KR20240004645A - Adamts 결합 면역글로불린의 투여 방법 - Google Patents
Adamts 결합 면역글로불린의 투여 방법 Download PDFInfo
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- KR20240004645A KR20240004645A KR1020237040747A KR20237040747A KR20240004645A KR 20240004645 A KR20240004645 A KR 20240004645A KR 1020237040747 A KR1020237040747 A KR 1020237040747A KR 20237040747 A KR20237040747 A KR 20237040747A KR 20240004645 A KR20240004645 A KR 20240004645A
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Abstract
골관절염(예를 들어, 무릎 골관절염) 치료를 위한 방법 및 투여 요법이 본원에 개시된다. 상기 방법 및 투여 요법은 치료적 유효량의 ADAMTS5 억제 폴리펩타이드의 투여를 포함한다.
Description
관련 출원에 대한 상호 참조
본 출원은 2022년 4월 1일자로 출원된 미국 가출원 번호 제63/362,372호, 및 2021년 4월 30일자로 출원된 미국 가출원 번호 제63/182,561호에 대한 우선권을 주장하며, 이들 각각은 모든 목적을 위해 그 전체 내용이 본원에 참조로 포함된다.
서열 목록
본 출원에는 ASCII 형식으로 전자 제출되었고 그 전체가 본원에 참조로 포함되는 서열 목록이 포함된다. 2022년 4월 20일자로 생성된 상기 ASCII 사본의 파일명은 PAT059112-WO-PCT_SL.txt이고 크기는 약 171,234 바이트이다.
기술분야
본 개시내용은 치료적 유효량의 ADAMTS 억제 폴리펩타이드를 투여함으로써 ADAMTS 활성이 관련된 질환 또는 장애를 치료하는 방법을 제공한다.
세계에서 가장 흔한 관절 장애인, 골관절염(OA)은 중증의 만성 진행성 관절 질환으로, 치료법이 알려져 있지 않으며, 조기 사망 위험 증가와 관련이 있다. 증상이 있는 무릎 및 고관절 OA가 생애 동안 발병할 위험은 각각 45% 및 25%이며; 무릎 및 고관절 치환술의 90% 이상을 차지한다. 전 세계적으로 OA에 걸린 사람의 수는 1990년부터 2019년까지 48% 증가했으며, 장수 및 비만 유병률 증가와 함께 무릎 OA의 부담도 계속해서 증가할 것으로 예상된다.
국제 골관절염 연구 협회(OARSI)에 따르면, 이 질환은 먼저 분자 이상(비정상적인 관절 조직 대사)으로 나타나고, 이어서 해부학적 및/또는 생리학적 이상(연골 분해, 뼈 재형성, 골극 형성, 관절 염증 및 정상적인 관절 기능 손실을 특징으로 함)으로 나타난다. 임상적으로, OA는 활동 제한, 수면 방해, 피로, 우울증, 불안, 및 궁극적으로는 독립성 상실 및 삶의 질 저하로 이어질 수 있는 관절 통증, 부기 및 경직과 관련이 있다.
임상 실무 지침에 따르면, OA의 비수술적 치료는 약리학적 및 비약리학적 양식(예컨대 환자 교육, 물리치료사 소개, 운동, 체중 감소, 보행 보조기, 무릎 교정기 및 신발 등)을 포함한다. 현재 이용 가능한 모든 OA 약물 치료는 통증을 일시적으로 감소시켜 증상 완화를 제공하지만, OA의 구조적 진행을 지연시키는 것으로 나타나지는 않았다. 또한, 이러한 치료법의 장기간 사용은, 낙상-관련 골절, 아편유사제를 투여받는 환자의 약물 의존 및/또는 남용, 심혈관 위험, 및 비스테로이드성 항염증제를 투여받는 OA 환자의 상부 위장관 출혈을 포함한, 심각한 부작용과 관련이 있다.
대증 약물요법의 적절한 시도가 실패할 경우, 슬관절 전치환술(TKR)이 고려된다. 그러나, 모든 환자가 결과에 만족하거나, 관절 치환술로 혜택을 받는 것은 아니다. 다발성 관절 및 동반질환의 유병률이 높은 OA 코호트에 대한 장기 결과 연구에서, 관절 치환술을 받은 환자 중 절반만이 통증 개선 및 장애 감소로 정의되는 양호한 수술 결과를 얻었다. 수명이 증가하고 OA 유병률이 증가함에 따라(심지어 젊은 연령층에서도), 관절 치환 수술 횟수가 계속 늘어나면서 공중 보건 부담도 커지고 있다.
전반적으로, OA의 부담은 상당하며, 여기에는 약리학적 및 수술적 치료 비용 증가, 삶과 가정을 질환에 적응시켜야 하는 개인 및 그 가족의 비용 증가, 업무 생산성 저하로 인한 사회에 대한 영향 등이 포함된다. 구조적 악화를 억제하고 증상을 개선함으로써 OA 질환의 진행을 늦추거나 중단시킬 수 있는 질환-변형 골관절염 약물(DMOAD)에 대한 상당한 미충족 수요가 있다. 많은 추정 약제가 조사되었지만, DMOAD로서 임상 용도로 승인된 약제는 없다.
주로 아그레카나제의 작용에 의해 발생하는 광범위한 아그레칸 손실은 다양한 관절 질환에서 감지할 수 있으며, OA의 특징이다. 트롬보스폰딘 모티프 5(ADAMTS11, ADMP-2, 및 아그레카나제-2로도 알려져 있는 ADAMTS5)를 갖는 디스인테그린 및 메탈로프로테이나제는 연골에 존재하는 주요 응집효소이며, ADAMTS5가 골관절염의 발병에 관여하는 주요 효소임을 다양한 증거가 나타낸다. 예를 들어, ADAMTS5 KO 마우스는 연골 변성으로부터 보호된다. 인간 연골 체외식편과 연골세포에서, ADAMTS5의 녹다운은 아그레칸 분해를 약화시켰는데, 이는 이 효소가 인간 조직에도 관여할 수 있음을 시사한다. ADAMTS5 생성된 아그레칸 단편은 또한 OA 환자의 활액 및 혈청에서도 검출된다. 따라서, ADAMTS5에 의한 아그레칸 단편 생성의 억제는 연골 변성을 중지하고 통증을 감소시킬 수 있는 잠재력을 가지고 있다.
본 개시내용은 치료적 유효량의 ADAMTS5 억제 폴리펩타이드를 인간 대상체에게 투여함으로써, 골관절염(예를 들어, 무릎 골관절염)을 치료하는 방법에 관한 것이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 3개의 상보성 결정 영역(CDR)을 포함하는 적어도 하나의 면역글로불린 단일 가변 도메인(ISVD)을 포함하며, 여기서 상보성 결정 영역은 CDR1 내지 CDR3이며, (i) CDR1은 서열번호 21, 35, 20, 22, 25, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34로 이루어진 군으로부터 선택되고; (ii) CDR2는 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52로 이루어진 군으로부터 선택되고; (iii) CDR3은 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70으로 이루어진 군으로부터 선택된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 3개의 CDR을 포함하는 적어도 하나의 ISVD를 포함하며, 여기서 CDR은 CDR1 내지 CDR3이며,
CDR1은 서열번호 21이고, CDR2는 서열번호 37이고, CDR3은 서열번호 55이거나;
CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 118이거나;
CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 71이거나;
CDR1은 서열번호 20이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이거나;
CDR1은 서열번호 22이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이거나;
CDR1은 서열번호 25이고, CDR2는 서열번호 40이고, CDR3은 서열번호 58이거나;
CDR1은 서열번호 33이고, CDR2는 서열번호 50이고, CDR3은 서열번호 68이거나;
CDR1은 서열번호 33이고, CDR2는 서열번호 51이고, CDR3은 서열번호 69이거나;
CDR1은 서열번호 28이고, CDR2는 서열번호 44이고, CDR3은 서열번호 62이거나;
CDR1은 서열번호 28이고, CDR2는 서열번호 45이고, CDR3은 서열번호 63이거나;
CDR1은 서열번호 28이고, CDR2는 서열번호 43이고, CDR3은 서열번호 61이거나;
CDR1은 서열번호 24이고, CDR2는 서열번호 39이고, CDR3은 서열번호 57이거나;
CDR1은 서열번호 23이고, CDR2는 서열번호 38이고, CDR3은 서열번호 56이거나;
CDR1은 서열번호 26이고, CDR2는 서열번호 41이고, CDR3은 서열번호 59이거나;
CDR1은 서열번호 27이고, CDR2는 서열번호 119이고, CDR3은 서열번호 60이거나;
CDR1은 서열번호 27이고, CDR2는 서열번호 42이고, CDR3은 서열번호 60이거나;
CDR1은 서열번호 29이고, CDR2는 서열번호 46이고, CDR3은 서열번호 64이거나;
CDR1은 서열번호 30이고, CDR2는 서열번호 47이고, CDR3은 서열번호 65이거나;
CDR1은 서열번호 31이고, CDR2는 서열번호 48이고, CDR3은 서열번호 66이거나;
CDR1은 서열번호 32이고, CDR2는 서열번호 49이고, CDR3은 서열번호 67이거나; 또는
CDR1은 서열번호 34이고, CDR2는 서열번호 52이고, CDR3은 서열번호 70이다.
일부 실시형태에서, CDR 1은 서열번호 21이고, CDR2는 서열번호 37이고, CDR3은 서열번호 55이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 3개의 CDR을 포함하는 적어도 하나의 ISVD를 포함하며, 여기서 CDR은 CDR1 내지 CDR3이며, CDR1은 서열번호이다. 일부 실시형태에서, ISVD는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택된다. 일부 실시형태에서, ISVD는 서열번호 129의 아미노산 1 내지 124이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 2개 이상의 ISVD를 포함하고, 여기서 a) 적어도 제1 ISVD는 ADAMTS5의 제1 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합하고; b) 적어도 제2 ISVD는 혈청 알부민의 제2 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합한다. 일부 실시형태에서, 제1 ISVD는 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택된다. 일부 실시형태에서, 혈청 알부민에 특이적으로 결합하는 제2 ISVD는 서열번호 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 또는 145로 이루어진 군으로부터 선택된다. 일부 실시형태에서, 제1 ISVD는 서열번호 129의 아미노산 1 내지 124이고, 제2 ISVD는 서열번호 138이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 서열번호 129(클론 577 2F3so-Alb), 서열번호 130(클론 579 2F3so-093-Alb), 서열번호 120(클론 4 2A12-Alb), 서열번호 121(클론 5 2D7-Alb), 서열번호 122(클론 6 2F3-Alb), 서열번호 123(클론 69 049-Alb), 서열번호 124(클론 70 9D3-Alb), 서열번호 125(클론 71 3B2-Alb), 서열번호 126(클론 129 2F3-093-Alb), 서열번호 127(클론 130 049-093-Alb), 및 서열번호 128(클론 131 9D3-093-Alb)로 이루어진 군으로부터 선택된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 서열번호 129(클론 577 2F3so-Alb)이다.
일부 실시형태에서, 본 개시내용은 인간 대상체에게 적어도 1회 용량의 75 내지 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 단계를 포함하는 골관절염 치료 방법을 제공한다. 일부 실시형태에서, 골관절염은 무릎 골관절염이다. 일부 실시형태에서, 용량은 75 mg, 150 mg, 또는 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 한달에 한번 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 ARGS 단편의 형성을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 KOOS 점수 및/또는 WOMAC 점수에 의해 측정된 바와 같이 골관절염에 걸린 관절의 통증을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 MRI의 자동 분할에 의해 결정된 바와 같이 골관절염에 걸린 관절의 구조를 유지한다.
일부 실시형태에서, 본 개시내용은 골관절염 치료에서의 ADAMTS5 억제 폴리펩타이드의 용도를 제공한다. 일부 실시형태에서, 치료는 인간 대상체에게 적어도 1회 용량의 75 내지 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 골관절염은 무릎 골관절염이다. 일부 실시형태에서, 용량은 75 mg, 150 mg, 또는 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 한달에 한번 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 ARGS 단편의 형성을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 KOOS 점수 및/또는 WOMAC 점수에 의해 측정된 바와 같이 골관절염에 걸린 관절의 통증을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 MRI의 자동 분할에 의해 결정된 바와 같이 골관절염에 걸린 관절의 구조를 유지한다.
일부 실시형태에서, 본 개시내용은 골관절염 치료, 예를 들어, 인간 대상체에게 적어도 1회 용량의 75 내지 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 단계를 포함하는 치료에 사용하기 위한 ADAMTS5 억제 폴리펩타이드를 제공한다. 일부 실시형태에서, 골관절염은 무릎 골관절염이다. 일부 실시형태에서, 용량은 75 mg, 150 mg, 또는 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 한달에 한번 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 ARGS 단편의 형성을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 KOOS 점수 및/또는 WOMAC 점수에 의해 측정된 바와 같이 골관절염에 걸린 관절의 통증을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 MRI의 자동 분할에 의해 결정된 바와 같이 골관절염에 걸린 관절의 구조를 유지한다.
일부 실시형태에서, 본 개시내용은 골관절염 치료용 약제의 제조에 사용하기 위한 ADAMTS5 억제 폴리펩타이드를 제공한다. 일부 실시형태에서, 용도는 인간 대상체에게 적어도 1회 용량의 75 내지 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 골관절염은 무릎 골관절염이다. 일부 실시형태에서, 용량은 75 mg, 150 mg, 또는 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 한달에 한번 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 ARGS 단편의 형성을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 KOOS 점수 및/또는 WOMAC 점수에 의해 측정된 바와 같이 골관절염에 걸린 관절의 통증을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 MRI의 자동 분할에 의해 결정된 바와 같이 골관절염에 걸린 관절의 구조를 유지한다.
일부 실시형태에서, 본 개시내용은 골관절염 치료에 사용하기 위한 ADAMTS5 억제 폴리펩타이드를 포함하는 약제학적 조성물을 제공한다. 일부 실시형태에서, 치료는 인간 대상체에게 적어도 1회 용량의 75 내지 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 골관절염은 무릎 골관절염이다. 일부 실시형태에서, 용량은 75 mg, 150 mg, 또는 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 한달에 한번 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 ARGS 단편의 형성을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 KOOS 점수 및/또는 WOMAC 점수에 의해 측정된 바와 같이 골관절염에 걸린 관절의 통증을 감소시킨다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 투여는 MRI의 자동 분할에 의해 결정된 바와 같이 골관절염에 걸린 관절의 구조를 유지한다.
도 1은 단일 용량 증량 연구에 대한 대상체 성향을 도시한다.
도 2은 다중 상승 용량 연구에 대한 대상체 성향을 도시한다.
도 3은 단일 투여 후 화합물 1의 혈청 농도를 선형 및 반-대수 척도(산술 평균 ± SD)로 도시하며, X축은 120시간(5일)으로 척도화된다.
도 4는 단일 투여 후 화합물 1의 혈청 농도를 선형 및 반-대수 척도(산술 평균 ± SD)로 도시하며, X축은 1776시간(74일)으로 척도화된다.
도 5는 모든 용량 수준 및 요법(매주 및 격주)에 대한 화합물 1의 혈청 농도-시간 프로파일을 선형 및 반-대수 척도(1일)로 도시한다.
도 6은 모든 용량 수준 및 요법(매주 및 격주)에 대한 화합물 1의 혈청 농도-시간 프로파일을 선형 및 반-대수 척도(모든 연구일)로 도시한다.
도 7은 건강한 남성 참가자의 화합물 1의 단일 투여 후 혈청 ARGS의 기준선으로부터의 변화율(%)을 도시한다. ARGS = 아그레칸 분해 네오에피토프.
도 8은 ARGS의 감소율(%)로 측정된 건강한 남성 참가자에 있어서의 화합물 1의 최대 억제 효과를 도시한다. ARGS = 아그레칸 분해 네오에피토프. IQR = 사분위간 범위. Emin = 최대 억제 효과(Imax); 박스의 아래쪽 가장자리와 위쪽 가장자리는 각각 25번째와 75번째 백분위수를 나타내며; 박스 안의 실선은 중앙값을 나타내고; 다이아몬드는 평균값을 나타낸다. 검정색 원은 값 범위가 IQR을 벗어나지만 1.5*IQR 내에 있음을 나타낸다.
도 9는 모든 용량 수준에 대한 기준선(%) 대 시간 프로파일 대비 중앙값(Q1 내지 Q3) 백분율 변화를 선형 척도로 도시한다. ARGS = 아그레칸 분해 네오에피토프. Q1S = 매주; Q2S = 격주.
도 2은 다중 상승 용량 연구에 대한 대상체 성향을 도시한다.
도 3은 단일 투여 후 화합물 1의 혈청 농도를 선형 및 반-대수 척도(산술 평균 ± SD)로 도시하며, X축은 120시간(5일)으로 척도화된다.
도 4는 단일 투여 후 화합물 1의 혈청 농도를 선형 및 반-대수 척도(산술 평균 ± SD)로 도시하며, X축은 1776시간(74일)으로 척도화된다.
도 5는 모든 용량 수준 및 요법(매주 및 격주)에 대한 화합물 1의 혈청 농도-시간 프로파일을 선형 및 반-대수 척도(1일)로 도시한다.
도 6은 모든 용량 수준 및 요법(매주 및 격주)에 대한 화합물 1의 혈청 농도-시간 프로파일을 선형 및 반-대수 척도(모든 연구일)로 도시한다.
도 7은 건강한 남성 참가자의 화합물 1의 단일 투여 후 혈청 ARGS의 기준선으로부터의 변화율(%)을 도시한다. ARGS = 아그레칸 분해 네오에피토프.
도 8은 ARGS의 감소율(%)로 측정된 건강한 남성 참가자에 있어서의 화합물 1의 최대 억제 효과를 도시한다. ARGS = 아그레칸 분해 네오에피토프. IQR = 사분위간 범위. Emin = 최대 억제 효과(Imax); 박스의 아래쪽 가장자리와 위쪽 가장자리는 각각 25번째와 75번째 백분위수를 나타내며; 박스 안의 실선은 중앙값을 나타내고; 다이아몬드는 평균값을 나타낸다. 검정색 원은 값 범위가 IQR을 벗어나지만 1.5*IQR 내에 있음을 나타낸다.
도 9는 모든 용량 수준에 대한 기준선(%) 대 시간 프로파일 대비 중앙값(Q1 내지 Q3) 백분율 변화를 선형 척도로 도시한다. ARGS = 아그레칸 분해 네오에피토프. Q1S = 매주; Q2S = 격주.
ADAMTS 효소의 활성이 관련된 개체의 질환 또는 장애를 치료하고/하거나 예방하는 방법이 본원에 제공된다. 일부 실시형태에서, ADAMTS 효소는 ADAMTS5이다. 방법은 ADAMTS의 활성을 억제하는 폴리펩타이드를 질환 또는 장애의 증상을 치료하거나 예방하는 데 효과적인 양으로 대상체에게 투여하는 단계를 포함한다. ADAMTS 억제 폴리펩타이드로 치료될 수 있는 질환 또는 장애의 예에는 관절병증 및 연골이영양증, 관절염 질환(예컨대, 골관절염, 류마티스 관절염, 통풍성 관절염, 건선성 관절염), 외상성 파열 또는 박리, 연골무형성증, 늑연골염, 척추후두간단 이형성증, 추간판 탈출증, 요추 디스크 변성 질환, 퇴행성 관절 질환, 재발성 다발연골염, 해부골연골염 및 골연골병증이 포함된다. 일부 실시형태에서, 질환 또는 장애는 관절염 질환이다. 일부 실시형태에서, 질환 또는 장애는 골관절염이다.
ADAMTS5 억제 폴리펩타이드는 WO 2018/220234 (WO ’234)에 이전에 설명되었으며, 이의 내용은 전체가 참고로 포함된다. WO ‘234 공개에서는 ADAMTS5 관련 질환 또는 장애에 대한 잠재적인 치료법으로서 ADAMTS5 억제 폴리펩타이드의 투여를 고려하고 있지만, 투여 요법 또는 투여량에 대한 어떠한 구체적인 지침도 제공하지 않는다. 대신, WO ‘234는 광범위한 잠재적 투여용량을 제공하고, 특정 투여 요법의 선택을 임상의에게 맡긴다. 따라서, ADAMTS5 억제 폴리펩타이드의 투여를 위한 치료적으로 유효한 투여량 및 투여 요법을 확립할 필요성이 남아있다. 본 발명자들은 이제 본원에 기술된 용량 및 투여 요법으로 그 요구를 충족시켰다.
정의
용어 "대상체"는 본 개시내용의 방법에 따른 치료가 제공되는 동물, 인간 또는 비-인간을 나타낸다. 수의학적 및 비-수의학적 적용이 고려된다. 용어에는 비제한적으로 포유류, 예컨대, 인간, 다른 영장류, 돼지, 설치류, 예컨대 마우스 및 래트, 토끼, 기니아 피그, 햄스터, 소, 말, 고양이, 개, 양 및 염소가 포함된다. 전형적인 대상체에는 인간, 농장 동물, 및 가내 애완동물, 예컨대 고양이 및 개가 포함된다.
용어 "치료", "치료하는" 또는 "치료하다"는 본원에서 바람직하지 않은 생리학적 변화 또는 장애(예를 들어, ADAMTS5 관련 장애, 예컨대, 관절염 질환(예를 들어, OA))의 진행, 중증도 및/또는 지속을 감소시키거나 완화시키거나, 또는 하나 이상의 치료제의 투여로 인한 장애의 하나 이상의 증상(예를 들어, 하나 이상의 식별 가능한 증상)의 개선으로 정의된다. 일부 실시형태에서, 용어 "치료", "치료하는" 또는 "치료하다"는 예를 들어, 식별 가능한 증상의 감소 또는 안정화에 의해 물리적으로의, 예를 들어 물리적 파라미터의 감소 또는 안정화에 의해 생리학적으로의, 또는 둘 다에 의한, OA와 같은 장애의 진행 감소 또는 안정화를 나타낸다. 본 개시내용의 목적을 위해, 유익하거나 요망되는 임상 결과는 검출 가능하건 검출 가능하지 않건, 증상의 경감, 질환 정도의 감소, 질환의 안정화된(즉, 악화되지 않는) 상태, 질환 진행의 지연 또는 둔화, 질환 상태의 개선 또는 완화, 및 전환(부분적이건 전체적이건)을 포함하지만, 이에 한정되지 않는다.
대상체가 생물학적 또는 의학적으로 이점이 있거나 치료로부터 삶의 질에서 이점이 있는 경우에 이 같은 대상체는 이 같은 치료를 "필요로" 한다.
"약제학적으로 허용가능한"이라는 용어는 활성 성분(들)의 생물학적 활성의 효과를 방해하지 않는 비독성 물질을 의미한다.
대상 화합물의 "투여" 또는 "투여하는"이라는 용어는 치료가 필요한 대상체에게 약물, 약물의 변형된 유도체 또는 전구약물을 제공하는 것을 의미한다.
