KR102175878B1

KR102175878B1 - Fviii 및 vwf 인자를 포함하는 키메라 단백질 및 그 용도

Info

Publication number: KR102175878B1
Application number: KR1020197002467A
Authority: KR
Inventors: 오인재; 이승훈; 조의철; 오미숙; 류재환; 김용재; 김소라; 박진현
Original assignee: 재단법인 목암생명과학연구소
Priority date: 2016-06-24
Filing date: 2017-06-23
Publication date: 2020-11-06
Anticipated expiration: 2037-06-23
Also published as: WO2017222337A1; KR20190018528A; US11046749B2; EP3476937A4; CN109790529A; JP6877469B2; JP2019522977A; US20190330311A1; EP3476937A1

Abstract

본원에 따른 키메라 단백질은 FVIII에 결합된 vWF 도메인으로 인해, 투여시 체내 반감기가 월등히 증가하여, 혈우병 A형의 치료제로서 환자의 편리성이 증대되는 것은 물론, 치료비의 절감을 가져올 수 있다.

Description

FVIII 및 VWF 인자를 포함하는 키메라 단백질 및 그 용도

본원은 혈우병의 치료에 사용되는 재조합 Factor VIII과 관련된 기술이다.

혈우병은 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, 혈우병 A가 약 80-85%를 차지한다.

혈우병은 유형에 따라 투여약제가 상이하며, 동일한 유형의 경우에도 투여부위에 따라 투여량과 방법이 다르다. 하지만 혈우병 치료의 목적은 지혈이며 치료는 효소대체요법(ERT, Enzyme Replacement Therapy)을 이용하여 예방적(prophylaxis)과 대증적(on demand)의 두 가지 측면에서 수행되는데, 현재 치료법은 예방적 측면으로 옮겨가는 추세이다.

ERT를 위해 사용되는 효소로 과거에는 전혈과 혈장에서 추출하여 농축한 FVIII (혈우병 A), FIX 인자 (혈우병 B)가 사용되었다. 하지만 전혈과 혈장에서 혈우인자를 추출할 때, AIDS나 HBV와 같은 바이러스에 감염된 사람의 혈액이 일부 사용되었고, 이러한 바이러스가 혈우인자(coagulant factor) 추출과정에서 적절히 제거되지 못함으로 인한 바이러스 감염과 같은 부작용과 합병증의 문제가 발생하였다. 따라서 최근에는 유전자 재조합 기술로 생산된 다양한 인자가 개발되어 사용되고 있으며, 예를 들면 온전한 형태의 FVIII, 또는 B 도메인이 결실된 형태, 특정 잔기에서의 변형을 통해 반감기가 증가된 다양한 FVIII 등이 개발되고 있다.

FVIII을 예방적 요법으로 사용할 때, FVIII의 혈중 반감기가 12시간(human)으로 짧아 2~3일에 한 번 투여해야 하는 불편함이 있다. 또한, I.V 투여이기 때문에 투여 횟수 감소가 환자 편의성 측면에서 봤을 때, 중요하다. 이에 FVIII의 혈중 반감기를 늘려준 long-acting FVIII이 최근 개발되었다.

그 중 한 가지는 FVIII의 C-말단에 항체의 Fc 도메인을 융합한 FVIII-Fc 융합 단백질(FVIII-Fc)이 개시되어 있고, 이 물질은 FcRn recycling을 이용하여 반감기를 증가시키는 전략을 사용하였다. 또한 FVIII에 PEG(polyethylene glycol)를 FVIII의 생체 내 제거(clearance)를 담당하는 것으로 알려진 LRP(Low density lipoprotein receptor related protein)과의 결합부위 근처에 접합시킨 페길화 FVIII이 몇 건 개시되어 있다. 하지만, 이들 long-acting FVIII들의 임상결과 반감기가 기존 12시간에서 평균 18시간 정도로 약 1.5배 밖에 증가하지 못 했으며, 이는 기존 주 3~4회의 투여 횟수가 주 2~3회 투여 횟수로 줄어든 것을 의미한다. 이렇게 FVIII-Fc와 페길화 FVIII의 반감기가 크게 증가하지 못 하는 이유는 FVIII이 혈중에서 vWF와 비공유 결합(non-covalent interaction)을 강하게 하고 있는 상태로 혈중에서 순환(circulation)하고 있기 때문이다. FVIII-Fc와 페길화 FVIII의 경우에도 혈중에서 혈중에 존재하는 vWF와 비공유 결합을 하게 되고, 결국 vWF의 반감기에 영향을 받아 vWF의 반감기(12시간, human)에 수렴하게 되는 한계가 있다 (Tiede A. Journal of Thrombosis and Haemostasis, 13 (Suppl. 1): S176-S179).

현재까지 개발된 치료제는 여전히 기능적 측면에서 투여 주기(정맥 주사)가 짧고, 또한 충분히 길지 못한 반감기로 인한 체내 효력 소실에 따라 잦은 출혈 빈도가 문제점으로 지적되고 있다. 따라서 투여 횟수를 최소 주 1회까지 줄여 주기 위한 반감기가 3배 이상 증가한 long-acting FVIII의 개발이 필요하다.

본원은 체내 체류 시간이 향상되어 주 1회 이하로 투여 가능한 FVIII을 제공하고자 한다.

