (서열 번호:56)였다: QVQLVESGGGSVQAGGSLRLSCVASTYTGCMGWFRQ APGKEREGVAALSSRGFAGHYTDSVKGRFSISRDYVKNAVYLQMNTVKPEDAAMYYCAAREGWECGETWLDRTAGGHTYWGQGTLVTVSS
실제 센서그램 과 BIAnalysis 소프트웨어로부터 생성된 센서그램 간에 카이 제곱 (c2) 분석을 실시하여 분석의 정확성을 결정하였다. 1- 2에 속하는 c2 값은 정확한 것으로 고려되고 1 미만은 매우 정확한 것으로 고려된다.
최고 피분석물 농도를 2배 연속 희석하여 표 2에 나타낸 피분석물 농도에서 완전한 동역학 분석을 수행하였다. HIV1-9 항-RT sdAb는 HIV-1 및 에볼라 VP24 피분석물 모두에 결합하였다.
실시예 3:
HIV1-9 (서열 번호:27) SDAB는 ELISA에서 HIV-1 역전사효소에 결합한다
HIV1-9 항-HIV-1 RT sdAb (서열 번호:27)에 관한 2가지 상이한 샘플들을 ELISA에서 코팅 항원, 2° 항체 및 HRP 농도의 체커보드에 대해 1 μg/mL에서 평가하였다. 코팅 항원은 각 웰 당 0.5, 0.025 및 0.125 μg/mL의 재조합 HIV-1 RT (Creative BioMart) (서열 번호:1)였다. 2차 항체는 1:5,000, 및 1:10,000로 희석시켜 비오티닐화된 토끼 항-라마의 것이었으며, HRP는 1:25,000 및 1:50,000로 희석시켰다. 여러 농도들에 있어서 신호-대-잡음 비 >20로 나타났다. ELISA 결과를 도 1 및 2에 나타낸다.
HIV1-9 항-HIV-1 RT sdAb (서열 번호:27)의 연속 희석 (1μg/mL 내지 0.0001 μg/mL)을 평가하기 위해 3가지 조합이 선택되었다.
결과를 도 3 및 4에 나타낸다. 사용된 2가지 HIV1-9 항-HIV-1 RT sdAb (서열 번호:27) 제재들은 매우 유사한 결과들을 가진다. 0.5 μg/mL 코팅, 1:5,000 희석의 2°항체 및 1:50,000 희석의 HRP에 관한 결과는 HIV1-9 항-HIV-1 RT sdAb (서열 번호:27)의 HIV1 RT (서열 번호:1)에 대한 결합을 보여주었으며 신호-대-잡음 비가 가장 높고 공백값은 약간 낮았다.
실시예 4:
VP24-5 (서열 번호:55) SDAB는 VP24에 결합한다
실시예 2에 기재된 바와 같이 단백질 결합 실험을 수행하였다. 단백질 결합에 사용된 리간드는 VP24-5 (서열 번호:55) 및 STAT3-VHH 14 (서열 번호:56)였다. 이 리간드들은 CM5 센서 칩의 유세포 2 및 4 상에서 각각 427 및 550의 반응 단위 (RU)로 아민 커플링 (EDC/NHS)에 의해 직접 고정화되었다. 유세포 1은 공백으로 두어 바탕 차감에 사용하였다. CM5 칩 상에서 비어있는 부위들은 1M 에탄올 아민으로 차단되었다. 결합 분석을 위해, 피분석물인, VP24 (서열 번호:53)를 센서 칩 위로 흘러가게 하고 실시간으로 모니터하였다. 표 3에서 보는 바와 같이, 관찰된 결합 속도 (ka) 및 해리 속도 (kd)로부터 친화성 상수 (KD= kd/ka)를 계산하였다.
표 4에 나타낸 바와 같이, 최고 피분석물 농도를 2배 연속 희석하여 상이한 피분석물 농도에서 완전한 동역학 분석을 수행하였다.
실시예 5:
VP24-5 (서열 번호:55) SDAB는 ELISA에서 에볼라 VP24 표적에 결합한다
VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)에 관한 2가지 상이한 샘플들을 ELISA에서 코팅 항원, 2°항체 및 HRP 농도의 체커보드에 대해 1 μg/mL에서 평가하였다. 코팅 항원은 각 웰 당 0.5, 0.025 및 0.125 μg/mL의 재조합 에볼라 VP24 (Creative BioMart) (서열 번호:53)였다. 2차 항체는 1:5,000, 및 1:10,000로 희석시켜 비오티닐화된 토끼 항-라마의 것이었다. HRP는 1:10,000 및 1:25,000로 희석하여 사용되었다. ELISA 결과를 도 5 및 6에 나타낸다. 신호-대-잡음 비는 낮았으며 보다 높은 농도로 분석을 반복하였다.
