KR20170091162A - 이중특이적 4가 항체 및 이의 제조 및 사용방법 - Google Patents
이중특이적 4가 항체 및 이의 제조 및 사용방법 Download PDFInfo
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- KR20170091162A KR20170091162A KR1020177020104A KR20177020104A KR20170091162A KR 20170091162 A KR20170091162 A KR 20170091162A KR 1020177020104 A KR1020177020104 A KR 1020177020104A KR 20177020104 A KR20177020104 A KR 20177020104A KR 20170091162 A KR20170091162 A KR 20170091162A
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Abstract
본원은 한 쌍의 중쇄 및 한 쌍의 경쇄를 갖는 IgG, 및 중쇄 또는 경쇄의 C 말단 또는 N 말단에 연결된 2개의 scFv 구성요소를 포함하는 이중특이적 4가 항체에 관한 것이다. 상기 이중특이적 4가 항체는 EGFR 패밀리의 2개의 다른 구성원에 대한 결합 특이성을 가질 수 있다.
Description
관련 출원에 대한 상호 참조
본 출원은 2014년 12월 22에 출원된, "이중특이적 항체"란 제목의, 미국 임시 출원 62095348의 우선권을 주장하고, 그 전체 내용은 본원에 참조로 포함된다.
서열 목록
본 출원과 관련된 서열 목록은 종이 복사본 대신에 텍스트 형태로 제공되고, 본 명세서에 참고 문헌으로 포함된다. 서열목록을 포함하는 텍스트 파일의 이름은 Sequence Listing_ST25_0003PCT2.txt이다. 상기 텍스트 파일은 227KB이고, 2015년 12월 18일에 생성되었으며, EFS-Web을 통해서 전자적으로 제출되었다.
기술 분야
본원은 일반적으로 항체 치료제의 기술분야에 관한 것이고, 더 구체적으로 EGFR 패밀리의 2개의 다른 구성원에 대한 이중특이적 4가 항체에 관한 것이다.
EGFR, HER2, HER3, HER4와 같은 ErbB/HER 수용체 패밀리의 구성원의 과발현 및/또는 탈조절(deregulation)은 암에서 종양형성에 중요한 역할을 하는 것으로 밝혀졌다. EGFR 또는 HER2의 돌연변이 및 증폭은 종양형성에 기여하는 다운스트림 신호전달 경로를 활성화시키는 비정상적 성장 신호를 생산한다. EGFR 및 HER2에 대한 치료적 항체 및 소-분자 억제제들이 암의 치료에 사용하기 위해 승인되었다(Arteaga et al., Nature Reviews Clinical Oncology 9 16-32, January 2012). EGFR 및 HER2와 같은 EGFR 패밀리의 구성원에 대한 단일클론 항체는, 결장암(Price et al., The Lancet Oncology 15(6), Pages 569-579, May 2014), 두경부 편평 세포 암종(Cohen, Cancer Treatment Reviews 40 (2014) 567-577), 유방암 및 위암(Arteaga et al., Nature Reviews Clinical Oncology 9 16-32, January 2012)에서 우수한 임상적 반응을 보여줬다. 세툭시맙(cetuximab), 파니투무맙(panitumumab) 및 니모투주맙(nimotuzumab)을 포함하는, 여러 치료적 항-EGFR 항체는 전이성 결장직장암, 두경부 편평 세포 암종 및 신경교종을 포함하는 여러 암에 대한 승인된 치료제이다(Price and Cohen, Curr Treat Options Oncol. 2012 Mar;13(1):35-46; Bode et al., Expert Opin Biol Ther. 2012 Dec;12(12):1649-59). 불행하게도, 초기에 이들 치료제에 반응하는 다수의 종양은 결국 약제에 대해 획득된 내성을 갖는다(Jackman et al. J Clin Oncol 2010; 28:357-60). 따라서, 더 나은 암 치료제에 대한 필요성이 존재한다.
발명의 요약
본원은 이중특이적 4가 항체를 제공한다. 이중특이적 4가 항체는 2개의 중쇄 및 2개의 경쇄를 갖는 면역글로불린 G(IgG) 모이어티, 및 중쇄 또는 경쇄의 C 말단 또는 N 말단에 공유결합으로 연결된 2개의 scFv 모이어티를 포함할 수 있다. IgG 모이어티는 EGFR 패밀리의 제1 구성원에 대해 결합 특이성을 가질 수 있다. scFv 모이어티는 EGFR 패밀리의 제2 구성원에 대해 결합 특이성을 가질 수 있다. IgG 모이어티 및 2개의 scFv 모이어티는 공유결합으로 연결되어 이중특이적 4가 항체로서 기능한다. 본원의 목표 및 이점은 첨부된 도면과 관련하여 바람직한 구현예의 상세한 설명으로 명백해질 것이다.
본원에 따르는 바람직한 구현예가 도면을 참조하여 설명되고, 동일한 참조 부호는 동일한 요소를 나타낸다.
도 1은 예시적 2가 단일특이적 면역글로불린 G(IgG) 항체의 도메인 구조를 도시하는 다이아그램이다.
도 2는 본 발명의 일 구현예에 따른 IgG 모이어티 및 2개의 scFv 모이어티를 포함하는 예시적 4가 이중특이적 항체의 도메인 구조를 도시하는 다이아그램이다.
도 3은 예시적 4가 이중특이적 항체 1X1, 1X2, 1X3, 1X4, 1X4.2, 1X5 및 1X6의 도메인 구조 다이아그램을 도시한다.
도 4는 5개의 아미노산 차이를 보여주는 SI-1X4 및 SI-1X4.2 간의 VH 도메인 서열 비교를 도시한다.
도 5 및 6은 BLI에 의한 단량체 EGFR 결합을 도시하는 그래프이다.
도 7, 8 및 9는 이중특이적 ELI 결합을 도시하는 그래프이다.
도 10은 이량체 EGFR ELISA를 도시하는 그래프이다.
도 11은, Octet에 의해 분석된, SI-1C5.2 및 SI-1X4.2의 단량체 EGFR과의 결합 동력학을 도시한다.
도 12는 A431 세포에 결합하는 SI-1X 항체의 유동 세포계측 분석을 도시한다.
도 13은 BxPC3 세포에 결합하는 SI-1X 항체의 유동 세포계측 분석을 도시한다.
도 14는 Fadu 세포에 결합하는 SI-1X4.2 항체의 유동 세포계측 분석을 도시한다.
도 15는 A431 세포에 결합하는 SI-1X4.2 항체의 유동 세포계측 분석을 도시한다.
도 16은 A431 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 17은 A431 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 18은 BxPC3 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 19는 BxPC3 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 20은 Fadu 세포 증식에 대한 SI-1X4.2 항체의 효과를 도시한다.
도 21은 A431 세포 증식에 대한 SI-1X4.2 항체의 효과를 도시한다.
도 22는 Fadu 세포에 대한 SI-1X 항체의 ADCC 활성을 도시한다.
도 23은 NCI-H1975 세포에 대한 SI-1X 항체의 ADCC 활성을 도시한다.
도 24는 SI-1X 항체의 안정성을 입증하기 위한 그들의 열 융융을 도시한다.
도 25는 7일의 기간 동안 SI-1X 항체의 혈청 안정성을 도시한다.
도 26은 래트에서 PK 연구를 위한 EGFR 코팅된 ELISA의 결과를 도시하는 그래프이다.
도 27은 래트에서 PK 연구를 위한 HER3 코팅된 ELISA의 결과를 도시하는 그래프이다.
도 28은 래트에서 PK 연구를 위한 샌드위치 ELISA의 결과를 도시하는 그래프이다.
도 29는 마우스 이종이식 연구에서 평균 종양 부피 대 일(day)의 플롯을 도시하는 그래프이다.
도 30은 마우스 이종이식 연구에서 상대적인 체중 대 주(week)의 플롯을 도시하는 그래프이다.
도 1은 예시적 2가 단일특이적 면역글로불린 G(IgG) 항체의 도메인 구조를 도시하는 다이아그램이다.
도 2는 본 발명의 일 구현예에 따른 IgG 모이어티 및 2개의 scFv 모이어티를 포함하는 예시적 4가 이중특이적 항체의 도메인 구조를 도시하는 다이아그램이다.
도 3은 예시적 4가 이중특이적 항체 1X1, 1X2, 1X3, 1X4, 1X4.2, 1X5 및 1X6의 도메인 구조 다이아그램을 도시한다.
도 4는 5개의 아미노산 차이를 보여주는 SI-1X4 및 SI-1X4.2 간의 VH 도메인 서열 비교를 도시한다.
도 5 및 6은 BLI에 의한 단량체 EGFR 결합을 도시하는 그래프이다.
도 7, 8 및 9는 이중특이적 ELI 결합을 도시하는 그래프이다.
도 10은 이량체 EGFR ELISA를 도시하는 그래프이다.
도 11은, Octet에 의해 분석된, SI-1C5.2 및 SI-1X4.2의 단량체 EGFR과의 결합 동력학을 도시한다.
도 12는 A431 세포에 결합하는 SI-1X 항체의 유동 세포계측 분석을 도시한다.
도 13은 BxPC3 세포에 결합하는 SI-1X 항체의 유동 세포계측 분석을 도시한다.
도 14는 Fadu 세포에 결합하는 SI-1X4.2 항체의 유동 세포계측 분석을 도시한다.
도 15는 A431 세포에 결합하는 SI-1X4.2 항체의 유동 세포계측 분석을 도시한다.
도 16은 A431 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 17은 A431 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 18은 BxPC3 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 19는 BxPC3 세포 증식에 대한 SI-1X 항체의 효과를 도시한다.
도 20은 Fadu 세포 증식에 대한 SI-1X4.2 항체의 효과를 도시한다.
도 21은 A431 세포 증식에 대한 SI-1X4.2 항체의 효과를 도시한다.
도 22는 Fadu 세포에 대한 SI-1X 항체의 ADCC 활성을 도시한다.
도 23은 NCI-H1975 세포에 대한 SI-1X 항체의 ADCC 활성을 도시한다.
도 24는 SI-1X 항체의 안정성을 입증하기 위한 그들의 열 융융을 도시한다.
도 25는 7일의 기간 동안 SI-1X 항체의 혈청 안정성을 도시한다.
도 26은 래트에서 PK 연구를 위한 EGFR 코팅된 ELISA의 결과를 도시하는 그래프이다.
도 27은 래트에서 PK 연구를 위한 HER3 코팅된 ELISA의 결과를 도시하는 그래프이다.
도 28은 래트에서 PK 연구를 위한 샌드위치 ELISA의 결과를 도시하는 그래프이다.
도 29는 마우스 이종이식 연구에서 평균 종양 부피 대 일(day)의 플롯을 도시하는 그래프이다.
도 30은 마우스 이종이식 연구에서 상대적인 체중 대 주(week)의 플롯을 도시하는 그래프이다.
상세한 설명
본원은 현재 알려진 항-EGFR 항체에 비해 우수한 치료학적 특성 또는 효능을 갖는 이중특이적 4가 항체를 제공한다. 일 구현예에서, 항체는, 제한되는 것 없이, EGFR 및 HER3을 포함하는 EGFR 패밀리의 2개의 구성원을 표적으로 한다. 이중특이적 4가 항체는 EGFR 및 HER3 모두가 매개된 신호전달을 억제함으로서 EGFR 억제제 또는 단일클론 항체 치료에서 내성을 극복 할 수 있다.
본원 및 첨부된 청구범위에서 사용된 바와 같이, 본 명세서 및 청구범위 전반에 걸쳐 단수 형태, 단어 "포함한다", 또는 "포함하는"과 같은 변이형은, 명시된 정수 또는 정수 그룹을 포함하는 것을 의미하는 것이지, 임의의 다른 정수 또는 정수 그룹을 배제시키는 것이 아니고, 다르게 지시하지 않는 한, 복수 지시 대상을 포함한다.
"항체 단편"은 온전한 항체의 일부, 바람직하게는 온전한 항체의 항원-결합 또는 가변 영역을 포함한다. 항체 단편의 예는 Fv, Fab, Fab', F(ab')2, Fab'-SH; 디아바디(diabody); 선형 항체[미국 특허 번호 5,641,870, 실시예 2; Zapata et al., Protein Eng. 8(10): 1057-1062 (1995)]; 단일쇄 항체 분자 (예, scFv)를 포함한다. 본원 및 본 명세서 전반에 걸쳐, 항체 및 다양한 항체 특성이 언급되며, 동일한 개시는 기능적 항체 단편(예, 이중 작용 Fab 단편)에도 적용된다.
일 양태에서, 이중특이적 4가 항체는 2개의 중쇄 및 2개의 경쇄를 갖는 면역글로불린 G(IgG) 모이어티, 및 중쇄 또는 경쇄의 C 말단 또는 N 말단에 공유결합으로 연결된 2개의 scFv 모이어티를 포함할 수 있다. IgG 모이어티는 EGFR 패밀리의 제1 구성원에 대해 결합 특이성을 가질 수 있다. scFv 모이어티는 EGFR 패밀리의 제2 구성원에 대해 결합 특이성을 가질 수 있다. IgG 모이어티는 scFv 모이어티에 대해 안정성을 제공할 수 있다. 이중특이적 4가 항체는 AKT 및 MAPK/ERK 경로 둘 다의 신호전달을 막을 수 있고 하나의 항원 또는 2개의 항원 모두를 발현하는 세포에 대한 항체 의존적 세포-매개된 세포독성(ADCC)을 매개할 수 있다. 일 구현예에서, 이중특이적 4가 항체는 동시에 둘 다의 항원에 결합할 수 있다. 일부 구현예에서, 이중특이적 4가 항체는 단일-특이적 항체 모(parent) 대조군 또는 단일-특이적 항체 모 대조군의 조합보다 시험관내 및 생체내 증식 어세이에서 더 강한 종양 억제를 제공한다.
일 구현예에서, 본원은 2개의 IgG1 중쇄, 2개의 카파 경쇄, 및 2개의 단일쇄 Fv(scFv) 도메인을 갖는 이중특이적 4가 항체를 제공한다. 2개의 IgG1 중쇄 및 카파 경쇄는 EGFR 패밀리의 제1 구성원에 대해 결합 특이성을 갖는 IgG 모이어티를 형성한다. 2개의 scFv 도메인은 EGFR 패밀리의 제2 구성원에 대해 결합 특이성을 갖고, 각각의 scFv 도메인은 (G4S)n로 알려진, (gly-gly-gly-gly-ser)n의 아미노산 서열을 갖는 커넥터에 의해 IgG1 중쇄들 중 어느 하나의 C-말단에 연결되어 IgG1-커넥터 연결을 제공한다. n은 적어도 1의 정수이다. 예를 들어, n은 2, 3, 4, 5, 6, 7, 8, 9, 10, 또는 17일 수 있다. 각각의 scFv 도메인은 N 말단-가변 중쇄-링커-가변 경쇄-C 말단 순서의 구조를 갖는다. 링커는 (G4S)m 로 알려진, (gly-gly-gly-gly-ser)m의 아미노산 서열을 가질 수 있다. m은 적어도 2 또는 적어도 3의 정수일 수 있다. 예를 들어, m은 3, 4, 5, 6, 11, 또는 12일 수 있다. 일부 구현예에서, 적어도 하나 또는 둘 다의 IgG1 중쇄는 인간화되거나 인간이다. 일부 구현예에서, 적어도 하나 또는 둘 다의 카파 경쇄는 인간화되거나 인간이다.
EGFR 패밀리 구성원은 EGFR, HER2, HER3, 이들의 단편 또는 유도체를 포함할 수 있다. 일부 구현예에서, EGFR 패밀리의 제1 구성원은 EGFR, HER2, 이들의 단편 또는 유도체일 수 있다. 일부 구현예에서 EGFR 패밀리의 제2 구성원은 HER3, 이들의 단편 또는 유도체일 수 있다. 일 구현예에서, IgG 모이어티는 HER3에 대해 결합 특이성을 가질 수 있다. 일 구현예에서, scFv 도메인은 EGFR에 대해 결합 특이성을 가질 수 있다. 일 구현예에서, IgG 모이어티는 HER3에 대해 결합 특이성을 가질 수 있고, scFv 도메인은 EGFR에 대해 결합 특이성을 가질 수 있다. 일 구현예에서, IgG 모이어티는 EGFR에 대해 결합 특이성을 가질 수 있다. 일 구현예에서 scFv 도메인은 HER3에 대해 결합 특이성을 가질 수 있다. 일 구현예에서, IgG 모이어티는 EGFR에 대해 결합 특이성을 가질 수 있고, scFv 도메인은 HER3에 대해 결합 특이성을 가질 수 있다.