한 양태에서 본원은 경쇄 및 중쇄를 포함하며 B 도메인의 전장 또는 그 일부가 결실된 인간 혈액응고 8인자(Factor VIII, FVIII); 및 하나 이상의 vWF D’D3 도메인을 포함하는 키메라 단백질을 제공한다. 본원에 따른 단백질은 야생형 FVIII 단백질과 비교하여 최소 2배 반감기가 연장된다.

본원에 따른 키메라 단백질에서, 상기 경쇄 및 중쇄는 한 개 폴리펩타이드로 또는 두 개의 폴리펩타이드로 발현될 수 있다.

본원에 따라 상기 한 개의 폴리펩타이드로 발현되는 경우, 상기 FVIII 및 상기 vWF D’D3 도메인을 연결하며, 그 사이에 위치하는 효소절단부위 갖는 연결체를 포함하며, 상기 vWF D’D3 도메인은 상기 연결체를 기준으로 그 N-말단이 상기 FVIII의 N-말단 또는 C-말단 방향, 또는 상기 vWF D’D3 도메인 및 상기 FVIII는 각각 상기 연결체를 기준으로 그 N-말단 방향 또는 C- 말단 방향에 위치한다. 일 구현예에서 예를 들면 N 부터 C 방향으로 FVIII-연결체-D’D3 또는 D’D3-연결체-FVIII의 순서로 배열될 수 있다.

본원에 따라 두 개의 폴리펩타이드로 발현되는 경우, 상기 vWF D’D3 도메인은 그 N-말단이 상기 중쇄에 포함된 상기 B 도메인의 C-말단에 연결될 수 있다.

일 구현예에서 본원에 따른 키메라 단백질에 포함될 수 있는 일부가 결실된 B 도메인은 서열번호 1의 서열에서, 1648 및 1649 잔기 위치를 기준으로 상기 잔기를 포함하여 N-말단 및/또는 C-말단 방향으로 각각 최소 5개의 아미노산이 결실된 것; 또는 상기 B 도메인이 최소 4개, 또는 4개 내지 6개의 당화부위를 포함하도록 일부가 결실된 것을 포함한다.

다른 구현예에서 본원에 따른 키메라 단백질에 포함될 수 있는 일부가 결실된 B 도메인은 서열번호 01의 서열을 기준으로 아미노산 잔기 741 내지 902 및 1654 내지 1689의 서열, 또는 서열번호 01의 서열을 기준으로 아미노산 잔기 741 내지 936의 서열로 표시된다.

또 다른 구현예에서 본원에 따른 키메라 단백질은 하나 이상의 Fc를 추가로 포함하며, 상기 Fc는 상기 vWF D’D3 도메인 및/또는 상기 FVIII에 연결될 수 있다.

본원에 따른 다른 구현예에서 본원에 따른 키메라 단백질은 두 개 이상의 vWF D’D3 도메인 및/또는 두 개 이상의 Fc를 추가로 포함할 수 있다. 이 경우, 복수 개의 vWF D’D3 도메인간, 그리고 복수 개의 Fc 간에는 서로 효소절단부위를 포함하거나 포함하지 않는 연결체로 연결되거나 및/또는 서로간에 공유결합을 통한 복합체, 예를 들면 두 개를 포함하는 경우 이량체를 형성할 수 있다. 여기에 사용된 효소절단부위 및 연결체는 본 명세서에 기재된 것을 참조 할 수 있다.

또 다른 구현예에서 본원에 따른 키메라 단백질에서 효소절단 부위를 포함하는 연결체가 사용되는 경우, 상기 효소절단부위는 트롬빈, FVIIa, FXa 또는 FXIa에 의해 절단될 수 있는 서열이고, 그 외의 서열은 [G₄S]_n 의 아미노산 서열로 표시되며, 상기 식에서 n= 0, 또는 1 내지 100 사이 정수, 특히 n은 4, 6, 8, 10, 16, 21, 22 또는 58이다.

또 다른 구현예에서 본원에 따른 키메라 단백질에서 연결체에 포함된 효소절단 부위에서 상기 트롬빈에 의해 절단될 수 있는 아미노산 서열은 DFLAEGGGVR (서열번호 36), TTKIKPR (서열번호 37), 또는 LVPRGS (서열번호 38)이고, 상기 FVIIa에 의해 절단될 수 있는 아미노산 서열은 ASKPQGRIVGG (서열번호 39), 상기 FXa에 의해 절단될 수 있는 아미노산 서열은 IDGR (서열번호 40) 또는 IEGR (서열번호 41)이고, 상기 FXIa에 의해 절단될 수 있는 서열은 SKLTRAETVF (서열번호 42)로 표시될 수 있다.

다른 양태에서 본원에 따른 키메라 단백질은 제 1 및 제 2 폴리펩타이드의 형태로 발현되며, 제 1 폴리펩타이드는 상기 FVIII의 중쇄 및 B 도메인의 전부 또는 일부를 포함하고, 상기 제2 폴리펩타이드는 상기 FVIII의 경쇄 또는 B 도메인의 일부를 포함하고, 상기 vWF D’D3 도메인은 상기 제 1 폴리펩타이드의 N-말단 또는 C-말단 방향, 또는 제 2 폴리펩타이드의 N-말단 또는 C-말단에 위치한다. vWF D’D3 도메인이 제1 폴리펩타이드 N-말단 또는 제 2 폴리펩타이드의 C-말단에 연결되는 경우 scFVIII의 N-말단 또는 C-말단에 연결되는 것과 유사한 구조를 갖으며, 이 경우 FVIII가 단쇄 또는 이쇄인지가 차이나는 부분이다.

