KR20210050535A - 항-bcma 단일 도메인 항체 및 그 적용 - Google Patents
항-bcma 단일 도메인 항체 및 그 적용 Download PDFInfo
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- KR20210050535A KR20210050535A KR1020217008611A KR20217008611A KR20210050535A KR 20210050535 A KR20210050535 A KR 20210050535A KR 1020217008611 A KR1020217008611 A KR 1020217008611A KR 20217008611 A KR20217008611 A KR 20217008611A KR 20210050535 A KR20210050535 A KR 20210050535A
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Abstract
항-BCMA 단일 도메인 항체 그룹, 그룹의 단일 도메인 항체 유전자, 그룹의 단일 도메인 항체를 포함하는 벡터, 키메릭 항원 수용체 및 키메릭 항원 수용체에 의해 변형된 T 세포, 및 그룹 내 단일 도메인 항체의 검출 및 치료 적용. 항-BCMA 단일 도메인 항체는 높은 활성, 높은 안정성, 높은 특이성 및 높은 결합 능력을 가지고 있다.
Description
본 발명은 생명공학 분야에 속한다. 특히, 본 발명의 내용은 B 세포 성숙 항원(BCMA)에 대한 단일 도메인 항체 그룹 및 그의 용도에 관한 것이다.
BCMA (B 세포 성숙 항원, BCMA)는 B 세포-활성화 인자 (BAFF) 또는 B 림프구 자극제 (BLyS) 및 증식 유도 리간드 (APRIL)에 결합할 수 있는 종양 괴사 인자 수용체 (TNFR) 슈퍼 패밀리의 구성원이다. 정상 세포에서, BCMA는 주로 형질세포와 일부 성숙 B 세포에 의해 발현되지만, 대부분의 B 세포 또는 다른 기관에서는 발현되지 않는 것으로 보고 되었다. 다발성 골수종 (MM)은 클론성 형질세포의 대량 증식을 특징으로하는 악성 종양이다. BCMA의 RNA는 일반적으로 MM 세포에서 검출되며, BCMA 단백질은 다발성 골수종 환자의 형질 세포 표면에서 검출될 수 있다. 따라서, MM의 면역 치료를 위한 후보 표적 항원은 BCMA이다. 현재, MM 치료는 관해를 유도할 수 있지만, 거의 모든 환자가 결국 재발하여 사망한다. 일부 단일 클론 항체 후보 약물은 전임상 연구 및 초기 임상 시험에서 MM을 치료할 가능성을 보여 주었지만, 합의에 의해 보편적으로 승인되지 않았으며, 단일 클론 항체 약물이 판매되지 않았다. 분명히, MM에 대한 새로운 면역 요법이 시급히 필요하며,이 질환을 위해 개발된 효과적인 항원-특이적 입양 T 세포 요법은 중요한 연구 진전이 될 것이다.
나노 바디로도 알려진 단일 도메인 항체 (sdAb)는 알파카 혈액에서 발견되는 경쇄가없는 중쇄 항체이다. 나노-입자 과학과 결합된 분자 생물학 기술을 사용함으로써, 벨기에 과학자들은 항원에 결합할 수 있는 새로운 저분자량 (low molecular) 항체 단편을 개발하였다. 간단한 구조, 강력한 침투력, 쉬운 발현 및 정제, 높은 친화성 및 안정성, 그리고 독성과 부작용이 없는 것 등과 같은 일련의 장점을 가지고 있다. 단일 도메인 항체 플랫폼 기술을 이용하여 다양한 표적 항원에 대한 단일 도메인 항체를 연구하여 생물 의학 분야에서 사용하고 있다.
본 발명은 치료 항체 후보 약물 및 BCMA를 표적으로하는 키메릭 항원 수용체 T 세포에 사용하기 위한 유망한 항-BCMA 단일 도메인 항체 그룹을 개발하는 것을 목표로 한다.
본 발명이 해결하고자하는 기술적 과제는 효과가 좋은 신규한 항-BCMA 단일 도메인 항체 군을 제공하는 것이다.
본 발명이 해결하고자하는 또 다른 기술적 과제는 항-BCMA 단일 도메인 항체의 다양한 용도를 개발하는 것이다.
상기 목적을 달성하기 위해 본 발명은 다음과 같은 기술적 해결책을 제공한다.
본 발명은 프레임워크 영역 (framework region) 및 상보성 결정 영역 (complementary determining region)을 포함하고, 상기 상보성 결정 영역은 서열번호 1 내지 66 으로부터 선택된 아미노산 서열을 가지는 것을 특징으로 하는 항-BCMA 단일 도메인 항체 그룹을 제공한다 (부록 (Annex) 1 : 스크리닝된 BCMA-단일 도메인 항체들 (BCMA-sdAbs)의 상보성 결정 영역의 아미노산 서열).
일부 실시 양태에서, 상보성 결정 영역의 아미노산 서열은 서열번호 1 내지 66 중 어느 한 아미노산 서열에 대해 80 % 이상, 85 % 이상, 90 % 이상, 95 % 이상 또는 99 % 이상의 동일성을 갖는다.
바람직하게는, 아미노산의 차이는 보존적 치환 (conservative substitution)이다.
일부 실시 양태에서, 그룹의 단일 도메인 항체는 서열번호 67 내지 132 중 어느 하나로부터 선택된 서열을 갖거나 서열번호 67 내지 132 중 어느 하나의 아미노산 서열이다 (부록 2 : 스크리닝된 BCMA-단일 도메인 항체들 (BCMA-sdAbs)의 아미노산 서열).
일부 실시 양태에서, 단일 도메인 항체의 아미노산 서열은 서열번호 67 내지 132 중 어느 한 아미노산 서열에 대해 80 % 이상, 85 % 이상, 90 % 이상, 95 % 이상 또는 99 % 이상의 동일성을 갖는다.
바람직하게는, 아미노산의 차이는 보존적 치환이며, 보다 바람직하게는 하나 이상의 보존적 치환이다.
본 발명은 서열번호 133 내지 198에서 선택된 뉴클레오타이드 서열을 갖거나 서열번호 133 내지 198 (부록 3 : 스크리닝된 BCMA-sdAbs의 뉴클레오타이드 서열)의 뉴클레오타이드 서열이거나, 또는 상기 단일 도메인 항체를 암호화하는 뉴클레오타이드 서열인 항-BCMA 단일 도메인 항체의 유전자 그룹을 제공한다.
일부 실시예에서, 단일 도메인 항체의 뉴클레오타이드 서열은 서열 번호 133 내지 198에 기재된 뉴클레오타이드 서열에 대해 80 % 이상, 85 % 이상, 90 % 이상, 95 % 이상 또는 99 % 이상의 동일성을 갖는다.
바람직하게는, 염기의 차이가 보존적 치환이며, 보다 바람직하게는 하나 이상의 보존적 치환이다.
본 발명은 상기 기재된 단일 도메인 항체 군으로부터 선택되는 하나 이상의 단일 도메인 항체를 갖는 폴리펩타이드를 제공한다.
바람직하게는, 복수의 단일 도메인 항체는 동일하거나 상이하다.
본 발명은 상기 기재된 단일 도메인 항체의 유전자 군으로부터 선택된 하나 이상의 유전자를 포함하는 발현 벡터를 제공한다.
바람직하게는, 발현 벡터는 원핵세포 발현 벡터, 진핵세포 발현 벡터, 또는 다른 세포 발현 벡터이다.
본 발명은 상기 발현 벡터를 포함하는 숙주 세포를 제공한다.
바람직하게는, 숙주 세포는 원핵 발현 세포, 진핵 발현 세포, 진균 세포 또는 효모 세포이고, 상기 원핵 발현 세포는 바람직하게는 Escherichia coli이다.
본 발명은 상기 단일 도메인 항체의 그룹으로부터 선택된 하나 또는 다수의 단일 도메인 항체를 갖는 키메릭 항원 수용체(chimeric antigen receptor)를 제공한다.
바람직하게는, 다수의 단일 도메인 항체는 동일하거나 상이하다.
본 발명은 상기 키메릭 항원 수용체에 의해서 변형된 키메릭 항원 수용체에 의해 변형된 T 세포를 제공한다.
본 발명은 상기 단일 도메인 항체 그룹으로부터 선택된 하나 이상의 단일 도메인 항체들을 활성 성분으로 포함하는 약학적 조성물을 제공한다.
본 발명은 상기 단일 도메인 항체 그룹으로부터 선택된 단일 도메인 항체를 인간화하여 수득된 인간화 항-BCMA 단일 도메인 항체를 제공한다.
본 발명은 상기 단일 도메인 항체 그룹에서 상기 단일 도메인 항체의 BCMA 검출 용도를 제공한다.
본 발명은 상기 단일 도메인 항체 그룹에서 상기 단일 도메인 항체의 BAFF와 BCMA 사이의 상호작용을 차단하기 위한 용도를 제공한다.
일부 실시예에서, 단일 도메인 항체는 세포 독성 제제 (cytotoxicity agent), 효소 (enzyme), 방사성 동위 원소, 형광 화합물 또는 화학발광 화합물 중 하나 이상에 연결된다.
본 발명은 상기 단일 도메인 항체 그룹에서 상기 단일 도메인 항체의 비정상 BCMA 발현과 관련된 질병을 치료하기 위한 약물을 제조하는데 있어서의 용도를 제공한다.
바람직하게는, 상기 비정상 BCMA 발현과 관련된 질병이 다발성 골수종 질병이다.
본 발명은 다음의 유익한 기술적 효과를 갖는다:
본 발명은 항-BCMA 단일 도메인 항체 그룹을 선별한다. 기존 항체들에 비해, 그룹 내 각각의 항-BCMA 단일 도메인 항체는 상대적으로 높은 활성, 강한 중화 또는 결합 능력을 갖는다. 단일 도메인 항체 그룹은 세포 표면에서 BCMA를 발현하는 인간 BCMA 항원 또는 종양 세포주에 특이적으로 결합할 수 있고, BCMA와 BAFF 항원의 결합을 효과적으로 차단할 수 있으며, 상응하는 신호 전달 경로(signal cascade) 효과를 생성할 수 있다. 단일 도메인 항체 그룹은 비정상적인 BCMA 발현과 관련된 다수의 질병을 검출 및/또는 치료하기 위해 사용될 수 있다.
이하, 첨부된 도면 및 실시예를 참조하여 본 발명을 상세히 설명하지만, 본 발명의 범위가 이에 한정되는 것은 아니다.
도 1은 1 차 PCR을 통한 일반적인 중쇄 항체 및 단일 사슬 항체의 유전자 증폭을 보여준다. 1 PCR 증폭 산물과 관련하여 (마커) (1500 BP, 1000 BP, 800 BP, 500 BP, 250 BP 및 100 BP), 800 BP 이상의 일반적인 중쇄 유전자 증폭 단편 및 800 BP 미만의 중쇄 항체 유전자 증폭 단편이 있다. 2 및 3은 PCR 증폭 산물로 약 500 BP 만을 갖는 중쇄 항체 유전자 증폭 단편이다.
도 2는 2 차 PCR 증폭에서 얻은 VHH 표적 유전자 단편을 나타낸 것이다. 마커 (1500 BP, 1200 BP, 1000 BP, 800 BP, 700 BP, 600 BP, 500 BP, 250 BP 및 100 BP). 1 내지 12는 약 500 BP를 갖는 중쇄 항체 VHH 유전자 증폭 단편인 PCR 증폭 산물이다.
도 3은 정제 전 발현된 BCMA-sdAbs의 SDS-PAGE 예시이다.
도 4는 니켈 컬럼에 의해 정제된 후 발현된 BCMA-sdAbs의 SDS-PAGE 예시를 보여준다.
도 5는 BCMA 단백질에 결합하는 정제된 BCMA 단일 도메인 항체의 농도 구배를 보여준다 (ELISA).
도 6은 BCMA 단일 도메인 항체가 BCMA 단백질에 대한 BAFF 단백질의 결합을 경쟁적으로 억제할 수 있음을 보여준다.
도 7은 종양 세포에 대한 BCMA CART의 사멸 효율을 보여준다.
도 2는 2 차 PCR 증폭에서 얻은 VHH 표적 유전자 단편을 나타낸 것이다. 마커 (1500 BP, 1200 BP, 1000 BP, 800 BP, 700 BP, 600 BP, 500 BP, 250 BP 및 100 BP). 1 내지 12는 약 500 BP를 갖는 중쇄 항체 VHH 유전자 증폭 단편인 PCR 증폭 산물이다.
도 3은 정제 전 발현된 BCMA-sdAbs의 SDS-PAGE 예시이다.
도 4는 니켈 컬럼에 의해 정제된 후 발현된 BCMA-sdAbs의 SDS-PAGE 예시를 보여준다.
도 5는 BCMA 단백질에 결합하는 정제된 BCMA 단일 도메인 항체의 농도 구배를 보여준다 (ELISA).
도 6은 BCMA 단일 도메인 항체가 BCMA 단백질에 대한 BAFF 단백질의 결합을 경쟁적으로 억제할 수 있음을 보여준다.
도 7은 종양 세포에 대한 BCMA CART의 사멸 효율을 보여준다.
본 발명은 높은 활성 및 높은 중화 또는 결합 능력의 잠재력을 갖는 단계 그룹에 의해 항-BCMA 단일 도메인 항체의 그룹을 선별한다. 이러한 단일 도메인 항체는 유사한 구조 (프레임 워크 영역 및 상보성 결정 영역으로 구성됨) 및 유사한 기능적 효과를 갖는다. 따라서 이들은 공통 구조 및 공통 특성 효과를 갖는 항-BCMA 단일 도메인 항체의 그룹으로 간주될 수 있다.
본원에서 사용된 용어 "BCMA"는 B 세포 활성화 인자 또는 B 림프구 자극제 및 증식 유도 리간드 (APRIL)에 결합할 수 있는 종양 괴사 인자 수용체 (TNFR) 슈퍼 패밀리의 구성원이다. 다발성 골수종 (MM)은 클론성 형질세포 (plasmocytes)의 대량 증식을 특징으로 하는 악성 종양이다. BCMA의 RNA는 일반적으로 MM 세포에서 검출되며, BCMA 단백질은 다발성 골수종 환자의 형질세포 표면에서 검출될 수 있다.
본원에서 사용된 용어 "다발성 골수종 (MM)"은 클론성 형질세포의 대량 증식을 특징으로 하는 악성 종양이다. 현재, MM 치료는 관해를 유도할 수 있지만 거의 모든 환자가 결국 재발하여 사망한다. 일부 단일 클론 항체는 전임상 연구 및 초기 임상 시험에서 MM을 치료할 가능성을 보여 주었으나, 보편적으로 승인되지는 않았다. 명백히, MM에 대한 새로운 항체와 새로운 면역 요법이 시급히 필요하다.
BCMA에 대한 새로운 항체가 개발 대상이며, 최종적으로 본 발명의 보호 대상이다. 본 발명의 범위는 수득된 항-BCMA 항체 및 그것의 다양한 형태 (예를 들어, 단일 도메인 항체)뿐만 아니라 항체를 성분으로 포함하는 물질 (예를 들어, 약제학적 조성물, 키트, 벡터, 키메릭 항원 수용체, 키메릭 항원 수용체 변형 T 세포 등), 용도 (예를 들어, 진단, 치료 또는 적용 등의 용도)를 포함한다. 그러나, 본 발명의 보호 대상이 이러한 예시된 내용에 제한되지 않음을 당업자는 이해하여야 한다.
본원에서 사용된 용어 "단일 도메인 항체 (sdAb)"는 항체에 단일 가변 도메인을 포함하는 단편을 지칭하며, 나노 바디로도 알려져 있다. 단일 도메인 항체는 완전한 항체처럼 특정 항원에 선택적으로 결합할 수 있다. 완전한 항체의 질량 (150-160kDa)에 비해, 단일 도메인 항체 (약 12-15kDa)는 훨씬 더 작다. 최초의 단일 도메인 항체는 인공 공학에 의해 알파카 중쇄 항체로 만들어졌으며 "VHH 세그먼트"로 알려져 있다. 바람직한 실시예에서, 본 발명은 알파카의 단일 도메인 항체를 사용하는 반면, 당업자는 본 발명이 또한 다른 종으로부터 유래된 단일 도메인 항체를 포함할 수 있음을 이해해야 한다. 제한없이, 본 발명의 단일 도메인 항체는 항-BCMA 단일 도메인 항체이다.
용어 "프레임워크 영역"은 골격 영역으로도 알려져 있다. 면역 글로불린의 H 사슬 및 L 사슬의 N-말단 근처에 있는 약 110 개의 아미노산 서열은 매우 다양한 반면, 다른 위치의 아미노산 서열은 상대적으로 일정하다. 따라서 경쇄와 중쇄는 가변 영역 (V)과 불변 영역 (C)으로 나누어질 수 있다. 가변 영역은 상보성 결정 영역 (CDR)으로도 알려진 HVR (초가변 영역) 및 프레임 영역 (FR)을 포함한다. FR의 가변성은 CDR의 가변성보다 적다. 총 4 개의 FR 분자, 즉 각각 FR1, FR2, FR3 및 FR4가 있다. 항체를 인식하는 동안 4 개의 FR 분자가 주름을 잡아(ckrimp) CDR 분자가 서로 가깝게 있다. 본 발명은 특정 프레임 워크 영역(들)에 제한되지 않으며, 당업자는 본 발명의 보호 범위를 벗어나지 않고 실제 요구 사항에 따라 적절한 프레임 워크 영역(들)을 선택하거나 획득할 수 있음을 이해해야 한다.
용어 "상보성 결정 영역 (CDR)", 전체 항체 분자를 불변 영역과 가변 영역으로 나눌 수 있다. 가변 영역에서, 일부 아미노산 잔기는 매우 가변적이며 이러한 아미노산 잔기의 구성 및 배열 순서가 더 다양한 경향의 영역을 초가변 영역(hypervariable region) 이라고 한다. L 사슬과 H 사슬의 V 영역에는 3 개의 초가변 영역 (HVR)이 있으며, 이는 공간 구조 측면에서 항원 결정 인자와 정밀한 보완을 형성할 수 있으며, 따라서 초가변 영역을 상보성 결정 영역이라고도 한다.
