KR20240027701A - 동결건조 제형의 재구성 방법 - Google Patents
동결건조 제형의 재구성 방법 Download PDFInfo
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- KR20240027701A KR20240027701A KR1020247001736A KR20247001736A KR20240027701A KR 20240027701 A KR20240027701 A KR 20240027701A KR 1020247001736 A KR1020247001736 A KR 1020247001736A KR 20247001736 A KR20247001736 A KR 20247001736A KR 20240027701 A KR20240027701 A KR 20240027701A
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Abstract
본 명세서에는 (a) 폴리펩티드, 당류, 계면활성제 및 완충제를 포함하는 동결건조 제형을 방향족 알코올, 페놀계 화합물 또는 방향족 측쇄를 갖는 아미노산을 포함하는 희석제로 재구성시키는 단계 및 (b) 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 12시간 이내에 투여하는 단계를 포함하는 방법이 기재되며, 여기서 폴리펩티드는 이중특이적 항체 작제물, 예컨대, 인간 DLL3 및 인간 CD3에 결합하는 이중특이적 항체 작제물이고, 선택적으로 서열번호 75 및 서열번호 9의 아미노산 서열을 포함한다.
Description
본 개시내용은 단백질 치료제 및 사용 방법의 분야에 관한 것이다.
관련 출원에 대한 상호 참조 및 참조에 의한 원용
본 출원은 2021년 6월 30일자로 출원된 미국 가출원 제63/216,616호에 대한 이익을 주장하며, 이의 전체 내용은 본 명세서에 참조에 의해 원용된다.
본 명세서와 동시에 제출되며 다음과 같이 확인되는 컴퓨터로 판독 가능한 뉴클레오티드/아미노산 서열목록은 그 전체가 참조로서 포함된다: "56395_Seqlisting.txt"인, 2022년 6월 29일에 생성된 362,780 바이트의 ASCII(텍스트) 파일.
현재 재조합 단백질과 같은 단백질-기반 약제는 상업적 규모의 정제 공정의 진보 덕분에 최초 제조 시 높은 순도로 얻어질 수 있다. 그러나, 단백질은 아주 조금만 안정적이고, 화학적 및 물리적으로 매우 분해되기 쉽다. 화학적 분해는 공유 결합에 관련된 변형, 예컨대, 탈아미드화, 산화, 절단, 클리핑(clipping)/단편화, 새로운 디설파이드 브릿지의 형성, 가수분해, 이성질체화 또는 탈글리코실화를 지칭한다. 물리적 분해는 단백질 언폴딩, 표면에 대한 바람직하지 않은 흡착 및 응집을 포함한다. 이러한 물리적 및 화학적 불안정성의 취급은 단백질 약제의 개발에서 가장 힘든 작업 중 하나이다(Chi et al., Pharm Res, Vol. 20, No. 9, Sept 2003, pp. 1325-1336, Roberts, Trends Biotechnol. 2014 Jul;32(7):372-80).
응집은 단백질 제형에서 관찰되는 물리적 불안정성의 주요 유형이다. 이는 초기의 고유한, 접힌 단백질로부터 고분자량 종(high molecular weight species: HMW)으로의 조립이다. 반감기 연장된 이중특이적 T 세포 관여(bispecific T cell engaging), 항원 결합 폴리펩티드, 예컨대, 반감기 연장 양태, 예컨대, Fc-분자를 포함하는 이중특이적 T 세포 관여자(BiTE®) 분자는 단백질 응집 및/또는 다른 분해 사건이 일어나기 쉽다. BiTE® 분자의 단백질 응집은 그것이 치료 단백질의 생물학적 활성도를 손상시킬 수 있기 때문에 문제가 된다. 추가로, (인간화 또는 완전 인간 단백질의 경우라 할지라도) 응집된 단백질의 존재는, 환자가 활성 단백질 단량체에 대한 면역 반응을 발달시킬 위험을 증가시켜, 중화 항체 및 약물 저항성 또는 다른 유해한 부작용을 초래할 수 있다는 우려가 있다(Mahler J Pharm Sci. 2009Sep;98(9):2909-34). 단백질 응집물은 예를 들어, 하류 가공의 연마 단계에서 불순물로 제거되지만, 임상 현장으로 배송되고 임상의가 취급한 후에 응집물이 형성될 수 있다.
환자에게 투여하기 위해 제조된 제형 중 고분자량 종의 양 및 치료 시점에 단백질 치료제를 사용하는 것과 연관된 불편함을 최소화하기 위한 제형 및 방법이 당업계에 필요하다.
본 개시내용은 (a) 폴리펩티드, 당류, 계면활성제 및 완충제를 포함하는 동결건조 제형을 방향족 알코올, 페놀계 화합물 또는 방향족 측쇄를 갖는 아미노산을 포함하는 희석제로 재구성시키는 단계 및 (b) 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 12시간 이내에 투여하는 단계를 포함하는 방법을 제공한다. 다양한 양태에서, 폴리펩티드는 이중특이적 항체 작제물이다. 다양한 양태에서, 폴리펩티드는 인간 DLL3 및 인간 CD3, 예컨대, 서열번호 75 및 서열번호 9의 아미노산 서열을 포함하는 폴리펩티드에 결합한다. 선택적으로, 희석제는 벤질 알코올, 페놀, m-크레졸 또는 페닐알라닌을 포함한다. 또한 선택적으로, 재구성된 제형의 pH는 약 4 내지 약 7이고/이거나 재구성된 제형은 약 1 ㎎/㎖ 내지 약 20 ㎎/㎖의 폴리펩티드를 포함한다. 다양한 양태에서, 완충제는 글루타메이트 완충제이고/이거나, 당류는 수크로스이고/이거나 계면활성제는 폴리소르베이트 80이다. 예를 들어, 예시적인 양태에서, 동결건조 전에 제형은 15 mM의 글루타메이트, 9%(w/V)의 수크로스 및 0.01%(w/V)의 폴리소르베이트 80을 포함하되, 제형은 4.2의 pH를 갖는다. 다양한 양태에서, 대상체는 암, 예컨대, 소세포폐암(small cell lung cancer: SCLC), 비소세포폐암(non-small cell lung cancer: NSCLC), 신경교종, 교모세포종, 흑색종, 신경내분비 전립선암, 신경내분비 췌장암, 간모세포종 또는 간세포 암종을 앓고 있다.
본 명세서의 다양한 실시형태는 다양한 상황 하에서 "포함하는"이라는 언어를 사용하여 제시되지만, "이루어진" 또는 "본질적으로 이루어진"이라는 언어를 사용하여 관련된 실시형태가 또한 기재될 수 있다는 것이 이해되어야 한다. 본 명세서는 특징을 "포함하는" 것으로 설명된 실시형태가 해당 특징으로 "이루어진" 또는 해당 특징으로 "본질적으로 이루어진" 실시형태를 포함하는 것으로 고려한다. 단수의 용어는 하나 이상을 지칭하며, 예를 들어, "면역글로불린 분자"는 하나 이상의 면역글로불린 분자를 표시하는 것으로 이해된다. 이렇게 해서 단수의 용어, "하나 이상" 및 "적어도 하나"는 본 명세서에서 상호 호환적으로 사용될 수 있다.
또한 값의 범위를 기재할 때, 기재하고 있는 특징은 범위 내에서 발견되는 개개 값일 수 있다는 것이 이해되어야 한다. 예를 들어, "약 pH 4 내지 약 pH 6의 pH"는 pH 4, 4.2, 4.6, 5.1, 5.5 등, 및 이러한 값 사이의 임의의 값일 수 있지만, 이들로 제한될 수 없다. 추가적으로, "약 pH 4 내지 약 pH 6의 pH"는, 해당 제형의 pH가 저장하는 동안 pH 4 내지 pH 6 범위에서 2의 pH 단위로 변함을 의도하는 것으로 해석되어서는 안 되고, 오히려 값은 용액의 pH에 대해 해당 범위에서 선택될 수 있고, pH는 대략 해당 pH에서 완충된 채로 남아있다는 의미로 해석되어서는 안 된다. 본 명세서에 기재된 임의의 범위에서, 범위의 양 종점은 범위에 포함된다. 그러나, 해당 표현은 또한, 낮은 쪽 종점 및/또는 높은 쪽 종점이 제외된 동일한 범위를 고려한다.
용어 "약"이 사용될 때, 열거된 숫자에 해당 열거된 숫자의 5%, 10%, 15% 이상을 더하거나 뺀 것을 의미한다. 의도한 실제 변동은 문맥으로부터 결정할 수 있다.
본 발명의 추가적인 특징 및 변화는 도면, 상세한 설명 및 첨부된 청구범위를 포함하는 본 출원의 전문으로부터 당업자에게 분명할 것이며, 모든 이러한 특징은 본 개시내용의 양태로서 의도된다. 마찬가지로, 본 명세서에 기재된 본 발명의 특징은 또한, 특징의 조합이 본 발명의 양태 또는 실시형태로서 상기 구체적으로 언급되는지의 여부와 상관없이, 본 발명의 양태로서 의도되는 추가적인 실시형태에 재조합될 수 있다. 또한, 본 발명에 중요한 것으로 본 명세서에 기재된 한정만이 그러한 것으로 간주되며, 중요한 것으로 본 명세서에 기재되지 않은 한정이 없는 본 발명의 변형은 본 발명의 양태로서 의도된다.
특허, 특허 출원, 문헌 간행물 등을 포함하는 본 명세서에 인용된 모든 참고 문헌은 이들의 전문이 본 명세서에 참조로 포함되어 있다.
도 1은 주사용 멸균수(sWFI, 어두운 색 원), 0.9% 벤질 알코올을 포함하는 WFI(bWFI, 어두운 색 삼각형), 염수("x"), 0.9% 벤질 알코올을 포함하는 염수(빈 삼각형), 폴리소르베이트 80(빈 다이아몬드) 또는 정맥내 용액 안정화제(IVSS, 어두운 색 다이아몬드)를 사용한 동결건조 제형의 재구성 후 시간(Hr)(x축)에 따른 크기 배제 크로마토그래프(SEC)(y축)에 의해서 인식된 고분자량 종(HMW%)의 백분율을 도시한 선 그래프이다. 연구를 8℃에서 수행하였다.
도 2는 주사용 멸균수(sWFI, 어두운 색 원 = 8℃, 빈 원 = 25℃), 페닐알라닌(어두운 색 정사각형= 8℃, 빈 정사각형 = 25℃) 또는 0.9% 벤질 알코올을 포함하는 WFI(bWFI, 어두운 색 삼각형 = 8℃, 빈 삼각형 = 25℃)를 사용하여 8℃ 및 25℃에서 동결건조 제형의 재구성 후 시간(Hr)(x축)에 따른 크기 배제 크로마토그래프(SEC)(y축)에 의해서 인식된 고분자량 종(HMW%)의 백분율을 도시한 선 그래프이다
도 3은 주사용 멸균수(sWFI, 어두운 색 원), 페닐알라닌(Phe, 어두운 색 정사각형), 페놀("x"), m-크레졸(어두운 색 다이아몬드) 또는 0.9%의 벤질 알코올을 포함하는 WFI(bWFI, 어두운 색 삼각형)을 사용한 동결건조 제형의 재구성 후 시간(Hr)(x축)에 따른 크기 배제 크로마토그래프(SEC)(y축)에 의해서 인식된 고분자량 종(HMW%)의 백분율을 도시한 선 그래프이다. 연구를 8℃에서 수행하였다.
도 4는 0.9%의 벤질 알코올을 포함하는 WFI를 사용한 동결건조 제형의 재구성 후 시간(분)(x축)에 따른 크기 배제 크로마토그래프(SEC)(y축)에 의해서 인식된 고분자량 종(HMW%)의 백분율을 도시한 선 그래프이다. 연구를 25℃에서 수행하였다. 8℃에서 SEC 측정을 수행하였다. 2개의 선은 2개의 동결건조된 샘플에서 수행된 별개의 분석을 나타낸다.
도 5는 서열번호 75 및 9를 포함하는 동결건조된 BiTE® 분자의 재구성 후 고분자량 종의 해리에 대한 벤질 알코올의 상이한 농도의 효과를 도시한 막대 그래프이다. 벤질 알코올 농도는 x축(1.0 mM, 10.0 mM, 41.6 mM 및 83.2 mM)에 제시하고, t90% hr은 y축에 제시한다.
도 6은 본 개시내용에 언급된 다양한 서열을 열거한 표이다.
도 2는 주사용 멸균수(sWFI, 어두운 색 원 = 8℃, 빈 원 = 25℃), 페닐알라닌(어두운 색 정사각형= 8℃, 빈 정사각형 = 25℃) 또는 0.9% 벤질 알코올을 포함하는 WFI(bWFI, 어두운 색 삼각형 = 8℃, 빈 삼각형 = 25℃)를 사용하여 8℃ 및 25℃에서 동결건조 제형의 재구성 후 시간(Hr)(x축)에 따른 크기 배제 크로마토그래프(SEC)(y축)에 의해서 인식된 고분자량 종(HMW%)의 백분율을 도시한 선 그래프이다
도 3은 주사용 멸균수(sWFI, 어두운 색 원), 페닐알라닌(Phe, 어두운 색 정사각형), 페놀("x"), m-크레졸(어두운 색 다이아몬드) 또는 0.9%의 벤질 알코올을 포함하는 WFI(bWFI, 어두운 색 삼각형)을 사용한 동결건조 제형의 재구성 후 시간(Hr)(x축)에 따른 크기 배제 크로마토그래프(SEC)(y축)에 의해서 인식된 고분자량 종(HMW%)의 백분율을 도시한 선 그래프이다. 연구를 8℃에서 수행하였다.
도 4는 0.9%의 벤질 알코올을 포함하는 WFI를 사용한 동결건조 제형의 재구성 후 시간(분)(x축)에 따른 크기 배제 크로마토그래프(SEC)(y축)에 의해서 인식된 고분자량 종(HMW%)의 백분율을 도시한 선 그래프이다. 연구를 25℃에서 수행하였다. 8℃에서 SEC 측정을 수행하였다. 2개의 선은 2개의 동결건조된 샘플에서 수행된 별개의 분석을 나타낸다.
도 5는 서열번호 75 및 9를 포함하는 동결건조된 BiTE® 분자의 재구성 후 고분자량 종의 해리에 대한 벤질 알코올의 상이한 농도의 효과를 도시한 막대 그래프이다. 벤질 알코올 농도는 x축(1.0 mM, 10.0 mM, 41.6 mM 및 83.2 mM)에 제시하고, t90% hr은 y축에 제시한다.
도 6은 본 개시내용에 언급된 다양한 서열을 열거한 표이다.