일부 구현에에서, 하나 또는 둘 다의 IgG1 중쇄의 C 말단은 아미노산 잔기를 결실한다. 예를 들어, C-말단에 커넥터가 융합되기 전에 IgG1의 C 말단으로부터 리신 잔기가 결실될 수 있다. 리신 잔기의 결실은 IgG1-커넥터 연결이 프로테아제 활성에 대해 저항하게 만든다.
일부 구현예에서, 하나 또는 둘 다의 IgG1 중쇄는 CH3 도메인에서 2개의 돌연변이를 포함한다. 예를 들어, 2개의 돌연변이는 인간 CH3 도메인에서 일반적인(common) 잔기로의 역전일 수 있다.
일부 구현예에서, IgG1 중쇄는 서열번호 7, 15, 23, 31, 39, 47, 및 127의 아미노산 서열 또는 이와 적어도 95%, 98% 또는 99% 유사성을 갖는 아미노산 서열을 가질 수 있다. 일부 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 56, 66, 76, 86, 98, 108, 118, 및 136의 아미노산 서열 또는 이와 적어도 95%, 98% 또는 99% 유사성을 갖는 아미노산 서열을 가질 수 있다. 일부 구현예에서, 카파 경쇄는 서열번호 3, 11, 19, 27, 35, 43, 51, 61, 71, 81, 92, 103, 113, 123, 및 131의 아미노산 서열 또는 이와 적어도 95%, 98% 또는 99% 유사성을 갖는 아미노산 서열을 가질 수 있다. 일부 구현예에서, 가변 경쇄는 서열번호 4, 12, 20, 28, 36, 44, 52, 62, 72, 82, 93, 104, 114, 124, 및 132의 아미노산 서열 또는 이와 적어도 95%, 98% 또는 99% 유사성을 갖는 아미노산 서열을 가질 수 있다. 일부 구현예에서, 가변 중쇄는 서열번호 8, 16, 24, 32, 40, 48, 57, 67, 77, 87, 99, 109, 119, 128, 및 137의 아미노산 서열 또는 이와 적어도 95%, 98% 또는 99% 유사성을 갖는 아미노산 서열을 가질 수 있다.
일부 구현예에서, IgG 모이어티는 HER3에 대해 결합 특이성을 갖고, scFv 도메인은 EGFR에 대해 결합 특이성을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 56의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 51의 아미노산 서열을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 76의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 71의 아미노산 서열을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 108의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 103의 아미노산 서열을 갖는다.
일부 구현예에서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖고, scFv 도메인은 HER3에 대해 결합 특이성을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 66의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 61의 아미노산 서열을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 86의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 81의 아미노산 서열을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 98의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 92의 아미노산 서열을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 118의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 113의 아미노산 서열을 갖는다. 일 구현예에서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 136의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 131의 아미노산 서열을 갖는다.
이중특이적 4가 항체는 암세포 성장을 억제하는 활성을 갖는다. 특정 구현예에서, 본 발명의 항체는 이것의 표적 EGFR 또는 HER3에 대해 ≤80nM, ≤50nM, ≤30nM, ≤20nM, ≤10nM, 또는 ≤0.1nM의 해리상수(Kd)를 갖는다. 항체는 표적 둘 다에 동시에 결합할 수 있다. 일부 구현예에서, 항체는 50nM 미만의 Kd로 EGFR 및 HER3에 결합한다. 일부 구현예에서, 항체는 40, 30, 25, 20, 19, 18 또는 10nM 미만의 Kd로 EGFR 및/또는 HER3에 결합한다. 일 구현에에서, 항체는 30nM 미만의 Kd로 EGFR에 결합하고 30nM 미만의 Kd로 HER3에 결합한다. 일 구현에에서, 항체는 50nM 미만의 Kd로 EGFR에 결합하고 50nM 미만의 Kd로 HER3에 결합한다.
다른 양태에서, 본원은 본원에 개시된 이중특이적 4가 항체 또는 이의 서브-구성요소를 암호화하는 분리된 핵산을 제공한다. 서브-구성요소는 IgG1 중쇄, 카파 경쇄, 가변 경쇄, 또는 가변 중쇄일 수 있다.
또 다른 양태에서, 본원은 본원에 개시된 이중특이적 4가 항체 또는 이의 서브-구성요소를 암호화하는 분리된 핵산을 갖는 발현벡터를 제공한다. 벡터는 숙주세포에서 발현될 수 있다. 숙주세포는 원핵세포 또는 진핵세포일 수 있다.
또 다른 양태에서, 본원은 본원에 개시된 이중특이적 4가 항체를 암호화하는 분리된 핵산 또는 이러한 핵산 서열을 포함하는 발현벡터를 갖는 숙주세포를 제공한다.
또 다른 양태에서, 본원은 이중특이적 4가 항체를 제조하는 방법을 제공한다. 일 구현예에서, 방법은 항체는 제조하기 위해 상기에서 기술된 숙주세포를 배양하는 단계를 포함할 수 있다.
또 다른 양태에서, 본원은 본원에 개시된 이중특이적 4가 항체 및 세포독성제를 포함하는 면역접합체를 제공한다.
또 다른 양태에서, 본원은 약학적 조성물을 제공한다. 약학적 조성물은 본원에 개시된 이중특이적 4가 항체 또는 면역접합체 및 약학적으로 허용가능한 담체를 포함할 수 있다. 일부 구현예에서, 조성물은 동위원소, 방사성 핵종, 독소, 치료제, 화학요법제 및 이들의 조합을 추가로 포함할 수 있다.
또 다른 양태에서, 본원은 암을 가진 개체를 치료하는 방법을 제공한다. 일 구현예에서, 본원에 개시된 이중특이적 4가 항체의 유효량을 개체에게 투여하는 단계를 포함한다. 암은, 예를 들어, EGFR, HER2, HER3 이들의 단편 또는 유도체를 포함하는, EGFR 패밀리의 적어도 두 개의 구성원을 발현하는 세포를 포함할 수 있다. 암은 유방암, 결장직장암, 췌장암, 두경부암, 흑색종, 난소암, 전립선암, 비-소세포 폐암, 신경교종, 식도암, 비인두암, 항문암, 직장암, 위암, 방광암, 자궁경부암, 또는 뇌암일 수 있습니다.
일 구현예에서, 상기 방법은 유효량의 치료제를 공동-투여하는 단계를 추가로 포함할 수 있다. 치료제는, 예를 들어, 항체, 화학요법제, 세포독성제, 효소, 또는 이들의 조합일 수 있다. 일부 구현예에서, 치료제는 항-에스트로겐제, 수용체 타이로신 억제제, 또는 이들의 조합일 수 있다. 일부 구현예에서, 치료제는 생물학적일 수 있다. 일 구현예에서, 치료제는 체크포인트 억제제일 수 있다. 일부 구현예에서, 치료제는 PD1, PDL1, CTLA4, 4-1BB, OX40, GITR, TIM3, LAG3, TIGIT, CD40, CD27, HVEM, BTLA, VISTA, B7H4, 이들의 유도체, 접합체, 또는 단편을 포함할 수 있다. 일부 구현예에서, 치료제는 카페시타빈(capecitabine), 시스플라틴(cisplatin), 트라스트주맙(trastuzumab), 풀베스트란트(fulvestrant), 타목시펜(tamoxifen), 레트로졸(letrozole), 엑세메스탄(exemestane), 아나스트로졸(anastrozole), 아미노글루테치미드(aminoglutethimide), 테스토락톤(testolactone), 보로졸(vorozole), 포르메스탄(formestane), 파드로졸(fadrozole), 레트로졸(letrozole), 엘로티닙(erlotinib), 라파티닙(lafatinib), 다사티닙(dasatinib), 제피티닙(gefitinib), 이마티닙(imatinib), 파조피닙(pazopinib), 라파티닙(lapatinib), 수니티닙(sunitinib), 닐로티닙(nilotinib), 소라페닙(sorafenib), 납-팔리탁셀(nab-palitaxel), 또는 이들의 유도체 일 수 있다. 일부 구현예에서, 이러한 치료가 필요한 개체는 인간이다.
일 구현예에서, 본원은 HER 수용체의 생물학적 활성을 억제하는 이중특이적 4가 항체의 유효량을 개체에 투여하여 개체를 치료하는 방법을 제공한다.
일 구현예에서, 본원은 이중특이적 4가 항체의 유효 농도를 갖는 용액을 제공한다. 일 구현예에서, 용액은 개체의 혈장이다.
IgG의 일반적인 구조의 다이아그램은 도 1에 도시된다.
일부 구현예에 따르는 이중특이적 4가 항체의 대표적인 구조의 다이아그램은 도 2에 도시된다. 이들 예에서, 이중특이적 4가 항체는 2개의 인간 IgG1 중쇄, 2개의 인간 카파 경괘, 및 2개의 단쇄 Fv(scFv) 도메인을 포함한다. 2개의 인간 IgG1 중쇄 및 인간 카파 경쇄는 EGFR 패밀리의 하나의 구성원에 대해 결합 특이성을 갖는 IgG 모이어티를 형성하고, 2개의 scFv 도메인 각각은 gly-gly-gly-gly-ser-gly-gly-gly-gly-ser((G4S)2)의 아미노산 서열을 갖는 커넥터에 의해 인간 IgG1 중쇄들 중 어느 하나의 C-말단 잔기와 연결된다. 각각의 scFv 도메인은 하기 순서이다: N-말단-가변 중쇄-링커-가변 경쇄-C 말단. 링커는 (G4S)3로 또한 알려진, gly-gly-gly-gly-ser-gly-gly-gly-gly-ser-gly-gly-gly-gly-ser의 아미노산 서열로 구성된다. 이중특이적 4가 항체의 일부 구현예에서, CH1, CH2, CH3, CL, 커넥터 및 링커 아미노산 서열은 동일하다. 각각의 이중특이적 4가 항체는 항체의 한쪽 끝에 2가 항-HER3 결합 특이성을 갖고 다른 한쪽 끝에 2가 항-EGRF 결합 특이성을 갖는다. 한 쌍의 항-HER3 가변 중쇄 및 가변 경쇄는 1C1으로 지칭되고, 네 쌍의 항-EGRF 가변 중쇄 및 가변 경쇄는 각각 1C3, 1C5, 1C5.2, 1C6 및 1C6.4로 지칭된다. 이중특이적 4가 항체는 1X1, 1X2, 1X3, 1X4, 1X4.2, 1X5, 1X5.2, 1X6, 및 1X6.4로 지칭된다.
또한, 대조군 분자 1C4(SI-1C4로 또한 지칭된다)가 일부 연구에서 사용된다. 1C4는 문헌[Schaefer et al., Cancer Cell. 2011 Oct 18; 20(4):472-86]에 기재된 2-in-1 플랫폼에 구축된 EGFR 및 HER3에 대한 이중특이적 항체이다. 1C4는 단클론 항체와 유사한 구조는 갖는다. 상기 분자는 각각의 Fab 아암에서 EGFR 또는 HER3를 결합할 수는 있으나, 각각의 Fab 아암에서 동시에 2개의 표적 모두를 결합할 수는 없다.
가변 경쇄, 가변 중쇄 및 단일쇄 Fv(scFv) DNA 단편은 외부업체를 통해 유전자 합성에 의해 생산되었다. 인간 감마-1 중쇄 및 인간 카파 경쇄 DNA 단편은 외부업체를 통해 유전자 합성에 의해 생산되었다. 상기 단편들은 제한 부위를 이용하여 DNA 연결에 의해 함께 조립되고 포유류 세포에서 일시적 발현을 위해 설계된 벡터에 클로닝된다. 벡터는 일시적 발현을 위해 요구되는 강한 CMV-유래된 프로모터, 및 기타 업스트림 및 다운스트림 인자를 포함한다. 생성된 IgG 발현 플라스미드는 DNA 시퀀싱에 의해 예측된 DNA 서열을 포함하는 것으로 확인되었다.
항체 구조물의 일시적 발현은 문헌(CSH Protocols; 2008; doi:10.1101/pdb.prot4977)에서 설명되는 바와 같이 선형 PEI를 사용하는 현탁-적응된 HEK293F 세포의 형질주입(transfection)을 사용하여 달성된다. 항체는 필요하다면 단백질 친화 크로마토그래피 및 크기 배제 크로마토그래피를 사용하여 생성된 형질주입 상층액으로부터 정제된다. 단백질 품질은 Superdex 200 칼럼에 의해 분석된다. 모든 어세이에 사용된 단백질은 90% 초과의 순도를 갖는다.
이중특이적 항체는, 이에 제한되지 않지만, 결장암, 두경부 편평 세포 암종, 폐암, 신경교종, 췌장암, 비인두암 및 기타 암 유형을 포함하는 EGFR 및 HER3 공동-발현되는 암 유형의 치료에 사용될 수 있다.
상기 이중특이적 항체는 4가 이중 특이성이다. 예시적인 항체는 IgG 및 2개의 scFv를 포함할 수 있고, 이것은 단일-특이적 항체 IgG와 비교하여 2개의 다른 결합 특이성을 제공한다. IgG 구성요소는 BiTE 기술(Lutterbuese et al., Proceedings of the National Academy of Sciences of the United States of America 107.28 (2010): 12605-12610. PMC. Web. 2 Dec. 2014) 및 기타 기술(US7332585B2)과 같이 scFV만을 사용한 다른 이중특이적 항체를 능가하는 안정성 및 향상된 혈청 반감기를 제공한다. Fc 성분이 없는 것들은 ADCC를 매개할 수 없지만(예: US7332585B2), 상기 항체는 또한 ADCC를 매개할 수 있다. 4가 이중 특이적 특성은 한번에 오직 하나의 항원에 결합할 수 있는 일부 다른 이중특이적 항체(Schanzer et al, Antimicrob. Agents Chemother. 2011, 55(5):2369; EP272942A1)를 능가하는, 동시 결합 능력을 갖는 이중특이적 항체를 제공한다.
설명의 편의를 위해, 이중특이적 항체의 서열 또는 이와 관련된 서열이 하기의 표 1에서 요약되었다.
이하의 실시예는 단지 설명을 위한 것이지 제한하려는 것은 아니다. 당업자는 본질적으로 동일하거나 유사한 결과를 산출하기 위해 변경 또는 변형될 수 있는 중요하지 않은 매개 변수의 다양성을 쉽게 인식할 것이다.
실시예
1: SI-
1X4
및 SI-
1X4
.2 사이의 서열 차이
SI-1X4.2는 SI-1X4의 변경이고 카밧(Kabat) 번호 체계를 사용하여 5개의 아미노산 변화(V71A, T75S, N76S, A93T 및 S107T)를 포함한다. 이러한 변화 중 일부, 특히 75, 76 및 93 위치의 변화는, 비록 이들이 CDR 루프에 있지는 않지만, 항원과 강력한 상호작용을 하고 결합 및 활성에 필수적이다. 도 4는 SI-1X4 및 SI-1X4.2 사이의 5개의 아미노산 차이를 보여준다.
실시예
2:
BLI를
이용한
EGFR
(Epidermal Growth Factor Receptor)에 대한 항체의 특성 확인
단량체 EGFR의 세포외 도메인 결합은 BLItz 기기(ForteBio, Inc.)에서 BLI(biolayer interferometry) 결합 어세이로 측정되었다. 25μg/mL의 SI-1C3, SI-1C4, SI-1C6, SI-1X1, SI-1X2, SI-1X5, 및 SI-1X6를 PBS에 희석하고 120초 동안 항-huIgG Fc BLItz 바이오센서 팁으로 캡쳐했다. 팁은 30초 동안 PBS로 씻고 588nM에서 결합하기 위해 EGFR(ProSpec Bio, PKA-344) 샘플로 이동했다. 팁에 대한 EGFR ECD의 결합은 120초의 결합(association) 시간 동안 생체막 간섭측정(biolayer interferometry) 신호(Δnm)로 기록되었다. 팁은 PBS로 이동되고 해리가 240초 동안 관찰되었다(*SI-1C6 해리 시간은 단지 120초 동안만 관찰되었다). 도 5 및 6은 항체-로딩된 바이오센서에 대한 EGFR의 결합 단계에서 시작하는 데이터를 보고한다. 각 도는 기준 항체로서 SI-1C4와의 비교를 보여준다.