본원에서 사용되는 용어 서열의 "동일성"은 "상동성"과 상호교환적으로 사용되며, BLAST와 같은 서열 정렬 소프트웨어에 의해 측정된 서열 간의 유사도를 지칭한다. 서열 정렬 방법 및 소프트웨어는 당업자에게 잘 알려져있다. 변형된 뉴클레오타이드 서열은 공지된 서열에서 하나 이상의 아미노산 또는 염기의 치환, 결실 및/또는 추가 (예를 들어, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 또는 그 이상)에 의해 수득될 수 있다. 예를 들어, 통상적인 수단 (예를 들어, 보존적 치환에 의해)을 통해 본 발명의 서열 번호 1 내지 198 서열 중 하나 이상에 기재된 바와 같은 아미노산 서열 또는 뉴클레오타이드 서열을 변형함으로써, 이들 서열에 대해 80 % 이상, 85 % 이상, 90 % 이상, 95 % 이상 또는 99 % 이상의 서열 동일성을 가지며 실질적으로 동일한 특성을 갖는 서열을 획득하는 것이 가능하며, 이는 본 발명의 보호 범위 내에 포함된다. 바람직하게는, 본 발명은 보존적 치환에 의해 서열 동일성을 획득하지만, 이에 제한되지는 않는다.
용어 "아미노산 서열"은 아미노산이 서로 연결되어 펩티드 사슬 (또는 폴리펩티드)을 형성하는 배열을 지칭하며, 여기서 아미노산 서열은 한 방향으로 만 읽을 수 있다. 100 가지 이상의 다양한 아미노산이 있으며, 그 중 20 가지가 일반적으로 사용된다. 본 발명은 아미노산 사슬에 다른 물질 (예를 들어, 당류, 지질 및 기타 변형)이 부착된 경우를 배제하지 않으며, 또한, 일반적으로 사용되는 20 개의 아미노산으로도 제한되지 않는다.
용어 "뉴클레오타이드 서열"은 DNA 또는 RNA의 염기 배열, 즉 DNA에서 A, T, G 및 C의 배열, 또는 mRNA에서 A, U, G 및 C의 배열을 지칭한다. 또한 rRNA, tRNA 및 mRNA의 염기 배열도 포함한다. 본 발명의 항체 유전자는 또한 DNA 서열 이외에 RNA (rRNA, tRNA 및 mRNA) 및 이들의 상보성 서열을 포함한다는 것을 이해해야 한다. 또한, 본 발명의 항체를 암호화하는 유전자는 본 발명의 서열 번호 133 내지 198에 제시된 서열과 동일하지 않으며, 본 발명의 항체를 암호화하지만 서열번호 133 내지 198에 제시된 뉴클레오타이드 서열과 상이한 유전자가 또한 본 발명의 보호 범위 내에 있다는 것도 이해될 것이다.
일부 실시예에서, 본 발명의 폴리펩티드, 제약 조성물, 키메릭 항체 수용체 또는 CART는 하나의 단일 도메인 항체를 포함하고, 본 발명이 이에 제한되지 않음을 이해해야 한다. 본 발명의 상기 물질은 둘, 셋 또는 다수의 단일 도메인 항체를 포함할 수 있으며, 다수의 단일 도메인 항체는 동일하거나 상이하다. 더욱이, 본 발명의 단일 도메인 항체에 추가하여, 본 발명에 포함되지 않은 다른 항체 또는 단일 도메인 항체도 본 발명의 범위를 벗어나지 않고 포함될 수 있다.
용어 "발현 벡터"는 표적 유전자가 발현될 수 있도록 클로닝 벡터의 기본 골격에 기초하여 발현 요소 (예를 들어, 프로모터, RBS 또는 터미네이터)를 포함하는 벡터를 의미한다. 발현 벡터는 표적 유전자, 프로모터, 터미네이터 및 마커 유전자의 네 부분으로 구성된다. 본 발명은 원핵 세포 발현 벡터, 진핵 세포 발현 벡터 또는 다른 세포 발현 벡터를 포함하지만 이에 제한되지 않는다.
"키메릭 항원 수용체 (CAR)"는 "키메릭 항원 수용체 T 세포 (CART)"의 핵심 성분으로, CART는 T 세포에 독립적인 방식으로 종양 항원을 인식할 수 있는 능력을 부여함으로써, CAR에 의해 변형된 T 세포는 자연적인(native) 표면 수용체에 비해 더 넓은 범위의 항원을 인지할 수 있다. CAR의 기본 디자인은 종양 관련 항원 결합 영역, 세포 외 힌지 영역, 막 관통 영역 및 세포 내 신호 영역을 포함한다.
본 발명의 실시예에서, 본 발명의 키메릭 항원 수용체 또는 키메릭 항원 수용체 T 세포는 동일하거나 상이할 수 있는 본 발명의 하나 또는 둘 이상의 단일 도메인 항체를 포함할 수 있다.
본 발명의 일 실시예에서, 본 발명의 "약제학적 조성물"은 동일하거나 상이할 수 있는 본 발명의 하나 또는 둘 이상의 단일 도메인 항체를 포함할 수 있다.
용어 "인간화" 항체는 항체의 불변 영역(즉, CH 및 CL 영역) 또는 전체 항체가 인간 항체 유전자에 의해 암호화되는 항체를 지칭한다. 인간화 항체는 인간 유기체에서 이종 항체의 면역 부반응(side reaction)을 크게 줄일 수 있다. 인간화 항체에는 키메릭 항체, 변형 항체 및 완전한 인간 항체를 포함한 여러 유형이 포함된다. 당업자는 본 발명의 범위 내에 있는 실제 요건에 따라 본 발명의 단일 도메인 항체의 적합한 인간화된 형태를 제조할 수 있다는 것을 이해할 것이다.
본원에서 사용되는 용어 "렌티 바이러스"는 인간 및 척추 동물을 감염시킬 수 있는 8 개의 바이러스를 포함하는 레트로 바이러스과의 한 속으로, 1 차 감염 세포는 주로 림프구 및 대식세포이며, 감염된 개체는 결국 질병을 발병하게 된다. 렌티 바이러스의 유형은 예를 들어 인간 면역 결핍 바이러스 (HIV), 유인원 면역 결핍 바이러스 (SIV), 말 감염성 빈혈 (EIA) 및 고양이 면역 결핍 바이러스 (FIV)를 포함한다. 렌티 바이러스 벡터 연구의 진행은 빠르고 집약적이다. 이 벡터는 외래 유전자를 숙주 염색체에 효과적으로 통합하여 지속적인 발현을 달성할 수 있다. 감염성 측면에서, 뉴런, 간세포, 심근 세포, 종양 세포, 내피 세포, 줄기 세포 및 기타 유형의 세포를 효과적으로 감염시켜 우수한 유전자 치료 효과를 얻을 수 있다. 또한, 당업자는 본 발명의 보호 범위 내에 있는 렌티 바이러스 이외의 다른 적합한 벡터를 선택할 수도 있다.
이하 실시예를 통해 본 발명을 상세히 설명한다. 그러나, 본 발명은 당업자에게 있어서 다른 변형이 잘 확립되어 있거나, 또는 직접적인 개시 및 첨부 된 청구 범위에 따라 명백하기 때문에 이들 예의 특정 세부 사항에 제한되지 않는다. 따라서, 본 발명의 상술한 설명을 기반으로 달성된 모든 기술은 본 발명의 범위에 속한다.
달리 명시되지 않는 한, 다음 실시예에 설명된 모든 실험 방법은 통상적인 방법이며; 모든 시약과 생체 물질은 달리 명시되지 않는 한, 상업적으로 이용 가능하다.
실시예 1 : 항-BCMA 항원-특이적 단일 도메인 항체 라이브러리의 구축
1) BCMA 항원을 이용한 알파카의 면역화
종래의 면역 방법에 따라 수행된다. 요약하면, 건강한 성인 알파카는 총 중량이 약 2 mg인 BCMA 항원 (인간 TNFRSF17/BCMA/CD269 단백질, Beijing Yiqiao Shenzhou로부터 구입, 제품 번호 10620-H15H)으로 목과 등에 다점(multipoint) 피하 주사를 맞았으며, 항원과 동일한 부피의 프로이드 어주번트(Freund 's adjuvant)를 첨가하였다. 면역은 4-6 회 수행하였다. 정확한 면역을 확인하기 위해 주사 부위에서의 질량 흡수를 수행하였다. 면역 간격은 7-15 일이었다. 네 번째 면역 후, 항원의 면역 역가를 결정하기 위해 혈청을 수집하였다. 역가가 10,000 배 이상 (ELISA 방법)에 도달하면 약 100 ml의 전혈을 채취하고, 림프구를 분리하여 이후 사용을 위해 -80 ℃에서 보관하였다.
2) 알파카 말초 혈액 림프구 분리 및 RNA 추출
알파카 말초 혈액 림프구는 지시에 따라 QIAGEN 키트 (QIAamp RNA Blood Mini Kit (50), 제품 번호 52304)를 사용하여 분리하였다. 간단히, 1 ml의 전혈에 5-10 ml의 적혈구 용해물을 첨가 하였다. 혼합물을 균일하게 혼합하고 얼음조에 30 분 동안 두었다. 적혈구가 용해된 후 2000 rpm 에서 10 분 동안 원심 분리하였다. 상등액은 버리고, 추가 1-2 ml의 적혈구 용해물을 첨가하고 균일하게 혼합하였다. 혼합물을 얼음조에 10 분 동안 두어 잔류 적혈구를 용해시킨 다음, 2000 rpm에서 10 분 동안 원심 분리하였다. 상등액은 버리고, 0.3 ml의 용해물을 첨가하여 백혈구와 균일하게 혼합하였다. 결과 혼합물은 이후 사용을 위해 -80 ℃에서 보관하였다.
RNA 정제는 지침에 따라 QIAGEN 키트 (QIAamp RNA Blood Mini Kit (50), 제품 번호 52304)를 사용하여 수행하였다. 간단히, 분리된 알파카 림프구 0.3 ml에 RLT 완충액 0.3 ml를 첨가하고, 혼합물은 잘 흔들어 섞어 주었다. 마지막 단계에서 혼합된 액체를 흡착 컬럼 (QIAshredderSpinColumn)이 장착된 수집 튜브로 옮기고, 14,000 rpm에서 2 분 동안 원심 분리하였다. 수집 튜브의 여과액을 새로운 원심 분리 튜브로 옮겼다. 여과액에 70 % 에탄올 0.5 ml를 첨가하고 뒤집어서 균일하게 혼합하였다. 혼합물을 10000 rmp에서 15 초 동안 원심 분리하고, 수집 튜브의 폐액을 버리고 흡착 컬럼을 수집 튜브에 다시 넣었다. 흡착 컬럼을 새로운 2 ml 수집 튜브로 옮기고, 0.7 ml의 완충액 RW1을 첨가하고, 혼합물을 10000 rmp에서 15 초 동안 원심 분리 하였다. 흡착 컬럼을 새로운 2 ml 수집 튜브로 옮기고, 완충액 RPE 0.5 ml를 첨가하고, 혼합물을 10000 rmp에서 15 초 동안 원심 분리하였다. 0.5 ml의 완충액 RPE를 첨가하고 혼합물을 3 분 동안 14000 rmp에서 원심 분리 하였다. 흡착 컬럼을 새로운 1.5 ml 원심 분리 튜브로 옮기고, 30-50 μl의 RNase가 없는 물을 공기 중의 흡착 막 중앙에 방울로 첨가하였다. 혼합물을 실온에서 2-5 분 동안 놓아두고, 1 분 동안 12,000 rpm에서 원심 분리 하였다. 플라스미드 용액을 원심 분리 관에 모아서 RNA 농도를 측정하였다.
3) 중쇄 항체의 가변 영역-VHH
cDNA의 첫 번째 사슬의 합성 : cDNA 합성 키트 (MiniBESTAgarose Gel DNA Extraction Kit ver.4.0, TAKARA Company)를 지침에 따라 사용하였다. 이 주형으로 두 세트의 프라이머를 사용하여 중쇄 항체의 VHH 유전자 단편의 PCR 증폭을 수행하였다. Nested PCR 방법을 사용하여, 첫 번째 PCR 증폭에서 800 bp 이상의 단편은 일반적인 중쇄 유전자 단편이고, 800 bp에서 500 bp 사이의 단편은 경쇄가 결실된 중쇄 항체 유전자 단편이다 (도 1 참조). 경쇄가 결실된 중쇄 항체의 유전자 단편은 겔 절단(gel cutting)에 의해 회수하였고, VHH 특이적 프라이머로 PCR 증폭하여 VHH 표적 유전자 (~ 500bp)를 얻기 위한 주형으로 사용하였다 (도 2 참조).
프라이머의 합성:
1 차 PCRFd5 '프라이머:
YF-1 : CGC CAT CAA GGT ACC AGT TGA (서열 번호:199)
YF-2 : GGG GTA CCT GTC ATC CAC GGA CCA GCT GA (서열 번호:200)
1 차 PCR Bd3 '프라이머:
YBN : CAG CCG GCC ATG GCC SMK GTR CAG CTG GTG GAK TCT GGG GGA G (서열 번호:201)
2 차 PCR 프라이머 :
YV-BACK : CAT GTG CATGGCCTA GAC TCG CGG CCCAGC CGG CCA TGG CC (서열 번호:202)
YV-FOR : CAT GTG TAG ATT CCT GGC CGG CCT GGC CTG AGG AGA CGG TGA CCT GG (서열 번호:203)
4) VHH 단편 및 파지 디스플레이 벡터의 연결(ligation) 및 TG1 형질전환용 세포(competent cell)의 전기적 형질 전환
VHH 단편 및 pHEN6 벡터 플라스미드를 SfI으로 단일 분해한 후, VHH 단편 및 pHEN6 벡터 (Conrath, KEM other. Antimicrob Agents Chemother (Antimicrobial Chemotherapy) 2001,45:(10) 2807-12), 중국 특허 ZL20111028003.1))를 리가아제(ligase)에 의해 연결하여 TG1 형질전환용 세포로 전기적으로 형질 전환하고 플레이트에 도말하고, 콜로니 PCR로 검출하여 항체 삽입율을 확인하였다. 재조합 유전자 클로닝 효율의 검출 : LB/Amp 플레이트에 전기적으로 형질전환된 박테리아 용액을 도말하여 32 ℃에서 밤새 배양하고, 다음 날 항체의 연결(ligation) 효율을 검증하기 위해 콜로니 PCR로 검출하였다. 파지-항체 라이브러리의 연결(ligation) 효율은 90 % 이상이었다. LB/Amp 플레이트에 전기적으로 형질전환된 박테리아 용액을 도말하고 32 ℃에서 밤새 배양하였다. 배양액을 2YT 배양 배지로 세척하고, 15 % 글리세롤을 첨가하였다. 혼합물을 -80 ℃에서 저장하였다.
5) VHH 파지 항체 라이브러리 제작
회복(rescue)을 위하여 헬퍼 파지 M13K07 (Invitrogen)을 항체 라이브러리에 추가하였다: 파지 항체 라이브러리는 통상적인 방법에 따라 제조하였고, 이후 사용을 위해 -80 ℃에서 보관하였다.
실시예 2 : BCMA의 단일 도메인 항체의 제조
BCMA-특이적 단일 도메인 항체의 스크리닝
1 차-라운드 : BCMA 단백질 농도 150 μg/ml, 150 μl/웰, 1 개의 마이크로포어 (micropore), 4 ℃에서 하룻밤 동안 배양한다.
2 차-라운드 : BCMA 단백질 농도 10-100 μg/ml, 150 μl/웰, 5 개의 마이크로포어 (micropore), 4 ℃에서 하룻밤 동안 배양한다.
3 차-라운드 : BCMA 단백질 농도 10-50 μg/ml, 150 μl/well, 5 개의 마이크로포어 (micropore), 4 ℃에서 하룻밤 동안 배양한다.
블로킹: 1 % CPBS, 300 μl/well, 37 ℃, 2 시간 동안 배양한다.
2. 파지 ELISA를 통한 양성 클론의 선택
3차 라운드에서 성장한 콜로니가 스크리닝된 한천 플레이트에서 단일 콜로니를 무작위로 선택하고, Amp 2YT 액체 배양 배지를 포함하는 96-웰 배양 플레이트에 접종 및 배양하고, 파지 항체의 발현을 유도하기 위하여 헬퍼 파지의 과감염(superinfection)을 실시하였다. 발현 상등액을 수확한 후, BCMA를 항원으로하여 ELISA 분석을 수행하였다. BCMA-양성 웰을 선택하고, 항-BCMA 단일 도메인 항체 클론의 유전자 서열을 확인하기 위해 DNA 시퀀싱을 수행하였다. 부록 3의 뉴클레오타이드 서열을 포함하는 일련의 단일 도메인 항체 유전자 서열을 획득하여 높은 특이성과 높은 활성을 갖는 단일 도메인 항체의 추가 발현 및 스크리닝에 사용하였다.
실시예 3 : 특정 BCMA 단일 도메인의 발현 플라스미드 구축
실시예 3에서 얻은 특이적 BCMA 단일 도메인 항체 유전자를 PCR로 증폭하여 제한 효소 BbsI 및 BamHI 부위를 갖는 PCR 산물을 얻었다. PCR 산물 및 벡터 (pSJF2 벡터) (kim ls. Biosic Biochem. 2002, 66 (5): 1148-51, 중국 특허 ZL 201110280031)를 각각 제한 효소 BbsI 및 BamHI로 처리하고, T4 리가아제에 의한 연결에 의해 재조합하여 Escherichia coli에서 효율적으로 발현될 수 있는 플라스미드 sdAb-pSJF2를 얻었으며, 그 서열의 정확성을 결정하기 위해 유전자 시퀀싱을 수행하였다.