현재 치료용 생명공학 제품의 고품질 및 내인성 인간 단백질에 대한 재조합 인간 단백질 및 항체의 유사성에 불구하고, 단백질 불안정성은 중요한 문제이다. 치료용 항체 작제물 제형의 취급은, 치료적 유효성에 부정적으로 영향을 미치고 환자에 대한 잠재적 면역원성을 증가시키는 분해 및 응집을 최소화하면서 보다 고차의 단백질 구조를 유지하여야 하기 때문에, 상당한 어려움과 연관된다. 다수의 단백질 치료제는 저장 및 수송과 연관된 문제를 해결하기 위해서 동결건조된다. 그러나 임상 현장에서의 치료제의 취급 및 준비는 원하지 않는 면역 반응 또는 부작용을 유발하거나 전반적인 효능에 영향을 줄 수 있는 바람직하지 않은 고분자량 종의 형성을 포함하여 불안정성을 촉진하는 조건을 도입한다. 예를 들어, 본 명세서에 기재된 이중특이적 T 세포 관여 항원 결합 폴리펩티드는 특정 조건 하에서 동결건조 제형의 재구성 시 응집물을 형성하는 경향을 갖는다. HMW 종의 수준은 시간 경과에 해리될 수 있지만, "평형"에 도달하는 데(즉, HMW 종의 꾸준한 목표 수준에 도달하는 데) 필요한 시간은 상당할 수 있다. 예를 들어, 본 명세서에 기재된 BiTE® 분자를 포함하는 동결건조 제형을 주사용수에 재구성하면 HMW 종의 형성이 급증하는데, 이는 8℃에서 해리시키는 데 24시간 초과가 필요하고 25℃에서는 12시간 초과가 필요하다. 이는 동결건조 제형이 HMW 종을 최소화하기 위한 노력으로 대상체에게 투여하기 전에 연장된 시간 기간 동안 재구성되고 저장되기 때문에 임상 현장에서 문제를 나타낸다. 이는 불편하고, 재구성된 제형을 위한 추가 저장 공간이 필요하며, 안정성에 추가 영향을 미칠 수 있는 개입 층을 추가한다. 놀랍게도, 방향족 알코올(예를 들어, 벤질 알코올), 페놀계 화합물(예를 들어, 페놀 또는 m-크레졸) 또는 방향족 측쇄를 갖는 아미노산(페닐알라닌)을 포함하는 희석제를 사용하여 본 명세서에 기재된 폴리펩티드의 동결건조 제형을 재구성시키는 것은 재구성된 조성물 중 HMW 종이 해리되는 데 필요한 시간을 상당히 감소시킨다. 따라서 재구성과 투여 사이의 시간이 단축되어 임상의와 환자에게 실질적인 이점을 제공한다.
본 개시내용은 (a) 폴리펩티드, 당류, 계면활성제 및 완충제를 포함하는 동결건조 제형을 방향족 알코올(예를 들어, 벤질 알코올), 페놀계 화합물(예를 들어, 페놀 또는 m-크레졸) 또는 방향족 측쇄를 갖는 아미노산(페닐알라닌)을 포함하는 희석제로 재구성시키는 단계 및 (b) 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 12시간 이내에 투여하는 단계를 포함하는 방법을 제공한다. 다양한 양태에서, 폴리펩티드는 인간 DLL3 및 인간 CD3에 결합하고, 선택적으로 서열번호 75 및 서열번호 9를 포함한다.
본 개시내용의 다양한 양태를 이하에 기재한다. 섹션 명칭의 사용은 단지 읽기의 편의를 위한 것이고, 특히 제한하려는 의도는 아니다. 전체 문서는 통합된 개시내용으로 여겨지도록 의도되고, 본 명세서에 기재된 특징의 모든 조합이 고려되는 것으로 이해되어야 한다.
폴리펩티드
예시적인 양태에서, 동결건조 제형의 폴리펩티드는 항체 또는 면역글로불린-유사 작제물인데, 이것은 전통적인 항체 포맷 및 이의 항원-결합 단편뿐만 아니라 항원 결합을 허용하는 항체 구조 특징에 기초한 작제물을 포함한다. 용어 "항체"는 온전한 항원 결합 면역글로불린을 지칭한다. 항체는 IgG1, IgG2, IgG3 또는 IgG4 중 어느 하나를 포함하는 IgA, IgD, IgE, IgG 또는 IgM 항체일 수 있다. 다양한 양태에서, 온전한 항체는 2개의 전장 중쇄 및 2개의 전장 경쇄를 포함한다. 항체는 가변 영역 및 불변 영역을 갖는다. IgG 형식에서, 가변 영역은 일반적으로 약 100개 내지 110개 이상의 아미노산이고, 3개의 상보성 결정 영역(CDR)을 포함하고, 주로 항원 인식을 담당하고, 상이한 항원에 결합하는 다른 항체들 중에서 실질적으로 상이하다. 가변 영역은 전형적으로 적어도 3개의 중쇄 또는 경쇄 CDR(문헌[Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Public Health Service N.I.H., Bethesda, Md.]; 또한 문헌[Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342: 877-883] 참조)을 프레임워크 영역(문헌[Kabat et al., 1991]에 의하면, 프레임워크 영역 1~4인, FR1, FR2, FR3 및 FR4로 표기됨; 또한 상기 문헌[Chothia and Lesk, 1987] 참조) 내에 포함한다. 불변 영역은 항체가 면역계의 세포와 분자를 동원할 수 있게 한다.
다양한 양태에서, 동결건조 제형의 단백질 또는 폴리펩티드는 2개의 항원 표적에 결합한다는 점에서 "이중특이적"이다. 2개 초과의 상이한 항원 표적(예를 들어, 3개의 상이한 항원 표적)에 결합하는 "다중특이적" 작제물이 또한 고려된다. "이중특이적" 항체 작제물은 일반적으로 제1 결합 도메인 및 제2 결합 도메인을 포함하되, 제1 결합 도메인은 하나의 항원 또는 표적(예를 들어, 표적 세포 표면 항원)에 결합하고, 제2 결합 도메인은 다른 항원 또는 표적(예를 들어, CD3)에 결합한다. 따라서, 항체 작제물은 선택적으로 두 상이한 항원 또는 표적에 대한 특이성을 포함한다. 용어 "표적 세포 표면 항원"은 세포에 의해 발현되고, 본 명세서에 기재된 바와 같은 항체 작제물에 접근 가능하도록 세포 표면에 존재하는 항원 구조를 지칭한다. 이는 단백질, 바람직하게는 단백질의 세포외 부분 또는 탄수화물 구조, 바람직하게는 단백질의 탄수화물 구조, 예컨대, 당단백질일 수 있다.
다중특이적(예를 들어, 이중특이적) 항체 및/또는 다중특이적(예를 들어, 이중특이적) 항체 작제물은 종래의 이중특이적 면역글로불린(예를 들어, BsIgG), 첨부된 하나 이상의 항원 결합 도메인을 포함하는 IgG(예를 들어, 경쇄 또는 중쇄의 아미노 또는 카르복시 말단은 부가적인 항원 결합 도메인, 예를 들어 단일 도메인 항체 또는 쌍을 이룬 항체 가변 도메인(예를 들어, Fv 또는 scFv)에 연결됨), BsAb 단편(예를 들어, 이중특이적 단일 쇄 항체), 다중특이적(예를 들어, 이중특이적) 융합 폴리펩티드(예를 들어, 효과기 모이어티에 융합된 항원 결합 도메인), 및 BsAb 접합체를 포함하지만 이들로 제한되지 않는다. 예를 들어, 문헌[Spiess et al., Molecular Immunology 67(2) Part A: 97-106 (2015)]을 참조하며, 이는 다양한 이중특이적 포맷을 기재하고 본 명세서에 참조에 의해 포함된다. 이중특이적 항체 작제물의 예는 디아바디, 단일 쇄 디아바디, 탠덤 scFv, 이중특이적 T 세포 관여자(BiTE®) 포맷(링커에 의해서 연결된 2개의 단일 쇄 가변 단편(scFv)으로 이루어진 융합 단백질), Fab2 이중특이체, 단일 쇄 Fab2 이중특이체뿐만 아니라 전장 항체(예를 들어, 다중특이적 작제물의 조립을 용이하게 하는 Fc 돌연변이를 갖는 전장 항체)를 포함하는 조작된 작제물을 포함하지만 이들로 제한되지 않는다. 본 개시내용은 또한 선택적으로 링커에 의해서 연결된 적어도 하나의 단일 도메인 항체(예를 들어, 2개의 단일 도메인 항체) 및 하나의 scFv를 포함하는 scFv-단일 도메인 항체를 고려한다. 또한 예를 들어, 문헌[Chames & Baty, 2009, mAbs 1[6]:1-9; and Holliger & Hudson, 2005, Nature Biotechnology 23[9]:1126-1136; Wu et al., 2007, Nature Biotechnology 25[11]:1290-1297; Michaelson et al., 2009, mAbs 1[2]:128-141]; 국제 특허 공개 제2009032782호 및 제2006020258호; 문헌[Zuo et al., 2000, Protein Engineering 13[5]:361-367]; 미국 특허 출원 공개 제20020103345호; 문헌[Shen et al., 2006, J Biol Chem 281[16]:10706-10714; Lu et al., 2005, J Biol Chem 280[20]:19665-19672; 및 Kontermann, 2012 MAbs 4(2):182]을 참조하며, 이들 모두는 본 명세서에 명확하게 포함된다. 다양한 양태에서, 폴리펩티드는 BiTE® 또는 BiTE® HLE 작제물이다.
용어 "결합 도메인"은 표적 분자(항원), 예컨대, CDH19, MSLN, DLL3, FLT3, EGFRvlll, BCMA, PSMA, CD33, CD19, CD70, CLDN18.2, MUC17 또는 CD3 상의 주어진 표적 에피토프 또는 주어진 표적 부위에 (특이적으로) 결합하는(즉, 이들과 상호작용하거나 이들을 인식하는) 도메인을 지칭한다. 이중특이적 항체 작제물에서, 예를 들어, (예를 들어, CDH19, MSLN, DLL3, FLT3, EGFRvIII, BCMA, PSMA, CD33, CD19, CD70, CLDN18.2 또는 MUC17을 인식하는) 제1 결합 도메인의 구조 및 기능, 및 바람직하게는 (CD3을 인식하는) 제2 결합 도메인의 구조 및 기능은 항체의, 예를 들어, 전장 또는 전체 면역글로불린 분자의 구조 및/또는 기능에 기반한다. 대안적으로, 구조 및 기능은 항체 또는 이의 단편의 가변 중쇄(VH) 및/또는 가변 경쇄(VL) 도메인으로부터 도출된다. 바람직하게는, 제1 결합 도메인은 3개의 경쇄 CDR(즉, VL 영역의 CDR1, CDR2 및 CDR3) 및/또는 3개의 중쇄 CDR(즉, VH 영역의 CDR1, CDR2 및 CDR3)의 존재를 특징으로 한다. 제2 결합 도메인은 바람직하게는 또한 표적 결합을 가능하게 하는 항체의 최소 구조 요건을 포함한다. 더 바람직하게는, 제2 결합 도메인은 적어도 3개의 경쇄 CDR(즉, VL 영역의 CDR1, CDR2 및 CDR3) 및/또는 3개의 중쇄 CDR(즉, VH 영역의 CDR1, CDR2 및 CDR3)을 포함한다. 다양한 양태에서, 항원 결합 도메인 중 하나 이상은 인간이거나 인간화되거나 키메라이다.
특정 실시형태에서, 동결건조된 단백질은 종양 항원(예를 들어, DLL3))에 결합하는 제1 결합 도메인, T 세포의 표면에서 인간 CD3에 결합하는 제2 결합 도메인 및 임의로, 아미노에서 카르복실 순서로 힌지-CH2 도메인-CH3 도메인-링커-힌지-CH2 도메인-CH3 도메인을 포함하는 제3 도메인을 포함하는 이중특이적 항체 작제물(예를 들어, 이중특이적 T 세포 관여 항원 결합 폴리펩티드)이다. 일부 양태에서, 제1 및 제2 결합 도메인 각각은 VH 영역 및 VL 영역을 포함한다.
항원 결합 폴리펩티드의 결합 도메인 및 가변 도메인(VH/VL)은 펩티드 링커(스페이서 펩티드)를 포함할 수 있거나 포함하지 않을 수 있다. 펩티드 링커는 하나의 가변 및/또는 결합 도메인을 또 다른 가변 및/또는 결합 도메인에 연결할 수 있다. 펩티드 링커는 또한 제3 도메인을 이중특이적 T 세포 관여, 항원 결합 폴리펩티드의 다른 도메인에 융합시키는 데 사용될 수 있다. 적합한 펩티드 링커 중에는 미국 특허 제4,751,180호 및 제4,935,233호 또는 국제 특허 출원 공개 번호 WO 88/09344에 기재된 것들이 있으며, 이의 개시내용은 그 전체가 본 명세서에 참조에 의해 원용된다. 펩티드 링커는 또한 본 명세서에 기재된 이중특이적 T 세포 관여 항원 결합 폴리펩티드에 다른 도메인 또는 모듈 또는 영역(예를 들어, 반감기 연장 도메인)을 부착시키기 위해 사용될 수 있다.
일부 양태에서, 단백질 또는 폴리펩티드는 제1 불변 영역 면역글로불린 도메인을 제외한 항체의 불변 영역을 포함하는 폴리펩티드를 지칭하는 "Fc" 또는 "Fc 영역" 또는 "Fc 도메인"의 전부 또는 일부를 포함하는 제3 도메인을 포함한다. 따라서, "Fc 도메인"은 IgA, IgD, 및 IgG의 마지막 2개의 불변 영역 면역글로불린 도메인, IgE 및 IgM의 마지막 3개의 불변 영역 면역글로불린 도메인, 및 이들 도메인에 N 말단인 가요성 힌지를 지칭한다. IgA 및 IgM의 경우, Fc는 J 쇄를 포함할 수 있다. IgG의 경우, Fc 도메인은 면역글로불린 도메인 Cγ2 및 Cγ3(Cγ2 및 Cγ3) 및 Cγ1(Cγ1)과 Cγ2(Cγ2) 사이의 하부 힌지 영역을 포함한다. 이중특이적 T 세포 관여 항원 결합 폴리펩티드는 바람직하게는 IgG 항체(이는 IgG1, IgG2, IgG3, 및 IgG4를 포함하지만 이들로 제한되지 않는 여러 서브클래스를 포함함)이다. Fc 영역의 경계가 변할 수 있지만, 인간 IgG 중쇄 Fc 영역은 보통 카르복실 말단에 대한 잔기 C226 또는 P230을 포함하도록 정의되고, 여기서 넘버링은 Kabat에서와 같이 EU 지표에 따른다. 일부 양태에서, 예를 들어, 하나 이상의 FcγR 수용체 또는 FcRn 수용체에 대한 결합을 변경하기 위해 Fc 영역에 아미노산 변형이 이루어진다.
일부 실시형태에서, 본 명세서에 기재된 동결건조 제형은 표적 세포 표면 항원에 결합하는 제1 결합 도메인 및 T 세포의 표면 상에서 인간 CD3에 결합하는 제2 결합 도메인을 포함하는 이중특이적 항체 작제물을 포함한다. 본 명세서에 기재된 임의의 양태에서, 표적 세포 표면 항원은 CDH19, MSLN, DLL3, FLT3, EGFR, EGFRvlll, BCMA, PSMA, CD33, CD19, CD70, MUC17 또는 CLDN18.2이다. 다양한 양태에서, 이중특이적 항체 작제물은 아미노에서 카르복실 순서로, 힌지-CH2 도메인-CH3 도메인-링커-힌지-CH2 도메인-CH3 도메인을 포함하는 제3 도메인을 포함한다. 일부 실시형태에서, 제1 및 제2 결합 도메인 각각은 VH 영역 및 VL 영역을 포함한다. 따라서, 일부 실시형태에서, 본 명세서에 기재된 제형은 인간 CD3 및 인간 CDH19, 또는 인간 CD3 및 인간 MSLN, 또는 인간 CD3 및 인간 DLL3, 또는 인간 CD3 및 인간 FLT3, 또는 인간 CD3 및 인간 EGFRvIII, 또는 인간 CD3 및 인간 BCMA, 또는 인간 CD3 및 PSMA, 또는 인간 CD3 및 인간 CD33, 또는 인간 CD3 및 인간 CD19, 인간 CD3 및 인간 CD70, 또는 인간 CD3 및 인간 MUC17, 또는 인간 CD3 및 인간 CLDN18.2에 결합하는 이중특이적 항체 작제물을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물의 제1 결합 도메인은 (a) 서열번호 24 내지 29, (b) 서열번호 34 내지 39, (c) 서열번호 78 내지 83, (d) 서열번호 10 내지 15, (e) 서열번호 46 내지 51, (f) 서열번호 88 내지 93, (g) 서열번호 67 내지 72, (h) 서열번호 56 내지 61, (i) 서열번호 112 내지 117, (j) 서열번호 100 내지 105, (k) 서열번호 148 내지 153, 서열번호 157 내지 162, 또는 서열번호 166 내지 171, 또는 서열번호 175 내지 180, (l) 서열번호 132 내지 137, 또는 (m) 서열번호 123 내지 128에 제시된 6개 CDR의 세트를 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물의 제1 결합 도메인은 서열번호 30, 40, 84, 16, 17, 52, 94, 73, 62, 118, 154, 163, 172, 181, 106, 138, 143 또는 129에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VH 영역을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물의 제1 결합 도메인은 서열번호 30, 40, 84, 16, 17, 52, 94, 73, 62, 118, 154, 163, 172, 181, 106, 138, 143 또는 129에 제시된 아미노산 서열을 포함하는 VH를 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물의 제1 결합 도메인은 서열번호 31, 41, 85, 18, 19, 53, 95, 74, 63, 119, 155, 164, 173, 182, 107, 139, 144 또는 130에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VL 영역을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물의 제1 결합 도메인은 서열번호 31, 41, 85, 18, 19, 53, 95, 74, 63, 119, 155, 164, 173, 182, 107, 139, 144 또는 130에 제시된 아미노산 서열을 포함하는 VL을 포함한다.