ELISA를 1 및 0.5 μg/mL VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)로 반복하였다. 각 웰 당 0.5 또는 1 μg/mL의 재조합 VP24 (서열 번호:53)를 사용하였다. 2차 항체는 1:1,000, 1:4,000, 1:10,000, 및 1:10,000로 희석시켜 비오티닐화된 토끼 항-라마의 것이었다. HRP는 1:25,000 및 1:50,000로 희석하여 사용되었다. ELISA 결과를 도 7 및 8에 나타낸다.
VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)의 연속 희석 (1μg/mL 내지 0.0001 μg/mL)을 평가하기 위해 3가지 조합이 선택되었다.
결과를 도 9 및 10에 나타낸다. 사용된 2개의 VP24-5 항-에볼라 VP24 sdAb (서열 번호:55) 제재들은 매우 유사한 결과를 가지며, VP24-5 항-에볼라 VP24 sdAb (서열 번호:55)의 재조합 VP24 (서열 번호:53)에 대한 결합을 보여준다.
본 발명을 바람직한 특정 구체예들과 관련하여 상당히 상세하게 기재하였으나, 다른 구체예들이 가능할 수 있다. 예를 들면, 본 발명의 방법들에 관하여 개시된 단계들은, 각 단계가 상기 방법에 필수적임을 나타내고자 하는 것이 아니라 대신 단지 예시적인 단계임을 나타내는 것이다. 그러므로 첨부된 청구범위는 본 출원에 포함된 바람직한 구체예들의 설명에 제한되어서는 안된다. 본 출원에서 인용된 모든 문헌들은 그 전체가 참고로 포함된다.
SEQUENCE LISTING
<110> Singh Biotechnology, LLC
<120> SINGLE DOMAIN ANTIBODIES
<130> 7304-51293-9PCT
<150> US 62/249,868
<151> 2015-11-02
<160> 56
<170> PatentIn version 3.5
<210> 1
<211> 259
<212> PRT
<213> Human immunodeficiency virus type 1
<400> 1
Pro Ile Ser Pro Ile Glu Thr Val Pro Val Lys Leu Lys Pro Gly Met
1 5 10 15
Asp Gly Pro Lys Val Lys Gln Trp Pro Leu Thr Glu Glu Lys Ile Lys
20 25 30
Ala Leu Val Glu Ile Cys Ala Glu Leu Glu Glu Glu Gly Lys Ile Ser
35 40 45
Arg Ile Gly Pro Glu Asn Pro Tyr Asn Thr Pro Val Phe Ala Ile Lys
50 55 60
Lys Lys Asp Ser Thr Lys Trp Arg Lys Leu Val Asp Phe Arg Glu Leu
65 70 75 80
Asn Lys Arg Thr Gln Asp Phe Trp Glu Val Gln Leu Gly Ile Pro His
85 90 95
Pro Ala Gly Leu Lys Lys Lys Lys Ser Val Thr Val Leu Asp Val Gly
100 105 110
Asp Ala Tyr Phe Ser Ile Pro Leu Asp Glu Asp Phe Arg Lys Tyr Thr
115 120 125
Ala Phe Thr Ile Pro Ser Thr Asn Asn Glu Thr Pro Gly Thr Arg Tyr
130 135 140
Gln Tyr Asn Val Leu Pro Gln Gly Trp Lys Gly Ser Pro Ala Ile Phe
145 150 155 160
Gln Ser Ser Met Thr Lys Ile Leu Glu Pro Phe Arg Lys Gln Asn Pro
165 170 175
Asp Ile Val Ile Tyr Gln Tyr Val Asp Asp Leu Tyr Val Gly Ser Asp
180 185 190
Leu Glu Ile Gly Gln His Arg Thr Lys Val Glu Glu Leu Arg Gln His
195 200 205
Leu Trp Arg Trp Gly Phe Tyr Thr Pro Asp Lys Lys His Gln Lys Glu
210 215 220
Pro Pro Phe Leu Trp Met Gly Tyr Glu Leu His Pro Asp Lys Trp Thr
225 230 235 240
Val Gln Pro Ile Val Leu Pro Glu Lys Asp Ser Trp Thr Val Asn Asp
245 250 255
Ile Gln Lys
<210> 2
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 2
gatgtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctgttta cagctacaac acaaactgca tgggttggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcagtt atttatgctg ctggtggatt aacatactat 180
gccgactccg tgaagggccg attcaccatc tcccaggaga atggcaagaa tacggtgtac 240
ctgacgatga accgcctgaa acctgaggac actgccatgt actactgtgc ggcaaagcga 300
tggtgtagta gctggaatcg cggtgaggag tataactact ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 3
<211> 399
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 3
caggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagactc tctgagactc 60
tcctgtgcag cctctggaaa cactgccagt aggttctcca tgggctggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcggct atttctgctg gtggtaggct tacatactat 180
gccgactccg tgaagggccg attcaccatc tcccgagaca acgccaagaa cacgctgtat 240
ctggacatga acaacctgaa acctgaggac actgccatgt actactgtgc cgcaattagt 300
gaccggatga ctggtattca ggctcttgcg gctctaccca gacttcgccc agaagactac 360
ggtaactggg gccaggggac cctggtcacc gtctcctca 399
<210> 4
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 4
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gaccctggtc accgtctcct ca 402
<210> 5
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 5
caggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggccaggg gacccaggtc accgtctcct ca 402
<210> 6
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 6
caggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccaat atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggccaggg gaccctggtc accgtctcct ca 402
<210> 7
<211> 401
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 7
aggtgcagct ggtggagtct gggggagact cggtgcaggc tggagggtct cttcaactct 60
cctgtaaagc ctctggatac acctacaata gtagagtcga tatcagatct atgggctggt 120
tccgccagta tccaggaaag gagcgcgagg gggtcgctac tattaatatt cgtaatagtg 180
tcacatacta tgccgactcc gtgaagggcc gattcaccat ctcccaagac aacgccaaga 240