1) VHH 표적 유전자 획득에 필요한 PCR 증폭 조건 및 50 μl PCR 시스템의 조성 :
PCR 반응 조건 :
5 '프라이머-GAA GAAGAA GAC AA CAG GCC SVK GTG MAG CTG GWG GAK TCT (서열 번호:204)
3 '프라이머-gaagatctccggatccTGAGGAGACGGTGACCTGGGT (서열 번호:205)
2) 표적 유전자와 벡터를 효소절단하고 연결(ligation)하여 TG1 세포로 형질 전환시켰다. 정확한 유전자 서열을 갖는 BCMA 단일 도메인 항체 발현 플라스미드를 얻기 위해 유전자 서열 분석을 수행한 표적 단편을 포함하는 클론을 동정하기 위하여 생성물을 PCR 수행하였다.
실시예 4 : 항-BCMA 단일 도메인 항체의 발현 및 정제
실시예 3에서 플라스미드 BCMAsdAb-pSJF2를 포함하는 균주를 암피실린을 함유하는 LB 배양 플레이트에 접종하여 37 ℃에서 하룻밤 동안 두었다. 단일 콜로니를 골라서 암피실린이 함유된 15 ml LB 배지액에 접종하여, 37 ℃ 진탕 배양기에서 하룻밤 동안 배양하였다. 10 ml의 배양액을 암피실린이 함유된 1 L의 2YT 배양액으로 옮기고 37 ℃ 진탕 배양기에서 240 rpm/분으로 배양하였다. OD 값이 0.4-0.6에 도달한 후, 0.5-1.0 mM IPTG를 첨가하고 추가로 하룻밤 동안 배양하였다. 상기 배양액을 원심 분리하여 박테리아를 수집하였다. 라이소자임(lysozym)을 첨가하여 박테리아를 용해하고 원심 분리한 후, 상층액의 가용성 단일 도메인 항체 단백질을 수집하였다. 니켈(Ni +)이온 친화성 크로마토그래피에 의해 순도 95 % 이상의 단백질을 얻었다. 도 3은 발현된 항-BCMA 단일 도메인 항체 단백질을 나타내고, 도 4는 니켈 컬럼으로 정제한, 발현된 BCMA-sdAbs의 SDS-PAGE 전기 영동 결과를 나타낸다.
실시예 5 : BCMA 단일 도메인 항체의 친화성 분석 검정
1) 샘플 준비
항원 : 1X 동적 완충액 (dynamic buffer) (1X PBS, 0.05 % Tween 20 함유, 0.1 % BSA, pH7.2 포함)으로 Bio-BCMA를 10μg/ml이 되도록 희석하였다;
단일 도메인 항체를 1X 운동 완충액 (kinetic buffer)을 사용하여 400 nM, 200 nM, 100 nM, 50 nM, 25 nM, 12.5 nM 및 6.25 nM으로 점차 희석하였다;
샘플 시험(test)
시험할 항원을 SA 센서를 통해 로딩하였다. 항원은 5 구배로 희석되었고, 모든 BCMA 단일 도메인 항체는 50 nm, 20 nm, 10 nm, 1 nm, 0.1 nm 및 0.01 nm의 친화성을 가졌다.
실시예 6 : 정제된 BCMA 단일 도메인 항체와 BCMA 항원 (ELISA)의 결합 시험
BCMA-FC 항원을 0.05 M NaHCO3 (pH 9.5)로 1 μg/ml이 되도록 희석하였다. 100 μl 항원으로 96 웰 플레이트를 4 ℃에서 하룻밤 동안 코팅하였다. 0.5 % BSA-PBS 300 μl 로 96 웰 플레이트를 37 ℃에서 2 시간 동안 블로킹하였다. 희석 농도가 다른 정제된 BCMA 단일 도메인 항체를 1 시간 동안 37 ℃에서 100 μl/well로 첨가하였다. 플레이트를 0.05 % PBST로 3 회 세척하였다. 1:5000 배로 희석된 쥐(mouse) anti-His-HRP를 1 시간 동안 37 ℃에서 100 μl/well로 첨가하였다. 플레이트를 0.05 % PBST로 3 회 세척하였다. 100 μl의 TMB를 첨가하고 20 분 동안 어두운 실온에 두었다. 100 μl의 1 mol/L HCl을 첨가하여 반응을 종결시켰다. 마이크로 플레이트 리더로 450 nm에서 샘플의 OD 값을 측정하였다. 도 5는 BCMA 단백질 (ELISA)에 결합하는 정제된 BCMA 단일 도메인 항체의 농도 구배를 보여준다. B35 (13) 및 B92 (6-1) 두 항체의 BCMA 항원에 대한 결합력이 상대적으로 낮은 것을 제외하고 나머지 11 개 항체의 BCMA 항원에 대한 결합력은 매우 높았다.
실시예 7 : BAFF 및 BCMA에 대한 BCMA 단일 도메인 항체의 결합 경쟁 억제 시험 (Binding competitive inhibition test)
BCMA가 BAFF에 결합할 수 있기 때문에, 기능적 BCMA 단일 도메인 항체는 BCMA에 대한 BAFF의 결합을 경쟁적으로 억제할 수 있어야 한다. BAFF 단백질을 1 μg/ml 농도로 하여, 100 μl/well로 분리 가능한 ELISA 플레이트를 코팅하고 4 ℃에서 하룻밤 동안 배양하였다. 블로킹을 위해 2 % BSA (300 μl/well)를 첨가하고 37 ℃에서 2 시간 동안 배양하였다. 최종 농도 10 μg/ml로 BCMA 단일 도메인 항체를 희석하였다. 100 μl BCMA (10 μg/ml) 단일 도메인 항체를 첨가하고, 2 μl의 BAFF (5 μg/ml) 단백질을 각 웰에 첨가하여 균일하게 혼합하였다. 염소 항 토끼(goat antiorabbit) IgG HRP (1:5000)를 100 μl/well로 희석하여 37 ℃에서 1 시간 동안 배양하였다. TMB 발색 용액 100 μl/well을 첨가하고 어두운 곳에서 10 분 동안 반응시켰다. 50 μl/well 로 2M H2SO4를 첨가하여 반응을 종결하였다. OD 값은 450 nm에서 측정하였다. 도 6은 BCMA 단일 도메인 항체가 BCMA 단백질에 BAFF 단백질이 결합하는 것을 경쟁적으로 억제할 수 있음을 보여준다. 서로 다른 BCMA 단일 도메인 항체는 BAFF 단백질과 BCMA 단백질의 결합을 경쟁적으로 억제할 수 있으며 억제율은 34 %에서 92 % 범위였다.
실시예 8 : CART 세포상의 특정 BCMA 항원을 표적으로 하는 인식 항체로서 BCMA 단일 도메인 항체에 대한 연구
벡터 구축
BCMA 단일 도메인 항체 유전자 및 2 세대 CAR 구조 유전자를 합성 하였다. BCMA CAR 유전자를 얻기 위해 두 유전자를 중복 PCR로 스플라이싱 하였다. 합성 유전자를 얻은 후, 분자 클로닝을 수행하였다. 먼저 두 개의 유전자 단편의 PCR 산물을 얻었다. 그 후, 오버랩(overlapping) PCR을 수행하여 두 개의 단편이 연결된 2 세대 CAR 구조를 갖는 BCMA CAR 유전자를 얻었다. Pre 벡터 및 BCMA CAR 유전자를 효소 분해, 연결(ligation), 형질 전환, 클로닝, 플라스미드 업그레이딩 및 시퀀싱을 통해, 올바른 서열을 가진 BCMA CAR-발현 렌티 바이러스 벡터 Pre-Lenti-EF1 BCMA를 얻었다.
2) 렌티바이러스 패키징
바이러스 패키징 전날, 293T 세포를 트립신으로 분해하여 150 cm 배양 접시에 도포하였다. 세포를 5 % CO2 배양기에서 8-24 시간 동안 배양하였다. 부착 세포가 전체 배양 접시 면적의 80 %에 도달하였을 때, 293T 세포를 형질 감염시켰다. Pre-Lenti-EF1 BCMA CAR:psPAX2:pMD2G = 4:3:1로하여 리포펙타민 2000으로 공동 형질 감염시켰다. 바이러스 상층액은 48 시간 후에 수집하였고, 죽은 293T 세포 및 세포 잔해물을 제거하기 위해 4 ℃, 1250 rpm에서 5 분 동안 원심 분리하였다. 그런 다음, 바이러스 상층액을 여과, 농축, 하위-포장(sub-packaged)하여 -80 ℃의 냉동고에 보관하였다.
CART 세포의 제조
건강한 지원자로부터 10 ml의 신선한 혈액을 채취하였다. 림프구 분리 용액으로 말초 혈액 단핵 세포 (PBMC)를 분리한 다음, T 세포를 분리하여 자성 비드로 정제하였다. 2 x 106 T cells/well을 6-웰 플레이트에 시드(seed)하고, IL-2 (1000 U/ml)를 포함하는 x-vivo 15 배양 배지에서 배양하고 항-CD3로 24 시간 동안 자극하였다. 24 시간 자극 후, BCMA 바이러스 용액을 첨가하고 밤새 감염시켰다. 둘째 날에는 2 ml의 배양 배지를 첨가 하였다. 감염 6-7 일 후, CAR의 발현을 유세포 분석으로 평가했습니다. 형질 감염된 T 세포에 의한 항-BCMA-CAR 발현의 양성 비율은 유세포 분석을 통해 비오틴화된 BCMA를 사용하여 분석되었다.
4) 사멸 활력의 결정
세포 사멸 시험에서는, LDH 검출 키트 (Promega)를 사용하여 검출하였다. CART 세포/T 세포:표적 세포를 각각 0.5:1, 1:1, 2:1 및 4:1의 4 가지 구배로 설정하였다. Daudi 세포 3 x 104/well, 나머지 웰은 X-VIVO 함유 배양 배지/1640 배양 배지로 200 μL를 보충하였다. 96-웰 플레이트를 37 ℃의 5 % CO2 배양기에서 배양하였다. 17 시간 후, 용해물 20 μl를 최대 방출 웰 (maximum release well)에 첨가하고, 세포를 균일하게 혼합하여 완전히 파열시켰다. 96-웰 플레이트를 CO2 인큐베이터에서 2 시간 동안 인큐베이션 하였다. 2 시간 후, 최대 방출 웰을 관찰하였다. 표적 세포가 완전히 용해된 후, 상층액 50 μL를 각 웰에서 바닥이 평평한 96-well plate로 흡입한 다음, 각 웰에 기질 용액 50 μL를 첨가하여 암실에서 30 분 동안 현상을 수행하였다. 30 분 후, 혼합물의 색 변화를 관찰하였으며, 최대 방출 MM.1S 웰과 CART 셀 웰의 색은 더 어두워야한다. 490 nm의 파장에서 측정하기 위해 마이크로 플레이트 리더를 사용하였다. 사멸 결과는 도 7에 나타냈다. BCMA 키메릭 항원 수용체 변형된 T 세포는 20 % 이상의 매우 높은 사멸 활성으로 BCMA 양성 세포를 특이적으로 사멸시킬 수 있으며, BCMA 음성 세포에 대해서는 사멸 효과가 없다.
부록 1
부록 2
부록 3
<110> SHENZHEN PREGENE BIOPHARMA CO.LTD.
<120> ANTI-BCMA SINGLE DOMAIN ANTIBODIES AND APPLICATION THEREOF
<130> 0087-PA-002KR
<160> 205
<170> SIPOSequenceListing 1.0
<210> 1
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<212> PRT
<213> artificial sequence
<400> 1
Thr Tyr Phe Met Ala Gly Gly Ile Arg Trp Ser Asp Gly Val Pro His
1 5 10 15
Tyr Ala Asp Ser Val Lys Gly Cys Ala Ser Arg Gly Ile Ala Asp Gly
20 25 30
Ser Asp Phe Gly Ser
35
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Ile Lys Ala Met Ala Ala Tyr Ile Arg Ser Gly Gly Thr Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Tyr Ser Pro Pro Gly Ser
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Arg Phe Pro Asp Leu Gly Pro
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Ala Asn Thr Met Ala Ala Arg Ile Ser Thr Asp Gly Arg Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Ala Asn Trp Leu Ser Lys Phe Asp
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Tyr
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Val Asn Ala Val Ala Ala Tyr Ile Arg Arg Ser Gly Ser Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Phe Gly Ser Asp Tyr Val
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Val Leu Gly Ser
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Ile Lys Ala Leu Ala Ala Tyr Ile Thr Ser Gly Gly Asn Thr Asn Tyr
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Ala Asp Ser Val Arg Gly Cys Asn Ala Asp Phe Gly Glu Gly Thr Ile
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Ile Ser Leu Gly Pro
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Ile Asn Ala Met Ala Ala Ala Leu Thr Ser Gly Gly Asn Thr His Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Phe Gly Thr Ala Gly Leu
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Val Val Leu Gly Pro
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Ile Asn Ala Met Ala Ala Tyr Ile Arg Ser Asn Gly Arg Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Tyr Gly Pro Pro Val Ser
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Ile Gly Pro
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Ile Lys Ala Met Ala Ala Ala Val Thr Ser Gly Gly Ser Thr His Tyr
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Leu Asp Ser Val Lys Gly Cys Asn Ala Asp Phe Gly Thr Asp Tyr Val
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Asp Leu Gly Pro
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Ile Asn Ala Met Gly Ala Ala Ile Thr Lys Ser Asn Asn Ile Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Gly Phe Phe Ala Leu Pro Gly Tyr
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Ser Ser Glu Glu Phe Gly Pro
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Met Asn Arg Met Gly Ala Asp Ile Arg Asp Gly Gly Ser Thr Ile Tyr
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Ser Asp Ser Val Lys Gly Cys Asn Ala Gly Arg Thr Gly Asp Arg Phe
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Asn Leu Val Ala Tyr
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Gly Tyr Ala Met Ala Ala Ala Ile Ser Ser Ser Ser Asn Ser Ala Pro
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Tyr Tyr Ala Asn Ser Val Lys Gly Cys Ala Ala Arg Tyr Gly Thr Lys
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Arg Tyr Val Ala Arg Glu Tyr Asp Ser
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Ile Asn Gly Met Gly Ala Arg Ile Asp Ser Arg Gly Ser Ala Tyr Tyr
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Ala Asp Phe Val Glu Gly Cys Phe Ala Trp Gln Gly Ala Glu Thr Tyr
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Thr Tyr Ala Met Ala Ala Tyr Ile Thr Asn Gly Gly Ser Thr Asp Tyr
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Ala Ala Ser Val Lys Gly Cys Asn Gly Ala Thr Arg Gly Ala Gln Leu
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Asn Tyr Ala Met Ala Ala Ala Ile Ser Val Ser Ala Asn Ser Ala Pro
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Tyr Tyr Ala Asn Ser Val Lys Gly Cys Ala Ala Arg Tyr Gly Thr Lys
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Arg Tyr Val Ala Arg Glu Tyr Asp Ser
35 40
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Leu Asn Ala Met Gly Ala Arg Ile Ala Ala Asp Gly Ser Thr His Tyr
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Ala Asp Ser Val Glu Gly Cys Phe Ala Trp Leu Gly Thr Asp Thr Tyr
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Asn Asn Ala Met Gly Ala Arg Ile Asp Ser Gly Gly Ile Thr Arg Tyr
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Ala Asp Ser Leu Lys Gly Cys Phe Ala His Val Gly Gly Thr Ile
20 25 30
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Ile Asn Ser Met Gly Ala Ser Ile Thr Gly Gly Gly Ser Ser Arg Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Thr Ile Pro Pro Ala Arg Thr Gln
20 25 30
Ser Asp His Gly Glu Trp Tyr Asp Tyr
35 40
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Ile Asn Met Ser Ala Thr Thr Arg His Asp Ser Thr His Tyr Ser Asp
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Ser Val Lys Gly Cys Ser Gly Phe Phe Leu Asp Gly Ser Thr Trp His
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Pro Tyr
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Ile Asn Ala Met Ala Ala Tyr Ile Arg Ser Asn Gly Ser Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Gly Phe Phe Thr Leu Pro Gly Tyr
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Ser Ser Glu Glu Phe Gly Pro
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Ile Asn Ala Met Gly Ala Gly Ile Thr Lys Gly Gly Arg Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Gly Leu Cys Ser Gly Arg Glu Cys
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Tyr Gly Asp Ser Leu Phe Ala Ala
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Ile Asn Ala Met Ala Ala Tyr Ile Arg Ser Asn Gly Arg Thr Asn Tyr
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Trp His Pro Tyr
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Asp Tyr Ala Ile Gly Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr His
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Tyr Ala Asp Ser Val Lys Gly Cys Ala Thr Pro Trp Val Thr Tyr Cys
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Pro Glu Asn Leu Leu Phe Ser Tyr
35 40
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Asp Tyr Ala Ile Gly Ser Cys Ile Thr Ser Ser Asp Gly Ser Thr Tyr
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Tyr Ala Asp Ser Val Lys Gly Cys Ala Thr Pro Trp Val Thr Tyr Cys
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Pro Glu Asn Leu Leu Phe Ser Tyr
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Ile Lys Ala Met Gly Ala Ala Ile Thr Ser Gly Gly Ser Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Gly Phe Phe Glu Tyr Arg Gly Leu
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Glu Gln Leu Gly Pro
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Ile Arg Ala Met Thr Ala Val Leu Thr Ser Ala Gly Lys Pro Met Tyr
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Val Val Leu Gly Pro
35
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Ile Glu Ala Met Gly Ala Ala Ile Thr Ser Gly Asp Ser Thr Asn Tyr
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Ala Asp Phe Val Lys Gly Cys Asn Ala Leu Met Val Val Arg Ala Gly
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Ser Asn Pro Glu Ile Gly Pro
35
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Asp Tyr Ala Ile Gly Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr
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Tyr Ala Asp Ser Val Lys Gly Cys Ala Thr Pro Trp Val Thr Tyr Cys
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Pro Glu Asn Leu Leu Phe Ser Tyr
35 40
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Leu Asp Ala Val Gly Ala Arg Ile Asp Arg Arg Gly Ser Thr Tyr Tyr
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Ala Val Ser Val Glu Gly Cys Phe Ala Trp Gln Gly Ala Glu Thr His
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Phe Asn Asp Met Gly Ala Ala Ile Thr Ser Ser Arg Asn Thr Leu Tyr
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Val Asp Ser Val Lys Gly Cys Asn Pro Tyr Pro Ser Pro Asn Asn Tyr
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Ile Asn Ala Met Gly Ala Ala Ile Thr Arg Ser Gly Lys Thr Asn Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Gly Phe Tyr Gly Ser Glu Phe Gly
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Pro
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Arg Tyr Ala Val Gly Ala Ser Ile Thr Trp Ser Gly Asp Tyr Thr Tyr
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Tyr Lys Asp Ser Val Lys Gly Cys Ala Ala Asp Lys Ser Ser Phe Arg
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Leu Arg Gly Pro Gly Leu Tyr Asp Tyr
35 40
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Tyr Tyr Ala Ile Gly Ser Cys Ile Ser Ser Arg Asp Gly Thr Thr His
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Tyr Ala Asp Ser Val Lys Gly Cys Ala Thr Pro Trp Val Thr Tyr Cys
20 25 30
Pro Glu Asn Leu Leu Phe Ser Tyr
35 40
<210> 33
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Tyr Tyr Ala Ile Gly Ser Ala Ile Ser Asn Ile Asp Asp Asp Thr Tyr
1 5 10 15
Tyr Glu Asp Ser Val Lys Gly Cys Ala Ala Asp Lys Asp Val Val Val
20 25 30
Val Arg Thr Gly Leu Ser Glu Ser Asp Tyr
35 40
<210> 34
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<400> 34
Ile Asn Ala Met Ala Ala Val Ile Thr Ser Gly Gly Arg Thr Met Tyr
1 5 10 15
Ala Glu Ser Val Lys Gly Cys Asn Gly Asp Trp Gly Ser Glu Gly Arg
20 25 30
Val Asp Leu Gly Pro
35
<210> 35
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<400> 35
Ile Gly Asp Met Glu Ala Ser Ile Ser Ala Gly Pro Glu Met Arg Ser
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Ala Gly Thr Pro Thr Tyr Ala Lys Ser Val Glu Gly Cys Asn Ala Asp
20 25 30
Val Leu Thr Tyr Tyr Asn Gly Arg Tyr Ser Arg Asp Val Tyr
35 40 45
<210> 36
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<400> 36
Ile Asn Met Ser Ala Thr Ile Thr Arg His Asp Ser Thr His Tyr Ser
1 5 10 15
Asp Ser Val Lys Gly Cys Ser Gly Phe Phe Leu Asp Gly Ser Thr Trp
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Arg Pro Tyr
35
<210> 37
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<400> 37
Gly Tyr Ala Val Ala Ala Ala Ile Ser Ser Ser Asp Asn Ser Ser Pro
1 5 10 15
Tyr Tyr Ala Asn Val Val Lys Gly Cys Ala Ala Arg Tyr Gly Thr Lys
20 25 30
Arg Tyr Val Ala Arg Glu Tyr Asp Ser
35 40
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<400> 38
Ile Asn Ala Met Ala Ala Tyr Ile Arg Ser Ser Gly Thr Thr Met Tyr
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Ala Asp Ser Val Lys Gly Cys Asn Gly Asp Tyr Ser Pro Pro Gly Ser
20 25 30
Thr Tyr Pro Asp Leu Gly Pro
35
<210> 39
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<400> 39
Asp Tyr Ala Ile Gly Ser Cys Ile Thr Ser Ser Asp Gly Ser Thr Tyr
1 5 10 15