일 구현예에서 제 1 및 제 2 폴레펩타이드의 형태로 발현되는 경우, 상기 vWF D’D3 도메인은 제 1 폴리펩타이드의 C-말단 방향에 위치한다.

본원에 따른 키메라 단백질은 하나 이상, 특히 두 개의 vWF D’D3 도메인을 포함할 수 있으며, vWF D’D3 도메인 간에 복합체(이량체)를 형성할 수 있다.

선택적으로 본원에 따른 키메라 단백질은 하나 이상의 Fc, 특히 두개의 Fc를 추가로 포함하며, 상기 Fc는 상기 vWF D’D3 도메인 및/또는 상기 제 2 폴리펩타이드에 연결될 수 있다. Fc 간에 복합체(이량체)를 형성할 수 있다.

일구현예에서 본원에 따른 키메라 단백질에서 Fc 또는 상기 vWF D’D3 도메인은 효소절단부위를 포함하거나 또는 포함하지 않는 연결체로 연결된다.

일 구현예에서 본원에 따른 키메라 단백질은 한 개의 폴리펩타이드로 발현되는 경우 서열번호 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21 또는 25로 표시되는 아미노산 서열 또는 이와 생물학적 기능이 균등하거나 또는 이와 90% 이상 상동성이 있는 아미노산 서열도 본원에 포함될 수 있다.

다른 구현예에서 본원에 따른 키메라 단백질은 두 개의 폴리펩타이드로 발현되는 경우 서열번호 4 및 5 (각각 중쇄 및 경쇄), 서열번호 23 및 24 (각각 중쇄 및 경쇄), 서열번호 26 및 27 (각각 중쇄 및 경쇄), 서열번호 28 및 29 (각각 중쇄 및 경쇄), 서열번호 30 및 31 (각각 중쇄 및 경쇄), 서열번호 32 및 33 (각각 중쇄 및 경쇄), 또는 서열번호 34 및 35 (각각 중쇄 및 경쇄)로 표시되는 아미노산 서열 또는 이와 생물학적 기능이 균등하거나 또는 이와 90% 이상 상동성이 있는 아미노산 서열도 본원에 포함될 수 있다.

본원에 따른 키메라 단백질은 FVIII의 A 도메인 및/또는 B 도메인 단편의 일부 아미노산 잔기에서 친수성 폴리머와 컨쥬게이션될 수 있고, 상기 컨쥬게이션되는 위치는 상기 B 도메인에서 서열번호 01의 서열을 기준으로 아미노산 잔기 754, 781, 782, 788, 789, 825, 및 897로 구성되는 군으로부터 선택되는 하나 이상의 위치이고; 상기 A 도메인에서 서열번호 01의 서열을 기준으로 아미노산 잔기 491, 495, 498 및 1806으로 구성되는 군으로부터 선택되는 하나 이상의 위치이고, 상기 컨쥬게이션되는 위치의 잔기, 특히 컨쥬게이션 되는 모든 위치의 잔기는 친수성 폴리머와의 접합을 위해 시스테인으로 치환된다.

일 구현예에서 친수성 폴리머는 폴리에틸렌글리콜(Polyethylene glycol), 폴리에틸렌 옥사이드, 덱스트란이다.

다른 구현예에서, 친수성 폴리머는 폴리에틸렌글리콜이고, 평균 분자량이 최소 20kDa이상, 특히 40kDa 또는 60kDa의 PEG가 사용된다.

일 구현예에서 본원에 따른 키메라 단백질은 FVIII의 B 도메인 단편, 특히 782번 잔기에서 개질된다.

다른 양태에서 본원은 상술한 키메라 단백질을 코딩하는 핵산, 상기 핵산을 포함하는 벡터, 상기 벡터를 포함하는 세포를 제공한다.

또 다른 양태에서 본원은 키메라 단백질, 이를 코딩하는 핵산, 상기 핵산을 포함하는 벡터, 상기 벡터를 포함하는 세포의 용도를 제공한다.

본원에 따른 발명의 용도는 혈우병 치료용 조성물, 혈우병 치료 방법, 혈액 응고용 조성물, 혈액 응고 방법, 또는 본원에 따른 단백질의 생산 방법을 포함한다.

본원에 따른 FVIII와 vWF 도메인이 결합된 키메라 단백질 또는 PEG로 개질된 형태의 키메라 단백질은 투여 시 체내 반감기가 월등히 증가하여, 기존 주 2~4회의 투여 횟수를 주 1회 이하로 줄여주어, 혈우병 A형의 치료제로서 환자의 편리성이 증대되는 것은 물론, 치료비의 절감을 가져올 수 있다.