acacggtgta tctgcaaatg aacgccctga aacctgagga cactgccatg tactactgtg 300
cgttgtcaga cagattcgcg gcgcaggtac ctgccaggta cggaatacgg ccctctgact 360
ataactactg gggccagggg accctggtca ccgtctcctc a 401
<210> 8
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 8
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 9
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 9
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 10
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 10
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc actgtctcct ca 402
<210> 11
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 11
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaagg cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ccattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgctaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 12
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 12
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc agcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 13
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 13
gaggtgcagc tggtggagtc tgggggagac tcagtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 14
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 14
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 15
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 15
gaggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctgttta cagctacaac acaaactgca tgggttggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcagtt atttatgctg ctggtggatt aacatactat 180
gccgactccg tgaagggccg attcaccatc tcccaggaga atggcaagaa cacggtgtac 240
ctgacgatga accgcctgaa acctgaggac actgccatgt actactgtgc ggcaaagcga 300
tggtgtagta gctggaatcg cggtgaggag tataactact ggggccaggg gacccaggtc 360
actgtctcct ca 372
<210> 16
<211> 384
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 16
caggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctggaaa cacctacagt agtagctact gcatgggctg gttccgccag 120
gctccaggga aggaccgcga gggggtcgcg cgtattttca ctcgaagtgg taccacatac 180
tatgccgact ccgtgaaggg ccgattcacc atttcccgtg acaacgccaa gaacacggtg 240
tatctgcaaa tgaacagcct gaaacctgaa gacgctgcca tgtactactg tgcggcagcc 300
caggggggtg cctgcatttc gtttacttcg ttcgcgaaga atttcgtgta ccggggccag 360
gggaccctgg tcactgtctc ctca 384
<210> 17
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 17
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gtcctctgac 360
tataactact ggggtgaggg gaccctggtc accgtctcct ca 402
<210> 18
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 18
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gtcctctgac 360
tataactact ggggtgaggg gaccctggtc accgtctcct ca 402
<210> 19
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 19
caggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc actgtctcct ca 402
<210> 20
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 20
caggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 21
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 21
catgtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gaccctggtc accgtctcct ca 402
<210> 22
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 22
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccaactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tatgactact ggggtgaggg gaccctggtc accgtctcct ca 402
<210> 23
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 23
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaaag cctctggata cacctacaat agtagagtcg atatcagatc tatgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat ggacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 24
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 24
gaggtgcagc tggtggagtc tgggggagac tcggtgcagg ctggagggtc tcttcaactc 60
tcctgtaagg cctctggata cacctacaat agtagagtcg atatcagatc tgtgggctgg 120
ttccgccagt atccaggaaa ggagcgcgag ggggtcgcta ctattaatat tcgtaatagt 180
gtcacatact atgccgactc cgtgaagggc cgattcacca tctcccaaga caacgccaag 240
aacacggtgt atctgcaaat gaacgccctg aaacctgagg acactgccat gtactactgt 300
gcgttgtcag acagattcgc ggcgcaggta cctgccaggt acggaatacg gccctctgac 360
tataactact ggggtgaggg gacccaggtc accgtctcct ca 402
<210> 25
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 25
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Val Tyr Ser Tyr Asn Thr Asn