Tyr Ala Asp Ser Val Lys Gly Cys Ala Thr Pro Trp Val Asn Tyr Cys
20 25 30
Pro Glu Asn Leu Leu Phe Ser Tyr Phe Ser Thr Tyr Phe Met Ala
35 40 45
<210> 40
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<400> 40
Ala Ala Ile Arg Trp Ser Asp Gly Val Pro His Tyr Thr Asp Ser Val
1 5 10 15
Lys Gly Cys Ala Ser Arg Gly Ile Ala Asp Gly Ser Asp Phe Gly Ser
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Tyr
<210> 41
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Ile Asp Ala Met Gly Ala Arg Leu Gly Ser Asn Gly Phe Thr Gln Tyr
1 5 10 15
Asp Ile Ser Val Glu Gly Cys Phe Ala Trp Leu Gly Gln Asp Thr Val
20 25 30
<210> 42
<211> 41
<212> PRT
<213> artificial sequence
<400> 42
Asn Tyr Ala Met Gly Ala Ser Val Thr Arg Ser Gly Asp Asn Thr Tyr
1 5 10 15
Tyr Lys Asp Ser Ala Lys Gly Cys Ala Ala Asp Lys Ser Ser Phe Arg
20 25 30
Leu Arg Gly Pro Gly Val Tyr Asp Tyr
35 40
<210> 43
<211> 43
<212> PRT
<213> artificial sequence
<400> 43
Val Met Leu Met Gly Ala Ser Ile Thr Ser Ala Asp Tyr Thr Thr Tyr
1 5 10 15
Ala Glu Ser Val Glu Gly Cys Lys Val Ile Ala Ala Thr Val Trp Gly
20 25 30
Gln Glu Thr Gln Val Arg Gln Gly Leu Thr Phe
35 40
<210> 44
<211> 37
<212> PRT
<213> artificial sequence
<400> 44
Ala Arg Ser Met Thr Ala Val Ile Met Gly Gly Gly Ser Thr Met Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Trp Gly Glu Val Gly Phe
20 25 30
Pro Asn Leu Gly Pro
35
<210> 45
<211> 41
<212> PRT
<213> artificial sequence
<400> 45
Thr Tyr Ala Ile Gly Ala Ala Ile Ser Arg Arg Gly Asn Lys Thr Asp
1 5 10 15
Tyr Ala Glu Ser Val Lys Gly Cys Ala Ala Ser Ala Arg Asn Phe Ile
20 25 30
Gly Thr Gln Pro Leu Asp Tyr Asp Tyr
35 40
<210> 46
<211> 39
<212> PRT
<213> artificial sequence
<400> 46
Asn Tyr Ala Leu Gly Ala Ala Ile Asp Trp Arg His Ser Ser Tyr Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Ala Ala Ser Ser Leu Phe Pro Ser Ser
20 25 30
Ala Pro Arg Gln Tyr Asp Tyr
35
<210> 47
<211> 40
<212> PRT
<213> artificial sequence
<400> 47
Asn Tyr Ala Met Gly Ala Ala Ile Val Gly Ser Gly Asp Ser Thr Arg
1 5 10 15
Tyr Ala Asp Ser Val Lys Gly Cys Ala Ser Ser Ser Asp Pro Arg Val
20 25 30
Tyr Ile Ala Ser Thr Leu Asp Tyr
35 40
<210> 48
<211> 36
<212> PRT
<213> artificial sequence
<400> 48
Met Phe Ile Met Gly Ala Ala Ile Ser Arg Asn Ser Asn Leu Thr Tyr
1 5 10 15
Tyr Phe Gln Ser Val Lys Gly Cys Asn Ala Asp Tyr Gly Pro Pro Val
20 25 30
Ser Ile Gly Pro
35
<210> 49
<211> 39
<212> PRT
<213> artificial sequence
<400> 49
Ile Lys Ala Met Gly Ala Gly Ile Val Ser Ser Gly Asn Thr Asn Tyr
1 5 10 15
Ala Asp Phe Val Lys Gly Cys Asn Ala Leu Val Val Val Thr Ser Ala
20 25 30
Ser Gly Pro Glu Leu Ala Ser
35
<210> 50
<211> 39
<212> PRT
<213> artificial sequence
<400> 50
Thr Tyr Phe Met Ala Ala Tyr Ile Arg Ser Gly Gly Thr Thr Asn Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Tyr Ser Pro Pro Gly Ser
20 25 30
Arg Phe Pro Asp Leu Gly Pro
35
<210> 51
<211> 38
<212> PRT
<213> artificial sequence
<400> 51
Asn Tyr Ala Ile Ala Ser Ser Thr Gly Ser Asp Gly Asn Leu Tyr Thr
1 5 10 15
Pro Ser Val Arg Gly Cys Val Ala Gly Lys Arg Pro Val Ile Thr Thr
20 25 30
Trp Ile Ala Leu Asp Ala
35
<210> 52
<211> 32
<212> PRT
<213> artificial sequence
<400> 52
Ile Asp Ser Met Arg Ala His Ile Thr Ser Thr Gly Arg Thr Asn Tyr
1 5 10 15
Ala Asp Ala Val Lys Gly Cys Asn Met Val Thr Thr Pro Tyr Met His
20 25 30
<210> 53
<211> 32
<212> PRT
<213> artificial sequence
<400> 53
Glu Asn Ala Met Gly Ala Ala Ile Thr Ser Ser Arg Ser Thr Leu Tyr
1 5 10 15
Ile Asp Ser Val Lys Gly Cys Asn Pro Tyr Pro Ser Pro Asn Ser Tyr
20 25 30
<210> 54
<211> 33
<212> PRT
<213> artificial sequence
<400> 54
Ala Asn Lys Met Gly Ala Arg Ile Ser Thr Asp Gly Arg Thr Asn Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Ala Asn Trp Leu Asp Lys Tyr Asp
20 25 30
Tyr
<210> 55
<211> 37
<212> PRT
<213> artificial sequence
<400> 55
Ala Arg Ser Met Thr Ala Val Ile Thr Ser Gly Gly Ser Thr Met Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Trp Gly Glu Val Gly Phe
20 25 30
Val Asn Leu Gly Pro
35
<210> 56
<211> 39
<212> PRT
<213> artificial sequence
<400> 56
Phe Asn Gly Val Ala Ala Val Ile Arg Ser Gly Gly Asn Thr Leu Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Val Asp Tyr Ser Pro Pro Gly Ser
20 25 30
Leu Val Pro Asp Leu Gly Pro
35
<210> 57
<211> 40
<212> PRT
<213> artificial sequence
<400> 57
Ile Asn Ala Met Gly Ala Ala Ile Thr Arg Gly Gly Ser Thr Asn Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Gly Leu Cys Ser Asp Asp Arg Cys
20 25 30
Tyr Gly Asp Ser Leu Phe Ala Pro
35 40
<210> 58
<211> 35
<212> PRT
<213> artificial sequence
<400> 58
Leu Asp Ala Val Gly Ala Arg Ile Asp Ser Arg Gly Ser Ala Tyr Tyr
1 5 10 15
Ala Asp Ser Val Glu Gly Cys Phe Ala Tyr Tyr Gly Ala Gln Ile Ser
20 25 30
Phe Gly Pro
35
<210> 59
<211> 33
<212> PRT
<213> artificial sequence
<400> 59
Leu Asp Ala Met Gly Ala His Ile Asp Asp Asp Arg Gly Thr Ala Tyr
1 5 10 15
Tyr Ala Asp Phe Val Lys Gly Cys Phe Ala Trp Gln Gly Ala Glu Thr
20 25 30
Tyr
<210> 60
<211> 37
<212> PRT
<213> artificial sequence
<400> 60
Val Asn Ala Val Ala Ala Tyr Ile Arg Arg Ser Gly Ser Thr Asn Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Ala Gly Arg Thr Gly Asp Arg Phe
20 25 30
Asn Leu Val Ala Tyr
35
<210> 61
<211> 40
<212> PRT
<213> artificial sequence
<400> 61
Thr Tyr Phe Met Ala Gly Gly Ile Arg Trp Ser Asp Gly Val Pro His
1 5 10 15
Tyr Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Tyr Ser Pro Pro Gly
20 25 30
Ser Arg Phe Pro Asp Leu Gly Pro
35 40
<210> 62
<211> 35
<212> PRT
<213> artificial sequence
<400> 62
Ile Lys Ala Met Ala Ala Tyr Ile Arg Ser Gly Gly Thr Asn Tyr Ala
1 5 10 15
Asp Ser Val Lys Gly Cys Ala Ser Arg Gly Ile Ala Asp Gly Ser Asp
20 25 30
Phe Gly Ser
35
<210> 63
<211> 39
<212> PRT
<213> artificial sequence
<400> 63
Leu Tyr Ala Met Gly Ala Tyr Ile Arg Ser Gly Gly Thr Thr Asn Tyr
1 5 10 15
Ala Asp Ser Val Lys Gly Cys Asn Ala Asp Tyr Ser Pro Pro Gly Ser
20 25 30
Arg Phe Pro Asp Leu Gly Pro
35
<210> 64
<211> 41
<212> PRT
<213> artificial sequence
<400> 64
Thr Tyr Ala Met Gly Ala Ala Ile Ser Arg Arg Gly Asn Lys Thr Asp
1 5 10 15
Tyr Ala Glu Ser Val Lys Gly Cys Ala Ala Ser Ala Arg Asn Phe Ile
20 25 30
Gly Thr Gln Pro Leu Asp Tyr Asp Tyr
35 40
<210> 65
<211> 36
<212> PRT
<213> artificial sequence
<400> 65
Gly Tyr Phe Met Ala Gly Gly Ile Arg Trp Ser Asp Gly Val Pro His
1 5 10 15
Tyr Ala Asp Ser Val Lys Cys Ala Ser Arg Gly Ile Ala Asp Gly Ser
20 25 30
Asp Phe Gly Ser
35
<210> 66
<211> 39
<212> PRT
<213> artificial sequence
<400> 66
Ile Asn Ala Met Gly Ala Ala Ile Thr Lys Ser Asn Asn Ile Asn Tyr
1 5 10 15
Ala Asp Ser Asx Lys Gly Cys Asn Gly Phe Phe Thr Leu Pro Gly Tyr
20 25 30
Ser Ser Glu Glu Phe Gly Pro
35
<210> 67
<211> 120
<212> PRT
<213> artificial sequence
<400> 67
Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Arg Thr Phe Ser Thr Tyr
20 25 30
Phe Met Ala Trp Phe Arg Gln Pro Pro Gly Lys Glu Arg Glu Tyr Val
35 40 45
Gly Gly Ile Arg Trp Ser Asp Gly Val Pro His Tyr Ala Asp Ser Val
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 Lys Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Arg Gly Ile Ala Asp Gly Ser Asp Phe Gly Ser Tyr Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 68
<211> 122
<212> PRT
<213> artificial sequence
<400> 68
Gln Val Lys Leu Glu 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 Lys
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Gly Gly Thr Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala 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 Asp Tyr Ser Pro Pro Gly Ser Arg Phe Pro Asp Leu Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 69
<211> 116
<212> PRT
<213> artificial sequence
<400> 69
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Ala Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Val Phe Ser Ala Asn
20 25 30
Thr Met Ala Trp Tyr Arg Arg Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Ser Thr Asp Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Arg Glu Lys Thr Val Phe Leu
65 70 75 80
Gln Met Asn Arg Leu Asn Pro Asp Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Asn Trp Leu Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 70
<211> 119
<212> PRT
<213> artificial sequence
<400> 70
Asp Val Gln Leu Gln Ala 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 Val Asn
20 25 30
Ala Val Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Arg Ser Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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 Asp Phe Gly Ser Asp Tyr Val Val Leu Gly Ser Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 71
<211> 120
<212> PRT
<213> artificial sequence
<400> 71
Gln Val Lys Leu Glu 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 Ser Ile Phe Ser Ile Lys
20 25 30
Ala Leu Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Thr Ser Gly Gly Asn Thr Asn Tyr Ala Asp Ser Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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 Asp Phe Gly Glu Gly Thr Ile Ile Ser Leu Gly Pro Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 72
<211> 120
<212> PRT
<213> artificial sequence
<400> 72
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 Glu Phe Ser Ile Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Leu Thr Ser Gly Gly Asn Thr His Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Trp 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 Asp Phe Gly Thr Ala Gly Leu Val Val Leu Gly Pro Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 73
<211> 118
<212> PRT
<213> artificial sequence
<400> 73
Glu Val Gln Leu Gln Ala 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
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Asn Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Asp Tyr Gly Pro Pro Val Ser Ile Gly Pro Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 74
<211> 118
<212> PRT
<213> artificial sequence
<400> 74
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 Val Ser Gly Ser Leu Leu Ser Ile Lys
20 25 30
Ala Met Ala Trp Phe Arg Gln Pro Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Val Thr Ser Gly Gly Ser Thr His Tyr Leu Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Thr Val His Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Phe Gly Thr Asp Tyr Val Asp Leu Gly Pro Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 75
<211> 122
<212> PRT
<213> artificial sequence
<400> 75
Asp Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Ile Phe Ser Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Lys Ser Asn Asn Ile Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Thr Asp Asn Ala 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
Gly Phe Phe Ala Leu Pro Gly Tyr Ser Ser Glu Glu Phe Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 76
<211> 120
<212> PRT
<213> artificial sequence
<400> 76
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 Val Ala Ser Gly Asn Ile Phe Asp Met Asn
20 25 30
Arg Met Gly Trp Tyr Arg Gln Pro Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Asp Ile Arg Asp Gly Gly Ser Thr Ile Tyr Ser Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Gly Arg Thr Gly Asp Arg Phe Asn Leu Val Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 77
<211> 124
<212> PRT
<213> artificial sequence
<400> 77
Asp Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln His Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Arg Thr Phe Ser Gly Tyr
20 25 30
Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu His Glu Phe Val
35 40 45
Ala Ala Ile Ser Ser Ser Ser Asn Ser Ala Pro Tyr Tyr Ala Asn Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
65 70 75 80
Tyr Leu Gln Met Asn Asn Leu Gln Thr Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Ala Arg Tyr Gly Thr Lys Arg Tyr Val Ala Arg Glu Tyr Asp
100 105 110
Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 78
<211> 115
<212> PRT
<213> artificial sequence
<400> 78
Asp Val Gln Leu Gln Ala Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Ile Arg Ser Ile Asn
20 25 30
Gly Met Gly Trp Ser Arg Val Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala Arg Ile Asp Ser Arg Gly Ser Ala Tyr Tyr Ala Asp Ser Val Glu
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Val Asp Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe
85 90 95
Ala Trp Gln Gly Ala Glu Thr Tyr Trp Gly Leu Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 79
<211> 118
<212> PRT
<213> artificial sequence
<400> 79
Gln Val Lys Leu Glu 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 Gly Asp Thr Tyr
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Asp Leu Val
35 40 45
Ala Tyr Ile Thr Asn Gly Gly Ser Thr Asp Tyr Ala Ala Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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
Gly Ala Thr Arg Gly Ala Gln Leu Val Phe Asp Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 80
<211> 124
<212> PRT
<213> artificial sequence
<400> 80
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln His Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Val Ser Ala Asn Ser Ala Pro Tyr Tyr Ala Asn Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Ala Arg Tyr Gly Thr Lys Arg Tyr Val Ala Arg Glu Tyr Asp
100 105 110
Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 81
<211> 115
<212> PRT
<213> artificial sequence
<400> 81
Gln Val Lys Leu Glu 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 Ser Val Ser Leu Asn
20 25 30
Ala Met Gly Trp Ser Arg Val Gln Pro Gly Ser Thr Arg Asp Phe Val
35 40 45
Ala Arg Ile Ala Ala Asp Gly Ser Thr His Tyr Ala Asp Ser Val Glu
50 55 60
Gly Arg Phe Thr Ile Ser Gly Asp Ala Ala Arg Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe
85 90 95
Ala Trp Leu Gly Thr Asp Thr Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 82
<211> 114
<212> PRT
<213> artificial sequence
<400> 82
Asp Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Asp Asn Asn
20 25 30
Ala Met Gly Trp Ser Arg Thr Pro Pro Gly Lys Gln Arg Glu Phe Val
35 40 45
Ala Arg Ile Asp Ser Gly Gly Ile Thr Arg Tyr Ala Asp Ser Leu Lys
50 55 60
Gly Arg Phe Thr Val Ser Arg Asp Thr Gly Lys Asn Thr Val Ser Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Gly Val Tyr Tyr Cys Phe
85 90 95
Ala His Val Gly Gly Thr Ile Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 83
<211> 124
<212> PRT
<213> artificial sequence
<400> 83
Gln 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 Leu Pro Ser Gly Gly Ile Phe Thr Ile Asn
20 25 30
Ser Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ser Ile Thr Gly Gly Gly Ser Ser Arg Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ile Met Ser Arg Asp Asn Ala Lys Asn Met 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
Thr Ile Pro Pro Ala Arg Thr Gln Ser Asp His Gly Glu Trp Tyr Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 84
<211> 118
<212> PRT
<213> artificial sequence
<400> 84
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Ser Ser Ile Phe Ser Ile Asn
20 25 30
Met Ser Trp Tyr Arg Gln Ala Pro Gly Asn Glu Arg Glu Leu Val Ala
35 40 45
Thr Ile Thr Arg His Asp Ser Thr His Tyr Ser Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asp Asp Lys Asn Thr Ile Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser Gly
85 90 95
Phe Phe Leu Asp Gly Ser Thr Trp His Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 85
<211> 122
<212> PRT
<213> artificial sequence
<400> 85
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 Val Ser Ile Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Gly Phe Phe Thr Leu Pro Gly Tyr Ser Ser Glu Glu Phe Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 86
<211> 123
<212> PRT
<213> artificial sequence
<400> 86
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 Glu Ser Ile Phe Ser Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Tyr Val