도 1은 본원에 따른 반감기가 증가된 재조합 FVIII의 반감기 증가 기전을 도식적으로 나타낸 것이다. FVIII의 생체 내 제거에 가장 큰 영향을 미치는 것으로 알려진 LRP 결합부위를 PEG와 vWF의 일부 도메인인 D’D3로 가려(masking)주는 것이 첫 번째 전략이다. 이와 동시에 본원에 따른 키메라 단백질에 vWF의 일부 도메인인 D’D3를 공유적으로 결합시켜 주어 혈중에 있는 내인성 vWF가 키메라 단백질에 결합하는 것을 막아주는 것이 두 번째 전략이다.
도 2a 및 2b는 각각 본원에 따른 단쇄(단일 폴리펩타이드) 및 이쇄(이중 폴리펩타이드)로 발현되는 키메라 단백질의 다양한 분자구조를 도식적으로 나타낸 것이다.
도 3은 본원의 일 구현예에 따른 단일 폴리펩타이드로 발현되는 키메라 단백질을 코딩하는 벡터를 도식적으로 나타낸 것이다.
도 4는 본원의 일 구현예에 따른 다양한 길이의 연결체를 포함하는 키메라 단백질 발현 및 정제 후 SDS-PAGE로 분석한 결과이다.
도 5는 본원의 일 구현예에 따른 다양한 길이의 연결체를 포함하는 키메라 단백질을 각각 중쇄, 경쇄 및 D’D3에 대한 항체로 분석한 웨스턴블랏 결과이며, 사용된 각 항체는 다음과 같다: 중쇄: Green mountain, GMA-012; 경쇄: Abcam, 41188 및 D’D3: Abcam, 96340.
도 6은 본원의 일 구현예에 따른 scFVIII/D’D3-60, -120 및 -300을 PEG로 개질한 페길화 키메라 단백질을 정제 후 SDS-PAGE로 분석한 결과이다.
도 7은 본원의 일 구현예에 따른 키메라 FVIII (scFVIII/D’D3-120-TH1), 페길화 키메라 FVIII (PEG-scFVIII/D’D3-120-TH1)의 vWF 결합 분석 결과로 비교군으로 Advate®를 사용하였다.
도 8은 본원의 일 구현예에 따른 키메라 FVIII (scFVIII/D’D3-120-TH1), 페길화 키메라 FVIII (PEG-scFVIII/D’D3-120-TH1)의 LRP 결합 분석 결과로 비교군으로 Advate®를 사용하였다.
도 9는 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (PEG-scFVIII/D’D3-120)의 HA mice에서의 PK 분석 결과로 비교군으로 Advate®를 사용하였다.
도 10은 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (40 kDa PEG-scFVIII/D’D3-120, 60 kDa PEG-scFVIII/D’D3-120)의 HA mice에서의 PK 분석 결과로 비교군으로 Advate®를 사용하였다.
도 11은 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (PEG-scFVIII/D’D3-60, PEG-scFVIII/D’D3/Fc-120, Fc)의 HA mice에서의 PK 결과로 비교군으로 Advate®를 사용하였다.
도 12는 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (PEG-scFVIII/D’D3-300, PEG-scFVIII/D’D3/D’D3-120)의 HA mice에서의 PK 결과로 비교군으로 Advate®를 사용하였다.
도 13은 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (PEG-scFVIII/D’D3-60, PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-300)의 HA mice에서의 PK 결과로 비교군으로 Advate®를 사용하였다.
도 14는 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-120-TH1, PEG-scFVIII/D’D3-120-TH2)의 HA mice에서의 PK 결과로 비교군으로 Advate®를 사용하였다.
도 15는 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (20 kDa linear PEG-scFVIII/D’D3-120-TH1, 20 kDa branch PEG-scFVIII/D’D3-120-TH1, 40 kDa branch PEG-scFVIII/D’D3-120-TH1)의 HA mice에서의 PK 결과로 비교군으로 Advate®를 사용하였다.
도 16은 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (PEG-scFVIII/D’D3-120-TH1)의 트롬빈 생성 분석 결과이다.
도 17은 본원의 일 구현예에 따라 제조한 페길화 키메라 FVIII (PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-120-TH1, PEG-scFVIII/D’D3-120-TH2)의 꼬리클립모델(tail clip model)에서의 급성효능연구결과로 비교군으로 Advate®를 사용하였다.
도 18은 본원의 일 구현예에 따라 CHO 세포에서 발현하여 제조한 페길화 키메라 FVIII (20 kDa linear PEG-scFVIII/D’D3-120-TH1, 40 kDa linear PEG-scFVIII/D’D3-120-TH1)의 HA 마우스에서의 PK 결과로 비교군으로 Advate®를 사용하였다.

본원은 FVIII이 내인성 vWF 단백질과 복합체를 형성하는 것을 방지 또는 억제하는 것과 동시에 FVIII이 LRP(Low density lipoprotein receptor related protein)에 결합하는 것을 막아주어 FVIII 단백질의 반감기를 연장하는 기술에 관한 것이다. 이로 인해 LRP 및 프로테아제 의존적 FVIII 제거를 지연시키는 것은 물론 vWF 의존적 제거를 동시에 감소시켜 반감기가 증가된다.

따라서 한 양태에서 본원은 인간 혈액응고 8인자(Factor VIII 또는 FVIII) 및 하나 이상의 vWF D’D3 도메인이 융합된 키메라 단백질에 관한 것이다.