본원에서 사용되는 용어 "투여 요법"은 일정 기간 동안에 걸친 약물의 투여 패턴을 구체적으로 나타내는 치료 계획을 지칭한다. 투여 요법은 질환의 치료에 사용되는 약물의 양 및 이의 투여의 횟수 및 빈도를 정의한다.
용어 "용량"은 1회에 투여되는 약물의 구체화된 양을 지칭한다. 본원에 사용된 바와 같이, 용량은 치료 효과를 이끌어내는 약물의 양이다.
용어 "치료적 유효량"은 대상체에서 예를 들어 증상을 적어도 부분적으로 개선하거나, 병태를 완화하거나, 진행을 늦추거나 지연시키거나, 장애 또는 질환을 역전시키는 것과 같은 원하는 생물학적 또는 의학적 반응을 이끌어내는 약물의 양을 의미한다.
용어 "ADAMTS5 억제 폴리펩타이드"는 ADAMTS5의 활성, 예컨대 프로테아제 활성을 억제하는 폴리펩타이드를 의미한다. 예를 들어, 프로테아제 활성은 아그레칸, 베르시칸, 브레비칸, 뉴로칸, 데코린, 및/또는 비글리칸의 절단일 수 있다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 ADAMTS5의 아그레카나제 활성을 길항한다.
ARGS, ARGS 단편, 및 ARGS 네오-에피토프라는 용어는 아그레칸 분해 네오에피토프를 의미한다. 일부 실시형태에서, ARGS 단편 또는 네오-에피토프는 서열 알라닌-아르기닌-글리신-세린(서열번호 175)을 포함할 수 있다.
2개 이상의 아미노산 서열을 비교하기 위해, 제1 아미노산 서열과 제2 아미노산 서열 사이의 "서열 동일성"(본원에서는 "아미노산 동일성"으로도 지칭됨)의 백분율은 [제2 아미노산 서열의 상응하는 위치에 있는 아미노산 잔기와 동일한 제1 아미노산 서열의 아미노산 잔기의 수]를 [제1 아미노산 서열의 아미노산 잔기의 총 수]로 나누고, [100%]를 곱하여 계산될 수 있으며, 여기서 제1 아미노산 서열과 비교하여, 제2 아미노산 서열의 아미노산 잔기의 각각의 결실, 삽입, 치환 또는 부가는 단일 아미노산 잔기(위치)에서의 차이, 즉 본원에 정의된 "아미노산 차이"로 간주된다. 대안적으로, 2개의 아미노산 서열 사이의 서열 동일성 정도는 아미노산 서열에 대한 서열 동일성 정도를 결정하기 위한 임의의 공지된 컴퓨터 알고리즘을 사용하여 계산될 수 있다.
2개의 아미노산 서열을 비교할 때, 용어 "아미노산(들) 차이"는 제2 서열과 비교하여 제1 서열의 위치에서의 단일 아미노산 잔기의 삽입, 결실 또는 치환을 의미하며; 2개의 아미노산 서열은 이러한 아미노산 차이를 1개, 2개 또는 그 이상 함유할 수 있는 것으로 이해된다. 아미노산(들) 차이는 ADAMTS 억제 폴리펩타이드의 특성을 개선하거나, 또는 적어도 원하는 속성들을 너무 많이 손상시키지 않는 임의의 1개, 2개, 3개, 4개 또는 최대 5개의 치환, 결실 또는 삽입, 또는 이들의 임의의 조합일 수 있다.
서열은 명세서 본문과 WIPO 표준 St.25에 따른 별도의 서열목록에 개시되어 있다. 특정 번호로 명시된 서열목록은 명세서 본문과 별도의 서열목록에서와 동일해야 한다. 예를 들어, 서열번호 1은 명세서 본문과 별도의 서열목록 모두에서 동일한 서열을 정의해야 한다. 명세서 본문의 서열 정의와 별도의 서열목록 사이에 불일치가 있는 경우(예를 들어 명세서 본문의 서열번호 1이 별도의 서열목록의 서열번호 2에 잘못 대응하고 있는 경우), 본 출원, 특히 특정 실시형태의 특정 서열에 대한 언급은 별도의 서열목록이 아닌 본 출원의 본문에 있는 서열에 대한 언급으로 이해되어야 한다. 즉, 명세서 본문의 서열 정의/명칭과 별도의 서열목록 사이의 불일치는 별도의 서열목록을 상세한 설명, 실시예, 도면 및 청구범위를 포함하는 출원 본문에 개시된 서열 및 그의 명칭으로 수정함으로써 해결되어야 한다.
ADAMTS5 결합 폴리펩타이드
본 개시내용은 적어도 하나의 면역글로불린 단일 가변 도메인(ISVD) 결합 ADAMTS5를 포함하는 폴리펩타이드의 투여에 관한 것이며, 여기서 ISVD 결합 ADAMTS5는 ADAMTS4, MMP1, 또는 MMP14에 결합하지 않는다. 일부 실시형태에서, 폴리펩타이드는 호모 사피엔스(Homo sapiens)(서열번호 149), 무스 무스쿨루스(Mus musculus)(서열번호 153), 카비아 포르셀루스(Cavia porcellus)(서열번호 152), 보스 타우루스(Bos taurus)(서열번호 150), 마카카 물라타(Macaca mulatta)(서열번호 154) 및/또는 라투스 노르베기쿠스(Rattus norvegicus)(서열번호 151)로부터의 ADAMTS5에 특이적으로 결합한다. 일부 실시형태에서, ADTAMS5 결합 폴리펩타이드는 호모 사피엔스 ADAMTS5(서열번호 149)에 결합한다(표 1 참조). 일부 실시형태에서, 본 개시내용은 ADAMTS5 억제 폴리펩타이드의 투여에 관한 것이다.
[표 1]
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 (일반) 구조를 갖는 아미노산 서열인 적어도 하나의 ISVD를 포함한다:
FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4
여기서 FR1 내지 FR4는 각각 프레임워크 영역 1 내지 4를 지칭하고, CDR1 내지 CDR3은 각각 상보성 결정 영역 1 내지 3을 지칭한다. 이 실시형태에서, 적어도 하나의 ISVD는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 117, 8, 12, 13, 14, 15, 18의 아미노산 서열, 또는 서열번호 129의 아미노산 1 내지 124(표 2 참조) 중 적어도 하나와 적어도 80%, 적어도 90%, 또는 적어도 95% 아미노산 동일성을 가지며, 아미노산 동일성의 정도를 결정하기 위한 목적으로, CDR 서열을 형성하는 아미노산 잔기는 무시된다. 이와 관련하여, 또한 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 117, 8, 12, 13, 14, 15, 18의 면역글로불린 단일 가변 도메인의 프레임워크 1 서열(서열번호 72 내지 84), 프레임워크 2 서열(서열번호 85 내지 94), 프레임워크 3 서열(서열번호 95 내지 113) 및 프레임워크 4 서열(서열번호 114 내지 115), 및 서열번호 129의 아미노산 1 내지 124를 열거하고 있는 표 3을 참조한다.
[표 2]
[표 3]
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 4개의 프레임워크 영역(각각 FR1 내지 FR4) 및 3개의 상보성 결정 영역(각각 CDR1 내지 CDR3)을 포함하며, 여기서 (i) CDR1은 서열번호 21, 35, 20, 22, 25, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34; 및 서열번호 21, 35, 20, 22, 25, 33, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34와 1, 2 또는 3개의 아미노산 차이(들)를 갖는 아미노산 서열로 이루어진 군으로부터 선택되며; (ii) CDR2는 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52; 및 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52와 1, 2 또는 3개의 아미노산 차이(들)를 갖는 아미노산 서열로 이루어진 군으로부터 선택되며; 및 (iii) CDR3은 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70; 및 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70과 1, 2, 3 또는 4개의 아미노산 차이(들)를 갖는 아미노산 서열로 이루어진 군으로부터 선택된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 4개의 프레임워크 영역(각각 FR1 내지 FR4) 및 3개의 상보성 결정 영역(각각 CDR1 내지 CDR3)으로 실질적으로 이루어지며, 여기서 (i) CDR1은 서열번호 21, 35, 20, 22, 25, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34; 및 서열번호 21, 35, 20, 22, 25, 33, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34와 1, 2 또는 3개의 아미노산 차이(들)를 갖는 아미노산 서열로 이루어진 군으로부터 선택되며; (ii) CDR2는 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52; 및 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52와 1, 2 또는 3개의 아미노산 차이(들)를 갖는 아미노산 서열로 이루어진 군으로부터 선택되며; 및 (iii) CDR3은 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70; 및 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70과 1, 2, 3 또는 4개의 아미노산 차이(들)를 갖는 아미노산 서열로 이루어진 군으로부터 선택된다. 예시적인 프레임워크 서열은 표 3에 개시되어 있으며 본원에 기술된 바와 같이 ISVD에서 사용될 수 있다. 일부 실시형태에서, 표 3에 개시된 CDR은 동일한 ISVD 작제물의 각각의 프레임워크 영역과 일치된다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 ISVD 군으로부터 선택되는 ISVD를 포함하며, 여기서 CDR1은 서열번호 21, 35, 20, 22, 25, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34로 이루어진 군으로부터 선택되고; CDR2는 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52로 이루어진 군으로부터 선택되고; CDR3은 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70으로 이루어진 군으로부터 선택된다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 ISVD 군으로부터 선택되는 ISVD를 포함하며, 여기서
CDR1은 서열번호 21이고, CDR2는 서열번호 37이고, CDR3은 서열번호 55이고;
CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 118이고;
CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 71이고;
CDR1은 서열번호 20이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이고;
CDR1은 서열번호 22이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이고;
CDR1은 서열번호 25이고, CDR2는 서열번호 40이고, CDR3은 서열번호 58이고;
CDR1은 서열번호 33이고, CDR2는 서열번호 50이고, CDR3은 서열번호 68이고;
CDR1은 서열번호 33이고, CDR2는 서열번호 51이고, CDR3은 서열번호 69이고;
CDR1은 서열번호 28이고, CDR2는 서열번호 44이고, CDR3은 서열번호 62이고;
CDR1은 서열번호 28이고, CDR2는 서열번호 45이고, CDR3은 서열번호 63이고;
CDR1은 서열번호 28이고, CDR2는 서열번호 43이고, CDR3은 서열번호 61이고;
CDR1은 서열번호 24이고, CDR2는 서열번호 39이고, CDR3은 서열번호 57이고;
CDR1은 서열번호 23이고, CDR2는 서열번호 38이고, CDR3은 서열번호 56이고;
CDR1은 서열번호 26이고, CDR2는 서열번호 41이고, CDR3은 서열번호 59이고;
CDR1은 서열번호 27이고, CDR2는 서열번호 119이고, CDR3은 서열번호 60이고;
CDR1은 서열번호 27이고, CDR2는 서열번호 42이고, CDR3은 서열번호 60이고;
CDR1은 서열번호 29이고, CDR2는 서열번호 46이고, CDR3은 서열번호 64이고;
CDR1은 서열번호 30이고, CDR2는 서열번호 47이고, CDR3은 서열번호 65이고;
CDR1은 서열번호 31이고, CDR2는 서열번호 48이고, CDR3은 서열번호 66이고;
CDR1은 서열번호 32이고, CDR2는 서열번호 49이고, CDR3은 서열번호 67이고; 그리고
CDR1은 서열번호 34이고, CDR2는 서열번호 52이고, CDR3은 서열번호 70이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 CDR1이 서열번호 21이고, CDR2가 서열번호 37이고, CDR3이 서열번호 55인, ISVD를 포함한다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택되는 ISVD를 포함한다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 ADAMTS5에 특이적으로 결합하는 2개 이상의 ISVD를 포함하며, 여기서 (a) 적어도 제1 ISVD는 ADAMTS5의 제1 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합하며; 여기서 (b) 적어도 제2 ISVD는 제1 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태와 상이한 ADAMTS5의 제2 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합한다. 일부 실시형태에서, ADAMTS5에 특이적으로 결합하는 제1 ISVD는 서열번호 2, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택된다. 일부 실시형태에서, 결합 ADAMTS5에 특이적으로 결합하는 제2 ISVD는 서열번호 118 또는 19이다. 일부 실시형태에서, ADAMTS5에 특이적으로 결합하는 2개 이상의 ISVD를 포함하는 ADAMTS5 억제 폴리펩타이드는 서열번호 126(클론 129 2F3-093-Alb), 서열번호 127(클론 130 049-093-Alb) 및 서열번호 128(클론 131 9D3-093-Alb)로 이루어진 군으로부터 선택된다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 상기 기재된 바와 같이 ADAMTS5에 특이적으로 결합하는 적어도 하나의 ISVD, 및 혈청 알부민, 예컨대 인간 혈청 알부민에 결합하는 적어도 하나의 ISVD를 포함한다. 일부 실시형태에서, ISVD 결합 혈청 알부민은 4개의 프레임워크 영역(각각 FR1 내지 FR4) 및 3개의 상보성 결정 영역(각각 CDR1 내지 CDR3)을 포함하거나, 이들로 본질적으로 이루어지며, 여기서 CDR1은 SFGMS(서열번호 146)이고, CDR2는 SISGSGSDTLYADSVKG(서열번호 147)이고, CDR3은 GGSLSR(서열번호 148)이다. 일부 실시형태에서, 인간 혈청 알부민에 결합하는 ISVD는 Alb8(서열번호 131), Alb23(서열번호 132), Alb129(서열번호 133), Alb132(서열번호 134), Alb11(서열번호 135), Alb11(S112K)-A(서열번호 136), Alb82(서열번호 137), Alb82-A(서열번호 138), Alb82-AA(서열번호 139), Alb82-AAA(서열번호 140), Alb82-G(서열번호 141), Alb82-GG(서열번호 142), Alb82-GGG(서열번호 143), Alb92(서열번호 144), 또는 Alb223(서열번호 145)으로 이루어진 군으로부터 선택된다. (표 4 참조)
[표 4]
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 적어도 하나의 ISVD 결합 ADAMTS5 및 ISVD 결합 혈청 알부민을 포함한다. 예를 들어, 일부 실시형태에서, ISVD 결합 ADAMTS5 및 ISVD 결합 혈청 알부민은 서열번호 129(클론 577 2F3*-Alb), 서열번호 130(클론 579 2F3*-093-Alb), 서열번호 120(클론 4 2A12-Alb), 서열번호 121(클론 5 2D7-Alb), 서열번호 122(클론 6 2F3-Alb), 서열번호 123(클론 69 049-Alb), 서열번호 124(클론 70 9D3-Alb), 서열번호 125(클론 71 3B2-Alb), 서열번호 126(클론 129 2F3-093-Alb), 서열번호 127(클론 130 049-093-Alb), 및 서열번호 128(클론 131 9D3-093-Alb)으로 이루어진 군으로부터 선택된다(표 2 참조).
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 서로 직접 연결되거나, 링커를 통해 연결된 적어도 2개의 ISVD를 포함한다. 적어도 2개의 ISVD가 링커를 통해 연결된 실시형태에서, 링커는 서열번호 158 내지 174(즉, 서열번호 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 및 174)로 이루어진 군으로부터 선택적으로 선택될 수 있다. 일부 실시형태에서, 링커는 서열번호 169의 서열을 포함한다. (표 5 참조).
[표 5]
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 서열번호 1 내지 19(즉, 서열번호 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 및 19), 116 내지 117, 또는 120 내지 130(즉, 서열번호 120, 121, 122, 123, 124, 125, 126, 127, 128, 129 및 130) 중 임의의 것과의 적어도 80%, 적어도 90%, 적어도 95% 또는 100% 서열 동일성을 갖는다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 적어도 2개의 ISVD를 포함하며, 여기서 적어도 2개의 ISVD는 동일하거나 상이할 수 있지만, 그 중 적어도 하나의 ISVD는 ADAMTS5에 대한 것이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 적어도 2개의 ISVD로 본질적으로 이루어지며, 여기서 적어도 2개의 ISVD는 동일하거나 상이할 수 있지만, 그 중 적어도 하나의 ISVD는 ADAMTS5에 대한 것이다. 일부 실시형태에서, ISVD 결합 ADAMTS5는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 117, 8, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택된다. 예시적인 2가, 이중특이성 ADAMTS5 억제 폴리펩타이드는 표 2(서열번호 120 내지 130, 즉, 서열번호 120, 121, 122, 123, 124, 125, 126, 127, 128, 129 및 130)에 제시되어 있다. 일부 실시형태에서, 2가, 이중특이성 ADAMTS5 폴리펩타이드는 서열번호 129 및 130을 포함한다.
치료 방법
본 개시내용은 ADAMTS5 활성으로부터 적어도 부분적으로 발병하는 질환 또는 장애의 치료 방법을 제공한다. 방법은 유효량(예를 들어, 치료적 유효량)의 ADAMTS5 억제 폴리펩타이드를 이를 필요로 하는 대상체에게 투여하는 것을 포함한다. 일부 실시형태에서, 대상체는 인간 대상체이다. ADAMTS5 억제 폴리펩타이드로 치료될 수 있는 질환 또는 장애의 예에는 관절병증 및 연골이영양증, 관절염 질환(예컨대, 골관절염, 류마티스 관절염, 통풍성 관절염, 건선성 관절염), 외상성 파열 또는 박리, 연골무형성증, 늑연골염, 척추후두간단 이형성증, 추간판 탈출증, 요추 디스크 변성 질환, 퇴행성 관절 질환, 재발성 다발연골염, 해부골연골염 및 골연골병증이 포함되지만, 이에 제한되지는 않는다. 일부 실시형태에서, 질환 또는 장애는 관절염 질환이다. 일부 실시형태에서, 질환 또는 장애는 골관절염이다. 일부 실시형태에서, 골관절염은 무릎, 손, 고관절, 또는 척추 골관절염이다.
질환 또는 장애가 골관절염인 실시형태에서, 본원에 기재된 투여 요법 중 하나에 따른 ADAMTS5 억제 화합물을 사용한 치료는 위약을 사용한 치료와 비교하여 골관절염의 진행을 늦추거나 정지시키고 골관절염과 연관된 증상을 감소시키거나 제거할 것으로 예상된다. 비제한적 일례에서, 치료는 무릎 부상 및 골관절염 결과 점수(KOOS) 또는 서부 온타리오 및 맥마스터 대학 골관절염 지수(WOMAC) 점수로 측정된 통증을 감소시킬 수 있다. 일부 실시형태에서, 치료는 골관절염과 연관된 경직을 감소시킬 수 있다. 일부 실시형태에서, 치료는 MRI의 자동화된 분할에 의해 결정된 바와 같이 연골 부피에 기초한 관절 구조의 실질적인 유지를 초래할 수 있다. 일부 실시형태에서, 본원에 기재된 투여 요법 중 하나에 따른 치료는 영향을 받은 관절의 기능을 개선하거나 유지(예를 들어, 추가 감소를 방지)할 수 있다. 일부 실시형태에서, 본원에 기재된 투여 요법 중 하나에 따른 치료는 골관절염에 걸린 관절의 생존을 연장하고/하거나 대상체의 삶의 질을 향상시킬 수 있다. 일부 실시형태에서, 본원에 기재된 투여 요법에 따른 치료는 관절 치환술 수술의 필요성을 예방하거나 지연시킬 수 있다. 이하에 기재된 투여 요법에 따른 치료는 인간 대상체가 더 이상 치료적 혜택을 받지 못할 때까지 계속될 수 있다.
일부 실시형태에서, 본원에 기재된 투여 요법에 따른 치료는 ARGS 단편의 형성을 감소시킬 것이다. ARGS 단편은 아그레칸의 ADAMTS5-유도 절단을 통해 생성된 아그레칸 분해 네오-에피토프이다. ARGS 단편의 예시적인 서열은 서열번호 175로 제공된다. 아그레칸 단편은 연골 기질에 유지되고, 이어서 기질 메탈로프로테아제(MMP)에 의해 절단되어 32-아미노산 단편을 방출한다. 이 32-아미노산 단편은 골관절염 환자의 윤활액에서 확인되었으며, Toll-유사 수용체-2(TLR-2)를 활성화하는 것으로 나타났다. TLR-2의 활성화는 골관절염의 영향을 받는 관절의 염증과 통증을 악화시키는 것으로 나타났다. 결과적으로, ARGS 단편의 억제는 골관절염의 영향을 받는 관절, 예를 들어 무릎 관절의 염증 및 통증을 감소시킬 것으로 예상된다.
ADAMTS5 억제 폴리펩타이드는 임의의 공지된 투여 방법에 따라 투여될 수 있다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 피하로 투여된다. 다른 가능한 투여 경로는 예를 들어, 피내, 근육내, 정맥내 및 관절내를 포함한다. ADAMTS5 억제 폴리펩타이드는 또한 환자에게 치료제를 투여하기 위한 임의의 공지된 수단(사전충전된 시린지, 바이알 및 시린지, 주사 펜, 자동주사기, i.v. 드립 및 백, 펌프, 패치 펌프 등을 포함하지만 이에 한정되지 않음)에 따라 투여될 수 있다. 이러한 물품을 이용해, 환자가 약물을 자가 투여(즉, 스스로 약물을 투여)할 수 있거나, 의사가 약물을 투여할 수 있다.
투여량 및 투여 요법
본 개시내용의 방법은 일부 실시형태에서, 투여 요법에 따른 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함할 수 있다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드에 대한 투여 요법은 ADAMTS5 억제 폴리펩타이드를 대상체에게 1회 이상 투여함으로써 개시될 수 있다. 일부 실시형태에서, 초기 용량의 투여 후, 대상체에게는 ADAMTS5 억제 폴리펩타이드의 1회 이상의 추가 치료적 유효량이 투여될 수 있다. 후속 치료적 유효량은 예를 들어, 매주 투여 일정에 따라, 또는 2주에 1회(격주), 3주에 1회, 4주에 1회, 6주에 1회, 2개월에 1회(격월), 10주에 1회, 3개월에 1회, 14주에 1회, 4개월에 1회, 18주에 1회, 5개월에 1회, 22주에 1회, 6개월에 1회, 7개월에 1회, 8개월에 1회, 9개월에 1회, 10개월에 1회, 11개월에 1회, 또는 12개월에 1회 투여될 수 있다. 일부 실시형태에서, 후속 용량은 매월 투여된다. ADAMTS5 억제 폴리펩타이드의 치료적 유효량은 각 용량에서 동일할 수 있거나 용량마다 다를 수 있다.
일부 실시형태에서, 투여 요법은 매주 1회 인간 대상체에게 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 격주로(즉, 2주마다 1회) 인간 대상체에게 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 매달 1회 인간 대상체에게 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 격월로(즉, 2개월에 1회) 인간 대상체에게 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함할 수 있다. 일부 실시형태에서, 투여 요법은 3개월마다 1회 인간 대상체에게 300 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함할 수 있다.
일부 실시형태에서, 투여 요법은 매주(즉, 약 7일마다 1회) 인간 대상체에게 150 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 격주로(2주마다 1회) 인간 대상체에게 150 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 매달 1회 인간 대상체에게 150 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 격월로(2개월에 1회) 인간 대상체에게 150 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함할 수 있다. 일부 실시형태에서, 투여 요법은 3개월마다 1회 인간 대상체에게 150 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함할 수 있다.