35 40 45
Ala Gly Ile Thr Lys Gly Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala 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
Gly Leu Cys Ser Gly Arg Glu Cys Tyr Gly Asp Ser Leu Phe Ala Ala
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 87
<211> 119
<212> PRT
<213> artificial sequence
<400> 87
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 Val Ser Ile Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Asn Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Gly Phe Phe Leu Asp Gly Ser Thr Trp His Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 88
<211> 123
<212> PRT
<213> artificial sequence
<400> 88
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Thr
65 70 75 80
Leu Gln Ile Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Pro Trp Val Thr Tyr Cys Pro Glu Asn Leu Leu Phe Ser Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 89
<211> 123
<212> PRT
<213> artificial sequence
<400> 89
Gln Val Lys Leu Glu 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 Asp Asp Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Thr Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asn Thr Val His
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Pro Trp Val Thr Tyr Cys Pro Glu Asn Leu Leu Phe Ser Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 90
<211> 120
<212> PRT
<213> artificial sequence
<400> 90
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Val Ser Gly Ser Ser Phe Ser Ile Lys
20 25 30
Ala Met Gly Trp Tyr Arg Leu Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala 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
Gly Phe Phe Glu Tyr Arg Gly Leu Glu Gln Leu Gly Pro Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 91
<211> 120
<212> PRT
<213> artificial sequence
<400> 91
Asp Val Gln Leu Gln Ala 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 Val Gly Ile Arg
20 25 30
Ala Met Thr Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Leu Thr Ser Ala Gly Lys Pro Met Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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 Asp Phe Gly Thr Pro Gly Ser Val Val Leu Gly Pro Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 92
<211> 122
<212> PRT
<213> artificial sequence
<400> 92
Gln Val Lys Leu Glu 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 Leu Ser Ile Glu
20 25 30
Ala Met Gly Trp Tyr Arg Gln Thr Leu Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Asp Ser Thr Asn Tyr Ala Asp Phe Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Lys Ala Lys Asn Met Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys Asn
85 90 95
Ala Leu Met Val Val Arg Ala Gly Ser Asn Pro Glu Ile Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 93
<211> 123
<212> PRT
<213> artificial sequence
<400> 93
Gln Val Lys Leu Glu 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 Asp Asp Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asn Thr Val His
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Pro Trp Val Thr Tyr Cys Pro Glu Asn Leu Leu Phe Ser Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 94
<211> 115
<212> PRT
<213> artificial sequence
<400> 94
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 Val Val Ser Ala Arg Gly Val Ser Leu Asp
20 25 30
Ala Val Gly Trp Ser Arg Val Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala Arg Ile Asp Arg Arg Gly Ser Thr Tyr Tyr Ala Val Ser Val Glu
50 55 60
Gly Arg Ser Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Leu Asp Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe
85 90 95
Ala Trp Gln Gly Ala Glu Thr His Trp Gly Leu Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 95
<211> 115
<212> PRT
<213> artificial sequence
<400> 95
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Val Ala Ser Gly Ser His Phe Ser Phe Asn
20 25 30
Asp Met Gly Trp Tyr Arg Gln Asp Pro Trp Lys Gly Arg Asp Leu Val
35 40 45
Ala Ala Ile Thr Ser Ser Arg Asn Thr Leu Tyr Val Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Pro Tyr Pro Ser Pro Asn Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 96
<211> 116
<212> PRT
<213> artificial sequence
<400> 96
Gln Val Lys Leu Glu 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 Pro Phe Thr Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Arg Ser Gly Lys Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gly Asp Asn Ala Leu Thr Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Asn Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Gly Phe Tyr Gly Ser Glu Phe Gly Pro Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 97
<211> 124
<212> PRT
<213> artificial sequence
<400> 97
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Ala Thr Leu Ser Cys Ser Ala Pro Gly Asp Thr Leu Ser Arg Tyr
20 25 30
Ala Val Gly Trp Phe Arg Gln Gly Pro Gly Gln Glu Arg Asp Phe Val
35 40 45
Ala Ser Ile Thr Trp Ser Gly Asp Tyr Thr Tyr Tyr Lys Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Val Asn Asn Met Val Tyr
65 70 75 80
Leu Arg Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ala Asp Lys Ser Ser Phe Arg Leu Arg Gly Pro Gly Leu Tyr Asp
100 105 110
Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 98
<211> 123
<212> PRT
<213> artificial sequence
<400> 98
Gln Val Lys Leu Glu 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 Asp Tyr Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Arg Asp Gly Thr Thr His Tyr Ala Asp Ser Val
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 Ile Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Pro Trp Val Thr Tyr Cys Pro Glu Asn Leu Leu Phe Ser Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 99
<211> 125
<212> PRT
<213> artificial sequence
<400> 99
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Phe Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu His Tyr Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val
35 40 45
Ser Ala Ile Ser Asn Ile Asp Asp Asp Thr Tyr Tyr Glu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Lys Asp Val Val Val Val Arg Thr Gly Leu Ser Glu Ser
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 100
<211> 120
<212> PRT
<213> artificial sequence
<400> 100
Gln Val Lys Leu Glu 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 Ser Ile Phe Gly Ile Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Ile Thr Ser Gly Gly Arg Thr Met Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Ala Ile Ser Arg Asp Val Ala 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
Gly Asp Trp Gly Ser Glu Gly Arg Val Asp Leu Gly Pro Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 101
<211> 129
<212> PRT
<213> artificial sequence
<400> 101
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Thr Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Arg Ser Ile Gly
20 25 30
Asp Met Glu Trp Tyr Arg Gln Ala Pro Gly Gln Gln Arg Glu Leu Val
35 40 45
Ala Ser Ile Ser Ala Gly Pro Glu Met Arg Ser Ala Gly Thr Pro Thr
50 55 60
Tyr Ala Lys Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ile
65 70 75 80
Lys Asn Met Met Trp Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
85 90 95
Ala Val Tyr Ser Cys Asn Ala Asp Val Leu Thr Tyr Tyr Asn Gly Arg
100 105 110
Tyr Ser Arg Asp Val Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 102
<211> 118
<212> PRT
<213> artificial sequence
<400> 102
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Ser Ser Ile Phe Ser Ile Asn
20 25 30
Met Ser Trp Tyr Arg Gln Ala Pro Gly Asn Glu Arg Glu Leu Val Ala
35 40 45
Thr Ile Thr Arg His Asp Ser Thr His Tyr Ser Asp Ser Val Lys Gly
50 55 60
Arg Phe Ala Ile Ser Arg Asp Asp Asp Lys Asn Thr Ile Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser Gly
85 90 95
Phe Phe Leu Asp Gly Ser Thr Trp Arg Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 103
<211> 124
<212> PRT
<213> artificial sequence
<400> 103
Asp Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Gly Tyr
20 25 30
Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Ser Ser Asp Asn Ser Ser Pro Tyr Tyr Ala Asn Val
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Gln Thr Glu Asp Thr Ala Leu Tyr Tyr
85 90 95
Cys Ala Ala Arg Tyr Gly Thr Lys Arg Tyr Val Ala Arg Glu Tyr Asp
100 105 110
Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 104
<211> 122
<212> PRT
<213> artificial sequence
<400> 104
Gln Val Lys Leu Glu 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 Ser Ile Phe Ser Ile Asn
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Ser Gly Thr Thr Met Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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
Gly Asp Tyr Ser Pro Pro Gly Ser Thr Tyr Pro Asp Leu Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 105
<211> 245
<212> PRT
<213> artificial sequence
<400> 105
Glu Val Gln Leu Gln Ala 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 Asp Asp Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Thr Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asn Thr Val His
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Pro Trp Val Asn Tyr Cys Pro Glu Asn Leu Leu Phe Ser Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gln Ala Gln Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Thr Ala Ser Gly Arg Thr Phe Ser Thr Tyr Phe Met Ala
145 150 155 160
Trp Phe Arg Gln Pro Pro Gly Lys Glu Arg Glu Tyr Val Gly Gly Ile
165 170 175
Arg Trp Ser Asp Gly Val Pro His Tyr Thr Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
195 200 205
Asn Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala Ser Arg
210 215 220
Gly Ile Ala Asp Gly Ser Asp Phe Gly Ser Tyr Gly Gln Gly Thr Gln
225 230 235 240
Val Thr Val Ser Ser
245
<210> 106
<211> 116
<212> PRT
<213> artificial sequence
<400> 106
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Ile Ile Phe Ser Ala Thr
20 25 30
Thr Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Leu Ile Thr Ser Asp Trp His Thr Lys Tyr Ala Asp Ser Val Lys
50 55 60
Asp Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Ser Thr Val His Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Tyr
85 90 95
Ala Arg Gln Ala Phe Ser Glu Pro Arg Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 107
<211> 115
<212> PRT
<213> artificial sequence
<400> 107
Gln Val Gln Leu Val Asp 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 Ser Gly Arg Ile Asp
20 25 30
Ala Met Gly Trp Ser Arg Val Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala Arg Leu Gly Ser Asn Gly Phe Thr Gln Tyr Asp Ile Ser Val Glu
50 55 60
Gly Arg Phe Thr Ile Ser Gly Asp Val Ala Lys Asn Thr Ile Tyr Leu
65 70 75 80
Gln Met Asp Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe
85 90 95
Ala Trp Leu Gly Gln Asp Thr Val Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 108
<211> 124
<212> PRT
<213> artificial sequence
<400> 108
Gln Val Gln Leu Val Asp Ser Gly Gly Gly Leu Val Lys Ala Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Ala Leu Phe Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Gly Pro Gly Lys Glu Arg Asp Phe Val
35 40 45
Ala Ser Val Thr Arg Ser Gly Asp Asn Thr Tyr Tyr Lys Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ala Asp Lys Ser Ser Phe Arg Leu Arg Gly Pro Gly Val Tyr Asp
100 105 110
Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 109
<211> 126
<212> PRT
<213> artificial sequence
<400> 109
Asp Val Gln Leu Val Asp Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Asp Gly Arg Val Met
20 25 30
Leu Met Gly Trp Tyr Arg Gln Ala Pro Gly Gln Gln Arg Asp Leu Val
35 40 45
Ala Ser Ile Thr Ser Ala Asp Tyr Thr Thr Tyr Ala Glu Ser Val Glu
50 55 60
Gly Arg Phe Thr Ile Ser Thr Asp Asn Asn Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys Lys
85 90 95
Val Ile Ala Ala Thr Val Trp Gly Gln Glu Thr Gln Val Arg Gln Gly
100 105 110
Leu Thr Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 110
<211> 120
<212> PRT
<213> artificial sequence
<400> 110
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 Val Ala Ser Gly Ser Ile Ser Ser Ala Arg
20 25 30
Ser Met Thr Trp Tyr Arg Gln Ala Leu Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Ile Met Gly Gly Gly Ser Thr Met Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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 Asp Trp Gly Gly Val Gly Phe Pro Asn Leu Gly Pro Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 111
<211> 123
<212> PRT
<213> artificial sequence
<400> 111
Asp Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Ile Gly Asp
1 5 10 15
Ser Val Arg Leu Ser Cys Ile Ala Ser Gly Gly Thr Phe Arg Thr Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Ala Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Arg Gly Asn Lys Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Glu Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Asp Asp Met Gly Val Tyr Tyr Cys Ala
85 90 95
Ala Ser Ala Arg Asn Phe Ile Gly Thr Gln Pro Leu Asp Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 112
<211> 122
<212> PRT
<213> artificial sequence
<400> 112
Gln Val Lys Leu Glu 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 Trp Asn Leu Gly Asn Tyr
20 25 30
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Asp Trp Arg His Ser Ser Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Met Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Lys Leu Glu Asp Thr Arg Leu Tyr Tyr Cys Ala
85 90 95
Ala Ser Ser Leu Phe Pro Ser Ser Ala Pro Arg Gln Tyr Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 113
<211> 123
<212> PRT
<213> artificial sequence
<400> 113
Asp Val Gln Leu Val Asp Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Thr Phe Ser Asn Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Arg Arg Pro Gly Leu Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Val Gly Ser Gly Asp Ser Thr Arg Tyr Ala Asp Ser Val
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 Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Ser Ser Asp Pro Arg Val Tyr Ile Ala Ser Thr Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 114
<211> 119
<212> PRT
<213> artificial sequence
<400> 114
Gln 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 Met Phe
20 25 30
Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Asn Ser Asn Leu Thr Tyr Tyr Phe Gln Ser Val
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 Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Ala Asp Tyr Gly Pro Pro Val Ser Ile Gly Pro Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 115
<211> 122
<212> PRT
<213> artificial sequence
<400> 115
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Trp Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Arg Ile Leu Ser Ile Lys
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Tyr Val
35 40 45
Ala Gly Ile Val Ser Ser Gly Asn Thr Asn Tyr Ala Asp Phe Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gly Asp Asn Ala Lys Asn Thr Val Phe 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 Leu Val Val Val Thr Ser Ala Ser Gly Pro Glu Leu Ala Ser Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 116
<211> 122
<212> PRT
<213> artificial sequence
<400> 116
Asp Val Gln Leu Val Asp Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Arg Thr Phe Ser Thr Tyr
20 25 30
Phe Met Ala Trp Phe Arg Gln Pro Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Gly Gly Thr Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala 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 Asp Tyr Ser Pro Pro Gly Ser Arg Phe Pro Asp Leu Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 117
<211> 121
<212> PRT
<213> artificial sequence
<400> 117
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asn Tyr
20 25 30
Ala Ile Ala Trp Phe Arg Gln Ala Pro Gly Arg Glu Arg Glu Trp Val
35 40 45