본원에 따른 키메라 단백질은 천연형태에서 경쇄와 중쇄로 구성되는 FVIII의 경쇄 및 중쇄를 하나의 폴리펩타이드로 발현되는 단쇄(sc, single chain)로, 또는 경쇄 및 중쇄가 각각 별개의 폴리펩타이드로 발현되는 이쇄(dc, dual chain)의 형태를 취할 수 있다.

일 구현예에서 본원에 따른 키메라 단백질이 단쇄(단일 폴리펩타이드)로 구현되며, 이 경우 vWF D’D3 도메인은 FVIII의 N- 또는 C- 말단 방향에 위치하며, 효소에 의한 절단 부위를 포함하는 아미노산 링커(또는 연결체)로 연결된다.

본원에 따른 키메라 단백질은 또한 이쇄(이중 폴리펩타이드)로 구현되며, 이 경우 vWF D’D3 도메인은 FVIII의 중쇄 또는 경쇄의 N- 또는 C- 말단 방향에 연결될 수 있다. 일 구현예에서는 특히 B 도메인의 C- 말단 방향에 연결된다.

본원에 따른 키메라 단백질에 포함될 수 있는 FVIII 단백질은 vWF와의 결합을 통해 본원에 따른 목적을 달성하는 한, 다양한 길이 또는 유래의 것이 사용될 수 있다.

FVIII는 A1-A2-B-A3-C1-C2 도메인으로 구성되며, 간세포에서 단쇄의 단백질로 합성된다. 합성 후 프로세싱을 거쳐 성숙되어 중쇄와 경쇄로 구성된 280 kDa의 헤테로이량체를 형성한다. 이 중 경쇄는 80kDa이며 A3-C1-C2 도메인으로 구성되고, 중쇄는 A1-A2-B 도메인으로 구성되고 분자량은 90-200kDa으로 B-도메인의 길이에 따라 분자량의 차이가 크다. 이러한 헤테로이량체는 혈액 내에서 vWF와 결합하여 비활성화 상태로 존재하다가, 혈관 손상과 같은 자극에 노출 시, 트롬빈에 의해 알지닌 잔기 뒤, 즉 서열번호 01의 서열을 기준으로 372, 740 및 1689번 잔기 뒤에서 절단된다. 그 결과 vWF로부터 분리되고, 활성화되어 A1, A2 및 A3-C1-C2의 삼량체가 형성된다. 이어 삼량체는 FIXa에 의한 FX의 활성화를 촉매하고, 빠르게 분해된다.

본원에 따른 키메라 단백질에 포함될 수 있는 FVIII 단백질은 응고 경로에서 전장 야생형 FVIII 인자의 기능을 보유하는 전장, 이의 기능적 단편, 변이체, 유사체 또는 유도체를 포함한다. FVIII 단백질은 FVIII 폴리펩타이드 또는 FVIII과 상호 교환적으로 사용된다. FVIII 기능의 예는 혈액 응고를 활성화시키는 능력, IX 인자에 대한 보조인자로서 작용하는 능력, 또는 Ca²⁺ 및 인지질의 존재 하에 IX 인자와 테나세 복합체(tenase complex)를 형성하는(이후 X 인자를 활성화 형태 Xa로 전환시킴) 능력을 포함하지만, 이들로 제한되지는 않는다.

또한 다양한 유래의 FVIII 단백질이 사용될 수 있으며, 예를 들면 인간, 돼지과, 고양이과, 래트 또는 쥣과 FVIII 단백질일 수 있다. FVIII 아미노산 및 핵산 서열의 비제한적인 예는 예컨대 GenBank NOs: NM_000132, NP_000123, 1012296A AAA52420.1, CAA25619.1, AAA52484.1, 1012298A, EAW72647.1, EAW72646.1, XP_001498954.1, ACK44290.1, ACO95359.1, NP_001138980.1, ABZ10503.1, NP_032003.2로 개시되어 있다.

본원에 따른 일 구현예에서는 인간 유래의 FVIII이 사용되며, 예를 들면 인간 FVIII은 서열번호 01의 서열(신호펩타이드는 포함하지 않음)로 표시될 수 있으며, 야생형 서열에서 중쇄는 서열번호 01의 서열을 기준으로 1-740 잔기, B 도메인은 a3 도메인을 포함하여 741-1689 잔기, 경쇄는 1690-2332 잔기까지이다.

또한 FVIII의 변이체, 유도체, 변형체, 돌연변이체, 복합체 또는 유사체 또한 당해 분야에 공지되어 있으며, 또 본 발명에 포함된다. 예를 들어, 미국 특허번호 제5,668,108호에 개시된 바와 같은 FVIII의 변이체는 위치 1241에 있는 아스파라긴산이 글루탐산에 의해 치환되고 첨부된 핵산 변화를 갖는 FVIII의 변이체를 개시하고; 미국 특허번호 제5,149,637호는 글리코실화되거나 또는 글리코실화되지 않은 C-말단 단편을 포함하는 FVIII 변이체를 기재하며; 또 미국 특허번호 제5,661,008호는 적어도 3개 아미노산 잔기에 의해 아미노산 1649 내지 2332에 연결된 아미노산 1-740을 포함하는 FVIII 변이체를 개시한다.