SI-1C3 및 SI-1X2는 Fab로 표시된 EGFR 결합 도메인을 공유하기 때문에, 그들의 결합 프로파일은 SI-1X1에 나타난 scFv 형태보다 유사하고 강하다(도 6). 각각은 SI-1C4와 비교해서 EGFR에 대한 off-rate가 매우 느리고 그들의 on-rate에 영향을 받지 않는다. SI-1X1는 EGFR에 대한 결합의 on-rate가 더 약한 것을 보여줄 수 있지만, 매우 강하게 결합한 채로 머물러있을 수 있다. 동일한 경향이 도 5에서 관찰되고, SI-1C6 및 SI-1X6에 표시된 EGFR 결합 도메인의 Fab 버전은 SI-1X5에 표시된 대표적인 scFv보다 빠른 속도로 결합한다. 이중특이적 항체의 Fab쪽에 EGFR 결합 도메인을 갖는 것은 scFv 버전보다 on-rate가 더 빠르게 결합하는 것으로 보이지만, 유사한 off-rate를 보인다. SI-1X3 및 SI-1X4는 이 어세이에서 단량체 EGFR 결합을 나타내지 않고(데이터는 보이지 않음) 이량체 EGFR 결합은 하기의 ELISA에서 조사된다.
실시예
3:
BLI을
이용한
EGFR
및
Her3에
대한 항체의 특성 확인
EGFR 및 Her3 세포외 도메인에 대한 이중특이적 결합은 BLItz 기기(ForteBio, Inc.)에서 BLI(biolayer interferometry) 결합 어세이를 통해 측정된다. 200nM의 SI-1C1, SI-1C3, SI-1C4, SI-1C6, SI-1X1, SI-1X2, SI-1X3, SI-1X4, SI-1X5, 및 SI-1X6는 1X 동력학 완충제(ForteBio, Inc.)로 희석되고 120초 동안 항-hulgG Fc BLItz 바이오센서 팁으로 캡쳐된다. 팁은 30초 동안 KB에서 씻고 200nM에서 결합하기 위해 EGFR 샘플(ProSpec Bio, PKA-344)로 이동했다. 팁에 대한 EGFR ECD의 결합은 120초의 결합(association) 시간 동안 생체막 간섭 측정 신호(Δnm)로 기록되었다. 팁은 KB로 이동되고 해리가 60초 동안 관찰되었다. 이 과정은 120초 동안 200nM에서 Her3 ECD 샘플(Sino Biological, 10201-H08H-10)로 반복되고 KB에서 60초 동안 유사한 해리 단계가 반복된다. 도 8-10 7-9는 항체-로딩된 바이오센서에 대한 EGFR의 결합 단계에서 시작하는 데이터를 보고한다. 항체가 Fc에 의해 센서에 결합되는 동안 EGFR 및 Her3의 동시 이중특이적 결합을 보여줄 수 있다. 도 7 및 도 8에서 관찰된 바와 같이, Fab(SI-1X2, SI-1X6)인 EGFR 결합 도메인의 전시는 그들의 scFv 형태(SI-1X1, SI-1X5, 각각)보다 강한 on-rate 결합을 갖는다. 여기, EGFR 및 Her3 둘 다는 동일한 Fab>>scFv on-rate 경향을 보여준다. SI-1X3 및 SI-1X4는 단량체 EGFR에 대한 결합을 보여주지 않지만, 각각의 분자가 SI-1X1, SI-1X2, SI-1X5 및 SI-1X6과 동일한 αHer3 결합 도메인을 사용하기 때문에 예상대로, 각각은 Her3에 결합하는 능력을 갖는다. SI-1X3 및 SI-1X4는 아래의 ELISA에서 이량체 EGFR 결합에 대해 조사된다.
실시예
4:
이량체
EGFR
ELISA
어세이
앞서 관찰된 바와 같이, SI-1X3 및 SI-1X4는 BLI 분석에서 단량체 형태의 EGFR에 결합할 수 없었다(도 9). SI-1C5, SI-1X3 및 SI-1X4에 사용된 αEGFR 결합 도메인이 시험관 내에서 EGFR에 결합하기 위해서는 2가 결합이 요구된다는 것이 제안되었다(Perez et al, Chin Clin Oncol 2014;3(1):5). 이를 관찰하기 위해, 우리는 이량체 형태의 EGFR을 이용하여 다른 EGFR 결합 항체에 상대적인 항체 결합을 위한 ELISA를 이용했다.
ELISA는 이량체 EGRF ECD 시약, SI-2C1, 융합된 내부에서 만든 토끼 Fc를 사용하여 수행하였다. EGFR은 Maxisorp immunoplates(Nunc) 위에 PBS에 3μg/mL로 4℃에서 하룻밤동안 코팅되었다. 플레이트는 3% BSA 및 0.05% Tween20 PBS로 상온에서 2시간 동안 블락킹했다. 항체는 1시간 동안 상온에서 PBST(1% BSA)에서 3배 희석된 50μg/mL(nM으로보고함)에서 시작된 SI-1C5, SI-1X3 및 SI-1X4를 제외하고는, 10ug/mL에서 캡쳐되었다. 염소 α인간 IgG-HRP 항체(Jackson ImmunoResearch, 109-035-098)는 PBST(1% BSA)에서 1:2000으로 희석에서 항체의 Fc 부분의 발견에 이용되었고 TMB(Thermo Scientific)에서 2M H2S04를 정지 용액으로 하여 5분 동안 현상시켰다. 각 단계 사이에서 PBST(1% BSA)로 3번 워싱이 수행되었다. 모든 데이터 포인트는 3 반복으로 수행되고 450nm에서 수집되었다(도 10). SI-1C5, SI-1X3, 및 SI-1X4 모두는 다른 분자와 비교해서 높은 농도에서 이 ELISA 포맷에서 이량체 EGFR ECD에 결합했다.
실시예 5: Octet을 이용한 1C5.2 및 1X4.2의 결합 동력학
동력학은 항-인간 Fc 센서(ForteBio, AHC #18-5060)를 가진 ForteBio Octet Red96 기기를 이용하여 결정되었다. 결합 실험을 30℃에서 1000RPM 혼합 중 수행했다. EGFR 단백질은 C-말단 폴리히스티딘 택을 가진 인간 EGFR의 세포외 도메인(Met1-Ser645)이다. 모든 샘플을 10X 동력학 완충제(ForteBio #18-5032)에서 희석했다. 1C5.2, 1X6 및 1X4.2를 10μg/ml로 각각 300초 동안 8개의 센서 위에 로딩하고 뒤이어 60초 동안 10X 동력학 완충제에서 기준선을 수행했다. EGFR 단백질과의 결합을 300초 동안 EGFR 단백질의 단일 농도(300, 100, 33.33, 11.11, 3.705, 1.235, 0.4116 및 0 nM)에서 각각의 센서에서 수행했다. 해리를 10X 동력학 완충제에서 900초 동안 수행했다. 1C5.2 및 1X4.2에 대한 전형적인 결합 및 해리 추적은 도 11에서 보여준다.
데이터 분석을 ForteBio Data Analysis Software v9.0을 이용해 수행했다. 소프트웨어 곡선-적정을 수행했고 각각의 1C5.2(표 2), 1X4.2(표 3) 및 1X6(표 4)에 대한 가장 최적화된 4개의 곡선 적정이 이용되었고 KD, k(on) 및 k(dis)를 결정하기 위해 평균을 냈다. SI-1C5.2 및 SI-1X4.2에 대한 평균 KD는 각각 19.2nM 및 18.4nM 이었다. SI-1C6의 평균 KD는 3.04nM 1C5.2이고 1X4.2는 실시예 1에 기재된 바와 같이 1C5 및 1X4와 비교하여 5개의 아미노산 변화를 함유했다. 이러한 변화는 도 10의 1C5 및 1X4에 대해 생성된 데이터와 비교할 때 EGFR ECD에 대한 향상된 결합을 설명했다.
실시예 6: 종양 세포주에 대한 예시적인 이중특이적 항체의 결합 테스트
이중특이적 항체 SI-1X1, SI-1X2, SI-1X3, SI-1X4, SI-1X5, 및 SI-1X6, 뿐만 아니라 동위원소 대조군은 종양 세포주, A431(유표피암, ATCC CRL-1555) 및 BxPC3 (췌장 선암, ATCC CRL-1687)에 대한 결합이 유동 세포 분석법에 의해 테스트되었다. 세포를 10% 소 태아 혈청을 함유한 RPMI-1640 배지에서 성장시키고 지수 성장 단계 동안의 분석을 위해 수확했다. 5 x 106 개의 세포 분획을 PBS로 워싱하고, 250μl PBS + 1% 소 혈청 알부민(BSA)로 재현탁하고 비-특이적 결합으로부터 막을 블락하기 위해 4℃에서 15분 동안 인큐베이션시켰다. PBS/1% BSA에서 10μg/ml로 희석된, 항체 250μl를 5μg/ml의 최종 항체 농도를 위해 각 샘플에 더했다. 세포를 4℃에서 1시간 동안 혼합하면서 1차 항체에서 인큐베이션시켰다. 세포를 1ml PBS/1% BSA로 2번 워싱하고 500μl의 PE-결합된 마우스-항-인간 IgG-Fc로 재현탁하고 4℃에서 45분 동안 혼합하면서 인큐베이션하였다. 세포를 다시 1ml PBS/1% BSA로 2번 워싱하고, 300ml PBS에 재현탁하고 FACScalibur 유동 세포 분석기를 이용하여 분석하였다. 각 샘플에 대해, FL-2 채널에서 10000번 수집되었다. FCS Express 소프트웨어를 이용하여 생성하고 SI-1X 그래프는 동위원소 대조군 염색으로부터의 그래프로 중첩되었다. 모든 6개의 이중특이적 항체는 세포 결합을 나타내는 대조군 염색과 관련하여 그래프 이동을 나타냈다. 이 데이터는 도 12(A431 세포 결합) 및 도 13(BxPC3 세포 결합)에서 나타난다.
실시예
7: 세포 결합
어세이에
의한 SI-
1C5
.2 및 SI-
1X4
.2의 특성
이중특이적 항체, SI-1X4.2, 단일특이적 항체, SI-1C5.2 및 SI-1C1, 뿐만 아니라 동위원소 대조군은 종양 세포주, A431(유표피암, ATCC CRL-1555)(도 14) 및 FaDu(식도 편평 세포 암종, ATCC HTB-43)(도 15)에 대한 결합이 유동 세포 분석법에 의해 테스트되었다. 세포를 10% 소 태아 혈청을 함유한 RPMI-1640 배지에서 성장시키고 지수 성장 단계 동안의 분석을 위해 수확했다. 세포를 PBS로 워싱하고 5x106개 세포/ml의 농도로 PBS + 5% 소 태아 혈청 알부민(FBS)로 재현탁하고 비-특이적 결합으로부터 막을 블락하기 위해 4℃에서 15분 동안 인큐베이션시켰다. 96-웰 플레이트에서 100μl의 세포 분획을 100μl의 항체 분획(PBS + 5% FBS에서 또한 희석된)에 더했다. 샘플을 45분 동안 얼음 위에서 1차 항체로 인큐베이션시켰다. 세포는 200μl의 PBS + 5% FBS로 두번 워싱하고 100μl의 PE-결합된 마우스-항-인간 IgG-Fc로 재현탁하고 얼음 위에서 30분 동안 인큐베이션하였다. 샘플을 다시 200μl의 PBS + 5% FBS로 두번 워싱하고, 200μl PBS로 재현탁하고 FACScalibur 유동 세포 분석기를 이용하여 분석하였다. 각 샘플에 대해, FL-2 채널에서 10000번 수집되었다. 그래프를 FCS Express 소프트웨어를 이용하여 분석하고 각 데이터 세트에 대해서 기하 평균 형광 강도(GFMI: geometric mean fluorescence intensity)를 결정했다. EC50 결합 값을 Graphpad Prism 소프트웨어를 이용하여 GFMI 대 항체 농도의 플롯에 의해 결정했다. 이중특이적 항체, SI-1X4.2는 단일특이적 항-EGFR 항체, SI-1C5.2와 세포주 둘 다에서의 유사한 EC50로서 유사한 결합 프로파일을 나타냈다. 아마도 세포의 표면에 낮은 수준의 Her3 발현 때문에 다른 단일특이적 항-Her3 항체, SI-1C1-은 두 세포주에 약하게 결합한다. 1C5.2 및 1X4.2는 실시예 1에 기재된 바와 같이 1C5 및 1X4와 비교하여 5개의 아미노산 변화를 함유했다. 이러한 변화는 모 분자, 1X4와 비교했을 때 표적 세포에 대한 향상된 결합을 설명했다.
실시예
8: 종양 세포주에서 SI-1X 항체의 항-증식 효과
항-Her3/EGFR 이중특이적 항체의 성장 억제 잠재성을 평가하기 위해, 유표피 암종 종양 세포주인 A431 세포(ATCC CRL-1555, Manassas, Va.)의 증식에 대한 효과를 테스트했다. 췌장 선암 종양 세포주인, BxPC3(ATCC CRL-1687, Manassas, Va.)의 증식에 대한 영향 또한 테스트했다. 각 세포주에 대하여, 96-웰 조직 배양 플레이트 안에 1% 소 태아 혈청을 함유하는 RPMI-1640 배지 100μl에 6000개의 세포/웰의 밀도로 세포를 시딩했다. 4시간 후에, 테스트 항체를 다양한 농도로, 0.0015nM 부터 100nM까지의 범위에서 추가했다. 테스트 항체의 존재 하에서 72시간 동안 세포를 배양했다. 각 웰에서, 20μl의 MTS 시약(Promega, Madison, WI)을 더하고 세포를 37℃에서 2시간 동안 인큐베이션했다. MTS는 활발히 증식하는 세포에 쉽게 흡수되어 포르마잔(490nm에서 빛을 쉽게 흡수함)으로 환원된 다음 배양 배지로 분비된다. 인큐베이션 후, BioTek(Winooski, VT) ELx800 흡광도 리더를 이용하여 OD490 값을 측정했다. 대조군 세포(배지만 처리한)에 대한 OD490 값을 기준 대사 활동을 확립하기 위해 항체 추가시 이러한 방식으로 획득했다. 증식은 72시간 OD490으로부터 대조군 기준 OD490을 빼는 것으로 계산될 수 있다. 항체 적정으로부터의 데이터는 이하의 공식에 따른 대조군 집단의 %로 표현된다: 대조군 집단의 % = (테스트 증식/대조군 증식)*100.
A431 세포 증식에 대한 다양한 이중특이적 항-Her3/항-EGFR 항체의 효과는 도 16 및 도 17에서 보여준다. SI-1X2는 대조군 항체 SI-1C1(항-Her3), SI-1C3(항-EGFR), 또는 SI-1C1 및 SI-1C3이 함께 적용된 것에 비해서 더 효과적인 항증식 효과를 보여준다. 비록 SI-1C3, 및 SI-1C1와 SI-1C3의 조합에서는 볼 수 없는 정도지만, SI-1X1은 항증식 효과를 나타냈다. 억제 플롯 뿐만 아니라 IC50 값이 도 17에서 보여진다. 유사한 결과가 SI-1X5 및 SI-1X6에서 관찰되었고, SI-1X6은 SI-1X5 및 대조군 항체 SI-1C1(항-Her3)보다 더 강력하지만, 대조군 항체 SI-1C6(항-EGFR) 및 SI-1C1 및 SI-1C6의 조합과 유사한 항증식 잠재력을 나타냈다. 이것은 도 17에서 IC50 값과 함께 볼 수 있다.
이 분자들을 BxPC3 세포주에서 항증식 효과를 위해 또한 테스트했다(도 18 및 도 19). 다시, SI-1X2는 대조군 항체 SI-1C1(항-Her3), SI-1C3(항-EGFR), 또는 SI-1C1 및 SI-1C3이 함께 적용된 것에 비해서 더 효과적인 항증식 효과를 보여준다. SI-1X1은 SI-1C1-보다 더 효과적이지만, SI-1C3 및 SI-1C1 및 SI-1C3의 조합보다는 약하다. 억제 곡선 및 IC50 값은 도 19에서 보여준다. BxPC3 증식은 대조군 항체 SI-1C1(항-Her3), SI-1C6(항-EGFR), 또는 SI-1C1 및 SI-1C6의 조합보다 SI-1X5 및 SI-1X6 둘 다에 의해 더 강하게 억제된다. 이 데이터는 IC50 값과 같이 도 19에서 보여진다.