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Val Ile Tyr Ala Ala Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Glu Asn Gly Lys Asn Thr Val Tyr
65 70 75 80
Leu Thr Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Lys Arg Trp Cys Ser Ser Trp Asn Arg Gly Glu Glu Tyr Asn
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 26
<211> 133
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 26
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Asp
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Thr Ala Ser Arg Phe
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Ser Ala Gly Gly Arg Leu Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Asp Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Ile Ser Asp Arg Met Thr Gly Ile Gln Ala Leu Ala Ala Leu
100 105 110
Pro Arg Leu Arg Pro Glu Asp Tyr Gly Asn Trp Gly Gln Gly Thr Leu
115 120 125
Val Thr Val Ser Ser
130
<210> 27
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Val Tyr Ser Tyr Asn Thr Asn
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Val Ile Tyr Ala Ala Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Glu Asn Gly Lys Asn Thr Val Tyr
65 70 75 80
Leu Thr Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Lys Arg Trp Cys Ser Ser Trp Asn Arg Gly Glu Glu Tyr Asn
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 28
<211> 128
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 28
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Thr Tyr Ser Ser Ser
20 25 30
Tyr Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Asp Arg Glu Gly
35 40 45
Val Ala Arg Ile Phe Thr Arg Ser Gly Thr Thr Tyr Tyr Ala Asp Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Ala Ala Met Tyr Tyr
85 90 95
Cys Ala Ala Ala Gln Gly Gly Ala Cys Ile Ser Phe Thr Ser Phe Ala
100 105 110
Lys Asn Phe Val Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 29
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 29
Glu Val Gln Leu Gly Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Val Tyr Ser Tyr Thr Thr Asn
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Val Ile Tyr Ser Ala Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Gly Lys Asn Thr Val Tyr
65 70 75 80
Leu Thr Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Lys Arg Trp Cys Ser Ser Trp Asn Arg Gly Glu Glu Tyr Asn
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 30
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 30
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Val Tyr Ser Tyr Asn Thr Asn
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Ala
35 40 45
Ala Val Ile Tyr Ala Ala Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Glu Asn Gly Lys Asn Thr Val Tyr
65 70 75 80
Leu Thr Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Lys Arg Trp Cys Ser Ser Trp Asn Arg Gly Glu Glu Tyr Asn
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 31
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 32
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 32
His Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Leu Val Thr Val Ser Ser
130
<210> 33
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 33
Gln Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Ser
130
<210> 34
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Leu Val Thr Val Ser Ser
130
<210> 35
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 35
Gln Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Gln Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 36
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 36
Gln Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 37
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Ser Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Leu Val Thr Val Ser Ser
130
<210> 38
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 38
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asp Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 39
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 39
His Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Gly Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Ser
130
<210> 40
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Val Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 41