본원에 따른 키메라 단백질에 포함될 수 있는 FVIII은 B 도메인이 결실된 FVIII을 포함하며, 이러한 FVIII은 예를 들면 미국 특허 제6,316,226호, 제6,346,513호, 제7,041,635호, 제5,789,203호, 제6,060,447호, 제5,595,886호, 제6,228,620호, 제5,972,885호, 제6,048,720호, 제5,543,502호, 제5,610,278호, 제5,171,844호, 제5,112,950호, 제4,868,112호 및 제6,458,563호에 개시된 것을 포함하나 이로 제한하는 것은 아니다.

또한 본원에 따른 키메라 단백질에 포함될 수 있는 FVIII은 B 도메인의 일부가 결실된 FVIII으로 중쇄 및 경쇄를 포함하나 퓨린(furin)과 같은 단백질분해효소에 의한 절단부위를 포함하지 않도록 일부 잔기가 결실된다.

일 구현예에서 일부가 결실된 B 도메인은 서열번호 01의 서열의 1648 및 1649 잔기 위치를 기준으로, 이를 포함하여 N-말단 및 C-말단 방향으로 각각 최소 5개의 아미노산이 결실된 것을 포함하거나 및/또는 4개 내지 6개의 당화부위를 포함하도록 일부가 결실된 B 도메인 단편을 포함한다.

일 구현예에서 본원에 따른 키메라 단백질에 포함될 수 있는 B 도메인의 일부가 결실된 FVIII에서, 상기 B 도메인 단편은 서열번호 01의 서열을 기준으로 아미노산 잔기 741 내지 902 및 1654 내지 1689를 포함하는 것이다.

다른 구현예에서는 이러한 B 도메인 단편은 서열번호 01의 서열을 기준으로 아미노산 잔기 741 내지 902 및 1654 내지 1689의 아미노산 서열을 포함하고 상기 잔기 중 일부, 특히 782번 아이소루이신 잔기가 친수성 폴리머로의 개질을 위해 시스테인으로 치환된 것을 포함하는 것이다.

또 다른 구현예에서 본원에 따른 키메라단백질에 포함될 수 있는, B 도메인의 일부가 결실된 FVIII는 서열번호 03으로 표시되는 아미노산 서열 또는 이와 90% 이상의 상동성이 있는 아미노산 서열을 갖는다. 상기 서열번호 03의 아미노산 서열에 포함된 B 도메인은 서열번호 01을 기준으로 741 - 902번 잔기를 포함한다.

본원에 따른 키메라 단백질에 포함될 수 있는 FVIII은 A 도메인 및/또는 B 도메인 단편의 일부 아미노산 잔기에서 친수성 폴리머와 컨쥬게이션되어 개질될 수 있다.

특히 본원에서는 개질을 통해 본원에 따른 키메라 단백질의 LRP 결합을 방해하기 위한 것으로, 부위 특이적으로 진행되며, 이를 달성할 수 있는 다양한 위치에서 개질될 수 있다.

본원에 따른 일 구현예에서 본원에 따른 키메라 단백질에서 컨쥬게이션되는 위치는 상기 A 도메인에서 서열번호 01의 서열을 기준으로 아미노산 잔기 491, 495, 498 및 1806으로 구성되는 군으로부터 선택되는 하나 이상의 위치; 그리고 상기 B 도메인에서 서열번호 01의 서열을 기준으로 아미노산 잔기 754, 781, 782, 788, 789, 825, 897로 구성되는 군으로부터 선택되는 하나 이상의 위치이다.

본원에 따른 다른 구현예에서 특히 B 도메인, 특히 상술한 위치에서 페길화된다.

본원에 따른 다른 구현예에서는 B 도메인의 782번 아이소루이신 잔기에서 개질되며, 특히 페길화되고, 페길화를 위해, 후술하는 바와 같이 상기 잔기가 시스테인으로 치환되거나 또는 시스테인기가 삽입될 수 있다.

본원에 따른 FVIII의 개질에 사용될 수 있는 친수성 폴리머는 본원에 따른 목적을 달성하는 한 당업계에 공지된 다양한 폴리머가 사용될 수 있으며, 예를 들면 폴리에틸렌글리콜(Polyethylene glycol), 폴리에틸렌 옥사이드, 덱스트란을 포함하나 이로 제한하는 것은 아니다.

본원에 따른 일 구현예에서는 PEG가 사용되며, 특히 20kDa 이상의 PEG가 사용된다. 본원에 따르면, PEG는 LRP 결합영역 근처에 결합되어 PEG hindrance에 의해 FVIII이 LRP에 결합하는 것을 저해 시키는 기능을 하며, 따라서 PEG의 길이가 너무 짧으면 이러한 hindrance를 충분히 주지 못 할 가능성이 있기 때문에 PEG의 길이가 20kDa 이상인 것이 중요하다. 일 구현예에서는 특히 40kDa, 60kDa 또는 그 이상의 PEG가 사용된다.

본원에 따른 개질에서 페길화에 사용되는 PEG는 공지된 다양한 작용기 (functional group)을 이용하여 해당 잔기에 연결될 수 있다.

본원에 따른 일 구현예에서 PEG는 부위 특이적으로 시스테인과 같은 잔기에 존재하는 자유 -SH기를 통해 연결되며, 이 경우 예를 들면 thiol, orthopyridyl disulfide, acryloyl, sulfone 또는 maleimide기, 특히 maleimide기를 통해 연결될 수 있으나, 이로 제한하는 것은 아니다.

