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KR102219859B1 - 재조합 단쇄 fviii 및 그 화학 접합물 - Google Patents

재조합 단쇄 fviii 및 그 화학 접합물 Download PDF

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KR102219859B1
KR102219859B1 KR1020197002468A KR20197002468A KR102219859B1 KR 102219859 B1 KR102219859 B1 KR 102219859B1 KR 1020197002468 A KR1020197002468 A KR 1020197002468A KR 20197002468 A KR20197002468 A KR 20197002468A KR 102219859 B1 KR102219859 B1 KR 102219859B1
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강관엽
이승훈
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오미숙
류재환
조의철
이기남
양선아
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Abstract

본원은 인간 혈액응고 8인자(Factor VIII)의 중쇄, 경쇄 및 단백질분해효소에 의한 절단부위를 포함하지 않으며, 최소 4개의 당화 부위를 포함하도록 일부가 결실된 B 영역 단편을 포함하는 단쇄 혈액응고 8인자(Factor VIII) 또는 상기 A 또는 B 영역의 일부 잔기가 페길화된 단쇄 혈액응고 8인자를 제공한다. 본원에 따른 단쇄 혈액응고 8인자는 치료 효능성은 그대로 유지하면서 단쇄의 형태로 제조되어 양산이 용이할 뿐 아니라 페길화를 통해 체내 반감기가 증가하여 혈우병 A형의 치료제로서 환자의 편리성을 증대시켰음은 물론 생산비용의 절감을 통해 치료비의 절감을 가져올 수 있다.

Description

재조합 단쇄 FVIII 및 그 화학 접합물
본원은 혈우병의 치료에 사용되는 재조합 단쇄 FVIII 단백질 제조 기술과 그 화학 접합물에 관한 것이다.
혈우병은 혈액 응고인자의 부족으로 지혈이 되지 않아 출혈이 지속적으로 생기는 질환이다. 혈액 내 응고인자는 I~XIII으로 구성되어 있으며, 이중 혈우병과 관련 있는 인자는 VIII, IX 및 XI이다. 혈우병은 상기 각 인자의 유전자 결함으로 발생되며, 부족한 응고인자의 종류에 따라 Factor VIII이 부족한 혈우병 A, Factor IX이 부족한 혈우병 B 및 Factor XI이 부족한 혈우병 C로 구분되며, 그 중 혈우병 A가 약 80-85%를 차지한다.
혈우병 치료의 목적은 지혈이며 치료는 효소대체요법(ERT, Enzyme Replacement Therapy)을 이용하여 예방적 또는 대증적(on demand)의 두 가지 방법에서 수행되는데, 현재 치료법은 예방적 측면으로 옮겨가는 추세이다.
ERT를 위해 사용되는 단백질 치료제로 과거에는 인간 유래 전혈과 혈장에서 추출하여 농축한 FVIII(혈우병 A), FIX 인자(혈우병 B)가 사용되었다. 하지만 인간 유래 원료 사용 인한 부작용과 합병증의 문제가 발생하였다. 따라서 최근에는 유전자 재조합 기술로 생산된 다양한 인자가 개발되어 사용되고 있다. FVIII 역시 유전자 재조합 기술로 생산되어 감염증과 합병증의 위험을 많이 낮추었으나 짧은 반감기로 인하여 환자에게서 자주 투여해야만하는 불편함을 안고있다. 그래서 다양한 체내 지속형 FVIII을 개발하여 환자의 삶의 질을 향상시키고자하는 노력이 계속되어왔다.
그 중 하나는 페길화된 FVIII로 FVIII의 생체내 제거(clearance)를 담당하는 것으로 알려진 LRP1(Low density lipoprotein receptor related protein)과의 결합을 낮추기 위하여 FVIII을 페길화한 것으로 이에 의해 FVIII의 소실이 방지되어 체내 반감기가 어느 정도 향상되었으나 기대에 못 미치는 수준이다. FVIII은 vWF와의 상호작용이 강하여 체내에서 대부분의 FVIII은 vWF와 결합한 상태로 존재하고 따라서 FVIII의 반감기가 FVIII에 결합되어 있는 vWF의 체내 반감기에 의해 결정된다. 그리고 이러한 상황은 페길화 FVIII에도 그대로 적용되어 페길화 이후 페길화 FVIII의 반감기 역시 vWF의 반감기에 의해 지배되어 반감기 향상이 기대 수준에 못 미치는 제한이 있었다.
다른 하나는 FVIII의 C-말단에 항체의 Fc 영역을 융합한 FVIII-Fc 융합 단백질(FVIII-Fc)로, FcRn에 의해 체내에서의 순환으로 인하여, FVIII 보다 체내 반감기가 길지만 FVIII-Fc 역시 체내에서 vWF와 결합하므로 체내 체류시간이 vWF의 반감기에 의해 지배 받는 문제점이 있었다.
이외에 혈우병 A 치료를 위해 기존의 FVIII이 아닌 다른 경로를 통해 FVIII의 혈액 응고인자로서의 기능을 대신하고 체내 지속 효과와 환자의 편의성을 도모하기 위한 개발 시도가 진행 중이다.
그 중 하나는 FVIII-mimetic bi-specific 항체로 이는 FIX(또는 activated FIX)과 FX에 특이적인 2종류의 Fab를 포함하는 온전한 IgG 형태의 이특이적 항체로 체내에서 FVIII의 기능을 대신하도록 고안된 것이다 (Kitazawa et al, Nature medicine 2012 18 (10): 1570-4.).
다른 하나는 항-TFPI(Tissue factor pathway inhibitor)의 사용이다. 이는 TFPI의 기능을 억제하는 물질로 항체, 펩타이드 이외에 앱타머의 형태로도 개발 중이다 (Hilden et al., BLOOD 2012, 119 (24): 5871-8.). TFPI는 TF(tissue factor)-activated FVII 복합체가 FX를 활성화하는 과정을 방해하여 FXa의 생성을 저하하고 FXa에 의해 트롬빈이 생성되지 않도록 하여 혈액응고의 진행을 정지시키는 기능을 한다.
또 다른 하나는 Anti-thrombin 억제제로 이는 혈중 트롬빈 억제제의 기능을 저해함으로써 트롬빈의 활성을 향상시켜 혈우병 동물 또는 혈우병 환자의 혈액 응고가 용이하게 하는 방식으로 작용한다.
그러나 이와 같은 접근법은 혈우병 A형 또는 B형에서 부족되는 FVIII와 FIX 단백질의 활성을 직접 대체하거나 보강하는 것이 아닌 간접적인 방법으로 FVIII의 활성을 모사하거나 우회하는 것으로 치료 기전이 복잡하여 임상에서 안전성과 효력이 충분히 입증되어야 한다.
대한민국 공개특허 공보 2014-0114266는 증가된 특이 활성도를 갖는 항혈우병 인자 VIII을 개시하고 있다.
현재까지 개발된 치료제는 기능적 측면에서 투여 주기(정맥 주사)가 짧고, 또한 짧은 반감기로 인한 체내 효력 소실에 따라 잦은 출혈 빈도가 문제점으로 지적되고 있다. 또한 생산성 측면에서 낮은 생산성과 고가의 치료비도 해결되어야 할 문제이다. 따라서 향상된 반감기를 갖으면서도 높은 생산성을 갖는 FVIII 인자의 개발이 필요하다.
본원은 체내 체류 시간이 향상되고 양산이 용이한 단쇄 FVIII을 제공하고자 한다.
한 양태에서 본원은 인간 혈액응고 8인자(Factor VIII)의 중쇄, 경쇄 및 일부가 결실된 B 영역 단편을 포함하며, 상기 일부가 결실된 B 영역 단편은 퓨린 단백질분해효소에 의한 절단부위를 포함하지 않도록 서열번호 1의 서열의 1648 및 1649 잔기를 포함하여 상기 잔기의 N-말단 및 C-말단 방향으로 각각 최소 5개의 아미노산이 결실되고, 4개 내지 6개의 당화 부위를 포함하도록 일부가 결실된 것인, 단쇄 혈액응고 8인자(Factor VIII)를 제공한다.
본원의 일 구현예에서 따르면 본원의 단쇄 혈액응고 8인자에 포함되는 B 영역 단편은 야생형 B domain 서열의 약 15% 내지 40%를 포함하는 것이나, 본원에 따른 효과를 달성하는 한 이로 제한하는 것은 아니다. 당업자라면, 상술한 단쇄 혈액응고 8인자에 포함되는 B 영역 단편의 조건을 고려하여 적절한 단쇄 혈액응고 8인자를 선택할 수 있다. 본원에서 B 영역은 후술하는 바와 같이 a3 영역을 포함하는 것으로 해석된다.
본원의 일 구현예 따르면 상술한 조건을 만족하는 일부가 결실된 B 영역 단편에서 결실된 부분은 연속적 또는 비연속적일 수 있으며, 서열번호 1의 서열을 기준으로 상기 일부가 결실된 B 영역 단편은 서열번호 1의 서열을 기준으로 (i) 아미노산 잔기 741 내지 902 및 1654 내지 1689; (ii) 아미노산 잔기 741 내지 965 및 1654 내지 1689의 아미노산 서열; 또는 (iii) 아미노산 잔기 741 내지 902, 1637 내지 1642 및 1654 내지 1689;의 서열로 표시될 수 있다.
본원의 일 구현예에 따르면, 본원의 단쇄 혈액응고 8인자는 서열번호 2 내지 7로 표시되는 아미노산 서열 또는 이와 약 90% 이상 상동성이 있는 서열을 갖는 것을 포함하는 것으로, 후술하는 상동성 결정 방법 및 본원에 따른 인자와 생물학적 기능 균등성에 대한 개시내용을 참조하여 적절하게 결정할 수 있을 것이다.
본원에 따른 일 구현예에서 서열번호 2 내지 7로 표시되는 아미노산 서열을 갖는 본원의 단쇄 혈액응고 8인자를 코딩하는 핵산분자는 서열번호 10 내지 15로 표시되거나, 또한 상기 핵산 서열이 세포에서의 발현을 위해 코돈 최적화된 서열로 치환된 것 또는 degenerate codon으로 인한 핵산 서열이 변이된 것을 또한 포함한다.
본원에 따른 단쇄 혈액응고 8인자는 CS 또는 APTT 방법으로 측정한 비활성이 이쇄 혈액응고 8인자 비활성의 90% 이상이다.
다른 양태에서 본원은 친수성 폴리머, 예를 들면 폴리에틸렌글리콜(Polyethylene glycol), 폴리에틸렌 옥사이드, 덱스트란 또는 폴리시알릭을 포함하는 폴리머와 접합되고, PEG가 사용되는 경우에는 접합 위치에서 acryloyl, sulfone 또는 maleimide를 통하여 접합 될 수 있다.
본원의 일 구현예에 따르면 접합된 혈액응고 8인자는 상기 A 영역 및/또는 B 영역 단편의 일부 아미노산 잔기에서 친수성 폴리머와 컨쥬게이션되고, 상기 컨쥬게이션되는 위치는 상기 B 영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 754, 781, 782, 788, 789, 825 및 897로 구성되는 군으로부터 선택되는 하나 이상의 위치이고; 상기 A-영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 491, 495, 498 및 1806으로 구성되는 군으로부터 선택되는 하나 이상의 위치이고, 상기 컨쥬게이션되는 위치의 잔기는 상기 친수성 폴리머와의 접합을 위해 시스테인으로 치환될 수 있다.
본원에 따른 일 구현예에서는 PEG와 접합되며, 특히 평균 분자량이 20kDa 이상의 PEG가 사용된다.
다른 양태에서 본원은 또한 본원에 따른 단쇄 혈액응고 8인자, 특히 서열번호 2 내지 7로 표시되는 단쇄 혈액응고 8인자, 또는 상기 아미노산 서열에서 친수성 폴리머와의 접합을 위해 상기 B 영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 754, 781, 782, 788, 789, 825 및 897로 구성되는 군으로부터 선택되는 하나 이상의 위치이고; 상기 A-영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 491, 495, 498 및 1806으로 구성되는 군으로부터 선택되는 하나 이상의 위치의 해당 아미노산 잔기가 시스테인으로 치환된 단쇄 혈액응고 8인자, 또는 치환된 시스테인기를 포함하는 단쇄 혈액응고 8인자를 코딩하는 핵산분자를 제공한다.
본원에 따른 일 구현예에서 시스테인이 도입된 잔기는 표 3에 기재된 바와 같고, 친수성 폴리머와의 접합을 위해 해당 잔기가 시스테인으로 치환된 핵산분자는 서열번호 17 내지 32로 표시되며, 이에 상응하는 아미노산 서열은 서열번호 33 내지 48로 표시된다. 또한 상기 핵산 서열이 세포에서의 발현을 위해 코돈 최적화된 서열로 치환된 것 또는 degenerate codon으로 인한 핵산 서열이 변이된 것을 또한 포함한다.
다른 양태에서 본원은 또한 본원에 따른 핵산분자를 포함하는 벡터, 상기 벡터를 포함하는 세포를 제공한다.
또 다른 양태에서 본원은 또한 본원에 따른 벡터 또는 세포를 이용한 단쇄 혈액응고 8인자의 생산방법을 제공하며, 일 구현예에 따르면 본원에 따른 방법은 본원에 따른 벡터를 진핵세포에 전달이입하는 단계, 또는 선택적으로 본원에 따른 벡터가 전달된 세포를 제공하는 단계: 상기 세포를 배양액 중에서 배양을 통하여 도입된 시스테인의 자유 티올 기를 시스테인이나 글루타티온에 의해 이황화(disulfide) 결합으로 마스킹 된 단쇄 FVIII 형태로 발현시키는 단계; 상기 배양액으로부터 발현된 단쇄 FVIII을 수집하여 환원제로 처리하여 마스킹 된 시스테인이나 글루타티온을 이탈시키는 단계; 및 상기 처리된 배양액을 페길화완충액으로 처리하는 단계를 포함한다.
다른 양태에서 본원은 또한 청구범위를 포함하는 본원에 개시된 어느 하나의 단쇄 혈액응고 8인자를 포함하는 혈우병 환자 또는 혈액의 응고가 필요한 환자에 사용하기 위한 혈액 응고 키트, 상기 단쇄 혈액응고 8인자의 혈우병 치료용 용도 또는 조성물, 또는 단쇄 혈액응고 8인자를 혈우병 환자 또는 혈액의 응고가 필요한 환자에게 치료적으로 유효한 양으로 투여하는 단계를 포함하는 혈액응고 방법을 제공한다.
본원에 따른 단쇄 FVIII는 경쇄 및 중쇄가, 일부 서열이 결실된 B-도메인으로 연결되며, 특히 정상적인 FVIII 발현 과정 중에 발생하는 furin 단백질분해효소에 의해 절단되는 절단부위를 포함하지 않으며, 최소 4개의 당화 부위를 포함하도록 일부가 결실된 B 영역을 포함한다. 본원에 따른 단쇄 혈액응고 8인자(Factor VIII) 또는 상기 A 또는 B 영역의 일부 잔기가 페길화된 단쇄 혈액응고 8인자는 활성은 그대로 유지하면서 단쇄의 형태로 제조되어 양산이 용이할 뿐 아니라 페길화를 통해 체내 반감기가 증가하여 혈우병 A형의 치료제로서 환자의 편리성을 증대시켰음은 물론 생산비용의 절감을 통해 치료비의 절감을 가져올 수 있다.
도 1은 본원의 일 구현예에 따른 페길화된 단쇄 FVIII 구조를 도식적으로 나타낸 것으로, 1648 잔기는 furin의 절단위치를 나타낸다.
도 2는 본원의 일 구현예에 따른 전장 FVIII으로부터 단쇄 FVIII 제작을 도식적으로 나타낸 것이다. Furin 절단부위(서열 1 기준으로 1648 번째 아미노산 서열)를 표시하였으며 도면에 기재된 숫자는 표시된 부위에 상응하는 각 영역을 아미노산 잔기로 나타낸 것이다.
도 3은 본원의 일 구현예에 따른 단쇄 FVIII 발현을 웨스턴블랏으로 분석한 결과이다.
도 4는 본원의 일 구현예에 따른 최적의 단쇄 FVIII의 페길화 위치 선정을 위해 테스트한 페길화 위치를 표시한 것이다.
도 5는 본원의 일 구현예에 따른 자유 시스테인이 도입된 변이형 단쇄 FVIII 발현 후 발현된 FVIII 활성을 분석한 결과이다.
도 6은 본원의 일 구현예에 따른 자유 시스테인이 도입된 변이형 단쇄 FVIII의 페길화 후 SDS-PAGE 분석 결과이며, 별표로 표시된 라인은 페길화 효율이 상대적으로 높은 것을 나타낸다.
도 7은 본원의 일 구현예에 따른 scFVIII의 PK(pharmacokinetics)를 상용화 FVIII 물질과 비교한 시험결과이다.
도 8a 및 8b는 각각 본원의 일 구현예에 따른 페길화 scFVIII의 tail bleeding 지혈 효력 시험을 상용화 FVIII 물질의 효능과 비교하기 위한 실험 방법의 개략도, 및 실험결과이다. 도 8b에서 PEG40kDa-scFVIII-B3를 나타낸다.
본원은 생산성과 체내 안정성이 증가된 단쇄형태로 발현될 수 있는 인간 혈액응고 8인자(Coagulation Factor VIII) 변이체의 개발 그리고 이러한 변이체의 페길화를 통하여 환자의 투여 주기의 편의성을 제고시킨 혈액응고 인자의 개발을 근거로 한다.
혈액응고 8인자는 A1-A2-B-A3-C1-C2 영역으로 구성되며, 간세포에서 단쇄의 단백질로 합성된다. 합성 후 프로세싱을 거쳐 성숙되어 중쇄와 경쇄로 구성된 280kDa의 헤테로이량체를 형성한다. 이 중 경쇄는 80kDa이며 A3-C1-C2 영역으로 구성되고, 중쇄는 A1-A2-B 영역으로 구성되고 분자량은 90-200kDa으로 B 영역의 길이와 당화 정도의 차이로 인해 분자량의 차이가 크다. A1 domain과 A2 domain 사이의 a1 domain 및 A2 domain과 B domain 사이의 a2 domain 그리고 a3 domain은 중쇄에 포함된다. 이러한 헤테로이량체는 혈액 내에서 vWF와 결합한 비활성화 상태로 존재하다가, 혈관 손상과 같은 자극에 노출시, 트롬빈에 의해 알지닌 372, 740 및 1689번 잔기 뒤에서 절단된다. 그 결과 vWF로부터 분리되어, 활성화되어 A1, A2 및 A3-C1-C2의 삼량체가 형성된다. 이어 삼량체는 FIXa에 의한 FX의 활성화를 촉매하고, 빠르게 비활성화된다.
단쇄 FVIII는 구조적으로 안정하고, 발현량이 증가하는 것으로 보고되어 있다 (WO2004/067566 참조). 이쇄 형태의 FVIII에서는 B 영역의 길이에 따른 발현량 차이가 있음이 보고되었다 (Miao et al., Blood. 2004 May 1;103(9):3412-9.).
본원에서는 단쇄 FVIII의 제작에 있어서 a3를 포함하는 B 영역의 길이와 서열에 따른 발현량 차이 이외에, 특이적 활성도(specific activity)와 APTT/CS 비에도 변화가 초래됨을 확인하였으며, B 영역의 길이 및 서열을 최적으로 조절하여 특이적 활성도와 APTT/CS 비가 이쇄의 천연형과 유사한 재조합 단쇄 FVIII을 제조하였다. 본원에 따른 단쇄 FVIII은 천연형 FVIII 고유의 특성을 유지하면서도 안정하고 발현량이 우수한 것으로 나타났다.
따라서 한 양태에서 본원은 인간 혈액응고 8인자(Factor VIII)의 중쇄 및 경쇄 부위가, 일부 서열이 결실된 B- 도메인으로 연결된 형태의 단쇄 FVIII으로, 특히 상기 일부 서열이 결실된 B- 도메인은 단백질분해효소(furin)에 의한 절단부위를 포함하지 않도록 서열번호 1의 1648 및 1649 잔기 위치를 기준으로 이를 포함하여 각각 N-말단 및 C-말단 방향으로 각각 최소 5개의 아미노산이 결실되고, 4개 내지 6개의 당화 부위를 포함하도록 일부가 결실된 B 영역 단편을 포함한다.
본원에 따른 단쇄 FVIII은 A1- A2- B 일부- A3- C1- C2 영역을 포함한다. 본원에 포함된 각 영역의 FVIII에서의 잔기 위치 및 그 서열은 공지된 것으로 인간 아미노산 서열 예를 들면 인간 FVIII은 서열번호 1의 서열로 표시될 수 있으며, 이를 기준으로 중쇄는 A1 및 A2 영역을 포함하는 1-740 잔기, B 영역은 741-1689 잔기, A3-, C1, 및 -C2 영역을 포함하는 경쇄는 1690-2332 잔기까지이다 (도 2; 및 Orlova et al., Acta Naturae. 2013 Apr-Jun; 5(2): 19-39. 참조). 본원에서 B 영역은 도 2에 기재된 a3 영역(1649 내지 1689)을 포함하여 언급하는 것이다.
이런 측면에서 본원에 따른 단쇄 FVIII는 A1-A2-B'-A3-C1-C2의 식으로 표시될 수 있으며, A1은 상기 A1 영역, A2는 A2 영역, B'은 B 영역의 일부, A3는 A3 영역, C1은 C1 영역, C2는 C2 영역을 의미하며, 상기 각 영역은 앞서 언급한 바를 참조할 수 있다.