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 41
Asp Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 42
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 42
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asn Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Ala
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asp Tyr Trp Gly Glu Gly Thr
115 120 125
Leu Val Thr Val Ser Ser
130
<210> 43
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 43
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn Ser Arg
20 25 30
Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly Lys Glu
35 40 45
Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
65 70 75 80
Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val Pro Thr
100 105 110
Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Gln Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 44
<211> 663
<212> PRT
<213> Homo sapiens
<400> 44
Met Gly Arg Tyr Arg Ile Arg Val Ala Thr Gly Ala Trp Leu Phe Ser
1 5 10 15
Gly Ser Tyr Asn Arg Val Gln Leu Trp Leu Val Gly Thr Arg Gly Glu
20 25 30
Ala Glu Leu Glu Leu Gln Leu Arg Pro Ala Arg Gly Glu Glu Glu Glu
35 40 45
Phe Asp His Asp Val Ala Glu Asp Leu Gly Leu Leu Gln Phe Val Arg
50 55 60
Leu Arg Lys His His Trp Leu Val Asp Asp Ala Trp Phe Cys Asp Arg
65 70 75 80
Ile Thr Val Gln Gly Pro Gly Ala Cys Ala Glu Val Ala Phe Pro Cys
85 90 95
Tyr Arg Trp Val Gln Gly Glu Asp Ile Leu Ser Leu Pro Glu Gly Thr
100 105 110
Ala Arg Leu Pro Gly Asp Asn Ala Leu Asp Met Phe Gln Lys His Arg
115 120 125
Glu Lys Glu Leu Lys Asp Arg Gln Gln Ile Tyr Cys Trp Ala Thr Trp
130 135 140
Lys Glu Gly Leu Pro Leu Thr Ile Ala Ala Asp Arg Lys Asp Asp Leu
145 150 155 160
Pro Pro Asn Met Arg Phe His Glu Glu Lys Arg Leu Asp Phe Glu Trp
165 170 175
Thr Leu Lys Ala Gly Ala Leu Glu Met Ala Leu Lys Arg Val Tyr Thr
180 185 190
Leu Leu Ser Ser Trp Asn Cys Leu Glu Asp Phe Asp Gln Ile Phe Trp
195 200 205
Gly Gln Lys Ser Ala Leu Ala Glu Lys Val Arg Gln Cys Trp Gln Asp
210 215 220
Asp Glu Leu Phe Ser Tyr Gln Phe Leu Asn Gly Ala Asn Pro Met Leu
225 230 235 240
Leu Arg Arg Ser Thr Ser Leu Pro Ser Arg Leu Val Leu Pro Ser Gly
245 250 255
Met Glu Glu Leu Gln Ala Gln Leu Glu Lys Glu Leu Gln Asn Gly Ser
260 265 270
Leu Phe Glu Ala Asp Phe Ile Leu Leu Asp Gly Ile Pro Ala Asn Val
275 280 285
Ile Arg Gly Glu Lys Gln Tyr Leu Ala Ala Pro Leu Val Met Leu Lys
290 295 300
Met Glu Pro Asn Gly Lys Leu Gln Pro Met Val Ile Gln Ile Gln Pro
305 310 315 320
Pro Asn Pro Ser Ser Pro Thr Pro Thr Leu Phe Leu Pro Ser Asp Pro
325 330 335
Pro Leu Ala Trp Leu Leu Ala Lys Ser Trp Val Arg Asn Ser Asp Phe
340 345 350
Gln Leu His Glu Ile Gln Tyr His Leu Leu Asn Thr His Leu Val Ala
355 360 365
Glu Val Ile Ala Val Ala Thr Met Arg Cys Leu Pro Gly Leu His Pro
370 375 380
Ile Phe Lys Phe Leu Ile Pro His Ile Arg Tyr Thr Met Glu Ile Asn
385 390 395 400
Thr Arg Ala Arg Thr Gln Leu Ile Ser Asp Gly Gly Ile Phe Asp Lys
405 410 415
Ala Val Ser Thr Gly Gly Gly Gly His Val Gln Leu Leu Arg Arg Ala
420 425 430
Ala Ala Gln Leu Thr Tyr Cys Ser Leu Cys Pro Pro Asp Asp Leu Ala
435 440 445
Asp Arg Gly Leu Leu Gly Leu Pro Gly Ala Leu Tyr Ala His Asp Ala
450 455 460
Leu Arg Leu Trp Glu Ile Ile Ala Arg Tyr Val Glu Gly Ile Val His
465 470 475 480
Leu Phe Tyr Gln Arg Asp Asp Ile Val Lys Gly Asp Pro Glu Leu Gln
485 490 495
Ala Trp Cys Arg Glu Ile Thr Glu Val Gly Leu Cys Gln Ala Gln Asp
500 505 510
Arg Gly Phe Pro Val Ser Phe Gln Ser Gln Ser Gln Leu Cys His Phe
515 520 525
Leu Thr Met Cys Val Phe Thr Cys Thr Ala Gln His Ala Ala Ile Asn
530 535 540
Gln Gly Gln Leu Asp Trp Tyr Ala Trp Val Pro Asn Ala Pro Cys Thr
545 550 555 560
Met Arg Met Pro Pro Pro Thr Thr Lys Glu Asp Val Thr Met Ala Thr
565 570 575
Val Met Gly Ser Leu Pro Asp Val Arg Gln Ala Cys Leu Gln Met Ala
580 585 590
Ile Ser Trp His Leu Ser Arg Arg Gln Pro Asp Met Val Pro Leu Gly
595 600 605
His His Lys Glu Lys Tyr Phe Ser Gly Pro Lys Pro Lys Ala Val Leu
610 615 620
Asn Gln Phe Arg Thr Asp Leu Glu Lys Leu Glu Lys Glu Ile Thr Ala
625 630 635 640
Arg Asn Glu Gln Leu Asp Trp Pro Tyr Glu Tyr Leu Lys Pro Ser Cys
645 650 655
Ile Glu Asn Ser Val Thr Ile
660
<210> 45
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 45
gaggtgcagc tggtggagtc tgggggaggt tcggtgcagg ctggagggtc tctgaggatc 60