본원에 따른 FVIII은 친수성 폴리머로의 개질을 위해 친수성 폴리머에 연결되는 잔기는 다른 잔기로 치환 또는 삽입 될 수 있으며, 치환 또는 삽입되는 잔기는 개질에 사용되는 물질에 따라 상이하며, 당업자라면 적절한 것을 선정할 수 있을 것이다.

본원에 따른 일 구현예에서는 개질로서 페길화가 사용되며, 이 경우 개질되는 잔기는 시스테인으로 치환 또는 시스테인 잔기가 적절한 위치에 삽입될 수 있다.

본원에 따른 일 구현예에서는 B 도메인의 782번 아이소루이신 잔기에서 개질되며, 특히 페길화되고, 페길화를 위해 상기 잔기가 시스테인으로 치환된다.

페길화 반응은 공지된 방법을 이용하여 수행될 수 있으며, 예를 들면 자유 시스테인의 마스킹을 위해 사용된 시스테인이나 글루타치온은 페길화 반응 전에 제거되어 도입한 시스테인의 free thiol이 복원되어야 하며, 이를 위해 TCEP, DTT, beta-mercaptoethanol, 시스테인, 글루타티온(환원형) 등의 환원제를 처리하는 과정과 이 과정에서 FVIII 본연의 이황화 본드가 환원적으로 절단된 것을 복원하기 위한 산화 과정을 포함하여 수행할 수 있다. 개질을 위해 시스테인으로 치환된 단백질의 발현은 당업계에 공지된 방법을 이용하여 수행될 수 있으며, 예를 들면 페길화되는 단백질의 경우, 도입된 자유 시스테인은 발현 도중이나 세포 밖으로 배출 후 배양액의 free thiol을 포함하는 저분자 물질인 시스테인 또는 글루타치온과 이황화 결합을 형성하기 때문에, 자유 시스테인을 마스킹하여 페길화 전 까지 안정화 시켜 페길화 효율을 높이는 것이 필요하다.

본원에 따른 키메라 단백질은 vWF D’D3 도메인을 포함한다.

vWF(또는 F8vWF)는 바이벨펠라드 소체(Weibel-Palade body)에서 내피조직, 거핵세포(혈소판의 α-과립) 및 내피하(subendothelian) 결합조직에서 생성되고 혈장에 존재하는 대형 다합체 당단백질이다. 염기성 vWF 단량체는 2813개(시그널펩타이드 포함하는 경우)의 아미노산으로 구성되고, 모든 단량체는 특이적 기능을 갖는 다수의 특이적 도메인, 즉 (FVIII 인자에 결합하는) D'/D3 도메인, (혈소판 GPIb-수용체, 헤파린 및/또는 가능하게는 콜라겐에 결합하는) A1 도메인, (콜라겐에 결합하는) A3 도메인, C1 도메인(RGD 도메인이 활성화될 때 이것은 혈소판 인테그린 αIIbβ3에 결합) 및 단백질의 C-말단의 "시스테인 매듭" 도메인을 포함하며, 시스테인 매듭은 혈소판 유래 성장 인자(PDGF), 형질전환 성장 인자-β(TGFβ) 및 β-인간 융모성 고나도트로핀(βHCG)에서도 발견된다.

vWF 아미노산 서열 및 vWF 또는 그의 일부를 코딩하는 핵산 서열의 비제한적인 예는 예컨대 GenBank NO: NP_000543, NM_000552, AAE20723, AAB59512, P04275, EAW88815, ACP57027, EAW88816, 및 AAD04919; 미국 특허번호 제5,260,274호; Titani etal., Biochemistry, 25:3171-84 (1986); 및 Sadler etal., PNAS, 82:6391-6398 (1985)로 공지되어 있다.

예를 들면 전장 인간 vWF의 아미노산 서열은 서열번호 02 (시그널펩타이드는 포함하지 않음)로 나타낸다. 서열번호 02를 기준으로 vWF의 "프로펩티드" 부분(D1-D2)은 아미노산 잔기 1 부터 Arg-741까지이고, 또 "성숙" vWF 단백질은 아미노산 잔기 742 내지 2791 까지이다. 개별 도메인은 D': 742 - 842; D3: 843 - 1248; A1: 1249 - 1457; A2: 1458 - 1650; A3: 1651 - 1850; D4: 1851 - 2232; C1: 2233 - 2311; C2: 2312 - 2380; C3: 2407 - 2474; C4: 2475 - 2555; C5: 2556 - 2624; C6: 2625 - 2700 및 CK: 2701 - 2791로 표시될 수 있다 (Lenting. P. J. BLOOD, 26 MARCH 2015. VOLUME 125, NUMBER 13). 또는 대안적인 vWF 도메인 맵핑 및 명명 시스템은 EXPASY 단백질 데이터베이스 명명법 (worldwideweb.uniprot.org/uniprot/P04275)에 의해 D1: 12 - 218; D2: 365 - 576; D': 754 - 805; D3: 844 - 1052; A1: 1255 - 1431; A2: 1476 - 1643; A3: 1669 - 1849; D4: 1927 - 2131; B: 2233 - 2306 (EXPASY에서는 C1으로 명명됨); C1: 2407 - 2473 (EXPASY에서는 C2로 명명됨); C2: 2558 - 2623 (EXPASY에서는 C3으로 명명됨); 및 CK: 2701 - 2790로 표시될 수 있다.