본원에 따른 단쇄 FVIII에 포함되는 일부가 결실된 B 영역(B')은 단백질분해효소 furin 절단부위가 결실된 것으로 일 구현예에서는 서열번호 1의 1648 및 1649 잔기를 포함하며 상기 각 잔기의 N-말단 및 C-말단 각 방향으로 최소 5개의 아미노산이 결실된 것이 포함된다. B 영역에는 다수의 당화 부위가 존재하며, 단백질의 당화는 단백질의 활성과 발현 과정 중 세포 내부 및 발현 후 세포 외부에서 안정성에도 영향을 미치기 때문에, 상기 B 영역의 결실부위를 결정함에 있어서 포함되는 당화 개수를 고려할 수 있다.
본원에 따른 일 구현예에서는 특히 당화 개수 4개 내지 6개가 포함되도록 B 영역의 결실부위가 결정된다.
또한 B 영역의 결실부위를 결정함에 있어서 본원에 따른 단쇄 FVIII에 포함되는 furin 절단부위가 결실된 B 영역은 전체 야생형 B-domain의 약 15~40%를 포함하는 한도에서 결정될 수 있다.
또한 본원에 따른 단쇄 FVIII에 포함되는 일부가 결실된 B 영역의 결실 부위는 연속적 또는 비연속적일 수 있다.
일 구현예에서 본원에 따른 단쇄 FVIII가 furin 절단부위를 포함하는 연속적으로 결실된 B 영역을 포함하는 경우는 서열번호 1의 서열을 기준으로 (i) 아미노산 잔기 741 내지 902 및 1654 내지 1689 (즉 B 영역의 903 내지 1653 잔기가 연속적으로 결실됨); (ii) 아미노산 잔기 741 내지 965 및 1654 내지 1689 (즉, B 영역의 966 내지 1653 잔기가 결실됨)로 표시되는 서열이거나, 또는 비연속적으로 결실된 B 영역을 포함하는 경우는 (iii) 아미노산 잔기 741 내지 902, 1637 내지 1642 및 1654 내지 1689의 서열로 표시된다.
다른 일 구현예에서 상기와 같은 결실된 B 영역을 포함하는, 본원에 따른 FVIII 아미노산 서열은 서열번호 2 내지 7로 표시될 수 있다.
본원 개시된 재조합 FVIII은 위와 같은 서열로 한정되는 것이 아니며, 이의 생물학적 균등물(biologically equivalents)을 포함하는 것이다. 생물학적 균등물이란, 본원에 개시된 아미노산 서열에 추가적인 변형을 가하였으나, 본원에 따른 폴리펩타이드와 실질적으로 동일한 활성을 갖는 것으로, 이러한 변형은, 예를 들어 아미노산 서열 잔기의 결실, 삽입 및/또는 치환을 포함하는 것이다.
일 구현예에서는 본원에 따른 재조합 FVIII 폴리펩타이드에 보존적 아미노산 치환이 일어난 것을 포함한다.
보존적 아미노산 치환(conservative amino acid substitution)이란 특정 폴리펩타이드가 갖는 활성을 실질적으로 영향을 미치거나 감소시키지 않는 치환을 의미하는 것으로, 예를 들면, 1 내지 15개의 보존적 치환, 1 내지 12개, 예를 들면 1, 2, 5, 7, 9, 12, 또는 15개의 보존적 아미노산 치환을 포함할 수 있다.
보존적 아미노산 치환은 당업계에 알려진 것으로 예를 들면 Blosum(BLOcks SUbstitution Matrix) 기반한 Creighton (1984) Proteins. W. H. Freeman and Company (Eds)의 기재된 사항; 및 Henikoff, S.; Henikoff, J.G. (1992). "Amino Acid Substitution Matrices from Protein Blocks". PNAS 89 (22): 10915-10919. doi:10.1073/pnas.89.22.10915; WO2009012175 A1 등에 기재된 것을 참조할 수 있다.
이러한 아미노산 변이 특히 치환은 아미노산 곁사슬 치환체의 상대적 유사성, 예컨대, 소수성, 친수성, 전하, 크기 등에 기초하여 이루어진다. 아미노산 곁사슬 치환체의 크기, 모양 및 종류에 대한 분석에 의하여, 아르기닌, 라이신과 히스티딘은 모두 양전하를 띤 잔기이고; 알라닌, 글라이신과 세린은 유사한 크기를 갖으며; 페닐알라닌, 트립토판과 타이로신은 유사한 모양을 갖는다. 따라서, 이러한 것을 고려하면, 아르기닌, 라이신과 히스티딘; 알라닌, 글라이신과 세린; 그리고 페닐알라닌, 트립토판과 타이로신은 생물학적으로 기능 균등물이라 할 수 있다.
또한 아미노산 치환을 도입하는 데 있어서, 아미노산의 소수성 인덱스(hydropathic index)가 고려될 수 있다. 각각의 아미노산은 소수성과 전하에 따라 소수성 인덱스가 부여되어 있다: 아이소루이신(+4.5); 발린(+4.2); 루이신(+3.8); 페닐알라닌(+2.8); 시스테인/시스타인(+2.5); 메티오닌(+1.9); 알라닌(+1.8); 글라이신(-0.4); 쓰레오닌(-0.7); 세린(-0.8); 트립토판(-0.9); 타이로신(-1.3); 프롤린(-1.6); 히스티딘(-3.2); 글루타메이트(-3.5); 글루타민(-3.5); 아스파르테이트(-3.5); 아스파라긴(-3.5); 라이신(-3.9); 및 아르기닌(-4.5). 상기와 같은 소수성 인덱스는 특히 단백질의 상호적인 생물학적 기능(interactive biological function)을 부여하는 데 있어서 중요하다. 유사한 소수성 인덱스를 가지는 아미노산으로 치환하여야 유사한 생물학적 활성을 보유할 수 있다는 것은 공지된 사실이다. 소수성 인덱스를 참조하여 변이를 도입시키는 경우, 바람직하게는 ±2 이내, 보다 바람직하게는 ±1 이내, 보다 더 바람직하게는 ±0.5 이내의 소수성 인덱스 차이를 나타내는 아미노산 간의 치환이 유리하다.
또한 유사한 친수성 수치(hydrophilicity value)를 가지는 아미노산 사이의 치환이 균등한 생물학적 활성을 갖는 단백질을 초래한다는 것도 잘 알려져 있다. 예를 들면 미국 특허 제4,554,101호에 개시된 바와 같이, 다음의 친수성 값이 각각의 아미노산 잔기에 부여되어 있다: 아르기닌(+3.0); 라이신(+3.0); 아스팔테이트(+3.0±1); 글루타메이트(+3.0±1); 세린(+0.3); 아스파라긴(+0.2); 글루타민(+0.2); 글라이신(0); 쓰레오닌(-0.4); 프롤린(-0.5±1); 알라닌(-0.5); 히스티딘(-0.5); 시스테인(-1.0); 메티오닌(-1.3); 발린(-1.5); 루이신(-1.8); 아이소루이신(-1.8); 타이로신(-2.3); 페닐알라닌(-2.5); 트립토판(-3.4).
또한 본원에 따른 재조합 단백질의 활성을 전체적으로 변경시키지 않는 아미노산 치환은 당해 분야에 공지되어 있다 (H. Neurath, R.L.Hill, The Proteins, Academic Press, New York, 1979). 예를 들면 가장 통상적으로 일어나는 치환은 아미노산 잔기 Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thr/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu 및 Asp/Gly 간의 치환을 들 수 있다.
따라서, 상술한 바와 같은 생물학적 균등성을 갖는 변이체는 본원에 개시된 아미노산 서열 또는 이를 코딩하는 핵산분자와 실질적 동일성을 갖는 것으로 본원의 범위에 포함된다.
이러한 실질적 동일성은 당업계의 공지된 서열비교 방법을 이용하여 결정될 수 있다. 본원에 개시된 서열과 임의의 다른 서열을 최대한 대응되도록 얼라인하고, 당업계에서 통상적으로 이용되는 알고리즘을 이용하여 얼라인된 서열을 분석한 경우에, 최소 80% 상동성, 특히 85% 이상, 더욱 특히 90%, 더더욱 특히 95% 이상의 상동성을 나타내는 서열은 실질적 동일성을 의미한다. 서열비교를 위한 얼라인먼트 방법은 당업계에 공지되어 있다. 예를 들면 Smith and Waterman, Adv. Appl. Math. (1981) 2:482; Needleman and Wunsch, J. Mol. Bio. (1970) 48:443; Pearson and Lipman, Methods in Mol. Biol. (1988) 24: 307-31; Higgins and Sharp, Gene (1988) 73:237-44; Higgins and Sharp, CABIOS (1989) 5:151-3; Corpet et al., Nuc. Acids Res. (1988) 16:10881-90; Huang et al., Comp. Appl. BioSci. (1992) 8:155-65 및 Pearson et al., Meth. Mol. Biol. (1994) 24:307-31에 개시되어 있다. NCBI Basic Local Alignment Search Tool(BLAST)(Altschul et al., J. Mol. Biol. (1990) 215:403-10)은 NCBI 등에서 접근 가능하며, blast, blastp, blasm, blastx, tblastn 및 tblastx와 같은 서열 분석 프로그램과 연동되어 이용할 수 있다. BLAST는 www.ncbi.nlm.nih.gov/BLAST/에서 접속 가능하며, 이 프로그램을 이용한 서열 상동성 비교 방법은 www.ncbi.nlm.nih.gov/BLAST/blast_help.html에서 확인할 수 있다.
본원에 따른 단쇄의 재조합 FVIII(recombinant single chain FVIII)는 활성 물질의 몰당 활성의 측면에서 야생형의 이쇄 FVIII과 비교하여 90% 이상, 95% 이상, 97% 이상, 98% 이상, 99% 이상, 또는 100%를 갖는 것을 포함하는 것이다. 야생형의 이쇄 FVIII과 이의 활성을 측정하는 방법은, 공지되어 있으며, 예를 들면 CS와 clotting assay(APTT: activated partial thromboplastin time)로 측정한 비활성 수치와 (APTT)/CS 비율을 결정하여 수행될 수 있다 (Coagulation Assays Circulation. 2005;112:e53-e60). 당업자라면 본원의 기재, 당업계의 기술 및 참고문헌의 기재를 고려하여 적절한 방법을 선택하여 활성을 측정하고 이에 기반하여 본원의 범위에 포함되는 단쇄 재조합 FVIII를 결정할 수 있을 것이다. 이쇄 FVIII은 상술한 바와 같이 퓨린에 의해 프로세스 되어 경쇄와 중쇄의 이량체로 구성된다. 본원에서는 천연형 FVIII의 재조합 단백질(Advate®)과 비교하였으며 이는 CHO 세포에서 재조합 형태로 발현한 FVIII으로 대부분이 다양한 B 영역의 길이를 포함하는 이쇄로 된 것으로 혈장 유래 천연형의 FVIII의 구성과 유사하다.
본원에 따른 단쇄 FVIII와 비교대상이 되는 이쇄 FVIII은 B 영역을 포함하거나 포함하지 않는다. B 영역을 포함하지 않는 이쇄는 주로 재조합 방법으로 의도적으로 B 영역을 제거하거나 천연형의 FVIII이 발현되는 과정에서 FXa(활성형 FX)와 트롬빈에 의한 단백 절단 프로세스에 의하여 B 영역을 포함하지 않는 이쇄가 생성될 수 있다. B 영역을 포함한 이쇄는 프로세싱과정 중에서 재조합 방법으로 B 영역의 일부 또는 전체를 포함하도록 하거나 천연형의 FVIII이 발현되는 과정에서 FXa(활성형 FX)와 트롬빈에 의한 단백 절단 프로세스에 의하여 B 영역의 일부 또는 전체를 포함하는 FVIII 이쇄가 생성될 수 있다. 그러나 본원의 단쇄와 직접 비교한 이쇄 FVIII은 B 영역 전체를 포함하는 천연형의 FVIII을 재조합 발현으로 발현한 것으로 세포 내부에서 외부로 배출 시 furin에 의한 프로세싱되어 B 영역 전체를 포함하는 이쇄 FVIII와 그 이후 트롬빈 또는 FIXa 또는 FXa에 의해 B 영역의 일부 또는 전체가 제거되어 B 영역을 전혀 포함하지 않거나 또는 B 영역의 일부를 포함하는 FVIII의 혼합물로 천연형 FVIII와 가장 유사한 재조합 FVIII이다.
다른 양태에서 본원은 본원에 따른 단쇄의 재조합 FVIII를 코딩하는 핵산분자 또는 폴리뉴클레오타이드, 상기 폴리뉴클레오타이드를 포함하는 벡터 또는 상기 벡터로 형질전환된 세포(주)에 관한 것이다.
본원에 따른 재조합 단쇄 FVIII를 코딩하는 핵산분자는, 본원에 따른 재조합 단쇄 FVIII가 발현되는 세포의 종류에 맞추어 코돈최적화(Codon optimized) 된 것을 포함하는 것이다. 본원에 따른 일 구현예서는 CHO 세포 코돈에 최적화되며, 이러한 핵산 서열은 서열번호 5의 단백질을 코딩하는 핵산 서열을 최적화한 것으로 이는 서열번호 15의 서열로 표시될 수 있다.
본원에 따른 재조합 단쇄 FVIII를 코딩하는 핵산분자는 또한 상술한 바와 같이 실질적으로 동일한 생물학적 균등물에 해당하는 FVIII를 코딩하는 것을 또한 포함하는 것이다.
또한 본원에 따른 단쇄의 재조합 FVIII를 코딩하는 핵산분자는 다양한 목적을 위해 다양한 발현 벡터에 클로닝되어 사용될 수 있다. 발현 벡터의 구체적 구성은 본원에 따른 단쇄 재조합 FVIII을 발현하고자 하는 숙주 세포에 따라 달라질 수 있으나, 본원에 따른 핵산분자의 mRNA로의 발현 또는 mRNA의 단백질로의 발현을 조절하는 서열, 예를 들면 프로모터 및/또는 인핸서 등과 같은 조절서열을 포함한다. 이러한 또는 다양한 다른 목적으로 사용될 수 있는 다양한 벡터 및 조절서열이 공지되어 있으며, 당업자라면 본원의 구체적 목적 및 효과를 고려하여 적절한 것으로 선택할 수 있을 것이며, 예를 들면 본원의 실시예 및 도면에 기재된 것을 포함할 수 있으나 이로 제한하는 것은 아니다.
본원에 따른 재조합 단쇄 FVIII를 코딩하는 핵산분자를 포함하는 벡터는 당업계의 공지된 방법을 통하여 제조될 수 있으며, 예를 들면 본원에 따른 재조합 단쇄 FVIII를 코딩하는 핵산분자를 벡터의 프로모터 및/또는 인핸서에 작동가능하게 연결한다. 일 구현예에서는 세포에서 외래 유전자를 발현시킬 수 있는 재조합 발현 벡터에 삽입되며, 이러한 벡터의 예로는 pMSGneo, pcDNA3.1(+) 등 일반 단백질 발현 벡터를 들 수 있으나, 이에 제한되지 않는다. pMSGneo 벡터의 경우 핵 기질(nuclear matrix)에 결합하는 MAR(Matrix attachment region) 인자가 포함된 발현 벡터로서, 상기 MAR 인자는 발현 벡터에 사용되는 경우 위치-독립적 발현(position-independent expression)을 유도하여 유전자 발현을 증대시키는 역할을 한다. 따라서, pMSGneo 벡터를 이용하는 경우 안정적이고 높은 발현량을 얻을 수 있다. 또한, pcDNA3.1(+) 벡터는 강력한 CMV 프로모터가 함유되어 있어 단백질 발현에 널리 사용되고 있다.
또한, 본원에 따른 재조합 단쇄 FVIII를 코딩하는 핵산분자를 포함하는 상기 재조합 발현 벡터는 다양한 목적을 위해 하기에 기술한 바와 같은 적절한 숙주세포에 형질전환 될 수 있다. 벡터에 포함된 핵산분자를 단백질로 발현하기 위해, 단백질을 코딩하는 핵산분자의 코딩 서열을 목적하는 세포에 적합하게 최적화 할 수 있다.
이런 측면에서 본원은 본원에 따른 벡터로 전달이입 또는 형질전환된 재조합세포에 관한 것이다. 이러한 세포는 본원에 따른 벡터의 증폭 및/또는 벡터에 포함된 핵산분자가 발현되어, 목적하는 단백질 생산에 사용될 수 있는, 원핵 및 진핵 세포를 모두 포함하는 것이다. 이러한 목적으로 사용될 수 있는 다양한 세포가 공지되어 있으며, 당업자라면 본원의 구체적 목적 및 효과를 고려하여 적절한 것으로 선택할 수 있을 것이며, 예를 들면 본원의 실시예 및 도면에 기재된 것을 포함할 수 있으나 이로 제한하는 것은 아니다. 예를 들면 대장균(E.coli), 포유동물 세포(Mammalian cell), 효모(Yeast), 식물 세포(Plant cell), 곤충 세포(Insect cell)를 포함한다. 본원에 따른 일 구현예에서는 재조합 FVIII의 발현을 위해, 진핵세포, 특히 포유동물 세포주가 사용된다. 당업자라면 본원에 따른 재조합 FVIII의 특징을 고려하여 이러한 특징을 갖는 단백질을 생산할 수 있는 적절한 세포주를 선별할 수 있을 것이며, 예를 들면 이러한 포유동물 세포주로는 당업계에 공지된 CHO, BHK, COS7, HEK 세포주 등을 사용할 수 있으며, 바람직하게는, CHO 세포주, 특히 CHO-S 세포주, CHO-DG44 또는 CHO-K1 세포주, 또는 HEK 세포주 특히 HEK293 세포주가 사용될 수 있으나 이로 제한하는 것은 아니다.
본원에 따른 벡터는 발현을 위해 상기와 같은 숙주세포로 전달된다. 이러한 숙주세포로의 벡터의 전달 방법은 당업계에 알려져 있으며, 예를 들면, 칼슘포스페이트 침전법, 샷건 방법, 리포좀을 이용한 방법, 나노니들 또는 전기천공법 등 당업계의 공지된 방법을 이용하여 수행될 수 있으나, 이로 제한하는 것은 아니다.
본원에 따른 단쇄 FVIII는 반감기의 상승을 목적으로 친수성 폴리머로 특정잔기에서 개질 된 것일 수 있다.
B 영역의 단백질 구조는 밝혀지지 않았다. B 영역은 구조가 유연하고 당화 정도가 심한 단백질로 음전하가 풍부한 것은 알려져 있으나 그 구조를 예측하기는 어렵다. 즉 분자 모델링 기법을 사용하여 B 영역의 구조를 예측하는 것이 이론적으로 가능하나 B 영역의 후번역 변형 및 당화에 의한 비균질성(heterogeneity)을 고려하면, B 영역 구조를 예측하기 어렵다. 이와 같이 B 영역 내의 개질 위치를 선정하기 위해서는 B 영역 단백질 구조의 표면에 대한 구조 정보가 필요하나 이에 대한 정보가 없어 페길화 위치를 선정하기는 매우 어렵다.
하지만 본원에서는 특히 단쇄 FVIII의 활성에 영향을 주지 않는 A 영역 및/또는 B 영역의 잔기를 예기치 않은 노력을 통하여 선정하고 이를 친수성 폴리머로 개질한 결과 고유의 활성은 유지하면서도 반감기가 향상된 단쇄 FVIII를 수득하였다.
본원에서는 특히 B 영역의 당화 인근의 잔기를 기준(0)으로 -6 ~ +6 잔기 사이를 페길화 위치로 선정하였다.
이러한 측면에서 본원은 A 영역 및/또는 B 영역 단편의 일부 아미노산 잔기에서 친수성 폴리머와 컨쥬게이션되고, 상기 컨쥬게이션되는 위치는 상기 B 영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 754, 781, 782, 788, 789, 825 및 897로 구성되는 군으로부터 선택되는 하나 이상의 위치이고; 상기 A-영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 491, 495, 498 및 1806으로 구성되는 군으로부터 선택되는 하나 이상의 위치이고, 상기 컨쥬게이션 되는 위치의 잔기는 상기 친수성 폴리머와의 접합을 위해 시스테인으로 치환되는, 단쇄 혈액응고 8인자에 관한 것이다.
본원에 따른 단쇄 FVIII의 개질에 사용될 수 있는 친수성 폴리머는 당업계의 공지된 다양한 폴리머가 사용될 수 있으며, 예를 들면 폴리에틸렌글리콜(Polyethylene glycol), 폴리에틸렌 옥사이드, 덱스트란, 폴리시알릭 등을 포함하나 이로 제한하는 것은 아니다. 이들 폴리머는 생체 적합성(비독성, 저독성) 친수성의 유연한 구조이고 단백질에 화학적으로 접합 시 접합 된 단백질이 비특이적인 상호 작용(interaction)으로 타 분자 및 물체의 표면에 붙어 활성이 소실되는 것을 방지하고 혈 중에서 단백질 분해 효소에 의해 비 활성화되는 것을 방지하는 역할을 한다.
본원에 따른 일 구현 예에서는 PEG가 사용되며, 특히 20kDa 이상의 PEG가 사용된다. PEG는 단백질에 접합되어 단백질 주위를 감싸는 효과를 부여함으로써 체내에서 scavenger receptor에 결합 후 소실되거나 inactivating protease에 의한 분해에 방어할 수 있게 된다. PEG는 사슬 모양의 고분자로 선형(linear) 또는 가지형(branched)으로 되어 있으며 작은 분자량의 PEG는 단백질을 충분히 감싸지 못하여 단백질을 완전히 방어하지 못한다. 그러므로 방어하고자 하는 단백질을 충분히 감싸기 위해서는 한계 수준이상의 분자량이어야 한다. 본원의 단쇄 FVIII의 페길화는 페길화 위치의 아미노산을 시스테인으로 치환 후 시스테인에 특이적인 acryloyl, sulfone 또는 maleimide기를 한쪽 끝에 포함하는 PEG를 통해 접합 될 수 있다.