일부 실시형태에서, 투여 요법은 매주 인간 대상체에게 75 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 격주로(즉, 2주마다 1회) 인간 대상체에게 75 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 매달 1회 인간 대상체에게 75 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법은 격월로(즉, 2개월에 1회) 인간 대상체에게 75 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함할 수 있다. 일부 실시형태에서, 투여 요법은 3개월마다 1회 인간 대상체에게 75 mg의 ADAMTS5 억제 폴리펩타이드를 투여하는 것을 포함할 수 있다.
대안적으로, 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드 투여 요법은 "로딩 요법" 및 "유지 요법"을 포함한다. "로딩 요법"은 대상체에게 1회 또는 여러 번 투여되는 ADAMTS5 억제 폴리펩타이드의 초기 치료적 유효 용량을 포함하는 1회 이상의 로딩 용량을 포함할 수 있다. "로딩 요법"이 1회 이상의 용량을 포함하는 실시형태에서, 용량은 일반적으로 1주에 1회, 2주에 1회(격주), 3주에 1회, 또는 매월 1회 투여된다. 일부 실시형태에서, "로딩 요법" 동안 투여되는 용량 또는 용량들은 "유지 요법"에서 투여되는 용량 또는 용량들보다 높다. 일부 실시형태에서, "로딩 요법"에서 투여되는 용량 또는 용량들은 "유지 요법" 동안 투여되는 것과 동일하며, 차이점은 "로딩 요법" 용량이 더 자주 투여된다는 점이다.
"로딩 요법"이 완료된 후, 후속 용량 또는 용량들은 "유지 요법"에 따라 투여되며, 여기서 치료적 유효 용량은 2주에 1회(격주), 월 1회, 6주 1회, 2개월 1회(격월), 10주 1회, 3개월 1회, 14주 1회, 4개월 1회, 18주 1회, 5개월 1회, 22주 1회, 6개월 1회, 7개월 1회, 8개월 1회, 9개월 1회, 10개월 1회, 11개월 1회, 또는 12개월 1회 투여된다. "유지 요법"을 포함하는 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 치료적 유효 용량은 "로딩 요법" 동안 투여되는 치료적 유효 용량보다 낮다. 일부 실시형태에서, "유지 요법"에서 투여되는 용량 또는 용량들은 "로딩 요법" 동안 투여되는 것과 동일하며, 차이점은 "유지 요법" 용량이 덜 빈번하게 투여된다는 점이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 2주, 4주, 6주, 8주, 10주 또는 12주 동안 주 1회 300 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 300 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 2주, 4주, 6주, 8주, 10주 또는 12주 동안 주 1회 300 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 150 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 4주, 6주, 8주, 10주 또는 12주 동안 2주마다 1회(격주) 300 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 300 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 4주, 6주, 8주, 10주 또는 12주 동안 2주마다 1회(격주) 300 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 150 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 1개월, 2개월, 3개월, 4개월, 5개월 또는 6개월 동안 매월 1회 300 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 150 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 1개월, 2개월, 3개월, 4개월, 5개월 또는 6개월 동안 매월 1회 300 mg의 용량으로 투여되고, 이어서 유지 요법 동안 2개월마다 1회(격월로) 300 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 1개월, 2개월, 3개월, 4개월, 5개월 또는 6개월 동안 매월 1회 300 mg의 용량으로 투여되고, 이어서 유지 요법 동안 2개월마다 1회(격월로) 150 mg으로 투여된다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 2주, 4주, 6주, 8주, 10주 또는 12주 동안 주 1회 150 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 150 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 2주, 4주, 6주, 8주, 10주 또는 12주 동안 주 1회 150 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 75 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 4주, 6주, 8주, 10주 또는 12주 동안 2주마다 1회(격주) 150 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 150 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 4주, 6주, 8주, 10주 또는 12주 동안 2주마다 1회(격주) 150 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 75 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 1개월, 2개월, 3개월, 4개월, 5개월 또는 6개월 동안 매월 1회 150 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 75 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 1개월, 2개월, 3개월, 4개월, 5개월 또는 6개월 동안 매월 1회 150 mg의 용량으로 투여되고, 이어서 유지 요법 동안 2개월마다 1회(격월로) 150 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 1개월, 2개월, 3개월, 4개월, 5개월 또는 6개월 동안 매월 1회 150 mg의 용량으로 투여되고, 이어서 유지 요법 동안 2개월마다 1회(격월로) 75 mg으로 투여된다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 2주, 4주, 6주, 8주, 10주 또는 12주 동안 주 1회 75 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 75 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 4주, 6주, 8주, 10주 또는 12주 동안 2주마다 1회(격주) 75 mg의 용량으로 투여되고, 이어서 유지 요법 동안 1개월에 1회 75 mg으로 투여된다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 로딩 요법 동안 1개월, 2개월, 3개월, 4개월, 5개월 또는 6개월 동안 매월 1회 75 mg의 용량으로 투여되고, 이어서 유지 요법 동안 2개월마다 1회(격월로) 75 mg으로 투여된다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드에 대한 투여 요법은 하나 이상의 투여 주기를 포함한다. 본원에 사용된 용어 "투여 주기"는 일정 기간(즉, 투여 기간) 동안의 약물 투여, 및 그 이후 약물 투여를 재개하기 전의 휴지기를 의미한다. 투여 주기는 해당 주기에서 약물을 처음 투여하는 시점부터 시작된다. 본원에 사용된 용어 "휴지기"는 대상체에게 약물을 투여하지 않는 기간(즉, 약물 치료를 보류하는 기간)을 의미한다. 예를 들어, 약물을 매일, 매주 또는 매월 단위로 투여하는 경우, 일정 기간, 예를 들어 며칠, 몇 주 또는 몇 달 동안 투여를 중단하면 휴지기가 있다. 투여 주기의 투여 기간 및/또는 휴지기는 주기 간에 동일하거나 상이할 수 있다. 예를 들어, 투여 기간이 주 1회인 경우 휴지기는 1주 이상이 될 수 있다. 투여되는 약물의 용량은 주기 간에 동일하거나 상이할 수 있는 것으로 고려된다.
일부 실시형태에서, 투여 주기는 1개월 이상, 예를 들어 1개월, 2개월, 3개월, 4개월, 5개월, 6개월, 7개월, 8개월, 9개월, 10개월, 11개월, 12개월 등을 포함한다. 12개월 투여 주기는 또한 연간 투여 주기라고도 할 수 있다. 일부 실시형태에서, 투여 주기는 6개월 투여 주기이다.
각각의 투여 주기는 투여 기간 동안 1회 이상의 투여를 포함할 수 있다. 일부 실시형태에서, 투여 주기는 투여 기간 동안 1회 용량의 투여를 포함한다. 일부 실시형태에서, 투여 주기는 투여 기간 동안 2회, 3회, 4회, 5회, 6회, 7회, 8회, 9회, 10회, 11회, 12회 등의 용량을 투여하는 것을 포함한다. 일부 실시형태에서, 투여 요법의 각 투여 주기는 동일한 수의 용량을 포함한다. 예를 들어, 3개의 투여 주기를 포함하는 투여 요법에서, 각각의 투여 주기는 ADAMTS5 억제 폴리펩타이드의 4회 용량의 투여를 포함할 수 있다. 또한, 일부 실시형태에서 투여되는 용량의 수는 동일한 투여 요법 내에서 투여 주기마다 달라질 수 있는 것으로 고려된다. 예를 들어, 3개의 투여 주기를 포함하는 투여 요법에서, 투여 주기 1은 3회 용량의 ADAMTS5 억제 폴리펩타이드의 투여를 포함할 수 있고, 투여 주기 2 및 3은 1회 용량의 ADAMTS5 억제 폴리펩타이드의 투여를 포함할 수 있다.
투여 기간 동안 2회 이상의 용량 투여를 포함하는 실시형태에서, 용량은 연속적인 기간(수주 또는 수개월) 동안 투여될 수 있다. 투여 기간 동안 2회 이상의 용량 투여를 포함하는 실시형태에서, 용량은 교대 기간, 예를 들어 격주 또는 격월로 투여될 수 있다. 교대 용량을 포함하는 실시형태에서, 휴지기는 투여 기간의 최종 용량이 투여될 때까지 시작되지 않을 것이다. 예를 들어, 격주로 투여되는 2회 용량을 포함하는 4주 투여 주기에서, 용량은 1주차와 3주차에 투여되고 휴지기는 4주차가 된다.
일부 실시형태에서, 휴지기는 투여 기간과 동일한 기간이다. 예를 들어, 투여 기간이 1개월이면, 휴지기는 1개월이다. 일부 실시형태에서, 휴지기는 투여 기간과 상이한 기간이다. 예를 들어, 투여 기간이 1개월이면 휴지기는 1주 또는 2개월일 수 있다. 투여 기간의 길이 및/또는 휴지기의 길이는 동일한 투여 요법 내에서 투여 주기마다 달라질 수 있는 것으로 고려된다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 1회 이상의 6개월 투여 주기를 포함하는 투여 요법으로 투여된다. 이 실시형태에서, 300 mg의 ADAMTS5 억제 폴리펩타이드는 연속 3개월 동안 매월 1회 투여되고 이어서 3개월의 휴지기가 이어진다. 일부 실시형태에서, 6개월 투여 주기는 300 mg 용량의 ADAMTS5 억제 폴리펩타이드를 5개월 연속으로 매월 1회 투여하고 이어서 1개월 휴지기가 이어지는 것을 포함한다. 대안적인 실시형태에서, 300 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주, 6주, 8주, 10주 또는 12주 동안 매주 1회 투여되며, 6개월 주기의 나머지 시간은 휴지기이다. 일부 실시형태에서, 300 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주 동안 주 1회의 빈도로 투여되며, 이어서 4개월 동안 1개월에 1회 투여된 후 1개월 휴지기가 있다. 일부 실시형태에서, 300 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주 동안 주 1회의 빈도로 투여된 다음, 4개의 150 mg 용량이 4개월 동안 1개월에 1회 투여된 후 1개월 휴지기가 있다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 1회 이상의 6개월 투여 주기를 포함하는 투여 요법으로 투여된다. 이 실시형태에서, 150 mg의 ADAMTS5 억제 폴리펩타이드는 연속 3개월 동안 매월 1회 투여되고 이어서 3개월의 휴지기가 이어진다. 일부 실시형태에서, 6개월 투여 주기는 150 mg 용량의 ADAMTS5 억제 폴리펩타이드를 5개월 연속으로 매월 1회 투여하고 이어서 1개월 휴지기가 이어지는 것을 포함한다. 일부 실시형태에서, 150 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주, 6주, 8주, 10주 또는 12주 동안 매주 1회 투여되며, 6개월 주기의 나머지 시간은 휴지기이다. 일부 실시형태에서, 150 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주 동안 주 1회의 빈도로 투여되며, 이어서 4개월 동안 1개월에 1회 투여된 후 1개월 휴지기가 있다. 일부 실시형태에서, 150 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주 동안 주 1회의 빈도로 투여된 다음, 4개의 75 mg 용량이 4개월 동안 1개월에 1회 투여된 후 1개월 휴지기가 있다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드는 1회 이상의 6개월 투여 주기를 포함하는 투여 요법으로 투여된다. 이 실시형태에서, 75 mg의 ADAMTS5 억제 폴리펩타이드는 연속 3개월 동안 매월 1회 투여되고 이어서 3개월의 휴지기가 이어진다. 일부 실시형태에서, 6개월 투여 주기는 75 mg 용량의 ADAMTS5 억제 폴리펩타이드를 5개월 연속으로 매월 1회 투여하고 이어서 1개월 휴지기가 이어지는 것을 포함한다. 일부 실시형태에서, 75 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주, 6주, 8주, 10주 또는 12주 동안 매주 1회 투여되며, 6개월 주기의 나머지 시간은 휴지기이다. 일부 실시형태에서, 75 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주 동안 주 1회의 빈도로 투여되며, 이어서 4개월 동안 1개월에 1회 투여된 후 1개월 휴지기가 있다. 일부 실시형태에서, 75 mg 용량의 ADAMTS5 억제 폴리펩타이드는 4주 동안 주 1회의 빈도로 투여된 다음, 4개의 50 mg 용량이 4개월 동안 1개월에 1회 투여된 후 1개월 휴지기가 있다.
투여 요법에서 투여 시기는 일반적으로 ADAMTS5 억제 폴리펩타이드의 첫 번째 투여일부터 측정된다. 그러나, 의료인마다 상이한 명명 규칙을 사용한다. 특히, 0주차는 일부 의료인에 의해 1주차로 지칭될 수 있는 한편, 0일차는 일부 의료인에 의해 1일차로 지칭될 수 있다. 따라서, 동일한 투여 일정을 지칭하면서, 예를 들어 의사마다 용량을 3주차 중/21일차, 3주차 중/22일차, 4주차 중/21일차, 4주차 중/22일차에 제공하는 것으로 표시하는 것이 가능하다. 일관성을 위해, 본원에서는 투여의 첫째 주를 1주차로 지칭하고, 투여의 첫째 날을 1일차로 지칭할 것이다. 그러나, 이 명명 관례는 단순히 일관성을 위해 사용되고, 제한으로 해석되지 않아야 함이 당업자에게 이해될 것이며, 즉 의사가 특정 주를 "제1주"로 나타내는지 "제2주"로 나타내는지와 무관하게 매주 투여는 ADAMTS5 억제 폴리펩타이드의 매주 용량의 제공이다. 용량은 정확한 시점에 제공될 필요가 없으며, 예를 들어, 대략 29일차에 예정된 용량은 그것이 적절한 주에 제공되는 한, 예를 들어, 24일차 내지 34일차에, 예를 들어, 30일차에 제공될 수 있음이 추가로 이해될 것이다. 또한, 이전 투여 후 4 내지 5주 후에 "1개월 용량"이 제공될 수 있다.
일부 실시형태에서, 방법은 유효량의 ADAMTS5 억제 폴리펩타이드를 1회 이상의 용량으로 투여하는 것을 추가로 포함할 수 있다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 50 내지 1000 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 75 내지 800 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 150 내지 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 300 내지 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 450 내지 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 450 내지 800 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 75 내지 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 75 내지 150 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 150 내지 300 mg이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 75 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 150 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 450 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 750 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 800 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 1000 mg이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 150 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 약 75 mg이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 50 내지 1000 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 75 내지 800 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 150 내지 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 300 내지 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 450 내지 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 450 내지 800 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 75 내지 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 75 내지 150 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 150 내지 300 mg이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 75 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 150 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 450 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 600 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 750 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 800 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 1000 mg이다.
일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 300 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 150 mg이다. 일부 실시형태에서, ADAMTS5 억제 폴리펩타이드의 용량은 75 mg이다.
실시예
다음 실시예는 본 개시내용의 다양한 실시형태를 예시하고자 한 것으로, 이를 제한하는 것으로 해석되지 않는다. 사용된 약어는 당업계에서 통상적인 것들이다.
실시예 1: 건강한 남성 대상체에게 피하 주사된 화합물 1(항-ADAMTS-5 나노바디)의 단일 증량 용량의 안전성, 내약성, 면역원성, 약동학 및 약력학을 평가하기 위한 단일-중심, I상, 무작위, 이중 맹검, 위약 대조, 최초 인간 시험
연구 설계: 이는 건강한 남성 대상체에서 피하 화합물 1(Comp 1)인, ADAMTS5 억제 폴리펩타이드의 단일 증량 용량의 안전성, 내약성, 면역원성, 약동학 및 약력학을 평가하기 위한 I상, 단일-중심, 무작위, 이중 맹검, 위약 대조, 인간 최초 시험이었다. 자격에 대한 주요 기준은 자원봉사자가 18~55세(포함)의 건강한 비흡연 남성이며 체질량지수(BMI)가 18.5 내지 29.9 kg/m2라는 것이었다.
대상체는 각각 9명의 대상체의 6개 용량 수준 코호트(1 mg, 5 mg, 20 mg, 75 mg, 150 mg, 300 mg)로 무작위 배정되었다. (도 1). 각 DL 코호트에서, 9명의 건강한 남성 참가자는 6:3 비율로 화합물 1 또는 위약을 단일 용량으로 투여받았다. 이 연구에는 연구 개입 후 1주간의 사내 기간이 포함되었다. 퇴원 후, 모든 대상체는 11일부터 61일까지 7번의 외래 방문과 75일에 후속 방문을 위해 다시 방문했다.
1차 연구 목적은 75일에 걸쳐 위약과 비교하여 화합물 1의 단일 증량 용량의 안전성 및 내약성을 평가하는 것이었다. 안전성 종점은 치료-관련 부작용(TEAE)과 심각한 부작용(SAE)의 성격, 빈도 및 중증도, 주사 부위의 국소 내약성, 및 ECG 매개변수였다. 2차 목적에는 화합물 1의 약동학 평가, 화합물 1과 ARGS 사이의 PK/PD 관계의 특성화 및 모델링, 혈청 ARGS의 기준선으로부터의 비례 변화 조사, 화합물 1의 면역원성 평가, 및 안전성 평가로서, 화합물 1 노출 대 보정된 QT 간격의 기울기의 특성화가 포함되었다.
PK 결과: 화합물 1은 투여 후 가장 빠른 시점(6시간)에 검출 가능한 전신 수준으로 빠르게 흡수되었다. 그런 다음, 평균 혈청 농도는 대략 24시간에서 120시간 사이에 상대적으로 변하지 않은 수준으로 안정되었다. 이후 농도는 용량 수준에 따라 다단계 방식으로 기울기가 다르게 감소하는 것으로 나타났다(도 3 및 도 4). 기하 평균 AUCinf 및 Cmax는 용량이 1 mg에서 300 mg으로 증가함에 따라 비례보다 더 크게 증가했다. 이와 유사하게, 관찰된 말단 Tt1/2는 용량 의존적이었고 용량이 증가함에 따라 비례적으로 증가했다.
혈청 PK 매개변수 및 관련 변동성은 아래에 제시되어 있다:
[표 6]
면역원성은 항-약물 항체(ADA)를 측정하여 평가했다. 화합물 1 치료군에서 4명의 대상체(11%)와 위약군에서 2명의 대상체(11%)가 확인된, 양성 ADA 반응을 보였다. 화합물 1을 투여받은 4명의 참가자 중 3명에서는 ADA 양성이 일시적이었고, 1명의 참가자에서는 투여 전 샘플을 포함한 모든 샘플이 양성이었다. ADA의 존재는 화합물 1에 대한 노출에 영향을 미치지 않는 것으로 나타났다.
PD 결과: 아그레칸은 연골의 세포외 기질에서 발견되는 주요 구조적 프로테오글리칸이며, ADAMTS-5의 단백질분해 활성에 의해 고갈되고 단축된다. ARGS는 ADAMTS-5에 의한 아그레칸 분해 동안 형성된 네오-에피토프이며, 혈청 내 이의 농도는 비임상 및 임상 조사에서 표적 관여 바이오마커로 사용되었다. ARGS 분석은 부분적으로 검증된 반정량적 샌드위치 ELISA를 사용하여 인간 혈청 샘플에서 수행되었다. 이 분석에서는 아그레칸의 G2 도메인을 표적으로 하는 비오틴화된 mAb가 스트렙타비딘 플레이트에 코팅된다. 혈청에 존재하는 ARGS-G2는 항체와 결합하고, 홀스-래디시 퍼옥시다아제에 연결된 ARGS 네오-에피토프에 특이적인 단일클론 항체로 검출된다. ARGS 농도는 화학발광 반응에 의해 밝혀졌다. 분석 감도는 55 pmol/L였다.
ARGS 반응은 전신 수준에서의 표적 참여를 시사하며, 혈청의 ARGS 반응에 대한 비임상 데이터를 기반으로 한 예측과 잘 일치했다. 기준선으로부터의 백분율 변화(CFB) 및 기준선 프로파일로부터의 백분율 변화는 24시간부터 ARGS 수준의 감소를 나타냈으며, 75 mg에서 300 mg까지의 용량과 20 mg 이하의 용량에서는 투여 후 대략 96시간까지 뚜렷한 차이를 보였다. (도 7). 평균 혈청 농도 백분율은 모든 시점에서 위약군보다 75 mg, 150 mg, 및 300 mg 용량군에서 더 낮았다. 그러나, 3개의 가장 높은 용량군 간의 용량 반응의 차별화는 분석 특성에 의해 제한되었다. 또한, CFB 변화 및 백분율 변화로 예시되는 ARGS 수준의 억제는 샘플링 기간이 끝날 때까지 75 mg, 150 mg 및 300 mg 용량 그룹에서 기준선 미만으로 유지되었다. 기준선(Emin=Imax, %)과 비교하여 각 참가자의 ARGS 최대 감소에 대한 설명 요약이 도 8에 도시되어 있다. 가장 강한 평균 최대 억제는 150 mg 용량에서 관찰되었다(74%).
안전성 결과: 건강한 남성 참가자를 대상으로 위약 또는 화합물 1을 최대 300 mg까지 단일 용량 피하(sc) 투여한 후 화합물 1 주사의 안전성 및 내약성을 평가하였다. 전체적으로, 36명의 참가자가 화합물 1에 노출되었으며, 각 용량군에서 6명이 노출되었고, 18명은 위약을 투여받았다(통합 분석).
피하 주사를 통해 투여된 최대 300 mg의 단일 용량의 화합물 1은 안전했고 연구 집단의 건강한 남성 대상체에 의해 잘 용인되었다. 연구 기간 동안 사망, SAE, 또는 치료 중단으로 이어진 치료-관련 부작용(TEAE)은 보고되지 않았다. 전체적으로, 40명(74.1%)의 참가자가 적어도 1회의 TEAE를 보고했으며; 위약군에는 12명(66.7%)의 참가자, 화합물 1군에는 28명(77.8%)의 참가자가 있었다.
가장 흔한 TEAE는 비인두염, 두통, 접촉성 피부염, 주사 부위 반응 및 근육통이었다. 대부분의 TEAE는 중증도가 경미했다. 150 mg의 화합물 1을 투여받은 한 참가자는 중증의 요통 TEAE(기존 요통의 악화)를 보고했는데, 이는 화합물 1과 관련이 없는 것으로 평가되었다. 참가자는 본 연구 기간 이전에도 요통 에피소드를 경험했다. 화합물 1을 투여받은 36명의 참가자 중 6명은 화합물 1과 관련된 것으로 간주되는 TEAE를 보고했다. 이는 주사 부위 반응이었으며, 이는 화합물 1을 투여받은 4명의 참가자(화합물 1을 투여받은 모든 참가자 중 11.1%: 75 mg 용량 코호트에서 2명의 참가자 및 150 mg 및 300 mg 용량 코호트에서 각각 1명), 복통, 주사 부위 소양증, 현기증 및 두통이 단일 발생했다. 전체적으로, 화합물 1 DL 코호트 사이, 그리고 위약과 화합물 1 치료 사이에서 TEAE 발생률에는 최소한의 차이가 있었다. 실험실 측정, 활력 징후, 12-리드 ECG 또는 국소 내약성을 기반으로 한 안전성 문제는 보고되지 않았다.