Ser Ser Thr Gly Ser Asp Gly Asn Leu Tyr Thr Pro Ser Val Arg Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Val Ala
85 90 95
Gly Lys Arg Pro Val Ile Thr Thr Trp Ile Ala Leu Asp Ala Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 118
<211> 115
<212> PRT
<213> artificial sequence
<400> 118
Asp Val Gln Leu Val Asp Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Thr Phe Ser Ser Ile Asp
20 25 30
Ser Met Arg Trp Phe Arg Arg Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala His Ile Thr Ser Thr Gly Arg Thr Asn Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Trp Leu
65 70 75 80
Gln Met Asp Asn Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Met Val Thr Thr Pro Tyr Met His Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 119
<211> 115
<212> PRT
<213> artificial sequence
<400> 119
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Ser Arg Phe Ser Glu Asn
20 25 30
Ala Met Gly Trp Tyr His Gln Ala Pro Asp Lys Gln Arg Thr Leu Val
35 40 45
Ala Ala Ile Thr Ser Ser Arg Ser Thr Leu Tyr Ile Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Ser Asn Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Pro Tyr Pro Ser Pro Asn Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 120
<211> 116
<212> PRT
<213> artificial sequence
<400> 120
Gln Val Lys Leu Glu 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 Leu Val Phe Ser Ala Asn
20 25 30
Lys Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Ser Thr Asp Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Lys Thr Val Phe Leu
65 70 75 80
Gln Met Asn Ser Leu Asn Pro Asp Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Asn Trp Leu Asp Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 121
<211> 120
<212> PRT
<213> artificial sequence
<400> 121
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Glu Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Ser Ile Ser Ser Ala Arg
20 25 30
Ser Met Thr Trp Tyr Arg Gln Ala His Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Ile Thr Ser Gly Gly Ser Thr Met Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala 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 Asp Trp Gly Glu Val Gly Phe Val Asn Leu Gly Pro Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 122
<211> 121
<212> PRT
<213> artificial sequence
<400> 122
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 Gly Phe Asn
20 25 30
Gly Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Val Ile Arg Ser Gly Gly Asn Thr Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val
85 90 95
Asp Tyr Ser Pro Pro Gly Ser Leu Val Pro Asp Leu Gly Pro Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 123
<211> 123
<212> PRT
<213> artificial sequence
<400> 123
Glu Val Gln Leu Glu 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 Ala Ser Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Arg Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Ser Cys Asn
85 90 95
Gly Leu Cys Ser Asp Asp Arg Cys Tyr Gly Asp Ser Leu Phe Ala Pro
100 105 110
Trp Gly Pro Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 124
<211> 118
<212> PRT
<213> artificial sequence
<400> 124
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 Leu Val Ser Gly Arg Gly Val Ser Leu Asp
20 25 30
Ala Val Gly Trp Ser Arg Val Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala Arg Ile Asp Ser Arg Gly Ser Ala Tyr Tyr Ala Asp Ser Val Glu
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Val Asp Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe
85 90 95
Ala Tyr Tyr Gly Ala Gln Ile Ser Phe Gly Pro Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 125
<211> 115
<212> PRT
<213> artificial sequence
<400> 125
Asp Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Arg Gly Val Asn Leu Asp
20 25 30
Ala Met Gly Trp Ser Arg Val Ala Pro Gly Lys Gln Arg Asp Phe Val
35 40 45
Ala His Ile Asp Asp Arg Gly Thr Ala Tyr Tyr Ala Asp Phe Val Lys
50 55 60
Gly Arg Ser Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Val Asp Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe
85 90 95
Ala Trp Gln Gly Ala Glu Thr Tyr Trp Gly Leu Gly Thr Arg Val Thr
100 105 110
Val Ser Ser
115
<210> 126
<211> 120
<212> PRT
<213> artificial sequence
<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 Val Ala Ser Gly Ser Ile Phe Ser Val Asn
20 25 30
Ala Val Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Arg Ser Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Gly Arg Thr Gly Asp Arg Phe Asn Leu Val Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 127
<211> 123
<212> PRT
<213> artificial sequence
<400> 127
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Arg Thr Phe Ser Thr Tyr
20 25 30
Phe Met Ala Trp Phe Arg Gln Pro Pro Gly Lys Glu Arg Glu Tyr Val
35 40 45
Gly Gly Ile Arg Trp Ser Asp Gly Val Pro His Tyr Ala Asp Ser Val
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 Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Ala Asp Tyr Ser Pro Pro Gly Ser Arg Phe Pro Asp Leu Gly Pro
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 128
<211> 119
<212> PRT
<213> artificial sequence
<400> 128
Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Ser Ile Phe Ser Ile Lys
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Gly Gly Thr Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Ser Arg Gly Ile Ala Asp Gly Ser Asp Phe Gly Ser Tyr Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 129
<211> 122
<212> PRT
<213> artificial sequence
<400> 129
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Ala
1 5 10 15
Ser Val Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Asn Ser Leu Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Tyr Ile Arg Ser Gly Gly Thr Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala 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 Asp Tyr Ser Pro Pro Gly Ser Arg Phe Pro Asp Leu Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 130
<211> 124
<212> PRT
<213> artificial sequence
<400> 130
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ile Gly Asp
1 5 10 15
Ser Val Arg Leu Ser Cys Ile Ala Ser Gly Gly Thr Phe Arg Thr Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Ala Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Arg Gly Asn Lys Thr Asp Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Met Gly Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Ala Arg Asn Phe Ile Gly Thr Gln Pro Leu Asp Tyr Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 131
<211> 120
<212> PRT
<213> artificial sequence
<400> 131
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Met Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Ser Phe Val Gly Tyr
20 25 30
Phe Met Ala Trp Phe Arg Gln Pro Pro Gly Lys Glu Arg Glu Tyr Val
35 40 45
Gly Gly Ile Arg Trp Ser Asp Gly Val Pro His Tyr Ala Asp Ser Val
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 Lys Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Arg Gly Ile Ala Asp Gly Ser Asp Phe Gly Ser Tyr Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 132
<211> 122
<212> PRT
<213> artificial sequence
<400> 132
Gln Val Lys 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
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Lys Ser Asn Asn Ile Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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
Gly Phe Phe Thr Leu Pro Gly Tyr Ser Ser Glu Glu Phe Gly Pro Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 133
<211> 360
<212> DNA
<213> artificial sequence
<400> 133
gaggtacagc tggtggaatc tgggggagga ttggcgcagg ctgggggctc tctgagactc 60
tcctgtacag cctctggacg caccttcagt acctatttca tggcctggtt ccgccagcct 120
ccagggaaag agcgtgaata cgtaggcggt attaggtgga gtgatggtgt tccacactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acgccaagaa cacggtgtat 240
ttgcaaatga acagcctgaa atctgaggac acggccgttt atttttgtgc atcacggggt 300
attgcggatg gatctgactt tggttcctac ggccagggga cccaggtcac cgtctcctca 360
360
<210> 134
<211> 360
<212> DNA
<213> artificial sequence
<400> 134
gaggtacagc tggtggaatc tgggggagga ttggcgcagg ctgggggctc tctgagactc 60
tcctgtacag cctctggacg caccttcagt acctatttca tggcctggtt ccgccagcct 120
ccagggaaag agcgtgaata cgtaggcggt attaggtgga gtgatggtgt tccacactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acgccaagaa cacggtgtat 240
ttgcaaatga acagcctgaa atctgaggac acggccgttt atttttgtgc atcacggggt 300
attgcggatg gatctgactt tggttcctac ggccagggga cccaggtcac cgtctcctca 360
360
<210> 135
<211> 348
<212> DNA
<213> artificial sequence
<400> 135
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctaagactc 60
tcctgtgcag cctctggact cgtcttcagt gccaatacca tggcctggta ccgccgggct 120
ccagggaagc agcgcgagtt ggtcgcacgt attagcactg acggacgtac aaactacgcg 180
gactccgtga agggccgatt caccatctcc agagacaacc gcgagaagac ggtgtttctg 240
caaatgaaca ggctgaaccc tgacgacacg gccgtctatt actgtaatgc aaactggctc 300
agtaaatttg actactgggg ccaggggacc caggtcaccg tctcctca 348
<210> 136
<211> 357
<212> DNA
<213> artificial sequence
<400> 136
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgtag cctctggaag catcttcagt gtcaatgccg tggcctggta ccgccaggct 120
ccagggaaac agcgcgagtt ggtcgcatat atacgtcgta gtggtagcac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacaca gccgtctatt actgtaatgc agatttcggt 300
agcgactatg tcgtcctcgg ttcctggggc caggggaccc aggtcaccgt ctcctca 357
<210> 137
<211> 360
<212> DNA
<213> artificial sequence
<400> 137
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcagt atcaaagcct tggcctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcatat attactagtg gtggtaacac aaactatgca 180
gactccgtga ggggccgatt caccatctcc agagacaacg ccaagaacac ggtatatctg 240
caaatgaaca gcctgaaacc tgaggacaca gccgtctatt actgtaatgc agatttcgga 300
gaagggacta tcatatccct tggaccctgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 138
<211> 360
<212> DNA
<213> artificial sequence
<400> 138
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag cgaattcagt atcaatgcca tggcgtggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcagca cttactagtg gtggtaacac tcactatgcg 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac gtggtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatgc agatttcgga 300
actgcgggtt tggtagtgct gggtccctgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 139
<211> 354
<212> DNA
<213> artificial sequence
<400> 139
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcgtcagt atcaatgcca tggcctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcatat attcgtagta atggccgcac aaactatgca 180
gactccgtga agggccgatt caccatttcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaact tgaggacacg gccgtctatt actgtaatgc agactacggg 300
cctccagtat ccattggtcc ttggggccag gggacccagg tcaccgtctc ctca 354
<210> 140
<211> 354
<212> DNA
<213> artificial sequence
<400> 140
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgtag tctctggaag tctcctcagt atcaaagcca tggcctggtt ccgccagcct 120
ccagggaagc agcgcgagtt ggtcgcagct gttactagtg gtggaagcac acactattta 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaacacggt gcatctgcaa 240
atgaacagcc tgaaacctga ggacacagct gtctattact gtaatgcaga tttcggtact 300
gactatgtcg acttagggcc ctggggccag gggacccagg tcaccgtctc ctca 354
<210> 141
<211> 366
<212> DNA
<213> artificial sequence
<400> 141
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag tctctggaag catcttcagt atcaatgcca tgggctggta ccgccaggct 120
ccagggaaac agcgcgagtt ggtcgcagct attactaaaa gtaataacat aaactatgca 180
gactccgtga agggccgatt caccatctcc acagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatgg attcttcgct 300
ttgcctgggt acagtagtga agaatttggt ccctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 142
<211> 360
<212> DNA
<213> artificial sequence
<400> 142
gaggtacagc tggtggaatc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgtag cctctggaaa catcttcgat atgaatcgga tgggctggta ccgccagcct 120
ccagggaagc agcgcgagtt ggtcgcagat attcgtgatg gcggttctac aatttattca 180
gattccgtga agggccgatt caccatctcc agagacaacg ccaagaacac gctgtatctg 240
caaatgaaca gcctgaaacc tgacgacaca gccgtgtatt attgtaatgc ggggcggaca 300
ggggatcgtt ttaatttggt ggcgtattgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 143
<211> 372
<212> DNA
<213> artificial sequence
<400> 143
gatgtgcagc tgcaggcgtc tgggggaggc ttggtgcagc acgggggctc tctgagactc 60
tcctgtgaag cctctggacg caccttcagt ggctatgcca tggcctggtt ccgccaggct 120
ccaggaaagg aacatgaatt tgtagcagct attagctcaa gtagtaatag tgccccatac 180
tatgcaaatt ccgtgaaggg ccgattcacc atctccagag acaacgccaa gaacacggtt 240
tatctacaaa tgaacaacct acaaactgag gacacggccg tttattactg tgcagcccgg 300
tacggtacga aacggtacgt cgcccgggag tatgactcgt ggggccaagg gacccaggtc 360
accgtctcct ca 372
<210> 144
<211> 345
<212> DNA
<213> artificial sequence
<400> 144
gatgtgcagc tgcaggcgtc tgggggaggc gtcgtgcagg ctggggggtc tctgagactc 60
tcctgtacag cctctggaag catccgcagt atcaatggca tgggctggtc gcgcgtggct 120
ccagggaagc agcgcgactt cgtcgcacgt attgatagta ggggtagcgc atactatgca 180
gactccgtag agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caagtggaca cgctgaaacc tgaggacacg gccgtctatt attgctttgc gtggcagggt 300
gcggaaacat attggggcct ggggacccag gtcaccgtct cctca 345
<210> 145
<211> 354
<212> DNA
<213> artificial sequence
<400> 145
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgcgactc 60
tcctgtgcag cctctggaag catcggcgat acctatgcca tggcctggta ccgccaggct 120
ccagggaagc agcgcgactt ggtcgcatat attactaatg gtggtagcac ggactacgca 180
gcctccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtctatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctact actgtaatgg agctacccgt 300
ggtgcacagt tagtcttcga ctggggccag gggacccagg tcaccgtctc ctca 354
<210> 146
<211> 372
<212> DNA
<213> artificial sequence
<400> 146
caggtaaagc tggaggagtc tgggggagga ttggtgcagc acgggggctc tctgagactc 60
tcctgtgcag cctctggagg cacgttcagt aactatgcca tggcctggtt ccgccaggct 120
ccaggaaagg agcgtgaatt tgtagcagct attagcgtga gtgctaatag tgccccatac 180
tatgcaaatt ccgtgaaggg ccgattcacc atctccagag acaacgccaa gaacacggtt 240
tatctgcaaa tgaacagcct aaaaactgag gacacggccg tttattactg tgcagcccgg 300
tacggtacga aacgatacgt cgcccgggag tatgactcgt ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 147
<211> 344
<212> DNA
<213> artificial sequence
<400> 147
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgcgactc 60
tcctgcgcag cctctggaag tagcgtcagt ctcaatgcca tgggctggtc gcgcgtgcaa 120
ccaggaagta cgcgcgactt cgtcgcacgg attgctgccg atggtagcac tcactatgca 180
gactccgtga gggccggttc accatctccg gggacgccgc caggaacacg gtgtatctac 240
aaatggattc gctgaaaccc gaagacacgg ccgtctatta ctgttttgcg tggctgggta 300
cggacacgta ctggggccag gggacccagg tcaccgtctc ctca 344
<210> 148
<211> 342
<212> DNA
<213> artificial sequence
<400> 148
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgacactc 60
tcctgtgcag cctctggaag catcggcgat aacaatgcca tgggctggtc ccgcacgcct 120
ccagggaagc agcgcgagtt cgtcgcacgt atagatagtg gggggatcac acgctatgca 180
gactccctga agggccgatt cactgtctcc agagacaccg gcaagaacac ggtgtctctg 240
caaatgaaca gcctgaaagc tgaggacaca ggcgtctatt actgttttgc acatgtcggt 300
ggtactatct ggggccaggg gacccaggtc accgtctcct ca 342
<210> 149
<211> 372
<212> DNA
<213> artificial sequence
<400> 149
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtttac cctctggagg catcttcact atcaatagca tgggctggta tcggcaggct 120
ccagggaaac agcgcgagtt ggtcgcaagt atcactggtg gtggtagttc acgttatgca 180
gactccgtga agggccgatt catcatgtcc agagacaacg ccaagaacat ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatac aatccccccg 300
gcccggaccc aaagcgatca tggggagtgg tatgactact ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 150
<211> 354
<212> DNA
<213> artificial sequence
<400> 150
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggagggtc tctgagactc 60
tcctgcgcag cctctagcag catcttcagt atcaatatga gctggtaccg ccaggctcca 120