즉, 본원에 따른 단쇄 FVIII은 친수성 폴리머로의 개질을 위해 특정 잔기가 치환될 수 있으며, 구체적으로 치환되는 잔기는 단쇄 FVIII 상에서 친수성 폴리머가 접합되는 위치에 따라 상이하며, 당업자라면 친수성 폴리머의 접합을 위하여 적절한 잔기로 개질 할 수 있을 것이다.
본원에 따른 일 구현예에서는 개질로서 페길화가 사용되며, 이 경우 개질되는 잔기는 시스테인으로 치환된다.
본원에 따른 일 구현예에서는 A2 영역 495번 발린 잔기 및/또는 B 영역의 782번 아이소루이신 잔기에서 개질되며, 특히 페길화되고, 페길화를 위해 상기 잔기가 시스테인으로 치환된다.
개질을 위해 시스테인으로 치환된 단백질의 발현은 당업계에 공지된 방법을 이용하여 수행될 수 있으며, 예를 들면 페길화되는 단백질의 경우, 도입된 자유 시스테인은 세포 내의 발현 도중이나 세포 밖으로 배출 후 free thiol을 포함하는 저분자 물질인 시스테인 또는 글루타치온과 이황화 결합을 형성하여 도입된 자유 시스테인을 마스킹하여 페길화 직전 환원 조건으로 도입된 자유 시스틴이 복원되기 전까지 도입된 자유시스틴을 안정화시켜 페길화 효율을 높이는 것이 필요하다.
페길화 반응은 공지된 방법을 이용하여 수행될 수 있으며, 예를 들면 자유 시스테인의 마스킹을 위해 사용된 시스테인이나 글루타치온은 페길화 반응 전에 제거되어 도입한 시스틴의 free thiol이 복원되어야 하며, 이를 위해 TCEP, DTT, beta-mercaptoethanol, 시스테인(cysteine), 글루타티온(환원형) 등의 환원제를 처리하는 과정과 이 과정에서 FVIII 본연의 이황화본드가 환원적으로 절단된 것을 복원하기 위한 산화 과정을 포함하여 수행할 수 있다.
발현된 재조합 단백질의 도입된 시스테인(cysteine)의 매스킹은 공지된 방법을 이용하여 수행될 수 있으며, 예를 들어 자유 시스테인의 마스킹을 위해 사용된 시스테인이나 글루타치온은 세포 배양 배지 성분에 추가로 첨가하거나, 세포 배양 배지 성분에 추가적인 첨가 없이 세포의 성장과 유지 과정에서 정상적으로 세포가 생성하여 축적하고 분비하는 시스테인 이나 글루타치온 성분이 사용될 수 있다.
다른 측면에서 본원은 또한 상술한 본원에 따른 벡터를 진핵세포에 전달이입하는 단계; 상기 세포를 배양액 중에서 배양하는 단계; 상기 배양액을 수집하여 시스테인(cysteine) 도입 FVIII을 정제하는 단계; 및 상기 정제된 시스테인(cysteine) 도입 FVIII을 페길화 완충액으로 처리하는 단계; 도입된 시스테인(cysteine)의 자유 티올기를 환원 과정을 통해 복원하는 단계; 환원 과정 중 분리된 단쇄 FVIII 단백질 내부의 이황화 결합을 복원하기 위하여 산화시키는 단계; 환원형의 티올기로 복원된 단쇄 FVIII 시스테인(cysteine)에 특이적으로 페길화시키는 단계 및 페길화 단쇄 FVIII을 분리하는 단계를 포함하는, 단쇄 응고인자 8의 생산방법에 관한 것이다.
본원에 따른 방법에 사용되는 구체적인 벡터, 세포 및 각 단계의 처리 과정은 본원 실시예에 기재된 것을 참고 할 수 있다.
본원에 따른 재조합 단쇄 FVIII는 혈액응고가 필요한 질환, 혈우병, 특히 혈우병 A 환자의 혈액응고 또는 혈우병 A의 치료에 유용하게 사용될 수 있다.
이에 본원은 또한, 본원의 청구범위를 포함하는 본원에 개시된 어느 하나의 단쇄 혈액응고 8인자를 포함하는 혈우병 환자 또는 혈액의 응고가 필요한 환자에 사용하기 위한 혈액 응고 키트, 상기 단쇄 혈액응고 8인자의 혈우병 치료용 용도 또는 조성물, 또는 단쇄 혈액응고 8인자를 암호화하는 염기 서열의 핵산을 포함하는 조성물 사용하는 혈우병 A형의 유전 치료 용도 및 그 치료에 사용될 단쇄 혈액응고 8인자를 암호화하는 염기 서열의 핵산을 포함하는 조성물 또는 단쇄 혈액응고 8인자를 혈우병 환자 또는 혈액의 응고가 필요한 환자에게 치료적으로 유효한 양으로 투여하는 단계를 포함하는 혈우병 치료 방법 또는 혈액응고 방법에 관한 것이다.
본원에 따른 재조합 단쇄 FVIII는 약학적으로 허용가능한 담체를 함께 포함하는 혈우병 치료용 약학 조성물의 형태로 제공될 수 있다.
또한 본원의 약학 조성물은 단독으로, 또는 기타 약물치료 및 생물학적반응조절제를 사용하는 방법들과 병용하여 사용할 수 있다.
본원의 조성물은 상기 언급한 유효성분 이외에 추가로 약학적 또는 생리학적으로 허용 가능한 담체를 1종 이상 포함하여 제조할 수 있다.
본원에서 사용된 용어 담체란 사용되는 투여량 및 농도에 노출되는 세포 또는 포유동물에 무독성인 약학적으로 허용가능한 담체, 부형제, 또는 안정화제를 의미하는 것이다. 이러한 담체의 예로는 식염수, 링거액, 완충 식염수, 포스페이트, 시트레이트 및 다른 유기산과 같은 완충액, 아스코르브산을 비롯한 산화방지제, 저분자량(약 10 잔기 미만) 폴리펩타이드, 단백질, 예를 들어 혈청 알부민, 젤라틴 또는 면역글로불린; 친수성 중합체, 예를 들어폴리비닐피롤리돈, 아미노산, 예를 들어 글리신, 글루타민, 아스파라긴, 아르기닌 또는 라이신, 단당류, 이당류 및 글루코스, 만노스 또는 덱스트린을 비롯한 기타 탄수화물, 킬레이트화제, 예를 들어 EDTA, 당 알콜, 예를 들어 만니톨 또는 소르비톨, 염 형성 카운터 이온, 예를 들어 나트륨, 및(또는) 비이온계 계면활성제, 예를 들어 트윈, 폴리에틸렌 글리콜(PEG) 및 플루로닉스(PLURONICS)를 들 수 있다.
필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형으로 제제화할 수 있다. 더 나아가 당해 기술분야의 적정한 방법으로 또는 레밍턴의 문헌(Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제형화할 수 있다.
본원의 조성물은 목적하는 방법에 따라 특히 비경구투여(예를 들어, 정맥 내, 피하, 복강 내)가 바람직하다. 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.
본원에 따른 조성물은 치료적으로 유효한 양으로 투여된다. 본원에서, "치료적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
본원에 따른 재조합 단쇄 FVIII는 그 자체 또는 상술한 바와 같은 조성물의 형태로 혈우병 또는 혈액응고가 필요한 대상체에게 치료적으로 유효한 양으로 투여되어, 혈액 응고 방법 또는 혈우병의 치료 방법의 형태로 제공될 수 있으며, 앞서 기재한 바를 참고할 수 있다.
본원에서 사용되는 용어, "치료"란 본 발명의 조성물의 투여에 의해 질환에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다. 본원에 따른 방법이 사용되는 대상체는 인간을 포함하는 영장류이나, 이로 제한하는 것은 아니다.
이하, 본 발명의 이해를 돕기 위해서 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 본 발명이 하기의 실시예에 한정되는 것은 아니다.
실시예
실시예 1. 단쇄(Single-chain) FVIII 구축
인간 혈액 응고 인자 VIII(Factor VIII) 고유의 특성을 유지하면서도 발현율이 높은 단쇄 형태의 인간 혈액 응고 인자 FVIII(single-chain FVIII, scFVIII)을 개발하기 위하여, FVIII의 a3를 포함하는 B 영역 길이를 조절하여 다양한 길이의 B 영역을 포함하는 재조합 scFVIII을 제작하여 발현하고 그 발현량과 활성(APTT, CS)을 분석하였다. 상세한 방법 및 결과는 아래와 같다.
실시예 1-1. scFVIII 제작
단쇄 형태로 발현되는 FVIII의 구축을 위해, furin 절단 위치인 1648 잔기(전장 FVIII 아미노산 서열을 나타내는 서열번호 0의 아미노산 서열기준)를 포함하는 B 영역의 일부가 결실된 FVIII를 구축하였다. 중쇄와 경쇄를 연결하는 B 영역 길이에 따라 최종 FVIII의 활성과 특성에 영향을 줄 수 있기 때문에, scFVIII에 포함되는 B 영역 길이 결정을 위해 표 1에 기재된 바와 같이 총 7종류의 FVIII를 구축하였다. 구축된 각각의 scFVIII은 B 영역의 N-terminal(서열번호 1의 741번째 아미노산 잔기)로부터 특정 길이의 B 영역을 포함하고 이러한 B 영역이 원래 보유하고 있는 당쇄를 그대로 포함하도록 제작되었다.
또한 경쇄와 중쇄 부위를 연결하는 B 영역에 의한 구조적인 방해를 최소화하여 천연형의 FVIII 활성과 유사한 특성을 갖도록 하기 위해, 경쇄 부위와 인접한 a3 domain의 일부가 다른 구조의 scFVIII 보다 많이 포함된 구조를 또한 제작하였다 (서열번호 6). 또한 CHO 세포에서 발현을 향상시키기 위하여 CHO 코돈으로 최적화된 scFVIII를 제작하였다 (핵산 서열번호 15).
B 영역이 결실된 각 scFVIII은 인간 FVIII 핵산서열(NM000132)을 기준으로 합성하였다. 먼저 scFVIII 유전자 발현벡터를 제조하기 위하여 인간 FVIII 핵산서열(NM000132)을 기준으로 G1 단백질 서열(Leader-Heavy chain-B domin (741-764, 1653-1689)-Light chain)을 암호화(인코딩)하고 5’에 NotI-AsisI과 3’에 XhoI-PacI 효소절단 부위를 포함하도록 GeneArt 사를 통해 유전자 전체를 합성하였다. 합성된 유전자를 pcDSW 벡터의 NotI/XhoI site에 클로닝하여 pcDSW-G1 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 AsisI/PacI 효소를 이용하여 절단 후 절단된 밴드 크기 비교를 통해 확인하였다. 이후 B 영역이 결실된 각 scFVIII (G2, G3, G4, G4-flex, G6)는 FVIII heavy chain의 A2 영역 내에 존재하는 BamHI site (GGATCC)부터 light chain 끝에 PacI 효소절단 부위를 포함하도록 GeneArt 사를 통해 각각의 scFVIII들에 해당하는 유전자를 합성한 후 기존에 완성된 pcDSW-G1 발현벡터를 효소 BamHI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 BamHI/PacI site로 자르고 pcDSW-G1 발현벡터의 BamHI/PacI site에 클로닝 하여 pcDSW-scFVIII 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 BamHI/PacI 효소를 이용하여 절단 후 크기 비교를 통해 확인하였다. 발현을 향상시키기 위하여 CHO 코돈으로 최적화된 scFVIII(G6_opt)은 GeneArt 사를 통해 5’에 NotI-AsisI과 3’에 XhoI-PacI 효소절단 부위가 포함되고 동물세포 발현에 적합하도록 코돈 최적화 및 유전자 합성을 완료하였다. 합성된 유전자를 pcDSW 벡터의 NotI/XhoI site에 클로닝 하여 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 BamHI 효소를 이용하여 절단 후 크기 비교를 통해 확인하였다.
[표 1] 본원에서 제작된 다양한 길이의 B 영역을 포함하는 scFVIII
Figure 112019008914961-pct00001
* 서열번호 1의 서열을 기준으로 기재
** 코딩핵산 서열을 CHO 세포의 코돈으로 최적화
실시예 1-2. 구축된 scFVIII 발현 및 활성 측정
scFVIII 발현
실시예 1-1에서 구축된 scFVIII를 세포에서 발현하였으며, 발현된 세포는 세포배양배지로 배양된다. 우선 발현을 위해 실시예 1-1에서 구축된 발현 벡터를 일시발현시스템인 Expi293F™ Expression System Kit (Thermofisher 사, Catalog Number A14635)를 사용하여 Expi293F™ 세포에 전달 이입하였다. 간략히 설명하면 형질전환 수행 24시간 전에 Expi293F™ 세포를 2.0 X 106 cells/mL로 Expi293 배양배지를 이용하여 예상 필요량에 맞추어 계대배양한 후 형질전환 수행 당일, 세포 수와 세포 생존율(viability)을 측정하여 세포 생존율이 95% 이상일 경우 형질전환을 진행하였다. 125mL flask에 7.5 X 107 cell을 Expi293 배양배지를 첨가하여 최종 25.5mL 볼륨으로 맞춰주었다 (30mL 기준). 실시예 1-1에서 구축된 발현 벡터 30μg을 Opti-MEM을 이용하여 총 볼륨이 1500μL이 되도록 섞어주었다. 80μL transfection reagent를 Opti-MEM을 이용하여 총 볼륨이 1500μL이 되도록 섞어주고 상온에서 5분간 incubation 해주었다. 5분 후 transfection reagent가 들어있는 Opti-MEM을 DNA가 들어있는 Opti-MEM에 넣어주고 부드럽게 섞어주었다. 그리고 20~30분간 상온에서 반응시켜 주었다. 3mL의 DNA : transfection reagent 복합체를 미리 준비해 놓은 125mL flask Expi293F™ 세포에 (Total volume : 28.5mL)에 한 방울씩 떨어뜨려 주고 37℃, 5% CO2 shacking incubator에서 125 rpm으로 배양하였다. 16~20시간 후에 Enhancer 1과 Enhancer 2를 각각 150μL, 1.5mL을 넣어주고 34℃, 5% CO2 shacking incubator에서 125 rpm으로 배양하였다. 배양 3일째 배지를 harvest하고 아래와 같이 scFVIII의 활성을 측정하였다.
발현된 scFVIII 활성 측정
현재 전장 형태와 B 영역 결실 형태 2종류의 재조합 FVIII이 임상적으로 사용되고 있다. 하지만 이들 두 종류 재조합 FVIII이 임상적으로 활성 및 효력에서 동등한지 이슈가 제기되고 있다 (GRUPPO, R. A. et al.. 2003. Comparative effectiveness of full-length and B-domain deleted factor VIII for prophylaxis-a metaanalysis. Haemophilia, 9, 251-60; LOLLAR, P. 2003. The factor VIII assay problem: neither rhyme nor reason. J Thromb Haemost, 1, 2275-9; MIKAELSSON, M. et al., 2001. Measurement of factor VIII activity of B-domain deleted recombinant factor VIII. Semin Hematol, 38, 13-23).
BDD-FVIII은 응고분석(APTT)으로 측정한 활성이 chromogenic assay(CS)로 측정한 활성보다 50%까지 낮은 반면 전장 형태의 FVIII은 두 가지 측정값이 유사한 것으로 나타났다 (BARROWCLIFFE et al., SEMIN THROMB HEMOST, vol. 28(3), 2002: 47 - 56). Clotting assay에서 BDD의 낮은 활성은 실제 long-term prophylaxis에서 BDD-FVIII이 전장 FVIII 보다 A형 혈우병 환자의 출혈을 예방하지 못하는 이유로 제기되고 있다 (GRUPPO, R. A., et al., 2003. Comparative effectiveness of full-length and B-domain deleted factor VIII for prophylaxis--a metaanalysis. Haemophilia, 9, 251-60; GRUPPO, R. A. et al., 2004. Meta-analytic evidence of increased breakthrough bleeding during prophylaxis with B-domain deleted factor VIII. Haemophilia, 10, 747-50; GRUPPO, R. A. et al., 2004. Increased breakthrough bleeding during prophylaxis with B-domain deleted factor VIII-a robust metaanalytic finding. Haemophilia, 10, 449-51).
따라서 본원에서는 전장 재조합 FVIII와 유사한 수치의 비(specific)활성(CS, APTT)과 비활성 비율(APTT/CS)을 갖는 scFVIII을 선정하기 위하여 실시예 1-1에서 구축된 각각의 scFVIII에 대해 CS와 clotting assay(APTT)로 측정한 비활성 수치와 비활성 비율((APTT)/CS)을 분석하였으며, 이를 scFVIII을 선정하는 기준으로 사용하였다. 비교군으로는 실제 생체 내의 FVIII와 유사한 전장, 이쇄 형태의 재조합 FVIII(Advate®, Baxalta) 제품을 비교 기준으로 사용하였다.
구체적으로 본원에서 사용한 FVIII 활성 측정 시험 방법은 one-stage method와 chromogenic method 두 가지이다. One-stage method는 FVIII deficient plasma, activator, phospholipids와 FVIII 시료를 섞어 준 후, 혈액응고 시간을 측정하여 시료의 FVIII 활성을 측정하는 방법이다. Chromogenic method는 FIXa, FX, thrombin, calcium, phospholipids와 FVIII 시료를 섞어 준 후, FVIII 시료에 의해 활성화된 FXa의 양을 측정하기 위해 FXa에 의해 잘리면서 발색하는 chromogenic substrate를 넣어주고, chromogenic substrate의 발색 정도에 따라 FVIII의 활성을 측정하는 방법이다. 이 두 방법의 차이는 one-stage method는 FVIII deficient plasma를 이용하고, 응고(clotting) 시간을 측정하는 것인데, chromogenic method는 FVIII deficient plasma를 이용하는 것이 아닌, FVIII의 activation에 필요한 인자와 활성화된 FVIII을 측정하기 위한 기질만 넣어준 후, 기질의 발색 정도를 측정하는 것이다.
One-stage method에 의한 활성 측정은 ACL TOP CTS 500 장비에 미리 만든 자동화된 분석법을 사용하여 다음과 같이 수행하였다. 시료를 FVIII deficient plasma를 사용하여 1 IU/mL 농도로 희석하고, 표준품은 NIBSC FVIII standard vial에 1mL 증류수를 넣어 녹인 후, FVIII deficient plasma를 사용하여 1 IU/mL 농도로 희석하여 준비하였다. 실험 장비의 rack type에 맞추어 소모 시약 및 측정 시료를 준비하였다. ACL TOP CTS 500 장비의 R rack에 순차적으로 calcium chloride vial을 바코드가 인식되도록 놓고, APTT-SP vial에는 magnetic stirring bar를 넣은 후, vial의 바코드가 인식되도록 R rack에 놓았다. FVIII deficient plasma는 측정 시료 개수 × 400μL를 준비하여 vial이 인식되지 않도록 주변부를 테이프를 붙이고 R rack에 놓았다. DA rack에는 G.O. buffer (Imidazole 3.4g, NaCl 5.8g, 1L, pH 7.4) 50mL에 알부민 2.63mL을 첨가한 vial을 놓았다. Sample cup에 앞에서 준비한 시료와 표준품을 400μL 이상 넣은 후, sample rack에 sample cup을 놓는다. ACL TOP program에서 미 인식된 시약 및 측정 시료의 정보를 입력하고, 미리 만든 자동화된 분석법을 실행하였다. 자동화 분석법의 모든 반응은 37도에서 다음과 같이 진행되었다. 우선 측정할 시료를 G.O 버퍼로 10배 pre-dilution 후 각각을 1, 3, 10배 더 희석하여 100%, 33,33%, 10% 시료를 만든다. 희석한 시료 50μL를 30-45초간 정치한 후 50μL FVIII deficient plasma와 섞어 준 후 60-70초간 정치시켰다. 다음 50μL (intermediate reagent) APTT-SP를 첨가 후 300-340초 정치하고 마지막으로 50μL start reagent (APTT-SP CaCl2)를 첨가한 후 응고 시간을 측정하였다.
Chromogenic method에 의한 활성 측정은 CHROMOGENIX(社)에서 판매하고 있는 chromogenic assay kit를 endpoint 방법으로 사용하였고, 제조사가 제공한 시험방법을 다음과 같이 본 시험에 적합하게 변형하여 시험을 진행하였다. 구체적으로 시료를 1× 희석버퍼를 사용하여 standard range (0.25-1 IU/mL)에 들어오도록 희석한다. 표준품(calibration plasma)을 0, 0.25, 0.5, 1 IU/mL 농도가 되게 1x 희석버퍼를 이용하여 준비하였다. 이렇게 준비한 시료와 표준품 10μL를 1x 희석버퍼 790μL로 희석한 후, 96 well plate에 50μL씩 분주하고, 37℃에서 5분간 정치하였다. Automatic dispenser pipette을 사용하여 factor reagent를 50μL 씩 각 well에 분주한 후 37℃에서 2분간 정치하여 발색시켰다. 발색된 시료에 50mL 2% citric acid를 넣어주어 반응을 정지하였다. 405nm 파장에서 흡광도를 측정하여 선형 calibration curve를 그린 후, 샘플의 흡광도를 calibration curve에 대입하여 시료의 활성을 측정하였다.
측정된 결과는 표 2에 기재되었다.