실시예 2: 증상있는 무릎 골관절염 참가자에게 피하 주사된 화합물 1(항-ADAMTS-5 나노바디)의 안전성, 내약성, 면역원성, 약동학 및 약력학을 평가하기 위한 Ib상, 단일-중심, 이중 맹검, 무작위, 위약 대조, 병행군, 다중 증량 용량 연구
연구 설계: 이는 증상있는 무릎 골관절염 환자에서 피하 화합물 1의 안전성, 내약성, 면역원성, PK 및 PD를 평가하기 위해 고안된 Ib상, 단일-중심, 무작위, 이중 맹검, 위약 대조, 병행군, 다중 증량 용량 연구였다. 이 연구는 KL 방사선 등급이 2 내지 4이고 Western Ontario McMaster Universities Osteoarthritis Index(WOMAC) 통증 하위 점수가 표적 무릎에서 100점 만점에 40점이 넘는 40 내지 75세(포함)의 남성 또는 여성 참가자에게 공개되었다. 무릎 X-선은 6개월 이내에 촬영되어야 하며, 방사선학적(KL) 점수를 확인하기 위해 무작위화 전에 방사선 전문의의 평가를 받아야 했다.
환자를 75 mg, 150 mg, 및 300 mg의 3가지 용량 수준 코호트 중 하나로 무작위 배정하여, 격주로 화합물 1 또는 위약(6:2의 비율)을 피하 투여받았다. (도 2). 이들 코호트 및 이전 단일 증량 용량 연구의 안전성 데이터는 어떠한 안전성 문제도 시사하지 않았기 때문에, 매주 300 mg을 투여하는 제4 코호트가 형성되었다. 연구의 1차 목적은 106일의 기간에 걸쳐 증상 있는 무릎 OA가 있는 참가자에서 화합물 1의 반복 투여에 대한 안전성 및 내약성을 평가하는 것이었다. 2차 목적은 화합물 1의 PK를 평가하고 이의 면역원성을 특성화하는 것이었다. 탐구 목적에는 혈청 ARGS(및 PK/PD 관계)의 억제에 대한 화합물 1의 효과 및 노출-QT 상호작용 예상 tmax를 평가하는 것이 포함되었다.
PK 결과: 1일째 단일 sc 주사 후, 화합물 1의 혈청 농도(5.831 ng/mL의 LLOQ 초과)가 75 mg, 150 mg, 및 300 mg EOW 및 300 mg 주간 화합물 1 코호트에서 검출되었다. 평균 화합물 1 혈청 농도는 75 mg 및 150 mg EOW 코호트의 경우 투여 후 24시간에 최고였고, 300 mg EOW 및 주간 코호트의 경우 투여 후 96시간에 최고조에 달했다. 각각의 명목 시점에 대해, 평균 화합물 1 농도는 용량 투여 EOW 코호트에서 용량에 따라 증가했다. 이러한 결과는 화합물 1이 투여 후 가장 빠른 샘플 시점(6시간)에 검출 가능한 전신 수준으로 빠르게 흡수되었음을 보여주었다(도 5).
용량 투여 EOW를 위한 29일 및 주간 용량 투여를 위한 36일에 다중 피하 주사 후, 평균 화합물 1 혈청 농도는 평균 농도가 투여 후 6시간에 최고조에 달했던 150 mg EOW 코호트를 제외하고 모든 코호트에 대해 투여 후 96시간에 최고조에 달했다. 일반적으로, 평균 화합물 1 농도는 EOW 코호트에서 용량에 따라 증가했다. 평균 화합물 1 농도는 매주 300 mg에 대해 투여 후 96시간째 36일에 가장 높았다(도 6).
1일째, 기하 평균 AUCtau 및 Cmax는 용량이 75 mg에서 300 mg EOW로 증량함에 따라 대략 용량-비례 증가를 나타냈다. 중간 화합물 1 Ttmax는 75 mg 및 150 mg EOW 코호트에서는 대략 24시간이었고, 300 mg EOW 및 주간 코호트에서는 대략 97시간이었다:
[표 7]
300 mg 주간 코호트에서 다중 투여 후, 화합물 1 노출은 처음 2주 동안 두 배로 증가했으며, Racc(Cmax) 값은 대략 2에 가깝다. 29일에, 중간 화합물 1 Ttmax는 300 mg 주간 코호트의 약 119시간과 비교하여 EOW 용량 투여 코호트에서 대략 95시간 내지 109시간 범위였다. AUCtau 및 Cmax의 축적은 일반적으로 용량 투여 EOW 코호트 전체에서 2배 이내인 반면, 주간 300 mg 코호트에서는 약 3배였다:
[표 8]
EOW 및 주간 코호트의 PK 매개변수는 다양한 투여 요법으로 인해 제한된 범위에서만 비교할 수 있다. 분명히, PK 농도 대 시간 플롯의 육안 검사를 기반으로 EOW 및 주간 코호트에서는 정상 상태에 도달하지 못했다. 용량 비례성 평가는 EOW 요법의 데이터만을 사용하여 수행되었다. 전체적으로, AUCtau 및 Cmax는 75 mg 내지 300 mg의 용량 범위에 걸쳐 대략 용량-비례 방식으로 증가하는 것으로 나타났다.
150 mg EOW 코호트의 참가자 1명, 300 mg EOW 코호트의 참가자 1명, 및 300 mg 주간 코호트의 참가자 3명이 ADA 테스트 결과 양성을 확인했다. 150 mg EOW 코호트의 참가자는 기존 ADA를 갖고 있었는데, 이는 치료 중에 증가되지 않았다. 요약하면, 참가자 24명 중 총 4명이 치료로 인한 ADA를 겪었다. 치료 후 ADA 테스트 양성 결과는 64일차(N = 2) 및 85일차(N = 2)부터 관찰되었다. ADA 음성 결과와 양성 결과간 AUCtau 데이터를 시각적으로 비교했다. 검출가능한 ADA가 없는 300 mg 주간 용량 수준 코호트의 참가자 1명을 제외하고, ADA 양성 결과가 나온 참가자에서 관찰된 AUCtau는 ADA 음성 결과가 나온 참가자의 AUCtau와 유사했다. 전체 샘플링 기간에 걸쳐 300 mg 주간 용량 수준 코호트에서 이 1명의 ADA 양성 참가자의 화합물 1 노출은 동일한 용량 코호트의 다른 참가자보다 낮았다. ADA 형성(64일 및 85일)과 화합물 1 노출 수준의 변화 사이에는 명확한 시간적 관계가 없었다.
PD 결과: 실시예 1에 기재된 방법과 동일한 방법으로 표적 관여 및 PD 바이오마커로서 ARGS를 측정하였다. 본 연구에서 분석한 LLOQ는 80 pmol/L이었다.
기준선으로부터의 백분율 변화(CFB) 및 CFB 백분율은 6시간부터 ARGS 수준이 감소함을 나타냈다(도 9). 수치적으로, 평균 CFB 혈청 농도는 대부분의 시점에서 위약군보다 4개 용량 수준 모두에서 일반적으로 더 낮았다: 즉, 목표 참여가 달성되었다(위약에 비해 평균 CFB ≥35%). 치료 종료 시 화합물 1 75 mg EOW에 대한 CFB 백분율(95% CI)의 최소 제곱 평균은 -76.8%(-90.7 내지 62.8%)였다. ARGS 농도의 약 50% 평균 감소(위약 대비)가 15일차부터 관찰되었으며, EOS(106일차)를 통해 유지되었다. 그러나, 4가지 치료 간 용량 반응의 차별화는 뚜렷하지 않았다.
안전성 결과: 주간 최대 300 mg의 화합물 1의 다중 sc 용량은 일반적으로, 평가된 집단에 대해 내약성이 좋고 안전한 것으로 간주되었다. 전체적으로, 서로 다른 화합물 1 코호트 사이, 그리고 화합물 1과 위약을 사용한 치료 사이에, TEAE의 발생률에는 최소한의 차이가 있었지만, 치료-관련 TEAE의 발생률은 고용량 코호트에서 더 높았다.
사망자는 관찰되지 않았다. 2명의 환자는 중증의 TEAE(3등급)를 나타냈다. 코호트 2(150 mg EOW)의 한 환자는 두 번째 투여 후 천식(3등급)을 보고했지만, 조사자는 이 경우가 독감에 의해 유발된 것이며 화합물 1과 관련이 없는 것으로 간주했다. 사건은 재발 없이 해결되었으며, 환자는 추가 합병증 없이 세 번째 용량을 투여받았다. 제2 참가자는 위약에 할당되었고 연구 치료와 관련이 있는 것으로 간주되지 않은 무릎 OA 통증의 증가(3등급)를 등록했으며, 치료에 대한 변경이 필요하지 않았으며 EOS 전에 해결되었다.
근골격계 TEAE로 인해 2명의 참가자가 연구에서 중단되었다. 용량 코호트 2(150 mg EOW)의 한 참가자는 근육 긴장 등급 1을 경험했으며, 세 번째 용량을 받기 전에 연구에서 제외되었다. 이 사건은 경미했고, 일상 활동을 방해하지 않았으며, 연구 치료와 관련이 없는 것으로 간주되었다. 참가자가 추적 조사에 실패했기 때문에 결과는 회복되지 않음/해결되지 않은 것으로 기록되었다. 코호트 4(주당 300 mg)에 할당된 두번째 참가자는 17일, 29일, 및 36일에 팔뚝, 엉덩이, 허벅지, 등 위쪽 및 종아리에 근육통 1등급을 보고했으며, 연구에서 영구적으로 중단되었지만 후속 방문에 참석했다. 환자는 통증 관리를 위한 치료를 받았고, AE는 중단 시 해결되었다. 사건은 치료와 관련된 것으로 간주되지 않았다.
10명의 환자가 연구 치료와 관련된 것으로 평가된 TEAE를 보고했다. 모든 치료에 대해 보고된 가장 흔한 TEAE는 두통, 관절통, 주사 부위 반응 및 근육 긴장이었다. 보고된 모든 주사 부위 반응은 중증도가 1등급이었으며, EOS 이전에 해결되었다. 2명의 참가자는 국소 치료를 받았고, 다른 보고된 사건은 개입 없이 해결되었다. 300 mg EOW를 투여받은 1명의 참가자는 주사 부위 통증을 보고했다. TEAE는 개입 없이 EOS 이전에 해결되었다. ADA 형성과 주사 부위 반응의 발생 사이에는 뚜렷한 상관관계가 없었다.
근육-관련 사건의 발생률은 위약에 비해 화합물 1을 투여받은 대상체에서 더 높았으며, 중증도는 300 mg EOW 및 300 mg 주간 코호트 환자에서 더 높았다. 이들 사건 중 어느 것도 관련 크레아틴 포스포키나제(CPK) 증가와 관련이 없었다.
실시예 3: 증상있는 무릎 골관절염 환자에서 화합물 1(항-ADAMTS-5 나노바디)의 효능, 안전성 및 내약성을 조사하는 무작위, 2군, 위약 대조, 참가자, 조사자 및 후원자 맹검, 개념 증명 연구
이는 증상있는 무릎 OA 환자의 통증 및 연골 보존에 대한 화합물 1의 효과를 확립하기 위한 개념 증명(POC) 연구이다. ADAMTS-5의 억제 구조와 통증에 대한 이점은 전임상 연구에서 입증되었지만, OA 환자를 위한 치료 표적으로서의 역할은 아직 정의되지 않았다. 증상있는 무릎 OA 환자의 표적 무릎 통증에 대한 화합물 1의 효과는 치료 12주 후에 평가할 것이며, 치료 52주 후에 표적 무릎의 연골 부피 보존에 대한 효과를 평가할 것이다.
연구 설계 - 이것은 증상있는 무릎 OA가 있는 약 98명의 환자에게 4주마다(q4w) 화합물 1 300 mg 대 위약을 피하 주사하는 것의 효능, 안전성 및 내약성을 조사할 목적으로 무작위, 2가지 치료군, 병행군, 참가자, 조사자 및 후원자 맹검, 위약 대조 설계를 사용하는 비확증 연구이다. 이 연구는 적격성을 평가하고 참가자의 금지 약물 사용을 줄이는 데 사용되는 최대 약 6주의 선별 기간으로 구성된다. -4일차부터 -1일차 방문 사이에 적격 참가자는 1:1의 비율로 치료군 중 하나에 무작위로 배정된다. 1일차에 무작위 참가자는 치료 기간에 들어가게 되며, 이 기간 동안 그들은 화합물 1 300 mg 또는 위약의 q4w sc 주사를 받게 된다. 마지막 연구 치료제 투여는 48주차에 이루어지며, 치료 종료(EOT) 방문은 4주 후인 52주차에 이루어진다. 연구 종료(EOS) 방문은 EOT 방문 후 8주 후인 60주차에 이루어진다. 스크리닝부터 EOS까지의 총 연구 기간은 최대 66주가 될 것으로 예상된다. 1차 분석은 1차 종료점(12주차의 KOOS 통증)을 평가하기 위해 모든 참가자가 12주차에 도달할때 수행된다.
스크리닝 기간은 3회 방문으로 구성된다:
ㆍ 스크리닝 1 - 사전 동의서에 서명한 후, 참가자는 적격성을 확인하기 위한 평가를 받게 된다. 필요한 평가는 참가자에게 최선의 이익이 되거나 물류상의 이유로 수일에 걸쳐 수행될 수 있다. X-선은 대상체 무릎에서 수행되며, 참가자의 적격성을 평가하기 위한 독립적인 검토자의 중앙 평가를 위해 전송된다. 금지된 병용 약물 치료를 받은 참가자는 스크리닝 1에서 휴약 기간을 시작한다. 스크리닝 1은 1일 이전 최대 40일까지 일정을 잡을 수 있지만, 이상적으로는 1일 이전에 가능한 한 가깝게 발생해야 한다.
ㆍ 스크리닝 2 - 1일차 이전 20일에서 9일 사이에 일정을 잡아야 한다. 참가자는 통증 평가 및 스크리닝 1 평가 결과의 검토를 위해 임상 현장으로 이동한다. 참가자가 여전히 적격인 경우, 이번 방문부터 12주차 방문까지 매일 통증 일기를 작성하고 이번 방문부터 4주차 방문까지 낮 동안 액티그래피 센서를 착용하도록 지시받게 된다.
ㆍ 스크리닝 3 (전화) - 통화 7일 전 통증일지 및 KOOS 통증 결과를 토대로 적격성을 재평가한다. 조사자는 -4일과 -1일 사이에 통화 일정을 잡아, 참가자가 최소 7일간의 통증 일기와 KOOS 통증 설문지를 완료할 수 있도록 할 수 있다. 적격성이 확인되면, 참가자는 치료군 중 하나에 무작위로 배정된다.
치료 기간 동안, 참가자는 효능, 안전성, PK 및 PD 평가를 받게 된다. 치료 기간은 16회 방문으로 구성된다:
ㆍ 1일차 치료 개시 방문: 첫 번째 연구 치료 투여.
ㆍ 참가자는 평가 일정에 설명된 대로 1일차, 5일차, 4주차, 8주차, 12주차에 현장 평가를 받게 된다.
ㆍ 12주차 이후 참가자는 현지 법률에서 허용하고 현지 역량에 따라 가능한 경우 외부 환경에서 일부 방문을 수행할 수 있다:
ㆍ 현장 방문: 28주차(무릎 MRI 포함) 및 40주차;
ㆍ 현장 또는 외부 방문(해당되는 경우): 16주, 20주, 24주, 32주, 36주, 44주, 48주. 외부 방문에는 QUC398 300 mg 또는 위약의 s.c. 투여, 뿐만 아니라 평가 일정에 따른 PRO에 의한 통증 평가 및 혈액/소변 샘플링이 포함된다.
ㆍ 현장 EOT 방문은 52주차, 즉 마지막 연구 치료제 투여 후 4주차에 이루어지며 무릎 MRI가 포함된다.
참가자는 EOT 방문 후 8주 동안 추적 관찰된다. 선택적 방문은 56주차에 이루어지며, 이 기간 동안 PK 및 PD 평가를 위해 혈액 샘플을 채취한다. 참가자는 현지 법률에서 허용하고 현지 역량에 따라 실행 가능한 경우 원격 환경에서 이 방문을 수행할 수 있다. 이러한 경우 현장 EOS 방문은 60주차, 즉 EOT 방문 후 8주차에 이루어진다.
연구 집단 - 연구 집단은 증상있는 경증 내지 중증 방사선학적 무릎 OA(Kellgren-Lawrence [KL] 2~4등급)을 앓고 있는 40 내지 80세의 남성 및 여성 성인 환자로 구성된다. 본 연구에서는 대략 98명의 참가자를 무작위로 배정할 계획이다. 조사자는 환자를 임상시험에 등록하기 전에 환자가 포함 기준을 모두 충족하고 제외 기준을 모두 충족하지 않는지 확인해야 한다. 조사자는 환자의 적격성을 고려할 때 추가 기준을 적용해서는 안 된다. 스크리닝 시 안전성 실험실 평가가 제외 기준 중 하나를 충족하지만 병태가 일시적이고 첫 번째 투여 전에 해결될 것으로 예상되는 경우, 평가는 무작위화 전에 한 번 반복될 수 있다. 반복 값이 배제인 것으로 유지되면, 참가자는 연구에서 제외된다.
결과 - 평가할 1차 종료점은 12주차에 표적 무릎의 OA 통증 완화에 있어서 화합물 1의 효능이다. 통증 완화는 12주차에 KOOS 통증 하위척도의 기준선으로부터의 변화로 측정할 것이다. KOOS 통증 하위척도 점수는 100점 척도로 분석되며, 점수가 낮을수록 통증이 심함을 의미한다. 화합물 1을 사용한 치료는 위약과 비교하여 표적 무릎의 OA 통증을 감소시킬 것으로 예상된다.
이 연구에서는 또한 여러 가지 2차 목표를 달성하는 데 있어서 위약과 비교하여 화합물 1의 효능을 평가할 것이다:
ㆍ 시간이 지남에 따라 표적 무릎의 OA 통증을 완화하는 화합물 1의 효능. 통증 완화는 KOOS 통증 하위척도의 기준선으로부터의 변화와 통증 수치 평가 척도(NRS)의 기준선으로부터의 변화로 측정된다. KOOS 통증 하위척도 점수는 100점 척도로 분석되며, 점수가 낮을수록 통증이 심함을 의미한다. 화합물 1을 사용한 치료는 위약과 비교하여 시간이 지남에 따라 표적 무릎의 OA 통증을 감소시킬 것으로 예상된다.
ㆍ 위약과 비교하여 표적 무릎의 내측 구획에서 연골을 보존하는 화합물 1의 효능. 연골 구조 및 구성에 대한 화합물 1의 효과를 모니터링하기 위해 MRI를 사용할 것이다. MRI는 연골의 부피와 두께 변화를 정량화하는 데 사용되며; 또한 그의 T2 이완 시간 및 소위 Radiomics 접근법을 기반으로 한 연골 품질의 변화, 연골 조직감에 대한 정보를 제공하기 위해 데이터-특성화 알고리즘을 사용하여 T2 맵에서 많은 특징을 추출하는 정량적 방법이 평가된다. MRI는 1일차, 28주차 및 52주차에 촬영된다. MRI는 방문 시 다른 임상 평가 전이나 후에 수행할 수 있으며, 물류상의 이유로 필요한 경우 다른 날에도 수행할 수 있지만 항상 방문 기간 내에 수행해야 한다. 화합물 1을 사용한 치료는 위약과 비교하여 표적 무릎의 연골을 보존할 것으로 예상된다.
ㆍ 위약과 비교하여 표적 무릎에서 OA의 임상 증상을 완화하고 기능을 개선하는 화합물 1의 효능. OA의 임상 증상 완화 및 기능 개선은 총 KOOS 점수의 변화, KOOS 하위척도의 변화, 및 NRS가 평가한 환자 종합 평가(PGA)의 기준선으로부터의 변화로 측정된다. 30초 의자 서기 테스트와 2분 걷기 테스트는 표준화된 성능 결과 측정이며, 치료 기간 전체 동안 및 완료 시 기능 변화를 평가하는 데에도 사용된다. 화합물 1을 사용한 치료는 위약과 비교하여 임상 증상의 완화 및 표적 무릎의 기능 개선을 가져올 것으로 예상된다.
번호가 매겨진 실시형태
첨부된 청구범위에도 불구하고, 다음의 번호가 매겨진 실시형태도 본원에서 고려되며, 본 개시내용의 일부를 형성한다.
실시형태 1. 75 내지 300 mg의 ADAMTS5 억제 폴리펩타이드를 인간 대상체에게 투여하는 단계를 포함하는, 치료를 필요로 하는 대상체의 골관절염을 치료하는 방법.
실시형태 2. 실시형태 1에 있어서, ADAMTS5 억제 폴리펩타이드는 3개의 상보성 결정 영역(CDR)을 포함하는 적어도 하나의 면역글로불린 단일 가변 도메인(ISVD)을 포함하며, 여기서 상보성 결정 영역은 CDR1 내지 CDR3이며, (i) CDR1은 서열번호 21, 35, 20, 22, 25, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34로 이루어진 군으로부터 선택되고; (ii) CDR2는 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52로 이루어진 군으로부터 선택되고; (iii) CDR3은 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70으로 이루어진 군으로부터 선택되는, 방법.
실시형태 3. 실시형태 2에 있어서, ADAMTS5 억제 폴리펩타이드는 3개의 CDR을 포함하는 적어도 하나의 ISVD를 포함하며, 여기서 CDR은 CDR1 내지 CDR3이며,
(i) CDR1은 서열번호 21이고, CDR2는 서열번호 37이고, CDR3은 서열번호 55이거나;
(ii) CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 118이거나;
(iii) CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 71이거나;
(iv) CDR1은 서열번호 20이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이거나;
(v) CDR1은 서열번호 22이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이거나;
(vi) CDR1은 서열번호 25이고, CDR2는 서열번호 40이고, CDR3은 서열번호 58이거나;
(vii) CDR1은 서열번호 33이고, CDR2는 서열번호 50이고, CDR3은 서열번호 68이거나;
(viii) CDR1은 서열번호 33이고, CDR2는 서열번호 51이고, CDR3은 서열번호 69이거나;
(ix) CDR1은 서열번호 28이고, CDR2는 서열번호 44이고, CDR3은 서열번호 62이거나;
(x) CDR1은 서열번호 28이고, CDR2는 서열번호 45이고, CDR3은 서열번호 63이거나;
(xi) CDR1은 서열번호 28이고, CDR2는 서열번호 43이고, CDR3은 서열번호 61이거나;
(xii) CDR1은 서열번호 24이고, CDR2는 서열번호 39이고, CDR3은 서열번호 57이거나;
(xiii) CDR1은 서열번호 23이고, CDR2는 서열번호 38이고, CDR3은 서열번호 56이거나;
(xiv) CDR1은 서열번호 26이고, CDR2는 서열번호 41이고, CDR3은 서열번호 59이거나;
(xv) CDR1은 서열번호 27이고, CDR2는 서열번호 119이고, CDR3은 서열번호 60이거나;
(xvi) CDR1은 서열번호 27이고, CDR2는 서열번호 42이고, CDR3은 서열번호 60이거나;
(xvii) CDR1은 서열번호 29이고, CDR2는 서열번호 46이고, CDR3은 서열번호 64이거나;
(xviii) CDR1은 서열번호 30이고, CDR2는 서열번호 47이고, CDR3은 서열번호 65이거나;
(xix) CDR1은 서열번호 31이고, CDR2는 서열번호 48이고, CDR3은 서열번호 66이거나;
(xx) CDR1은 서열번호 32이고, CDR2는 서열번호 49이고, CDR3은 서열번호 67이거나; 또는
(xxi) CDR1은 서열번호 34이고, CDR2는 서열번호 52이고, CDR3은 서열번호 70인, 방법.