gggaacgagc gcgagttggt cgcaactatt acacggcatg atagcacaca ctattcagac 180
tccgtgaagg gccgattcac catctccaga gacgacgaca agaacacgat atatctgcaa 240
atgaacagcc tgaaacctga ggacacggcc gtctattact gttctgggtt ttttctggac 300
ggtagtacct ggcacccata ttggggccag gggacccagg tcaccgtctc ctca 354
<210> 151
<211> 366
<212> DNA
<213> artificial sequence
<400> 151
gaggtacagc tggtggaatc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcgtcagt atcaatgcca tggcctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcatat attcgtagta atggcagcac aaactatgca 180
gactccgtga agggccgatt caccatttcc agagacaacg ccaagaacac ggtctacctg 240
caaatgaaca gcctgaaact tgaggacacg gccgtctatt attgtaatgg attcttcact 300
ttgcctgggt acagtagtga agaatttggt ccctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 152
<211> 429
<212> DNA
<213> artificial sequence
<400> 152
gaggtacagc tggtggaatc tgggggaggc ttggtgcagc ctggagggtc tctgagactc 60
tcctgtgcag cctctgagag catcttcagt atcaacgcca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagta tgtcgcaggc attactaagg gtgggcgtac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacgacg ccaagaatac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgg tttgtgctca 300
ggcagagagt gttatgggga ctcccttttt gccgcctggg gccaggggac ccaggtcacc 360
gtctcctcag gatccgaaca aaaactgatc agcgaagaag atctgaacca tcaccatcac 420
cattagtga 429
<210> 153
<211> 357
<212> DNA
<213> artificial sequence
<400> 153
gaggtacagc tggtggaatc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcgtcagt atcaatgcca tggcctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcatat attcgtagta atggccgcac aaactatgca 180
gactccgtga agggccgatt caccatttcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaact tgaggacacg gccgtctatt actgttctgg gttttttctg 300
gacggtagta cctggcaccc atattggggc cagggcaccc aggtcaccgt ctcctca 357
<210> 154
<211> 369
<212> DNA
<213> artificial sequence
<400> 154
gaggtacagc tggtggaatc tgggggagga ttggcgcagg ctgggggctc tctgagactc 60
tcctgtgcag cctctggatt cactttcgat gattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgtgaggg ggtctcatgt attagtagta gtgatggtag cacacactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca atgccaggaa cacggtgact 240
ctgcaaataa acagcctgaa acctgaggat acggccgttt attactgtgc gaccccctgg 300
gtgacctatt gccccgagaa ccttctgttt agttactggg gccaggggac ccaggtcacc 360
gtctcctca 369
<210> 155
<211> 369
<212> DNA
<213> artificial sequence
<400> 155
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggatt cactttcgat gattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgcgaggg ggtctcatgt attacgagta gtgatggtag cacatactat 180
gcagactctg tgaagggccg attcaccatc tccagagaca atgccaacaa cacggtgcat 240
ctgcaaataa gcaacctaaa acctgaggat acggccgttt attactgtgc gaccccctgg 300
gtgacctact gccccgagaa ccttctgttt agttactggg gccaggggac ccaggtcacc 360
gtctcctca 369
<210> 156
<211> 360
<212> DNA
<213> artificial sequence
<400> 156
gaggtacagc tggtggaatc tgggggaggc ttggtgcagg ctggggggtc tctgacactc 60
tcctgtgcag tctctggaag cagcttcagt atcaaggcca tgggctggta ccgcctggct 120
ccagggaagc agcgcgagtt ggtcgcagca attactagtg gtggtagcac gaactatgcg 180
gactccgtga agggccgatt caccatctcc agagacagcg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacaca gccgtctatt actgtaatgg ttttttcgag 300
tataggggtc ttgaacaatt gggcccctgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 157
<211> 360
<212> DNA
<213> artificial sequence
<400> 157
gatgtgcagc tgcaggcgtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcgtcggt atccgtgcca tgacgtggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcagtt cttactagtg ctggtaaacc tatgtatgcc 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtatatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaacgc agatttcggg 300
actccgggtt cagtagtact gggtccttgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 158
<211> 366
<212> DNA
<213> artificial sequence
<400> 158
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcctcagt atcgaggcca tgggctggta ccgccagact 120
cttgggaagc agcgcgaatt ggtcgcagct attactagtg gtgatagcac aaactatgca 180
gacttcgtga agggccgatt caccatctcc agagacaagg ccaagaacat ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt tctgtaatgc cctaatggta 300
gttagggctg gctcgaatcc cgaaattggt ccctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 159
<211> 369
<212> DNA
<213> artificial sequence
<400> 159
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgcag cctctggatt cactttcgat gattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgtgaggg ggtctcatgt attagtagta gtgatggtag cacatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca atgccaagaa cacggtgtat 240
ctgcaaataa acagcctgaa acctgaggat acggccgttt attactgtgc gaccccctgg 300
gtgacctact gccccgagaa ccttctgttt agttactggg gccaggggac ccaggtcacc 360
gtctcctca 369
<210> 160
<211> 345
<212> DNA
<213> artificial sequence
<400> 160
gaggtacagc tggtggaatc tgggggagga ttggtgcagc ctggggggtc tctgagactg 60
tcctgtgtag tctctgcaag gggcgtcagt ctcgatgccg tgggctggtc gcgcgtggct 120
ccagggaagc agcgcgactt cgtcgcacgt attgatcgaa ggggtagtac atactatgca 180
gtgtccgtag agggccgatc caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caactggaca cgctgaaacc tgaggacacg gccgtctatt attgttttgc atggcagggt 300
gcggaaacac attggggcct ggggacccag gtcaccgtct cctca 345
<210> 161
<211> 345
<212> DNA
<213> artificial sequence
<400> 161
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgaccctc 60
tcctgtgtag cctctggaag ccacttcagt ttcaatgaca tgggctggta tcgccaggat 120
ccgtggaagg ggcgcgactt ggtcgcggct attactagta gtcgtaacac actttatgta 180
gactccgtga agggccggtt caccatctcc agagacgacg ccaagaacac ggtgtatcta 240
caaatgaaca acctgaaacc tgaggacaca gccgtctatt actgtaaccc gtacccttcc 300
ccaaataact actggggcca ggggacccag gtcaccgtct cctca 345
<210> 162
<211> 348
<212> DNA
<213> artificial sequence
<400> 162
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag ccccttcacg atcaatgcca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcagca attactcgta gtggtaagac gaactatgca 180
gactccgtga agggccgatt caccatctcc ggagacaacg ccctgaccac ggtgtatctg 240
caaatgaaca acctgcaacc tgaagacacg gccgtctatt actgtaatgg gttctacggg 300
tctgaatttg ggccctgggg ccaggggacc caggtcaccg tctcctca 348
<210> 163
<211> 372
<212> DNA
<213> artificial sequence
<400> 163
caggtaaagc tggaggagtc tgggggagga ttggtccagg ctgggggctc tgcgacgctc 60
tcctgttcag cccctggaga caccttaagt agatacgccg tgggctggtt ccgccagggg 120
ccagggcagg agcgtgattt tgtagcatcc attacctgga gtggtgatta cacatactat 180
aaagactccg tgaagggccg attcaccatc tccagagaca gtgtcaacaa catggtgtat 240
ctgcgaatga acagcctgaa acctgaggac acggccctgt attactgtgc agccgataag 300
agttccttta gactccgagg ccctggatta tatgactaca ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 164
<211> 369
<212> DNA
<213> artificial sequence
<400> 164
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggatt cactttcgat tattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgcgaggg ggtctcatgt attagtagta gggatggtac cacccactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca atgccaagaa cacggtgtat 240
ctgcaaatag acagcctgaa acctgaggat acggccgttt attactgtgc gaccccctgg 300
gtgacctact gccccgagaa ccttctgttt agttactggg gccaggggac ccaggtcacc 360
gtctcctca 369
<210> 165
<211> 375
<212> DNA
<213> artificial sequence
<400> 165
caggtaaagc tggaggagtc tgggggaggc ttcgtacagc ctggggggtc actgagactc 60
tcctgtgcag cctcgggatt cagtttgcat tattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgcgagtg ggtctctgcc attagtaata ttgatgatga cacatactat 180
gaagactccg tgaagggccg attcaccatc tccagagaca acgccaagaa cacggcgtat 240
ctgcaaatga acaacctgaa acctgaggac acggccgttt attactgtgc agcagataag 300
gatgtagtgg tagtgcgtac gggtctcagc gagtctgact attggggcca ggggacccag 360
gtcaccgtct cctca 375
<210> 166
<211> 360
<212> DNA
<213> artificial sequence
<400> 166
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcggt atcaatgcca tggcctggta ccgccaggct 120
ccagggaagc agcgcgaact ggtcgcagtt attaccagtg gtggacgcac aatgtatgca 180
gagtccgtga agggccgatt cgccatctcc agagacgtcg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacaca gccgtctatt actgtaatgg agactggggg 300
tcggagggta gggtggacct tggaccctgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 167
<211> 387
<212> DNA
<213> artificial sequence
<400> 167
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggac gctgagactc 60
tcctgtgccg cctcgggaag cattcgcagt atcggcgaca tggagtggta ccgccaggct 120
ccaggacagc agcgcgagtt ggtcgcaagt attagtgctg gccctgagat gcgtagtgct 180
ggtaccccaa cttatgcaaa gtccgtggag ggccgattca ccatctccag agacaacatc 240
aagaacatga tgtggctgca aatgaacagc ctgagacctg aagacacggc cgtctattcc 300
tgtaatgccg acgttctgac gtactataat ggtagatact cccgagatgt ctactggggc 360
caggggaccc aggtcaccgt ctcctca 387
<210> 168
<211> 354
<212> DNA
<213> artificial sequence
<400> 168
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgcgcag cctctagcag catcttcagt atcaatatga gctggtaccg ccaggctcca 120
gggaacgagc gcgagttggt cgcaactatt acacgacatg atagtacaca ctattcagac 180
tccgtgaagg gccgattcgc catctccaga gacgacgaca agaacacgat atatctgcaa 240
atgaacagcc tgaaacctga ggacacggcc gtctattact gttctggatt ttttctggac 300
ggtagtacct ggcggccata ttggggccag gggacccagg tcaccgtctc ctca 354
<210> 169
<211> 372
<212> DNA
<213> artificial sequence
<400> 169
gatgtgcagc tgcaggcgtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggacg caccctcagt ggctatgccg tggcctggtt ccgccaggct 120
ccaggaaagg agcgtgagtt tgtagcagcc attagctcga gtgataatag tagcccatat 180
tatgcaaatg tcgtgaaggg tcgattcacc atctccagag acaacgccaa gaacacggtt 240
tatctgcaaa tgaacagcct gcaaactgag gacacggccc tttattactg tgcagcccgg 300
tacggtacga aacggtacgt cgcccgggag tatgactcgt ggggtcaggg gacccaggtc 360
accgtctcct ca 372
<210> 170
<211> 366
<212> DNA
<213> artificial sequence
<400> 170
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctagaag catcttcagt atcaatgcca tggcctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcatat attcgtagta gtggtaccac aatgtatgcg 180
gattccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt attgtaacgg agattactcc 300
ccgcccggca gcacgtaccc tgacttaggt ccctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 171
<211> 795
<212> DNA
<213> artificial sequence
<400> 171
gaggtgcagc tgcaggcgtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggatt cactttcgat gattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgcgaggg ggtctcatgt attacgagta gtgatggtag cacatactat 180
gcagactctg tgaagggccg attcaccatc tctagagaca atgccaacaa cacggtgcat 240
ctgcaaataa gcaacctaaa acctgaggat acggccgttt attactgtgc gaccccctgg 300
gtgaactact gccccgagaa ccttctgttt agttactggg gccaggggac ccaggtcacc 360
gtctcctcac aggcccaggt acagctggtg gaatctgggg gaggattggc gcaggctggg 420
ggctctctga gactctcctg tacagcctct ggacgcacct tcagtaccta tttcatggcc 480
tggttccgcc agcctccagg gaaagagcgt gaatacgtag gcggtattag gtggagtgat 540
ggtgttccac actatacaga ctccgtgaag ggccgattca ccatctccag agacaacgcc 600
aagaacacgg tgtatttgca aatgaacagc ctgaaatctg aggacacggc cgtttatttt 660
tgtgcatcac ggggtattgc ggatggatct gactttggtt cctacggcca ggggacccag 720
gtcaccgtct cctcaggatc cgaacaaaaa ctgatcagcg aagaagatct gaaccatcac 780
catcaccatt agtga 795
<210> 172
<211> 348
<212> DNA
<213> artificial sequence
<400> 172
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtggag catctggaat tatttttagt gccactacca tggcctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcactg attactagtg attggcacac aaagtatgca 180
gactccgtga aggaccgatt ctccatttcc agagacaacg ccaagagcac ggtgcacctg 240
caaatgaaca gcctgagatc tgaagacaca gcagtctatt tttgttatgc ccgccaagcc 300
ttcagtgagc ctcgttgggg ccaggggacc caggtcaccg tctcctca 348
<210> 173
<211> 345
<212> DNA
<213> artificial sequence
<400> 173
caggtacagc tggtggattc tgggggaggc ttggtgcagc ctggggggtc tctgagattg 60
tcctgtgcag cctctggaag cagcggcaga atcgatgcca tgggctggtc gcgcgtggct 120
ccagggaagc agcgcgactt cgtcgcacgt cttggcagta atggattcac acagtatgac 180
atctccgtgg agggccgatt caccatctcc ggggacgtcg ccaagaatac gatatatctg 240
caaatggaca cgctgaaacc tgaggacacg gccgtctatt actgttttgc gtggctgggg 300
caagataccg tgtggggcca ggggacccag gtcaccgtct cctca 345
<210> 174
<211> 372
<212> DNA
<213> artificial sequence
<400> 174
caggtacagc tggtggattc tgggggagga ttggtaaagg ctggggcatc tctgagactc 60
tcctgtgcag cctctggaga cgccttattt aactacgcca tgggctggtt tcgccagggg 120
ccagggaagg agcgtgactt tgtagcatct gttaccagga gtggtgataa tacatactat 180
aaagactccg cgaagggccg attcaccatc tccagagacg acgccaagaa cacggtatat 240
ctgcaaatga acagcctgaa acctgaggac acggccgttt atttctgtgc agcagataag 300
agttccttta ggctccgagg ccctggagta tatgactaca ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 175
<211> 378
<212> DNA
<213> artificial sequence
<400> 175
caggtacagc tggtggattc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgcag tctctggaag cgacggccga gtcatgctca tgggctggta ccgccaggct 120
ccagggcagc agcgcgacct ggtcgcatct attactagtg cagattacac aacctatgca 180
gaatccgtcg agggccgatt caccatctcc acagacaaca acaagaacac agtgtatcta 240
caaatgaaca gcctgaagcc tgaagacaca gccgtctatt tttgtaaagt aattgcggcg 300
acggtctggg gccaggagac ccaggtcagg cagggtttga cattctgggg ccaggggacc 360
caggtcaccg tctcctca 378
<210> 176
<211> 360
<212> DNA
<213> artificial sequence
<400> 176
gaggtacagc tggtggaatc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgtag cctctggaag catctccagt gccagatcca tgacctggta ccgccaggct 120
ctagggaagc agcgcgagtt ggtcgcagtg attatgggtg gcggtagcac gatgtatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatcta 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt attgtaatgc agactggggg 300
ggagtcgggt ttccgaactt aggtccctgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 177
<211> 372
<212> DNA
<213> artificial sequence
<400> 177
gatgtgcagc tgcaggcgtc tgggggagga ttggtgcaaa ttggggactc tgtgagactc 60
tcctgtatag cctctggagg caccttcaga acttatgcta tcggttggtt ccgccaggct 120
ccaggggctg agcgtgaatt tgtagctgcc attagccggc gcggtaataa gacagattat 180
gcagagtccg tgaagggccg attcacagtc tccagagaca acgccgagaa tacggtgtat 240
ttgcaaatga acagcctgaa acctgatgac atgggcgttt attactgtgc agcgtcggcg 300
cgtaatttca tcggcaccca gccacttgat tatgactact ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 178
<211> 366
<212> DNA
<213> artificial sequence
<400> 178
caggtaaagc tggaggagtc tgggggagga ttggtacagg ctgggggctc tctgagactc 60
tcctgtgcag cctctggatg gaaccttggt aattatgcct tgggctggtt ccgccaggct 120
ccagggaagg agcgtgagtt tgtagcagct atcgactggc gtcatagttc atactatgca 180
gactccgtga agggccgatt caccatctcc agagacaaca ccaagaacat ggtgtatctg 240
caaatgagca gcctgaaact tgaggacacg cgcctttatt actgtgcagc atcaagccta 300
ttccctagta gtgctccccg tcagtatgac tactggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 179
<211> 369
<212> DNA
<213> artificial sequence
<400> 179
caggtacagc tggtggattc tgggggagga ttggtgcagg ctgggggctc tctgagactc 60
tcctgtgtag cctctggacg caccttcagt aattatgcca tgggctggta ccgccgacgt 120
ccagggctgg agcgtgaatt tgtagcagct attgttggga gtggtgatag cacaaggtat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acgccaagaa cacggtgtat 240
ctgcaaatga acacgctgaa acctgaggac acggccgttt attactgtgc gtcatcctcc 300
gacccgcggg tttatatagc aagtactctc gattactggg gccaggggac ccaggtcacc 360
gtctcctca 369
<210> 180
<211> 357
<212> DNA
<213> artificial sequence
<400> 180
caggtacagc tggtggaatc tgggggagga ttggtgcagg ctgggggctc tctgagactc 60
tcctgtgcag cctctggacg caccttcagt atgtttatca tgggctggtt ccgccaggct 120
ccagggaagg agcgtgaatt agtagcagct attagccgga atagtaatct cacatactat 180
tttcagtccg tgaaaggccg attcaccatc tccagagaca acgccaagaa cacggtgtat 240
ttgcaaatga acagcctgaa acttgaggac acggccgtct attactgtaa tgcagactac 300
gggcctccag tatccattgg tccttggggc caggggaccc aggtcaccgt ctcctca 357
<210> 181
<211> 366
<212> DNA
<213> artificial sequence
<400> 181
caggtaaagc tggaggagtc tgggggaggc tgggtgcagc ctggggggtc tctgagactc 60