실시예
9: 종양 세포주에서 SI-
1C5
.2 및 SI-
1X4
.2의 항-증식 효과
항-Her3/EGFR 이중특이적 항체의 성장 억제 잠재성을 평가하기 위해, FaDu(식도 편평 세포 암종, ATCC HTB-43) 및 A431 (유표피 암종, ATCC CRL-1555) 세포의 증식에 대한 효과를 테스트했다. 96-웰 조직 배양 플레이트 안에 1% 소 태아 혈청을 함유하는 RPMI-1640 배지 100μl에 6000개의 세포/웰의 밀도로 세포를 시딩했다. 4시간 후에, 테스트 항체를 다양한 농도로, 0.0015nM 부터 100nM까지의 범위에서 추가했다. 테스트 항체의 존재 하에서 72시간 동안 세포를 배양했다. 각 웰에서, 11μl의 alamar blue 시약(Thermo Scientific)을 더하고 세포를 37℃에서 2시간 동안 인큐베이션했다. alamar blue는 활발히 증식하는 세포에 쉽게 흡수되어, 환원되고, 배양 배지로 분비된다. alamar blue의 환원된 형태는 강한 형광을 가진다. 인큐베이션 후, 형광은 535nm의 여기 파장 및 595nm의 방사 파장을 이용하는 Molecular Devices(Sunnyvale, CA) FilterMax F5 다중-모드 플레이트 리더를 사용하여 형광을 측정하였다. 대조군 세포(배지만 처리한)의 형광값을 기준 대사 활성을 확립하기 위해 항체 추가 시 이러한 방식으로 획득했다. 증식은 72시간 형광값으로부터 대조군 기준 형광을 빼는 것으로 계산될 수 있다. 항체 적정으로부터의 데이터는 이하의 공식에 따른 대조군 집단의 %로 표현된다: 대조군 집단의 % = (테스트 증식/대조군 증식)*100.
FaDu 및 A431 세포 증식에 대한 SI-1C5.2 및 SI-1X4.2의 효과는 도 20 및 도 21에서 각각 보여준다. 두 세포주 모두에서, SI-1X4.2는 대조군 항체, SI-1C5.2(항-EGFR Mab), SI-1C1(항-Her3 Mab) 또는 SI-1C1 및 SI-1C7이 함께 적용하는 것보다 향상된 효과적인 항-증식 효과를 보여준다.
실시예
10: SI-1X
이중특이적
항체의
ADCC
활성
여러 종양 세포주에 대한 세포 독성을 매개하는 SI-1X 항체의 능력을 테스트하였다. 정상적인, 건강한 지원자로부터 전혈을 얻었다. 혈액을 동등한 부피의 인산염 완충 식염수(PBS)로 희석했다. 희석된 혈액의 20ml 분획을 주의깊게 15ml Ficol Pacque PLUS(GE Life Sciences cat# 17-1440-02; Pittsburgh, PA)에 겹쳐놓았다. 튜브를 40분 동안 300g에서 브레이크 없이 원심분리시켰다. 원심분리 후 대부분의 혈장 층을 주의깊게 흡인하고 버피 코트(PBMC를 함유하는)를 주의깊게 가능한 최소량으로 피펫으로 제거하였다. PBMC를 50ml 튜브에 모으고, PBS를 추가하여 각 튜브를 50ml로 만들었다. 튜브를 1300RPM에서 10분 동안 원심분리시키고 상층액을 주의깊게 흡인했다. 세포를 40ml PBS로 재현탁하고 다시 원심분리시켰다. 이 과정을 총 2회 워싱을 위해 반복하였다. 마지막 워싱 후, 세포를 30ml RPMI-1630 + 10% FBS로 재현탁하고 37℃, 5% CO2에서 하룻밤동안 인큐베이션시켰다.
테스트된 표적세포는 두경부 편평 세포 암종 세포주인, FaDu(ATCC HTB-43, Manassus, VA) 및 비-소 세포 폐 선암 세포주인 NCI-H1975(ATCC CRL-5908, Manassus, VA)였다. 표적 세포를 다음과 같이 칼세인으로 표지하였다. 세포를 단일층으로 성장시키고 아큐타아제(accutase)와 함께 인큐베이션 하여 세포를 떼었다. 세포를 혈청이 없는 RPMI로 두 번 워싱하였다. 4x106 개의 세포/ml의 세포 1ml을 1ml RPMI (혈청 없는) + 20μM 칼세인 AM (Sigma cat# C1359; St. Louis, MO)과 혼합하였다. 세포를 30분 동안 37℃에서 인큐베이션시키고, 매 10분마다 부드럽게 혼합했다. 표지 후, 세포를 14ml RPMI + 10% FBS + 2.5mM 프로베네시드(어세이 배지)로 두 번 워싱했다. 프로베네시드(Sigma cat# P8761; St. Louis, MO)는 음이온성 수송체 억제제이고 세포내 칼세인의 자발적 분비를 억제한다고 알려져있다. 세포를 20ml 어세이 배지로 재현탁하고 2시간 동안 37℃, 5% CO2에서 회복시켰다. 세포를 어세이 배지로 한번 워싱하고 200,000개 세포/ml로 희석시켰다. 50μl의 분획(10,000개의 세포)의 칼세인-표지 세포를 96-웰 둥근-바닥 플레이트에 분획하였다. 50μl의 항체(3x 최종 농도)를 세포에 더하고 얼음 위에서 40분 동안 결합하도록 하였다. 이전의 PBMC를 5분 동안 300g에서 원심분리시키고, 20ml 신선한 어세이 배지로 재현탁하고, 세포 수를 세어, 6x106개 세포/ml로 희석하였다. 50μl PBMC(300,000)을 4시간 동안 37℃, 5% CO2에서 인큐베이션 시킨 각 웰 및 플레이트에 더했다. 각 항체를 50nM에서 시작하여 0.00005nM로 내려가는, 10-배 연속 희석을 통하여 삼중복으로 적정하였다. 대조군 웰은 최대 자발적 칼세인 분비를 측정하기 위해 항체 및 이펙터 세포의 부재에서 표지된 표적 세포를 함유하게 설정하였다.
4시간 인큐베이션이 끝난 후, 8% IGEPAL CA-630(Sigma cat# I8896; St. Louis, MO)을 함유하는 50μl의 어세이 배지를 표지된 표적 세포만 함유하는 대조군 웰에 가했다(최대 칼세인 분비를 측정하기 위함). 50μl의 어세이 배지를 다른 모든 웰에 더해서 웰 당 총 부피를 200μl으로 하였다. 플레이트를 10분 동안 2000RPM으로 원심분리시키고 150μl 상층액을 주의깊게 V-바닥 96웰 플레이트로 옮겼다. 이 플레이트들을 추가적으로 10분 동안 2000RPM에서 원심분리시키고 100ml 상층액을 주의깊게 검정, 투명-바닥 96-웰 플레이트로 옮겼다. 상층액의 칼세인을 485nM의 여기 파장 및 535nM의 방출 파장을 이용하여 각 샘플의 형광 측정에 의해 정량화하였다. 특이적 용해의 퍼센트를 다음과 같이 계산하였다:
% 특이적 용해 = [(테스트 샘플 값 - 자발적 분비)/(최대 분비 - 자발적 분비)]*100
이 데이터는 도 22 및 도 23에서 보여준다. 두 세포주의 경우, SI-1X6.4는 세포독성을 매개했지만, 대조군 항체, SI-1C6.2, SI-1C7, 또는 SI-1C6.2 + SI-1C7의 조합보다 특히 더 효과적이지 않았다. SI-1X6.4는 우리의 기준 항체, SI-1C4보다 낮은 EC50으로 세포독성을 매개했다. 두 세포주의 경우, SI-1X4.2은 대조군 항체와 동일한 정도에 대해서 세포독성을 매개했다. 그러나, 기준인, SI-1C4 세포 독성을 매개로 효과적이지 않았다. 이는 SI-1X4.2의 낮은 친화성 때문으로 보인다.
실시예
11: SI-1X
이중특이적
항체의 열 안정성
단백질 열 안정성 분석을 위해 단백질 열 시프트 연구를 수행하였다. 단백질 융융 반응을 Protein Thermal Shift Buffer TM 및 the Protein Thermal Shift Dye TM (Applied Biosystems)를 이용하여 설정하였다. 간략하게, 20ul 반응 혼합물은 5ug 단백질, 5ul Protein Thermal Shift Buffer TM 및 2.5μ 8X 희석된 Protein Thermal Shift TM 염료를 함유한다. 네거티브 대조군을 위해, PBS가 대신 사용된다. 반응 혼합물을 MicroAmp Optical Reaction Plate에 더하고 MicroAmp Optical Adhesive Film로 밀봉했다. 각 샘플은 4 반복으로 구성된다. 단백질 융융 반응은 Applied Biosystem Real-Time PCR System에서 25 - 90℃ 에서 1% 증가로 실행되고 Protein Thermal Shift SoftwareTM로 분석된다. 도 24는 SI-1X2, SI-1X4.2, SI-1X6.4, SI-1C3, SI-1C3, SI-1C6.2, SI-1C5.2 및 SI-1C7의 열 곡선을 보여준다. 표 5는 이 분자들의 Tm을 보여준다. Tm은 단백질의 50%가 미접힘되는데 요구되는 온도로 정의된다. 이중특이적 분자, 1X2, 1X4.2 및 1X6는 모두 66℃ 주변의 Tm을 갖고, 이는 모든 MAbs(1C3, 1C6.2, 1C5.2) 및 Fc-scFv(1C7) 분자들과 비교될 수 있다.
실시예
12: SI-1X
이중특이적
항체의 혈청 안정성
분자 SI-1C5.2, SI-1C6.2, SI-1X4.2, 및 SI-1X6.4의 혈청 안정성은 95% 인간 혈청(Atlanta Biologics, S40110)에서 100μg/mL로 인큐베이션 후 ELISA에 의한 단량체 EGFR ECD와의 상대적인 결합에 의해 0일째, 3일째, 및 7일째에 37℃에서 및 추가로 분해가 발생하는 것으로 알려진 조건을 제공하는 7일째의 55℃에서 결정되었다. ELISA 플레이트를 PBS에서 3μg/mL 단량체 EGFR ECD로 4℃에서 하룻밤동안 코팅했다. 코팅된 ELISA 플레이트를 2시간 동안 25℃에서 3% BSA PBST로 블락하고 PBST로 3번 워싱했다. SI-1C6.2 및 SI-1C6.4를 1% BSA PBST로 1:10으로 희석하고 플레이트에 걸쳐 4X로 희석했다. SI-1C5.2 및 SI-1C4.2를 1% BSA PBST로 1:2로 희석하고 플레이트에 걸쳐 4X로 희석하고 1시간 동안 25℃에서 인큐베이션 했다. 1% BSA PBST에서 1μg/mL Her3 ECD 토끼 IgG1 (SI-1R1)로 1시간 동안 25℃에서 항원 캡쳐 하기 전에 PBST로 3번 더 워싱했다. 1% BSA PBST에서 1:5000로 희석한 염소 항-토끼 IgG-HRP(Bio-Rad 172-1019) 2차 항체를 1시간 동안 25℃에서 적용되기 전에 PBST로 3번 더 워싱하였다. 10분 동안 100μl 2M H2S04로의 최종 퀀치하여 100μl Pierce 1-step Ultra TMB ELISA(Pierce, 34028)로 현상하기 전에 PBST로 3번 최종 워싱하였다. 플레이트를 450nm에서 판독했다. ELISA 데이터를 GraphPad Prism 6을 이용하여 플랏 및 곡선을 만들었다.
ELISA의 결과는 도 25에서 EC50에 의해 보고되고 37℃에서 유지될 때 약간의 분해의 유리한 프로파일을 나타냈다. 55℃에 놓았을 때, EC50은 분자가 분해 조건을 겪을 때 대략 로그로 이동한다. SI-1C5.2의 EC50 값은 37℃에서 0일째에 589.7pM에서 7일째에 755.2pM으로 이동하고(Δ165.5pM), 55℃에서 7일째에는 6.522nM으로 이동한다(Δ5932.3pM). SI-1C6에 대한 EC50 값은 37℃에서 0일째에 218.2pM에서 7일째에 226.6pM으로 이동하고(Δ8.4pM), 55℃에서 7일째에는 1.322nM으로 이동한다(Δ1103pM). SI-1X4.2의 EC50 값은 37 ℃에서 0일째에 429.3pM에서 7일째에 466.7pM으로 이동하고(Δ37.4pM), 55℃에서 7 일째에 4.248nM로 이동한다(Δ3818.7pM). SI-1X6의 EC50 값은 37℃에서 0일째에 209.3pM에서 7일째에 237.3pM으로 이동하고(Δ28pM), 55℃에서 7일째에는 4.112nM으로 이동한다(Δ3902.7pM).
실시예 13: SI-1X 분자의 PK 반감기
생체내에서의 그들의 반감기를 테스트하기 위해, 약물동력학 실험을 SD 래트에서 수행하였다. 이중특이적 항체(1C6 10mg/kg, 1X6 10mg/kg, 1X2 10mg/kg, 1X4 32mg/kg)의 단일, 정맥내 꼬리 정맥 주사를 체중(192-212g 범위)으로 무작위 선정된 4마리의 암컷 래트의 그룹이 받았다. 혈액(~150μL)을 매 시점에 안와 신경총으로부터 뽑고, 혈청을 위해 처리하고, 분석까지 -80℃에서 보관했다. 연구 기간은 28일이었다.
항체 농도를 세 가지 ELISA 어세이를 이용하여 결정하였다. 어세이 1(EGFR ECD 코팅된 ELISA)에서, 재조합 EGFR-토끼 Fc를 플레이트에 코팅하고, 웰을 PBST(0.05% Tween이 들어있는 인산염 완충 식염수)로 워싱하고 1% BSA인 PBST로 블락했다. 혈청 또는 혈청 희석 기준을 추가하고, PBST로 워싱하고, 표지된 토끼-항-인간 IgG (BOSTER)를 추가하고, 추가적으로 PBST로 워싱했다. TMB를 더하고 플레이트를 어둠속에서 2.5분 인큐베이션시켰다. 색 반응을 2M 황산을 추가하여 정지시켰다. 플레이트를 450nm 파장에서 판독했다. 어세이 2(Her3 코팅된 ELISA)를 위해, 혈청을 유사한 ELISA를 이용하여 검출하고, 재조합 HER3-His를 캡쳐 제제로 이용했다. 어세이 3(샌드위치 ELISA)을 위해, 재조합 HER3-His를 코팅하고, 혈청 또는 혈청 희석 기준을 더하고, 뒤이어 PBST로 워싱하고, PBST에 EGFR-토끼 Fc를 추가, 및 PBST 워싱을 추가로 하였다. HRP-표지된 염소-항-토끼 IgG(BOSTER)를 더했다. PK 매개변수를 비-구분 모델로 결정했다.
도 26 내지 28은 각각의 세가지 다른 어세이로 4개의 항체에 대한 혈청 농도 데이터를 보여준다. 생체내 PK 연구로부터 적합한 PK 파라미터를 표 6에서 제공한다. PK 데이터는 혈청으로부터 항체의 제거를 특징짓는 베타 단계를 나타내는, 반감기 및 최대의 관찰된 혈청 농도를 나타내는, Cmax, 농도 시간 곡선 하에 면적을 나타내는, AUC를 포함한다.
실시예
14: 마우스 이종이식 연구
실시예는 Fadu의 임상 모델(두경부 편평 암종 이종이식 모델)에서 EGFR, HER3의 동반 차단의 SI-1X2, SI-1X4.2 및 SI-1X6의 활성을 테스트하고, 세툭시맙 및 항-HER3 항체와 조합된 세툭시맙과 그들의 효능을 비교하였다.