실시형태 4. 실시형태 3에 있어서, 상기 ADAMTS5 억제 폴리펩타이드는 3개의 CDR을 포함하는 적어도 하나의 ISVD를 포함하고, 여기서 CDR은 CDR1 내지 CDR3이고, CDR1은 서열번호 21이고, CDR2는 서열번호 37이고, CDR3은 서열번호 55인, 방법.
실시형태 5. 실시형태 1에 있어서, 상기 ISVD는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택되는, 방법.
실시형태 6. 실시형태 5에 있어서, 상기 ISVD는 서열번호 129의 아미노산 1 내지 124인, 방법.
실시형태 7. 실시형태 1에 있어서, 상기 ADAMTS5 억제 폴리펩타이드는 2개 이상의 ISVD를 포함하고, 여기서 a) 적어도 제1 ISVD는 ADAMTS5의 제1 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합하고; b) 적어도 제2 ISVD는 혈청 알부민의 제2 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합하는, 방법.
실시형태 8. 실시형태 7에 있어서, 상기 제1 ISVD는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택되는, 방법.
실시형태 9. 실시형태 8에 있어서, 상기 제1 ISVD는 서열번호 129의 아미노산 1 내지 124인, 방법.
실시형태 10. 실시형태 7에 있어서, 제2 ISVD는 서열번호 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 또는 145로 이루어진 군으로부터 선택되는, 방법.
실시형태 11. 실시형태 10에 있어서, 제2 ISVD는 서열번호 138인, 방법.
실시형태 12. 실시형태 7에 있어서, 제1 ISVD는 서열번호 129의 아미노산 1 내지 124이고, 제2 ISVD는 서열번호 138인, 방법.
실시형태 13. 실시형태 1에 있어서, 상기 ADAMTS5 억제 폴리펩타이드는 서열번호 129(클론 577 2F3so-Alb), 서열번호 130(클론 579 2F3so-093-Alb), 서열번호 120(클론 4 2A12-Alb), 서열번호 121(클론 5 2D7-Alb), 서열번호 122(클론 6 2F3-Alb), 서열번호 123(클론 69 049-Alb), 서열번호 124(클론 70 9D3-Alb), 서열번호 125(클론 71 3B2-Alb), 서열번호 126(클론 129 2F3-093-Alb), 서열번호 127(클론 130 049-093-Alb), 및 서열번호 128(클론 131 9D3-093-Alb)로 이루어진 군으로부터 선택되는, 방법.
실시형태 14. 실시형태 13에 있어서, 상기 ADAMTS5 억제 폴리펩타이드는 서열번호 129(클론 577 2F3so-Alb)인, 방법.
실시형태 15. 실시형태 1 내지 14 중 어느 하나에 있어서, 상기 골관절염은 무릎 골관절염인, 방법.
실시형태 16. 실시형태 1 내지 15 중 어느 하나에 있어서, 상기 ADAMTS5 억제 폴리펩타이드의 용량이 150 mg인, 방법.
실시형태 17. 실시형태 1 내지 15 중 어느 하나에 있어서, 상기 ADAMTS5 억제 폴리펩타이드의 용량이 300 mg인, 방법.
실시형태 18. 실시형태 1 내지 17 중 어느 하나에 있어서, 상기 ADAMTS5 억제 폴리펩타이드는 1개월 1회 투여되는, 방법.
실시형태 19. 실시형태 1 내지 18 중 어느 하나에 있어서, 상기 ADAMTS5 억제 폴리펩타이드의 투여는 ARGS 단편의 형성을 감소시키는, 방법.
실시형태 20. 실시형태 1 내지 19 중 어느 하나에 있어서, ADAMTS5 억제 폴리펩타이드의 투여는 KOOS 점수 또는 WOMAC 점수에 의해 측정된 바와 같이 골관절염에 걸린 관절의 통증을 감소시키는, 방법.
실시형태 21. 실시형태 1 내지 20 중 어느 하나에 있어서, ADAMTS5 억제 폴리펩타이드의 투여는 MRI의 자동 분할에 의해 결정된 바와 같이 골관절염에 걸린 관절의 구조를 유지하는, 방법.
SEQUENCE LISTING
<110> NOVARTIS AG
MERCK PATENT GMBH
<120> METHODS FOR THE ADMINISTRATION OF ADAMTS BINDING IMMUNOGLOBULINS
<130> PAT059112-WO-PCT
<140>
<141>
<150> 63/362,372
<151> 2022-04-01
<150> 63/182,561
<151> 2021-04-30
<160> 175
<170> PatentIn version 3.5
<210> 1
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Asp Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Gly Arg Thr Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Asp Glu Ala Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
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<400> 2
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Leu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Glu Arg Thr Tyr Tyr Val Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Glu Glu Tyr Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 124
<212> PRT
<213> Artificial Sequence
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<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 3
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ala Val Ser Val Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Gly Arg Thr Tyr Tyr Thr Asp Ser Val
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Lys Asp Arg Phe Thr Ile Ala Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Asp Glu Ala Ala
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Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
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<223> Description of Artificial Sequence: Synthetic
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Asp
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Thr Tyr
20 25 30
Phe Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Asp Phe Val
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Ala Ala Ile Ser Arg Asn Gly Ala Arg Thr Tyr Tyr Tyr Asp Ser Val
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Ala Gly Leu Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
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Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Ala Ala Arg Ile Ser Pro Ser Asp Pro Ser Asn Glu Asp Gly Tyr
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Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 5
<211> 126
<212> PRT
<213> Artificial Sequence
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<223> Description of Artificial Sequence: Synthetic
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<400> 5
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 Arg Arg Thr Phe Ser Ser Tyr
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Val Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Gly Asp Ser Thr Tyr Tyr Tyr Asp Ser Leu
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Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val His
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Ile Cys
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Ala Ala Ser Arg Ala Pro Ser Phe Arg Thr Ile Asp Ala Ile Asn Tyr
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Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 6
<211> 126
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 6
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Phe Ser Gly Pro Gly Arg Thr Phe Ala
20 25 30
Arg Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Asn Arg Asp
35 40 45
Phe Ile Thr Gly Ile Ser Gly Ser Gly Asp Ser Thr Tyr Tyr Val Tyr
50 55 60
Pro Met Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met
65 70 75 80
Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala Asp Arg Glu Ile Asn Arg Ile Ala Asn Asp Lys Glu
100 105 110
Leu Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 7
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Thr Phe Ser Ser
20 25 30
Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Ala Phe
35 40 45
Val Ala Thr Ile Trp Ser Gly Gly Leu Thr Val Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Glu Ala Val Gly Thr Tyr Tyr Thr Pro Asp Gly Trp Thr Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 8
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 8
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Arg Arg Asn
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Leu
35 40 45
Ala Gly Ile Asn Trp Ser Gly Gly Thr Thr Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp
65 70 75 80
Leu Gln Met Ile Ser Pro Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Gly Asp Ile Gly Thr Leu Val Asn Asp Glu Asn Pro Arg
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 9
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Pro Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Asp Phe Val
35 40 45
Ala Ala Ile Thr Arg Ser Arg Gly Thr Thr Tyr Tyr Leu Asp Ser Thr
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Arg Ser Pro Gly Asp Pro Ser Arg Thr Tyr Leu Tyr Glu
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 10
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Pro Ser Gly Phe Thr Phe Ser Pro Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Asp Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Arg Gly Thr Thr Tyr Tyr Leu Asp Ser Thr
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asp Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Arg Ser Pro Gly Asp Pro Ser Arg Thr Tyr Leu Tyr Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 11
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Pro Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Asp Phe Val
35 40 45
Ala Ala Ile Ser Trp Ser Arg Gly Ile Leu Tyr Tyr Thr Asp Ser Thr
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr
65 70 75 80
Leu Gln Met Asp Asn Leu Asn Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Arg Ser Pro Gly Asp Pro Ser Arg Thr Tyr Leu Tyr Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 12
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Leu Ser Ser Ser
20 25 30
Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Thr Trp Ser Gly Gly Arg Ala Tyr Tyr Ala Asp Val Ser
50 55 60
Asp Phe Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Lys Asn
65 70 75 80
Thr Val Asn Leu Gln Met Lys Gly Leu Lys Pro Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Ala Ala Leu Ala Ile Pro Val Thr Met Ser Pro His
100 105 110
Glu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 13
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Asp Val Val Val Asn
20 25 30
Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Asp Ile Thr Thr Gly Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Gln Val Gly Asp Ser Asp Asp Asp Val Trp Tyr Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 14
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 14
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 Ser Ile Phe Ser Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Glu Val Asp Ala Gly Ile Tyr Ala Tyr Gly Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 15
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Gln Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Ser Trp Asn Thr Phe Thr Thr Tyr Tyr Val Asp Ser Val
50 55 60
Lys Asp Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Arg Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gly Gly Ser Pro Arg Gln His Glu Pro Tyr Glu Tyr Arg
100 105 110
Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 16
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Arg Arg Thr Ile Ser Ser Gly
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Arg Trp Ser Ser Gly Met Pro Tyr Tyr Leu Asp Ser Val
50 55 60
Met Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Ser
65 70 75 80
Leu Gln Met Asn Ser Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Arg Ser Ala Phe Arg Asp Pro Ser Phe Asp Val Asn Tyr
100 105 110
Glu Tyr Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 17
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Arg Thr Ile Ser Ser Gly
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Arg Trp Ser Ser Gly Ile Thr Phe Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Gly Asp Asn Ala Lys Asn Thr Val Ser
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Arg Ser Ala Leu Arg Asp Pro Ser Phe Glu Val Asn Tyr
100 105 110
Glu Tyr Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 18
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 18
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Ser Ile Phe Ser Ile Asp
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Ser Val Thr Thr Gly Ala Ser Pro Asn Tyr Gly Asp Ser Val Thr
50 55 60
Gly Arg Phe Thr Ala Ser Arg Asp Arg Ala Lys Asn Ala Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Leu Ile Met Thr Ile Pro Gly Gly Ser Gln Ile Met Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 19
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Tyr Pro Met Ala Trp
20 25 30
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Val Ser
35 40 45
Trp Gly Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val Gln Gly Arg Phe
50 55 60
Thr Val Ser Arg Asp Tyr Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn
65 70 75 80
Ser Leu Lys Pro Glu Asp Ala Ala Val Tyr Tyr Cys Ala Gly Asp Pro
85 90 95
Trp Gly Arg Leu Phe Arg Val Lys Asp Asn Tyr Ser Asp Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 20
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 20
Gly Arg Thr Phe Ser Ser Tyr Ala Met Gly
1 5 10
<210> 21
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 21
Gly Arg Thr Val Ser Ser Tyr Ala Met Gly
1 5 10
<210> 22
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 22
Gly Ser Ala Val Ser Val Asn Ala Met Ala
1 5 10
<210> 23
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 23
Gly Arg Thr Phe Ser Thr Tyr Phe Val Gly
1 5 10
<210> 24
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 24
Arg Arg Thr Phe Ser Ser Tyr Val Met Ala
1 5 10
<210> 25
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 25
Gly Pro Gly Arg Thr Phe Ala Arg Tyr Ala Met Gly
1 5 10
<210> 26
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 26
Gly Arg Thr Thr Phe Ser Ser Tyr Ala Met Gly
1 5 10
<210> 27
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 27
Gly Leu Thr Phe Arg Arg Asn Ala Met Gly
1 5 10
<210> 28
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 28
Gly Phe Thr Phe Ser Pro Tyr Tyr Met Gly
1 5 10
<210> 29
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 29
Gly Arg Ala Leu Ser Ser Ser Ile Met Gly
1 5 10
<210> 30
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 30
Gly Ser Asp Val Val Val Asn Asp Met Gly
1 5 10
<210> 31
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 31
Gly Ser Ile Phe Ser Ile Asn Val Met Gly
1 5 10
<210> 32
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 32
Gly Leu Thr Phe Ser Ser Tyr Thr Met Gly
1 5 10
<210> 33
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 33
Arg Arg Thr Ile Ser Ser Gly Thr Met Gly
1 5 10
<210> 34
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 34
Gly Ser Ile Phe Ser Ile Asp Ala Met Gly
1 5 10
<210> 35
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 35
Gly Arg Tyr Pro Met Ala
1 5
<210> 36
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 36
Gly Ile Ser Arg Ser Ala Gly Arg Thr Tyr
1 5 10
<210> 37
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 37
Gly Ile Ser Arg Ser Ala Glu Arg Thr Tyr
1 5 10
<210> 38
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 38
Ala Ile Ser Arg Asn Gly Ala Arg Thr Tyr Tyr
1 5 10
<210> 39
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 39
Ala Ile Ser Arg Ser Gly Asp Ser Thr Tyr
1 5 10
<210> 40
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 40
Gly Ile Ser Gly Ser Gly Asp Ser Thr Tyr
1 5 10
<210> 41
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 41
Thr Ile Trp Ser Gly Gly Leu Thr Val
1 5
<210> 42
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 42
Gly Ile Asn Trp Ser Gly Gly Thr Thr Tyr
1 5 10
<210> 43
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 43
Ala Ile Thr Arg Ser Arg Gly Thr Thr Tyr
1 5 10
<210> 44
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 44
Ala Ile Ser Arg Ser Arg Gly Thr Thr Tyr
1 5 10
<210> 45
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 45
Ala Ile Ser Trp Ser Arg Gly Ile Leu Tyr
1 5 10
<210> 46
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 46
Ala Ile Thr Trp Ser Gly Gly Arg Ala Tyr Tyr Ala Asp
1 5 10
<210> 47
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 47
Asp Ile Thr Thr Gly Gly Arg Thr Asn
1 5
<210> 48
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 48
Ala Ile Ile Ser Gly Gly Arg Thr Asn
1 5
<210> 49
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 49
Ala Ile Ser Trp Asn Thr Phe Thr Thr Tyr
1 5 10
<210> 50
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 50
Ala Ile Arg Trp Ser Ser Gly Met Pro Tyr
1 5 10
<210> 51
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 51
Ala Ile Arg Trp Ser Ser Gly Ile Thr Phe
1 5 10
<210> 52
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 52
Ser Val Thr Thr Gly Ala Ser Pro Asn
1 5
<210> 53
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 53
Gly Val Ser Trp Gly Gly Asp Arg Thr Tyr
1 5 10
<210> 54
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 54
Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Asp Glu Ala Ala Tyr
1 5 10 15
<210> 55
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 55
Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Glu Glu Tyr Ala Tyr
1 5 10 15
<210> 56
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 56
Ala Arg Ile Ser Pro Ser Asp Pro Ser Asn Glu Asp Gly Tyr Asp Tyr
1 5 10 15
<210> 57
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 57
Ser Arg Ala Pro Ser Phe Arg Thr Ile Asp Ala Ile Asn Tyr Tyr Asp
1 5 10 15
Tyr
<210> 58
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 58
Asp Arg Glu Ile Asn Arg Ile Ala Asn Asp Lys Glu Leu Asp Phe
1 5 10 15
<210> 59
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 59
Glu Ala Val Gly Thr Tyr Tyr Thr Pro Asp Gly Trp Thr Tyr
1 5 10
<210> 60
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 60
Asp Gly Asp Ile Gly Thr Leu Val Asn Asp Glu Asn Pro Arg Tyr
1 5 10 15
<210> 61
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 61
Gly Arg Ser Pro Gly Asp Pro Ser Arg Thr Tyr Leu Tyr Glu Tyr
1 5 10 15
<210> 62
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 62
Gly Arg Ser Pro Gly Asp Pro Ser Arg Thr Tyr Leu Tyr Asp Tyr
1 5 10 15
<210> 63
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 63
Ser Arg Ser Pro Gly Asp Pro Ser Arg Thr Tyr Leu Tyr Asp Tyr
1 5 10 15
<210> 64
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 64
Ala Leu Ala Ile Pro Val Thr Met Ser Pro His Glu Tyr Pro Tyr
1 5 10 15
<210> 65
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 65
Gln Val Gly Asp Ser Asp Asp Asp Val Trp Tyr Ala Tyr
1 5 10
<210> 66
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 66
Glu Val Asp Ala Gly Ile Tyr Ala Tyr Gly Tyr
1 5 10
<210> 67
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 67
Ala Gly Gly Ser Pro Arg Gln His Glu Pro Tyr Glu Tyr Arg Val
1 5 10 15
<210> 68
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 68
Asp Arg Ser Ala Phe Arg Asp Pro Ser Phe Asp Val Asn Tyr Glu Tyr
1 5 10 15
<210> 69
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 69
Asp Arg Ser Ala Leu Arg Asp Pro Ser Phe Glu Val Asn Tyr Glu Tyr
1 5 10 15
<210> 70
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 70
Ile Met Thr Ile Pro Gly Gly Ser Gln Ile Met Tyr
1 5 10
<210> 71
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 71
Asp Pro Trp Gly Arg Leu Phe Arg Val Lys Asp Asn Tyr Ser Asp
1 5 10 15
<210> 72
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 72
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 73
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 73
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 74
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 74
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Asp
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 75
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 75
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
20 25
<210> 76
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 76
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Phe Ser
20 25
<210> 77
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 77
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser
20 25
<210> 78
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 78
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Pro Ser
20 25
<210> 79
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 79
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser
20 25
<210> 80
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 80
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 81
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 81
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 82
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 82
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 83
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 83
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 84
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 84
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 85
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 85
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Asp Phe Val Ala
1 5 10
<210> 86
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 86
Trp Phe Arg Leu Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
1 5 10
<210> 87
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 87
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Asp Phe Val Ala
1 5 10
<210> 88
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 88
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
1 5 10
<210> 89
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 89
Trp Phe Arg Gln Ala Pro Gly Lys Asn Arg Asp Phe Ile Thr
1 5 10
<210> 90
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 90
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Ala Phe Val Ala
1 5 10
<210> 91
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 91
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Leu Ala
1 5 10
<210> 92
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 92
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
1 5 10
<210> 93
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 93
Trp Phe Arg Gln Ala Pro Gly Gln Glu Arg Glu Phe Val Ser
1 5 10
<210> 94
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 94
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 95
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 95
Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala
1 5 10 15
Lys Asn Thr Val Tyr Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 96
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 96
Tyr Val Asp Ser Leu Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala
1 5 10 15
Lys Asn Thr Val Tyr Leu His Met Asn Arg Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 97
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 97
Tyr Thr Asp Ser Val Lys Asp Arg Phe Thr Ile Ala Arg Asp Ser Ala
1 5 10 15
Lys Asn Thr Val Tyr Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 98
<211> 38
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 98
Tyr Asp Ser Val Ala Gly Leu Phe Thr Ile Ser Arg Asp Asn Ala Lys
1 5 10 15
Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala
20 25 30
Val Tyr Tyr Cys Ala Ala
35
<210> 99
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 99
Tyr Tyr Asp Ser Leu Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Thr Val His Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Ile Cys Ala Ala
35
<210> 100
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 100
Tyr Val Tyr Pro Met Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Met Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 101
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 101
Tyr Ala Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 102
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 102
Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Thr Val Asp Leu Gln Met Ile Ser Pro Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 103
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 103
Tyr Leu Asp Ser Thr Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Thr Met Tyr Leu Gln Met Asn Ser Leu Asn Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 104
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 104
Tyr Leu Asp Ser Thr Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Asn Asp Thr Val Tyr Leu Gln Met Asn Ser Leu Asn Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 105
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 105
Tyr Thr Asp Ser Thr Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Thr Met Tyr Leu Gln Met Asp Asn Leu Asn Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 106
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 106
Val Ser Asp Phe Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly
1 5 10 15
Lys Asn Thr Val Asn Leu Gln Met Lys Gly Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 107
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 107
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val
1 5 10 15
Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Asn Ala
35
<210> 108
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 108
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
1 5 10 15
Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Asn Ala
35
<210> 109
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 109
Tyr Val Asp Ser Val Lys Asp Arg Phe Thr Val Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Thr Leu Tyr Leu Arg Met Asn Ser Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 110
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 110
Tyr Leu Asp Ser Val Met Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala
1 5 10 15
Lys Asn Thr Val Ser Leu Gln Met Asn Ser Leu Gln Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 111
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 111
Tyr Pro Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Gly Asp Asn Ala
1 5 10 15
Lys Asn Thr Val Ser Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Ala Ala
35
<210> 112
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 112
Tyr Gly Asp Ser Val Thr Gly Arg Phe Thr Ala Ser Arg Asp Arg Ala
1 5 10 15
Lys Asn Ala Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys Asn Leu
35
<210> 113
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 113
Tyr Ala Asp Ser Val Gln Gly Arg Phe Thr Val Ser Arg Asp Tyr Ala
1 5 10 15
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Ala
20 25 30
Ala Val Tyr Tyr Cys Ala Gly
35
<210> 114
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 114
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 115
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 115
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 116
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 116
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Tyr Pro Met Ala Trp
20 25 30
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Val Ser
35 40 45
Trp Gly Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val Gln Gly Arg Phe
50 55 60
Thr Val Ser Arg Asp Tyr Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn
65 70 75 80
Ser Leu Lys Pro Glu Asp Ala Ala Val Tyr Tyr Cys Ala Gly Asp Pro
85 90 95
Trp Gly Arg Leu Phe Arg Val Lys Asp Gln Tyr Ser Asp Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 117
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 117
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Arg Arg Asn
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Leu
35 40 45
Ala Gly Ile Ser Trp Ser Gly Gly Thr Thr Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp
65 70 75 80
Leu Gln Met Ile Ser Pro Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Gly Asp Ile Gly Thr Leu Val Asn Asp Glu Asn Pro Arg
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 118
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 118
Asp Pro Trp Gly Arg Leu Phe Arg Val Lys Asp Gln Tyr Ser Asp
1 5 10 15
<210> 119
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 119
Gly Ile Ser Trp Ser Gly Gly Thr Thr Tyr
1 5 10
<210> 120
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 120
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Asp Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Gly Arg Thr Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Asp Glu Ala Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
165 170 175
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly
180 185 190
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
195 200 205
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
210 215 220
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
225 230 235 240
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
245 250 255
Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val
260 265 270
Ser Ser
<210> 121
<211> 276
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 121
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Phe Ser Gly Pro Gly Arg Thr Phe Ala
20 25 30
Arg Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Asn Arg Asp
35 40 45
Phe Ile Thr Gly Ile Ser Gly Ser Gly Asp Ser Thr Tyr Tyr Val Tyr
50 55 60
Pro Met Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met
65 70 75 80
Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala Asp Arg Glu Ile Asn Arg Ile Ala Asn Asp Lys Glu
100 105 110
Leu Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
165 170 175
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
180 185 190
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
195 200 205
Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser
210 215 220
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
225 230 235 240
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
245 250 255
Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val
260 265 270
Thr Val Ser Ser
275
<210> 122
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 122
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Leu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Glu Arg Thr Tyr Tyr Val Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Glu Glu Tyr Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
165 170 175
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly
180 185 190
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
195 200 205
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
210 215 220
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
225 230 235 240
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
245 250 255
Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val
260 265 270
Ser Ser
<210> 123
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 123
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Arg Arg Asn
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Leu
35 40 45
Ala Gly Ile Ser Trp Ser Gly Gly Thr Thr Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp
65 70 75 80
Leu Gln Met Ile Ser Pro Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Gly Asp Ile Gly Thr Leu Val Asn Asp Glu Asn Pro Arg
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
165 170 175
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly
180 185 190
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
195 200 205
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
210 215 220
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
225 230 235 240
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
245 250 255
Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val
260 265 270
Ser Ser
<210> 124
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 124
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ala Val Ser Val Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Gly Arg Thr Tyr Tyr Thr Asp Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ala Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Asp Glu Ala Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
165 170 175
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly
180 185 190
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
195 200 205
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
210 215 220
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
225 230 235 240
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
245 250 255
Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val
260 265 270
Ser Ser
<210> 125
<211> 275
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Arg Arg Thr Ile Ser Ser Gly
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Arg Trp Ser Ser Gly Met Pro Tyr Tyr Leu Asp Ser Val
50 55 60
Met Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Ser
65 70 75 80
Leu Gln Met Asn Ser Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Arg Ser Ala Phe Arg Asp Pro Ser Phe Asp Val Asn Tyr
100 105 110
Glu Tyr Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
165 170 175
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
180 185 190
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
195 200 205
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
210 215 220
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
225 230 235 240
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
245 250 255
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
260 265 270
Val Ser Ser
275
<210> 126
<211> 429
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 126
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Leu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Glu Arg Thr Tyr Tyr Val Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Glu Glu Tyr Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser
165 170 175
Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Tyr Pro Met Ala Trp Phe
180 185 190
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Val Ser Trp
195 200 205
Gly Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val Gln Gly Arg Phe Thr
210 215 220
Val Ser Arg Asp Tyr Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
225 230 235 240
Leu Lys Pro Glu Asp Ala Ala Val Tyr Tyr Cys Ala Gly Asp Pro Trp
245 250 255
Gly Arg Leu Phe Arg Val Lys Asp Gln Tyr Ser Asp Trp Gly Gln Gly
260 265 270
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
290 295 300
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
305 310 315 320
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
325 330 335
Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg
340 345 350
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
355 360 365
Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
370 375 380
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
385 390 395 400
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
405 410 415
Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
420 425
<210> 127
<211> 429
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 127
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Arg Arg Asn
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Leu
35 40 45
Ala Gly Ile Ser Trp Ser Gly Gly Thr Thr Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp
65 70 75 80
Leu Gln Met Ile Ser Pro Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Gly Asp Ile Gly Thr Leu Val Asn Asp Glu Asn Pro Arg
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser
165 170 175
Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Tyr Pro Met Ala Trp Phe
180 185 190
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Val Ser Trp
195 200 205
Gly Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val Gln Gly Arg Phe Thr
210 215 220
Val Ser Arg Asp Tyr Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
225 230 235 240
Leu Lys Pro Glu Asp Ala Ala Val Tyr Tyr Cys Ala Gly Asp Pro Trp
245 250 255
Gly Arg Leu Phe Arg Val Lys Asp Gln Tyr Ser Asp Trp Gly Gln Gly
260 265 270
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
290 295 300
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
305 310 315 320
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
325 330 335
Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg
340 345 350
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
355 360 365
Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
370 375 380
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
385 390 395 400
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
405 410 415
Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
420 425
<210> 128
<211> 429
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 128
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ala Val Ser Val Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Gly Arg Thr Tyr Tyr Thr Asp Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ala Arg Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Asp Glu Ala Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser
165 170 175
Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Tyr Pro Met Ala Trp Phe
180 185 190
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Val Ser Trp
195 200 205
Gly Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val Gln Gly Arg Phe Thr
210 215 220
Val Ser Arg Asp Tyr Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
225 230 235 240
Leu Lys Pro Glu Asp Ala Ala Val Tyr Tyr Cys Ala Gly Asp Pro Trp
245 250 255
Gly Arg Leu Phe Arg Val Lys Asp Gln Tyr Ser Asp Trp Gly Gln Gly
260 265 270
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
290 295 300
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
305 310 315 320
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
325 330 335
Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg
340 345 350
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
355 360 365
Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
370 375 380
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
385 390 395 400
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
405 410 415
Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
420 425
<210> 129
<211> 275
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 129
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Glu Arg Thr Tyr Tyr Val Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Glu Glu Tyr Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser
165 170 175
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly
180 185 190
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
195 200 205
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
210 215 220
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
225 230 235 240
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr
245 250 255
Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val
260 265 270
Ser Ser Ala
275
<210> 130
<211> 430
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 130
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Ser Ala Glu Arg Thr Tyr Tyr Val Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ala Asp Leu Asp Pro Asn Arg Ile Phe Ser Arg Glu Glu Tyr Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
145 150 155 160
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser
165 170 175
Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Pro Met Ala Trp Phe
180 185 190
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Val Ser Trp
195 200 205
Gly Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
210 215 220
Ile Ser Arg Asp Tyr Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
225 230 235 240
Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Gly Asp Pro Phe
245 250 255
Gly Arg Leu Phe Arg Val Lys Asp Gln Tyr Ser Asp Trp Gly Gln Gly
260 265 270
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
290 295 300
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
305 310 315 320
Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
325 330 335
Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg
340 345 350
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
355 360 365
Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
370 375 380
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
385 390 395 400
Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
405 410 415
Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ala
420 425 430
<210> 131
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 131
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 132
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 132
Glu Val Gln Leu Leu 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 Phe Arg Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 133
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 133
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala
115
<210> 134
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 134
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala
115
<210> 135
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 135
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 136
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 136
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys
100 105 110
Val Ser Ser Ala
115
<210> 137
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 137
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 138
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 138
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala
115
<210> 139
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 139
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ala
115
<210> 140
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ala Ala
115
<210> 141
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 141
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly
115
<210> 142
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 142
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly
115
<210> 143
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 143
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly
115
<210> 144
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 144
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 145
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 145
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala
115
<210> 146
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 146
Ser Phe Gly Met Ser
1 5
<210> 147
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 147
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 148
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 148
Gly Gly Ser Leu Ser Arg
1 5
<210> 149
<211> 930
<212> PRT
<213> Homo sapiens
<400> 149
Met Leu Leu Gly Trp Ala Ser Leu Leu Leu Cys Ala Phe Arg Leu Pro
1 5 10 15
Leu Ala Ala Val Gly Pro Ala Ala Thr Pro Ala Gln Asp Lys Ala Gly
20 25 30
Gln Pro Pro Thr Ala Ala Ala Ala Ala Gln Pro Arg Arg Arg Gln Gly
35 40 45
Glu Glu Val Gln Glu Arg Ala Glu Pro Pro Gly His Pro His Pro Leu
50 55 60
Ala Gln Arg Arg Arg Ser Lys Gly Leu Val Gln Asn Ile Asp Gln Leu
65 70 75 80
Tyr Ser Gly Gly Gly Lys Val Gly Tyr Leu Val Tyr Ala Gly Gly Arg
85 90 95
Arg Phe Leu Leu Asp Leu Glu Arg Asp Gly Ser Val Gly Ile Ala Gly
100 105 110
Phe Val Pro Ala Gly Gly Gly Thr Ser Ala Pro Trp Arg His Arg Ser