[표 2] 발현된 재조합 scFVIII의 활성 측정 결과
Figure 112019008914961-pct00002
발현결과, 배양액 중 scFVIII 발현량은 B 영역의 길이가 증가함에 따라 증가하여 B 영역의 길이가 아미노산 198개 이상인 scF4, scF5, scF6, scF7 에서는 발현량이 현저히 증가됨을 확인하였다. 또한 B 영역의 길이가 아미노산 92개 이상인 scF3, scF4, scF5, scF6, scF7 에서는 비교 기준으로 사용한 재조합 형태의 전장의 FVIII (Advate®, Baxalta 제품)과 유사 수준의 비활성을 보였고 APTT/CS 비율에 있어서도 기준으로 사용한 Advate®와 유사하였다. 반면 scFVIII의 B 영역 길이가 상기 실시예의 scF1, scF2, scF3 같이 128개 아미노산 단백서열 길이보다 짧은 경우 발현량이 현저히 낮았으며 B 영역 길이가 상기 실시예의 scF1, scF2 같이 84개 아미노산 단백서열 길이보다 짧은 경우 비활성이 비교 기준으로 사용한 전장의 FVIII인 Advate® 보다 현저히 낮았다.
단쇄 FVIII은 활성화 단계에서 중쇄와 경쇄를 연결하는 B 영역을 포함하는 부위에서 트롬빈 절단에 의해 활성화된다. 중쇄와 경쇄의 연결 부위인 B 영역의 길이가 짧을 경우 짧은 연결체 길이에 의한 구조적 제한으로 단쇄 FVIII이 트롬빈에 의해 활성형 FVIII으로 전환이 정상적이지 않아 활성에 영향을 줄 것으로 판단된다. 그러나 이쇄 FVIII의 경우는 이와 같은 구조적 제한이 없어 B 영역의 길이에 상관없이 트롬빈에 의한 활성화가 원활할 것으로 판단되며 이는 기존의 B 영역이 완전 제거된 이쇄 FVIII의 활성이 B 영역을 포함하는 전장의 FVIII의 활성과 유사하다는 것으로부터 알 수 있다. 본원에서는 예기치 않은 노력을 통하여 단쇄 FVIII의 B 영역의 길이와 서열을, 트롬빈 활성화에 영향을 주지 않도록 선정하여 중쇄와 경쇄 사이의 트롬빈 활성화 부위(1689-1690 및 740-741; 서열번호 1의 서열 기준)가 천연형(즉 야생형)의 FVIII와 유사하게 활성화되어 비활성이, 비교로 사용한 전장의 FVIII외 유사한 단쇄 FVIII을 수득하였다.
실시예 1-3. 구축된 scFVIII 발현 패턴 분석
본원에 구축된 단쇄 FVIII의 배양에서의 안정성은 웨스턴블랏 분석을 통해 확인하였다.
이를 위해 배양액과 LDS sample buffer를 각각 3:1의 비율로 혼합하여 4-12% bis-tris(BT) 젤에 혼합한 시료 30μL를 로딩한 후 150 volt로 약 1시간 동안 러닝하였다. 러닝이 완료된 젤을 Nitrocellulose(NC) 막에 전달한 후, blocking 버퍼(Thermo Scientific)에 한 시간 정치하였다. 이어 FVIII의 heavy chain (GMA-012, Green Mountain Antibodies) 및 light chain (ab41188, Abcam)을 인식하는 1차 항체를 TBST 버퍼에 희석하여 제조한 후, blocking이 완료된 NC 막에서 넣어 주고 1시간 반응을 수행하였다. 이어 TBST 버퍼를 사용하여 5분 간격으로 3회 세척 후, TBST 버퍼로 희석된 2차 항체(Goat anti-mouse IgG-HRP conjugate)를 NC membrane와 10분간 반응시켰다. 이후 TBST 버퍼를 사용하여 5분 간격으로 5회 세척하였다. 이어 ECL Prime Western Blotting Detection Reagent을 뿌려주어 NC 막을 발색시킨 후, 암실에서 Hyperfilm ECL (GE healthcare)에 막을 현상하였다. 결과는 도 3에 기재된 바와 같이, 단쇄 형태로 제작된 FVIII은 모두 단쇄 형태로 발현되는 것을 확인하였다. 또한 배양액으로 분비된 단쇄 FVIII은 B 영역의 길이가 짧을수록 배양액에서 분해가 덜하여 더 안정한 것으로 나타났다. 상기 실시예에서와 같이 B 영역의 길이가 비교적 짧은 scF1, scF2, scF3의 안정성은 scF4, scF5, scF6, scF7 보다 우수하나 상대적으로 발현량이 낮거나 또는 비활성이 낮았다.
본원에서는 천연형의 이쇄 FVIII으로부터 유래한 다양한 길이의 B 영역을 갖는 단쇄 FVIII을 제작하고 그 특성을 분석하였으며 B 영역의 길이가 발현량, 비활성, 안정성에 미치는 영향을 평가하여 천연형의 FVIII과 활성 특성과 유사하고 발현량이 높은 재조합 단쇄 FVIII을 제작할 수 있었다.
실시예 2. scFVIII의 페길화
페길화 위치 선정
B 영역의 일부를 포함하는 단쇄 FVIII에서 B 영역의 서열과 길이는 FVIII 활성 특성에 영향을 주어 재조합 혈액응고 FVIII의 활성과 특성에 영향을 줄 수 있기 때문에, 본 실시예에서는 천연형 이쇄 FVIII의 활성 특성을 보존할 수 있는 길이와 서열의 B 영역으로 구성된 실시예 1에서 제작된 scFVIII을 기본으로 체내 지속성을 부여하기 위하여 페길화 위치를 선정하였다.
B 영역내 페길화 반응 효율의 최적화를 위하여 B 영역의 여러 위치에서 페길화를 진행하였다. 페길화는 단백질의 표면 잔기를 대상으로 하기 때문에 페길화 위치를 선정하기 위해서는 B 영역의 3차원 구조가 필요하나, B 영역은 그 구조가 알려져 있지 않아 페길화 위치를 선정하는데 어려움 있었다. 본원에서 선정한 B 영역의 페길화 위치는 B 영역의 당쇄 주위를 선택적으로 페길화 하였다. 즉 당쇄는 단백질 구조의 밖에 위치하여 B 영역의 당쇄 주위 잔기는 항상 밖으로 향할 확률이 높아 페길화에 유리할 것으로 판단되었다. 그러나 당쇄에 밀접할수록 잔기는 당쇄에 의한 입체적 방해(steric hindrance)에 의해 PEG의 접근이 방해받아 페길화가 어려울 수 있는 문제점이 있었다. 본원에서는 예기치 않은 노력을 통해 당쇄로부터 적정 거리에 위치하여 B 영역의 단백 구조에서 밖으로 향하는 동시에 당쇄에 의해 steric hindrance를 받지 않아 페길화 효율이 보장되는 당쇄 근처의 잔기를 선정하였다.
본 실시예에서는 표 3 및 도 4에 기재된 바와 같이 실시예 1에서 구축된 G4를 기준으로 B 영역의 당쇄 사슬 근처, 즉, N-당쇄 기준으로 +6, -6 잔기 사이의 다양한 위치에 시스테인이 도입된 재조합 scFVIII 변이체를 제작하고 도입된 시스테인에 선택적으로 페길화를 진행하였다. 이러한 페길화는 G4, single-chain FVIII를 대상으로 설명하였으나 동일한 논리로 본원에서 구축된 당쇄를 포함하는 다른 scFVIII의 페길화에도 적용될 수 있다.
실시예 2-1. 특정 부위가 시스테인으로 치환된 scFVIII 발현 벡터 제작
시스테인 치환 부위 및 FVIII heavy chain의 A2 영역 내에 존재하는 BamHI site (GGATCC)부터 light chain과 PacI 효소절단 부위가 포함되도록 GeneArt 사를 통해 유전자를 합성한 후 실시예 1-1에 제작된 발현벡터 pcDSW-scFVIII G4에 효소 BamHI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 BamHI/PacI site에 클로닝 하여 cysteine이 치환된 pcDSW-scFVIII G4 (B1, B2, B3, B4, B5, B6, B7, A3-1 또는 4L) 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 서열분석을 통해 확인하였다. 그 외에 cysteine이 도입된 scFVIII G4 (A2-1, A2-2 또는 A2-3)은 cysteine 치환 부위를 포함하는 FVIII heavy chain의 A1 영역에 존재하는 AsisI 효소절단 부위부터 A2 영역 내에 존재하는 KpnI site (GGTACC)까지 GeneArt 사를 통해 유전자를 합성한 후 실시예 1-1에서 제작된 발현벡터 pcDSW-scFVIII G4에 효소 AsisI/KpnI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 AsisI/KpnI 부위에 클로닝 하여 cysteine이 치환된 pcDSW-scFVIII G4 (A2-1, A2-2 또는 A2-3)발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 서열분석을 통해 확인하였다.
상기 구축된 cysteine이 도입된 mscFVIII 발현 벡터를 이용하여 실시예 1-2와 동일하게 일시 발현(transient expression)을 실시하였다. 각각의 시스틴 도입 FVIII의 발현량은 하기 표 3에 기재되어 있다. 표 3에서와 같이 cysteine이 B 영역의 glycan 사슬 주위에 도입된 scFVIII 변이체는 정상적으로 배양액에 발현되는 것으로 나타났다. 발현량은 cysteine 도입 이전의 scFVIII 보다 다소 낮은 수준이었으며 이는 scFVIII에 도입된 cysteine이 발현 과정 및 배양액 내에서 scFVIII의 안정성에 영향을 주기 때문인 것으로 생각된다.
실시예 2-2. 페길화
페길화 위치를 스크리닝하기 위해 실시예 2-1에서와 같이 Cysteine이 도입된 scFVIII 변이체의 페길화는 다음과 같이 수행되었다. 세포 배양액 50mL을 5kDa MWCO (분자량 cutoff)로 20배 농축한 후, 최종 1M NaCl 되게 5M NaCl conc solution 첨가. 평형 버퍼 (20mM Histidine, 500mM NaCl, 0.1%(w/v) Tween®80, pH 7.0)로 평형화된 0.1mL 부피의 V8 select resin (GE 사)과 농축 시료를 충분히 함께 교반한 후 평형 버퍼로 세척 후 용출 버퍼 (20mM Histidine, 500mM NaCl, 0.1%(w/v) Tween®80, pH 7.0, 50%(v/v) propylene glycol)로 용출하였다. 용출된 시료는 5kDa MWCO 막을 사용하여 pegylation 버퍼 (20mM Histidine, 500mM NaCl, 0.1%(w/v) Tween®80, pH 7.0, 5%(w/v) sucrose)로 교환한 후 TCEP를 최종 0.2mM 처리하여 1시간 동안 4도에서 반응하였다. 이어 반응물의 TCEP를 제거하기 위해 페길화 버퍼 (20mM Histidine, 500mM NaCl, 0.1%(w/v) Tween®80, pH 7.0, 5%(w/v) sucrose)로 탈염 후, maleimide PEG 40kDa (NOF 사)를 1:20 몰비 (scFVIII : maleimide PEG 40kDa)로 첨가하여 1시간 동안 4도 조건에서 반응하였다.
Cysteine이 도입된 scFVIII 변이체는 세포 배양을 통한 발현 시 도입된 cysteine이 cysteine 이나 glutathione에 의해 disulfide bond로 masking 되므로 페길화를 위해서는 masking 하고 있는 cysteine과 glutathione을 제거해야 한다. 본원에서는 도입된 cysteine의 자유 티올기를 masking 하고 있는 cysteine 이나 glutathione을 이탈시키기 위하여 TCEP(tris(2-carboxyethyl)phosphine)를 처리 후 탈염 컬럼(PD10)을 통하여 TCEP를 제거한 후 cysteine에 특이적인 maleimide-PEG (40kDa)를 처리하여 페길화 하였다.
페길화 정도를 분석하기 위하여 페길화 반응물에 대한 SDS PAGE를 수행하였다.
결과는 도 6에 기재되어 있다. Cysteine이 도입된 G4scFVIII 변이체는 배양액 내에 활성 형태로 발현되었고 페길화가 용이하게 진행됨을 확인하였다. Cysteine 도입 위치에 따라 발현량과 페길화율에 차이가 있었으며 이는 도입된 cysteine 위치에 따라 FVIII의 안정성과 페길화 반응에 차이가 있기 때문인 것으로 생각된다.
[표 3] scFVIII 접합부위가 cys로 치환된 mutant 발현량 및 페길화 효율
Figure 112019008914961-pct00003
*: 상기 표 3의 잔기는 서열번호 1의 서열을 기준으로 함
실시예 3. 페길화 scFVIII 생산
본 실시예에서는 실시예 2에서 선정된 위치에 페길화된 scFVIII를 다음과 같이 생산하였다. 또한 페길화 scFVIII을 생산하고 체내 지속형 혈액 응고 FVIII으로서의 활성과 페길화가 혈액 응고 FVIII의 활성에 미치는 영향을 평가하였다. G4, scFVIII의 B 영역 부위의 782번째 isoleucine이 cysteine으로 치환된 scFVIII인 B3의 위치 특이적 페길화 접합물을 생산 후 CS와 OS (APTT) 방법으로 활성을 측정하였고 이쇄 형태의 재조합 혈액 응고 FVIII인 Advate®와 비교하였다.
실시예 3-1. 세포 배양
실시예 2-1에서 구축된 cysteine이 도입된 scFVIII G4 (B3)과 scFVIII G4 (A2_1)를 각각의 세포에서 발현하고 배양하였다. 구체적으로 우선 발현을 위해 실시예 2-1에서 구축된 발현 벡터를 Expi293F™ 세포에 Expi293F™ Expression System Kit (Thermofisher 사, Catalog Number A14635)을 제조자의 방법대로 사용하여 전달 이입하였다. 요약하면, 형질전환시 세포 수와 세포 생존율(viability)을 측정하여 세포 생존율이 95% 이상일 경우 형질전환을 진행하였다. 125mL flask에 7.5 X 107 cell 되도록 Expi293 배양배지를 첨가하여 25.5mL로 맞춰주었다. 실시예 2-2에서 구축된 발현 벡터 30μg를 Opti-MEM을 이용하여 총 볼륨이 1500μL이 되도록 섞어주었다. 80μL transfection reagent를 Opti-MEM을 이용하여 총 볼륨이 1500μL이 되도록 섞어주고 상온에서 5분간 배양하였다. 5분 후 transfection reagent가 들어있는 Opti-MEM을 DNA가 들어있는 Opti- MEM에 넣어주고 부드럽게 섞어주었다. 그리고 20~30분간 상온에서 반응시켜 주었다. 3mL의 DNA : transfection reagent 복합체를 미리 준비해 놓은 125mL flask Expi293F™ 세포에 (Total volume: 28.5mL)에 한 방울씩 떨어뜨려주고 37℃, 5% CO2 shacking incubator에서 125 rpm으로 배양하였다. 16~20시간 후에 Enhancer 1과 Enhancer 2를 각각 150μL, 1.5mL을 넣어주고 34℃, 5% CO2 교반인큐베이터에서 125 rpm으로 배양하였다. 배양 2일째 세포를 모두 원심분리하여 기존의 배양배지를 완전히 제거하고 30mL의 새로운 배양배지에 세포를 모두 풀어준 후 34℃, 5% CO2 shacking incubator에서 125 rpm으로 배양하였다. 도입 3일 차에 scFVIII를 발현하는 세포를 모두 원심 분리하여 배양액을 회수하였다. 배지 회수 후 남은 세포를 동일한 부피의 새로운 배양배지에 세포를 모두 풀어준 후 1일간 34℃에서 배양을 실시하였다. 본 과정을 배양 5일차까지 반복하여 3일, 4일, 5일 배양액을 회수하여 cysteine 도입된 scFVIII의 활성 분석 및 정제를 진행하였다.
실시예 3-2. 페길화 및 정제
페길화 및 정제 공정은 크게 5단계로 구성되어 있으며, 실시예 3-1에서 배양한 3, 4, 5일차 배양액을 풀링(pooling)하여 정제를 진행하였다.
첫 번째 단계에서는 배양액에서 FVIII을 분리정제 하는 공정으로 FVIII 정제용으로 GE에서 개발한 VIIISelect resin을 이용하였다. VIIISelect resin을 컬럼에 패킹한 후, 2% citric acid로 컬럼을 세척하였다. 평형 버퍼 (20mM Histidine, 5mM CaCl2, 1M NaCl, 0.02% Tween®80, pH 7.0)를 흘려주어 평형을 잡았다. 풀링한 배양액에 최종 1M NaCl 농도가 되도록 5M NaCl 버퍼를 넣어주고, pH를 7.0으로 적정한 후, 컬럼에 로딩하였다. 배양액 로딩 후, 평형 버퍼를 UV가 baseline으로 떨어질 때까지 흘려주어 평형을 잡았다. 용출 버퍼 (20mM Histidine, 5mM CaCl2, 0.9M Arginine, 45% propyleneglycol, 0.02% Tween®80, pH 6.5)를 흘려주어 scFVIII을 용출하였다.
이어 두 번째 단계에서는 첫 번째 단계의 용출액에 섞여 있는 propylene glycol을 빠른 속도로 제거해주는 공정으로 GE사의 SP fast flow resin을 이용하였다. SP fast flow resin을 컬럼에 패킹한 후, 세척 버퍼 (0.5M NaOH, 1M NaCl)를 흘려주어 컬럼을 세척한다. 평형 버퍼 (20mM Histidine, 5mM CaCl2, 0.02% Tween®80, pH 7.0)를 흘려주어 평형을 잡았다. VIIISelect 공정의 용출액을 평형 버퍼로 10배 희석한 후, pH를 7.0으로 적정하고, 컬럼에 로딩하였다. 로딩 후, 평형 버퍼를 UV가 baseline으로 떨어질 때까지 흘려주어 평형을 잡았다. 용출 버퍼 (20mM Histidine, 5mM CaCl2, 400mM NaCl, 0.02% Tween®80, pH 6.5)를 흘려주어 scFVIII을 빠르게 용출하였다.
세 번째 단계에서는 정제한 scFVIII에 PEG를 접합시켜 주는 공정이다. 정제된 scFVIII 용액에 최종농도가 0.1mM이 되도록 TCEP를 첨가한 후 4℃에서 1시간 정치시켜 삽입한 cysteine을 환원시켰다. 페길화 버퍼 (20mM Histidine, 5mM CaCl2, 200mM NaCl, 0.02% Tween®80, pH 7.0)로 평형이 잡힌 PD-10 컬럼(GE healthcare)을 사용하여 잔존 TCEP를 제거하였다. 환원된 FVIII 자체의 이황화 결합을 산화시켜주기 위하여 4℃에서 2시간 정치하였다. scFVIII G4 (B3)의 PEG 접합은 DMSO에 녹인 40kDa 크기의 branched 형태의 methoxy maleimide PEG 용액 (50mg/mL)을 단백질 당 PEG 비율을 1:20이 되도록 넣어준 후 4℃에서 12-16시간 정치하였다. scFVIII G4 (A2_1) PEG 접합은 60kDa 크기의 branched 형태의 methoxy maleimide PEG를 사용하여 동일하게 진행하였다.
이어 네 번째 단계에서는 PEGylation 과정 중에 생긴 impurity인 PEG가 붙지 않은 scFVIII과 PEG가 2개 이상 붙은 scFVIII을 제거하는 공정으로 GE사의 SP fast flow resin을 이용하였다. SP fast flow resin을 컬럼에 패킹한 후, 세척 버퍼 (0.5M NaOH, 1M NaCl)를 흘려주어 컬럼을 세척하였다. 평형 버퍼 (20mM Histidine, 5mM CaCl2, 0.02% Tween®80, pH 7.0)를 흘려주어 평형을 잡았다. PEGylation 공정의 용출액을 평형 버퍼로 10배 희석한 후, pH를 7.0으로 적정하고, 컬럼에 로딩하였다. 로딩 후, 평형 버퍼를 UV가 베이스라인으로 떨어질 때까지 흘려주어 평형을 잡았다. 용출 버퍼 (20mM Histidine, 5mM CaCl2, 50-400mM NaCl, 0.02% Tween®80, pH 6.5)의 NaCl 농도를 단계별로 올려 주며, PEG-scFVIII을 선택적으로 용출하였다.
마지막으로 다섯 번째 단계에서는 네 번째 단계에서 용출한 PEG-scFVIII을 농축하는 공정으로, 이를 위해 Millipore사의 amicon 30kDa를 이용하여 25 IU/mL 농도가 되게 농축을 하였다.
실시예 3-3. 활성 측정
실시에 3-2에서 사용한 정제된 페길화 scFVIII (PEG-scFVIII-B3, PEG-scFVIII-A2-2)의 활성은 CS와 APTT 방법으로 측정하였다. CS 시험법은 실시예 1-2에 기재된 방법과 동일하게 수행하였고 APTT 시험법은 실시예 1-2에 기재된 방법을 변형하여 진행하였다. APTT 방법으로 페길화 FVIII의 활성 측정 시 활성제(activator)로 colloidal silica 계열의 APTT-SP를 사용하면 본래의 활성보다 낮은 활성 값이 분석되고 ellagic acid 계열의 synthAFax (IL) 사용하면 정상적인 활성이 측정된다고 알려져 있다 (Gu. J. M. et al., 2014. Evaluation of the activated partial thromboplastin time assay for clinical monitoring of PEGylated recombinant factor VIII (BAY 94-9027) for haemophilia A. Haemophilia, 20, 593-600). 페길화 scFVIII 특성을 고려하여 APTT 시험 시 활성제로 synthAFax를 사용하였고 그 외 시험법은 실시예 1-2와 동일한 방법을 사용하였다. 결과는 표 4에 기재되어 있다.