모든 마우스 연구를 기관 동물 관리를 통하여 실시하였고 기관의 지시에 따른 위원회-승인된 동물 프로토콜을 이용하였다. 6주차 암컷 Balb/c 누드 마우스를 Beijing Vital River Laboratories에서 구매하였고 12시간 조명 주기 및 음식 및 물의 자의섭식이 가능한 공기-여과된 층류 캐비닛에 보관하였다. 80%의 파워 및 0.01의 P값으로 위약과 25%의 처리군 사이의 평균 차이를 측정하기 위해 동물군의 크기를 계산하였다. 이종이식편을 가진 숙주 마우스를 무작위로 동등하게 대조군 또는 처리군 중 하나로 할당했다. 동물 실험을 대조 및 비-맹검 방식으로 수행했다. 세포주-유래된 이종이식 연구를 위해, 마우스 당 2×106개의 Fadu가 현탁된 150μl의 배양 배지를 마우스 피하에 주사하였다.
일단 종양의 평균 부피가 100-250mm3에 도달하면, 마우스를 군 당 6마리의 마우스로, 9개의 군으로 무작위로 선정하였다. 비히클 대조군, 1C6(25mg/kg), 1C4(25mg/kg), 1C6+1C1(25mg/kg+50mg/kg), SI-1X2(25mg/kg), SI-1X6(10mg/kg), SI-1X6(25mg/kg), 및 SI-1X4.2(10mg/kg), SI-1X4 (25mg/kg). 모든 테스트 입자를 1주일에 한번 정맥 주사를 통해 투여하였다. 종양을 전체 기간 동안 3일 마다 디지털 캘리퍼스로 측정하였고 부피를 다음 식을 이용하여 결정하였다: 1/2×길이×너비2. 마우스의 체중을 첫 투여 전에 기록하고 처리 기간 및 회복 기간 동안 매주 기록하였다.
모든 SI-1X2, SI-1X6 및 SI-1X4.2 및 SI-1X6 조합의 테스트 군은 저용량 SI-1X4.2의 10㎎/kg 군을 제외한 SI-1C6의 양성 대조군과 비교하여 유의미한 종양 성장 억제를 나타냈다(도 29-30). 또한, 저용량 SI-1X4.2의 10㎎/kg 군을 제외하고 처리를 중단 후 2주차에 재발이 관찰되지 않았다.
약학적 조성물
용어 “유효량”은 원하는 효과, 즉 개체에서 질병을 개선을 달성하기 위해 효과적인 약물의 양을 의미한다. 질병이 암인 경우, 약물의 유효량은 이에 제한되지 않으나, 암세포 성장, 암세포 증식, 암세포 운동성, 말초기관에 암세포 침투, 종양 전이, 및 종양 성장을 포함하는 다음의 예시적인 특정의 하나 이상을 억제할 수 있다. 질병이 암인 경우, 개체에 투여시 약물의 유효량은 선택적으로 다음 중 하나 이상을 수행할 수 있다: 종양 성장의 감속 또는 정지, 종양 크기 감소(예를 들어, 부피 또는 덩어리), 암과 관련된 하나 이상의 증상의 어느 정도의 완화, 무진행 생존 연장, 목표 반응의 결과(예를 들어, 부분적 반응 또는 완전한 반응을 포함), 및 전반적인 생존 기간 증가. 약물이 존재하는 암세포의 성장을 방지 및/또는 죽일 수 있는 정도까지, 세포분열 억제 및/또는 세포독성을 나타낸다.
치료를 필요로 하는 인간 환자와 같은 개체에게 투여하기 위한 적합한 조성물의 제형에 관하여, 본원에 개시된 항체는 선택된 투여 경로에 따라 당해 분야에 공지된 약학적으로 허용가능한 담체와 혼합 또는 조합될 수 있다. 본원에 개시된 항체의 적용 방식에는 특별한 제한이 없고, 적합한 투여 경로 및 적합한 조성물의 선택은 과도한 실험 없이 당업계에 공지되어 있다.
비록 투여의 많은 형태가 가능하지만, 예시적인 투여 형태는, 특히 정맥 내 또는 동맥 내 투여를 위한, 주사를 위한 용액일 수 있다. 보통, 주사를 위한 적합한 약학적 조성물은 이에 제한되지 않지만, 완충제, 계면활성제 또는 안정제와 같은 약학적으로 허용가능한 담체 또는 부형체를 포함할 수 있다. 예시적인 계면활성제는, 이에 제한되지 않지만, 폴리소르베이트를 포함할 수 있다. 예시적인 안정제는, 이에 제한되지 않지만, 인간 알부민을 포함할 수 있다.
유사하게, 당업자는 암과 같은 병증을 효과적으로 치료하기 위해 본원에 개시된 항체의 유효량 또는 유효 농도를 결정하는 능력을 갖는다. 약학적 조성물에서 다양한 성분의 비율과 같은 기타 매개변수, 투여 용량 및 빈도는 과도한 실험 없이 당업자에 의해 얻을 수 있다. 예를 들어, 주사를 위한 적합한 용액은, 이에 제한되지 않지만, 1ml 당 약 1 내지 약 20mg, 약 1 내지 약 10mg의 항체를 함유할 수 있다. 예시적인 용량은, 이에 제한되지 않지만, 체중 Kg 당 약 0.1 내지 약 20mg, 약 1 내지 약 5mg일 수 있다. 예시적인 투여 빈도는, 이에 제한되지 않지만, 하루에 1번 또는 1주일에 3번 일 수 있다.
본원은 특정 구현예 또는 실시예를 참조하여 설명되었지만, 구현예들은 예시적인 것이며, 본원의 범위는 그렇게 제한되지 않는다는 것을 이해할 수 있을 것이다. 본원의 대체의 구현예는 본원이 속하는 기술분야의 당업자에게 명백할 수 있다. 이러한 대체의 구현예는 본원의 범위에 포함되는 것으로 간주된다. 따라서, 본원의 범위는 첨부된 청구범위에 의해 한정되고 상기 설명에 의해 뒷받침 된다.
SEQUENCE LISTING
<110> SystImmune, Inc.
<120> BISPECIFIC TETRAVALENT ANTIBODIES AND METHODS OF MAKIING AND
USING THEREOF
<130> IPA170540-US
<150> US 62095348
<151> 2014-12-22
<160> 138
<170> PatentIn version 3.5
<210> 1
<211> 654
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 1
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc ctacgtacgg tggctgcacc atctgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 654
<210> 2
<211> 333
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 2
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc cta 333
<210> 3
<211> 218
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 3
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 4
<211> 110
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 4
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val
100 105 110
<210> 5
<211> 1344
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 5
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaa 1344
<210> 6
<211> 354
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 6
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagc 354
<210> 7
<211> 448
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 7
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 8
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 8
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 9
<211> 642
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 9
Gly Ala Cys Ala Thr Cys Cys Ala Gly Ala Thr Gly Ala Cys Cys Cys
1 5 10 15
Ala Gly Thr Cys Thr Cys Cys Ala Thr Cys Cys Thr Cys Cys Cys Thr
20 25 30
Gly Thr Cys Thr Gly Cys Ala Thr Cys Thr Gly Thr Ala Gly Gly Ala
35 40 45
Gly Ala Cys Ala Gly Ala Gly Thr Cys Ala Cys Cys Ala Thr Cys Ala
50 55 60
Cys Thr Thr Gly Cys Cys Ala Gly Gly Cys Gly Ala Gly Thr Cys Ala
65 70 75 80
Gly Gly Ala Cys Ala Thr Cys Ala Gly Cys Ala Ala Cys Thr Ala Thr
85 90 95
Thr Thr Ala Ala Ala Thr Thr Gly Gly Thr Ala Thr Cys Ala Gly Cys
100 105 110
Ala Gly Ala Ala Ala Cys Cys Ala Gly Gly Gly Ala Ala Ala Gly Cys
115 120 125
Cys Cys Cys Thr Ala Ala Ala Cys Thr Cys Cys Thr Gly Ala Thr Cys
130 135 140
Thr Ala Cys Gly Ala Thr Gly Cys Ala Thr Cys Cys Ala Ala Thr Thr
145 150 155 160
Thr Gly Gly Ala Ala Ala Cys Ala Gly Gly Gly Gly Thr Cys Cys Cys
165 170 175
Ala Thr Cys Ala Ala Gly Gly Thr Thr Cys Ala Gly Thr Gly Gly Ala
180 185 190
Ala Gly Thr Gly Gly Ala Thr Cys Thr Gly Gly Gly Ala Cys Ala Gly
195 200 205
Ala Thr Thr Thr Thr Ala Cys Thr Thr Thr Cys Ala Cys Cys Ala Thr
210 215 220
Cys Ala Gly Cys Ala Gly Cys Cys Thr Gly Cys Ala Gly Cys Cys Thr
225 230 235 240
Gly Ala Ala Gly Ala Thr Ala Thr Thr Gly Cys Ala Ala Cys Ala Thr
245 250 255
Ala Thr Thr Thr Cys Thr Gly Thr Cys Ala Ala Cys Ala Cys Thr Thr
260 265 270
Thr Gly Ala Thr Cys Ala Thr Cys Thr Cys Cys Cys Gly Cys Thr Cys
275 280 285
Gly Cys Thr Thr Thr Cys Gly Gly Cys Gly Gly Ala Gly Gly Gly Ala
290 295 300
Cys Cys Ala Ala Gly Gly Thr Gly Gly Ala Ala Ala Thr Thr Ala Ala
305 310 315 320
Ala Cys Gly Thr Ala Cys Gly Gly Thr Gly Gly Cys Thr Gly Cys Ala
325 330 335
Cys Cys Ala Thr Cys Thr Gly Thr Cys Thr Thr Cys Ala Thr Cys Thr
340 345 350
Thr Cys Cys Cys Gly Cys Cys Ala Thr Cys Thr Gly Ala Thr Gly Ala
355 360 365
Gly Cys Ala Gly Thr Thr Gly Ala Ala Ala Thr Cys Thr Gly Gly Ala
370 375 380
Ala Cys Thr Gly Cys Cys Thr Cys Thr Gly Thr Thr Gly Thr Gly Thr
385 390 395 400
Gly Cys Cys Thr Gly Cys Thr Gly Ala Ala Thr Ala Ala Cys Thr Thr
405 410 415
Cys Thr Ala Thr Cys Cys Cys Ala Gly Ala Gly Ala Gly Gly Cys Cys
420 425 430
Ala Ala Ala Gly Thr Ala Cys Ala Gly Thr Gly Gly Ala Ala Gly Gly
435 440 445
Thr Gly Gly Ala Thr Ala Ala Cys Gly Cys Cys Cys Thr Cys Cys Ala
450 455 460
Ala Thr Cys Gly Gly Gly Thr Ala Ala Cys Thr Cys Cys Cys Ala Gly
465 470 475 480
Gly Ala Gly Ala Gly Thr Gly Thr Cys Ala Cys Ala Gly Ala Gly Cys
485 490 495
Ala Gly Gly Ala Cys Ala Gly Cys Ala Ala Gly Gly Ala Cys Ala Gly
500 505 510
Cys Ala Cys Cys Thr Ala Cys Ala Gly Cys Cys Thr Cys Ala Gly Cys
515 520 525
Ala Gly Cys Ala Cys Cys Cys Thr Gly Ala Cys Gly Cys Thr Gly Ala
530 535 540
Gly Cys Ala Ala Ala Gly Cys Ala Gly Ala Cys Thr Ala Cys Gly Ala
545 550 555 560
Gly Ala Ala Ala Cys Ala Cys Ala Ala Ala Gly Thr Cys Thr Ala Cys
565 570 575
Gly Cys Cys Thr Gly Cys Gly Ala Ala Gly Thr Cys Ala Cys Cys Cys
580 585 590
Ala Thr Cys Ala Gly Gly Gly Cys Cys Thr Gly Ala Gly Cys Thr Cys
595 600 605
Gly Cys Cys Cys Gly Thr Cys Ala Cys Ala Ala Ala Gly Ala Gly Cys
610 615 620
Thr Thr Cys Ala Ala Cys Ala Gly Gly Gly Gly Ala Gly Ala Gly Thr
625 630 635 640
Gly Thr
<210> 10
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 10
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggcgagtca ggacatcagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaaactcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatattt ctgtcaacac tttgatcatc tcccgctcgc tttcggcgga 300
gggaccaagg tggaaattaa a 321
<210> 11
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 11
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 Asp Ala Ser Asn Leu Glu 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 Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 12
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 12
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 Asp Ala Ser Asn Leu Glu 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 Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 1347
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 13
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccgtcagc agtggtgatt actactggac ctggatccgg 120
cagtccccag ggaagggact ggagtggatt ggacacatct attacagtgg gaacaccaat 180
tataacccct ccctcaagag ccgactcacc atatcaattg acacgtccaa gactcagttc 240
tccctgaagc tgagttctgt gaccgctgcg gacacggcca tttattactg tgtgcgagat 300
cgagtgactg gtgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagcgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaa 1347
<210> 14
<211> 357
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 14
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccgtcagc agtggtgatt actactggac ctggatccgg 120
cagtccccag ggaagggact ggagtggatt ggacacatct attacagtgg gaacaccaat 180
tataacccct ccctcaagag ccgactcacc atatcaattg acacgtccaa gactcagttc 240
tccctgaagc tgagttctgt gaccgctgcg gacacggcca tttattactg tgtgcgagat 300
cgagtgactg gtgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagc 357
<210> 15
<211> 449
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 15
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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 16
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 16
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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 17
<211> 642
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 17
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca gaatattgct actgatgtag cctggtatca acagaaacca 120
ggaaaagctc cgaagcttct gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gtagcggttc cgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa agtgagccgg agccgtacac gttcggacag 300
ggtaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 18
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 18
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca gaatattgct actgatgtag cctggtatca acagaaacca 120
ggaaaagctc cgaagcttct gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gtagcggttc cgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa agtgagccgg agccgtacac gttcggacag 300
ggtaccaagg tggagatcaa a 321
<210> 19
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 19
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 Asn Ile Ala Thr Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Glu Pro Glu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 20
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 20
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 Asn Ile Ala Thr Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Glu Pro Glu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 21
<211> 1353
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 21
gaggtgcagc tggtcgagtc tggcggcgga ctggtgcagc ccggtggctc tctgcgactg 60
tcttgtgccg cctctggctt caccctcagt ggcgattgga tccactgggt gcgacaggct 120
cccggaaagg gcctggagtg ggtgggtgag atctctgctg ccggtggcta caccgattac 180
gccgactctg tgaagggccg attcaccatc tctgccgaca cctctaagaa caccgcctac 240
ctgcagatga actctctgcg agccgaggac accgctgtgt actactgtgc acgagaaagt 300
agagtttcct tcgaagccgc catggactac tggggccagg gcaccctggt gaccgtgtcc 360
tctgctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 660
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200
gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320
acgcagaaga gcctctccct gtctccgggt aaa 1353
<210> 22
<211> 363
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 22
Gly Ala Gly Gly Thr Gly Cys Ala Gly Cys Thr Gly Gly Thr Cys Gly
1 5 10 15
Ala Gly Thr Cys Thr Gly Gly Cys Gly Gly Cys Gly Gly Ala Cys Thr
20 25 30
Gly Gly Thr Gly Cys Ala Gly Cys Cys Cys Gly Gly Thr Gly Gly Cys
35 40 45
Thr Cys Thr Cys Thr Gly Cys Gly Ala Cys Thr Gly Thr Cys Thr Thr
50 55 60
Gly Thr Gly Cys Cys Gly Cys Cys Thr Cys Thr Gly Gly Cys Thr Thr
65 70 75 80
Cys Ala Cys Cys Cys Thr Cys Ala Gly Thr Gly Gly Cys Gly Ala Thr
85 90 95
Thr Gly Gly Ala Thr Cys Cys Ala Cys Thr Gly Gly Gly Thr Gly Cys
100 105 110
Gly Ala Cys Ala Gly Gly Cys Thr Cys Cys Cys Gly Gly Ala Ala Ala
115 120 125
Gly Gly Gly Cys Cys Thr Gly Gly Ala Gly Thr Gly Gly Gly Thr Gly
130 135 140
Gly Gly Thr Gly Ala Gly Ala Thr Cys Thr Cys Thr Gly Cys Thr Gly
145 150 155 160
Cys Cys Gly Gly Thr Gly Gly Cys Thr Ala Cys Ala Cys Cys Gly Ala
165 170 175
Thr Thr Ala Cys Gly Cys Cys Gly Ala Cys Thr Cys Thr Gly Thr Gly
180 185 190
Ala Ala Gly Gly Gly Cys Cys Gly Ala Thr Thr Cys Ala Cys Cys Ala
195 200 205
Thr Cys Thr Cys Thr Gly Cys Cys Gly Ala Cys Ala Cys Cys Thr Cys
210 215 220
Thr Ala Ala Gly Ala Ala Cys Ala Cys Cys Gly Cys Cys Thr Ala Cys
225 230 235 240
Cys Thr Gly Cys Ala Gly Ala Thr Gly Ala Ala Cys Thr Cys Thr Cys
245 250 255
Thr Gly Cys Gly Ala Gly Cys Cys Gly Ala Gly Gly Ala Cys Ala Cys
260 265 270
Cys Gly Cys Thr Gly Thr Gly Thr Ala Cys Thr Ala Cys Thr Gly Thr
275 280 285
Gly Cys Ala Cys Gly Ala Gly Ala Ala Ala Gly Thr Ala Gly Ala Gly
290 295 300
Thr Thr Thr Cys Cys Thr Thr Cys Gly Ala Ala Gly Cys Cys Gly Cys
305 310 315 320
Cys Ala Thr Gly Gly Ala Cys Thr Ala Cys Thr Gly Gly Gly Gly Cys
325 330 335
Cys Ala Gly Gly Gly Cys Ala Cys Cys Cys Thr Gly Gly Thr Gly Ala
340 345 350
Cys Cys Gly Thr Gly Thr Cys Cys Thr Cys Thr
355 360
<210> 23
<211> 451
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Gly Asp
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Glu Ile Ser Ala Ala Gly Gly Tyr Thr Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Glu Ser Arg Val Ser Phe Glu Ala Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 24
<211> 121
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Gly Asp
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Glu Ile Ser Ala Ala Gly Gly Tyr Thr Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Glu Ser Arg Val Ser Phe Glu Ala Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 25
<211> 657
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 25
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attactcgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657
<210> 26
<211> 336
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 26
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attact 336
<210> 27
<211> 219
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 27
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 Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Gln Gln Thr Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Phe Gln Tyr
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 28
<211> 112
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 28
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 Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Gln Gln Thr Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Phe Gln Tyr
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
100 105 110
<210> 29
<211> 1359
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 29
caagttcaac ttcaacaatc tggtgctgaa gttaaaaaac ctggttcttc tgttaaagtt 60
tcttgtaaag cctctggtta tacttttact aattattata tttattgggt tcgtcaagct 120
cctggtcaag gtcttgaatg gattggtggt attaatccta cttctggtgg ttctaatttt 180
aatgaaaaat ttaaaactcg tgttactatt actgttgatg aatctacgaa cactgcttat 240
atggaacttt cttctcttcg ttctgaagat actgcttttt atttttgtgc gcgtcaaggt 300
ctttggtttg attctgatgg tcgtggtttt gatttttggg gtcaaggttc cactgttact 360
gtctcgagcg ctagcaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 420
acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 540
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 600
acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 660
gttgagccca aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaactc 720
ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 780
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 840
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1080
cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1260
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacgc agaagagcct ctccctgtct ccgggtaaa 1359
<210> 30
<211> 369
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 30
caagttcaac ttcaacaatc tggtgctgaa gttaaaaaac ctggttcttc tgttaaagtt 60
tcttgtaaag cctctggtta tacttttact aattattata tttattgggt tcgtcaagct 120
cctggtcaag gtcttgaatg gattggtggt attaatccta cttctggtgg ttctaatttt 180
aatgaaaaat ttaaaactcg tgttactatt actgttgatg aatctacgaa cactgcttat 240
atggaacttt cttctcttcg ttctgaagat actgcttttt atttttgtgc gcgtcaaggt 300
ctttggtttg attctgatgg tcgtggtttt gatttttggg gtcaaggttc cactgttact 360
gtctcgagc 369
<210> 31
<211> 453
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 31
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Val Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Ala Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Ser Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 32
<211> 123
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 32
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Val Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Ala Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Ser Thr Val Thr Val Ser Ser
115 120
<210> 33
<211> 657
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 33
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attactcgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657
<210> 34
<211> 336
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 34
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attact 336
<210> 35
<211> 218
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 35
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 36
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 36
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 37
<211> 1356
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 37
caggtgcagc tgcagcagag cggcgccgag gtgaagaagc ccggcagcag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactactaca tctactgggt gcggcaggcc 120
cccggccagg gcctggagtg gatcggcggc atcaacccca ccagcggcgg cagcaacttc 180