일부 실시형태에서, 제1 결합 도메인은 (a) 서열번호 30에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 31에 제시된 아미노산 서열을 포함하는 VL 영역; (b) 서열번호 40에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 41에 제시된 아미노산 서열을 포함하는 VL 영역; (c) 서열번호 84에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 85에 제시된 아미노산 서열을 포함하는 VL 영역; (d) 서열번호 16 또는 17에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 18 또는 19에 제시된 아미노산 서열을 포함하는 VL 영역; (e) 서열번호 52에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 53에 제시된 아미노산 서열을 포함하는 VL 영역; (f) 서열번호 94에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 95에 제시된 아미노산 서열을 포함하는 VL 영역; (g) 서열번호 73에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 74에 제시된 아미노산 서열을 포함하는 VL 영역; (h) 서열번호 62에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 63에 제시된 아미노산 서열을 포함하는 VL 영역; (i) 서열번호 118에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 119에 제시된 아미노산 서열을 포함하는 VL 영역; (j) 서열번호 154, 163, 172 또는 181에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 155, 164, 173 또는 182에 제시된 아미노산 서열을 포함하는 VL 영역; (k) 서열번호 106에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 107에 제시된 아미노산 서열을 포함하는 VL 영역; (l) 서열번호 138 또는 143에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 139 또는 144에 제시된 아미노산 서열을 포함하는 VL 영역; 또는 (m) 서열번호 129에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 130에 제시된 아미노산 서열을 포함하는 VL 영역을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물의 제2 결합 도메인은 서열번호 1 내지 6에 제시된 6개 CDR의 세트를 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물의 제2 결합 도메인은 서열번호 7에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VH 영역을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물의 제2 결합 도메인은 서열번호 7에 제시된 아미노산 서열을 포함하는 VH를 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물의 제2 결합 도메인은 서열번호 8에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VL 영역을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물의 제2 결합 도메인은 서열번호 8에 제시된 아미노산 서열을 포함하는 VL을 포함한다. 일부 실시형태에서, 제2 결합 도메인은 서열번호 7에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 8에 제시된 아미노산 서열을 포함하는 VL 영역을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 85의 아미노산 서열을 포함하는 항-CD19 가변 경쇄 도메인 및 서열번호 84의 아미노산 서열을 포함하는 항-CD19 가변 중쇄 도메인을 포함하는 CD19에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 86의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 이중특이적 항체 작제물은 서열번호 87에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 41의 아미노산 서열을 포함하는 항-MSLN 가변 경쇄 도메인 및 서열번호 40의 아미노산 서열을 포함하는 항-MSLN 가변 중쇄 도메인을 포함하는 MSLN에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 42의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 이중특이적 항체 작제물은 서열번호 43, 44 또는 45에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 63의 아미노산 서열을 포함하는 항-FLT3 가변 경쇄 도메인 및 서열번호 62의 아미노산 서열을 포함하는 항-FLT3 가변 중쇄 도메인을 포함하는 FLT3에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 64의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 65 또는 66에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 31의 아미노산 서열을 포함하는 항-EGFRvIII 가변 경쇄 도메인 및 서열번호 30의 아미노산 서열을 포함하는 항-EGFRvIII 가변 중쇄 도메인을 포함하는 EGFRvIII에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 32의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 33에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 95의 아미노산 서열을 포함하는 항-BCMA 가변 경쇄 도메인 및 서열번호 94의 아미노산 서열을 포함하는 항-BCMA 가변 중쇄 도메인을 포함하는 BCMA에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 96의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 98 또는 서열번호 97에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 119 또는 107의 아미노산 서열을 포함하는 항-PSMA 가변 경쇄 도메인 및 서열번호 118 또는 106의 아미노산 서열을 포함하는 항-PSMA 가변 중쇄 도메인을 포함하는 PSMA에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 120 또는 108의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 121, 122, 109, 110 또는 111에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 18 또는 19의 아미노산 서열을 포함하는 항-CD33 가변 경쇄 도메인 및 서열번호 16 또는 17의 아미노산 서열을 포함하는 항-CD33 가변 중쇄 도메인을 포함하는 CD33에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 일 실시형태에서, 이중특이적 항체 작제물은 서열번호 189 또는 190의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 20, 21, 22 또는 23에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 53의 아미노산 서열을 포함하는 항-CDH19 가변 경쇄 도메인 및 서열번호 52의 아미노산 서열을 포함하는 항-CCDH19 가변 중쇄 도메인을 포함하는 CDH19에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 54의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 55에 제시된 아미노산 서열을 포함한다.
이중특이적 항체 작제물은 서열번호 155, 164, 173 또는 182의 아미노산 서열을 포함하는 항-MUC17 가변 경쇄 도메인 및 서열번호 154, 163, 172 또는 181의 아미노산 서열을 포함하는 항-MUC17 가변 중쇄 도메인을 포함하는 MUC17에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 194의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 195에 제시된 아미노산 서열을 포함하는 제2 결합 도메인을 (선택적으로 서열번호 196의 아미노산 서열을 포함하는 Fc 도메인과 함께) 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 156, 165, 174 또는 183에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 139 또는 144의 아미노산 서열을 포함하는 항-cldn18.2 가변 경쇄 도메인 및 서열번호 138 또는 143의 아미노산 서열을 포함하는 항-cldn18.2 가변 중쇄 도메인을 포함하는 cldn18.2에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 일 실시형태에서, 이중특이적 항체 작제물은 서열번호 140 또는 145의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 9의 아미노산 서열을 포함하는 제2 결합 도메인을 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 141, 142, 146 또는 147에 제시된 아미노산 서열을 포함한다.
일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 130의 아미노산 서열을 포함하는 항-CD70 가변 경쇄 도메인 및 서열번호 129의 아미노산 서열을 포함하는 항-CD70 가변 중쇄 도메인을 포함하는 CD70에 결합하는 제1 결합 도메인, 서열번호 7의 아미노산 서열을 포함하는 항-CD3 가변 중쇄 도메인 및 서열번호 8의 아미노산 서열을 포함하는 항-CD3 가변 경쇄 도메인을 포함하는 제2 결합 도메인을 포함한다. 예를 들어, 실시형태에서, 이중특이적 항체 작제물은 서열번호 191의 아미노산 서열을 포함하는 제1 결합 도메인 및 서열번호 192에 제시된 아미노산 서열을 포함하는 제2 결합 도메인을 (선택적으로 서열번호 193의 아미노산 서열을 포함하는 Fc 도메인과 함께) 포함한다. 일부 실시형태에서, 이중특이적 항체 작제물은 서열번호 131에 제시된 아미노산 서열을 포함한다.
다양한 양태에서, 동결건조 제형은 인간 DLL3(델타-유사 리간드 3; UniProtKB - Q9NYJ7) 및 인간 CD3(분화 클러스터 3)에 결합하는 폴리펩티드를 포함한다. 이와 관련하여, 폴리펩티드는 항원 결합 도메인이 항원(즉, DLL3 또는 CD3)에 대한 항원 결합 폴리펩티드의 결합을 촉진하는 입채배좌를 채택하도록 하는 스캐폴드 또는 프레임워크 부분을 포함하는 항원-결합 단백질 또는 폴리펩티드이다. 본 개시내용의 다양한 양태에서, 폴리펩티드는 서열번호 75 및 9의 아미노산 서열을 포함하는 항원 결합 도메인을 포함한다. 항원 결합 도메인의 구조 및 기능은 항체의, 예를 들어, 전장 또는 전체 면역글로불린 분자의 구조 및/또는 기능을 기반으로 하고/하거나 항체의 가변 중쇄(VH) 및/또는 가변 경쇄(VL) 도메인으로부터 유도될 수 있다. 결합 도메인은 표적 결합을 허용하는 최소한의 구조적 요건과 함께 전형적으로 3개의 경쇄 CDR(즉, VL 영역의 CDR1, CDR2 및 CDR3) 및/또는 3개의 중쇄 CDR(즉, VH 영역의 CDR1, CDR2 및 CDR3)의 존재를 특징으로 한다. 일부 양태에서, 결합 도메인은 예를 들어, 가변 중쇄, scFv 링커 및 가변 경쇄 도메인을 포함하는 단일 쇄 항원 결합 폴리펩티드를 포함한다. 선택적으로, 가변 경쇄의 C 말단은 scFv 링커의 N 말단에 부착되고, 이의 C 말단은 가변 중쇄의 N 말단에 부착되지만(N-vh-링커-vl-C), 이 형태는 엇바뀔 수 있다(N-vl-링커-vh-C). 대안적으로, 가변 중쇄의 C 말단은 scFv 링커의 N 말단에 부착될 수 있지만, 이의 C 말단은 가변 경쇄의 N 말단에 부착되지만(N-vl-링커-vh-C), 이 형태는 엇바뀔 수 있다(N-vh-링커-vl-C).
본 명세서에 기재된 제형은, 다양한 양태에서, 인간 CD3 및 인간 DLL3에 결합하는 폴리펩티드(예를 들어, 이중특이적 T 세포 관여 항원 결합 폴리펩티드)를 포함한다. 일부 양태에서, 폴리펩티드는 DLL3에 결합하고 서열번호 67 내지 72에 제시된 6개 CDR의 세트를 포함하는 제1 결합 도메인을 포함한다. 일부 양태에서, DLL3 결합 도메인은 서열번호 73에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VH 영역을 포함한다. 일부 양태에서, 폴리펩티드의 DLL3 결합 도메인은 서열번호 74에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VL 영역을 포함한다. 예를 들어, DLL3 결합 도메인은 서열번호 73에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 74에 제시된 아미노산 서열을 포함하는 VL 영역을 포함할 수 있고, 예컨대, 결합 도메인은 서열번호 75의 아미노산을 포함한다. 일부 양태에서, 폴리펩티드의 CD3 결합 도메인은 서열번호 1 내지 6에 제시된 6개 CDR의 세트를 포함한다. 예를 들어, CD3 결합 도메인은 선택적으로 서열번호 7에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VH 영역을 포함한다. 일부 양태에서, 폴리펩티드의 CD3 결합 도메인은 서열번호 8에 제시된 아미노산 서열과 적어도 90% 동일한(예를 들어, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 포함하는 VL 영역을 포함한다. 일부 양태에서, 제2 결합 도메인은 서열번호 7에 제시된 아미노산 서열을 포함하는 VH 영역 및 서열번호 8에 제시된 아미노산 서열을 포함하는 VL 영역을 포함하고, 예컨대, 결합 도메인은 서열번호 9의 아미노산 서열을 포함한다. 일부 양태에서, 폴리펩티드는 서열번호 76 또는 77에 제시된 아미노산 서열을 포함한다.
다양한 실시형태에서, 이중특이적 T 세포 관여 항원 결합 폴리펩티드는 AMG 757이라고도 알려진 탈라타맙(tarlatamab)(International Nonproprietary Names for Pharmaceutical Substances(INN): Proposed INN: List 123, WHO Drug Information 34(2): 395-397 (2020))이다. 탈라타맙은 면역글로불린 scFv-scFv-scFc, 항-[호모 사피엔스 DLL3(델타-유사 리간드 3)] 및 항-[호모 사피엔스 CD3E(CD3 엡실론, Leu-4)], 단클론성 항체 단일 쇄(scFv)2-scFc, 이중특이적; IG 단일 쇄 scFv-scFv-scFc, 항-DLL3 및 항-CD3E(1-982)[scFv-VH-V-카파 항-DLL3(1-241)[VH(호모 사피엔스 IGHV4-59*01 G49>C(44)(96.9%)-(IGHD)-IGHJ4*01(100%)) CDR-IMGT[8.7.12](26-33.51-57.96-107)(1-118)-15-량체 트리스(테트라글리실-세릴) 링커(119-133)-V-KAPPA(호모 사피엔스 IGKV3-20*01(91.7%)-IGKJ2*01 Q120>C(234)(90.9%)) CDRIMGT[7.3.9](160-166.184-186.223-231)(134-241)]-6-량체 세릴-테트라글리실-세릴 링커(242-247)-scFv-VH-V-람다 항CD3E(248-496)[VH(무스 무스쿨루스 IGHV10-1*02(91.9%)-(IGHD)-IGHJ3*01(86.7%)/호모 사피엔스 IGHV3-73*01(87.0%)-(IGHD)-IGHJ5*01(100%)) CDR-IMGT[8.10.16](273-280.298-307.346-361)(248-372)-15량체-트리스(테트라글리실-세릴) 링커(373-387)-V-LAMBDA(호모 사피엔스 IGLV7-43*01(85.1%)-IGLJ3*02(100%)) CDR-IMGT[9.3.9](413-421.439- 441.478-486)(388-496)]-4량체-테트라글리실 링커(497-500)-scFc(h-CH2-CH3)-(h-CH2-CH3)(501-982)[호모 사피엔스 IGHG1*03 h-CH2-CH3, nG1m1(힌지 6-15(501-510), CH2 R83>C (572), N84.4>G (577), V85>C (582)(511-620), CH3 E12(636), M14(638)(621-725), CHS>del)(501-725)-30량체 헥사키스(테트라글리실-세릴) 링커(726-755)-호모 사피엔스 IGHG1*03 h-CH2-CH3, nG1m1(힌지 6-15(756-765), CH2 R83>C(827), N84.4>G 832), V85>C(837)(766-875), CH3 E12(891), M14(893)(876-980), CHS(981-982))(756-982)(비글리코실화됨, 중국 햄스터 난소(CHO) 세포에서 생산됨); 면역조절제, 항신생물제이다.
선택적으로, 폴리펩티드는 서열번호 20, 서열번호 21, 서열번호 22, 서열번호 23, 서열번호 33, 서열번호 43, 서열번호 44, 서열번호 45, 서열번호 55, 서열번호 65, 서열번호 66, 서열번호 76, 서열번호 77, 서열번호 87, 서열번호 97, 서열번호 98, 서열번호 99, 서열번호 109, 서열번호 110, 서열번호 111, 서열번호 121, 서열번호 122, 서열번호 131, 서열번호 141, 서열번호 142, 서열번호 146, 서열번호 147, 서열번호 156, 서열번호 165, 서열번호 174, 서열번호 183, 서열번호 184, 서열번호 185, 서열번호 186, 서열번호 187 또는 서열번호 188에 제시된 아미노산 서열, 예컨대, 서열번호 76, 서열번호 77, 서열번호 97, 서열번호 98, 서열번호 99, 서열번호 156, 서열번호 165, 서열번호 174 또는 서열번호 183에 제시된 아미노산 서열을 포함한다.