[표 4]
Figure 112019008914961-pct00004
실험 결과, PEG-scFVIII-B3, PEG-scFVIII-A2-2은 비교물질로 사용한 전장의 B 영역을 포함하는 이쇄(two chain) FVIII인 Advate® 대비 APTT/CS 비율이(APTT/CS) 유사하였고 B 영역이 제거된 이쇄 FVIII인 Xyntha와 APTT/CS 비율이 상이함을 확인하였다. 이는 천연형의 FVIII의 활성이 CS와 APTT에서 거의 동일한 것을 고려할 때 본원에서 제작된 scFVIII 단백질은 단쇄화와 페길화에 의해 혈액 응고 FVIII의 활성 특성에 변화가 초래되지 않았음을 나타내는 것이다. Xyntha는 B-domain이 완전히 제거된 이쇄 재조합 FVIII으로 본 실시예에서 혈액응고 활성(APTT)이 CS에 비하여 감소하였으며 이는 혈액응고 활성이 B 영역의 완전 제거 시 감소된다는 기존의 보고와 상통한다. PEG-scFVIII-B3과 PEG-scFVIII-A2-2은 단쇄화 및 페길화 이후에도 혈액응고 활성이 유지되는 것을 고려할 때 본원에 따른 이 두 물질은 혈우병 치료제로서 장점을 갖는 것으로 판단된다.
실시예 4. 동물 PK 시험
상기와 같이 페길화 scFVIII의 체내 반감기를 펜실바니아 대학에서 분양받아 번식하며 genotyping으로 확인된 11-12주령의 혈우병 A형 마우스 모델 (B6;129S4-F8tm1Kaz/J(FVIII-knock-out))에서 비교물질인 Advate®와 비교하였다. 시험 물질은 scFVIII인 G4, G4의 B 영역 부위의 782 isoleucine이 cysteine으로 치환된 후 40kDa branched PEG maleimide로 위치 특이적 페길화가 된 PEG40kDa-G4scFVIII-B3 (실시예 3 참조), G4의 A2 영역의 495번째 valine이 cysteine으로 치환된 후 60kDa branched PEG maleimide로 위치 특이적 페길화된 PEG60kDa-G4scFVIII-A2-2 그리고 이쇄의 재조합 FVIII인 Advate®이다.
약물 약동학에 사용된 시험 동물은 혈우병 마우스(female)로 각 시료당 3마리의 혈우병 마우스에 125 IU/kg 수준으로 tail 정맥에 투여하였다. 투여 후 시간 별로(5min, 4hr, 8hr, 16hr, 24hr, 32hr, 40hr, 48hr, 56hr, 72hr) 혈액을 안와로부터 채취하여 항 응고제(3.2% sodium citrate)를 10% 처리한 후 원심 분리하여 혈장을 분리하였다. 혈장 내 존재하는 FVIII의 활성은 실시예 1-2에 기재된 바와 같이 CS assay 측정 시약을 사용하여 측정하였다. 시간별로 각 시료 군의 마우스로부터 채취한 혈장 내 FVIII 활성의 평균의 profile은 도 7과 같다.
PK parameter 분석은 혈장 내 FVIII CS 활성 측정값의 평균과 표준 편차를 WinNonlin software를 이용하여 NCA(Non Compartmental Analysis) 방법을 통해 산출하였으며 그 결과는 표 5와 같다. 약물의 반감기는 B3 ≒ A2-2 > G4 > Advate® 순으로 나타났다(표 5). Mean data를 기준으로 판단했을 때, 약물의 반감기는 Advate® 기준으로 B3는 약 1.9배, A2-2는 약 1.8배, G4는 약 1.2배 정도 증가 되었다 (표 5).
[표 5] PK 결과
Figure 112019008914961-pct00005
실시예 5. 동물 PD 시험 (Long-term)
마우스에서 tail bleeding의 응고 효과를 다음과 같이 측정하였다.
실험개요는 도 8a에 기재된 바와 같다. 구체적으로 11-12주령의 수컷 C57BL/6 mouse(오리엔트 바이오 공급) 및 11-12주령의 펜실바니아 대학에서 분양받아 번식하며 genotyping으로 확인된 혈우병 A형 마우스 (B6;129S4-F8tm1Kaz/J(FVIII-knock-out), FVIII KO mice)를 시험에 사용하였다. C57BL/6 mouse는 7일 동안 순화과정을 거쳤다. 시험 당일, 15mL conical tube(1개/마리)에 saline을 14mL까지 채우고, 가열된 수조에 담가서 saline의 온도가 37℃가 되도록 맞추었다. 시험물질 투여 전 mouse의 체중을 측정하여 기록하였다. 엔토발(Pentobarbital Sodium)을 60mg/kg의 농도로 복강 내 투여하여 mouse를 마취하였다. 마우스 체중대비(마우스 체중은 19-25g 사이임) 시험 물질 투여량을 계산한 후, jugular vein으로 시험물질을 정맥 투여하였다. 투여 5분 후에 마우스 꼬리를 끝에서 4mm 절단한 후, 즉시 saline이 담긴 conical tube에 꼬리를 약 2cm 담그고, 30분간 유지시켜 혈액을 수집하였다.
시험 물질은 실시예 3에서 제조된 PEG-scFVIII-B3로 Advate®와 비교하였다. 투여량(투여량 및 투여 부피) 그리고 각 시험 물질 군에 포함된 마우스의 배분은 아래 표 6과 같다.
[표 6]
Figure 112019008914961-pct00006
각 마우스 별로 30분간 모은 혈액을 1500 x g에서 5분간 원심 분리하여 상층액을 제거한 후, 10mL pipet을 이용하여 conical tube에 3차 증류수를 10mL까지 넣은 후 vortex를 이용하여 혈액을 완전히 용혈시켰다. Blood loss 측정은 Hemoglobin assay kit(sigma, MAK115-1KT)에서 제공하는 매뉴얼에 따라 수행하였다. 요약하면, 1.5mL eppendorf tube에 3차 증류수 0.9mL과 용혈 샘플 0.1mL을 넣고 잘 섞어서 10배 희석한 후 96 well plate에 50μL의 3차 증류수 와 50μL의 calibrator를 넣고 (duplication) 그 위에 200μL의 3차 증류수를 넣었다. 각 마우스 용혈 샘플 50μL을 well에 넣고 (duplication), 그 위에 reagent 200μL을 넣었다. 넣은 물질들이 잘 섞일 수 있도록 96 well plate를 가볍게 두드린 후 Multimode plate reader를 이용하여 400nm에서 흡광도를 측정하였다.
흡광도 측정값은 GraphPad Prism ver 5.01의 One way ANOVA with Dunnett’s multiple comparison test를 사용하여 blood loss 값(Hb nmol)을 통계적으로 비교하였다. p-value가 0.05보다 클 경우, 통계적으로 유의한 차이가 아니라고 평가하고, p-value가 0.05보다 작을 경우, 통계적으로 유의한 차이라고 평가하였다.
시험 결과 40kDaPEG-G4scFVIII-B3 및 Advate® 50, 100, 200 IU/kg 투여군의 blood loss 값은 HA군의 blood loss 값과 비교 시, 모두 통계적으로 유의한 차이를 보였으며, HA mouse에 40kDaPEG-G4scFVIII-B3과 Advate®를 투여한 후, acute tail-clipping test를 진행한 결과 두 시험 물질 모두 농도 의존적으로 blood loss의 양을 감소시키는 것으로 나타났다 (도 8b 참조).
정리하면 본원에서는 발현이 우수하고 천연 FVIII 활성을 최대한 보유하고 안정하여 배양액에서 분해가 방지되는 scFVIII을 선정하기 위하여 다양한 길이와 서열의 B 영역을 포함하는 scFVIII을 제작하고 발현한 후 활성을 측정하고, 안정성을 확인하는 과정을 통하여 혈우병 A형 치료제로서 유용한 특성을 보유한 scFVIII을 개발하였다. 또한 본원에서 개발한 scFVIII을 바탕으로 다양한 페길화 접합체를 제작하여 체내 반감기가 향상되어 치료제로서 유용성이 향상된 FVIII 페길화 접합체를 개발하였다.
이상에서 본원의 예시적인 실시예에 대하여 상세하게 설명하였지만 본원의 권리범위는 이에 한정되는 것은 아니고 다음의 청구범위에서 정의하고 있는 본원의 기본 개념을 이용한 당업자의 여러 변형 및 개량 형태 또한 본원의 권리범위에 속하는 것이다.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본 발명에 도입된다.
<110> Mogam Institute for Biomedical Research <120> Recombinant single chain Factor VIII and chemical conjugates thereof <130> PCT201705003 <150> KR 2016-0079442 <151> 2016-06-24 <160> 48 <170> KopatentIn 2.0 <210> 1 <211> 2332 <212> PRT <213> Homo sapiens <400> 1 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met Pro Val His 900 905 910 Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys Ser Ser Pro 915 920 925 Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu Asn Asn Asp 930 935 940 Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu Ser Ser Trp 945 950 955 960 Gly Lys Asn Val Ser Ser Thr Glu Ser Gly Arg Leu Phe Lys Gly Lys 965 970 975 Arg Ala His Gly Pro Ala Leu Leu Thr Lys Asp Asn Ala Leu Phe Lys 980 985 990 Val Ser Ile Ser Leu Leu Lys Thr Asn Lys Thr Ser Asn Asn Ser Ala 995 1000 1005 Thr Asn Arg Lys Thr His Ile Asp Gly Pro Ser Leu Leu Ile Glu Asn 1010 1015 1020 Ser Pro Ser Val Trp Gln Asn Ile Leu Glu Ser Asp Thr Glu Phe Lys 1025 1030 1035 1040 Lys Val Thr Pro Leu Ile His Asp Arg Met Leu Met Asp Lys Asn Ala 1045 1050 1055 Thr Ala Leu Arg Leu Asn His Met Ser Asn Lys Thr Thr Ser Ser Lys 1060 1065 1070 Asn Met Glu Met Val Gln Gln Lys Lys Glu Gly Pro Ile Pro Pro Asp 1075 1080 1085 Ala Gln Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Glu 1090 1095 1100 Ser Ala Arg Trp Ile Gln Arg Thr His Gly Lys Asn Ser Leu Asn Ser 1105 1110 1115 1120 Gly Gln Gly Pro Ser Pro Lys Gln Leu Val Ser Leu Gly Pro Glu Lys 1125 1130 1135 Ser Val Glu Gly Gln Asn Phe Leu Ser Glu Lys Asn Lys Val Val Val 1140 1145 1150 Gly Lys Gly Glu Phe Thr Lys Asp Val Gly Leu Lys Glu Met Val Phe 1155 1160 1165 Pro Ser Ser Arg Asn Leu Phe Leu Thr Asn Leu Asp Asn Leu His Glu 1170 1175 1180 Asn Asn Thr His Asn Gln Glu Lys Lys Ile Gln Glu Glu Ile Glu Lys 1185 1190 1195 1200 Lys Glu Thr Leu Ile Gln Glu Asn Val Val Leu Pro Gln Ile His Thr 1205 1210 1215 Val Thr Gly Thr Lys Asn Phe Met Lys Asn Leu Phe Leu Leu Ser Thr 1220 1225 1230 Arg Gln Asn Val Glu Gly Ser Tyr Asp Gly Ala Tyr Ala Pro Val Leu 1235 1240 1245 Gln Asp Phe Arg Ser Leu Asn Asp Ser Thr Asn Arg Thr Lys Lys His 1250 1255 1260 Thr Ala His Phe Ser Lys Lys Gly Glu Glu Glu Asn Leu Glu Gly Leu 1265 1270 1275 1280 Gly Asn Gln Thr Lys Gln Ile Val Glu Lys Tyr Ala Cys Thr Thr Arg 1285 1290 1295 Ile Ser Pro Asn Thr Ser Gln Gln Asn Phe Val Thr Gln Arg Ser Lys 1300 1305 1310 Arg Ala Leu Lys Gln Phe Arg Leu Pro Leu Glu Glu Thr Glu Leu Glu 1315 1320 1325 Lys Arg Ile Ile Val Asp Asp Thr Ser Thr Gln Trp Ser Lys Asn Met 1330 1335 1340 Lys His Leu Thr Pro Ser Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys 1345 1350 1355 1360 Glu Lys Gly Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Leu Thr Arg 1365 1370 1375 Ser His Ser Ile Pro Gln Ala Asn Arg Ser Pro Leu Pro Ile Ala Lys 1380 1385 1390 Val Ser Ser Phe Pro Ser Ile Arg Pro Ile Tyr Leu Thr Arg Val Leu 1395 1400 1405 Phe Gln Asp Asn Ser Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys 1410 1415 1420 Asp Ser Gly Val Gln Glu Ser Ser His Phe Leu Gln Gly Ala Lys Lys 1425 1430 1435 1440 Asn Asn Leu Ser Leu Ala Ile Leu Thr Leu Glu Met Thr Gly Asp Gln 1445 1450 1455 Arg Glu Val Gly Ser Leu Gly Thr Ser Ala Thr Asn Ser Val Thr Tyr 1460 1465 1470 Lys Lys Val Glu Asn Thr Val Leu Pro Lys Pro Asp Leu Pro Lys Thr 1475 1480 1485 Ser Gly Lys Val Glu Leu Leu Pro Lys Val His Ile Tyr Gln Lys Asp 1490 1495 1500 Leu Phe Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu Asp Leu 1505 1510 1515 1520 Val Glu Gly Ser Leu Leu Gln Gly Thr Glu Gly Ala Ile Lys Trp Asn 1525 1530 1535 Glu Ala Asn Arg Pro Gly Lys Val Pro Phe Leu Arg Val Ala Thr Glu 1540 1545 1550 Ser Ser Ala Lys Thr Pro Ser Lys Leu Leu Asp Pro Leu Ala Trp Asp 1555 1560 1565 Asn His Tyr Gly Thr Gln Ile Pro Lys Glu Glu Trp Lys Ser Gln Glu 1570 1575 1580 Lys Ser Pro Glu Lys Thr Ala Phe Lys Lys Lys Asp Thr Ile Leu Ser 1585 1590 1595 1600 Leu Asn Ala Cys Glu Ser Asn His Ala Ile Ala Ala Ile Asn Glu Gly 1605 1610 1615 Gln Asn Lys Pro Glu Ile Glu Val Thr Trp Ala Lys Gln Gly Arg Thr 1620 1625 1630 Glu Arg Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg His Gln Arg 1635 1640 1645 Glu Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr 1650 1655 1660 Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr 1665 1670 1675 1680 Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg 1685 1690 1695 His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser 1700 1705 1710 Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro 1715 1720 1725 Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr 1730 1735 1740 Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly 1745 1750 1755 1760 Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg 1765 1770 1775 Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr 1780 1785 1790 Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys 1795 1800 1805 Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala 1810 1815 1820 Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp 1825 1830 1835 1840 Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu 1845 1850 1855 Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr 1860 1865 1870 Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser 1875 1880 1885 Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn 1890 1895 1900 Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala 1905 1910 1915 1920 Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln 1925 1930 1935 Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn 1940 1945 1950 Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys 1955 1960 1965 Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu 1970 1975 1980 Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys 1985 1990 1995 2000 Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val 2005 2010 2015 Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile 2020 2025 2030 Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro 2035 2040 2045 Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr 2050 2055 2060 Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile 2065 2070 2075 2080 Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu 2085 2090 2095 Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp 2100 2105 2110 Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly 2115 2120 2125 Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile 2130 2135 2140 Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser 2145 2150 2155 2160 Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met 2165 2170 2175 Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala 2180 2185 2190 Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala 2195 2200 2205 Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn 2210 2215 2220 Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val 2225 2230 2235 2240 Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr 2245 2250 2255 Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr 2260 2265 2270 Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp 2275 2280 2285 Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg 2290 2295 2300 Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg 2305 2310 2315 2320 Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 2325 2330 <210> 2 <211> 1467 <212> PRT <213> Artificial Sequence <220> <223> G2 (scF2) <400> 2 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp 785 790 795 800 Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp 805 810 815 Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg His 820 825 830 Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser 835 840 845 Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln 850 855 860 Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln 865 870 875 880 Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro 885 890 895 Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg Asn 900 905 910 Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu 915 920 925 Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys Pro 930 935 940 Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala Pro 945 950 955 960 Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val 965 970 975 Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu Val 980 985 990 Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr Val 995 1000 1005 Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp 1010 1015 1020 Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile 1025 1030 1035 1040 Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala Ile 1045 1050 1055 Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp 1060 1065 1070 Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile 1075 1080 1085 His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu 1090 1095 1100 Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr 1105 1110 1115 1120 Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu 1125 1130 1135 Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr 1140 1145 1150 Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg 1155 1160 1165 Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys 1170 1175 1180 Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys 1185 1190 1195 1200 Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile 1205 1210 1215 His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr 1220 1225 1230 Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln 1235 1240 1245 Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn 1250 1255 1260 Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile Ile 1265 1270 1275 1280 Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser Thr 1285 1290 1295 Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro 1300 1305 1310 Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser 1315 1320 1325 Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg 1330 1335 1340 Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn Asn 1345 1350 1355 1360 Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr 1365 1370 1375 Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val 1380 1385 1390 Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu 1395 1400 1405 Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser 1410 1415 1420 Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr 1425 1430 1435 1440 Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg Met 1445 1450 1455 Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1460 1465 <210> 3 <211> 1511 <212> PRT <213> Artificial Sequence <220> <223> G3 (scF3) <400> 3 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser 835 840 845 Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn 850 855 860 Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala 865 870 875 880 Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val 885 890 895 Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val 900 905 910 Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg 915 920 925 Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala 930 935 940 Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg 945 950 955 960 Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg 965 970 975 Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys 980 985 990 Thr Tyr Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu 995 1000 1005 Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys 1010 1015 1020 Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn 1025 1030 1035 1040 Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala 1045 1050 1055 Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu 1060 1065 1070 Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp 1075 1080 1085 Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile 1090 1095 1100 Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg 1105 1110 1115 1120 Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His 1125 1130 1135 Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met 1140 1145 1150 Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu 1155 1160 1165 Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His 1170 1175 1180 Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys 1185 1190 1195 1200 Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile 1205 1210 1215 Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu 1220 1225 1230 His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser 1235 1240 1245 Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys 1250 1255 1260 Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe 1265 1270 1275 1280 Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly 1285 1290 1295 Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser 1300 1305 1310 Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile 1315 1320 1325 Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu 1330 1335 1340 Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu 1345 1350 1355 1360 Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr 1365 1370 1375 Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln 1380 1385 1390 Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp 1395 1400 1405 Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr 1410 1415 1420 Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu 1425 1430 1435 1440 Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn 1445 1450 1455 Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val 1460 1465 1470 Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His 1475 1480 1485 Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly 1490 1495 1500 Cys Glu Ala Gln Asp Leu Tyr 1505 1510 <210> 4 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4 (scF4) <400> 4 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 5 <211> 1644 <212> PRT <213> Artificial Sequence <220> <223> G6 (scF5) <400> 5 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met Pro Val His 900 905 910 Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys Ser Ser Pro 915 920 925 Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu Asn Asn Asp 930 935 940 Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu Ser Ser Trp 945 950 955 960 Gly Lys Asn Val Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr 965 970 975 Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr 980 985 990 Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg 995 1000 1005 His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser 1010 1015 1020 Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro 1025 1030 1035 1040 Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr 1045 1050 1055 Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly 1060 1065 1070 Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg 1075 1080 1085 Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr 1090 1095 1100 Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys 1105 1110 1115 1120 Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala 1125 1130 1135 Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp 1140 1145 1150 Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu 1155 1160 1165 Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr 1170 1175 1180 Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser 1185 1190 1195 1200 Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn 1205 1210 1215 Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala 1220 1225 1230 Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln 1235 1240 1245 Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn 1250 1255 1260 Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys 1265 1270 1275 1280 Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu 1285 1290 1295 Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys 1300 1305 1310 Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val 1315 1320 1325 Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile 1330 1335 1340 Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro 1345 1350 1355 1360 Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr 1365 1370 1375 Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile 1380 1385 1390 Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu 1395 1400 1405 Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp 1410 1415 1420 Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly 1425 1430 1435 1440 Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile 1445 1450 1455 Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser 1460 1465 1470 Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met 1475 1480 1485 Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala 1490 1495 1500 Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala 1505 1510 1515 1520 Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn 1525 1530 1535 Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val 1540 1545 1550 Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr 1555 1560 1565 Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr 1570 1575 1580 Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp 1585 1590 1595 1600 Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg 1605 1610 1615 Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg 1620 1625 1630 Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1635 1640 <210> 6 <211> 1587 <212> PRT <213> Artificial Sequence <220> <223> G4_flex (scF6) <400> 6 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Ser Gln Asn Pro Pro Val Thr Leu Gln Ser 900 905 910 Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys 915 920 925 Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg 930 935 940 Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg 945 950 955 960 Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg 965 970 975 Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu 980 985 990 Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn 995 1000 1005 Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp 1010 1015 1020 Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe 1025 1030 1035 1040 Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu 1045 1050 1055 Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp 1060 1065 1070 Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys 1075 1080 1085 Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser 1090 1095 1100 Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro 1105 1110 1115 1120 Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr 1125 1130 1135 Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg 1140 1145 1150 Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys 1155 1160 1165 Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu 1170 1175 1180 Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu 1185 1190 1195 1200 Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly His 1205 1210 1215 Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn 1220 1225 1230 Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys Ala 1235 1240 1245 Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala Gly 1250 1255 1260 Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu 1265 1270 1275 1280 Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly 1285 1290 1295 Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly 1300 1305 1310 Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val 1315 1320 1325 Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala 1330 1335 1340 Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr 1345 1350 1355 1360 Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly 1365 1370 1375 Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His 1380 1385 1390 Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro 1395 1400 1405 Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys 1410 1415 1420 Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile 1425 1430 1435 1440 Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala 1445 1450 1455 Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser Asn 1460 1465 1470 Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val Asp 1475 1480 1485 Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val Lys 1490 1495 1500 Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser 1505 1510 1515 1520 Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val Lys 1525 1530 1535 Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu 1540 1545 1550 Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp 1555 1560 1565 Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala Gln 1570 1575 1580 Asp Leu Tyr 1585 <210> 7 <211> 1644 <212> PRT <213> Artificial Sequence <220> <223> G6_opt (scF7) <400> 7 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met Pro Val His 900 905 910 Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys Ser Ser Pro 915 920 925 Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu Asn Asn Asp 930 935 940 Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu Ser Ser Trp 945 950 955 960 Gly Lys Asn Val Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr 965 970 975 Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr 980 985 990 Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg 995 1000 1005 His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser 1010 1015 1020 Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro 1025 1030 1035 1040 Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr 1045 1050 1055 Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly 1060 1065 1070 Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg 1075 1080 1085 Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr 1090 1095 1100 Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys 1105 1110 1115 1120 Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala 1125 1130 1135 Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp 1140 1145 1150 Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu 1155 1160 1165 Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr 1170 1175 1180 Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser 1185 1190 1195 1200 Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn 1205 1210 1215 Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala 1220 1225 1230 Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln 1235 1240 1245 Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn 1250 1255 1260 Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys 1265 1270 1275 1280 Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu 1285 1290 1295 Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys 1300 1305 1310 Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val 1315 1320 1325 Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile 1330 1335 1340 Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro 1345 1350 1355 1360 Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr 1365 1370 1375 Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile 1380 1385 1390 Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu 1395 1400 1405 Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp 1410 1415 1420 Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly 1425 1430 1435 1440 Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile 1445 1450 1455 Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser 1460 1465 1470 Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met 1475 1480 1485 Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala 1490 1495 1500 Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala 1505 1510 1515 1520 Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn 1525 1530 1535 Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val 1540 1545 1550 Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr 1555 1560 1565 Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr 1570 1575 1580 Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp 1585 1590 1595 1600 Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg 1605 1610 1615 Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg 1620 1625 1630 Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1635 1640 <210> 8 <211> 1444 <212> PRT <213> Artificial Sequence <220> <223> G1 (scF1) <400> 8 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Thr Thr Leu Gln 755 760 765 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 770 775 780 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 785 790 795 800 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 805 810 815 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 820 825 830 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 835 840 845 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 850 855 860 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 865 870 875 880 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 885 890 895 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 900 905 910 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 915 920 925 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 930 935 940 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 945 950 955 960 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 965 970 975 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 980 985 990 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 995 1000 1005 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 1010 1015 1020 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 1025 1030 1035 1040 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 1045 1050 1055 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 1060 1065 1070 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 1075 1080 1085 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 1090 1095 1100 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 1105 1110 1115 1120 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 1125 1130 1135 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 1140 1145 1150 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 1155 1160 1165 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 1170 1175 1180 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 1185 1190 1195 1200 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 1205 1210 1215 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 1220 1225 1230 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 1235 1240 1245 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 1250 1255 1260 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 1265 1270 1275 1280 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 1285 1290 1295 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 1300 1305 1310 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 1315 1320 1325 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 1330 1335 1340 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 1345 1350 1355 1360 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 1365 1370 1375 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 1380 1385 1390 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 1395 1400 1405 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 1410 1415 1420 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 1425 1430 1435 1440 Gln Asp Leu Tyr <210> 9 <211> 6999 <212> DNA <213> Homo sapiens <400> 9 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cttgagtgaa 2820 gaaaataatg attcaaagtt gttagaatca ggtttaatga atagccaaga aagttcatgg 2880 ggaaaaaatg tatcgtcaac agagagtggt aggttattta aagggaaaag agctcatgga 2940 cctgctttgt tgactaaaga taatgcctta ttcaaagtta gcatctcttt gttaaagaca 3000 aacaaaactt ccaataattc agcaactaat agaaagactc acattgatgg cccatcatta 3060 ttaattgaga atagtccatc agtctggcaa aatatattag aaagtgacac tgagtttaaa 3120 aaagtgacac ctttgattca tgacagaatg cttatggaca aaaatgctac agctttgagg 3180 ctaaatcata tgtcaaataa aactacttca tcaaaaaaca tggaaatggt ccaacagaaa 3240 aaagagggcc ccattccacc agatgcacaa aatccagata tgtcgttctt taagatgcta 3300 ttcttgccag aatcagcaag gtggatacaa aggactcatg gaaagaactc tctgaactct 3360 gggcaaggcc ccagtccaaa gcaattagta tccttaggac cagaaaaatc tgtggaaggt 3420 cagaatttct tgtctgagaa aaacaaagtg gtagtaggaa agggtgaatt tacaaaggac 3480 gtaggactca aagagatggt ttttccaagc agcagaaacc tatttcttac taacttggat 3540 aatttacatg aaaataatac acacaatcaa gaaaaaaaaa ttcaggaaga aatagaaaag 3600 aaggaaacat taatccaaga gaatgtagtt ttgcctcaga tacatacagt gactggcact 3660 aagaatttca tgaagaacct tttcttactg agcactaggc aaaatgtaga aggttcatat 3720 gacggggcat atgctccagt acttcaagat tttaggtcat taaatgattc aacaaataga 3780 acaaagaaac acacagctca tttctcaaaa aaaggggagg aagaaaactt ggaaggcttg 3840 ggaaatcaaa ccaagcaaat tgtagagaaa tatgcatgca ccacaaggat atctcctaat 3900 acaagccagc agaattttgt cacgcaacgt agtaagagag ctttgaaaca attcagactc 3960 ccactagaag aaacagaact tgaaaaaagg ataattgtgg atgacacctc aacccagtgg 4020 tccaaaaaca tgaaacattt gaccccgagc accctcacac agatagacta caatgagaag 4080 gagaaagggg ccattactca gtctccctta tcagattgcc ttacgaggag tcatagcatc 4140 cctcaagcaa atagatctcc attacccatt gcaaaggtat catcatttcc atctattaga 4200 cctatatatc tgaccagggt cctattccaa gacaactctt ctcatcttcc agcagcatct 4260 tatagaaaga aagattctgg ggtccaagaa agcagtcatt tcttacaagg agccaaaaaa 4320 aataaccttt ctttagccat tctaaccttg gagatgactg gtgatcaaag agaggttggc 4380 tccctgggga caagtgccac aaattcagtc acatacaaga aagttgagaa cactgttctc 4440 ccgaaaccag acttgcccaa aacatctggc aaagttgaat tgcttccaaa agttcacatt 4500 tatcagaagg acctattccc tacggaaact agcaatgggt ctcctggcca tctggatctc 4560 gtggaaggga gccttcttca gggaacagag ggagcgatta agtggaatga agcaaacaga 4620 cctggaaaag ttccctttct gagagtagca acagaaagct ctgcaaagac tccctccaag 4680 ctattggatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 4740 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 4800 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 4860 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 4920 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 4980 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 5040 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 5100 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 5160 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 5220 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 5280 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 5340 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 5400 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 5460 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 5520 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 5580 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 5640 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 5700 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 5760 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 5820 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 5880 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 5940 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 6000 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 6060 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 6120 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 6180 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 6240 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 6300 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 6360 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 6420 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 6480 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 6540 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 6600 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 6660 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 6720 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 6780 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 6840 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 6900 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 6960 atggaggttc tgggctgcga ggcacaggac ctctactga 6999 <210> 10 <211> 4404 <212> DNA <213> Artificial Sequence <220> <223> G2 <400> 10 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtactctt cagtcagatc aagaggaaat tgactatgat 2400 gataccatat cagttgaaat gaagaaggaa gattttgaca tttatgatga ggatgaaaat 2460 cagagccccc gcagctttca aaagaaaaca cgacactatt ttattgctgc agtggagagg 2520 ctctgggatt atgggatgag tagctcccca catgttctaa gaaacagggc tcagagtggc 2580 agtgtccctc agttcaagaa agttgttttc caggaattta ctgatggctc ctttactcag 2640 cccttatacc gtggagaact aaatgaacat ttgggactcc tggggccata tataagagca 2700 gaagttgaag ataatatcat ggtaactttc agaaatcagg cctctcgtcc ctattccttc 2760 tattctagcc ttatttctta tgaggaagat cagaggcaag gagcagaacc tagaaaaaac 2820 tttgtcaagc ctaatgaaac caaaacttac ttttggaaag tgcaacatca tatggcaccc 2880 actaaagatg agtttgactg caaagcctgg gcttatttct ctgatgttga cctggaaaaa 2940 gatgtgcact caggcctgat tggacccctt ctggtctgcc acactaacac actgaaccct 3000 gctcatggga gacaagtgac agtacaggaa tttgctctgt ttttcaccat ctttgatgag 3060 accaaaagct ggtacttcac tgaaaatatg gaaagaaact gcagggctcc ctgcaatatc 3120 cagatggaag atcccacttt taaagagaat tatcgcttcc atgcaatcaa tggctacata 3180 atggatacac tacctggctt agtaatggct caggatcaaa ggattcgatg gtatctgctc 3240 agcatgggca gcaatgaaaa catccattct attcatttca gtggacatgt gttcactgta 3300 cgaaaaaaag aggagtataa aatggcactg tacaatctct atccaggtgt ttttgagaca 3360 gtggaaatgt taccatccaa agctggaatt tggcgggtgg aatgccttat tggcgagcat 3420 ctacatgctg ggatgagcac actttttctg gtgtacagca ataagtgtca gactcccctg 3480 ggaatggctt ctggacacat tagagatttt cagattacag cttcaggaca atatggacag 3540 tgggccccaa agctggccag acttcattat tccggatcaa tcaatgcctg gagcaccaag 3600 gagccctttt cttggatcaa ggtggatctg ttggcaccaa tgattattca cggcatcaag 3660 acccagggtg cccgtcagaa gttctccagc ctctacatct ctcagtttat catcatgtat 3720 agtcttgatg ggaagaagtg gcagacttat cgaggaaatt ccactggaac cttaatggtc 3780 ttctttggca atgtggattc atctgggata aaacacaata tttttaaccc tccaattatt 3840 gctcgataca tccgtttgca cccaactcat tatagcattc gcagcactct tcgcatggag 3900 ttgatgggct gtgatttaaa tagttgcagc atgccattgg gaatggagag taaagcaata 3960 tcagatgcac agattactgc ttcatcctac tttaccaata tgtttgccac ctggtctcct 4020 tcaaaagctc gacttcacct ccaagggagg agtaatgcct ggagacctca ggtgaataat 4080 ccaaaagagt ggctgcaagt ggacttccag aagacaatga aagtcacagg agtaactact 4140 cagggagtaa aatctctgct taccagcatg tatgtgaagg agttcctcat ctccagcagt 4200 caagatggcc atcagtggac tctctttttt cagaatggca aagtaaaggt ttttcaggga 4260 aatcaagact ccttcacacc tgtggtgaac tctctagacc caccgttact gactcgctac 4320 cttcgaattc acccccagag ttgggtgcac cagattgccc tgaggatgga ggttctgggc 4380 tgcgaggcac aggacctcta ctga 4404 <210> 11 <211> 4536 <212> DNA <213> Artificial Sequence <220> <223> G3 <400> 11 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctactc ttcagtcaga tcaagaggaa 2520 attgactatg atgataccat atcagttgaa atgaagaagg aagattttga catttatgat 2580 gaggatgaaa atcagagccc ccgcagcttt caaaagaaaa cacgacacta ttttattgct 2640 gcagtggaga ggctctggga ttatgggatg agtagctccc cacatgttct aagaaacagg 2700 gctcagagtg gcagtgtccc tcagttcaag aaagttgttt tccaggaatt tactgatggc 2760 tcctttactc agcccttata ccgtggagaa ctaaatgaac atttgggact cctggggcca 2820 tatataagag cagaagttga agataatatc atggtaactt tcagaaatca ggcctctcgt 2880 ccctattcct tctattctag ccttatttct tatgaggaag atcagaggca aggagcagaa 2940 cctagaaaaa actttgtcaa gcctaatgaa accaaaactt acttttggaa agtgcaacat 3000 catatggcac ccactaaaga tgagtttgac tgcaaagcct gggcttattt ctctgatgtt 3060 gacctggaaa aagatgtgca ctcaggcctg attggacccc ttctggtctg ccacactaac 3120 acactgaacc ctgctcatgg gagacaagtg acagtacagg aatttgctct gtttttcacc 3180 atctttgatg agaccaaaag ctggtacttc actgaaaata tggaaagaaa ctgcagggct 3240 ccctgcaata tccagatgga agatcccact tttaaagaga attatcgctt ccatgcaatc 3300 aatggctaca taatggatac actacctggc ttagtaatgg ctcaggatca aaggattcga 3360 tggtatctgc tcagcatggg cagcaatgaa aacatccatt ctattcattt cagtggacat 3420 gtgttcactg tacgaaaaaa agaggagtat aaaatggcac tgtacaatct ctatccaggt 3480 gtttttgaga cagtggaaat gttaccatcc aaagctggaa tttggcgggt ggaatgcctt 3540 attggcgagc atctacatgc tgggatgagc acactttttc tggtgtacag caataagtgt 3600 cagactcccc tgggaatggc ttctggacac attagagatt ttcagattac agcttcagga 3660 caatatggac agtgggcccc aaagctggcc agacttcatt attccggatc aatcaatgcc 3720 tggagcacca aggagccctt ttcttggatc aaggtggatc tgttggcacc aatgattatt 3780 cacggcatca agacccaggg tgcccgtcag aagttctcca gcctctacat ctctcagttt 3840 atcatcatgt atagtcttga tgggaagaag tggcagactt atcgaggaaa ttccactgga 3900 accttaatgg tcttctttgg caatgtggat tcatctggga taaaacacaa tatttttaac 3960 cctccaatta ttgctcgata catccgtttg cacccaactc attatagcat tcgcagcact 4020 cttcgcatgg agttgatggg ctgtgattta aatagttgca gcatgccatt gggaatggag 4080 agtaaagcaa tatcagatgc acagattact gcttcatcct actttaccaa tatgtttgcc 4140 acctggtctc cttcaaaagc tcgacttcac ctccaaggga ggagtaatgc ctggagacct 4200 caggtgaata atccaaaaga gtggctgcaa gtggacttcc agaagacaat gaaagtcaca 4260 ggagtaacta ctcagggagt aaaatctctg cttaccagca tgtatgtgaa ggagttcctc 4320 atctccagca gtcaagatgg ccatcagtgg actctctttt ttcagaatgg caaagtaaag 4380 gtttttcagg gaaatcaaga ctccttcaca cctgtggtga actctctaga cccaccgtta 4440 ctgactcgct accttcgaat tcacccccag agttgggtgc accagattgc cctgaggatg 4500 gaggttctgg gctgcgaggc acaggacctc tactga 4536 <210> 12 <211> 4536 <212> DNA <213> Artificial Sequence <220> <223> G4 <400> 12 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctactc ttcagtcaga tcaagaggaa 2520 attgactatg atgataccat atcagttgaa atgaagaagg aagattttga catttatgat 2580 gaggatgaaa atcagagccc ccgcagcttt caaaagaaaa cacgacacta ttttattgct 2640 gcagtggaga ggctctggga ttatgggatg agtagctccc cacatgttct aagaaacagg 2700 gctcagagtg gcagtgtccc tcagttcaag aaagttgttt tccaggaatt tactgatggc 2760 tcctttactc agcccttata ccgtggagaa ctaaatgaac atttgggact cctggggcca 2820 tatataagag cagaagttga agataatatc atggtaactt tcagaaatca ggcctctcgt 2880 ccctattcct tctattctag ccttatttct tatgaggaag atcagaggca aggagcagaa 2940 cctagaaaaa actttgtcaa gcctaatgaa accaaaactt acttttggaa agtgcaacat 3000 catatggcac ccactaaaga tgagtttgac tgcaaagcct gggcttattt ctctgatgtt 3060 gacctggaaa aagatgtgca ctcaggcctg attggacccc