aacgagaagt tcaagacccg ggtgaccatc accgccgacg agagcagcac caccgcctac 240
atggagctga gcagcctgcg gagcgaggac accgccttct acttctgcac ccggcagggc 300
ctgtggttcg acagcgacgg ccggggcttc gacttctggg gccagggcac caccgtgacc 360
gtgagcagcg ctagcaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 420
acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 540
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 600
acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 660
gttgagccca aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaactc 720
ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 780
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 840
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1080
cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1260
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacgc agaagagcct ctccctgtct ccgggt 1356
<210> 38
<211> 369
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 38
caggtgcagc tgcagcagag cggcgccgag gtgaagaagc ccggcagcag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactactaca tctactgggt gcggcaggcc 120
cccggccagg gcctggagtg gatcggcggc atcaacccca ccagcggcgg cagcaacttc 180
aacgagaagt tcaagacccg ggtgaccatc accgccgacg agagcagcac caccgcctac 240
atggagctga gcagcctgcg gagcgaggac accgccttct acttctgcac ccggcagggc 300
ctgtggttcg acagcgacgg ccggggcttc gacttctggg gccagggcac caccgtgacc 360
gtgagcagc 369
<210> 39
<211> 452
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 39
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Thr Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly
450
<210> 40
<211> 123
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 40
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Thr Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 41
<211> 642
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 41
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 42
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 42
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 43
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 43
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 44
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 44
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 45
<211> 1347
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 45
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagcgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaa 1347
<210> 46
<211> 357
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 46
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagc 357
<210> 47
<211> 449
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 47
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 48
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 48
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 49
<211> 654
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 49
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc ctacgtacgg tggctgcacc atctgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 654
<210> 50
<211> 333
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 50
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc cta 333
<210> 51
<211> 218
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 51
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 52
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 52
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 53
<211> 2100
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 53
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaaggcggt ggaggatccg gcggtggtgg atcacaggtg 1380
cagctgcagg agtcgggccc aggactggtg aagccttcgg agaccctgtc cctcacctgc 1440
actgtctctg gtggctccgt cagcagtggt gattactact ggacctggat acggcagtcc 1500
ccagggaagg gactggagtg gattggacac atctattaca gtgggaacac caattataac 1560
ccctccctca agagccgact caccatatca attgacacgt ccaagactca gttctccctg 1620
aagctgagtt ctgtgaccgc tgcggacacg gccatttatt actgtgtgcg agatcgagtg 1680
actggtgctt ttgatatctg gggccaaggg acaatggtca ccgtctcgag cggtggaggc 1740
ggttcaggcg gaggtggttc cggcggtggc ggctccgaca tccagatgac ccagtctcca 1800
tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccaggc gagtcaggac 1860
atcagcaact atttaaattg gtatcagcag aaaccaggga aagcccctaa actcctgatc 1920
tacgatgcat ccaatttgga aacaggggtc ccatcaaggt tcagtggaag tggatctggg 1980
acagatttta ctttcaccat cagcagcctg cagcctgaag atattgcaac atatttctgt 2040
caacactttg atcatctccc gctcgctttc ggcggaggga ccaaggtgga aattaaacgt 2100
<210> 54
<211> 354
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 54
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagc 354
<210> 55
<211> 726
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 55
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccgtcagc agtggtgatt actactggac ctggatacgg 120
cagtccccag ggaagggact ggagtggatt ggacacatct attacagtgg gaacaccaat 180
tataacccct ccctcaagag ccgactcacc atatcaattg acacgtccaa gactcagttc 240
tccctgaagc tgagttctgt gaccgctgcg gacacggcca tttattactg tgtgcgagat 300
cgagtgactg gtgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagcggt 360
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgacatcca gatgacccag 420
tctccatcct ccctgtctgc atctgtagga gacagagtca ccatcacttg ccaggcgagt 480
caggacatca gcaactattt aaattggtat cagcagaaac cagggaaagc ccctaaactc 540
ctgatctacg atgcatccaa tttggaaaca ggggtcccat caaggttcag tggaagtgga 600
tctgggacag attttacttt caccatcagc agcctgcagc ctgaagatat tgcaacatat 660
ttctgtcaac actttgatca tctcccgctc gctttcggcg gagggaccaa ggtggaaatt 720
aaacgt 726
<210> 56
<211> 700
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 56
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
450 455 460
Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys
465 470 475 480
Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp Tyr Tyr Trp Thr Trp
485 490 495
Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Ile Gly His Ile Tyr
500 505 510
Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr
515 520 525
Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe Ser Leu Lys Leu Ser Ser
530 535 540
Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys Val Arg Asp Arg Val
545 550 555 560
Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
580 585 590
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
595 600 605
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
610 615 620
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
625 630 635 640
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
645 650 655
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
660 665 670
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
675 680 685
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
690 695 700
<210> 57
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 57
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 58
<211> 242
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 58
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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser
145 150 155 160
Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
165 170 175
Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val
180 185 190
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
195 200 205
Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln His
210 215 220
Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val Glu Ile
225 230 235 240
Lys Arg
<210> 59
<211> 642
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 59
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggcgagtca ggacatcagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaaactcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatattt ctgtcaacac tttgatcatc tcccgctcgc tttcggcgga 300
gggaccaagg tggaaattaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 60
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 60
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggcgagtca ggacatcagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaaactcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatattt ctgtcaacac tttgatcatc tcccgctcgc tttcggcgga 300
gggaccaagg tggaaattaa a 321
<210> 61
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 61
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 Asp Ala Ser Asn Leu Glu 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 Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 62
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 62
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 Asp Ala Ser Asn Leu Glu 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 Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 63
<211> 2109
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 63
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccgtcagc agtggtgatt actactggac ctggatccgg 120
cagtccccag ggaagggact ggagtggatt ggacacatct attacagtgg gaacaccaat 180
tataacccct ccctcaagag ccgactcacc atatcaattg acacgtccaa gactcagttc 240
tccctgaagc tgagttctgt gaccgctgcg gacacggcca tttattactg tgtgcgagat 300
cgagtgactg gtgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagcgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaaggc ggtggaggat ccggcggtgg tggatcacag 1380
gtgcagctgc aggagtcggg gggaggcctg gtcaagcctg gagggtccct gagactctcc 1440
tgtgcagcct ctggattcac ctttagtagt tattggatga gctgggtccg ccaggctcca 1500
gggaaggggc tggagtgggt ggccaacata aaccgcgatg gaagtgcgag ttactatgtg 1560
gactctgtga agggccgatt caccatctcc agagacgacg ccaagaactc actgtatctg 1620
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgag agatcgtggg 1680
gtgggctact tcgatctctg gggccgtggc accctggtca ccgtctcgag cggtggaggc 1740
ggttcaggcg gaggtggttc cggcggtggc ggctcccagt ctgccctgac tcagcctgcc 1800
tccgtgtctg ggtctcctgg acagtcgatc accatctcct gcactggaac cagcagtgac 1860
gttggtggtt ataactttgt ctcctggtac caacaacacc caggcaaagc ccccaaactc 1920
atgatctatg atgtcagtga tcggccctca ggggtgtctg atcgcttctc cggctccaag 1980
tctggcaaca cggcctccct gatcatctct ggcctccagg ctgacgacga ggctgattat 2040
tactgcagct catatgggag cagcagcact catgtgattt tcggcggagg gaccaaggtg 2100
accgtccta 2109
<210> 64
<211> 357
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 64
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccgtcagc agtggtgatt actactggac ctggatccgg 120
cagtccccag ggaagggact ggagtggatt ggacacatct attacagtgg gaacaccaat 180
tataacccct ccctcaagag ccgactcacc atatcaattg acacgtccaa gactcagttc 240
tccctgaagc tgagttctgt gaccgctgcg gacacggcca tttattactg tgtgcgagat 300
cgagtgactg gtgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagc 357
<210> 65
<211> 732
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 65
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcggtgga 360
ggcggttcag gcggaggtgg ttccggcggt ggcggctccc agtctgccct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttataactt tgtctcctgg taccaacaac acccaggcaa agcccccaaa 540
ctcatgatct atgatgtcag tgatcggccc tcaggggtgt ctgatcgctt ctccggctcc 600
aagtctggca acacggcctc cctgatcatc tctggcctcc aggctgacga cgaggctgat 660
tattactgca gctcatatgg gagcagcagc actcatgtga ttttcggcgg agggaccaag 720
gtgaccgtcc ta 732
<210> 66
<211> 703
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 66
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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln
450 455 460
Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser
465 470 475 480
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Trp Met Ser Trp Val
485 490 495
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Asn Ile Asn Arg
500 505 510
Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr
515 520 525
Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser
530 535 540
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly
545 550 555 560
Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
580 585 590
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
595 600 605
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
610 615 620
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
625 630 635 640
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
645 650 655
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
660 665 670
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
675 680 685
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu
690 695 700
<210> 67
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 67
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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 68
<211> 243
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 68
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg 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 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser
130 135 140
Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser
145 150 155 160
Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly
165 170 175
Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly
180 185 190
Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
195 200 205
Ile Ile Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser
210 215 220
Ser Tyr Gly Ser Ser Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Thr Val
<210> 69
<211> 654
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 69
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc ctacgtacgg tggctgcacc atctgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 654
<210> 70
<211> 333
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 70
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc cta 333
<210> 71
<211> 218
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 71
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 72
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 72
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 73
<211> 2127
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 73
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaaggcggt ggaggatccg gcggtggtgg atcacaagtt 1380
caacttcaac aatctggtgc tgaagttaaa aaacctggtt cttctgttaa agtttcttgt 1440
aaagcctctg gttatacttt tactaattat tatatttatt gggttcgtca agctcctggt 1500
caaggtcttg aatggattgg tggtattaat cctacttctg gtggttctaa ttttaatgaa 1560
aaatttaaaa ctcgtgttac tattactgtt gatgaatcta cgaacactgc ttatatggaa 1620
ctttcttctc ttcgttctga agatactgct ttttattttt gtgcgcgtca aggtctttgg 1680
tttgattctg atggtcgtgg ttttgatttt tggggtcaag gttccactgt tactgtctcg 1740
agcggtggag gcggttcagg cggaggtggt tccggcggtg gcggctccga tattcaaatg 1800
actcaatctc cttcttctct ttctgcttct gttggtgatc gtgttactat tacttgtcgt 1860
tcttctcaaa atattgttca ttctaatggt aatacttatc ttgattggta tcaacaaact 1920
cctggtaaag ctcctaaact tcttatttat aaagtttcta atcgtttttc tggtgttcct 1980
tctcgttttt ctggttctgg ttctggtact gattttactt ttactatttc ttctcttcaa 2040
cctgaagata ttgctactta ttattgtttt caatattctc atgttccttg gacttttggt 2100
caaggtacta aacttcaaat tactcgt 2127
<210> 74
<211> 354
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 74
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagc 354
<210> 75
<211> 753
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 75
caagttcaac ttcaacaatc tggtgctgaa gttaaaaaac ctggttcttc tgttaaagtt 60
tcttgtaaag cctctggtta tacttttact aattattata tttattgggt tcgtcaagct 120
cctggtcaag gtcttgaatg gattggtggt attaatccta cttctggtgg ttctaatttt 180
aatgaaaaat ttaaaactcg tgttactatt actgttgatg aatctacgaa cactgcttat 240
atggaacttt cttctcttcg ttctgaagat actgcttttt atttttgtgc gcgtcaaggt 300
ctttggtttg attctgatgg tcgtggtttt gatttttggg gtcaaggttc cactgttact 360
gtctcgagcg gtggaggcgg ttcaggcgga ggtggttccg gcggtggcgg ctccgatatt 420
caaatgactc aatctccttc ttctctttct gcttctgttg gtgatcgtgt tactattact 480
tgtcgttctt ctcaaaatat tgttcattct aatggtaata cttatcttga ttggtatcaa 540
caaactcctg gtaaagctcc taaacttctt atttataaag tttctaatcg tttttctggt 600
gttccttctc gtttttctgg ttctggttct ggtactgatt ttacttttac tatttcttct 660
cttcaacctg aagatattgc tacttattat tgttttcaat attctcatgt tccttggact 720
tttggtcaag gtactaaact tcaaattact cgt 753
<210> 76
<211> 709
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 76
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln
450 455 460
Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys
465 470 475 480
Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Tyr Ile Tyr Trp Val Arg
485 490 495
Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Gly Ile Asn Pro Thr
500 505 510
Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe Lys Thr Arg Val Thr Ile
515 520 525
Thr Val Asp Glu Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu
530 535 540
Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys Ala Arg Gln Gly Leu Trp
545 550 555 560
Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe Trp Gly Gln Gly Ser Thr
565 570 575
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
580 585 590
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
595 600 605
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Asn
610 615 620
Ile Val His Ser Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Gln Gln Thr
625 630 635 640
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe
645 650 655
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
660 665 670
Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr
675 680 685
Cys Phe Gln Tyr Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys
690 695 700
Leu Gln Ile Thr Arg
705
<210> 77
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 77
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 78
<211> 251
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 78
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Val Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Ala Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Ser Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu
165 170 175