tcctgtacag cctctggatt cacttttgat gacactgaca tgggctggta ccgccagact 120
ctaggaaatg ggtgcgagtt ggtttctcag attagtaatg atggtagtac attctataga 180
gattccgtga agggccgatt caccatctcc tgggaccgcg tcaacaacac ggtgtatctg 240
caaatgagcg ccctgagacc tgaggacacg gccatgtatt actgcaatat caacgggtgt 300
aggagaccct cgtacaatct tcacttgaac gcatggggcc aggggacaca ggtcaccgtc 360
tcctca 366
<210> 46
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 46
caggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgacactg 60
tcctgtgtag cctctggata cggctacagt gccacgtgca tgggctggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcgtct atttcacctt atggtgttag aaccttctat 180
gccgactccg cgaaaggccg attcaccgtc tcccgagaca acgccaagaa cacgctgtat 240
ctgcaaatga acagcctgaa acctgaggac acgtccgtgt actactgtgc ggccggttcg 300
ggcgttggtg tttgttcact ttcgtatcca tacacctact ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 47
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 47
caggtgcagc tggtggagtc tgggggaggc tcggtgcggg ctggagagtc tctgagactc 60
tcctgtgtag cctctagatc catctatgtt tggtactgca tgggctggtt ccgccaggct 120
gcagggaagg agcgcgaggg ggtcggaagt atgttcgttg gtggcggtag gacatattat 180
gacgactccg tcaagggccg attcaccatc tcccaagaca aggccaagaa cacgctgtat 240
ctgcaaatgg acaacctggc acctgaagac actgccatgt attactgtgc ggctgggcgc 300
tgcggtggca actggctgag aagcaatgct ttcgacaaat ggggccaggg gacactggtc 360
accgtctcct ca 372
<210> 48
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 48
gatgtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag ccactggaaa cacctacatt agccgctgca tgggctggtt ccgccagcct 120
ccagggaagg agcgcgaggt ggtcgcacgt atttataccg actctggtaa tacatactat 180
cccgacgccg tggagggccg attcaccatc tcccaagaca acgccaagaa cacgatatat 240
ctgcaaatga acagcctgaa acctgacgac accgccgtgt actactgtgt gctctcagag 300
gccgtctgta caaaagaacc tggggacttt cgttactggg gccaggggac ccaggtcact 360
gtctcctca 369
<210> 49
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 49
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Ile Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Thr
20 25 30
Asp Met Gly Trp Tyr Arg Gln Thr Leu Gly Asn Gly Cys Glu Leu Val
35 40 45
Ser Gln Ile Ser Asn Asp Gly Ser Thr Phe Tyr Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Trp Asp Arg Val Asn Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Ser Ala Leu Arg Pro Glu Asp Thr Ala Met Tyr Tyr Cys Asn
85 90 95
Ile Asn Gly Cys Arg Arg Pro Ser Tyr Asn Leu His Leu Asn Ala Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 50
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 50
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Val Ala Ser Gly Tyr Gly Tyr Ser Ala Thr
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ser Ile Ser Pro Tyr Gly Val Arg Thr Phe Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ser Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ser Gly Val Gly Val Cys Ser Leu Ser Tyr Pro Tyr Thr
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 51
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 51
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Arg Ala Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Arg Ser Ile Tyr Val Trp Tyr
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Ala Gly Lys Glu Arg Glu Gly Val
35 40 45
Gly Ser Met Phe Val Gly Gly Gly Arg Thr Tyr Tyr Asp Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Lys Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asp Asn Leu Ala Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Gly Arg Cys Gly Gly Asn Trp Leu Arg Ser Asn Ala Phe Asp
100 105 110
Lys Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 52
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 52
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Asn Thr Tyr Ile Ser Arg
20 25 30
Cys Met Gly Trp Phe Arg Gln Pro Pro Gly Lys Glu Arg Glu Val Val
35 40 45
Ala Arg Ile Tyr Thr Asp Ser Gly Asn Thr Tyr Tyr Pro Asp Ala Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Ile Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Leu Ser Glu Ala Val Cys Thr Lys Glu Pro Gly Asp Phe Arg Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 53
<211> 190
<212> PRT
<213> Ebola virus
<400> 53
Ala Lys Ala Thr Gly Arg Tyr Asn Leu Ile Ser Pro Lys Lys Asp Leu
1 5 10 15