ttctggtctg ccacactaac 3120 acactgaacc ctgctcatgg gagacaagtg acagtacagg aatttgctct gtttttcacc 3180 atctttgatg agaccaaaag ctggtacttc actgaaaata tggaaagaaa ctgcagggct 3240 ccctgcaata tccagatgga agatcccact tttaaagaga attatcgctt ccatgcaatc 3300 aatggctaca taatggatac actacctggc ttagtaatgg ctcaggatca aaggattcga 3360 tggtatctgc tcagcatggg cagcaatgaa aacatccatt ctattcattt cagtggacat 3420 gtgttcactg tacgaaaaaa agaggagtat aaaatggcac tgtacaatct ctatccaggt 3480 gtttttgaga cagtggaaat gttaccatcc aaagctggaa tttggcgggt ggaatgcctt 3540 attggcgagc atctacatgc tgggatgagc acactttttc tggtgtacag caataagtgt 3600 cagactcccc tgggaatggc ttctggacac attagagatt ttcagattac agcttcagga 3660 caatatggac agtgggcccc aaagctggcc agacttcatt attccggatc aatcaatgcc 3720 tggagcacca aggagccctt ttcttggatc aaggtggatc tgttggcacc aatgattatt 3780 cacggcatca agacccaggg tgcccgtcag aagttctcca gcctctacat ctctcagttt 3840 atcatcatgt atagtcttga tgggaagaag tggcagactt atcgaggaaa ttccactgga 3900 accttaatgg tcttctttgg caatgtggat tcatctggga taaaacacaa tatttttaac 3960 cctccaatta ttgctcgata catccgtttg cacccaactc attatagcat tcgcagcact 4020 cttcgcatgg agttgatggg ctgtgattta aatagttgca gcatgccatt gggaatggag 4080 agtaaagcaa tatcagatgc acagattact gcttcatcct actttaccaa tatgtttgcc 4140 acctggtctc cttcaaaagc tcgacttcac ctccaaggga ggagtaatgc ctggagacct 4200 caggtgaata atccaaaaga gtggctgcaa gtggacttcc agaagacaat gaaagtcaca 4260 ggagtaacta ctcagggagt aaaatctctg cttaccagca tgtatgtgaa ggagttcctc 4320 atctccagca gtcaagatgg ccatcagtgg actctctttt ttcagaatgg caaagtaaag 4380 gtttttcagg gaaatcaaga ctccttcaca cctgtggtga actctctaga cccaccgtta 4440 ctgactcgct accttcgaat tcacccccag agttgggtgc accagattgc cctgaggatg 4500 gaggttctgg gctgcgaggc acaggacctc tactga 4536 <210> 13 <211> 4935 <212> DNA <213> Artificial Sequence <220> <223> G6 <400> 13 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cttgagtgaa 2820 gaaaataatg attcaaagtt gttagaatca ggtttaatga atagccaaga aagttcatgg 2880 ggaaaaaatg tatcgactct tcagtcagat caagaggaaa ttgactatga tgataccata 2940 tcagttgaaa tgaagaagga agattttgac atttatgatg aggatgaaaa tcagagcccc 3000 cgcagctttc aaaagaaaac acgacactat tttattgctg cagtggagag gctctgggat 3060 tatgggatga gtagctcccc acatgttcta agaaacaggg ctcagagtgg cagtgtccct 3120 cagttcaaga aagttgtttt ccaggaattt actgatggct cctttactca gcccttatac 3180 cgtggagaac taaatgaaca tttgggactc ctggggccat atataagagc agaagttgaa 3240 gataatatca tggtaacttt cagaaatcag gcctctcgtc cctattcctt ctattctagc 3300 cttatttctt atgaggaaga tcagaggcaa ggagcagaac ctagaaaaaa ctttgtcaag 3360 cctaatgaaa ccaaaactta cttttggaaa gtgcaacatc atatggcacc cactaaagat 3420 gagtttgact gcaaagcctg ggcttatttc tctgatgttg acctggaaaa agatgtgcac 3480 tcaggcctga ttggacccct tctggtctgc cacactaaca cactgaaccc tgctcatggg 3540 agacaagtga cagtacagga atttgctctg tttttcacca tctttgatga gaccaaaagc 3600 tggtacttca ctgaaaatat ggaaagaaac tgcagggctc cctgcaatat ccagatggaa 3660 gatcccactt ttaaagagaa ttatcgcttc catgcaatca atggctacat aatggataca 3720 ctacctggct tagtaatggc tcaggatcaa aggattcgat ggtatctgct cagcatgggc 3780 agcaatgaaa acatccattc tattcatttc agtggacatg tgttcactgt acgaaaaaaa 3840 gaggagtata aaatggcact gtacaatctc tatccaggtg tttttgagac agtggaaatg 3900 ttaccatcca aagctggaat ttggcgggtg gaatgcctta ttggcgagca tctacatgct 3960 gggatgagca cactttttct ggtgtacagc aataagtgtc agactcccct gggaatggct 4020 tctggacaca ttagagattt tcagattaca gcttcaggac aatatggaca gtgggcccca 4080 aagctggcca gacttcatta ttccggatca atcaatgcct ggagcaccaa ggagcccttt 4140 tcttggatca aggtggatct gttggcacca atgattattc acggcatcaa gacccagggt 4200 gcccgtcaga agttctccag cctctacatc tctcagttta tcatcatgta tagtcttgat 4260 gggaagaagt ggcagactta tcgaggaaat tccactggaa ccttaatggt cttctttggc 4320 aatgtggatt catctgggat aaaacacaat atttttaacc ctccaattat tgctcgatac 4380 atccgtttgc acccaactca ttatagcatt cgcagcactc ttcgcatgga gttgatgggc 4440 tgtgatttaa atagttgcag catgccattg ggaatggaga gtaaagcaat atcagatgca 4500 cagattactg cttcatccta ctttaccaat atgtttgcca cctggtctcc ttcaaaagct 4560 cgacttcacc tccaagggag gagtaatgcc tggagacctc aggtgaataa tccaaaagag 4620 tggctgcaag tggacttcca gaagacaatg aaagtcacag gagtaactac tcagggagta 4680 aaatctctgc ttaccagcat gtatgtgaag gagttcctca tctccagcag tcaagatggc 4740 catcagtgga ctctcttttt tcagaatggc aaagtaaagg tttttcaggg aaatcaagac 4800 tccttcacac ctgtggtgaa ctctctagac ccaccgttac tgactcgcta ccttcgaatt 4860 cacccccaga gttgggtgca ccagattgcc ctgaggatgg aggttctggg ctgcgaggca 4920 caggacctct actga 4935 <210> 14 <211> 4764 <212> DNA <213> Artificial Sequence <220> <223> G4-flex <400> 14 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagttctc aaaacccacc agtcactctt cagtcagatc aagaggaaat tgactatgat 2760 gataccatat cagttgaaat gaagaaggaa gattttgaca tttatgatga ggatgaaaat 2820 cagagccccc gcagctttca aaagaaaaca cgacactatt ttattgctgc agtggagagg 2880 ctctgggatt atgggatgag tagctcccca catgttctaa gaaacagggc tcagagtggc 2940 agtgtccctc agttcaagaa agttgttttc caggaattta ctgatggctc ctttactcag 3000 cccttatacc gtggagaact aaatgaacat ttgggactcc tggggccata tataagagca 3060 gaagttgaag ataatatcat ggtaactttc agaaatcagg cctctcgtcc ctattccttc 3120 tattctagcc ttatttctta tgaggaagat cagaggcaag gagcagaacc tagaaaaaac 3180 tttgtcaagc ctaatgaaac caaaacttac ttttggaaag tgcaacatca tatggcaccc 3240 actaaagatg agtttgactg caaagcctgg gcttatttct ctgatgttga cctggaaaaa 3300 gatgtgcact caggcctgat tggacccctt ctggtctgcc acactaacac actgaaccct 3360 gctcatggga gacaagtgac agtacaggaa tttgctctgt ttttcaccat ctttgatgag 3420 accaaaagct ggtacttcac tgaaaatatg gaaagaaact gcagggctcc ctgcaatatc 3480 cagatggaag atcccacttt taaagagaat tatcgcttcc atgcaatcaa tggctacata 3540 atggatacac tacctggctt agtaatggct caggatcaaa ggattcgatg gtatctgctc 3600 agcatgggca gcaatgaaaa catccattct attcatttca gtggacatgt gttcactgta 3660 cgaaaaaaag aggagtataa aatggcactg tacaatctct atccaggtgt ttttgagaca 3720 gtggaaatgt taccatccaa agctggaatt tggcgggtgg aatgccttat tggcgagcat 3780 ctacatgctg ggatgagcac actttttctg gtgtacagca ataagtgtca gactcccctg 3840 ggaatggctt ctggacacat tagagatttt cagattacag cttcaggaca atatggacag 3900 tgggccccaa agctggccag acttcattat tccggatcaa tcaatgcctg gagcaccaag 3960 gagccctttt cttggatcaa ggtggatctg ttggcaccaa tgattattca cggcatcaag 4020 acccagggtg cccgtcagaa gttctccagc ctctacatct ctcagtttat catcatgtat 4080 agtcttgatg ggaagaagtg gcagacttat cgaggaaatt ccactggaac cttaatggtc 4140 ttctttggca atgtggattc atctgggata aaacacaata tttttaaccc tccaattatt 4200 gctcgataca tccgtttgca cccaactcat tatagcattc gcagcactct tcgcatggag 4260 ttgatgggct gtgatttaaa tagttgcagc atgccattgg gaatggagag taaagcaata 4320 tcagatgcac agattactgc ttcatcctac tttaccaata tgtttgccac ctggtctcct 4380 tcaaaagctc gacttcacct ccaagggagg agtaatgcct ggagacctca ggtgaataat 4440 ccaaaagagt ggctgcaagt ggacttccag aagacaatga aagtcacagg agtaactact 4500 cagggagtaa aatctctgct taccagcatg tatgtgaagg agttcctcat ctccagcagt 4560 caagatggcc atcagtggac tctctttttt cagaatggca aagtaaaggt ttttcaggga 4620 aatcaagact ccttcacacc tgtggtgaac tctctagacc caccgttact gactcgctac 4680 cttcgaattc acccccagag ttgggtgcac cagattgccc tgaggatgga ggttctgggc 4740 tgcgaggcac aggacctcta ctga 4764 <210> 15 <211> 4945 <212> DNA <213> Artificial Sequence <220> <223> G6_opt <400> 15 ctgcttctcc gccacccggc ggtactacct gggcgccgtg gaactgtcct gggactacat 60 gcagtccgac ctgggcgagc tgcccgtgga cgccagattc cccccaagag tgcccaagtc 120 cttccccttc aacacctccg tggtgtacaa gaaaaccctg ttcgtggaat tcaccgacca 180 cctgttcaat atcgccaagc ctcggccccc ttggatgggc ctgctgggcc ctacaatcca 240 ggccgaggtg tacgacaccg tggtgatcac cctgaagaac atggcctccc accccgtgtc 300 cctgcacgcc gtgggcgtgt cctactggaa ggcctctgag ggcgccgagt acgacgacca 360 gacctcccag cgcgagaaag aggacgacaa ggtgttccct ggcggctccc acacctacgt 420 gtggcaggtg ctgaaagaaa acggccctat ggcctccgac cctctgtgcc tgacctactc 480 ctacctgtcc cacgtggacc tggtgaaaga cctgaactcc ggcctgatcg gcgccctgct 540 ggtgtgcaga gagggctccc tggccaaaga aaagacccag accctgcaca agttcatcct 600 gctgttcgcc gtgttcgacg agggcaagtc ctggcactcc gagacaaaga actccctgat 660 gcaggaccgg gacgccgcct ctgccagagc ctggcctaag atgcacaccg tgaacggcta 720 cgtgaaccgg tccctgcccg gactgatcgg ctgccaccgg aagtccgtgt actggcacgt 780 gatcggcatg ggcaccaccc ccgaggtgca ctccatcttt ctggaaggcc acacctttct 840 ggtgcgaaac caccggcagg cctccctgga aatctcccct atcaccttcc tgaccgctca 900 gaccctgctg atggacctgg gccagttcct gctgttttgc cacatctcca gccaccagca 960 cgacggcatg gaagcctacg tgaaggtgga ctcctgcccc gaggaacccc agctgcggat 1020 gaagaacaac gaggaagccg aggactacga cgacgacctg accgactccg agatggacgt 1080 ggtgcgattc gacgacgaca actcccccag cttcatccag atcagatccg tggccaagaa 1140 gcaccccaag acctgggtgc actatatcgc cgccgaggaa gaggactggg actacgcccc 1200 tctggtgctg gcccctgacg accggtccta caagtcccag tacctgaaca acggccccca 1260 gcggatcggc cggaagtaca agaaagtgcg gttcatggcc tacaccgacg agacattcaa 1320 gaccagagag gccatccagc acgagtccgg catcctgggc cccctgctgt acggcgaagt 1380 gggcgacaca ctgctgatca tcttcaagaa ccaggcctcc cggccctaca acatctaccc 1440 ccacggcatc accgacgtgc ggcccctgta ctctcggcgg ctgcctaagg gcgtgaagca 1500 cctgaaggac ttccccatcc tgcccggcga gatcttcaag tacaagtgga ccgtgaccgt 1560 ggaagatggc cccaccaagt ccgaccccag atgcctgacc cggtactact cctccttcgt 1620 gaacatggaa cgggacctgg ccagcggcct gattggacct ctgctgatct gctacaaaga 1680 atccgtggac cagcggggca accagatcat gtccgacaag cggaacgtga tcctgttcag 1740 cgtgttcgat gagaaccggt cctggtatct gaccgagaac atccagcggt ttctgcccaa 1800 ccctgccggc gtgcagctgg aagatcccga gttccaggcc tccaacatca tgcacagcat 1860 caatggctac gtgttcgact ccctgcagct gagcgtgtgc ctgcacgagg tggcctactg 1920 gtacatcctg tccatcggcg cccagaccga cttcctgtcc gtgttcttct ccggctacac 1980 cttcaagcac aagatggtgt acgaggatac cctgaccctg ttccccttct ccggcgaaac 2040 cgtgttcatg tccatggaaa accccggcct gtggatcctg ggctgccaca actccgactt 2100 ccggaaccgg ggcatgaccg ccctgctgaa ggtgtcctcc tgcgacaaga acaccggcga 2160 ctactacgag gactcttacg aggacatctc cgcctacctg ctgtccaaga acaacgccat 2220 cgagccccgg tccttcagcc agaactcccg gcacccttcc acccggcaga agcagttcaa 2280 cgccaccacc atccccgaga acgacatcga aaagaccgac ccttggtttg cccaccggac 2340 ccccatgccc aagatccaga acgtgtcctc ctctgacctg ctgatgctgc tgcggcagtc 2400 ccccacccct cacggcctgt ctctgagcga cctgcaggaa gctaagtacg agactttctc 2460 cgacgacccc tcccctggcg ccatcgactc caacaactcc ctgtccgaga tgacccactt 2520 ccggccccag ctgcaccact ccggcgacat ggtgttcacc cccgagtctg gcctgcagct 2580 gcggctgaac gagaagctgg gcaccacagc cgccaccgag ctgaagaaac tggacttcaa 2640 ggtgtccagc acctccaaca acctgatctc caccatccct tccgacaacc tggccgctgg 2700 caccgacaac acctcttccc tgggccctcc ctccatgccc gtgcactacg actcccagct 2760 ggacaccacc ctgttcggca agaagtccag ccccctgacc gagtccggcg gacccctgtc 2820 cctgtctgag gaaaacaacg actccaagct gctggaatct ggcctgatga actcccagga 2880 atcctcctgg ggcaagaatg tgtccaccct gcagagcgac caggaagaga tcgattacga 2940 cgacaccatc tccgtggaaa tgaagaaaga ggatttcgac atctacgacg aggacgagaa 3000 ccagtcccct cggtccttcc agaagaaaac ccggcactac tttatcgccg ctgtggaacg 3060 gctgtgggac tacggcatgt cctcctcccc ccacgtgctg cggaacagag cccagtccgg 3120 ctccgtgccc cagttcaaga aagtggtgtt ccaggaattc acagacggca gcttcaccca 3180 gcccctgtac cggggcgagc tgaatgagca cctgggactg ctgggacctt acatcagagc 3240 tgaggtggaa gataacatca tggtgacatt ccggaaccag gccagcagac cctactcctt 3300 ctactccagc ctgatctcct acgaagagga ccagcggcag ggcgctgagc cccggaagaa 3360 cttcgtgaag cccaacgaga ctaagaccta cttctggaag gtgcagcacc acatggctcc 3420 taccaaggac gagttcgact gcaaggcctg ggcctacttc tccgatgtgg acctggaaaa 3480 ggacgtgcac agcgggctga ttggcccact gctggtgtgc cacaccaaca ccctgaaccc 3540 cgcccacggc agacaggtga cagtgcagga attcgccctg ttcttcacca tcttcgacga 3600 gacaaagtcc tggtacttca ccgagaatat ggaacggaac tgcagagccc cctgcaacat 3660 ccagatggaa gatcctacct tcaaagagaa ctaccggttc cacgccatca acggctacat 3720 catggacacc ctgcccggcc tggtgatggc ccaggaccag agaatccggt ggtatctgct 3780 gtccatgggc tccaacgaga atatccactc catccacttc tccggccacg tgttcaccgt 3840 gcggaagaaa gaagagtaca agatggccct gtacaacctg taccccggcg tgttcgagac 3900 agtggaaatg ctgccctcca aggccggcat ctggcgggtg gaatgtctga tcggcgagca 3960 tctgcacgcc ggaatgtcta ccctgttcct ggtgtactcc aacaagtgcc agacccccct 4020 gggcatggcc tccggccaca tccgggattt ccagatcacc gcctctggcc agtacggcca 4080 gtgggcccct aagctggccc ggctgcacta cagcggctcc atcaacgcct ggtctaccaa 4140 agagcccttc agctggatca aggtggacct gctggccccc atgatcatcc atggcatcaa 4200 gacccagggc gccagacaga agttctcctc cctgtacatc tcccagttca tcatcatgta 4260 ctccctggat ggcaagaagt ggcagaccta ccggggcaac tccaccggca ccctgatggt 4320 gttcttcggc aacgtggact cctccggcat caagcacaac atcttcaacc cccccatcat 4380 tgcccggtac atccggctgc accccaccca ctactccatc cggtctaccc tgcggatgga 4440 actgatgggc tgcgacctga acagctgctc catgcctctg ggcatggaat ccaaggccat 4500 ctccgacgcc cagatcacag ccagctccta cttcaccaac atgttcgcca cctggtcccc 4560 cagcaaggcc agactgcatc tgcagggccg gtccaacgct tggcggcctc aggtgaacaa 4620 ccccaaagaa tggctgcagg tggacttcca gaaaaccatg aaggtgacag gcgtgaccac 4680 ccagggcgtg aaatccctgc tgacctctat gtacgtgaaa gagttcctga tcagctcctc 4740 ccaggacggc caccagtgga ccctgttctt tcagaacggc aaagtgaaag tgttccaggg 4800 caaccaggac tccttcaccc ctgtggtgaa ctccctggac cccccactgc tgaccagata 4860 cctgcggatc cacccccagt cttgggtgca ccagatcgcc ctgagaatgg aagtgctggg 4920 atgcgaggcc caggatctgt actga 4945 <210> 16 <211> 4335 <212> DNA <213> Artificial Sequence <220> <223> G1 <400> 16 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atactactct tcagtcagat caagaggaaa ttgactatga tgataccata 2340 tcagttgaaa tgaagaagga agattttgac atttatgatg aggatgaaaa tcagagcccc 2400 cgcagctttc aaaagaaaac acgacactat tttattgctg cagtggagag gctctgggat 2460 tatgggatga gtagctcccc acatgttcta agaaacaggg ctcagagtgg cagtgtccct 2520 cagttcaaga aagttgtttt ccaggaattt actgatggct cctttactca gcccttatac 2580 cgtggagaac taaatgaaca tttgggactc ctggggccat atataagagc agaagttgaa 2640 gataatatca tggtaacttt cagaaatcag gcctctcgtc cctattcctt ctattctagc 2700 cttatttctt atgaggaaga tcagaggcaa ggagcagaac ctagaaaaaa ctttgtcaag 2760 cctaatgaaa ccaaaactta cttttggaaa gtgcaacatc atatggcacc cactaaagat 2820 gagtttgact gcaaagcctg ggcttatttc tctgatgttg acctggaaaa agatgtgcac 2880 tcaggcctga ttggacccct tctggtctgc cacactaaca cactgaaccc tgctcatggg 2940 agacaagtga cagtacagga atttgctctg tttttcacca tctttgatga gaccaaaagc 3000 tggtacttca ctgaaaatat ggaaagaaac tgcagggctc cctgcaatat ccagatggaa 3060 gatcccactt ttaaagagaa ttatcgcttc catgcaatca atggctacat aatggataca 3120 ctacctggct tagtaatggc tcaggatcaa aggattcgat ggtatctgct cagcatgggc 3180 agcaatgaaa acatccattc tattcatttc agtggacatg tgttcactgt acgaaaaaaa 3240 gaggagtata aaatggcact gtacaatctc tatccaggtg tttttgagac agtggaaatg 3300 ttaccatcca aagctggaat ttggcgggtg gaatgcctta ttggcgagca tctacatgct 3360 gggatgagca cactttttct ggtgtacagc aataagtgtc agactcccct gggaatggct 3420 tctggacaca ttagagattt tcagattaca gcttcaggac aatatggaca gtgggcccca 3480 aagctggcca gacttcatta ttccggatca atcaatgcct ggagcaccaa ggagcccttt 3540 tcttggatca aggtggatct gttggcacca atgattattc acggcatcaa gacccagggt 3600 gcccgtcaga agttctccag cctctacatc tctcagttta tcatcatgta tagtcttgat 3660 gggaagaagt ggcagactta tcgaggaaat tccactggaa ccttaatggt cttctttggc 3720 aatgtggatt catctgggat aaaacacaat atttttaacc ctccaattat tgctcgatac 3780 atccgtttgc acccaactca ttatagcatt cgcagcactc ttcgcatgga gttgatgggc 3840 tgtgatttaa atagttgcag catgccattg ggaatggaga gtaaagcaat atcagatgca 3900 cagattactg cttcatccta ctttaccaat atgtttgcca cctggtctcc ttcaaaagct 3960 cgacttcacc tccaagggag gagtaatgcc tggagacctc aggtgaataa tccaaaagag 4020 tggctgcaag tggacttcca gaagacaatg aaagtcacag gagtaactac tcagggagta 4080 aaatctctgc ttaccagcat gtatgtgaag gagttcctca tctccagcag tcaagatggc 4140 catcagtgga ctctcttttt tcagaatggc aaagtaaagg tttttcaggg aaatcaagac 4200 tccttcacac ctgtggtgaa ctctctagac ccaccgttac tgactcgcta ccttcgaatt 4260 cacccccaga gttgggtgca ccagattgcc ctgaggatgg aggttctggg ctgcgaggca 4320 caggacctct actga 4335 <210> 17 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_A2_1 <400> 17 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga tgtccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 18 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_A2_2 <400> 18 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gttgtaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 19 <211> 4803 <212> DNA <213> Artificial Sequence <220> <223> G4_A2_3 <400> 19 agaggaatgt catcctgttt tctgtatttg atgagaaccg aagctggtac ctcacagaga 60 atatacaacg ctttctcccc aatccagctg gagtgcagct tgaggatcca gagttccaag 120 cctccaacat catgcacagc atcaatggct atgtttttga tagtttgcag ttgtcagttt 180 gtttgcatga ggtggcatac tggtacattc taagcattgg agcacagact gacttccttt 240 ctgtcttctt ctctggatat accttcaaac acaaaatggt ctatgaagac acactcaccc 300 tattcccatt ctcaggagaa actgtcttca tgtcgatgga aaacccaggt ctatggattc 360 tggggtgcca caactcagac tttcggaaca gaggcatgac cgccttactg aaggtttcta 420 gttgtgacaa gaacactggt gattattacg aggacagtta tgaagatatt tcagcatact 480 tgctgagtaa aaacaatgcc attgaaccaa gaagcttctc ccagaattca agacacccta 540 gcactaggca aaagcaattt aatgccacca caattccaga aaatgacata gagaagactg 600 acccttggtt tgcacacaga acacctatgc ctaaaataca aaatgtctcc tctagtgatt 660 tgttgatgct cttgcgacag agtcctactc cacatgggct atccttatct gatctccaag 720 aagccaaata tgagactttt tctgatgatc catcacctgg agcaatagac agtaataaca 780 gcctgtctga aatgacacac ttcaggccac agctccatca cagtggggac atggtattta 840 cccctgagtc aggcctccaa ttaagattaa atgagaaact ggggacaact gcagcaacag 900 agttgaagaa acttgatttc aaagtttcta gtacatcaaa taatctgatt tcaacaattc 960 catcagacaa tttggcagca ggtactgata atacaagtac tcttcagtca gatcaagagg 1020 aaattgacta tgatgatacc atatcagttg aaatgaagaa ggaagatttt gacatttatg 1080 atgaggatga aaatcagagc ccccgcagct ttcaaaagaa aacacgacac tattttattg 1140 ctgcagtgga gaggctctgg gattatggga tgagtagctc cccacatgtt ctaagaaaca 1200 gggctcagag tggcagtgtc cctcagttca agaaagttgt tttccaggaa tttactgatg 1260 gctcctttac tcagccctta taccgtggag aactaaatga acatttggga ctcctggggc 1320 catatataag agcagaagtt gaagataata tcatggtaac tttcagaaat caggcctctc 1380 gtccctattc cttctattct agccttattt cttatgagga agatcagagg caaggagcag 1440 aacctagaaa aaactttgtc aagcctaatg aaaccaaaac ttacttttgg aaagtgcaac 1500 atcatatggc acccactaaa gatgagtttg actgcaaagc ctgggcttat ttctctgatg 1560 ttgacctgga aaaagatgtg cactcaggcc tgattggacc ccttctggtc tgccacacta 1620 acacactgaa ccctgctcat gggagacaag tgacagtaca ggaatttgct ctgtttttca 1680 ccatctttga tgagaccaaa agctggtact tcactgaaaa tatggaaaga aactgcaggg 1740 ctccctgcaa tatccagatg gaagatccca cttttaaaga gaattatcgc ttccatgcaa 1800 tcaatggcta cataatggat acactacctg gcttagtaat ggctcaggat caaaggattc 1860 gatggtatct gctcagcatg ggcagcaatg aaaacatcca ttctattcat ttcagtggac 1920 atgtgttcac tgtacgaaaa aaagaggagt ataaaatggc actgtacaat ctctatccag 1980 gtgtttttga gacagtggaa atgttaccat ccaaagctgg aatttggcgg gtggaatgcc 2040 ttattggcga gcatctacat gctgggatga gcacactttt tctggtgtac agcaataagt 2100 gtcagactcc cctgggaatg gcttctggac acattagaga ttttcagatt acagcttcag 2160 gacaatatgg acagtgggcc ccaaagctgg ccagacttca ttattccgga tcaatcaatg 2220 cctggagcac caaggagccc ttttcttgga tcaaggtgga tctgttggca ccaatgatta 2280 ttcacggcat caagacccag ggtgcccgtc agaagttctc cagcctctac atctctcagt 2340 ttatcatcat gtatagtctt gatgggaaga agtggcagac ttatcgagga aattccactg 2400 gaaccttaat ggtcttcttt ggcaatgtgg attcatctgg gataaaacac aatattttta 2460 accctccaat tattgctcga tacatccgtt tgcacccaac tcattatagc attcgcagca 2520 ctcttcgcat ggagttgatg ggctgtgatt taaatagttg cagcatgcca ttgggaatgg 2580 agagtaaagc aatatcagat gcacagatta ctgcttcatc ctactttacc aatatgtttg 2640 ccacctggtc tccttcaaaa gctcgacttc acctccaagg gaggagtaat gcctggagac 2700 ctcaggtgaa taatccaaaa gagtggctgc aagtggactt ccagaagaca atgaaagtca 2760 caggagtaac tactcaggga gtaaaatctc tgcttaccag catgtatgtg aaggagttcc 2820 tcatctccag cagtcaagat ggccatcagt ggactctctt ttttcagaat ggcaaagtaa 2880 aggtttttca gggaaatcaa gactccttca cacctgtggt gaactctcta gacccaccgt 2940 tactgactcg ctaccttcga attcaccccc agagttgggt gcaccagatt gccctgagga 3000 tggaggttct gggctgcgag gcacaggacc tctactgaat gcaaatagag ctctccacct 3060 gcttctttct gtgccttttg cgattctgct ttagtgccac cagaagatac tacctgggtg 3120 cagtggaact gtcatgggac tatatgcaaa gtgatctcgg tgagctgcct gtggacgcaa 3180 gatttcctcc tagagtgcca aaatcttttc cattcaacac ctcagtcgtg tacaaaaaga 3240 ctctgtttgt agaattcacg gatcaccttt tcaacatcgc taagccaagg ccaccctgga 3300 tgggtctgct aggtcctacc atccaggctg aggtttatga tacagtggtc attacactta 3360 agaacatggc ttcccatcct gtcagtcttc atgctgttgg tgtatcctac tggaaagctt 3420 ctgagggagc tgaatatgat gatcagacca gtcaaaggga gaaagaagat gataaagtct 3480 tccctggtgg aagccataca tatgtctggc aggtcctgaa agagaatggt ccaatggcct 3540 ctgacccact gtgccttacc tactcatatc tttctcatgt ggacctggta aaagacttga 3600 attcaggcct cattggagcc ctactagtat gtagagaagg gagtctggcc aaggaaaaga 3660 cacagacctt gcacaaattt atactacttt ttgctgtatt tgatgaaggg aaaagttggc 3720 actcagaaac aaagaactcc ttgatgcagg atagggatgc tgcatctgct cgggcctggc 3780 ctaaaatgca cacagtcaat ggttatgtaa acaggtctct gccaggtctg attggatgcc 3840 acaggaaatc agtctattgg catgtgattg gaatgggcac cactcctgaa gtgcactcaa 3900 tattcctcga aggtcacaca tttcttgtga ggaaccatcg ccaggcgtcc ttggaaatct 3960 cgccaataac tttccttact gctcaaacac tcttgatgga ccttggacag tttctactgt 4020 tttgtcatat ctcttcccac caacatgatg gcatggaagc ttatgtcaaa gtagacagct 4080 gtccagagga accccaacta cgaatgaaaa ataatgaaga agcggaagac tatgatgatg 4140 