일부 양태에서, 재구성된 제형은 약 0.5 ㎎/㎖ 내지 약 50 ㎎/㎖(예를 들어, 약 1 ㎎/㎖ 내지 약 20 ㎎/㎖ 또는 약 15 ㎎/㎖) 범위 농도의 폴리펩티드(예를 들어, 이중특이적 T 세포 관여 항원 결합 폴리펩티드)를 포함한다. 일부 양태에서, 재구성된 제형은 약 1 ㎎/㎖, 약 2 ㎎/㎖, 약 3 ㎎/㎖, 약 4 ㎎/㎖, 약 5 ㎎/㎖, 약 6 ㎎/㎖, 약 7 ㎎/㎖, 약 8 ㎎/㎖, 약 9 ㎎/㎖, 약 10 ㎎/㎖, 약 11 ㎎/㎖, 약 12 ㎎/㎖, 약 13 ㎎/㎖, 약 14 ㎎/㎖, 약 15 ㎎/㎖, 약 16 ㎎/㎖, 약 17 ㎎/㎖, 약 18 ㎎/㎖, 약 19 ㎎/㎖ 또는 약 20 ㎎/㎖ 또는 이들 종점 사이의 임의의 범위 농도의 폴리펩티드를 포함한다. 대안적으로, 재구성된 제형은 약 25 ㎎/㎖, 약 30 ㎎/㎖, 약 35 ㎎/㎖, 약 40 ㎎/㎖, 약 45 ㎎/㎖ 또는 약 50 ㎎/㎖ 또는 이들 종점 사이의 임의의 범위 농도의 폴리펩티드를 포함한다. 다양한 양태에서, 재구성된 제형은 적어도 약 1 ㎎/㎖, 약 2 ㎎/㎖, 약 3 ㎎/㎖, 약 4 ㎎/㎖, 약 5 ㎎/㎖, 약 6 ㎎/㎖, 약 7 ㎎/㎖, 약 8 ㎎/㎖, 약 9 ㎎/㎖ 또는 약 10 ㎎/㎖이고 약 15 ㎎/㎖, 20 ㎎/㎖, 25 ㎎/㎖, 약 30 ㎎/㎖, 약 35 ㎎/㎖, 약 40 ㎎/㎖, 약 45 ㎎/㎖ 또는 약 50 ㎎/㎖ 이하의 농도의 폴리펩티드를 포함한다. 예를 들어, 재구성된 제형은 선택적으로 약 15 ㎎/㎖ 농도의 폴리펩티드를 포함한다.
완충제
본 개시내용의 제형은 선택적으로 아세테이트 완충제, 글루타메이트 완충제, 시트레이트 완충제, 석시네이트 완충제, 타르트레이트 완충제, 푸마레이트 완충제, 말레에이트 완충제, 히스티딘 완충제, 포스페이트 완충제 또는 이들의 조합인 완충제를 포함한다. 선택적으로, 완충제는 글루타메이트 완충제이다.
일부 양태에서, 완충제는 약 4 내지 약 7, 약 4 내지 약 6, 약 4 내지 약 5 또는 약 4.2의 pH를 유지하는 농도로 제형에 존재한다. 제형에 대한 pH의 효과는 가속화된 안정성 연구 및 열량 측정 선별 연구와 같은 몇몇 접근법 중 임의의 한 가지 이상을 사용하여 특징규명될 수 있다(Remmele R.L. Jr., et al., Biochemistry, 38(16): 5241-7 (1999)). 동결건조 제형의 맥락에서, 완충제는 약 0.1 mM 내지 약 1000 mM(1 M), 예컨대, 약 5 mM 내지 약 200 mM(예를 들어, 약 5 mM 내지 약 100 mM)의 농도로 동결건조 전 제형(pre-lyophilized formulation)에 존재할 수 있다. "동결건조 전 제형"이라는 것은 동결건조 직전의 제형을 의미한다. 다양한 양태에서, 완충제는 약 10 mM 내지 50 약 mM 농도로 동결건조 전 제형에 존재한다. 적합한 완충제 농도는 약 200 mM 이하의 농도를 포함한다. 일부 양태에서, 완충제의 농도는 (i) 적어도 약 1 mM, 적어도 약 2 mM, 적어도 약 3 mM, 적어도 약 4 mM, 적어도 약 5 mM, 적어도 약 6 mM, 적어도 약 7 mM, 적어도 약 8 mM, 적어도 약 9 mM, 적어도 약 10 mM, 적어도 약 11 mM, 적어도 약 12 mM, 적어도 약 13 mM, 적어도 약 14 mM 또는 적어도 약 15 mM이고 (ii) 약 20 mM 이하, 약 30 mM 이하, 약 40 mM 이하, 약 50 mM 이하, 약 60 mM 이하, 약 70 mM 이하, 약 80 mM 이하, 약 90 mM 이하, 약 100 mM 이하 또는 약 200 mM 이하이다. 일부 양태에서, 동결건조 전 제형 중의 완충제는 약 190 mM, 약 180 mM, 약 170 mM, 약 160 mM, 약 150 mM, 약 140 mM, 약 130 mM, 약 120 mM, 약 110 mM, 약 100 mM, 약 80 mM, 약 70 mM, 약 60 mM, 약 50 mM, 약 40 mM, 약 30 mM, 약 20 mM, 약 19 mM, 약 18 mM, 약 17 mM, 약 16 mM, 약 15 mM, 약 14 mM, 약 13 mM, 약 12 mM, 약 11 mM, 약 10 mM 또는 약 5 mM의 농도로 존재한다. 일부 양태에서, 동결건조 전 제형 중의 완충제(예를 들어, 글루타메이트)의 농도는 약 15 mM이다.
계면활성제
본 명세서에 기재된 제형은 계면활성제를 포함한다. 예시적인 계면활성제는 폴리소르베이트 20, 폴리소르베이트 40, 폴리소르베이트 60, 폴리소르베이트 80, 폴록사머 188, 폴록사머 407, Triton® X-100(2-[4-(2,4,4-트리메틸펜탄-2-일)페녹시]에탄올; CAS # 9002-93-1), 폴리옥시에틸렌, PEG 3350 및 PEG 4000뿐만 아니라 이들의 조합을 포함하지만 이들로 제한되지 않는다. 선택적으로, 완충제는 폴리소르베이트 80이다.
일부 양태에서, 동결건조 전 제형은 약 0.001% 내지 약 5% w/v의 농도로 계면활성제를 포함한다. 예를 들어, 농도는 다양한 예에서 약 0.001% 내지 약 0.5%(예컨대, 약 0.004 내지 약 0.5% w/v 또는 약 0.001 내지 약 0.01% w/v 또는 약 0.004 내지 약 0.01% w/v)이다. 일부 양태에서, 동결건조 전 제형은 (i) 적어도 약 0.001%, 적어도 약 0.002%, 적어도 약 0.003%, 적어도 약 0.004%, 적어도 약 0.005%, 적어도 약 0.007%, 적어도 약 0.01%, 적어도 약 0.05%, 적어도 약 0.1%, 적어도 약 0.2%, 적어도 약 0.3%, 적어도 약 0.4%, 적어도 약 0.5%, 적어도 약 0.6%, 적어도 약 0.7%, 적어도 약 0.8%, 적어도 약 0.9% 또는 적어도 약 1.0% w/v 및 (ii) 약 2.0% 이하, 약 1.9% 이하, 약 1.8% 이하, 약 1.7% 이하, 약 1.6% 이하, 약 1.5% 이하, 약 1.4% 이하, 약 1.3% 이하, 약 1.2% 이하, 약 1.1% 이하, 약 1.0% 이하, 약 0.9% 이하, 약 0.8% 이하, 약 0.7% 이하, 약 0.6% 이하 또는 약 0.5% w/v 이하의 농도로 계면활성제를 포함한다. 일부 양태에서, 제형은 약 0.005% 내지 약 0.01% w/v, 예컨대, 0.01% w/v의 농도로 포함된 계면활성제를 포함한다. 일부 양태에서, 계면활성제는 폴리소르베이트 80이고, 폴리소르베이트 80은 약 0.01% w/v의 농도로 존재한다.
당류
본 명세서에 기재된 제형은 당류를 포함한다. 본 개시내용의 일부 양태에서, 당류는 단당류 또는 이당류이다. 예를 들어, 당류는 선택적으로 글루코스, 갈락토스, 프룩토스, 자일로스, 수크로스, 락토스, 말토스, 트레할로스, 소르비톨, 만니톨 또는 자일리톨 또는 이들의 조합이다. 일부 양태에서, 당류는 수크로스이다.
일부 양태에서, 제형은 동결건조 전에 당류를 약 0.01% 내지 약 20% w/v 또는 약 1% 내지 약 15% 또는 약 5% 내지 약 12% 또는 약 7% 내지 약 12% w/v 농도로 포함한다. 일부 양태에서, 제형은 동결건조 전에 적어도 하나의 당류를 (i) 적어도 약 0.5%, 적어도 약 1%, 적어도 약 2%, 적어도 약 3%, 적어도 약 4%, 적어도 약 5%, 적어도 약 6%, 적어도 약 7%, 적어도 약 8%, 적어도 약 9%, 적어도 약 10%, 적어도 약 11%, 적어도 약 12%, 적어도 약 13%, 적어도 약 14% 또는 적어도 약 15% w/v 및 (ii) 약 20% 이하, 약 18% 이하, 약 16% 이하, 약 15% 이하, 약 14% 이하, 약 13% 이하, 약 12% 이하, 약 11% 이하, 약 10% 이하, 약 9% 이하, 약 8% 이하, 약 7% 이하, 약 6% 이하 또는 약 5% w/v 이하의 농도로 포함한다. 더 추가의 양태에서, 제형은 적어도 1종의 당류를 약 7%, 약 7.5%, 약 8%, 약 8.5%, 약 9%, 약 9.5%, 약 10%, 약 10.5%, 약 11%, 약 11.5% 또는 약 12% w/v의 농도로 포함한다. 일부 양태에서, 적어도 1종의 당류는 제형에서 약 9% w/v의 농도이다. 일부 양태에서, 당류는 수크로스이고, 제형에 약 7 내지 약 10% w/v 범위, 예컨대, 9%로 존재한다.
선택적으로, 제형은 동결건조 전에, 15 mM의 글루타메이트, 9%(w/V)의 수크로스 및 0.01%(w/V)의 폴리소르베이트 80을 포함한다. 제형의 pH는 선택적으로 약 4.2이다.
응집/고분자량 종
본 명세서에서 사용되는 용어 "응집"은 예를 들어 반 데르 발스 힘 또는 화학 결합을 통한 분자 사이의 직접적인 상호 인력을 지칭한다. 특히, 응집은 단백질이 축적되고 함께 무리를 짓는 것으로 이해된다. 응집물은 무정형 응집물 및 올리고머를 포함할 수 있고, 전형적으로 고분자량(HMW) 종, 즉 응집되지 않은 분자인 생성물 분자보다 더 높은 분자량을 갖는 분자로 지칭된다. 단백질 응집물(HMW 종)은 일반적으로 크기(작은 조립체(이량체)에서 큰 조립체(눈에 보이지 않거나(subvisible) 심지어는 눈에 보이는 입자)까지의 범위 및 나노미터에서 마이크로미터 범위까지의 직경 범위), 모폴로지(대략 구체에서 피브릴형까지), 단백질 구조(천연 대 비천연/변성됨), 분자간 결합의 유형(공유 대 비공유), 가역성 및 용해성이 상이할 수 있다. 가용성 응집물은 대략 1 내지 100 nm의 크기 범위를 포함하고, 단백질 미립자는 육안으로 보이지 않는(약 0.1 내지 100 nm) 범위 및 가시적(100 nm 초과) 범위를 포함한다.
단백질 제형의 안정성은 여러 방식으로 정량화할 수 있다. 일부 양태에서, 폴리펩티드 제형(예를 들어, 이중특이적 T 세포 관여 항원 결합 폴리펩티드 제형)의 안정성은 크기 배제 고성능 액체 크로마토그래피(size exclusion high performance liquid chromatography: SE-HPLC), 크기 배제 초고성능 액체 크로마토그래피(size exclusion ultra high performance liquid chromatography: SE-UHPLC), 양이온 교환 고성능 액체 크로마토그래피(cation exchange high performance liquid chromatography: CE-HPLC), 동적 광산란, 분석적 초원심분리(analytical ultracentrifugation: AUC), 장 흐름 분획법(field flow fractionation: FFF), 등전점 전기영동 및 이온 교환 크로마토그래피(ion exchange chromatography: IEX)를 특징으로 한다. 일부 양태에서, 폴리펩티드 제형의 안정성은 소듐-도데실 설페이트 모세관 전기영동(CE-SDS) 및/또는 소듐-도데실 설페이트 폴리아크릴아미드 겔 전기영동(SDS-PAGE)에 의해 측정된 부분 해리를 특징으로 한다. 일부 양태에서, 제형의 안정성은 환원 모세관 전기영동-소듐 도데실 설페이트(rCE-SDS)에 의해 평가된다.
제형의 안정성은 폴리펩티드(예를 들어, 이중특이적 T 세포 관여 항원 결합 폴리펩티드)의 고분자량(HMW) 종의 양 또는 미리 결정된 온도 하에서 그리고 다양한 시점(예를 들어, 동결건조 제형의 재구성 후 다양한 시점)에 폴리펩티드(예를 들어, 이중특이적 T 세포 관여 항원 결합 폴리펩티드)의 HMW 종의 양의 증가율에 의해서 특징규명될 수 있다. 예를 들어, HMW 종의 양은 대략 8℃ 또는 25℃에서 1시간, 2시간, 6시간, 10시간, 12시간, 15시간, 24시간, 25시간 또는 그 초과에 결정될 수 있다. 일부 양태에서, HMW 종의 감소율은 대략 8℃ 또는 25℃에서 1시간, 2시간, 6시간, 12시간, 24시간, 25시간 또는 그 초과에 결정될 수 있다. 일부 양태에서, 제형에서 이중특이적 T 세포 관여, 항원 결합 폴리펩티드의 HMW 종은 SE-UHPLC에 의해서 결정된다.
일부 양태에서, 본 명세서에 기재된 바와 같은 폴리펩티드(예를 들어, 이중특이적 T 세포 관여, 항원 결합 폴리펩티드)의 임의의 특정 종, 예컨대, 온전한 BiTE® 분자 또는 주요 종 또는 고분자량(HMW) 종(즉, 응집물)의 상대적인 값은 총 생성물의 각각 값에 대해 표현된다. 예를 들어, 일부 양태에서, 재구성 제형은 4% 이하, 3.5% 이하, 3% 이하 또는 2.5% 이하(예를 들어, 3.5% 또는 3%, 2.5% 또는 2% 또는 1.9% 또는 1.8% 또는 1.7% 또는 1.6% 또는 1.5% 또는 1.4% 또는 1.3% 또는 1.2% 또는 1.1% 또는 1% 또는 0.5%)의 이중특이적 T 세포 관여 항원 결합 폴리펩티드의 HMW 종을 포함한다. 다양한 양태에서, 재구성 제형은 3% 이하의 이중특이적 T 세포 관여 항원 결합 폴리펩티드의 HMW 종을 포함한다. 일부 양태에서, 제형에서 폴리펩티드(예를 들어, 이중특이적 T 세포 관여 항원 결합 폴리펩티드)의 HMW 종은 SE-UHPLC에 의해서 측정된다. 선택적으로, 재구성 제형은 8℃에서 저장되는 경우 25시간에 또는 25℃에서 저장되는 경우 12시간에 상기에 언급된 HMW 종의 양을 포함한다.