115 120 125
His Cys Phe Tyr Arg Gly Thr Val Asp Gly Ser Pro Arg Ser Leu Ala
130 135 140
Val Phe Asp Leu Cys Gly Gly Leu Asp Gly Phe Phe Ala Val Lys His
145 150 155 160
Ala Arg Tyr Thr Leu Lys Pro Leu Leu Arg Gly Pro Trp Ala Glu Glu
165 170 175
Glu Lys Gly Arg Val Tyr Gly Asp Gly Ser Ala Arg Ile Leu His Val
180 185 190
Tyr Thr Arg Glu Gly Phe Ser Phe Glu Ala Leu Pro Pro Arg Ala Ser
195 200 205
Cys Glu Thr Pro Ala Ser Thr Pro Glu Ala His Glu His Ala Pro Ala
210 215 220
His Ser Asn Pro Ser Gly Arg Ala Ala Leu Ala Ser Gln Leu Leu Asp
225 230 235 240
Gln Ser Ala Leu Ser Pro Ala Gly Gly Ser Gly Pro Gln Thr Trp Trp
245 250 255
Arg Arg Arg Arg Arg Ser Ile Ser Arg Ala Arg Gln Val Glu Leu Leu
260 265 270
Leu Val Ala Asp Ala Ser Met Ala Arg Leu Tyr Gly Arg Gly Leu Gln
275 280 285
His Tyr Leu Leu Thr Leu Ala Ser Ile Ala Asn Arg Leu Tyr Ser His
290 295 300
Ala Ser Ile Glu Asn His Ile Arg Leu Ala Val Val Lys Val Val Val
305 310 315 320
Leu Gly Asp Lys Asp Lys Ser Leu Glu Val Ser Lys Asn Ala Ala Thr
325 330 335
Thr Leu Lys Asn Phe Cys Lys Trp Gln His Gln His Asn Gln Leu Gly
340 345 350
Asp Asp His Glu Glu His Tyr Asp Ala Ala Ile Leu Phe Thr Arg Glu
355 360 365
Asp Leu Cys Gly His His Ser Cys Asp Thr Leu Gly Met Ala Asp Val
370 375 380
Gly Thr Ile Cys Ser Pro Glu Arg Ser Cys Ala Val Ile Glu Asp Asp
385 390 395 400
Gly Leu His Ala Ala Phe Thr Val Ala His Glu Ile Gly His Leu Leu
405 410 415
Gly Leu Ser His Asp Asp Ser Lys Phe Cys Glu Glu Thr Phe Gly Ser
420 425 430
Thr Glu Asp Lys Arg Leu Met Ser Ser Ile Leu Thr Ser Ile Asp Ala
435 440 445
Ser Lys Pro Trp Ser Lys Cys Thr Ser Ala Thr Ile Thr Glu Phe Leu
450 455 460
Asp Asp Gly His Gly Asn Cys Leu Leu Asp Leu Pro Arg Lys Gln Ile
465 470 475 480
Leu Gly Pro Glu Glu Leu Pro Gly Gln Thr Tyr Asp Ala Thr Gln Gln
485 490 495
Cys Asn Leu Thr Phe Gly Pro Glu Tyr Ser Val Cys Pro Gly Met Asp
500 505 510
Val Cys Ala Arg Leu Trp Cys Ala Val Val Arg Gln Gly Gln Met Val
515 520 525
Cys Leu Thr Lys Lys Leu Pro Ala Val Glu Gly Thr Pro Cys Gly Lys
530 535 540
Gly Arg Ile Cys Leu Gln Gly Lys Cys Val Asp Lys Thr Lys Lys Lys
545 550 555 560
Tyr Tyr Ser Thr Ser Ser His Gly Asn Trp Gly Ser Trp Gly Ser Trp
565 570 575
Gly Gln Cys Ser Arg Ser Cys Gly Gly Gly Val Gln Phe Ala Tyr Arg
580 585 590
His Cys Asn Asn Pro Ala Pro Arg Asn Asn Gly Arg Tyr Cys Thr Gly
595 600 605
Lys Arg Ala Ile Tyr Arg Ser Cys Ser Leu Met Pro Cys Pro Pro Asn
610 615 620
Gly Lys Ser Phe Arg His Glu Gln Cys Glu Ala Lys Asn Gly Tyr Gln
625 630 635 640
Ser Asp Ala Lys Gly Val Lys Thr Phe Val Glu Trp Val Pro Lys Tyr
645 650 655
Ala Gly Val Leu Pro Ala Asp Val Cys Lys Leu Thr Cys Arg Ala Lys
660 665 670
Gly Thr Gly Tyr Tyr Val Val Phe Ser Pro Lys Val Thr Asp Gly Thr
675 680 685
Glu Cys Arg Leu Tyr Ser Asn Ser Val Cys Val Arg Gly Lys Cys Val
690 695 700
Arg Thr Gly Cys Asp Gly Ile Ile Gly Ser Lys Leu Gln Tyr Asp Lys
705 710 715 720
Cys Gly Val Cys Gly Gly Asp Asn Ser Ser Cys Thr Lys Ile Val Gly
725 730 735
Thr Phe Asn Lys Lys Ser Lys Gly Tyr Thr Asp Val Val Arg Ile Pro
740 745 750
Glu Gly Ala Thr His Ile Lys Val Arg Gln Phe Lys Ala Lys Asp Gln
755 760 765
Thr Arg Phe Thr Ala Tyr Leu Ala Leu Lys Lys Lys Asn Gly Glu Tyr
770 775 780
Leu Ile Asn Gly Lys Tyr Met Ile Ser Thr Ser Glu Thr Ile Ile Asp
785 790 795 800
Ile Asn Gly Thr Val Met Asn Tyr Ser Gly Trp Ser His Arg Asp Asp
805 810 815
Phe Leu His Gly Met Gly Tyr Ser Ala Thr Lys Glu Ile Leu Ile Val
820 825 830
Gln Ile Leu Ala Thr Asp Pro Thr Lys Pro Leu Asp Val Arg Tyr Ser
835 840 845
Phe Phe Val Pro Lys Lys Ser Thr Pro Lys Val Asn Ser Val Thr Ser
850 855 860
His Gly Ser Asn Lys Val Gly Ser His Thr Ser Gln Pro Gln Trp Val
865 870 875 880
Thr Gly Pro Trp Leu Ala Cys Ser Arg Thr Cys Asp Thr Gly Trp His
885 890 895
Thr Arg Thr Val Gln Cys Gln Asp Gly Asn Arg Lys Leu Ala Lys Gly
900 905 910
Cys Pro Leu Ser Gln Arg Pro Ser Ala Phe Lys Gln Cys Leu Leu Lys
915 920 925
Lys Cys
930
<210> 150
<211> 636
<212> PRT
<213> Bos taurus
<400> 150
Met Leu Leu Gly Trp Ala Ala Leu Met Leu Cys Ala Leu Arg Leu Pro
1 5 10 15
Pro Val Ala Ala Gly Pro Thr Ala Ala Pro Ala Gln Asp Lys Ala Gly
20 25 30
Gln Pro Arg Ala Ala Ala Val Ala Ala Ala Ala Gln Pro Arg Gly Arg
35 40 45
Arg Gly Glu Glu Ala Gln Glu Pro Ala Glu Pro Pro Gly His Pro His
50 55 60
Pro Leu Ala Pro Gln Arg Gly Ser Arg Gly Leu Val Gln Asn Ile Asp
65 70 75 80
Gln Leu Tyr Ser Gly Gly Gly Lys Val Gly Tyr Leu Val Tyr Ala Gly
85 90 95
Gly Arg Arg Phe Leu Leu Asp Leu Glu Arg Asp Asp Ser Val Gly Ala
100 105 110
Ala Gly Leu Val Pro Ala Gly Gly Gly Pro Asn Ala Thr Arg Arg His
115 120 125
Arg Gly His Cys Phe Tyr Arg Gly Thr Val Asp Gly Ser Pro Arg Ser
130 135 140
Leu Ala Val Phe Asp Leu Cys Gly Gly Leu Asp Gly Phe Phe Ala Val
145 150 155 160
Lys Arg Ala Arg Tyr Thr Leu Gln Pro Leu Leu Arg Gly Pro Trp Ala
165 170 175
Glu Ala Glu Gly Asp Ala Arg Val Tyr Gly Asp Glu Ser Ala Arg Ile
180 185 190
Leu His Val Tyr Thr Arg Glu Gly Phe Ser Phe Glu Ala Leu Pro Pro
195 200 205
Arg Thr Ser Cys Glu Thr His Ala Ser Pro Pro Gly Ala Arg Glu Arg
210 215 220
Pro Pro Ala Pro Ser Arg Pro Asp Gly Arg Trp Ala Leu Ala Pro Gln
225 230 235 240
Gln Leu Pro Gly Gln Ser Ala Pro Ser Ser Asp Gly Ser Gln Gly Pro
245 250 255
Arg Thr Trp Trp Arg Arg Arg Arg Arg Ser Ile Ser Arg Ala Arg Gln
260 265 270
Val Glu Leu Leu Leu Val Ala Asp Ala Ser Met Ala Arg Met Tyr Gly
275 280 285
Arg Gly Leu Gln His Tyr Leu Leu Thr Leu Ala Ser Ile Ala Asn Lys
290 295 300
Leu Tyr Ser His Ala Ser Ile Glu Asn His Ile Arg Leu Val Val Val
305 310 315 320
Lys Val Val Val Leu Gly Asp Lys Asp Lys Ser Leu Glu Val Ser Lys
325 330 335
Asn Ala Ala Thr Thr Leu Lys Asn Phe Cys Lys Trp Gln His Gln His
340 345 350
Asn Gln Leu Gly Asp Asp His Glu Glu His Tyr Asp Ala Ala Ile Leu
355 360 365
Phe Thr Arg Glu Asp Leu Cys Gly His His Ser Cys Asp Thr Leu Gly
370 375 380
Met Ala Asp Val Gly Thr Ile Cys Ser Pro Glu Arg Ser Cys Ala Val
385 390 395 400
Ile Glu Asp Asp Gly Leu His Ala Ala Phe Thr Val Ala His Glu Ile
405 410 415
Gly His Leu Leu Gly Leu Ser His Asp Asp Ser Lys Phe Cys Glu Glu
420 425 430
Asn Phe Gly Ser Thr Glu Asp Lys Arg Leu Met Ser Ser Ile Leu Thr
435 440 445
Ser Ile Asp Ala Ser Lys Pro Trp Ser Lys Cys Thr Ser Ala Thr Ile
450 455 460
Thr Glu Phe Leu Asp Asp Gly His Gly Asn Cys Leu Leu Asp Leu Pro
465 470 475 480
Arg Lys Gln Ile Pro Gly Pro Glu Glu Leu Pro Gly Gln Thr Tyr Asp
485 490 495
Ala Ser Gln Gln Cys Asn Leu Thr Phe Gly Pro Glu Tyr Ser Val Cys
500 505 510
Pro Gly Met Asp Val Cys Ala Arg Leu Trp Cys Ala Val Val Arg Gln
515 520 525
Gly Gln Met Val Cys Leu Thr Lys Lys Leu Pro Ala Val Glu Gly Thr
530 535 540
Pro Cys Gly Lys Gly Arg Ile Cys Leu Gln Gly Lys Cys Val Asp Lys
545 550 555 560
Thr Lys Lys Lys Tyr Tyr Ser Thr Ser Ser His Gly Asn Trp Gly Ser
565 570 575
Trp Gly Ser Trp Gly Gln Cys Ser Arg Ser Cys Gly Gly Gly Val Gln
580 585 590
Phe Ala Tyr Arg His Cys Asn Asn Pro Ala Pro Arg Asn Asn Gly Arg
595 600 605
Tyr Cys Thr Gly Lys Arg Ala Ile Tyr Arg Ser Cys Ser Val Thr Pro
610 615 620
Cys Pro His His His His His His His His His His
625 630 635
<210> 151
<211> 629
<212> PRT
<213> Rattus norvegicus
<400> 151
Met Arg Leu Glu Trp Ala Ser Leu Leu Leu Leu Leu Leu Leu Leu Cys
1 5 10 15
Ala Ser Cys Leu Ala Leu Ala Ala Asp Asn Pro Ala Ala Ala Pro Ala
20 25 30
Gln Asp Lys Thr Arg Gln Pro Arg Ala Ala Ala Ala Ala Ala Gln Pro
35 40 45
Asp Gln Arg Gln Trp Glu Glu Thr Gln Glu Arg Gly His Pro Gln Pro
50 55 60
Leu Ala Arg Gln Arg Arg Ser Ser Gly Leu Val Gln Asn Ile Asp Gln
65 70 75 80
Leu Tyr Ser Gly Gly Gly Lys Val Gly Tyr Leu Val Tyr Ala Gly Gly
85 90 95
Arg Arg Phe Leu Leu Asp Leu Glu Arg Asp Asp Thr Val Gly Ala Ala
100 105 110
Gly Gly Ile Val Thr Ala Gly Gly Leu Ser Ala Ser Ser Gly His Arg
115 120 125
Gly His Cys Phe Tyr Arg Gly Thr Val Asp Gly Ser Pro Arg Ser Leu
130 135 140
Ala Val Phe Asp Leu Cys Gly Gly Leu Asp Gly Phe Phe Ala Val Lys
145 150 155 160
His Ala Arg Tyr Thr Leu Lys Pro Leu Leu Arg Gly Ser Trp Ala Glu
165 170 175
Ser Glu Arg Val Tyr Gly Asp Gly Ser Ser Arg Ile Leu His Val Tyr
180 185 190
Thr Arg Glu Gly Phe Ser Phe Glu Ala Leu Pro Pro Arg Thr Ser Cys
195 200 205
Glu Thr Pro Ala Ser Pro Ser Gly Ala Gln Glu Ser Pro Ser Val His
210 215 220
Ser Ser Ser Arg Arg Arg Thr Glu Leu Ala Pro Gln Leu Leu Asp His
225 230 235 240
Ser Ala Phe Ser Pro Ala Gly Asn Ala Gly Pro Gln Thr Trp Trp Arg
245 250 255
Arg Arg Arg Arg Ser Ile Ser Arg Ala Arg Gln Val Glu Leu Leu Leu
260 265 270
Val Ala Asp Ser Ser Met Ala Lys Met Tyr Gly Arg Gly Leu Gln His
275 280 285
Tyr Leu Leu Thr Leu Ala Ser Ile Ala Asn Arg Leu Tyr Ser His Ala
290 295 300
Ser Ile Glu Asn His Ile Arg Leu Ala Val Val Lys Val Val Val Leu
305 310 315 320
Thr Asp Lys Ser Leu Glu Val Ser Lys Asn Ala Ala Thr Thr Leu Lys
325 330 335
Asn Phe Cys Lys Trp Gln His Gln His Asn Gln Leu Gly Asp Asp His
340 345 350
Glu Glu His Tyr Asp Ala Ala Ile Leu Phe Thr Arg Glu Asp Leu Cys
355 360 365
Gly His His Ser Cys Asp Thr Leu Gly Met Ala Asp Val Gly Thr Ile
370 375 380
Cys Ser Pro Glu Arg Ser Cys Ala Val Ile Glu Asp Asp Gly Leu His
385 390 395 400
Ala Ala Phe Thr Val Ala His Glu Ile Gly His Leu Leu Gly Leu Ser
405 410 415
His Asp Asp Ser Lys Phe Cys Glu Glu Asn Phe Gly Ser Thr Glu Asp
420 425 430
Lys Arg Leu Met Ser Ser Ile Leu Thr Ser Ile Asp Ala Ser Lys Pro
435 440 445
Trp Ser Lys Cys Thr Ser Ala Thr Ile Thr Glu Phe Leu Asp Asp Gly
450 455 460
His Gly Asn Cys Leu Leu Asp Val Pro Arg Lys Gln Ile Leu Gly Pro
465 470 475 480
Glu Glu Leu Pro Gly Gln Thr Tyr Asp Ala Thr Gln Gln Cys Asn Leu
485 490 495
Thr Phe Gly Pro Glu Tyr Ser Val Cys Pro Gly Met Asp Val Cys Ala
500 505 510
Arg Leu Trp Cys Ala Val Val Arg Gln Gly Gln Met Val Cys Leu Thr
515 520 525
Lys Lys Leu Pro Ala Val Glu Gly Thr Pro Cys Gly Lys Gly Arg Ile
530 535 540
Cys Leu Gln Gly Lys Cys Val Asp Lys Thr Lys Lys Lys Tyr Tyr Ser
545 550 555 560
Thr Ser Ser His Gly Asn Trp Gly Ser Trp Gly Pro Trp Gly Gln Cys
565 570 575
Ser Arg Ser Cys Gly Gly Gly Val Gln Phe Ala Tyr Arg His Cys Asn
580 585 590
Asn Pro Ala Pro Arg Asn Ser Gly Arg Tyr Cys Thr Gly Lys Arg Ala
595 600 605
Ile Tyr Arg Ser Cys Ser Val Ile Pro Cys Pro His His His His His
610 615 620
His His His His His
625
<210> 152
<211> 632
<212> PRT
<213> Cavia porcellus
<400> 152
Met Leu Leu Gly Trp Ala Ser Leu Leu Leu Cys Ala Phe Arg Leu Pro
1 5 10 15
Gln Ala Ala Ala Ser Ala Ala Ala Ala Pro Ala Gln Asp Lys Ala Gly
20 25 30
Gln Pro Arg Ala Ala Ala Ala Ala Pro Gln Pro Arg Arg Arg Gln Gly
35 40 45
Glu His Ala Pro Leu Arg Val Glu Pro Pro Gly His Pro His Ala Leu
50 55 60
Ala Pro Gln Arg Arg Gly Arg Gly Leu Leu Gln Ser Ile Asp Arg Leu
65 70 75 80
Tyr Ser Gly Gly Gly Lys Val Gly Tyr Leu Val Tyr Ala Gly Gly Arg
85 90 95
Arg Phe Leu Leu Asp Leu Glu Arg Asp Gly Ser Val Gly Ala Ala Gly
100 105 110
Leu Phe Pro Ala Gly Gly Gly Leu Ser Ala Pro Arg Arg His Arg Ser
115 120 125
His Cys Phe Tyr Arg Gly Thr Val Asp Gly Ser Pro Arg Ser Leu Ala
130 135 140
Val Phe Asp Leu Cys Gly Gly Leu Arg Gly Phe Phe Ala Val Lys His
145 150 155 160
Ala Arg Tyr Thr Val Lys Pro Leu Leu Arg Gly Pro Trp Ala Glu Ala
165 170 175
Asp Thr Pro Arg Val Tyr Gly Asp Glu Ser Ala Arg Ile Pro His Val
180 185 190
Tyr Thr Arg Glu Gly Phe Ser Phe Glu Ala Leu Pro Pro Arg Ala Ser
195 200 205
Cys Glu Thr Pro Ala Ser Gln Pro Gly Pro His Glu Arg Pro Pro Ala
210 215 220
His Asn Ser Pro Gly Arg His Ser Thr Val Asp Pro Gln Leu Pro Glu
225 230 235 240
Leu Ser Ala Leu Ser Pro Ala Gly Asp Pro Gly Gln Gln Ile Trp Trp
245 250 255
Arg Arg Arg Arg Arg Ser Ile Ser Arg Ala Arg Gln Val Glu Leu Leu
260 265 270
Leu Val Ala Asp Gly Ser Met Ala Lys Met Tyr Gly Arg Gly Leu Gln
275 280 285
His Tyr Leu Leu Thr Leu Ala Ser Ile Ala Asn Arg Leu Tyr Ser His
290 295 300
Ala Ser Ile Glu Asn His Ile Arg Leu Ala Val Val Lys Val Val Val
305 310 315 320
Leu Gly Asp Lys Asp Lys Ser Leu Glu Val Ser Lys Asn Ala Ala Thr
325 330 335
Thr Leu Lys Asn Phe Cys Lys Trp Gln His Gln His Asn Gln Leu Gly
340 345 350
Asp Asp His Glu Glu His Tyr Asp Ala Ala Ile Leu Phe Thr Arg Glu
355 360 365
Asp Leu Cys Gly His His Ser Cys Asp Thr Leu Gly Met Ala Asp Val
370 375 380
Gly Thr Ile Cys Ser Pro Glu Arg Ser Cys Ala Val Ile Glu Asp Asp
385 390 395 400
Gly Leu His Ala Ala Phe Thr Val Ala His Glu Ile Gly His Leu Leu
405 410 415
Gly Leu Ser His Asp Asp Ser Lys Phe Cys Glu Glu Asn Phe Gly Leu
420 425 430
Thr Glu Asp Lys Arg Leu Met Ser Ser Ile Leu Thr Ser Ile Asp Ala
435 440 445
Ser Lys Pro Trp Ser Lys Cys Thr Ser Ala Thr Met Thr Glu Phe Leu
450 455 460
Asp Asp Gly His Gly Asn Cys Leu Leu Asp Val Pro Arg Lys Gln Ile
465 470 475 480
Pro Ser Pro Glu Glu Leu Pro Gly Gln Thr Tyr Asp Ala Thr Gln Gln
485 490 495
Cys Asn Leu Thr Phe Gly Pro Glu Tyr Ser Val Cys Pro Gly Met Asp
500 505 510
Val Cys Ala Arg Leu Trp Cys Ala Val Val Arg Gln Gly Gln Met Val
515 520 525
Cys Leu Thr Lys Lys Leu Pro Ala Val Glu Gly Thr Pro Cys Gly Lys
530 535 540
Gly Arg Ile Cys Leu Gln Gly Lys Cys Val Asp Lys Thr Lys Lys Lys
545 550 555 560
Tyr Tyr Ser Thr Ser Ser His Gly Asn Trp Gly Ser Trp Gly Pro Trp
565 570 575
Gly Gln Cys Ser Arg Ser Cys Gly Gly Gly Val Gln Phe Ala Tyr Arg
580 585 590
His Cys Asn Asn Pro Ala Pro Arg Asn Ser Gly Arg Tyr Cys Thr Gly
595 600 605
Lys Arg Ala Ile Tyr Arg Ser Cys Ser Val Thr Pro Cys Pro His His
610 615 620
His His His His His His His His
625 630
<210> 153
<211> 632
<212> PRT
<213> Mus musculus
<400> 153
Met Arg Leu Glu Trp Ala Pro Leu Leu Leu Leu Leu Leu Leu Leu Ser
1 5 10 15
Ala Ser Cys Leu Ser Leu Ala Ala Asp Ser Pro Ala Ala Ala Pro Ala
20 25 30
Gln Asp Lys Thr Arg Gln Pro Gln Ala Ala Ala Ala Ala Ala Glu Pro
35 40 45
Asp Gln Pro Gln Gly Glu Glu Thr Arg Glu Arg Gly His Leu Gln Pro
50 55 60
Leu Ala Gly Gln Arg Arg Ser Gly Gly Leu Val Gln Asn Ile Asp Gln
65 70 75 80
Leu Tyr Ser Gly Gly Gly Lys Val Gly Tyr Leu Val Tyr Ala Gly Gly
85 90 95
Arg Arg Phe Leu Leu Asp Leu Glu Arg Asp Asp Thr Val Gly Ala Ala
100 105 110
Gly Ser Ile Val Thr Ala Gly Gly Gly Leu Ser Ala Ser Ser Gly His
115 120 125
Arg Gly His Cys Phe Tyr Arg Gly Thr Val Asp Gly Ser Pro Arg Ser
130 135 140
Leu Ala Val Phe Asp Leu Cys Gly Gly Leu Asp Gly Phe Phe Ala Val
145 150 155 160
Lys His Ala Arg Tyr Thr Leu Lys Pro Leu Leu Arg Gly Ser Trp Ala
165 170 175
Glu Tyr Glu Arg Ile Tyr Gly Asp Gly Ser Ser Arg Ile Leu His Val
180 185 190
Tyr Asn Arg Glu Gly Phe Ser Phe Glu Ala Leu Pro Pro Arg Ala Ser
195 200 205
Cys Glu Thr Pro Ala Ser Pro Ser Gly Pro Gln Glu Ser Pro Ser Val
210 215 220
His Ser Arg Ser Arg Arg Arg Ser Ala Leu Ala Pro Gln Leu Leu Asp
225 230 235 240
His Ser Ala Phe Ser Pro Ser Gly Asn Ala Gly Pro Gln Thr Trp Trp
245 250 255
Arg Arg Arg Arg Arg Ser Ile Ser Arg Ala Arg Gln Val Glu Leu Leu
260 265 270
Leu Val Ala Asp Ser Ser Met Ala Arg Met Tyr Gly Arg Gly Leu Gln
275 280 285
His Tyr Leu Leu Thr Leu Ala Ser Ile Ala Asn Arg Leu Tyr Ser His
290 295 300
Ala Ser Ile Glu Asn His Ile Arg Leu Ala Val Val Lys Val Val Val
305 310 315 320
Leu Thr Asp Lys Asp Thr Ser Leu Glu Val Ser Lys Asn Ala Ala Thr
325 330 335
Thr Leu Lys Asn Phe Cys Lys Trp Gln His Gln His Asn Gln Leu Gly
340 345 350
Asp Asp His Glu Glu His Tyr Asp Ala Ala Ile Leu Phe Thr Arg Glu
355 360 365
Asp Leu Cys Gly His His Ser Cys Asp Thr Leu Gly Met Ala Asp Val
370 375 380
Gly Thr Ile Cys Ser Pro Glu Arg Ser Cys Ala Val Ile Glu Asp Asp
385 390 395 400
Gly Leu His Ala Ala Phe Thr Val Ala His Glu Ile Gly His Leu Leu
405 410 415
Gly Leu Ser His Asp Asp Ser Lys Phe Cys Glu Glu Asn Phe Gly Thr
420 425 430
Thr Glu Asp Lys Arg Leu Met Ser Ser Ile Leu Thr Ser Ile Asp Ala
435 440 445
Ser Lys Pro Trp Ser Lys Cys Thr Ser Ala Thr Ile Thr Glu Phe Leu
450 455 460
Asp Asp Gly His Gly Asn Cys Leu Leu Asp Leu Pro Arg Lys Gln Ile
465 470 475 480
Leu Gly Pro Glu Glu Leu Pro Gly Gln Thr Tyr Asp Ala Thr Gln Gln
485 490 495
Cys Asn Leu Thr Phe Gly Pro Glu Tyr Ser Val Cys Pro Gly Met Asp
500 505 510
Val Cys Ala Arg Leu Trp Cys Ala Val Val Arg Gln Gly Gln Met Val
515 520 525
Cys Leu Thr Lys Lys Leu Pro Ala Val Glu Gly Thr Pro Cys Gly Lys
530 535 540
Gly Arg Val Cys Leu Gln Gly Lys Cys Val Asp Lys Thr Lys Lys Lys
545 550 555 560
Tyr Tyr Ser Thr Ser Ser His Gly Asn Trp Gly Ser Trp Gly Pro Trp
565 570 575
Gly Gln Cys Ser Arg Ser Cys Gly Gly Gly Val Gln Phe Ala Tyr Arg
580 585 590
His Cys Asn Asn Pro Ala Pro Arg Asn Ser Gly Arg Tyr Cys Thr Gly
595 600 605
Lys Arg Ala Ile Tyr Arg Ser Cys Ser Val Thr Pro Cys Pro His His
610 615 620
His His His His His His His His
625 630
<210> 154
<211> 632
<212> PRT
<213> Macaca mulatta
<400> 154
Met Leu Leu Gly Trp Ala Ser Leu Leu Leu Cys Ala Phe Arg Leu Pro
1 5 10 15
Leu Ala Ala Ala Gly Pro Ala Ala Ala Pro Ala Gln Asp Lys Ala Gly
20 25 30
Gln Pro Ala Thr Ala Ala Ala Ala Ala Gln Pro Arg Arg Arg Gln Gly
35 40 45
Glu Glu Val Gln Glu Arg Thr Glu Pro Pro Gly His Pro His Pro Leu
50 55 60
Ala Gln Arg Arg Ser Ser Lys Gly Leu Val Gln Asn Ile Asp Gln Leu
65 70 75 80
Tyr Ser Gly Gly Gly Lys Val Gly Tyr Leu Val Tyr Ala Gly Gly Arg
85 90 95
Arg Phe Leu Leu Asp Leu Glu Arg Asp Gly Ser Val Gly Thr Ala Gly
100 105 110
Phe Val Pro Thr Glu Gly Gly Thr Ser Ala Pro Trp Arg His Arg Ser
115 120 125
His Cys Phe Tyr Arg Gly Thr Val Asp Gly Ser Pro Arg Ser Leu Ala
130 135 140
Val Phe Asp Leu Cys Gly Gly Leu Asp Gly Phe Phe Ala Val Lys His
145 150 155 160
Ala Arg Tyr Thr Leu Lys Pro Leu Leu Arg Gly Pro Trp Ala Glu Glu
165 170 175
Glu Thr Arg Arg Val Tyr Gly Asp Gly Ser Ala Arg Ile Leu His Val
180 185 190
Tyr Thr Arg Glu Gly Phe Ser Phe Glu Ala Leu Gln Pro Arg Ala Ser
195 200 205
Cys Glu Thr Pro Ala Ser Thr Pro Glu Pro His Glu Arg Pro Pro Ala
210 215 220
His Ser Asn Pro Gly Gly Arg Ala Ala Leu Ala Ser Gln Leu Leu Asp
225 230 235 240
Gln Ser Ala Val Ser Pro Ala Gly Gly Pro Gly Pro Gln Thr Trp Trp
245 250 255
Arg Arg Arg Arg Arg Ser Ile Ser Arg Ala Arg Gln Val Glu Leu Leu
260 265 270
Leu Val Ala Asp Ala Ser Met Ala Arg Leu Tyr Gly Arg Gly Leu Gln
275 280 285
His Tyr Leu Leu Thr Leu Ala Ser Ile Ala Asn Arg Leu Tyr Ser His
290 295 300
Ala Ser Ile Glu Asn His Ile Arg Leu Ala Val Val Lys Val Val Val
305 310 315 320
Leu Gly Asp Lys Asp Lys Ser Leu Glu Val Ser Lys Asn Ala Ala Thr
325 330 335
Thr Leu Lys Asn Phe Cys Lys Trp Gln His Gln His Asn Gln Leu Gly
340 345 350
Asp Asp His Glu Glu His Tyr Asp Ala Ala Ile Leu Phe Thr Arg Glu
355 360 365
Asp Leu Cys Gly His His Ser Cys Asp Thr Leu Gly Met Ala Asp Val
370 375 380
Gly Thr Ile Cys Ser Pro Glu Arg Ser Cys Ala Val Ile Glu Asp Asp
385 390 395 400
Gly Leu His Ala Ala Phe Thr Val Ala His Glu Ile Gly His Leu Leu
405 410 415
Gly Leu Ser His Asp Asp Ser Lys Phe Cys Glu Glu Thr Phe Gly Ser
420 425 430
Thr Glu Asp Lys Arg Leu Met Ser Ser Ile Leu Thr Ser Ile Asp Ala
435 440 445
Ser Lys Pro Trp Ser Lys Cys Thr Ser Ala Thr Ile Thr Glu Phe Leu
450 455 460
Asp Asp Gly His Gly Asn Cys Leu Leu Asp Gln Pro Arg Lys Gln Ile
465 470 475 480
Leu Gly Pro Glu Glu Leu Pro Gly Gln Thr Tyr Asp Ala Thr Gln Gln
485 490 495
Cys Asn Leu Thr Phe Gly Pro Glu Tyr Ser Val Cys Pro Gly Met Asp
500 505 510
Val Cys Ala Arg Leu Trp Cys Ala Val Val Arg Gln Gly Gln Met Val
515 520 525
Cys Leu Thr Lys Lys Leu Pro Ala Val Glu Gly Thr Pro Cys Gly Lys
530 535 540
Gly Arg Ile Cys Leu Gln Gly Lys Cys Val Asp Lys Thr Lys Lys Lys
545 550 555 560
Tyr Tyr Ser Thr Ser Ser His Gly Asn Trp Gly Ser Trp Gly Ser Trp
565 570 575
Gly Gln Cys Ser Arg Ser Cys Gly Gly Gly Val Gln Phe Ala Tyr Arg
580 585 590
His Cys Asn Asn Pro Ala Pro Arg Asn Asn Gly Arg Tyr Cys Thr Gly
595 600 605
Lys Arg Ala Ile Tyr Arg Ser Cys Gly Leu Met Pro Cys Pro His His
610 615 620
His His His His His His His His
625 630
<210> 155
<211> 2415
<212> PRT
<213> Homo sapiens
<400> 155
Met Thr Thr Leu Leu Trp Val Phe Val Thr Leu Arg Val Ile Thr Ala
1 5 10 15
Ala Val Thr Val Glu Thr Ser Asp His Asp Asn Ser Leu Ser Val Ser
20 25 30
Ile Pro Gln Pro Ser Pro Leu Arg Val Leu Leu Gly Thr Ser Leu Thr
35 40 45
Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val Thr Thr Ala Pro
50 55 60
Ser Thr Ala Pro Leu Ala Pro Arg Ile Lys Trp Ser Arg Val Ser Lys
65 70 75 80
Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly Arg Val Arg Val
85 90 95
Asn Ser Ala Tyr Gln Asp Lys Val Ser Leu Pro Asn Tyr Pro Ala Ile
100 105 110
Pro Ser Asp Ala Thr Leu Glu Val Gln Ser Leu Arg Ser Asn Asp Ser
115 120 125
Gly Val Tyr Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Glu Ala
130 135 140
Thr Leu Glu Val Val Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile
145 150 155 160
Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
165 170 175
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
180 185 190
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
195 200 205