Asp Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
180 185 190
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
210 215 220
Asp Ile Ala Thr Tyr Tyr Cys Phe Gln Tyr Ser His Val Pro Trp Thr
225 230 235 240
Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg
245 250
<210> 79
<211> 657
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 79
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attactcgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657
<210> 80
<211> 336
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 80
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attact 336
<210> 81
<211> 219
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 81
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 Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Gln Gln Thr Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Phe Gln Tyr
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 82
<211> 112
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 82
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 Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Gln Gln Thr Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Phe Gln Tyr
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
100 105 110
<210> 83
<211> 2121
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 83
caagttcaac ttcaacaatc tggtgctgaa gttaaaaaac ctggttcttc tgttaaagtt 60
tcttgtaaag cctctggtta tacttttact aattattata tttattgggt tcgtcaagct 120
cctggtcaag gtcttgaatg gattggtggt attaatccta cttctggtgg ttctaatttt 180
aatgaaaaat ttaaaactcg tgttactatt actgttgatg aatctacgaa cactgcttat 240
atggaacttt cttctcttcg ttctgaagat actgcttttt atttttgtgc gcgtcaaggt 300
ctttggtttg attctgatgg tcgtggtttt gatttttggg gtcaaggttc cactgttact 360
gtctcgagcg ctagcaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 420
acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 540
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 600
acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 660
gttgagccca aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaactc 720
ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 780
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 840
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1080
cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1260
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacgc agaagagcct ctccctgtct ccgggtaaag gcggtggagg atccggcggt 1380
ggtggatcac aggtgcagct gcaggagtcg gggggaggcc tggtcaagcc tggagggtcc 1440
ctgagactct cctgtgcagc ctctggattc acctttagta gttattggat gagctgggtc 1500
cgccaggctc cagggaaggg gctggagtgg gtggccaaca taaaccgcga tggaagtgcg 1560
agttactatg tggactctgt gaagggccga ttcaccatct ccagagacga cgccaagaac 1620
tcactgtatc tgcaaatgaa cagcctgaga gctgaggaca cggctgtgta ttactgtgcg 1680
agagatcgtg gggtgggcta cttcgatctc tggggccgtg gcaccctggt caccgtctcg 1740
agcggtggag gcggttcagg cggaggtggt tccggcggtg gcggctccca gtctgccctg 1800
actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 1860
accagcagtg acgttggtgg ttataacttt gtctcctggt accaacaaca cccaggcaaa 1920
gcccccaaac tcatgatcta tgatgtcagt gatcggccct caggggtgtc tgatcgcttc 1980
tccggctcca agtctggcaa cacggcctcc ctgatcatct ctggcctcca ggctgacgac 2040
gaggctgatt attactgcag ctcatatggg agcagcagca ctcatgtgat tttcggcgga 2100
gggaccaagg tgaccgtcct a 2121
<210> 84
<211> 369
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 84
caagttcaac ttcaacaatc tggtgctgaa gttaaaaaac ctggttcttc tgttaaagtt 60
tcttgtaaag cctctggtta tacttttact aattattata tttattgggt tcgtcaagct 120
cctggtcaag gtcttgaatg gattggtggt attaatccta cttctggtgg ttctaatttt 180
aatgaaaaat ttaaaactcg tgttactatt actgttgatg aatctacgaa cactgcttat 240
atggaacttt cttctcttcg ttctgaagat actgcttttt atttttgtgc gcgtcaaggt 300
ctttggtttg attctgatgg tcgtggtttt gatttttggg gtcaaggttc cactgttact 360
gtctcgagc 369
<210> 85
<211> 732
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 85
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcggtgga 360
ggcggttcag gcggaggtgg ttccggcggt ggcggctccc agtctgccct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttataactt tgtctcctgg taccaacaac acccaggcaa agcccccaaa 540
ctcatgatct atgatgtcag tgatcggccc tcaggggtgt ctgatcgctt ctccggctcc 600
aagtctggca acacggcctc cctgatcatc tctggcctcc aggctgacga cgaggctgat 660
tattactgca gctcatatgg gagcagcagc actcatgtga ttttcggcgg agggaccaag 720
gtgaccgtcc ta 732
<210> 86
<211> 707
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 86
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Val Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Ala Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Ser Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
450 455 460
Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser
465 470 475 480
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Trp
485 490 495
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
500 505 510
Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val Lys
515 520 525
Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr Leu
530 535 540
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
545 550 555 560
Arg Asp Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu
565 570 575
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
580 585 590
Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly
595 600 605
Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp
610 615 620
Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys
625 630 635 640
Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val
645 650 655
Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile
660 665 670
Ile Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser
675 680 685
Tyr Gly Ser Ser Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Val
690 695 700
Thr Val Leu
705
<210> 87
<211> 123
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 87
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Val Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Ala Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Ser Thr Val Thr Val Ser Ser
115 120
<210> 88
<211> 244
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 88
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg 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 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser
130 135 140
Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser
145 150 155 160
Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly
165 170 175
Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly
180 185 190
Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
195 200 205
Ile Ile Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser
210 215 220
Ser Tyr Gly Ser Ser Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Thr Val Leu
<210> 89
<211> 657
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 89
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attactcgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657
<210> 90
<211> 336
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 90
gatattcaaa tgactcaatc tccttcttct ctttctgctt ctgttggtga tcgtgttact 60
attacttgtc gttcttctca aaatattgtt cattctaatg gtaatactta tcttgattgg 120
tatcaacaaa ctcctggtaa agctcctaaa cttcttattt ataaagtttc taatcgtttt 180
tctggtgttc cttctcgttt ttctggttct ggttctggta ctgattttac ttttactatt 240
tcttctcttc aacctgaaga tattgctact tattattgtt ttcaatattc tcatgttcct 300
tggacttttg gtcaaggtac taaacttcaa attact 336
<210> 91
<211> 336
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 91
gacatccaga tgacccagtc cccttccagc ctgtccgctt ccgtgggcga cagggtgacc 60
atcacctgca ggtcctccca gaacatcgtg cactccaacg gcaataccta cctggactgg 120
taccagcaga cccccggcaa ggcccctaag ctgctgatct acaaggtgag caaccggttc 180
agcggcgtgc cttcccggtt ttccggatcc ggctccggca cagacttcac cttcaccatc 240
tcctccctgc aacccgagga catcgccacc tactactgct tccagtactc ccatgtgccc 300
tggaccttcg gccagggcac caagctgcag atcacc 336
<210> 92
<211> 218
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 92
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 93
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 93
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 94
<211> 2118
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 94
caggtgcagc tgcagcagag cggcgccgag gtgaagaagc ccggcagcag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactactaca tctactgggt gcggcaggcc 120
cccggccagg gcctggagtg gatcggcggc atcaacccca ccagcggcgg cagcaacttc 180
aacgagaagt tcaagacccg ggtgaccatc accgccgacg agagcagcac caccgcctac 240
atggagctga gcagcctgcg gagcgaggac accgccttct acttctgcac ccggcagggc 300
ctgtggttcg acagcgacgg ccggggcttc gacttctggg gccagggcac caccgtgacc 360
gtgagcagcg ctagcaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 420
acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 540
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 600
acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 660
gttgagccca aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaactc 720
ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 780
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 840
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1080
cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1260
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacgc agaagagcct ctccctgtct ccgggtggcg gtggagggtc cggcggtggt 1380
ggatcacagg tgcaattgca ggagtcgggg ggaggcctgg tcaagcctgg agggtccctg 1440
agactctcct gtgcagcctc tggattcacc tttagtagtt attggatgag ctgggtccgc 1500
caggctccag ggaaggggct ggagtgggtg gccaacataa accgcgatgg aagtgcgagt 1560
tactatgtgg actctgtgaa gggccgattc accatctcca gagacgacgc caagaactca 1620
ctgtatctgc aaatgaacag cctgagagct gaggacacgg ctgtgtatta ctgtgcgaga 1680
gatcgtgggg tgggctactt cgatctctgg ggccgtggca ccctggtcac cgtctcgagc 1740
ggtggaggcg gttcaggcgg aggtggttcc ggcggtggcg gctcccagtc tgccctgact 1800
cagcctgcct ccgtgtctgg gtctcctgga cagtcgatca ccatctcctg cactggaacc 1860
agcagtgacg ttggtggtta taactttgtc tcctggtacc aacaacaccc aggcaaagcc 1920
cccaaactca tgatctatga tgtcagtgat cggccctcag gggtgtctga tcgcttctcc 1980
ggctccaagt ctggcaacac ggcctccctg atcatctctg gcctccaggc tgacgacgag 2040
gctgattatt actgcagctc atatgggagc agcagcactc atgtgatttt cggcggaggg 2100
accaaggtga ccgtccta 2118
<210> 95
<211> 369
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 95
caggtgcagc tgcagcagag cggcgccgag gtgaagaagc ccggcagcag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactactaca tctactgggt gcggcaggcc 120
cccggccagg gcctggagtg gatcggcggc atcaacccca ccagcggcgg cagcaacttc 180
aacgagaagt tcaagacccg ggtgaccatc accgccgacg agagcagcac caccgcctac 240
atggagctga gcagcctgcg gagcgaggac accgccttct acttctgcac ccggcagggc 300
ctgtggttcg acagcgacgg ccggggcttc gacttctggg gccagggcac caccgtgacc 360
gtgagcagc 369
<210> 96
<211> 369
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 96
caggtgcagc tgcagcaatc cggcgccgag gtgaagaagc ctggctccag cgtgaaggtg 60
tcctgcaagg cctccggcta caccttcacc aactactaca tctactgggt gaggcaggct 120
cctggccagg gactggagtg gatcggcggc atcaacccta cctccggcgg ctccaacttc 180
aacgagaagt tcaagacccg ggtgaccatc accgccgatg agagctccac caccgcctac 240
atggagctgt cctccctgag gtccgaggac accgcctttt acttctgcac caggcaggga 300
ctgtggttcg actccgacgg ccggggcttc gatttttggg gccagggcac cacagtgacc 360
gtgtcctcc 369
<210> 97
<211> 732
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 97
caggtgcaat tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcggtgga 360
ggcggttcag gcggaggtgg ttccggcggt ggcggctccc agtctgccct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttataactt tgtctcctgg taccaacaac acccaggcaa agcccccaaa 540
ctcatgatct atgatgtcag tgatcggccc tcaggggtgt ctgatcgctt ctccggctcc 600
aagtctggca acacggcctc cctgatcatc tctggcctcc aggctgacga cgaggctgat 660
tattactgca gctcatatgg gagcagcagc actcatgtga ttttcggcgg agggaccaag 720
gtgaccgtcc ta 732
<210> 98
<211> 706
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 98
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Thr Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
450 455 460
Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu
465 470 475 480
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Trp Met
485 490 495
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Asn
500 505 510
Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val Lys Gly
515 520 525
Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr Leu Gln
530 535 540
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
545 550 555 560
Asp Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val
565 570 575
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser
595 600 605
Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val
610 615 620
Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala
625 630 635 640
Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser
645 650 655
Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile
660 665 670
Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr
675 680 685
Gly Ser Ser Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Val Thr
690 695 700
Val Leu
705
<210> 99
<211> 123
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 99
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Thr Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 100
<211> 244
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 100
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg 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 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser
130 135 140
Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser
145 150 155 160
Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly
165 170 175
Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly
180 185 190
Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
195 200 205
Ile Ile Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser
210 215 220
Ser Tyr Gly Ser Ser Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Thr Val Leu
<210> 101
<211> 654
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 101
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc ctacgtacgg tggctgcacc atctgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 654
<210> 102
<211> 333
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 102
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatc tatgatgtca gtgatcggcc ctcaggggtg 180
tctgatcgct tctccggctc caagtctggc aacacggcct ccctgatcat ctctggcctc 240
caggctgacg acgaggctga ttattactgc agctcatatg ggagcagcag cactcatgtg 300
attttcggcg gagggaccaa gctgaccgtc cta 333
<210> 103
<211> 218
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 103
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 104
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 104
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 105
<211> 2100
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 105
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaaggcggt ggaggatccg gcggtggtgg atcacaggtg 1380
cagctgaagc agtcaggacc tggcctagtg cagccctcac agagcctgtc catcacctgc 1440
acagtctctg gtttctcatt aactaactat ggtgtacact gggttcgcca gtctccagga 1500
aagggtctgg agtggctggg agtgatatgg agtggtggaa acacagacta taatacacct 1560
ttcacatcca gactgagcat caacaaggac aattccaaga gccaagtttt ctttaaaatg 1620
aacagtctgc aatctaatga cacagccata tattactgtg ccagagccct cacctactat 1680
gattacgagt ttgcttactg gggccaaggg actctggtca ctgtctctag cggtggaggc 1740
ggttcaggcg gaggtggttc cggcggtggc ggctccgaca tcttgctgac tcagtctcca 1800
gtcatcctgt ctgtgagtcc aggagaaaga gtcagtttct cctgcagggc cagtcagagt 1860
attggcacaa acatacactg gtatcagcaa agaacaaatg gttctccaag gcttctcata 1920
aagtatgctt ctgagtctat ctctgggatt ccttccaggt ttagtggcag tggatcaggg 1980
acagatttta ctcttagcat caacagtgtg gagtctgaag atattgcaga ttattactgt 2040
caacaaaata ataactggcc aaccacgttc ggtgctggga ccaagctgga gctgaaacgt 2100
<210> 106
<211> 354
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 106
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagc 354
<210> 107
<211> 726
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 107
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagcggt 360
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgacatctt gctgactcag 420
tctccagtca tcctgtctgt gagtccagga gaaagagtca gtttctcctg cagggccagt 480
cagagtattg gcacaaacat acactggtat cagcaaagaa caaatggttc tccaaggctt 540
ctcataaagt atgcttctga gtctatctct gggattcctt ccaggtttag tggcagtgga 600
tcagggacag attttactct tagcatcaac agtgtggagt ctgaagatat tgcagattat 660
tactgtcaac aaaataataa ctggccaacc acgttcggtg ctgggaccaa gctggagctg 720
aaacgt 726
<210> 108
<211> 700
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 108
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln
450 455 460
Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys
465 470 475 480
Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg
485 490 495
Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly
500 505 510
Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn
515 520 525
Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln
530 535 540
Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr
545 550 555 560
Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
580 585 590
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
595 600 605
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
610 615 620
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
625 630 635 640
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
645 650 655
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
660 665 670
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
675 680 685
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
690 695 700
<210> 109
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 109