재구성 및 투여
본 개시내용의 방법은 동결건조 제형을 방향족 알코올, 페놀계 화합물 또는 방향족 측쇄를 갖는 아미노산을 포함하는 희석제로 재구성시키는 단계 및 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 12시간 내에 투여하는 단계를 포함한다. 놀랍게도, 본 명세서에 기재된 동결건조 제형을 벤젠-고리 함유 화합물, 예컨대, 방향족 알코올(예를 들어, 벤질 알코올), 페놀계 화합물(예를 들어, 페놀 또는 m-크레졸) 또는 방향족 측쇄를 갖는 아미노산(예를 들어, 페닐알라닌)을 포함하는 희석제로 재구성시키는 것은 HMW 종이 목표 수준까지 소멸하는 데 필요한 시간을 상당히 감소시켜, 이전에 생각했던 것보다 재구성 후 훨씬 더 빨리 대상체에게 재구성된 제형을 투여할 수 있게 한다. 다양한 양태에서, 희석제는 벤질 알코올, 페놀, m-크레졸 또는 페닐알라닌 또는 상기 중 임의의 것의 조합을 포함한다. 대안적으로 또는 추가로, 희석제는 벤조산, 벤조산나트륨, 티메로살, 페녹시에탄올, 메틸파라벤, 페녹시에탄올, 프로필파라벤, 티로신 또는 트립토판 또는 상기 중 임의의 것의 조합을 포함할 수 있다. 대안적으로 또는 추가로, 희석제는 NaCl 및 벤질 알코올(예를 들어, 0.9% 벤질 알코올) 또는 IVSS(정맥내 용액 안정화제)를 포함한다. 선택적으로, 희석제는 0.9%의 벤질 알코올, 0.8%의 페놀 또는 0.9%의 m-크레졸을 포함한다. 선택적으로, 희석제는 약 1 mM 내지 약 100 mM의 본 명세서에 기재된 희석제 조성물 중 임의의 것(예를 들어, 벤질 알코올, 페놀, 페닐알라닌 또는 m-크레졸)을 포함한다. 예를 들어, 다양한 양태에서, 희석제는 적어도 약 40 mM의 벤질 알코올(예를 들어, 적어도 약 45 mM의 벤질 알코올 또는 적어도 약 50 mM의 벤질 알코올)을 포함한다. 임의의 적합한 비히클, 예컨대, 멸균수 또는 멸균 주사용수가 희석제로 사용될 수 있다. 비히클은 선택적으로 식염수를 포함하지 않는다.
다양한 양태에서, 방법은 재구성된 제형을 대상체에게 재구성 12시간 이내, 10시간 이내, 9시간 이내, 8시간 이내, 7시간 이내, 6시간 이내, 5시간 이내, 4시간 이내, 3시간 이내, 2시간 이내 또는 1시간 이내에 투여하는 단계를 포함한다. 이러한 맥락에서, "재구성"은 동결건조된 케이크의 용액 중의 용해를 의미한다. 다양한 양태에서, 방법은 재구성된 제형을 대상체에게 재구성 60분 이내, 45분 이내, 30분 이내 또는 15분 이내에 투여하는 단계를 포함한다.
일부 예에서, 재구성된 제형은 이를 필요로 하는 대상체에게 투여하기 위해서 추가로 희석된다. 예를 들어, 재구성된 제형은 대상체에게 증가된 용량을 제공하기 위해서 i.v. 백(즉, 본 명세서에서 "전신 전달 시스템"이라고도 지칭됨)에서 다른 담체와 혼합될 수 있다. 이와 관련하여, 재구성된 제형은 선택적으로 재구성 12시간 이내, 12시간 이내, 10시간 이내, 9시간 이내, 8시간 이내, 7시간 이내, 6시간 이내, 5시간 이내, 4시간 이내, 3시간 이내, 2시간 이내 또는 1시간 이내에 전신 전달 시스템에 혼입된다. 다양한 양태에서, 방법은 재구성된 제형을 전신 전달 시스템에 재구성 60분 이내, 45분 이내, 30분 이내 또는 15분 이내에 혼입시키는 단계를 포함한다.
바람직하게는, 제형은 비경구로, 예를 들어, 정맥내로, 피하로 또는 근육내로 투여된다. 비경구 투여는 주사, 예컨대, 볼러스(bolus) 주사에 의해 또는 주입, 예컨대, 지속 주입에 의해 달성될 수 있다. 투여는 장기간 방출을 위해 데포를 통해 달성될 수 있다. 일부 양태에서, 제형은 초기 볼러스 다음에 약물 제품의 치료적 순환 수준을 유지하기 위한 지속적 주입에 의해 정맥내로 투여된다. 일부 양태에서, 제형은 1회 용량으로서 투여된다. 제형을 투여하기 위한 의학적 장치의 예는 미국 특허 제4,475,196호; 제4,439,196호; 제4,447,224호; 제4,447,233호; 제4,486,194호; 제4,487,603호; 제4,596,556호; 제4,790,824호; 제4,941,880호; 제5,064,413호; 제5,312,335호; 제5,312,335호; 제5,383,851호; 및 제5,399,163호에 기재되어 있다.
용도
본 명세서에 기재된 제형은 암 치료를 필요로 하는 대상체에서의 암 치료에서 약제학적 제형으로서 유용하다. "를 필요로 하는 대상체" 또는 "치료를 필요로 하는" 대상체라는 용어는 장애를 앓고 있는 대상체뿐만 아니라 장애가 임상적으로 아직 나타나지 않은 대상체를 포함한다. "대상체" 또는 "환자"는 예방적 또는 치료적 처치를 받는 인간 및 기타 포유류 대상체를 포함한다. 포유동물 대상체는 인간, 비인간 영장류, 개, 고양이, 기니피그, 토끼, 래트, 마우스, 말, 소, 젖소 등을 포함하고, 인간이 바람직하다. 본 개시내용의 재구성된 제형은 약제학적으로 허용 가능하다. 즉, 약제학적 제형이 투여되는 대상체에서 유의미한 바람직하지 않은 국소 또는 전신 효과를 유발하지 않으면서 목적하는 치료 효과를 이끌어낼 수 있다. 용어 "약제학적으로 허용 가능한"은 동물 및 보다 특별하게는 인간에서 사용하기 위해서 규제 기관에 의해서 또는 다른 일반적으로 인식되는 약전에 의해서 승인된 것을 의미할 수 있으나, 규제 기관에 의해 승인된 것들에 한정되지 않는다.
선택적으로, 대상체는 암(예를 들어, 종양)을 앓고 있다. 다양한 양태에서, 암은 정상 세포에 비해서 종양 또는 암 세포의 표면에서 DLL3을 과발현한다. 종양 또는 암의 예는 폐암(바람직하게는 SCLC), 유방암, 자궁경부암, 결장암, 결장직장암, 자궁내막암, 두경부암, 간암, 난소암, 췌장암, 전립선암, 피부암, 위암, 고환암, 갑상선암, 부신암, 신장암, 방광암, 자궁암, 식도암, 요로상피암, 뇌종양 또는 암, 림프종, 암종, 육종 및 상기 중 임의의 것으로부터 유래된 전이성 암 질환을 포함하지만 이들로 제한되지 않는다. 다양한 양태에서, 종양 또는 암은 소세포폐암 (SCLC), 비소세포폐암(NSCLC), 신경교종, 교모세포종, 흑색종, 신경내분비 전립선암, 신경내분비 췌장암, 간모세포종, 간세포 암종 또는 상기 중 임의의 것으로부터 유래된 전이성 암 질환이다. 선택적으로, 종양 또는 암은 SCLC, NSCLC, 신경교종, 교모세포종 또는 신경내분비 전립선암이다.
본 개시내용은 투여를 필요로 하는 대상체에게 치료적 유효량의 재구성된 제형을 본 명세서에 제공된 재구성 후 시간 프레임 내에 투여하는 단계를 포함하는, 암(예컨대, 상기에 기재된 암 중 임의의 것)의 치료 방법을 제공한다. "치료"라는 용어는 치료적 치료 및 예방적 또는 예방용 조치(예를 들어, 질환, 질환의 증상 또는 질환에 대한 소인을 치료, 치유, 완화, 경감, 변경, 개선, 호전, 향상 또는 영향을 미치기 위한 조치) 둘 다를 지칭한다. "치료"는 본 명세서에 기재된 재구성된 제형의 투여에 의한 종양 또는 암(예를 들어, 전이성 암)을 갖는 환자의 질환 상태의 임의의 개선을 포함한다. 이러한 개선은 또한 환자의 종양 또는 암(예를 들어, 전이성 암)의 진행의 둔화 또는 중단으로서 보일 수 있다. 본 명세서에서 사용되는 바와 같은 "예방"이라는 용어는 재구성된 제형을 이를 필요로 하는 대상체에게 투여하는 것에 의한, 종양 또는 암(예를 들어, 전이성 암)을 갖는 환자의 발생 또는 재발의 회피를 의미한다.
암의 치료는 다수의 방식 중 임의의 것에 의해서 결정될 수 있다. 대상체의 웰빙의 임의의 개선이 고려된다(예를 들어, 본 명세서에 기재된 임의의 매개변수의 적어도 또는 약 10% 감소, 적어도 또는 약 20% 감소, 적어도 또는 약 30% 감소, 적어도 또는 약 40% 감소, 적어도 또는 약 50% 감소, 적어도 또는 약 60% 감소, 적어도 또는 약 70% 감소, 적어도 또는 약 80% 감소, 적어도 또는 약 90% 감소 또는 적어도 또는 약 95% 감소). 예를 들어, 치료적 반응은 하기 질환 개선 중 하나 이상을 지칭할 것이다: (1) 신생 세포 수의 감소; (2) 신생 세포사의 증가; (3) 신생 세포 생존의 저해; (5) 종양 성장 또는 새로운 병변의 출현의 저해(즉, 일정 정도로 둔화, 바람직하게는 멈춤); (6) 종양 크기 또는 부담의 감소; (7) 임상적으로 검출 가능한 질환의 부재, (8) 암 마커 수준의 감소; (9) 증가된 환자 생존율; 및/또는 (10) 질환 또는 병태와 연관된 한 가지 이상의 증상(예를 들어, 통증)으로부터의 일부 경감. 예를 들어, 치료 효능은 치료 후에 종양 종괴 및/또는 부피의 변화를 검출함으로써 결정될 수 있다. 종양의 크기는 CT, PET, 유방 조영술, 초음파 또는 촉진뿐만 아니라 캘리퍼스 측정 또는 생검 또는 수술적 절제 후 종양의 병리학적 검사에 의해서 측정된 바와 같은 초기 크기 및 치수와 비교될 수 있다. 반응은 예를 들어, 종양 부피의 백분율 변화를 사용하여 정량적으로 특징규명될 수 있다(예를 들어, 본 개시내용의 방법은 종양 부피를 적어도 10%, 적어도 20%, 적어도 30%, 적어도 40%, 적어도 50%, 적어도 60%, 적어도 70%, 적어도 80% 또는 적어도 90% 감소시킴). 다양한 양태에서, 본 발명의 방법은 대상체에서 치료를 모니터링하는 것을 추가로 포함한다.
키트
추가적인 양태로서, 재구성 및/또는 대상체에의 투여를 용이하게 하는 방식으로 패키징된 본 명세서에 기재된 1종 이상의 제형을 포함하는 키트가 본 명세서에 기재된다. 예를 들어, 이러한 키트는 용기, 예컨대, 밀봉된 병, 용기, 일회용 또는 다회 사용 바이알, 사전 충전 주사기 또는 사전 충전 주입 장치에 패키징된 본 명세서에 기재된 동결건조 제형을 상기에 기재된 바와 같은 재구성 희석제와 함께 포함한다. 적합한 비히클 또는 담체, 예컨대, 비경구 투여를 위해 제형 중에서 통상적인 다른 물질로 보충될 가능성이 있는 주사용수, 생리적 식염수 용액 또는 인공 뇌척수액이 제공될 수 있다. 일 양태에서, 제형은 단위 투약 형태로 패키징된다. 키트는 특정 투여 경로에 따라 제형을 투여하는 데 적합한 장치를 더 포함할 수 있다. 바람직하게는, 키트는 본 명세서에 기재된 폴리펩티드 또는 본 명세서에 기재된 제형의 용도를 기재하는 라벨을 추가로 포함한다.
본 개시내용의 양태
본 개시내용의 다양한 대표적인 양태가 하기에 제공된다:
양태 1. 방법으로서, (a) 폴리펩티드, 당류, 계면활성제 및 완충제를 포함하는 동결건조 제형을 방향족 알코올, 페놀계 화합물 또는 방향족 측쇄를 갖는 아미노산을 포함하는 희석제로 재구성시키는 단계 및 (b) 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 12시간 이내에 투여하는 단계를 포함하고, 폴리펩티드는 인간 DLL3 및 인간 CD3에 결합하는, 방법.
양태 2. 양태 1에 있어서, 희석제는 벤질 알코올, 페놀, m-크레졸 또는 페닐알라닌을 포함하는, 방법.
양태 3. 양태 1 또는 양태 2에 있어서, 재구성된 제형의 pH는 약 4 내지 약 7인, 방법.
양태 4. 양태 1 내지 3 중 어느 하나에 있어서, 제형은 4.2의 pH를 갖는, 방법.
양태 5. 양태 1 내지 4 중 어느 하나에 있어서, 재구성된 제형은 약 1 ㎎/㎖ 내지 약 20 ㎎/㎖의 폴리펩티드를 포함하는, 방법.
양태 6. 양태 1 내지 5 중 어느 하나에 있어서, 재구성된 제형은 약 15 ㎎/㎖의 폴리펩티드를 포함하는, 방법.
양태 7. 양태 1 내지 6 중 어느 하나에 있어서, 완충제는 아세테이트 완충제, 글루타메이트 완충제, 시트레이트 완충제, 락트산 완충제, 석시네이트 완충제, 타르트레이트 완충제, 푸마레이트 완충제, 말레에이트 완충제, 히스티딘 완충제 또는 포스페이트 완충제인, 방법.
양태 8. 양태 7에 있어서, 완충제는 글루타메이트 완충제인, 방법.
양태 9. 양태 1 내지 8 중 어느 하나에 있어서, 완충제는 동결건조 전에 5 내지 200 mM 범위의 농도로 존재하는, 방법.
양태 10. 양태 9에 있어서, 완충제는 동결건조 전에 10 내지 50 mM 범위의 농도로 존재하는, 방법.
양태 11. 양태 1 내지 10 중 어느 하나에 있어서, 당류는 단당류 또는 이당류인, 방법.
양태 12. 양태 1 내지 11 중 어느 하나에 있어서, 당류는 글루코스, 갈락토스, 프룩토스, 자일로스, 수크로스, 락토스, 말토스, 트레할로스, 소르비톨, 만니톨 또는 자일리톨인, 방법.
양태 13. 양태 12에 있어서, 당류는 수크로스인, 방법.
양태 14. 양태 1 내지 13 중 어느 하나에 있어서, 당류는 동결건조 전에 1 내지 15%(w/v) 범위의 농도로 존재하는, 방법.
양태 15. 양태 1 내지 14 중 어느 하나에 있어서, 계면활성제는 폴리소르베이트 20, 폴리소르베이트 40, 폴리소르베이트 60, 폴리소르베이트 80, 폴록사머 188, 폴록사머 407, Triton® X-100, 폴리옥시에틸렌, PEG 3350, PEG 4000 또는 이들의 조합인, 방법.
양태 16. 양태 15에 있어서, 계면활성제는 폴리소르베이트 80인, 방법.
양태 17. 양태 1 내지 16 중 어느 하나에 있어서, 계면활성제는 동결건조 전에 0.001% 내지 0.5%(w/v) 범위의 농도로 존재하는, 방법.
양태 18. 양태 1 내지 17 중 어느 하나에 있어서, 제형은 동결건조 전에 15 mM의 글루타메이트, 9%(w/V)의 수크로스 및 0.01%(w/V)의 폴리소르베이트 80을 포함하고, 제형은 4.2의 pH를 갖는, 방법.
양태 19. 양태 1 내지 18 중 어느 하나에 있어서, 폴리펩티드는 서열번호 18 및 서열번호 9의 아미노산 서열을 포함하는, 방법.
양태 20. 양태 1 내지 19 중 어느 하나에 있어서, 폴리펩티드는 서열번호 19 또는 서열번호 20에 제시된 아미노산 서열을 포함하는, 방법.
양태 21. 양태 1 내지 20 중 어느 하나에 있어서, 희석제는 0.9%의 벤질 알코올을 포함하는, 방법.
양태 22. 양태 1 내지 20 중 어느 하나에 있어서, 희석제는 페놀을 포함하는, 방법.