Glu Lys Gly Val Val Leu Ser Asp Leu Cys Asn Phe Leu Val Ser Gln
20 25 30
Thr Ile Gln Gly Trp Lys Val Tyr Trp Ala Gly Ile Glu Phe Asp Val
35 40 45
Thr His Lys Gly Met Ala Leu Leu His Arg Leu Lys Thr Asn Asp Phe
50 55 60
Ala Pro Ala Trp Ser Met Thr Arg Asn Leu Phe Pro His Leu Phe Gln
65 70 75 80
Asn Pro Asn Ser Thr Ile Glu Ser Pro Leu Trp Ala Leu Arg Val Ile
85 90 95
Leu Ala Ala Gly Ile Gln Asp Gln Leu Ile Asp Gln Ser Leu Ile Glu
100 105 110
Pro Leu Ala Gly Ala Leu Gly Leu Ile Ser Asp Trp Leu Leu Thr Thr
115 120 125
Asn Thr Asn His Phe Asn Met Arg Thr Gln Arg Val Lys Glu Gln Leu
130 135 140
Ser Leu Lys Met Leu Ser Leu Ile Arg Ser Asn Ile Leu Lys Phe Ile
145 150 155 160
Asn Lys Leu Asp Ala Leu His Val Val Asn Tyr Asn Gly Leu Leu Ser
165 170 175
Ser Ile Glu Ile Ile Leu Glu Phe Asn Ser Ser Leu Ala Ile
180 185 190
<210> 54
<211> 486
<212> DNA
<213> Artificial Sequence
<220>
<223> Camelid
<400> 54
atgggtgatg tgcagctggt ggagtctggg ggagactcgg tgcgggctgg agggtctctt 60
caaatgggtg atgtgcagct ggtggagtct gggggagact cggtgcgggc tggagggtct 120
cttcaactct cctgtaaagc ctctggatac acctacaata gtagagtcga tatcagatct 180
atgggctggt tccgccagta tccaggaaag gagcgcgagg gggtcgctac tattaatatt 240
cgtaatagtg tcacatacta tgccgactcc gtgaagggcc gattcaccat ctcccaagac 300
aacgccaaga acacggtgta tctgcaaatg aacgccctga aacctgagga cactgccatg 360
tactactgtg cgttgtcaga cagattcgcg gcgcaggtac ctgccaggta cggaatacgg 420
ccctctgact ataactactg gggtgagggg accctggtca ccgtctcctc aagctctggt 480
ctcgag 486
<210> 55
<211> 141
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 55
Met Gly Asp Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Arg Ala
1 5 10 15
Gly Gly Ser Leu Gln Leu Ser Cys Lys Ala Ser Gly Tyr Thr Tyr Asn
20 25 30
Ser Arg Val Asp Ile Arg Ser Met Gly Trp Phe Arg Gln Tyr Pro Gly
35 40 45
Lys Glu Arg Glu Gly Val Ala Thr Ile Asn Ile Arg Asn Ser Val Thr
50 55 60
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn
65 70 75 80
Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp
85 90 95
Thr Ala Met Tyr Tyr Cys Ala Leu Ser Asp Arg Phe Ala Ala Gln Val
100 105 110
Pro Ala Arg Tyr Gly Ile Arg Pro Ser Asp Tyr Asn Tyr Trp Gly Glu
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ser Ser Gly Leu Glu
130 135 140
<210> 56
<211> 126
<212> PRT
<213> Artificial Sequence
<220>
<223> Camelid
<400> 56
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Thr Tyr Thr Gly Cys Met Gly
20 25 30
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ala Leu
35 40 45
Ser Ser Arg Gly Phe Ala Gly His Tyr Thr Asp Ser Val Lys Gly Arg
50 55 60
Phe Ser Ile Ser Arg Asp Tyr Val Lys Asn Ala Val Tyr Leu Gln Met
65 70 75 80
Asn Thr Val Lys Pro Glu Asp Ala Ala Met Tyr Tyr Cys Ala Ala Arg
85 90 95
Glu Gly Trp Glu Cys Gly Glu Thr Trp Leu Asp Arg Thr Ala Gly Gly
100 105 110
His Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Claims (35)
- 항-인간 면역결핍 바이러스 제1형 (HIV-1) 역전사효소 단일 도메인 항체 (sdAb).
- 서열 번호:27에 제시된 아미노산 서열을 포함하는, 항-HIV-1 역전사효소 sdAb.
- 청구항 1 또는 2에 따른 항-HIV-1 역전사효소 sdAb를 사용하는, 대상체에서 질병의 치료, 질병 발달 의 예방, 또는 질병 재발의 예방 방법으로서, 유효량의 항-HIV-1 역전사효소 sdAb를 필요로 하는 대상체에 투여하는 것을 포함하는 방법.
- 청구항 3에 있어서, 대상체는 포유동물임을 특징으로 하는 방법.
- 청구항 4에 있어서, 포유동물은 인간임을 특징으로 하는 방법.
- 청구항 3에 있어서, 항-HIV-1 역전사효소 sdAb는 하나 또는 그 이상의 화합물들과 조합하여 투여됨을 특징으로 하는 방법.
- 청구항 6에 있어서, 하나 또는 그 이상의 화합물들은 프로테아제 억제제임을 특징으로 하는 방법.
- 청구항 3에 있어서, 필요로 하는 대상체에 대한 유효량의 항-HIV-1 역전사효소 sdAb의 투여는 정맥내 투여, 근육내 투여, 경구 투여, 직장 투여, 장관 투여, 비장관 투여, 안구내 투여, 피하 투여, 경피 투여, 점안액으로서 투여, 코 스프레이로서 투여, 흡입 또는 분무에 의한 투여, 국소 투여, 삽입가능한 (implantable) 약물로서의 투여를 포함함을 특징으로 하는 방법.
- 서열 번호:27에 제시된 아미노산 서열을 포함하는, 단리된 폴리펩티드.
- 청구항 9의 폴리펩티드에 대해 지시되는 항체.
- 다음 단계를 포함하는, 대상체의 샘플에서, 항-HIV-1 역전사효소 sdAb 수준의 측정 방법:
서열 번호:27에 제시된 아미노산 서열을 포함하는 폴리펩티드의 하나 또는 그 이상의 도메인들에 대해 지시되는 마우스 단클론 항체를 생성하는 단계;
대상체로부터 샘플을 얻는 단계;
상기 마우스 단클론 항체 및 상기 샘플로 정량적 면역분석을 수행하여, 대상체에서 sdAb의 양을 결정하는 단계; 및
대상체에서 sdAb의 양을 정량화하는 단계. - 청구항 11에 있어서, 정량적 면역분석은 효소-결합 면역흡착 검사 (ELISA), 특이적 피분석물 표지 및 재포획 검사 (specific analyte labeling and recapture assay, SALRA), 액체 크로마토그래피, 질량 분광법, 형광-활성 세포 분류법, 또는 이의 조합을 포함함을 특징으로 하는 방법.
- 항-에볼라 VP24 단일 도메인 항체 (sdAb).
- 서열 번호:55에 제시된 아미노산 서열을 포함하는, 항-에볼라 VP24 sdAb.
- 청구항 13 또는 14에 따른 항-에볼라 VP24 sdAb를 사용하는, 대상체에서 질병의 치료, 질병 발달 의 예방, 또는 질병 재발의 예방 방법으로서, 유효량의 항-에볼라 VP24 sdAb를 필요로 하는 대상체에 투여하는 것을 포함하는 방법.