atcttactga ttctgaaatg gatgtggtca ggtttgatga tgacaactct ccttccttta 4200 tccaaattcg ctcagttgcc aagaagcatc ctaaaacttg ggtacattac attgctgctg 4260 aagaggagga ctgggactat gctcccttag tcctcgcccc cgatgacaga agttataaaa 4320 gtcaatattt gaacaatggc cctcagcgga ttggtaggaa gtacaaaaaa gtccgattta 4380 tggcatacac agatgaaacc tttaagactc gtgaagctat tcagcatgaa tcaggaatct 4440 tgggaccttt actttatggg gaagttggag acacactgtt gattatattt aagaatcaag 4500 caagcagacc atataacatc taccctcacg gaatcactga tgtccgtcct ttgtattcaa 4560 ggagattacc aaaaggtgta aaacattgta aggattttcc aattctgcca ggagaaatat 4620 tcaaatataa atggacagtg actgtagaag atgggccaac taaatcagat cctcggtgcc 4680 tgacccgcta ttactctagt ttcgttaata tggagagaga tctagcttca ggactcattg 4740 gccctctcct catctgctac aaagaatctg tagatcaaag aggaaaccag ataatgtcag 4800 aca 4803 <210> 20 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_A3_1 <400> 20 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actgtgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 21 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_B1 <400> 21 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaat gccaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 22 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_1D <400> 22 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa attgtataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 23 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_2D <400> 23 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagacttgt ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 24 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_3R <400> 24 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacactgtac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 25 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_B2 <400> 25 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 tgtatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 26 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_B3 <400> 26 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaatgtcaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 27 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_B4 <400> 27 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc ttgtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 28 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_B5 <400> 28 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag catgtgacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 29 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_4L <400> 29 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgattgt ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 30 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_B6 <400> 30 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag catgtgacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 31 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_B7 <400> 31 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa atgacataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcatg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgataccat atcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 32 <211> 4746 <212> DNA <213> Artificial Sequence <220> <223> G4_1I1D <400> 32 gccaccagaa gatactacct gggtgcagtg gaactgtcat gggactatat gcaaagtgat 60 ctcggtgagc tgcctgtgga cgcaagattt cctcctagag tgccaaaatc ttttccattc 120 aacacctcag tcgtgtacaa aaagactctg tttgtagaat tcacggatca ccttttcaac 180 atcgctaagc caaggccacc ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt 240 tatgatacag tggtcattac acttaagaac atggcttccc atcctgtcag tcttcatgct 300 gttggtgtat cctactggaa agcttctgag ggagctgaat atgatgatca gaccagtcaa 360 agggagaaag aagatgataa agtcttccct ggtggaagcc atacatatgt ctggcaggtc 420 ctgaaagaga atggtccaat ggcctctgac ccactgtgcc ttacctactc atatctttct 480 catgtggacc tggtaaaaga cttgaattca ggcctcattg gagccctact agtatgtaga 540 gaagggagtc tggccaagga aaagacacag accttgcaca aatttatact actttttgct 600 gtatttgatg aagggaaaag ttggcactca gaaacaaaga actccttgat gcaggatagg 660 gatgctgcat ctgctcgggc ctggcctaaa atgcacacag tcaatggtta tgtaaacagg 720 tctctgccag gtctgattgg atgccacagg aaatcagtct attggcatgt gattggaatg 780 ggcaccactc ctgaagtgca ctcaatattc ctcgaaggtc acacatttct tgtgaggaac 840 catcgccagg cgtccttgga aatctcgcca ataactttcc ttactgctca aacactcttg 900 atggaccttg gacagtttct actgttttgt catatctctt cccaccaaca tgatggcatg 960 gaagcttatg tcaaagtaga cagctgtcca gaggaacccc aactacgaat gaaaaataat 1020 gaagaagcgg aagactatga tgatgatctt actgattctg aaatggatgt ggtcaggttt 1080 gatgatgaca actctccttc ctttatccaa attcgctcag ttgccaagaa gcatcctaaa 1140 acttgggtac attacattgc tgctgaagag gaggactggg actatgctcc cttagtcctc 1200 gcccccgatg acagaagtta taaaagtcaa tatttgaaca atggccctca gcggattggt 1260 aggaagtaca aaaaagtccg atttatggca tacacagatg aaacctttaa gactcgtgaa 1320 gctattcagc atgaatcagg aatcttggga cctttacttt atggggaagt tggagacaca 1380 ctgttgatta tatttaagaa tcaagcaagc agaccatata acatctaccc tcacggaatc 1440 actgatgtcc gtcctttgta ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat 1500 tttccaattc tgccaggaga aatattcaaa tataaatgga cagtgactgt agaagatggg 1560 ccaactaaat cagatcctcg gtgcctgacc cgctattact ctagtttcgt taatatggag 1620 agagatctag cttcaggact cattggccct ctcctcatct gctacaaaga atctgtagat 1680 caaagaggaa accagataat gtcagacaag aggaatgtca tcctgttttc tgtatttgat 1740 gagaaccgaa gctggtacct cacagagaat atacaacgct ttctccccaa tccagctgga 1800 gtgcagcttg aggatccaga gttccaagcc tccaacatca tgcacagcat caatggctat 1860 gtttttgata gtttgcagtt gtcagtttgt ttgcatgagg tggcatactg gtacattcta 1920 agcattggag cacagactga cttcctttct gtcttcttct ctggatatac cttcaaacac 1980 aaaatggtct atgaagacac actcacccta ttcccattct caggagaaac tgtcttcatg 2040 tcgatggaaa acccaggtct atggattctg gggtgccaca actcagactt tcggaacaga 2100 ggcatgaccg ccttactgaa ggtttctagt tgtgacaaga acactggtga ttattacgag 2160 gacagttatg aagatatttc agcatacttg ctgagtaaaa acaatgccat tgaaccaaga 2220 agcttctccc agaattcaag acaccctagc actaggcaaa agcaatttaa tgccaccaca 2280 attccagaaa attgtataga gaagactgac ccttggtttg cacacagaac acctatgcct 2340 aaaatacaaa atgtctcctc tagtgatttg ttgatgctct tgcgacagag tcctactcca 2400 catgggctat ccttatctga tctccaagaa gccaaatatg agactttttc tgatgatcca 2460 tcacctggag caatagacag taataacagc ctgtctgaaa tgacacactt caggccacag 2520 ctccatcaca gtggggacat ggtatttacc cctgagtcag gcctccaatt aagattaaat 2580 gagaaactgg ggacaactgc agcaacagag ttgaagaaac ttgatttcaa agtttctagt 2640 acatcaaata atctgatttc aacaattcca tcagacaatt tggcagcagg tactgataat 2700 acaagtactc ttcagtcaga tcaagaggaa attgactatg atgatacctg ttcagttgaa 2760 atgaagaagg aagattttga catttatgat gaggatgaaa atcagagccc ccgcagcttt 2820 caaaagaaaa cacgacacta ttttattgct gcagtggaga ggctctggga ttatgggatg 2880 agtagctccc cacatgttct aagaaacagg gctcagagtg gcagtgtccc tcagttcaag 2940 aaagttgttt tccaggaatt tactgatggc tcctttactc agcccttata ccgtggagaa 3000 ctaaatgaac atttgggact cctggggcca tatataagag cagaagttga agataatatc 3060 atggtaactt tcagaaatca ggcctctcgt ccctattcct tctattctag ccttatttct 3120 tatgaggaag atcagaggca aggagcagaa cctagaaaaa actttgtcaa gcctaatgaa 3180 accaaaactt acttttggaa agtgcaacat catatggcac ccactaaaga tgagtttgac 3240 tgcaaagcct gggcttattt ctctgatgtt gacctggaaa aagatgtgca ctcaggcctg 3300 attggacccc ttctggtctg ccacactaac acactgaacc ctgctcatgg gagacaagtg 3360 acagtacagg aatttgctct gtttttcacc atctttgatg agaccaaaag ctggtacttc 3420 actgaaaata tggaaagaaa ctgcagggct ccctgcaata tccagatgga agatcccact 3480 tttaaagaga attatcgctt ccatgcaatc aatggctaca taatggatac actacctggc 3540 ttagtaatgg ctcaggatca aaggattcga tggtatctgc tcagcatggg cagcaatgaa 3600 aacatccatt ctattcattt cagtggacat gtgttcactg tacgaaaaaa agaggagtat 3660 aaaatggcac tgtacaatct ctatccaggt gtttttgaga cagtggaaat gttaccatcc 3720 aaagctggaa tttggcgggt ggaatgcctt attggcgagc atctacatgc tgggatgagc 3780 acactttttc tggtgtacag caataagtgt cagactcccc tgggaatggc ttctggacac 3840 attagagatt ttcagattac agcttcagga caatatggac agtgggcccc aaagctggcc 3900 agacttcatt attccggatc aatcaatgcc tggagcacca aggagccctt ttcttggatc 3960 aaggtggatc tgttggcacc aatgattatt cacggcatca agacccaggg tgcccgtcag 4020 aagttctcca gcctctacat ctctcagttt atcatcatgt atagtcttga tgggaagaag 4080 tggcagactt atcgaggaaa ttccactgga accttaatgg tcttctttgg caatgtggat 4140 tcatctggga taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg 4200 cacccaactc attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta 4260 aatagttgca gcatgccatt gggaatggag agtaaagcaa tatcagatgc acagattact 4320 gcttcatcct actttaccaa tatgtttgcc acctggtctc cttcaaaagc tcgacttcac 4380 ctccaaggga ggagtaatgc ctggagacct caggtgaata atccaaaaga gtggctgcaa 4440 gtggacttcc agaagacaat gaaagtcaca ggagtaacta ctcagggagt aaaatctctg 4500 cttaccagca tgtatgtgaa ggagttcctc atctccagca gtcaagatgg ccatcagtgg 4560 actctctttt ttcagaatgg caaagtaaag gtttttcagg gaaatcaaga ctccttcaca 4620 cctgtggtga actctctaga cccaccgtta ctgactcgct accttcgaat tcacccccag 4680 agttgggtgc accagattgc cctgaggatg gaggttctgg gctgcgaggc acaggacctc 4740 tactga 4746 <210> 33 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_A2_1 <400> 33 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Cys Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 34 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_A2_2 <400> 34 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Cys Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 35 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_A2_3 <400> 35 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Cys Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 36 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_A3_1 <400> 36 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Cys Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 37 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_B1 <400> 37 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Cys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 38 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_1D <400> 38 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Cys Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 39 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_2D <400> 39 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Cys Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 40 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_3R <400> 40 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Cys Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 41 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_B2 <400> 41 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Cys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 42 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_B3 <400> 42 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Cys Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 43 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_B4 <400> 43 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Cys Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 44 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_B5 <400> 44 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Cys Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 45 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_4L <400> 45 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Cys Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 46 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_B6 <400> 46 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Cys Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 47 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_B7 <400> 47 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Cys Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580 <210> 48 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> G4_1I1D <400> 48 Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr 1 5 10 15 Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro 20 25 30 Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys 35 40 45 Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro 50 55 60 Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val 65 70 75 80 Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val 85 90 95 Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala 100 105 110 Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val 115 120 125 Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn 130 135 140 Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser 145 150 155 160 His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu 165 170 175 Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu 180 185 190 His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp 195 200 205 His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser 210 215 220 Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg 225 230 235 240 Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His 245 250 255 Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu 260 265 270 Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile 275 280 285 Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly 290 295 300 Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met 305 310 315 320 Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg 325 330 335 Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp 340 345 350 Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe 355 360 365 Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His 370 375 380 Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu 385 390 395 400 Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro 405 410 415 Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr 420 425 430 Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile 435 440 445 Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile 450 455 460 Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile 465 470 475 480 Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys 485 490 495 His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys 500 505 510 Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys 515 520 525 Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala 530 535 540 Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp 545 550 555 560 Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe 565 570 575 Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln 580 585 590 Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe 595 600 605 Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser 610 615 620 Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu 625 630 635 640 Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr 645 650 655 Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro 660 665 670 Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp 675 680 685 Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala 690 695 700 Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu 705 710 715 720 Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala 725 730 735 Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg 740 745 750 Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Cys Ile Glu Lys 755 760 765 Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn 770 775 780 Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro 785 790 795 800 His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe 805 810 815 Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser 820 825 830 Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val 835 840 845 Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly 850 855 860 Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser 865 870 875 880 Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala 885 890 895 Gly Thr Asp Asn Thr Ser Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp 900 905 910 Tyr Asp Asp Thr Cys Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile 915 920 925 Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr 930 935 940 Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met 945 950 955 960 Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val 965 970 975 Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe 980 985 990 Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu 995 1000 1005 Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe 1010 1015 1020 Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser 1025 1030 1035 1040 Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val 1045 1050 1055 Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met 1060 1065 1070 Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser 1075 1080 1085 Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu 1090 1095 1100 Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val 1105 1110 1115 1120 Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys 1125 1130 1135 Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys 1140 1145 1150 Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His 1155 1160 1165 Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala 1170 1175 1180 Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu 1185 1190 1195 1200 Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys 1205 1210 1215 Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe 1220 1225 1230 Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu 1235 1240 1245 Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu 1250 1255 1260 Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His 1265 1270 1275 1280 Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala 1285 1290 1295 Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser 1300 1305 1310 Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met 1315 1320 1325 Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser 1330 1335 1340 Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys 1345 1350 1355 1360 Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe 1365 1370 1375 Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro 1380 1385 1390 Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg 1395 1400 1405 Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser 1410 1415 1420 Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr 1425 1430 1435 1440 Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys 1445 1450 1455 Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val 1460 1465 1470 Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys 1475 1480 1485 Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met 1490 1495 1500 Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp 1505 1510 1515 1520 Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln 1525 1530 1535 Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr 1540 1545 1550 Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu 1555 1560 1565 Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr 1570 1575 1580

Claims (23)

  1. 인간 혈액응고 8인자(Factor VIII)의 중쇄, 경쇄 및 일부가 결실된 B 영역 단편을 포함하며, 상기 일부가 결실된 B 영역 단편은 퓨린 단백질분해효소에 의한 절단부위를 포함하지 않으며, 최소 4개의 당화 부위를 포함하는 것으로,
    상기 일부가 결실된 B 영역 단편은 서열번호 1의 서열을 기준으로 (i) 아미노산 잔기 741 내지 902 및 1654 내지 1689; (ii) 아미노산 잔기 741 내지 965 및 1654 내지 1689의 아미노산 서열; 또는 (iii) 아미노산 잔기 741 내지 902, 1637 내지 1642 및 1654 내지 1689의 아미노산 서열이고,
    상기 혈액응고 8인자는 A 영역, B 영역 또는 A 영역 및 B 영역 단편의 일부 아미노산 잔기에서 친수성 폴리머와 컨쥬게이션되고, 상기 컨쥬게이션되는 위치는 상기 B 영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 754, 781, 782, 788, 789, 825 및 897로 구성되는 군으로부터 선택되는 하나 이상의 위치이고; 상기 A 영역에서 서열번호 1의 서열을 기준으로 아미노산 잔기 491, 495, 498 및 1806으로 구성되는 군으로부터 선택되는 하나 이상의 위치이며,
    상기 컨쥬게이션되는 위치의 잔기는 상기 친수성 폴리머와의 접합을 위해 시스테인으로 치환되는 것인, 단쇄 혈액응고 8인자.
  2. 제 1 항에 있어서,
    상기 일부가 결실된 B 영역 단편은 4개 내지 6개의 당화 부위를 포함하는 것인, 단쇄 혈액응고 8인자.
  3. 삭제
  4. 제 1 항에 있어서,
    상기 단쇄 혈액응고 8인자는 서열번호 4, 서열번호 5, 서열번호 6 또는 서열번호 7로 표시되는 서열 또는 이와 90% 이상 상동성이 있는 서열을 갖는 것인, 단쇄 혈액응고 8인자.
  5. 제 1 항에 있어서,
    상기 단쇄 혈액응고 8인자는 CS 또는 APTT 방법으로 측정한 비활성이 이쇄 혈액응고 8인자 비활성의 90% 이상인, 단쇄 혈액응고 8인자.
  6. 삭제
  7. 제 1 항에 있어서,
    상기 친수성 폴리머는 폴리에틸렌글리콜(Polyethylene glycol), 폴리에틸렌 옥사이드, 덱스트란 또는 폴리시알릭을 포함하고, 상기 PEG는 상기 위치에서 acryloyl, sulfone 또는 maleimide를 통하여 연결된 것인, 단쇄 혈액응고 8인자.
  8. 제 7 항에 있어서,
    상기 PEG는 평균 분자량이 20kDa 이상인 단쇄 혈액응고 8인자.
  9. 제 1 항에 있어서,
    상기 단쇄 혈액응고 8인자는 서열번호 4 내지 7 중 어느 하나의 아미노산 서열로 표시되는, 단쇄 혈액응고 8인자.
  10. 삭제
  11. 제 1 항에 따른 단백질을 코딩하는 핵산분자.
  12. 제 11 항에 있어서,
    상기 핵산분자는 서열번호 12 내지 15 중 어느 하나인, 핵산분자.
  13. 제 11 항에 따른 핵산분자를 포함하는 벡터.
  14. 제 13 항에 따른 벡터를 포함하는 세포.
  15. 제 13 항에 따른 벡터를 진핵세포에 전달이입하는 단계; 또는 선택적으로 제 14 항에 따른 세포를 제공하는 단계;
    상기 세포를 배양액 중에서 배양을 통하여 도입된 시스테인의 자유 티올 기를 시스테인 또는 글루타티온에 의해 이황화(disulfide) 결합으로 마스킹 된 단쇄 FVIII형태로 발현시키는 단계;
    상기 배양액으로부터 발현된 단쇄 FVIII을 수집하여 환원제로 처리하여 마스킹 된 시스테인이나 글루타티온을 이탈 시키는 단계; 및
    상기 처리된 배양액을 페길화완충액으로 처리하는 단계를 포함하는, 단쇄 혈액응고 8인자의 생산방법.
  16. 삭제
  17. 삭제
  18. 삭제
  19. 삭제
  20. 삭제
  21. 삭제
  22. 제 1 항, 제 2 항, 제 4 항, 제 5 항 및 제 7 항 내지 제 9 항 중 어느 한 항에 따른 단쇄 혈액응고 8인자 및 약학적으로 허용가능한 담체를 포함하는, 혈우병 치료용 조성물.
  23. 삭제
KR1020197002468A 2016-06-24 2017-06-23 재조합 단쇄 fviii 및 그 화학 접합물 KR102219859B1 (ko)

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