양태 23. 양태 1 내지 20 중 어느 하나에 있어서, 희석제는 m-크레졸을 포함하는, 방법.
양태 24. 양태 1 내지 20 중 어느 하나에 있어서, 희석제는 페닐알라닌을 포함하는, 방법.
양태 25. 양태 1 내지 24 중 어느 하나에 있어서, 단계 (b)는 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 6시간 이내에 투여하는 단계를 포함하는, 방법.
양태 26. 양태 1 내지 24 중 어느 하나에 있어서, 단계 (b)는 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 4시간 이내에 투여하는 단계를 포함하는, 방법.
양태 27. 양태 1 내지 24 중 어느 하나에 있어서, 단계 (b)는 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 2시간 이내에 투여하는 단계를 포함하는, 방법.
양태 28. 양태 1 내지 24 중 어느 하나에 있어서, 단계 (b)는 상기 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 1시간 이내에 투여하는 단계를 포함하는, 방법.
양태 29. 양태 1 내지 24 중 어느 하나에 있어서, 대상체는 암을 앓고 있는, 방법.
양태 30. 양태 29에 있어서, 암은 소세포폐암(SCLC), 비소세포폐암(NSCLC), 신경교종, 교모세포종, 흑색종, 신경내분비 전립선암, 신경내분비 췌장암, 간모세포종 또는 간세포 암종인, 방법.
양태 31. 양태 29에 있어서, 암은 SCLC, NSCLC, 신경교종, 교모세포종 또는 신경내분비 전립선암인, 방법.
양태 32. 방법으로서, (a) 폴리펩티드, 당류, 계면활성제 및 완충제를 포함하는 동결건조 제형을 방향족 알코올, 페놀계 화합물 또는 방향족 측쇄를 갖는 아미노산을 포함하는 희석제로 재구성시키는 단계 및 (b) 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 12시간 이내에 투여하는 단계를 포함하고, 폴리펩티드는 이중특이적 항체 작제물, 예컨대, 이중특이적 T 세포 관여자인, 방법.
양태 33. 양태 32에 있어서, 희석제는 벤질 알코올, 페놀, m-크레졸 또는 페닐알라닌을 포함하는, 방법.
양태 34. 양태 32 또는 양태 33에 있어서, 재구성된 제형의 pH는 약 4 내지 약 7, 선택적으로 예컨대, 4.2의 pH인, 방법.
양태 35. 양태 32 내지 34 중 어느 하나에 있어서, 재구성된 제형은 약 1 ㎎/㎖ 내지 약 20 ㎎/㎖의 폴리펩티드, 예컨대, 약 15 ㎎/㎖의 폴리펩티드를 포함하는, 방법.
양태 36. 양태 32 내지 35 중 어느 하나에 있어서, 상기 완충제는 아세테이트 완충제, 글루타메이트 완충제, 시트레이트 완충제, 락트산 완충제, 석시네이트 완충제, 타르트레이트 완충제, 푸마레이트 완충제, 말레에이트 완충제, 히스티딘 완충제 또는 포스페이트 완충제, 선택적으로 글루타메이트 완충제인, 방법.
양태 37. 양태 32 내지 36 중 어느 하나에 있어서, 완충제는 동결건조 전에 5 내지 200 mM 범위의 농도, 예컨대, 동결건조 전에 10 내지 50 mM 범위의 농도로 존재하는, 방법.
양태 38. 양태 32 내지 37 중 어느 하나에 있어서, 당류는 단당류 또는 이당류인, 방법.
양태 39. 양태 32 내지 38 중 어느 하나에 있어서, 당류는 글루코스, 갈락토스, 프룩토스, 자일로스, 수크로스, 락토스, 말토스, 트레할로스, 소르비톨, 만니톨 또는 자일리톨, 선택적으로 수크로스인, 방법.
양태 40. 양태 32 내지 39 중 어느 하나에 있어서, 당류는 동결건조 전에 1 내지 15%(w/v) 범위의 농도로 존재하는, 방법.
양태 41. 양태 32 내지 40 중 어느 하나에 있어서, 계면활성제는 폴리소르베이트 20, 폴리소르베이트 40, 폴리소르베이트 60, 폴리소르베이트 80, 폴록사머 188, 폴록사머 407, Triton® X-100, 폴리옥시에틸렌, PEG 3350, PEG 4000 또는 이들의 조합이고, 선택적으로 계면활성제는 폴리소르베이트 80인, 방법.
양태 42. 양태 32 내지 41 중 어느 하나에 있어서, 계면활성제는 동결건조 전에 0.001% 내지 0.5%(w/v) 범위의 농도로 존재하는, 방법.
양태 43. 양태 32 내지 42 중 어느 하나에 있어서, 제형은 동결건조 전에 15 mM의 글루타메이트, 9%(w/V)의 수크로스 및 0.01%(w/V)의 폴리소르베이트 80을 포함하고, 제형은 4.2의 pH를 갖는, 방법.
양태 44. 양태 32 내지 43 중 어느 하나에 있어서, 희석제는 0.9%의 벤질 알코올, 페놀, m-크레졸 및/또는 페닐알라닌을 포함하는, 방법.
양태 45. 양태 32 내지 44 중 어느 하나에 있어서, 단계 (b)는 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 6시간 이내, 재구성 4시간 이내, 재구성 2시간 이내 또는 재구성 1시간 이내에 투여하는 단계를 포함하는, 방법.
양태 46. 양태 32 내지 45 중 어느 하나에 있어서, 대상체는 암, 예컨대, 소세포폐암(SCLC), 비소세포폐암(NSCLC), 신경교종, 교모세포종, 흑색종, 신경내분비 전립선암, 신경내분비 췌장암, 간모세포종 또는 간세포 암종을 앓고 있는, 방법.
양태 47. 양태 32 내지 46 중 어느 하나에 있어서, 폴리펩티드는 본 명세서에 제공된 서열 목록에 제시된 임의의 아미노산 서열, 예컨대, 서열번호 20, 서열번호 21, 서열번호 22, 서열번호 23, 서열번호 33, 서열번호 43, 서열번호 44, 서열번호 45, 서열번호 55, 서열번호 65, 서열번호 66, 서열번호 76, 서열번호 77, 서열번호 87, 서열번호 97, 서열번호 98, 서열번호 99, 서열번호 109, 서열번호 110, 서열번호 111, 서열번호 121, 서열번호 122, 서열번호 131, 서열번호 141, 서열번호 142, 서열번호 146, 서열번호 147, 서열번호 156, 서열번호 165, 서열번호 174, 서열번호 183, 서열번호 184, 서열번호 185, 서열번호 186, 서열번호 187 또는 서열번호 188에 제시된 아미노산 서열(예를 들어, 서열번호 76, 서열번호 77, 서열번호 97, 서열번호 98, 서열번호 99, 서열번호 156, 서열번호 165, 서열번호 174 또는 서열번호 183에 제시된 아미노산 서열)을 포함한다.
하기 실시예는 단순히 본 발명을 예시하기 위해 제공되며 어떠한 방식으로든 그 범위를 제한하지 않는다.
실시예
본 실시예는 본 개시내용의 방법을 사용하여 동결건조된 폴리펩티드(HLE-BiTE®) 제형을 재구성할 때 HMW 종을 분할시키는 데 필요한 시간의 감소를 입증한다.
동결건조된 HLE-BiTE® 제형(15 mM의 글루타메이트, 9%(w/V)의 수크로스, 및 0.01%(w/V)의 폴리소르베이트 80; 서열번호 75 및 9를 포함하는 BiTE® 분자("BiTE®-A"))을 재구성 연구를 위해서 사용하였다. 재구성을 위해서 사용된 희석제는 주사용 멸균수(sWFI), 0.9%의 벤질 알코올(bWFI)을 포함하는 WFI, 0.9%의 식염수, 0.9%의 벤질 알코올을 포함하는 식염수, sWFI + 0.01% PS80, 5% IVSS(정맥내 용액 안정화제) + sWFI, 정제수 중 페닐알라닌, 정제수 중 페놀 및 정제수 중 m-크레졸을 포함하였다. 재구성을 수행하기 위해서, 먼저 동결건조 제형 및 재구성 희석제를 8℃ 또는 25℃에서 1시간 동안 평형화시켰다. 그런 다음, 적절한 양의 재구성 희석제를 멸균 바이알 내의 동결건조 제형에 첨가하여 15 ㎎/㎖의 최종 단백질 농도를 만들었다. 재구성 시간은 3분 미만이었으며, 그 동안 모든 동결건조된 케이크를 완전히 용해시켰고, 용액을 샘플 균질성을 위해 부드럽게 휘저었다. 재구성된 샘플을 미리 설정된 8℃ 또는 25℃를 사용하여 즉시 초고성능 액체 크로마토그래피(UPLC) 샘플 매니저로 옮겼다. 재구성부터 크기 배제 초고성능 액체 크로마토그래피(SE-UHPLC) 시점의 첫 번째 주입까지의 예상 시간은 5분 미만이었다. 각각의 SE-UHPLC 주입에 대해서, 10 ㎍의 샘플을 ACQUITY UPLC 시스템(Waters, 미국 메사추세츠주 밀리포드 소재)에 연결된 BEH200 UPLC 컬럼(1.7 ㎛ 4.6Х150 mm)에 로딩하였다. 이동상은 0.4 ㎖/분의 유속에서 pH 6.8에서 250 mM 염화나트륨을 포함하는 100 mM 인산나트륨이었다. UPLC 샘플 매니저는 8℃ 또는 25℃에서 유지되었다. 결과를 Chromeleon® 소프트웨어를 사용하여 분석하였고, 피크 적분은 220 nm에서의 UV 흡광도를 사용하여 계산하였다. 재구성된 희석제의 pH 및 농도는 이후 표준 pH 프로브(Mettler Toledo, 미국 오하이오주 소재) 및 1.8의 흡광계수를 사용하여 280 nm에서 UV 흡광도를 사용하여 측정하였다.
도 1은 8℃에서 수행된 재구성 연구를 예시한다. sWFI 및 폴리소르베이트 80을 희석제로 사용하여 재구성된 제형이 "평형"(즉, HMW 종의 일관된 % 수준)에 도달하기 위해서 24시간 초과가 필요하였다. 식염수, IVSS 및 식염수 + 벤질 알코올은 재구성된 제형에서 HMW의 백분율을 상당히 증가시켰으며, HMW 수준은 연구 전반에 걸쳐 계속해서 상승하였다. 놀랍게도, bWFI를 희석제로 사용하면 재구성 1시간 이내에 평형을 나타내었다. 도 2는 8℃ 및 25℃에서 평형까지의 시간과 비교한, sWFI 및 bWFI를 사용하여 25℃에서 수행된 유사한 연구 결과를 제공한다. HMW 종은 sWFI 및 bWFI 둘 다에 대해서 25℃에서 더 빨리 해리되었다. 두 온도 모두에서 bWFI는 sWFI에 비해 해리 과정을 상당히 가속화하였고, 25℃에서 1시간 이내에 평형이 달성되었다. bWFI는 1% 미만의 HMW 종을 포함하는 재구성 제형을 생성하였다. 실제로, 25℃에서 HMW 종의 백분율은 재구성 20분 이내에 약 1% 이하까지 감소하였고, 적어도 100분 동안 그 수준을 유지하였다. 도 4를 참조하기 바란다.
도 3에 예시된 결과를 제공하기 위해 추가 희석제를 연구하였다. 도 3은 8℃에서 연구 동안 수집된 데이터를 예시한다. 페닐알라닌, 페놀 및 m-크레졸은 sWFI에 비해 HMW 종 해리를 가속화하였다. sWFI 이외의 시험된 모든 희석제를 사용하면 재구성 후 10시간까지 1.5% 미만의 HMW 종을 갖는 재구성된 제형이 생성되었으며, bWFI-기반 재구성 제형은 가장 낮은 수준의 HMW 종을 나타내었다.
상기에 제시된 것과 유사한 물질 및 방법을 사용하여 추가 연구를 수행하였다. 바이알 내의 4개의 동결건조된 BITE를 주사용 멸균수(sWFI), 정균 WFI(bWFI), 0.9%의 식염수 및 페놀을 포함하는 재구성 배지와 함께 사용하였다. BiTE®-A는 서열번호 75 및 9(CDR 서열 서열번호 67 내지 72 및 1 내지 6 포함)를 포함하였고; BiTE®-B는 서열번호 156(CDR 서열 서열번호 148 내지 153 및 1 내지 6 포함)을 포함하였으며; BiTE®-C는 서열번호 97(CDR 서열 서열번호 88 내지 93 및 1 내지 6 포함)을 포함하였고; BiTE®-D는 서열번호 98(CDR 서열 서열번호 88 내지 93 및 1 내지 6 포함)을 포함하였다. 또한, BiTE®-A(서열번호 75 및 9를 포함하는 BiTE® 분자)에 대해, 정균 식염수, sWFI + 0.01% PS80, 5% IVSS(정맥내 용액 안정화제) + sWFI, 페닐알라닌 및 m-크레졸을 사용하여 연구를 수행하였다. 재구성을 위해, 동결건조된 BiTE 바이알 및 모든 재구성 용액을 먼저 특정 온도, 즉, 25℃ 또는 8℃에서 1시간 동안 평형화하였다. 그런 다음, 동결건조된 바이알에 적절한 부피의 재구성 용액을 첨가하였다. 동결건조된 케이크가 완전히 용해될 때까지 최대 3분 동안 샘플을 재구성하였다. 그런 다음 샘플 균질성을 위해 샘플을 부드럽게 휘저었다. 그런 다음 재구성된 샘플을 8℃ 또는 25℃로 미리 설정된 UPLC 샘플 매니저로 즉시 옮겼다. 재구성부터 SE-UHPLC에서의 첫 번째 주입까지의 예상 시간은 5분 미만이었다. SE-UPLC의 경우, ACQUITY UPLC 시스템(Waters, 미국 메사추세츠주 밀리포드 소재)에 연결된 SEC 컬럼에 적절한 양의 샘플을 로딩하였다. UPLC 샘플 매니저는 8℃ 또는 25℃에서 유지되었다. 결과를 Chromeleon® 소프트웨어를 사용하여 분석하였고, 피크 적분은 UV 흡광도 또는 형광 검출을 사용하여 계산하였다. 재구성된 샘플의 pH 및 농도는 이후 표준 pH 프로브(Mettler Toledo, 미국 오하이오주 소재) 및 280 nm에서 UV 흡광도를 사용하여 측정하였다.
상이한 BiTE에 대한 재구성 매질의 효과를 비교하기 위해서, t 90% 는 초기 고분자량 종(HMW)의 90%가 단량체로 다시 해리되는 데 필요한 시간 기간으로 정의되고; t90%는 다음과 같이 계산된다:
[HMW]는 고분자량 종의 농도이고, [HMW]t0은 시간 0에서 고분자량 종의 농도이며, 1차 방정식이 해리 곡선에 피팅되고, k는 속도 상수이다.
연구 결과를 도 5 및 표 1에 제시한다. 도 5는 상기에 정의된 바와 같은 t90%에 제시된 바와 같이, 25℃에서 15 ㎎/㎖로 재구성된 BiTE®-A의 HMW% 해리에 대한 벤질 알코올 농도의 효과를 예시한다. HMW 종의 해리는 모든 농도의 벤질 알코올에서 개선되었으며, 40 mM을 초과하는 농도(예를 들어, 41.6 mM 및 83.2 mM)는 2시간 이내의 "재구성 지속 시간"(즉, 재구성 후 시간, 여기서 형성된 초기 고분자량 종(HMW)의 90%가 다시 단량체로 해리됨)으로 이어진다. 이 데이터는 1시간 미만의 재구성 지속 시간이 41.6 mM보다 높은(예를 들어, 42 mM보다 높은) 벤질 알코올 농도로 달성될 수 있음을 나타낸다.