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 110
<211> 242
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 110
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr Gln Ser Pro Val Ile
130 135 140
Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser
145 150 155 160
Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly
165 170 175
Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile
180 185 190
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser
195 200 205
Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln
210 215 220
Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
225 230 235 240
Lys Arg
<210> 111
<211> 642
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 111
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 112
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 112
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 113
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 113
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 114
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 114
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 115
<211> 2109
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 115
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagcgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaaggc ggtggaggat ccggcggtgg tggatcacag 1380
gtgcagctgc aggagtcggg gggaggcctg gtcaagcctg gagggtccct gagactctcc 1440
tgtgcagcct ctggattcac ctttagtagt tattggatga gctgggtccg ccaggctcca 1500
gggaaggggc tggagtgggt ggccaacata aaccgcgatg gaagtgcgag ttactatgtg 1560
gactctgtga agggccgatt caccatctcc agagacgacg ccaagaactc actgtatctg 1620
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgag agatcgtggg 1680
gtgggctact tcgatctctg gggccgtggc accctggtca ccgtctcgag cggtggaggc 1740
ggttcaggcg gaggtggttc cggcggtggc ggctcccagt ctgccctgac tcagcctgcc 1800
tccgtgtctg ggtctcctgg acagtcgatc accatctcct gcactggaac cagcagtgac 1860
gttggtggtt ataactttgt ctcctggtac caacaacacc caggcaaagc ccccaaactc 1920
atgatctatg atgtcagtga tcggccctca ggggtgtctg atcgcttctc cggctccaag 1980
tctggcaaca cggcctccct gatcatctct ggcctccagg ctgacgacga ggctgattat 2040
tactgcagct catatgggag cagcagcact catgtgattt tcggcggagg gaccaaggtg 2100
accgtccta 2109
<210> 116
<211> 357
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 116
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagc 357
<210> 117
<211> 732
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 117
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcggtgga 360
ggcggttcag gcggaggtgg ttccggcggt ggcggctccc agtctgccct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttataactt tgtctcctgg taccaacaac acccaggcaa agcccccaaa 540
ctcatgatct atgatgtcag tgatcggccc tcaggggtgt ctgatcgctt ctccggctcc 600
aagtctggca acacggcctc cctgatcatc tctggcctcc aggctgacga cgaggctgat 660
tattactgca gctcatatgg gagcagcagc actcatgtga ttttcggcgg agggaccaag 720
gtgaccgtcc ta 732
<210> 118
<211> 703
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 118
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln
450 455 460
Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser
465 470 475 480
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Trp Met Ser Trp Val
485 490 495
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Asn Ile Asn Arg
500 505 510
Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr
515 520 525
Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser
530 535 540
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly
545 550 555 560
Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
580 585 590
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
595 600 605
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
610 615 620
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
625 630 635 640
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
645 650 655
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu
660 665 670
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser
675 680 685
Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu
690 695 700
<210> 119
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 119
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 120
<211> 244
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 120
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg 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 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser
130 135 140
Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser
145 150 155 160
Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly
165 170 175
Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly
180 185 190
Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
195 200 205
Ile Ile Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser
210 215 220
Ser Tyr Gly Ser Ser Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Thr Val Leu
<210> 121
<211> 642
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 121
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 122
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 122
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 123
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 123
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 124
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 124
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 125
<211> 1344
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 125
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagcgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggt 1344
<210> 126
<211> 357
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 126
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagc 357
<210> 127
<211> 448
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 127
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 128
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 128
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 129
<211> 642
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 129
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 130
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 130
gacatcttgc tgactcagtc tccagtcatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagtattggc acaaacatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gattccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa aataataact ggccaaccac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 131
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 131
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 132
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 132
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 133
<211> 2106
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 133
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagcgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtggcggt ggagggtccg gcggtggtgg atcacaggtg 1380
caattgcagg agtcgggggg aggcctggtc aagcctggag ggtccctgag actctcctgt 1440
gcagcctctg gattcacctt tagtagttat tggatgagct gggtccgcca ggctccaggg 1500
aaggggctgg agtgggtggc caacataaac cgcgatggaa gtgcgagtta ctatgtggac 1560
tctgtgaagg gccgattcac catctccaga gacgacgcca agaactcact gtatctgcaa 1620
atgaacagcc tgagagctga ggacacggct gtgtattact gtgcgagaga tcgtggggtg 1680
ggctacttcg atctctgggg ccgtggcacc ctggtcaccg tctcgagcgg tggaggcggt 1740
tcaggcggag gtggttccgg cggtggcggc tcccagtctg ccctgactca gcctgcctcc 1800
gtgtctgggt ctcctggaca gtcgatcacc atctcctgca ctggaaccag cagtgacgtt 1860
ggtggttata actttgtctc ctggtaccaa caacacccag gcaaagcccc caaactcatg 1920
atctatgatg tcagtgatcg gccctcaggg gtgtctgatc gcttctccgg ctccaagtct 1980
ggcaacacgg cctccctgat catctctggc ctccaggctg acgacgaggc tgattattac 2040
tgcagctcat atgggagcag cagcactcat gtgattttcg gcggagggac caaggtgacc 2100
gtccta 2106
<210> 134
<211> 357
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 134
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180
acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300
tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctagc 357
<210> 135
<211> 732
<212> DNA
<213> artificial sequence
<220>
<223> Synthesized
<400> 135
caggtgcagc tgcaggagtc ggggggaggc ctggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaccgcg atggaagtgc gagttactat 180
gtggactctg tgaagggccg attcaccatc tccagagacg acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatcgt 300
ggggtgggct acttcgatct ctggggccgt ggcaccctgg tcaccgtctc gagcggtgga 360
ggcggttcag gcggaggtgg ttccggcggt ggcggctccc agtctgccct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttataactt tgtctcctgg taccaacaac acccaggcaa agcccccaaa 540
ctcatgatct atgatgtcag tgatcggccc tcaggggtgt ctgatcgctt ctccggctcc 600
aagtctggca acacggcctc cctgatcatc tctggcctcc aggctgacga cgaggctgat 660
tattactgca gctcatatgg gagcagcagc actcatgtga ttttcggcgg agggaccaag 720
gtgaccgtcc ta 732
<210> 136
<211> 702
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 136
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
450 455 460
Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys
465 470 475 480
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Trp Met Ser Trp Val Arg
485 490 495
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Asn Ile Asn Arg Asp
500 505 510
Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile
515 520 525
Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Val
545 550 555 560
Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
580 585 590
Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser
595 600 605
Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn
610 615 620
Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met
625 630 635 640
Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe Ser
645 650 655
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ile Ile Ser Gly Leu Gln
660 665 670
Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Ser Ser Ser
675 680 685
Thr His Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu
690 695 700
<210> 137
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 137
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 138
<211> 244
<212> PRT
<213> artificial sequence
<220>
<223> Synthesized
<400> 138
Gln Val Gln Leu Gln 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 Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Arg Asp Gly Ser Ala Ser Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser 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 Arg Gly Val Gly Tyr Phe Asp Leu Trp Gly Arg 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 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser
130 135 140
Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser
145 150 155 160
Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly
165 170 175
Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly
180 185 190
Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
195 200 205
Ile Ile Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser
210 215 220
Ser Tyr Gly Ser Ser Ser Thr His Val Ile Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Thr Val Leu
Claims (62)
- 2개의 IgG1 중쇄; 2개의 카파 경쇄; 및 2개의 단일쇄 Fv(scFv) 도메인을 포함하고,
상기 2개의 IgG1 중쇄 및 카파 경쇄는 EGFR 패밀리의 제1 구성원에 대해 결합 특이성을 갖는 IgG 모이어티를 형성하고;
상기 2개의 scFv 도메인은 EGFR 패밀리의 제2 구성원에 대해 결합 특이성을 갖고, 각각의 scFv 도메인은 (gly-gly-gly-gly-ser)n의 아미노산 서열을 갖는 커넥터에 의해 IgG1 중쇄들 중 어느 하나의 C-말단에 연결되어 IgG1-커넥터 연결을 제공하고, n은 적어도 1의 정수이고;
각각의 scFv 도메인은 N 말단-가변 중쇄-링커-가변 경쇄-C 말단 또는 N 말단-가변 경쇄-링커-가변 중쇄-C 말단 순서의 구조를 갖고, 상기 링커는 (gly-gly-gly-gly-ser)m의 아미노산 서열을 포함하고, m은 적어도 3의 정수인,
이중특이적 4가 항체.
- 제1항에 있어서, n이 1 내지 10의 정수인, 이중특이적 4가 항체.
- 제1항에 있어서, m이 3, 4, 5, 또는 6인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 IgG1 중쇄는 인간화되거나 인간 IgG1 중쇄인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG1 중쇄 둘 다는 인간화되거나 인간 IgG1 중쇄인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 카파 경쇄는 인간화되거나 인간 카파 경쇄인, 이중특이적 4가 항체.
- 제1항에 있어서, 카파 경쇄 둘 다는 인간화되거나 인간 카파 경쇄인, 이중특이적 4가 항체.
- 제1항에 있어서, EGFR 패밀리의 제1 또는 제2 구성원은 HER3, EGFR, 이들의 단편 또는 유도체를 포함하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, EGFR 패밀리의 제1 또는 제2 구성원은 HER3, EGFR, 이들의 단편 또는 유도체로 이루어진 군으로부터 독립적으로 선택되는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 HER3에 대해 결합 특이성을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, scFv 도메인은 EGFR에 대해 결합 특이성을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 HER3에 대해 결합 특이성을 갖고 동시에 scFv 도메인은 EGFR에 대해 결합 특이성을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, scFv 도메인은 HER3에 대해 결합 특이성을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖고 동시에 scFv 도메인은 HER3에 대해 결합 특이성을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 IgG1 중쇄의 C 말단은 아미노산 잔기를 결실한 것인, 이중특이적 4가 항체.
- 제16항에 있어서, 아미노산 잔기는 리신인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG1-커넥터 연결은 프로테아제 활성에 대해 저항하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 IgG1 중쇄는 CH3 도메인에 2개의 돌연변이를 포함하고, 상기 2개의 돌연변이는 인간 CH3 도메인에서 일반적인 잔기로의 역전인 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 IgG1 중쇄는 서열번호 7, 15, 23, 31, 39, 47, 및 127을 포함하는 아미노산을 포함하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 56, 66, 76, 86, 98, 108, 118, 및 136을 포함하는 아미노산을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 카파 경쇄는 서열번호 3, 11, 19, 27, 35, 43, 51, 61, 71, 81, 92, 103, 113, 123, 및 131을 포함하는 아미노산 서열을 포함하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 가변 경쇄는 서열번호 4, 12, 20, 28, 36, 44, 52, 62, 72, 82, 93, 104, 114, 124, 및 132를 포함하는 아미노산 서열을 포함하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 적어도 하나의 가변 중쇄는 서열번호 8, 16, 24, 32, 40, 48, 57, 67, 77, 87, 99, 109, 119, 128, 및 137을 포함하는 아미노산 서열을 포함하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 HER3에 대해 결합 특이성을 갖고, scFv 도메인은 EGFR에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 56의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 51의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 HER3에 대해 결합 특이성을 갖고, scFv 도메인은 EGFR에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 76의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 71의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 HER3에 대해 결합 특이성을 갖고, scFv 도메인은 EGFR에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 108의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 103의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖고, scFv 도메인은 HER3에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 66의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 61의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖고, scFv 도메인은 HER3에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 86의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 81의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖고, scFv 도메인은 HER3에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 98의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 92의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖고, scFv 도메인은 HER3에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 118의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 113의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, IgG 모이어티는 EGFR에 대해 결합 특이성을 갖고, scFv 도메인은 HER3에 대해 결합 특이성을 갖고;
IgG1 중쇄, 커넥터, 및 scFv 도메인은 서열번호 136의 아미노산 서열을 갖고, 카파 경쇄는 서열번호 131의 아미노산 서열을 갖는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 항체는 암 세포 성장을 억제하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 항체는 50nM 미만의 Kd로 EGFR 및 HERS에 결합하는 것인, 이중특이적 4가 항체.
- 제1항에 있어서, 항체는 동시에 50nM 미만의 Kd로 EGFR과 결합하고 50nM 미만의 Kd로 HER3와 결합하는 것인, 이중특이적 4가 항체.
- 서열번호 7, 15, 23, 31, 39, 47, 및 127로부터 선택되는 아미노산 서열을 포함하는, 제1항의 이중특이적 4가 항체에 대한 IgG1 중쇄.
- 서열번호 3, 11, 19, 27, 35, 43, 51, 61, 71, 81, 92, 103, 113, 123, 및 131로부터 선택되는 아미노산 서열을 포함하는, 제1항의 이중특이적 4가 항체에 대한 카파 경쇄.
- 서열번호 4, 12, 20, 28, 36, 44, 52, 62, 72, 82, 93, 104, 114, 124, 및 132로부터 선택되는 아미노산 서열을 포함하는, 제1항의 이중특이적 4가 항체에 대한 가변 경쇄.
- 서열번호 8, 16, 24, 32, 40, 48, 57, 67, 77, 87, 99, 109, 119, 128, 및 137으로부터 선택되는 아미노산 서열을 포함하는, 제1항의 이중특이적 4가 항체에 대한 가변 중쇄.
- 제1항의 항체, 제36항의 IgG1 중쇄, 제37항의 카파 경쇄, 제38항의 가변 경쇄, 또는 제39항의 가변 중쇄를 암호화하는 분리된 핵산.
- 제40항의 분리된 핵산을 포함하는 발현 벡터.
- 제41항에 있어서, 벡터가 세포에서 발현될 수 있는 것인, 발현 벡터.
- 제40항의 핵산을 포함하는 숙주세포.
- 제43항의 발현 벡터를 포함하는 숙주세포.
- 제44항에 있어서, 숙주 세포가 원핵세포 또는 진핵세포인, 숙주세포.
- 항체를 제조하기 위해 제43항 내지 제45항 중 어느 한 항의 숙주세포를 배양하는 단계를 포함하는, 항체 제조방법.
- 제1항의 항체 및 세포독성제를 포함하는 면역접합체.
- 제1항의 이중특이적 4가 항체 및 약학적으로 허용가능한 담체를 포함하는, 약학적 조성물.
- 제48항에 있어서, 방사성 동위원소, 방사성 핵종, 독소, 치료제, 화학요법제 또는 이들의 조합을 추가로 포함하는, 약학적 조성물.
- 제47항의 면역접합체 및 약학적으로 허용가능한 담체를 포함하는, 약학적 조성물.
- 제1항의 이중특이적 4가 항체의 유효량을 암을 가진 개체에게 투여하는 단계를 포함하는, 상기 개체의 치료방법.
- 제51항에 있어서, 암은 EGFR 패밀리의 적어도 2개의 구성원을 발현하는 세포를 포함하는 것인, 방법.
- 제51항에 있어서, 암은 유방암, 결장직장암, 췌장암, 두경부암, 흑색종, 난소암, 전립선암, 비-소세포 폐암, 신경교종, 식도암, 비인두암, 항문암, 직장암, 위암, 방광암, 자궁경부암, 또는 뇌암을 포함하는 것인, 방법.
- 제51항에 있어서, 유효량의 치료제를 공동-투여하는 단계를 추가로 포함하는 것인, 방법.
- 제54항에 있어서, 치료제는 항체, 화학요법제, 효소, 또는 이들의 조합을 포함하는 것인, 방법.
- 제54항에 있어서, 치료제는 항-에스트로겐제, 수용체 타이로신 억제제, 또는 이들의 조합을 포함하는 것인, 방법.
- 제54항에 있어서, 치료제는 카페시타빈(capecitabine), 시스플라틴(cisplatin), 트라스트주맙(trastuzumab), 풀베스트란트(fulvestrant), 타목시펜(tamoxifen), 레트로졸(letrozole), 엑세메스탄(exemestane), 아나스트로졸(anastrozole), 아미노글루테치미드(aminoglutethimide), 테스토락톤(testolactone), 보로졸(vorozole), 포르메스탄(formestane), 파드로졸(fadrozole), 레트로졸(letrozole), 엘로티닙(erlotinib), 라파티닙(lafatinib), 다사티닙(dasatinib), 제피티닙(gefitinib), 이마티닙(imatinib), 파조피닙(pazopinib), 라파티닙(lapatinib), 수니티닙(sunitinib), 닐로티닙(nilotinib), 소라페닙(sorafenib), 납-팔리탁셀(nab-palitaxel), 이들의 유도체 또는 조합을 포함하는 것인, 방법.
- 제54항에 있어서, 치료제는 체크포인트 억제제를 포함하는 것인, 방법.
- 제54항에 있어서, 치료제는 PD1, PDL1, CTLA4, 4-1BB, OX40, GITR, TIM3, LAG3, TIGIT, CD40, CD27, HVEM, BTLA, VISTA, B7H4, 이들의 유도체 또는 조합을 포함하는 것인, 방법.
- 제51항에 있어서, 개체는 인간인, 방법.
- 제1항의 항체의 유효량을 개체에 투여하여 HER 수용체의 생물학적 활성을 억제하는 단계를 포함하는, 상기 개체에서 HER 수용체의 생물학적 활성을 억제하는 방법.
- 제1항의 이중특이적 4가 항체의 유효 농도를 포함하고, 개체의 혈장인, 용액.
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