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
210 215 220
Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu
225 230 235 240
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe
245 250 255
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu
260 265 270
Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly His Val Tyr Leu
275 280 285
Ala Trp Gln Ala Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
290 295 300
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
305 310 315 320
Asn Leu Leu Gly Val Arg Thr Val Tyr Val His Ala Asn Gln Thr Gly
325 330 335
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
340 345 350
Asp Phe Val Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Glu
355 360 365
Asp Ile Thr Val Gln Thr Val Thr Trp Pro Asp Met Glu Leu Pro Leu
370 375 380
Pro Arg Asn Ile Thr Glu Gly Glu Ala Arg Gly Ser Val Ile Leu Thr
385 390 395 400
Val Lys Pro Ile Phe Glu Val Ser Pro Ser Pro Leu Glu Pro Glu Glu
405 410 415
Pro Phe Thr Phe Ala Pro Glu Ile Gly Ala Thr Ala Phe Ala Glu Val
420 425 430
Glu Asn Glu Thr Gly Glu Ala Thr Arg Pro Trp Gly Phe Pro Thr Pro
435 440 445
Gly Leu Gly Pro Ala Thr Ala Phe Thr Ser Glu Asp Leu Val Val Gln
450 455 460
Val Thr Ala Val Pro Gly Gln Pro His Leu Pro Gly Gly Val Val Phe
465 470 475 480
His Tyr Arg Pro Gly Pro Thr Arg Tyr Ser Leu Thr Phe Glu Glu Ala
485 490 495
Gln Gln Ala Cys Pro Gly Thr Gly Ala Val Ile Ala Ser Pro Glu Gln
500 505 510
Leu Gln Ala Ala Tyr Glu Ala Gly Tyr Glu Gln Cys Asp Ala Gly Trp
515 520 525
Leu Arg Asp Gln Thr Val Arg Tyr Pro Ile Val Ser Pro Arg Thr Pro
530 535 540
Cys Val Gly Asp Lys Asp Ser Ser Pro Gly Val Arg Thr Tyr Gly Val
545 550 555 560
Arg Pro Ser Thr Glu Thr Tyr Asp Val Tyr Cys Phe Val Asp Arg Leu
565 570 575
Glu Gly Glu Val Phe Phe Ala Thr Arg Leu Glu Gln Phe Thr Phe Gln
580 585 590
Glu Ala Leu Glu Phe Cys Glu Ser His Asn Ala Thr Ala Thr Thr Gly
595 600 605
Gln Leu Tyr Ala Ala Trp Ser Arg Gly Leu Asp Lys Cys Tyr Ala Gly
610 615 620
Trp Leu Ala Asp Gly Ser Leu Arg Tyr Pro Ile Val Thr Pro Arg Pro
625 630 635 640
Ala Cys Gly Gly Asp Lys Pro Gly Val Arg Thr Val Tyr Leu Tyr Pro
645 650 655
Asn Gln Thr Gly Leu Pro Asp Pro Leu Ser Arg His His Ala Phe Cys
660 665 670
Phe Arg Gly Ile Ser Ala Val Pro Ser Pro Gly Glu Glu Glu Gly Gly
675 680 685
Thr Pro Thr Ser Pro Ser Gly Val Glu Glu Trp Ile Val Thr Gln Val
690 695 700
Val Pro Gly Val Ala Ala Val Pro Val Glu Glu Glu Thr Thr Ala Val
705 710 715 720
Pro Ser Gly Glu Thr Thr Ala Ile Leu Glu Phe Thr Thr Glu Pro Glu
725 730 735
Asn Gln Thr Glu Trp Glu Pro Ala Tyr Thr Pro Val Gly Thr Ser Pro
740 745 750
Leu Pro Gly Ile Leu Pro Thr Trp Pro Pro Thr Gly Ala Glu Thr Glu
755 760 765
Glu Ser Thr Glu Gly Pro Ser Ala Thr Glu Val Pro Ser Ala Ser Glu
770 775 780
Glu Pro Ser Pro Ser Glu Val Pro Phe Pro Ser Glu Glu Pro Ser Pro
785 790 795 800
Ser Glu Glu Pro Phe Pro Ser Val Arg Pro Phe Pro Ser Val Glu Leu
805 810 815
Phe Pro Ser Glu Glu Pro Phe Pro Ser Lys Glu Pro Ser Pro Ser Glu
820 825 830
Glu Pro Ser Ala Ser Glu Glu Pro Tyr Thr Pro Ser Pro Pro Glu Pro
835 840 845
Ser Trp Thr Glu Leu Pro Ser Ser Gly Glu Glu Ser Gly Ala Pro Asp
850 855 860
Val Ser Gly Asp Phe Thr Gly Ser Gly Asp Val Ser Gly His Leu Asp
865 870 875 880
Phe Ser Gly Gln Leu Ser Gly Asp Arg Ala Ser Gly Leu Pro Ser Gly
885 890 895
Asp Leu Asp Ser Ser Gly Leu Thr Ser Thr Val Gly Ser Gly Leu Thr
900 905 910
Val Glu Ser Gly Leu Pro Ser Gly Asp Glu Glu Arg Ile Glu Trp Pro
915 920 925
Ser Thr Pro Thr Val Gly Glu Leu Pro Ser Gly Ala Glu Ile Leu Glu
930 935 940
Gly Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu Pro Ser Gly Glu
945 950 955 960
Val Leu Glu Thr Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu Pro
965 970 975
Ser Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val Glu Asp Ile Ser
980 985 990
Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val Glu
995 1000 1005
Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala
1010 1015 1020
Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu
1025 1030 1035
Glu Thr Thr Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser
1040 1045 1050
Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val Glu Asp Ile Ser
1055 1060 1065
Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val
1070 1075 1080
Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala
1085 1090 1095
Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val
1100 1105 1110
Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro
1115 1120 1125
Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile
1130 1135 1140
Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly
1145 1150 1155
Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr
1160 1165 1170
Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu
1175 1180 1185
Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu
1190 1195 1200
Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp
1205 1210 1215
Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro
1220 1225 1230
Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu
1235 1240 1245
Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly
1250 1255 1260
Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly
1265 1270 1275
Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val Glu
1280 1285 1290
Glu Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala
1295 1300 1305
Pro Gly Val Asp Glu Ile Ser Gly Leu Pro Ser Gly Glu Val Leu
1310 1315 1320
Glu Thr Thr Ala Pro Gly Val Glu Glu Ile Ser Gly Leu Pro Ser
1325 1330 1335
Gly Glu Val Leu Glu Thr Ser Thr Ser Ala Val Gly Asp Leu Ser
1340 1345 1350
Gly Leu Pro Ser Gly Gly Glu Val Leu Glu Ile Ser Val Ser Gly
1355 1360 1365
Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Val Glu Thr
1370 1375 1380
Ser Ala Ser Gly Ile Glu Asp Val Ser Glu Leu Pro Ser Gly Glu
1385 1390 1395
Gly Leu Glu Thr Ser Ala Ser Gly Val Glu Asp Leu Ser Arg Leu
1400 1405 1410
Pro Ser Gly Glu Glu Val Leu Glu Ile Ser Ala Ser Gly Phe Gly
1415 1420 1425
Asp Leu Ser Gly Val Pro Ser Gly Gly Glu Gly Leu Glu Thr Ser
1430 1435 1440
Ala Ser Glu Val Gly Thr Asp Leu Ser Gly Leu Pro Ser Gly Arg
1445 1450 1455
Glu Gly Leu Glu Thr Ser Ala Ser Gly Ala Glu Asp Leu Ser Gly
1460 1465 1470
Leu Pro Ser Gly Lys Glu Asp Leu Val Gly Ser Ala Ser Gly Asp
1475 1480 1485
Leu Asp Leu Gly Lys Leu Pro Ser Gly Thr Leu Gly Ser Gly Gln
1490 1495 1500
Ala Pro Glu Thr Ser Gly Leu Pro Ser Gly Phe Ser Gly Glu Tyr
1505 1510 1515
Ser Gly Val Asp Leu Gly Ser Gly Pro Pro Ser Gly Leu Pro Asp
1520 1525 1530
Phe Ser Gly Leu Pro Ser Gly Phe Pro Thr Val Ser Leu Val Asp
1535 1540 1545
Ser Thr Leu Val Glu Val Val Thr Ala Ser Thr Ala Ser Glu Leu
1550 1555 1560
Glu Gly Arg Gly Thr Ile Gly Ile Ser Gly Ala Gly Glu Ile Ser
1565 1570 1575
Gly Leu Pro Ser Ser Glu Leu Asp Ile Ser Gly Arg Ala Ser Gly
1580 1585 1590
Leu Pro Ser Gly Thr Glu Leu Ser Gly Gln Ala Ser Gly Ser Pro
1595 1600 1605
Asp Val Ser Gly Glu Ile Pro Gly Leu Phe Gly Val Ser Gly Gln
1610 1615 1620
Pro Ser Gly Phe Pro Asp Thr Ser Gly Glu Thr Ser Gly Val Thr
1625 1630 1635
Glu Leu Ser Gly Leu Ser Ser Gly Gln Pro Gly Val Ser Gly Glu
1640 1645 1650
Ala Ser Gly Val Leu Tyr Gly Thr Ser Gln Pro Phe Gly Ile Thr
1655 1660 1665
Asp Leu Ser Gly Glu Thr Ser Gly Val Pro Asp Leu Ser Gly Gln
1670 1675 1680
Pro Ser Gly Leu Pro Gly Phe Ser Gly Ala Thr Ser Gly Val Pro
1685 1690 1695
Asp Leu Val Ser Gly Thr Thr Ser Gly Ser Gly Glu Ser Ser Gly
1700 1705 1710
Ile Thr Phe Val Asp Thr Ser Leu Val Glu Val Ala Pro Thr Thr
1715 1720 1725
Phe Lys Glu Glu Glu Gly Leu Gly Ser Val Glu Leu Ser Gly Leu
1730 1735 1740
Pro Ser Gly Glu Ala Asp Leu Ser Gly Lys Ser Gly Met Val Asp
1745 1750 1755
Val Ser Gly Gln Phe Ser Gly Thr Val Asp Ser Ser Gly Phe Thr
1760 1765 1770
Ser Gln Thr Pro Glu Phe Ser Gly Leu Pro Ser Gly Ile Ala Glu
1775 1780 1785
Val Ser Gly Glu Ser Ser Arg Ala Glu Ile Gly Ser Ser Leu Pro
1790 1795 1800
Ser Gly Ala Tyr Tyr Gly Ser Gly Thr Pro Ser Ser Phe Pro Thr
1805 1810 1815
Val Ser Leu Val Asp Arg Thr Leu Val Glu Ser Val Thr Gln Ala
1820 1825 1830
Pro Thr Ala Gln Glu Ala Gly Glu Gly Pro Ser Gly Ile Leu Glu
1835 1840 1845
Leu Ser Gly Ala His Ser Gly Ala Pro Asp Met Ser Gly Glu His
1850 1855 1860
Ser Gly Phe Leu Asp Leu Ser Gly Leu Gln Ser Gly Leu Ile Glu
1865 1870 1875
Pro Ser Gly Glu Pro Pro Gly Thr Pro Tyr Phe Ser Gly Asp Phe
1880 1885 1890
Ala Ser Thr Thr Asn Val Ser Gly Glu Ser Ser Val Ala Met Gly
1895 1900 1905
Thr Ser Gly Glu Ala Ser Gly Leu Pro Glu Val Thr Leu Ile Thr
1910 1915 1920
Ser Glu Phe Val Glu Gly Val Thr Glu Pro Thr Ile Ser Gln Glu
1925 1930 1935
Leu Gly Gln Arg Pro Pro Val Thr His Thr Pro Gln Leu Phe Glu
1940 1945 1950
Ser Ser Gly Lys Val Ser Thr Ala Gly Asp Ile Ser Gly Ala Thr
1955 1960 1965
Pro Val Leu Pro Gly Ser Gly Val Glu Val Ser Ser Val Pro Glu
1970 1975 1980
Ser Ser Ser Glu Thr Ser Ala Tyr Pro Glu Ala Gly Phe Gly Ala
1985 1990 1995
Ser Ala Ala Pro Glu Ala Ser Arg Glu Asp Ser Gly Ser Pro Asp
2000 2005 2010
Leu Ser Glu Thr Thr Ser Ala Phe His Glu Ala Asn Leu Glu Arg
2015 2020 2025
Ser Ser Gly Leu Gly Val Ser Gly Ser Thr Leu Thr Phe Gln Glu
2030 2035 2040
Gly Glu Ala Ser Ala Ala Pro Glu Val Ser Gly Glu Ser Thr Thr
2045 2050 2055
Thr Ser Asp Val Gly Thr Glu Ala Pro Gly Leu Pro Ser Ala Thr
2060 2065 2070
Pro Thr Ala Ser Gly Asp Arg Thr Glu Ile Ser Gly Asp Leu Ser
2075 2080 2085
Gly His Thr Ser Gln Leu Gly Val Val Ile Ser Thr Ser Ile Pro
2090 2095 2100
Glu Ser Glu Trp Thr Gln Gln Thr Gln Arg Pro Ala Glu Thr His
2105 2110 2115
Leu Glu Ile Glu Ser Ser Ser Leu Leu Tyr Ser Gly Glu Glu Thr
2120 2125 2130
His Thr Val Glu Thr Ala Thr Ser Pro Thr Asp Ala Ser Ile Pro
2135 2140 2145
Ala Ser Pro Glu Trp Lys Arg Glu Ser Glu Ser Thr Ala Ala Ala
2150 2155 2160
Pro Ala Arg Ser Cys Ala Glu Glu Pro Cys Gly Ala Gly Thr Cys
2165 2170 2175
Lys Glu Thr Glu Gly His Val Ile Cys Leu Cys Pro Pro Gly Tyr
2180 2185 2190
Thr Gly Glu His Cys Asn Ile Asp Gln Glu Val Cys Glu Glu Gly
2195 2200 2205
Trp Asn Lys Tyr Gln Gly His Cys Tyr Arg His Phe Pro Asp Arg
2210 2215 2220
Glu Thr Trp Val Asp Ala Glu Arg Arg Cys Arg Glu Gln Gln Ser
2225 2230 2235
His Leu Ser Ser Ile Val Thr Pro Glu Glu Gln Glu Phe Val Asn
2240 2245 2250
Asn Asn Ala Gln Asp Tyr Gln Trp Ile Gly Leu Asn Asp Arg Thr
2255 2260 2265
Ile Glu Gly Asp Phe Arg Trp Ser Asp Gly His Pro Met Gln Phe
2270 2275 2280
Glu Asn Trp Arg Pro Asn Gln Pro Asp Asn Phe Phe Ala Ala Gly
2285 2290 2295
Glu Asp Cys Val Val Met Ile Trp His Glu Lys Gly Glu Trp Asn
2300 2305 2310
Asp Val Pro Cys Asn Tyr His Leu Pro Phe Thr Cys Lys Lys Gly
2315 2320 2325
Thr Val Ala Cys Gly Glu Pro Pro Val Val Glu His Ala Arg Thr
2330 2335 2340
Phe Gly Gln Lys Lys Asp Arg Tyr Glu Ile Asn Ser Leu Val Arg
2345 2350 2355
Tyr Gln Cys Thr Glu Gly Phe Val Gln Arg His Met Pro Thr Ile
2360 2365 2370
Arg Cys Gln Pro Ser Gly His Trp Glu Glu Pro Arg Ile Thr Cys
2375 2380 2385
Thr Asp Ala Thr Thr Tyr Lys Arg Arg Leu Gln Lys Arg Ser Ser
2390 2395 2400
Arg His Pro Arg Arg Ser Arg Pro Ser Thr Ala His
2405 2410 2415
<210> 156
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 156
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ile Ile Asn
20 25 30
Val Val Arg Trp Tyr Arg Arg Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Asn Ala Asn Tyr Val Asp Ser Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn
85 90 95
Val Pro Thr Thr His Tyr Gly Gly Val Tyr Tyr Gly Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120
<210> 157
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 157
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Trp Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ala Tyr Arg Arg Arg Arg Ala Ser Ser Asn Arg Gly Leu Trp Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
<210> 158
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 158
Ala Ala Ala
1
<210> 159
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 159
Gly Gly Gly Gly Ser
1 5
<210> 160
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 160
Ser Gly Gly Ser Gly Gly Ser
1 5
<210> 161
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 161
Gly Gly Gly Gly Gly Gly Gly Ser
1 5
<210> 162
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 162
Gly Gly Gly Gly Ser Gly Gly Gly Ser
1 5
<210> 163
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 163
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 164
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 164
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 165
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 165
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly
1 5 10 15
Gly Ser
<210> 166
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 166
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 167
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 167
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 168
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 168
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
<210> 169
<211> 35
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 169
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser
35
<210> 170
<211> 40
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 170
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser
35 40
<210> 171
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 171
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 172
<211> 24
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 172
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys
1 5 10 15
Thr His Thr Cys Pro Pro Cys Pro
20
<210> 173
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 173
Glu Pro Lys Thr Pro Lys Pro Gln Pro Ala Ala Ala
1 5 10
<210> 174
<211> 62
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 174
Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro Arg Cys
1 5 10 15
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
20 25 30
Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu
35 40 45
Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
50 55 60
<210> 175
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 175
Ala Arg Gly Ser
1
Claims (21)
- 75 내지 300 mg의 ADAMTS5 억제 폴리펩타이드를 인간 대상체에게 투여하는 단계를 포함하는, 치료를 필요로 하는 대상체의 골관절염을 치료하는 방법.
- 제1항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드는 3개의 상보성 결정 영역(CDR)을 포함하는 적어도 하나의 면역글로불린 단일 가변 도메인(ISVD)을 포함하며, 여기서 상보성 결정 영역은 CDR1 내지 CDR3이고,
(i) CDR1은 서열번호 21, 35, 20, 22, 25, 33, 28, 24, 23, 26, 27, 29, 30, 31, 32 및 34로 이루어진 군으로부터 선택되고;
(ii) CDR2는 서열번호 37, 53, 36, 40, 50, 51, 44, 45, 43, 39, 38, 41, 119, 42, 46, 47, 48, 49 및 52로 이루어진 군으로부터 선택되고;
(iii) CDR3은 서열번호 55, 118, 71, 54, 58, 68, 69, 62, 63, 61, 57, 56, 59, 60, 64, 65, 66, 67 및 70으로 이루어진 군으로부터 선택되는, 방법. - 제2항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드는 3개의 CDR을 포함하는 적어도 하나의 ISVD를 포함하며, 여기서 CDR은 CDR1 내지 CDR3이며,
(i) CDR1은 서열번호 21이고, CDR2는 서열번호 37이고, CDR3은 서열번호 55이거나;
(ii) CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 118이거나;
(iii) CDR1은 서열번호 35이고, CDR2는 서열번호 53이고, CDR3은 서열번호 71이거나;
(iv) CDR1은 서열번호 20이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이거나;
(v) CDR1은 서열번호 22이고, CDR2는 서열번호 36이고, CDR3은 서열번호 54이거나;
(vi) CDR1은 서열번호 25이고, CDR2는 서열번호 40이고, CDR3은 서열번호 58이거나;
(vii) CDR1은 서열번호 33이고, CDR2는 서열번호 50이고, CDR3은 서열번호 68이거나;
(viii) CDR1은 서열번호 33이고, CDR2는 서열번호 51이고, CDR3은 서열번호 69이거나;
(ix) CDR1은 서열번호 28이고, CDR2는 서열번호 44이고, CDR3은 서열번호 62이거나;
(x) CDR1은 서열번호 28이고, CDR2는 서열번호 45이고, CDR3은 서열번호 63이거나;
(xi) CDR1은 서열번호 28이고, CDR2는 서열번호 43이고, CDR3은 서열번호 61이거나;
(xii) CDR1은 서열번호 24이고, CDR2는 서열번호 39이고, CDR3은 서열번호 57이거나;
(xiii) CDR1은 서열번호 23이고, CDR2는 서열번호 38이고, CDR3은 서열번호 56이거나;
(xiv) CDR1은 서열번호 26이고, CDR2는 서열번호 41이고, CDR3은 서열번호 59이거나;
(xv) CDR1은 서열번호 27이고, CDR2는 서열번호 119이고, CDR3은 서열번호 60이거나;
(xvi) CDR1은 서열번호 27이고, CDR2는 서열번호 42이고, CDR3은 서열번호 60이거나;
(xvii) CDR1은 서열번호 29이고, CDR2는 서열번호 46이고, CDR3은 서열번호 64이거나;
(xviii) CDR1은 서열번호 30이고, CDR2는 서열번호 47이고, CDR3은 서열번호 65이거나;
(xix) CDR1은 서열번호 31이고, CDR2는 서열번호 48이고, CDR3은 서열번호 66이거나;
(xx) CDR1은 서열번호 32이고, CDR2는 서열번호 49이고, CDR3은 서열번호 67이거나; 또는
(xxi) CDR1은 서열번호 34이고, CDR2는 서열번호 52이고, CDR3은 서열번호 70인, 방법. - 제3항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드는 3개의 CDR을 포함하는 적어도 하나의 ISVD를 포함하고, 여기서 CDR은 CDR1 내지 CDR3이고, CDR1은 서열번호 21이고, CDR2는 서열번호 37이고, CDR3은 서열번호 55인, 방법. - 제1항에 있어서,
상기 ISVD는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택되는, 방법. - 제5항에 있어서,
상기 ISVD는 서열번호 129의 아미노산 1 내지 124인, 방법. - 제1항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드는 2개 이상의 ISVD를 포함하고,
a) 적어도 제1 ISVD는 ADAMTS5의 제1 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합하고;
b) 적어도 제2 ISVD는 혈청 알부민의 제2 항원 결정기, 에피토프, 부분, 도메인, 서브유닛 또는 형태에 특이적으로 결합하는, 방법. - 제7항에 있어서,
상기 제1 ISVD는 서열번호 2, 116, 19, 1, 3, 6, 16, 17, 10, 11, 9, 5, 4, 7, 8, 117, 12, 13, 14, 15, 18, 및 서열번호 129의 아미노산 1 내지 124로 이루어진 군으로부터 선택되는, 방법. - 제8항에 있어서,
상기 제1 ISVD는 서열번호 129의 아미노산 1 내지 124인, 방법. - 제7항에 있어서,
상기 제2 ISVD는 서열번호 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 또는 145로 이루어진 군으로부터 선택되는, 방법. - 제10항에 있어서,
상기 제2 ISVD는 서열번호 138인, 방법. - 제7항에 있어서,
상기 제1 ISVD는 서열번호 129의 아미노산 1 내지 124이고, 제2 ISVD는 서열번호 138인, 방법. - 제1항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드는 서열번호 129(클론 577 2F3so-Alb), 서열번호 130(클론 579 2F3so-093-Alb), 서열번호 120(클론 4 2A12-Alb), 서열번호 121(클론 5 2D7-Alb), 서열번호 122(클론 6 2F3-Alb), 서열번호 123(클론 69 049-Alb), 서열번호 124(클론 70 9D3-Alb), 서열번호 125(클론 71 3B2-Alb), 서열번호 126(클론 129 2F3-093-Alb), 서열번호 127(클론 130 049-093-Alb), 및 서열번호 128(클론 131 9D3-093-Alb)로 이루어진 군으로부터 선택되는, 방법. - 제13항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드는 서열번호 129(클론 577 2F3so-Alb)인, 방법. - 제1항 내지 제14항 중 어느 한 항에 있어서,
상기 골관절염은 무릎 골관절염인, 방법. - 제1항 내지 제15항 중 어느 한 항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드의 용량은 150 mg인, 방법. - 제1항 내지 제15항 중 어느 한 항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드의 용량은 300 mg인, 방법. - 제1항 내지 제17항 중 어느 한 항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드는 1개월 1회 투여되는, 방법. - 제1항 내지 제18항 중 어느 한 항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드의 투여는 ARGS 단편의 형성을 감소시키는, 방법. - 제1항 내지 제19항 중 어느 한 항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드의 투여는 KOOS 점수 또는 WOMAC 점수에 의해 측정된 바와 같이 골관절염에 걸린 관절의 통증을 감소시키는, 방법. - 제1항 내지 제20항 중 어느 한 항에 있어서,
상기 ADAMTS5 억제 폴리펩타이드의 투여는 MRI의 자동 분할에 의해 결정된 바와 같이 골관절염에 걸린 관절의 구조를 유지하는, 방법.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202163182561P | 2021-04-30 | 2021-04-30 | |
| US63/182,561 | 2021-04-30 | ||
| US202263362372P | 2022-04-01 | 2022-04-01 | |
| US63/362,372 | 2022-04-01 | ||
| PCT/IB2022/054001 WO2022229922A1 (en) | 2021-04-30 | 2022-04-29 | Methods for the administration of adamts binding immunoglobulins |
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| Publication Number | Publication Date |
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| KR20240004645A true KR20240004645A (ko) | 2024-01-11 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1020237040747A KR20240004645A (ko) | 2021-04-30 | 2022-04-29 | Adamts 결합 면역글로불린의 투여 방법 |
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| Country | Link |
|---|---|
| US (1) | US20240218081A1 (ko) |
| EP (1) | EP4330290A1 (ko) |
| JP (1) | JP2024515816A (ko) |
| KR (1) | KR20240004645A (ko) |
| AU (1) | AU2022266254A1 (ko) |
| BR (1) | BR112023022194A2 (ko) |
| CA (1) | CA3216512A1 (ko) |
| IL (1) | IL308047A (ko) |
| MX (1) | MX2023012763A (ko) |
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| WO (1) | WO2022229922A1 (ko) |
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| TWI802576B (zh) | 2017-06-02 | 2023-05-21 | 德商馬克專利公司 | 與ａｄａｍｔｓ結合之免疫球蛋白 |
-
2022
- 2022-04-29 JP JP2023566404A patent/JP2024515816A/ja active Pending
- 2022-04-29 US US18/557,721 patent/US20240218081A1/en active Pending
- 2022-04-29 TW TW111116370A patent/TW202309100A/zh unknown
- 2022-04-29 CA CA3216512A patent/CA3216512A1/en active Pending
- 2022-04-29 EP EP22722899.6A patent/EP4330290A1/en active Pending
- 2022-04-29 WO PCT/IB2022/054001 patent/WO2022229922A1/en active Application Filing
- 2022-04-29 BR BR112023022194A patent/BR112023022194A2/pt unknown
- 2022-04-29 KR KR1020237040747A patent/KR20240004645A/ko unknown
- 2022-04-29 AU AU2022266254A patent/AU2022266254A1/en active Pending
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| WO2022229922A1 (en) | 2022-11-03 |
| IL308047A (en) | 2023-12-01 |
| CA3216512A1 (en) | 2022-11-03 |
| BR112023022194A2 (pt) | 2024-02-06 |
| JP2024515816A (ja) | 2024-04-10 |
| AU2022266254A1 (en) | 2023-12-14 |
| US20240218081A1 (en) | 2024-07-04 |
| TW202309100A (zh) | 2023-03-01 |
| EP4330290A1 (en) | 2024-03-06 |
| MX2023012763A (es) | 2023-11-13 |
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