하기 표 1은 상기에서 정의된 바와 같은 t90%로 제시된 바와 같은 25℃에서 다양한 BiTE®의 해리 시간에 대한 시험된 재구성 매질의 효과를 입증하는 연구 결과를 요약한다. 시험된 모든 샘플에 대해서, 벤질 알코올 및 페놀 둘 다는 WFI에 비해 재구성 지속 기간을 상당히 단축시켰고, 전형적으로는 1시간 미만 대 9+ 시간이다. BiTE®-B 및 BiTE®-C의 경우, 빠른 동역학으로 인해서 1시간 미만이 보고된다. 다른 조건과 달리, 식염수는 BiTE®-A, BiTE®-B 및 BiTE®-C에 대한 응집(Agg.)을 촉진하고 BiTE®-D에 대한 t90%를 19.1시간에서 26.1시간으로 연장하였다.
실시예는 0.9%의 벤질 알코올, 페닐알라닌, 페놀 또는 m-크레졸을 포함하는 WFI를 포함하는 희석제를 사용한 본 명세서에 기재된 동결건조된 폴리펩티드 제형(예를 들어, HLE-BiTE® 제품 제형)의 재구성이 WFI 단독을 포함하여 시험된 다른 희석제에 비해서 HMW 종의 해리에 필요한 시간을 상당히 단축시켰음을 입증한다. 1.5% 미만의 HMW 종을 포함하는 재구성된 제형은 이들 희석제를 사용하여 8℃에서 재구성 15시간 이내에 달성되었다. 0.9%의 벤질 알코올을 포함하는 희석제(bWFI)는 재구성 후 HMW 종을 해리시키는 데 필요한 시간을 단축시키고(즉, 평형에 도달하는 시간을 가속화시키고) HMW 종 함량이 감소된 최종 재구성된 제형을 달성하는 데 있어서도 시험된 다른 희석제보다 성능이 뛰어났다. 본 명세서에 보고된 데이터는, 방향족 알코올, 페놀계 화합물 또는 방향족 측쇄를 갖는 아미노산을 포함하는 희석제의 사용이 1.5시간 미만을 포함하는 바람직한 재구성 지속 시간을 달성한다는 것을 추가로 입증한다. 시험된 모든 작제물에 대해 주사용수 또는 식염수를 사용한 재구성에 비해 재구성 지속 시간이 크게 단축되었다.
바람직한 양태에 중점을 두고 본 발명을 설명하였지만, 바람직한 화합물 및 방법의 변형이 사용될 수 있다는 점과 본 발명이 본 명세서에 구체적으로 설명된 바와 달리 실시될 수 있는 것이 의도된다는 점은 당업자에게 명백할 것이다. 따라서, 본 발명은 다음의 청구범위에 의해 정해지는 본 발명의 사상 및 범위 내에 포함되는 모든 변형을 포함한다.
SEQUENCE LISTING
<110> Amgen Inc.
<120> METHOD OF RECONSTITUTING LYOPHILIZED FORMULATION
<130> 01017/56395/PC
<150> US 63/216,616
<151> 2021-06-30
<160> 197
<170> PatentIn version 3.5
<210> 1
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 1
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 2
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 2
Gly Thr Lys Phe Leu Ala Pro
1 5
<210> 3
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 3
Val Leu Trp Tyr Ser Asn Arg Trp Val
1 5
<210> 4
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 4
Lys Tyr Ala Met Asn
1 5
<210> 5
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 5
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 6
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 6
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 7
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 8
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 8
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
85 90 95
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 9
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 10
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 10
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
1 5 10 15
Ala
<210> 11
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 11
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 12
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 12
Gln Gln Ser Ala His Phe Pro Ile Thr
1 5
<210> 13
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 13
Asn Tyr Gly Met Asn
1 5
<210> 14
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 14
Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe Gln
1 5 10 15
Gly
<210> 15
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 15
Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr
1 5 10
<210> 16
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 16
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 17
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 17
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 18
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 18
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser
20 25 30
Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Ser Ala His Phe Pro Ile Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile
100 105 110
Lys
<210> 19
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 19
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser
20 25 30
Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Ser Ala His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile
100 105 110
Lys
<210> 20
<211> 505
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu
500 505
<210> 21
<211> 530
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 21
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala
65 70 75 80
Asp Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met
145 150 155 160
Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr
165 170 175
Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys
180 185 190
Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
195 200 205
Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe
210 215 220
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro
225 230 235 240
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe
245 250 255
Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly
260 265 270
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
275 280 285
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
290 295 300
Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
305 310 315 320
Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
325 330 335
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
340 345 350
Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile
370 375 380
Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
405 410 415
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
420 425 430
Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
435 440 445
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
450 455 460
Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser
465 470 475 480
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
485 490 495
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg
500 505 510
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His
515 520 525
His His
530
<210> 22
<211> 993
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 22
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr
500 505 510
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
515 520 525
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
530 535 540
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
545 550 555 560
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
565 570 575
Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val
580 585 590
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
595 600 605
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
610 615 620
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
625 630 635 640
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
645 650 655
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
660 665 670
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
675 680 685
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
690 695 700
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
705 710 715 720
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
725 730 735
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
740 745 750
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
755 760 765
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
770 775 780
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
785 790 795 800
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
805 810 815
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
820 825 830
Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys
835 840 845
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
850 855 860
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
865 870 875 880
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
885 890 895
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
900 905 910
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
915 920 925
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
930 935 940
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
945 950 955 960
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
965 970 975
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
980 985 990
Lys
<210> 23
<211> 511
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 24
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 24
Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser
1 5 10 15
<210> 25
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 25
Arg Ile Ser Arg Arg Phe Ser
1 5
<210> 26
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 26
Met Gln Ser Thr His Val Pro Arg Thr
1 5
<210> 27
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 27
Asn Tyr Gly Met His
1 5
<210> 28
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 28
Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val Arg
1 5 10 15
Gly
<210> 29
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 29
Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp Tyr
1 5 10 15
<210> 30
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 30
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 31
Asp Thr Val Met Thr Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro
35 40 45
Pro Arg Leu Leu Ile Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 32
<211> 251
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 32
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr
130 135 140
Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
165 170 175
Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
180 185 190
Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg
225 230 235 240
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
245 250
<210> 33
<211> 506
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 33
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr
130 135 140
Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
165 170 175
Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
180 185 190
Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg
225 230 235 240
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
500 505
<210> 34
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 34
Asp Tyr Tyr Met Thr
1 5
<210> 35
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 35
Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 36
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 36
Asp Arg Asn Ser His Phe Asp Tyr
1 5
<210> 37
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 37
Arg Ala Ser Gln Gly Ile Asn Thr Trp Leu Ala
1 5 10
<210> 38
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 38
Gly Ala Ser Gly Leu Gln Ser
1 5
<210> 39
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 39
Gln Gln Ala Lys Ser Phe Pro Arg Thr
1 5
<210> 40
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 40
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Ser Phe Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 239
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 42
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 43
<211> 494
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 43
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490
<210> 44
<211> 982
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 44
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
485 490 495
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
500 505 510
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
515 520 525
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
530 535 540
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
545 550 555 560
Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser
565 570 575
Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
580 585 590
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
595 600 605
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
610 615 620
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
625 630 635 640
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
645 650 655
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
660 665 670
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
675 680 685
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
690 695 700
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
705 710 715 720
Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 45
<211> 982
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 45
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
485 490 495
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
500 505 510
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
515 520 525
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
530 535 540
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
545 550 555 560
Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser
565 570 575
Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
580 585 590
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
595 600 605
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
610 615 620
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
625 630 635 640
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
645 650 655
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
660 665 670
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
675 680 685
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
690 695 700
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
705 710 715 720
Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 46
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 46
Ser Tyr Gly Met His
1 5
<210> 47
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 47
Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Asp
<210> 48
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 48
Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 49
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 49
Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser
1 5 10
<210> 50
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 50
Gln Asp Thr Lys Arg Pro Ser
1 5
<210> 51
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 51
Gln Ala Trp Glu Ser Ser Thr Val Val
1 5
<210> 52
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 52
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 53
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 53
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr
20 25 30
Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr
35 40 45
Gln Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser
100 105
<210> 54
<211> 247
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 54
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser
245
<210> 55
<211> 507
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 55
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 56
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 56
Asn Ala Arg Met Gly Val Ser
1 5
<210> 57
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 57
His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Asn
1 5 10 15
<210> 58
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 58
Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp Tyr
1 5 10
<210> 59
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 59
Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
1 5 10
<210> 60
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 60
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 61
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 61
Leu Gln His Asn Ser Tyr Pro Leu Thr
1 5
<210> 62
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 62
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 63
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105
<210> 64
<211> 246
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 64
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys
245
<210> 65
<211> 501
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 65
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu
500
<210> 66
<211> 989
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 66
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 67
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 67
Ser Tyr Tyr Trp Ser
1 5
<210> 68
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 68
Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 69
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 69
Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr
1 5 10
<210> 70
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 70
Arg Ala Ser Gln Arg Val Asn Asn Asn Tyr Leu Ala
1 5 10
<210> 71
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 71
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 72
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 72
Gln Gln Tyr Asp Arg Ser Pro Leu Thr
1 5
<210> 73
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 73
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 74
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 74
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Asn Asn Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Arg Ser Pro
85 90 95
Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 75
<211> 241
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 75
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys
<210> 76
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 76
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
<210> 77
<211> 982
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 77
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 78
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 78
Ser Tyr Gly Met His
1 5
<210> 79
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 79
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 80
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 80
Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val
1 5 10
<210> 81
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 81
Arg Ser Ser Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp
1 5 10 15
<210> 82
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 82
Leu Gly Ser Asn Arg Ala Ser
1 5
<210> 83
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 83
Met Gln Ala Leu Gln Thr Pro Phe Thr
1 5
<210> 84
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 84
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 85
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 85
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys
20 25 30
Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105 110
<210> 86
<211> 503
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 86
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys
20 25 30
Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Glu Val
245 250 255
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
260 265 270
Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met
275 280 285
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg
290 295 300
Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val
305 310 315 320
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr
325 330 335
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
355 360 365
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln
385 390 395 400
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
405 410 415
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val
420 425 430
Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys
435 440 445
Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
450 455 460
Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala
465 470 475 480
Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly
485 490 495
Gly Thr Lys Leu Thr Val Leu
500
<210> 87
<211> 991
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 87
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys
20 25 30
Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Glu Val
245 250 255
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
260 265 270
Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met
275 280 285
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg
290 295 300
Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val
305 310 315 320
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr
325 330 335
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
355 360 365
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln
385 390 395 400
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
405 410 415
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val
420 425 430
Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys
435 440 445
Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
450 455 460
Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala
465 470 475 480
Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly
485 490 495
Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr
500 505 510
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
515 520 525
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
530 535 540
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
545 550 555 560
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
565 570 575
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
580 585 590
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
595 600 605
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
610 615 620
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
625 630 635 640
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
645 650 655
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
660 665 670
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
675 680 685
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
690 695 700
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
705 710 715 720
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His
755 760 765
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
770 775 780
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
785 790 795 800
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
805 810 815
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
820 825 830
Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser
835 840 845
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
850 855 860
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
865 870 875 880
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
885 890 895
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
900 905 910
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
915 920 925
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
930 935 940
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
945 950 955 960
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
965 970 975
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 88
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 88
Asn His Ile Ile His
1 5
<210> 89
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 89
Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe Gln
1 5 10 15
Gly
<210> 90
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 90
Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr
1 5 10
<210> 91
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 91
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 92
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 92
Tyr Thr Ser Arg Leu His Thr
1 5
<210> 93
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 93
Gln Gln Gly Asn Thr Leu Pro Trp Thr
1 5
<210> 94
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 94
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 95
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 95
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 96
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 96
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 97
<211> 986
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 97
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 98
<211> 504
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 98
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 99
<211> 986
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 99
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 100
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 100
Asp Tyr Tyr Met Tyr
1 5
<210> 101
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 101
Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys
1 5 10 15
Gly
<210> 102
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 102
Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr
1 5 10
<210> 103
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 103
Lys Ala Ser Gln Asn Val Asp Ala Asn Val Ala
1 5 10
<210> 104
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 104
Ser Ala Ser Tyr Val Tyr Trp
1 5
<210> 105
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 105
Gln Gln Tyr Asp Gln Gln Leu Ile Thr
1 5
<210> 106
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 106
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 107
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ala Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 108
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 108
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 109
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 109
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 110
<211> 986
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 110
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 111
<211> 984
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 111
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 112
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 112
Asp Tyr Tyr Met Tyr
1 5
<210> 113
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 113
Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys
1 5 10 15
Gly
<210> 114
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 114
Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr
1 5 10
<210> 115
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 115
Lys Ala Ser Gln Asn Val Asp Thr Asn Val Ala
1 5 10
<210> 116
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 116
Ser Ala Ser Tyr Val Tyr Trp
1 5
<210> 117
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 117
Gln Gln Tyr Asp Gln Gln Leu Ile Thr
1 5
<210> 118
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 118
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 119
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 119
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 120
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 120
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 121
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 121
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 122
<211> 986
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 122
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 123
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 123
Thr Tyr Ala Met Ser
1 5
<210> 124
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 124
Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val Glu
1 5 10 15
Gly
<210> 125
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 125
His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr
1 5 10
<210> 126
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 126
Arg Ala Ser Gln Ser Val Arg Ser Thr Tyr Leu Ala
1 5 10
<210> 127
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 127
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 128
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 128
Gln Gln Tyr Gly Asp Leu Pro Phe Thr
1 5
<210> 129
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 129
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 130
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 130
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Thr
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Gly Asp Leu Pro
85 90 95
Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 131
<211> 986
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 131
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
145 150 155 160
Ser Gln Ser Val Arg Ser Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr
180 185 190
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Ser Cys
210 215 220
Gln Gln Tyr Gly Asp Leu Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 132
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 132
Gly Tyr Tyr Met His
1 5
<210> 133
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 133
Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 134
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 134
Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 135
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 135
Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala
1 5 10
<210> 136
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 136
Thr Ala Ser Ser Leu Gln Ser
1 5
<210> 137
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 137
Gln Gln Ala Asn Ser Phe Pro Ile Thr
1 5
<210> 138
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 138
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 139
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 139
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
85 90 95
Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 140
<211> 247
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 140
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys
245
<210> 141
<211> 502
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 141
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu
500
<210> 142
<211> 990
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 142
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys
500 505 510
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
515 520 525
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
530 535 540
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
545 550 555 560
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
565 570 575
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
580 585 590
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
595 600 605
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
610 615 620
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
625 630 635 640
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
645 650 655
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
660 665 670
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
675 680 685
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
690 695 700
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
705 710 715 720
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr
755 760 765
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
770 775 780
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
785 790 795 800
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
805 810 815
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
820 825 830
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
835 840 845
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
850 855 860
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
865 870 875 880
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
885 890 895
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
900 905 910
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
915 920 925
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
930 935 940
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
945 950 955 960
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
965 970 975
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 143
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 143
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 144
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 144
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
85 90 95
Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 145
<211> 247
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 145
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys
245
<210> 146
<211> 502
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 146
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu
500
<210> 147
<211> 990
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 147
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys
500 505 510
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
515 520 525
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
530 535 540
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
545 550 555 560
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
565 570 575
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
580 585 590
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
595 600 605
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
610 615 620
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
625 630 635 640
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
645 650 655
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
660 665 670
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
675 680 685
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
690 695 700
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
705 710 715 720
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr
755 760 765
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
770 775 780
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
785 790 795 800
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
805 810 815
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
820 825 830
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
835 840 845
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
850 855 860
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
865 870 875 880
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
885 890 895
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
900 905 910
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
915 920 925
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
930 935 940
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
945 950 955 960
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
965 970 975
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 148
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 148
Asn His Gly Met His
1 5
<210> 149
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 149
Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ala Val Lys
1 5 10 15
Gly
<210> 150
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 150
Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr
1 5 10
<210> 151
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 151
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Ser
1 5 10
<210> 152
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 152
Gln Asp Ala Lys Arg Pro Ser
1 5
<210> 153
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 153
Gln Ala Phe His Gln Ser Thr Trp Val
1 5
<210> 154
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 154
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 155
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 155
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Ser Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Ala Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Phe His Gln Ser Thr Trp Val
85 90 95
Phe Gly Cys Gly Thr Gln Leu Thr Val Leu
100 105
<210> 156
<211> 985
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 156
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Pro
130 135 140
Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly
145 150 155 160
Asp Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Ser Gly
165 170 175
Gln Ser Pro Val Leu Val Ile Tyr Gln Asp Ala Lys Arg Pro Ser Gly
180 185 190
Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu
195 200 205
Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
Ala Phe His Gln Ser Thr Trp Val Phe Gly Cys Gly Thr Gln Leu Thr
225 230 235 240
Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
500 505 510
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
515 520 525
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
530 535 540
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
545 550 555 560
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
565 570 575
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
580 585 590
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
595 600 605
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
610 615 620
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
625 630 635 640
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
645 650 655
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
660 665 670
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
675 680 685
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
690 695 700
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
705 710 715 720
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
755 760 765
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
770 775 780
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
785 790 795 800
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
805 810 815
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
820 825 830
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
835 840 845
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
850 855 860
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
865 870 875 880
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
885 890 895
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
900 905 910
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
915 920 925
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
930 935 940
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
945 950 955 960
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
965 970 975
Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 157
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 157
Asn His Ala Met His
1 5
<210> 158
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 158
Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 159
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 159
Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr
1 5 10
<210> 160
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 160
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Ser
1 5 10
<210> 161
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 161
Gln Asp Arg Lys Arg Pro Ser
1 5
<210> 162
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 162
Gln Ala Tyr Asp Ala Ser Thr Trp Val
1 5
<210> 163
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 163
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 164
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 164
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Ser Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Arg Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Tyr Asp Ala Ser Thr Trp Val
85 90 95
Phe Gly Cys Gly Thr Gln Leu Thr Val Leu
100 105
<210> 165
<211> 985
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 165
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Pro
130 135 140
Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly
145 150 155 160
Asp Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Ser Gly
165 170 175
Gln Ser Pro Val Leu Val Ile Tyr Gln Asp Arg Lys Arg Pro Ser Gly
180 185 190
Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu
195 200 205
Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
Ala Tyr Asp Ala Ser Thr Trp Val Phe Gly Cys Gly Thr Gln Leu Thr
225 230 235 240
Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
500 505 510
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
515 520 525
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
530 535 540
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
545 550 555 560
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
565 570 575
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
580 585 590
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
595 600 605
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
610 615 620
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
625 630 635 640
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
645 650 655
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
660 665 670
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
675 680 685
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
690 695 700
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
705 710 715 720
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
755 760 765
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
770 775 780
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
785 790 795 800
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
805 810 815
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
820 825 830
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
835 840 845
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
850 855 860
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
865 870 875 880
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
885 890 895
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
900 905 910
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
915 920 925
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
930 935 940
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
945 950 955 960
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
965 970 975
Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 166
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 166
Gly Tyr Tyr Trp Ser
1 5
<210> 167
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 167
Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 168
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 168
Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn
1 5 10
<210> 169
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 169
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Ser
1 5 10
<210> 170
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 170
Gln Asp Arg Lys Arg Pro Ser
1 5
<210> 171
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 171
Gln Ala Trp Gly Ser Ser Thr Ala Val
1 5
<210> 172
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 172
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 173
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 173
Ser Tyr Glu Leu Thr Gln Pro Ser Ser Val Ser Val Pro Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Arg Lys Arg Pro Ser Gly Val Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Gly Ser Ser Thr Ala Val
85 90 95
Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 174
<211> 984
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 174
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Ser Ser
130 135 140
Val Ser Val Pro Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp
145 150 155 160
Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ser Pro Val Leu Val Ile Tyr Gln Asp Arg Lys Arg Pro Ser Gly Val
180 185 190
Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr
195 200 205
Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala
210 215 220
Trp Gly Ser Ser Thr Ala Val Phe Gly Cys Gly Thr Lys Leu Thr Val
225 230 235 240
Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 175
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 175
Gly Tyr Tyr Trp Ser
1 5
<210> 176
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 176
Asp Ile Asp Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 177
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 177
Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Tyr
1 5 10
<210> 178
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 178
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Asn
1 5 10
<210> 179
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 179
His Asp Asn Lys Arg Pro Ser
1 5
<210> 180
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 180
Gln Ala Tyr Gly Ile Ser Ser Ala Val
1 5
<210> 181
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 181
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 182
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 182
Ser Tyr Glu Leu Thr Gln Pro Ala Ser Ala Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Ile Leu Val Ile Tyr
35 40 45
His Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Tyr Gly Ile Ser Ser Ala Val
85 90 95
Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 183
<211> 984
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 183
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Ala Ser
130 135 140
Ala Ser Val Ser Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp
145 150 155 160
Lys Leu Gly Asp Lys Tyr Ala Asn Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ser Pro Ile Leu Val Ile Tyr His Asp Asn Lys Arg Pro Ser Gly Ile
180 185 190
Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr
195 200 205
Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala
210 215 220
Tyr Gly Ile Ser Ser Ala Val Phe Gly Cys Gly Thr Lys Leu Thr Val
225 230 235 240
Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 184
<211> 989
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 184
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 185
<211> 987
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 185
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
755 760 765
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
770 775 780
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
785 790 795 800
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
805 810 815
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys
820 825 830
Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val
835 840 845
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
850 855 860
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
865 870 875 880
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
885 890 895
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
900 905 910
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
915 920 925
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
930 935 940
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
945 950 955 960
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
965 970 975
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 186
<211> 501
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 186
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu
500
<210> 187
<211> 989
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 187
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 188
<211> 987
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 188
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
755 760 765
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
770 775 780
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
785 790 795 800
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
805 810 815
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys
820 825 830
Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val
835 840 845
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
850 855 860
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
865 870 875 880
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
885 890 895
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
900 905 910
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
915 920 925
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
930 935 940
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
945 950 955 960
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
965 970 975
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 189
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 189
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
245 250
<210> 190
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 190
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
245 250
<210> 191
<211> 244
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 191
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
145 150 155 160
Ser Gln Ser Val Arg Ser Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr
180 185 190
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Ser Cys
210 215 220
Gln Gln Tyr Gly Asp Leu Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser
<210> 192
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 192
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
1 5 10 15
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
20 25 30
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
65 70 75 80
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
100 105 110
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
130 135 140
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
145 150 155 160
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
165 170 175
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
180 185 190
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
195 200 205
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
210 215 220
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
225 230 235 240
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
245 250
<210> 193
<211> 484
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 193
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
275 280 285
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
290 295 300
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
305 310 315 320
Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr
325 330 335
Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
340 345 350
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
370 375 380
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
385 390 395 400
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
405 410 415
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
420 425 430
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
435 440 445
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
450 455 460
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
465 470 475 480
Ser Pro Gly Lys
<210> 194
<211> 242
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 194
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Ser Ser
130 135 140
Val Ser Val Pro Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp
145 150 155 160
Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ser Pro Val Leu Val Ile Tyr Gln Asp Arg Lys Arg Pro Ser Gly Val
180 185 190
Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr
195 200 205
Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala
210 215 220
Trp Gly Ser Ser Thr Ala Val Phe Gly Cys Gly Thr Lys Leu Thr Val
225 230 235 240
Leu Ser
<210> 195
<211> 250
<212> PRT
<213> Artificial Seuqence
<220>
<223> Synthetic Polypeptide
<400> 195
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
1 5 10 15
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
20 25 30
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
65 70 75 80
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
100 105 110
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
130 135 140
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
145 150 155 160
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
165 170 175
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
180 185 190
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
195 200 205
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
210 215 220
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
225 230 235 240
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
245 250
<210> 196
<211> 484
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<400> 196
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
275 280 285
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
290 295 300
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
305 310 315 320
Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr
325 330 335
Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
340 345 350
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
370 375 380
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
385 390 395 400
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
405 410 415
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
420 425 430
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
435 440 445
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
450 455 460
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
465 470 475 480
Ser Pro Gly Lys
<210> 197
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Linker
<400> 197
Gly Gly Gly Gly
1
Claims (34)
- 방법으로서,
(a) 폴리펩티드, 당류, 계면활성제 및 완충제를 포함하는 동결건조 제형을 방향족 알코올, 페놀계 화합물 또는 방향족 측쇄를 갖는 아미노산을 포함하는 희석제로 재구성시키는 단계 및
(b) 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 12시간 이내에 투여하는 단계를 포함하고,
상기 폴리펩티드는 이중특이적 항체 작제물인, 방법. - 제1항에 있어서, 상기 희석제는 벤질 알코올, 페놀, m-크레졸 또는 페닐알라닌을 포함하는, 방법.
- 제1항 또는 제2항에 있어서, 상기 재구성된 제형의 pH는 약 4 내지 약 7인, 방법.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 제형은 4.2의 pH를 갖는, 방법.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 상기 재구성된 제형은 약 1 ㎎/㎖ 내지 약 20 ㎎/㎖의 폴리펩티드를 포함하는, 방법.
- 제1항 내지 제5항 중 어느 한 항에 있어서, 상기 재구성된 제형은 약 15 ㎎/㎖의 폴리펩티드를 포함하는, 방법.
- 제1항 내지 제6항 중 어느 한 항에 있어서, 상기 완충제는 아세테이트 완충제, 글루타메이트 완충제, 시트레이트 완충제, 락트산 완충제, 석시네이트 완충제, 타르트레이트 완충제, 푸마레이트 완충제, 말레에이트 완충제, 히스티딘 완충제 또는 포스페이트 완충제인, 방법.
- 제7항에 있어서, 상기 완충제는 글루타메이트 완충제인, 방법.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 상기 완충제는 동결건조 전에 5 내지 200 mM 범위의 농도로 존재하는, 방법.
- 제9항에 있어서, 상기 완충제는 동결건조 전에 10 내지 50 mM 범위의 농도로 존재하는, 방법.
- 제1항 내지 제10항 중 어느 한 항에 있어서, 상기 당류는 단당류 또는 이당류인, 방법.
- 제1항 내지 제11항 중 어느 한 항에 있어서, 상기 당류는 글루코스, 갈락토스, 프룩토스, 자일로스, 수크로스, 락토스, 말토스, 트레할로스, 소르비톨, 만니톨 또는 자일리톨인, 방법.
- 제12항에 있어서, 상기 당류는 수크로스인, 방법.
- 제1항 내지 제13항 중 어느 한 항에 있어서, 상기 당류는 동결건조 전에 1 내지 15%(w/v) 범위의 농도로 존재하는, 방법.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 계면활성제는 폴리소르베이트 20, 폴리소르베이트 40, 폴리소르베이트 60, 폴리소르베이트 80, 폴록사머 188, 폴록사머 407, Triton® X-100, 폴리옥시에틸렌, PEG 3350, PEG 4000 또는 이들의 조합인, 방법.
- 제15항에 있어서, 상기 계면활성제는 폴리소르베이트 80인, 방법.
- 제1항 내지 제16항 중 어느 한 항에 있어서, 상기 계면활성제는 동결건조 전에 0.001% 내지 0.5%(w/v) 범위의 농도로 존재하는, 방법.
- 제1항 내지 제17항 중 어느 한 항에 있어서, 상기 제형은 동결건조 전에 15 mM의 글루타메이트, 9%(w/V)의 수크로스 및 0.01%(w/V)의 폴리소르베이트 80을 포함하고, 상기 제형은 4.2의 pH를 갖는, 방법.
- 제1항 내지 제18항 어느 한 항에 있어서, 상기 희석제는 0.9%의 벤질 알코올을 포함하는, 방법.
- 제1항 내지 제18항 어느 한 항에 있어서, 상기 희석제는 페놀을 포함하는, 방법.
- 제1항 내지 제18항 어느 한 항에 있어서, 상기 희석제는 m-크레졸을 포함하는, 방법.
- 제1항 내지 제18항 어느 한 항에 있어서, 상기 희석제는 페닐알라닌을 포함하는, 방법.
- 제1항 내지 제22항 중 어느 한 항에 있어서, 단계 (b)는 상기 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 6시간 이내에 투여하는 단계를 포함하는, 방법.
- 제1항 내지 제22항 중 어느 한 항에 있어서, 단계 (b)는 상기 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 4시간 이내에 투여하는 단계를 포함하는, 방법.
- 제1항 내지 제22항 중 어느 한 항에 있어서, 단계 (b)는 상기 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 2시간 이내에 투여하는 단계를 포함하는, 방법.
- 제1항 내지 제22항 중 어느 한 항에 있어서, 단계 (b)는 상기 재구성된 제형을 이를 필요로 하는 대상체에게 재구성 1시간 이내에 투여하는 단계를 포함하는, 방법.
- 제1항 내지 제22항 중 어느 한 항에 있어서, 상기 대상체는 암을 앓고 있는, 방법.
- 제1항 내지 제27항 중 어느 한 항에 있어서, 폴리펩티드는 DLL3 및 CD3에 결합하는, 방법.
- 제1항 내지 제28항 중 어느 한 항에 있어서, 상기 폴리펩티드는 서열번호 75 및 서열번호 9의 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제29항 중 어느 한 항에 있어서, 상기 폴리펩티드는 서열번호 76 또는 서열번호 77에 제시된 아미노산 서열을 포함하는, 방법.
- 제27항 내지 제30항 중 어느 한 항에 있어서, 상기 암은 소세포폐암(SCLC), 비소세포폐암(NSCLC), 신경교종, 교모세포종, 흑색종, 신경내분비 전립선암, 신경내분비 췌장암, 간모세포종 또는 간세포 암종인, 방법.
- 제31항에 있어서, 상기 암은 SCLC, NSCLC, 신경교종, 교모세포종 또는 신경내분비 전립선암인, 방법.
- 제1항 내지 제27항 중 어느 한 항에 있어서, 상기 폴리펩티드는 서열번호 20, 서열번호 21, 서열번호 22, 서열번호 23, 서열번호 33, 서열번호 43, 서열번호 44, 서열번호 45, 서열번호 55, 서열번호 65, 서열번호 66, 서열번호 76, 서열번호 77, 서열번호 87, 서열번호 97, 서열번호 98, 서열번호 99, 서열번호 109, 서열번호 110, 서열번호 111, 서열번호 121, 서열번호 122, 서열번호 131, 서열번호 141, 서열번호 142, 서열번호 146, 서열번호 147, 서열번호 156, 서열번호 165, 서열번호 174, 서열번호 183, 서열번호 184, 서열번호 185, 서열번호 186, 서열번호 187 또는 서열번호 188에 제시된 아미노산 서열을 포함하는, 방법.
- 제33항에 있어서, 상기 폴리펩티드는 서열번호 76, 서열번호 77, 서열번호 97, 서열번호 98, 서열번호 99, 서열번호 156, 서열번호 165, 서열번호 174 또는 서열번호 183에 제시된 아미노산 서열을 포함하는, 방법.
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WO2006020258A2 (en) | 2004-07-17 | 2006-02-23 | Imclone Systems Incorporated | Novel tetravalent bispecific antibody |
KR20100052545A (ko) | 2007-08-28 | 2010-05-19 | 바이오겐 아이덱 엠에이 인코포레이티드 | Igf―1r의 다중 에피토프에 결합하는 조성물 |
TW202346349A (zh) * | 2015-07-31 | 2023-12-01 | 德商安美基研究(慕尼黑)公司 | Dll3及cd3抗體構築體 |
CA3060856A1 (en) * | 2017-05-05 | 2018-11-08 | Amgen Inc. | Pharmaceutical composition comprising bispecific antibody constructs for improved storage and administration |
CN110869050A (zh) * | 2017-07-28 | 2020-03-06 | 豪夫迈·罗氏有限公司 | 双特异性抗体配制剂 |
UY38041A (es) * | 2017-12-29 | 2019-06-28 | Amgen Inc | Construcción de anticuerpo biespecífico dirigida a muc17 y cd3 |
BR112021006220A2 (pt) * | 2018-10-01 | 2021-07-06 | Amgen Inc | métodos para reduzir a agregação de anticorpos biespecíficos |
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