- 청구항 15에 있어서, 대상체는 포유동물임을 특징으로 하는 방법.
- 청구항 16에 있어서, 포유동물은 인간임을 특징으로 하는 방법.
- 청구항 15에 있어서, 항-에볼라 VP24 sdAb는 하나 또는 그 이상의 화합물들과 조합하여 투여됨을 특징으로 하는 방법.
- 청구항 18에 있어서, 하나 또는 그 이상의 화합물들은 항-바이러스 화합물임을 특징으로 하는 방법.
- 청구항 14에 있어서, 필요로 하는 대상체에 대한 유효량의 항-에볼라 VP24 sdAb의 투여는 정맥내 투여, 근육내 투여, 경구 투여, 직장 투여, 장관 투여, 비장관 투여, 안구내 투여, 피하 투여, 경피 투여, 점안액으로서 투여, 코 스프레이로서 투여, 흡입 또는 분무에 의한 투여, 국소 투여, 삽입가능한 (implantable) 약물로서의 투여를 포함함을 특징으로 하는 방법.
- 서열 번호:55에 제시된 아미노산 서열을 포함하는, 단리된 폴리펩티드.
- 청구항 21의 폴리펩티드에 대해 지시되는 항체.
- 다음 단계를 포함하는, 대상체의 샘플에서, 항-에볼라 VP24 sdAb 수준의 측정 방법:
서열 번호:55에 제시된 아미노산 서열을 포함하는 폴리펩티드의 하나 또는 그 이상의 도메인들에 대해 지시되는 마우스 단클론 항체를 생성하는 단계;
대상체로부터 샘플을 얻는 단계;
상기 마우스 단클론 항체 및 상기 샘플로 정량적 면역분석을 수행하여, 대상체에서 sdAb의 양을 결정하는 단계; 및
대상체에서 sdAb의 양을 정량화하는 단계. - 청구항 23에 있어서, 정량적 면역분석은 효소-결합 면역흡착 검사 (ELISA), 특이적 피분석물 표지 및 재포획 검사, 액체 크로마토그래피, 질량 분광법, 형광-활성 세포 분류법, 또는 이의 조합을 포함함을 특징으로 하는 방법.
- 항-아라키도네이트 12-리폭시게나아제 (ALOX12) 단일 도메인 항체 (sdAb).
- 서열 번호:49, 서열 번호:50, 서열 번호:51, 또는 서열 번호:52에 제시된 아미노산 서열을 포함하는 항-ALOX12 sdAb.
- 청구항 25 또는 26에 따른 항-ALOX12 sdAb를 사용하는, 대상체에서 질병의 치료, 질병 발달 의 예방, 또는 질병 재발의 예방 방법으로서, 유효량의 항-ALOX12 sdAb를 필요로 하는 대상체에 투여하는 것을 포함하는 방법.
- 청구항 27에 있어서, 대상체는 포유동물임을 특징으로 하는 방법.
- 청구항 28에 있어서, 포유동물은 인간임을 특징으로 하는 방법.
- 청구항 27에 있어서, 항-ALOX12 sdAb는 하나 또는 그 이상의 화합물들과 조합하여 투여됨을 특징으로 하는 방법.
- 청구항 27에 있어서, 필요로 하는 대상체에 대한 유효량의 항-ALOX12 sdAb의 투여는 정맥내 투여, 근육내 투여, 경구 투여, 직장 투여, 장관 투여, 비장관 투여, 안구내 투여, 피하 투여, 경피 투여, 점안액으로서 투여, 코 스프레이로서 투여, 흡입 또는 분무에 의한 투여, 국소 투여, 삽입가능한 약물로서의 투여를 포함함을 특징으로 하는 방법.
- 서열 번호:49, 서열 번호:50, 서열 번호:51, 또는 서열 번호:52에 제시된 아미노산 서열을 포함하는, 단리된 폴리펩티드.
- 청구항 32의 폴리펩티드에 대해 지시되는 항체.
- 다음 단계를 포함하는, 대상체의 샘플에서, 항-ALOX12 sdAb 수준의 측정 방법:
서열 번호:49, 서열 번호:50, 서열 번호:51, 또는 서열 번호:52에 제시된 아미노산 서열을 포함하는 폴리펩티드의 하나 또는 그 이상의 도메인들에 대해 지시되는 마우스 단클론 항체를 생성하는 단계;
대상체로부터 샘플을 얻는 단계;
상기 마우스 단클론 항체 및 상기 샘플로 정량적 면역분석을 수행하여, 대상체에서 sdAb의 양을 결정하는 단계; 및
대상체에서 sdAb의 양을 정량화하는 단계. - 청구항 34에 있어서, 정량적 면역분석은 효소-결합 면역흡착 검사 (ELISA), 특이적 피분석물 표지 및 재포획 검사, 액체 크로마토그래피, 질량 분광법, 형광-활성 세포 분류법, 또는 이의 조합을 포함함을 특징으로 하는 방법.
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