tcctgtgtag tctctggaag gatcctcagt atcaaggcca tgggctggta ccgccaggct 120
cctgggaagc agcgcgagta cgtcgcaggt attgttagca gtggtaatac aaactatgca 180
gacttcgtga agggccgatt caccatctcc ggagacaacg ccaagaacac ggtgtttctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgc cctagtggtc 300
gttactagtg cctcgggtcc cgagttggct tcctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 182
<211> 366
<212> DNA
<213> artificial sequence
<400> 182
gatgtacagc tggtggattc tgggggagga ttggcgcagg ctgggggctc tctgagactc 60
tcctgtacag cctctggacg caccttcagt acctatttca tggcctggtt ccgccagcct 120
ccagggaagc agcgcgagtt ggtcgcatac attcgtagtg gtggtacgac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacatcg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgcaatgc agattactcc 300
ccgcccggca gccggttccc tgacttaggt ccctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 183
<211> 363
<212> DNA
<213> artificial sequence
<400> 183
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgacactc 60
tcctgcgcag cctctggatt caccttggat aattatgcca tagcgtggtt ccgccaggcc 120
ccagggaggg agcgcgagtg ggtctcatca actggtagtg atggtaactt atatacaccg 180
tccgtgaggg gccgattcac catttccaga gacaacgcca agaacacggt gtatctgcaa 240
atgaacagcc tgaaacctga ggacacggcc gtttattatt gtgtagcagg gaagagaccg 300
gtaattacta catggattgc tttggacgca tggggccagg ggacccaggt caccgtctcc 360
tca 363
<210> 184
<211> 345
<212> DNA
<213> artificial sequence
<400> 184
gatgtacagc tggtggattc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgcag cctctggaac attctccagt atcgattcca tgcgctggtt ccggcgggct 120
ccaggaaagg agcgcgaatt tgtcgcacat attactagca cgggtaggac aaactatgca 180
gacgccgtga agggccgatt taccatctct agagacaacg ccaagaacac gatgtggctg 240
caaatggaca acctgaaacc tgacgacacg gccgtctatt attgcaatat ggtgacgact 300
ccttatatgc actggggcca ggggacccag gtcaccgtct cctca 345
<210> 185
<211> 345
<212> DNA
<213> artificial sequence
<400> 185
caggtaaagc tggaggagtc tgggggaggc ttggtgcagg ctggggggtc tctgaaactc 60
tcctgtgtag cctctggaag ccgcttcagt gaaaatgcca tgggctggta tcaccaggct 120
ccagacaaac agcgcacctt ggtcgcagct attactagta gtcgtagcac tctttatata 180
gactccgtga agggccgctt caccatctcc agagacaacg ccaagaacac ggtatatctg 240
caaatgagca acctgaaacc tgaggacacc ggcgtctatt actgtaaccc gtacccttcc 300
ccaaattcct actggggcca ggggacccag gtcaccgtct cctca 345
<210> 186
<211> 348
<212> DNA
<213> artificial sequence
<400> 186
caggtaaagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctaagactc 60
tcctgtgcag cctctggact cgtcttcagt gccaataaga tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcacgt attagcactg acggacgtac aaactatgcg 180
gactccgtga agggccgatt caccatctcc agagacaacg ccgagaagac ggtgtttctg 240
caaatgaaca gcctgaatcc tgacgacacg gccgtctatt actgtaatgc aaactggctc 300
gataaatatg actactgggg ccaggggacc caggtcaccg tctcctca 348
<210> 187
<211> 360
<212> DNA
<213> artificial sequence
<400> 187
caggtaaagc tggaggagtc tgggggaggc ttggtggagc ctggggggtc tctgagactc 60
tcctgtgtgg cctctggaag catctccagt gccagatcca tgacctggta ccgccaggct 120
cacgggaagc agcgcgagtt ggtcgcagtt attactagtg gcggtagcac aatgtatgca 180
gactccgtga agggccgatt caccatctcc agagacagcg ccaagaacac ggtgtatcta 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt attgtaatgc agactggggg 300
gaagtcgggt ttgtgaactt aggtccctgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 188
<211> 366
<212> DNA
<213> artificial sequence
<400> 188
gaggtacagc tggtggaatc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcggt ttcaatggcg tggcctggtt ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcagtt attcgtagtg gtggtaacac gctctatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatgt agattactcc 300
ccgcccggta gtctggttcc tgacttaggt ccctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 189
<211> 369
<212> DNA
<213> artificial sequence
<400> 189
gaggtacagc tggaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcgccagt atcaatgcca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcagct attactagag gtggtagcac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtatatctg 240
caaatgaaca gcctgaaacc ggaggacacg gccgtctatt catgtaatgg tttgtgctca 300
gacgatcggt gttatgggga ctcccttttt gccccctggg gcccggggac ccaggtcacc 360
gtctcctca 369
<210> 190
<211> 354
<212> DNA
<213> artificial sequence
<400> 190
gaggtacagc tggtggaatc tgggggagga ttggtgcagc ctggggggtc tctgagactg 60
tcctgtctag tctctggaag gggcgtcagt ctcgatgccg tgggctggtc gcgcgtggct 120
ccagggaagc agcgcgactt cgtcgcacgt attgatagta ggggtagcgc atactatgca 180
gactccgtag agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caagtggaca cgctgaaacc tgaggacacg gccgtctatt attgttttgc gtactacggg 300
gctcaaatat cttttggtcc gtggggccag gggacccagg tcaccgtctc ttca 354
<210> 191
<211> 405
<212> DNA
<213> artificial sequence
<400> 191
gatgtgcagc tgcaggcgtc tgggggagga ttggtgcagc ctggggggtc tctgagactg 60
tcctgtgtag tctctggaag gggcgtcaat ctcgatgcca tgggctggtc gcgcgtggct 120
ccagggaagc agcgcgactt cgtcgcacat attgatgata ggggtaccgc atactatgca 180
gacttcgtaa agggccgatc caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caagtggaca cgctgaaacc tgaggacacg gccgtctatt attgctttgc gtggcagggt 300
gcggaaacat attggggcct ggggacccgg gtcaccgtct cctcaggatc cgaaccaaaa 360
ctgatcaacg aagaacatct gaaccatcac catcaccatt attga 405
<210> 192
<211> 360
<212> DNA
<213> artificial sequence
<400> 192
gaggtacagc tggtggaatc tgggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgtag cctctggaag catcttcagt gtcaatgccg tggcctggta ccgccaggct 120
ccagggaaac agcgcgagtt ggtcgcatat atacgtcgta gtggtagcac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaatg ccaagaacac gctgtatctg 240
caaatgaaca gcctgaaacc tgacgacaca gccgtgtatt attgtaatgc ggggcggaca 300
ggggatcgtt ttaatttggt ggcgtattgg ggccagggga cccaggtcac cgtctcctca 360
360
<210> 193
<211> 369
<212> DNA
<213> artificial sequence
<400> 193
gaggtacagc tggtggaatc tgggggagga ttggcgcagg ctgggggctc tctgagactc 60
tcctgtacag cctctggacg caccttcagt acctatttca tggcctggtt ccgccagcct 120
ccagggaaag agcgtgaata cgtaggcggt attaggtgga gtgatggtgt tccacactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acgccaagaa cacggtgtat 240
ttgcaaatga acagcctgaa acctgaggac acggccgtct attactgcaa tgcagattac 300
tccccgcccg gcagccggtt ccctgactta ggtccctggg gccaggggac ccaggtcacc 360
gtctcctca 369
<210> 194
<211> 356
<212> DNA
<213> artificial sequence
<400> 194
gaggtgcagc tgcaggcgtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgtag cctctggaag catcttcagt atcaaagcca tggcctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcatac attcgtagtg gtggtacgac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacatcg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccgtttatt tttgtgcatc acggggtatt 300
gcggatggat ctgctttggt tcctacggcc aggggaccca ggtcaccgtc tcctca 356
<210> 195
<211> 366
<212> DNA
<213> artificial sequence
<400> 195
gaggtacagc tggtggaatc tgggggaggc ttggtgcagg ctggggcctc cgtgagactc 60
tcctgtgcag cctctggacg cgccaacagt ttgtatgcca tgggctggtt ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcatac attcgtagtg gtggtacgac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacatcg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgcaatgc agattactcc 300
ccgcccggca gccggttccc tgacttaggt ccctggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 196
<211> 372
<212> DNA
<213> artificial sequence
<400> 196
gaggtacagc tggtggaatc tgggggagga ttggtgcaaa ttggggactc tgtgagactc 60
tcctgtatag cctctggagg caccttcaga acttatgcta tgggttggtt ccgccaggct 120
ccaggggctg agcgtgaatt tgtagctgcc attagccggc gcggtaataa gacagattat 180
gcagagtccg tgaagggccg attcacagtc tccagagaca acgccgagaa tacggtgtat 240
ttgcaaatga acagcctgaa acctgatgac atgggcgttt attactgtgc agcgtcggcg 300
cgtaatttca tcggcaccca gccacttgat tatgactact ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 197
<211> 360
<212> DNA
<213> artificial sequence
<400> 197
caggtaaagc tggaggagtc tgggggagga atggtgcagg ctgggggctc tctgagactc 60
tcctgtgtag cctctggacg ctccttcgtt ggctatttca tggcctggtt ccgccagcct 120
ccagggaaag agcgtgaata cgtaggcggt attaggtgga gtgatggtgt tccacactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acgccaagaa cacggtgtat 240
ttgcaaatga acagcctgaa atctgaggac acggccgttt atttttgtgc atcacggggt 300
attgcggatg gatctgactt tggttcctac ggccagggga cccaggtcac cgtctcctca 360
360
<210> 198
<211> 366
<212> DNA
<213> artificial sequence
<400> 198
gaggtacagc tggtggaatc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcagt atcaatgcca tgggctggta ccgccaggct 120
ccagggaagc agcgcgaatt ggtcgcagct attactaaaa gtaataacat aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt attgtaatgg attcttcact 300
ttgcctgggt acagtagtga agaatttggt ccctggggcc tggggaccca ggtcaccgtc 360
tcctca 366
<210> 199
<211> 21
<212> DNA
<213> artificial sequence
<400> 199
cgccatcaag gtaccagttg a 21
<210> 200
<211> 29
<212> DNA
<213> artificial sequence
<400> 200
ggggtacctg tcatccacgg accagctga 29
<210> 201
<211> 43
<212> DNA
<213> artificial sequence
<400> 201
cagccggcca tggccsmkgt rcagctggtg gaktctgggg gag 43
<210> 202
<211> 41
<212> DNA
<213> artificial sequence
<400> 202
catgtgcatg gcctagactc gcggcccagc cggccatggc c 41
<210> 203
<211> 47
<212> DNA
<213> artificial sequence
<400> 203
catgtgtaga ttcctggccg gcctggcctg aggagacggt gacctgg 47
<210> 204
<211> 41
<212> DNA
<213> artificial sequence
<400> 204
gaagaagaag acaacaggcc svkgtgmagc tggwggaktc t 41
<210> 205
<211> 37
<212> DNA
<213> artificial sequence
<400> 205
gaagatctcc ggatcctgag gagacggtga cctgggt 37
Claims (18)
- 항-BCMA 단일 도메인 항체 그룹에 있어서, 상기 단일 도메인 항체는 프레임워크영역 (framework regions) 및 상보성 결정 영역 (complementary determining regions)을 포함하고, 상기 상보성 결정 영역은 서열번호 1 내지 66으로부터 선택된 아미노산 서열을 가지는 것을 특징으로 하는 항-BCMA 단일 도메인 항체 그룹.
- 제 1 항에 있어서, 상기 상보성 결정 영역의 아미노산 서열은 서열번호 1 내지 66 중 어느 한 아미노산 서열에 대해 80 % 이상, 85 % 이상, 90 % 이상, 95 % 이상 또는 99 % 이상의 동일성을 갖으며, 바람직하게는 아미노산 간의 차이가 보존적 치환 (conservative substitution)인, 항-BCMA 단일 도메인 항체 그룹.
- 제 1 항에 있어서, 상기 그룹의 단일 도메인 항체는 서열번호 67 내지 132 중 어느 하나로부터 선택된 서열을 갖거나 서열번호 67 내지 132 중 어느 하나의 아미노산 서열인 항-BCMA 단일 도메인 항체 그룹.
- 제 3 항에 있어서, 상기 단일 도메인 항체의 아미노산 서열은 서열번호 67 내지 132 중 어느 한 아미노산 서열에 대해 80 % 이상, 85 % 이상, 90 % 이상, 95 % 이상 또는 99 % 이상의 동일성을 가지며, 바람직하게는 아미노산 간의 차이가 보존적 치환인, 항-BCMA 단일 도메인 항체 그룹.
- 항-BCMA 단일 도메인 항체들의 유전자 그룹에 있어서, 상기 단일 도메인 항체 유전자는 서열번호 133 내지 198 중 어느 하나로부터 선택된 뉴클레오타이드 서열을 가지거나, 서열번호 133 내지 198 중 어느 한 뉴클레오타이드 서열이거나, 또는 제 3 항 또는 제 4 항에 따른 단일 도메인 항체를 암호화하는 뉴클레오타이드 서열인, 항-BCMA 단일 도메인 항체들의 유전자 그룹.
- 제 5 항에 있어서, 서열번호 133 내지 198 중 어느 한 뉴클레오타이드 서열에 대해 80 % 이상, 85 % 이상, 90 % 이상, 95 % 이상 또는 99 % 이상의 동일성을 가지며, 바람직하게는 상기 염기 간의 차이가 보존적 치환인, 항-BCMA 단일 도메인 항체들의 유전자 그룹.
- 제 1 항 내지 제 4 항 중 어느 한 항에 따른 상기 단일 도메인 항체 그룹으로부터 선택된 하나 이상의 단일 도메인 항체를 가지는 폴리펩타이드로, 상기 둘 이상의 단일 도메인 항체들은 같거나 다른 것을 특징으로 하는 폴리펩타이드.
- 제 5 항 또는 제 6 항에 따른 상기 단일 도메인 항체들의 유전자 그룹으로부터 선택된 하나 이상의 유전자를 포함하는 발현 벡터에 있어서, 상기 발현 벡터는 바람직하게는 원핵 세포 발현 벡터, 진핵 세포 발현 벡터 또는 다른 세포 발현 벡터이며, 더욱 바람직하게는 렌티바이러스 벡터인 발현 벡터.
- 제 8 항에 따른 상기 발현 벡터를 포함하는 숙주 세포에 있어서, 상기 숙주 세포는 바람직하게는 원핵 발현 세포, 진핵 발현 세포, 진균 세포 또는 효모 세포이고, 상기 원핵 발현 세포는 바람직하게는 Escherichia coli인 숙주세포.
- 제 1 항 내지 제 4 항 중 어느 한 항에 따른 상기 단일 도메인 항체 그룹으로부터 선택된 하나 이상의 단일 도메인 항체를 가지는 키메릭 항원 수용체로, 상기 둘 이상의 단일 도메인 항체들은 같거나 다른 것을 특징으로 하는 키메릭 항원 수용체 (chimeric antigen receptor).
- 제 10 항에 따른 키메릭 항원 수용체에 의해 변형된 T 세포.
- 제 1 항 내지 제 4 항 중 어느 한 항에 따른 상기 단일 도메인 항체 그룹으로부터 선택된 하나 이상의 단일 도메인 항체들을 활성 성분으로 포함하는 약학적 조성물.
- 제 1 항 내지 제 4 항 중 어느 한 항에 따른 상기 단일 도메인 항체 그룹으로부터 선택된 단일 도메인 항체를 인간화하여 수득된 인간화 항-BCMA 단일 도메인 항체.
- 제 1 항 내지 제 4 항 중 어느 한 항에 따른 상기 단일 도메인 항체 그룹에서 상기 단일 도메인 항체의 BCMA 검출 용도.
- 제 1 항 내지 제 4 항 중 어느 한 항에 따른 상기 단일 도메인 항체 그룹에서 상기 단일 도메인 항체의 BAFF와 BCMA 사이의 상호작용을 차단하기 위한 용도.
- 제 16 항에 있어서, 상기 단일 도메인 항체가 세포 독성 제제 (cytotoxicity agent), 효소상 (enzyme phase), 방사성 동위 원소, 형광 화합물 또는 화학발광 화합물 중 하나 이상에 연결된 것을 특징으로 하는 용도.
- 제 1 항 내지 제 4 항 중 어느 한 항에 따른 상기 단일 도메인 항체 그룹에서 상기 단일 도메인 항체의 비정상 BCMA 발현과 관련된 질병을 치료하기 위한 약물을 제조하는데 있어서의 용도.
- 제 17 항에 있어서, 상기 비정상 BCMA 발현과 관련된 질병이 다발성 골수종 질병인 것을 특징으로 하는 용도.
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CN201810972054 | 2018-08-24 | ||
PCT/CN2019/095507 WO2020038147A1 (zh) | 2018-08-24 | 2019-07-10 | 抗bcma的单域抗体及其应用 |
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US (1) | US20220251226A1 (ko) |
EP (1) | EP3845244A4 (ko) |
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KR (1) | KR20210050535A (ko) |
CN (1) | CN111542343B (ko) |
AU (1) | AU2019323389B2 (ko) |
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EA (1) | EA202190608A1 (ko) |
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CN109970855A (zh) * | 2019-04-12 | 2019-07-05 | 深圳普瑞金生物药业有限公司 | Il23单域抗体的vhh链、il23单域抗体、核苷酸序列及试剂盒 |
CN111909271B (zh) * | 2020-08-12 | 2021-03-23 | 深圳市茵冠生物科技有限公司 | 一种基于单域抗体的bcma嵌合抗原受体及其应用 |
US20230193292A1 (en) * | 2020-08-20 | 2023-06-22 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Bcma-binding single variable structural domain and antigen-binding molecule |
CN112028996B (zh) * | 2020-10-30 | 2021-01-22 | 南京北恒生物科技有限公司 | 靶向bcma的单域抗体及其用途 |
CN112592405B (zh) * | 2020-12-08 | 2022-05-03 | 博奥信生物技术(南京)有限公司 | 抗人bcma纳米抗体及其制备方法和应用 |
CN112538115B (zh) * | 2020-12-08 | 2022-05-03 | 博奥信生物技术(南京)有限公司 | 一种抗人bcma纳米抗体及其制备方法和应用 |
CA3234046A1 (en) * | 2021-10-07 | 2023-04-13 | Mehdi Arbabi-Ghahroudi | Anti-bcma single domain antibodies and therapeutic constructs |
CN114195896B (zh) * | 2021-12-06 | 2022-07-05 | 东莞清实生物科技有限公司 | 一种基于单域抗体的bcma嵌合抗原受体及其应用 |
WO2023217067A1 (zh) * | 2022-05-09 | 2023-11-16 | 上海先博生物科技有限公司 | 工程化免疫效应细胞及其与CBL-b抑制剂联用的应用 |
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CN104804092B (zh) * | 2014-01-29 | 2018-03-27 | 天津胜发生物技术有限公司 | 一种抗b细胞生长刺激因子的纳米抗体及其用途 |
MY181834A (en) * | 2014-07-21 | 2021-01-08 | Novartis Ag | Treatment of cancer using humanized anti-bcma chimeric antigen receptor |
RU2747457C2 (ru) * | 2014-07-24 | 2021-05-05 | Блубёрд Био, Инк. | Химерные антигенные рецепторы к bcma |
PT3628687T (pt) * | 2014-12-12 | 2021-10-20 | Bluebird Bio Inc | Recetores do antigénio quimérico bcma |
US20180094280A1 (en) * | 2015-03-20 | 2018-04-05 | Bluebird Bio, Inc. | Vector formulations |
CN105384825B (zh) * | 2015-08-11 | 2018-06-01 | 南京传奇生物科技有限公司 | 一种基于单域抗体的双特异性嵌合抗原受体及其应用 |
CN105777911B (zh) * | 2016-04-12 | 2019-07-02 | 上海优卡迪生物医药科技有限公司 | 抗bcma嵌合抗原受体、编码基因、重组表达载体及其构建方法和应用 |
CN105837693A (zh) * | 2016-05-30 | 2016-08-10 | 李斯文 | 一种基于bcma的抗原嵌合受体及其制备方法和应用 |
CN109134665B (zh) * | 2018-08-24 | 2021-06-11 | 上海先博生物科技有限公司 | 一种基于单域抗体的bcma嵌合抗原受体及应用 |
CN109694413A (zh) * | 2019-01-17 | 2019-04-30 | 深圳市前海精准生物科技有限公司 | 一种基于bmca纳米抗体序列的嵌合抗原受体及其应用 |
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2019
- 2019-07-10 JP JP2021534412A patent/JP7289562B2/ja active Active
- 2019-07-10 CA CA3110262A patent/CA3110262C/en active Active
- 2019-07-10 US US17/270,788 patent/US20220251226A1/en active Pending
- 2019-07-10 SG SG11202101675UA patent/SG11202101675UA/en unknown
- 2019-07-10 AU AU2019323389A patent/AU2019323389B2/en active Active
- 2019-07-10 EP EP19852395.3A patent/EP3845244A4/en active Pending
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- 2019-07-10 CN CN201980006291.6A patent/CN111542343B/zh active Active
- 2019-07-10 WO PCT/CN2019/095507 patent/WO2020038147A1/zh unknown
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US20220251226A1 (en) | 2022-08-11 |
AU2019323389A1 (en) | 2021-04-15 |
JP7289562B2 (ja) | 2023-06-12 |
SG11202101675UA (en) | 2021-03-30 |
WO2020038147A1 (zh) | 2020-02-27 |
BR112021003410A2 (pt) | 2021-05-18 |
EA202190608A1 (ru) | 2021-06-01 |
CA3110262A1 (en) | 2020-02-27 |
EP3845244A1 (en) | 2021-07-07 |
CN111542343A (zh) | 2020-08-14 |
CA3110262C (en) | 2024-05-14 |
AU2019323389B2 (en) | 2024-03-21 |
EP3845244A4 (en) | 2022-09-07 |
JP2021534823A (ja) | 2021-12-16 |
CN111542343B (zh) | 2023-08-18 |
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