본원에 따른 키메라 단백질에 포함되는 vWF D'D3 도메인은 FVIII와 융합되어 본원에 따른 재조합 FVIII이 내인성 vWF (전장 vWF)에 결합하는 것을 억제한다.

본원에 따른 키메라 단백질에 포함되는 vWF D'D3 도메인은 이러한 활성을 보유하는 한 다양한 길이 또는 유래의 것이 사용되며, 이의 변이체, 유도체, 변형체, 돌연변이체, 복합체 또는 유사체를 포함한다.

일 구현예에서 본원에 따른 키메라 단백질에 포함되는 vWF의 D'D3 도메인은 서열번호 02를 기준으로 742번 내지 1248번 아미노산 또는 이와 적어도 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 상동성을 나타내고, 본원에 따른 재조합 FVIII에 대한 내인성 vWF의 결합을 방지한다.

앞서 언급한 바와 같이 본원에 따른 키메라 단백질은 FVIII의 경쇄 및 중쇄를 하나의 폴리펩타이드로 발현하는 단일 폴리펩타이드 또는 경쇄 및 중쇄 각각을 별개의 폴리펩타이드로 발현하는 이중 폴리펩타이드로 구현될 수 있다.

도 2a를 참조하면 본원에 따른 키메라 단백질이 단쇄 또는 단일 폴리펩타이드로 구현되는 경우, vWF D’D3 도메인은 FVIII의 N- 또는 C- 말단 방향에 위치할 수 있으며, 체내에서 D’D3의 분리를 위해 효소절단 부위를 포함하는 아미노산 링커(또는 연결체)로 연결될 수 있다.

일 구현예에서 본원에 따른 키메라 단백질에 포함되는 FVIII과 D'D3 도메인은 연결체로서 [G₄S]_n 의 아미노산 서열로 표시되는(상기 식에서 G는 글라이신, S는 세린이고, n은 1 내지 100 사이 정수) 연결체와 연결될 수 있으며, 상기 연결체는 효소절단 부위를 포함한다. 연결체는 D’D3와 FVIII를 연결하며, D’D3가 FVIII의 vWF 결합 위치에 정확하게 결합할 수 있게 유연성을 부여해 주는 기능을 갖고 있다. 구체적으로 본원에서는 D’D3를 FVIII에 융합시킬 수 있는 위치는 FVIII 중쇄의 N-말단, C-말단, FVIII 경쇄의 N-말단 또는 C-말단 이고, D’D3 도메인에서 N-말단에 해당하는 D’도메인이 FVIII의 A3 도메인 쪽에 결합하고, D3 도메인이 FVIII의 C2 도메인 쪽에 결합하는 것을 고려하면, FVIII 경쇄의 C-말단에 D’D3를 융합시켰을 때가 D’도메인과 FVIII의 A3 도메인의 거리가 가장 멀 때인 것으로 분석되었다. 따라서 D’D3를 FVIII에 융합시킬 때 D’D3가 FVIII에 제대로 잘 결합하게 하기 위해서 유연성 있는 링커를 선택하였다. 그리고 기존에 발표된 FVIII의 결정구조를 근거로 C2 도메인의 C-말단부터 A3 도메인의 N-말단까지 직선 거리를 측정하고, 이 거리를 아미노산 개수로 환산하여 링커의 길이를 선별하였다. 그렇기 때문에 링커의 길이가 상기 직선 거리보다 짧게 되면, D’도메인이 FVIII의 A3 도메인까지 가지 못 하기 때문에 상기 연결체의 길이가 너무 짧으면 D’D3가 FVIII 결합 위치에 정확하게 결합할 수 없다. 그러므로 상술한 조건을 만족하는 충분한 길이의 연결체가 필요하다. D’D3를 융합 하는 위치에 따라 상기 연결체의 최적 길이는 변할 수 있다. 이러한 기능을 갖는 한 다양한 길이의 연결체가 사용될 수 있다. 일 구현예에서는 n은 최소 4이다. 다른 구현예는 상기 식에서 n은 4, 6, 8, 10, 16, 21, 22 또는 58 일 수 있다.

또한, 상기 연결체는 효소절단 부위를 포함하고 있기 때문에 FVIII이 활성화 될 때, vWF D’D3, 또는 vWF D’D3 및 연결체가 FVIII으로부터 잘려 나갈 수 있게 해주는 기능도 갖고 있다.

본원에 따른 연결체에 포함되는 효소절단 부위는 연결체의 N- 또는 C-말단 방향에 연결될 수 있다.

본원에 따른 일 구현예에서 효소절단부위는 트롬빈에 의해 절단될 수 있는 부위로, 이러한 부위는 DFLAEGGGVR (서열번호 36), TTKIKPR (서열번호 37), 또는 LVPRGS (서열번호 38)로 표시될 수 있다. 이 경우, 본원에 따른 키메라 단백질은 투여시 체내에서 트롬빈에 의해 절단되어 FVIIIa로 활성화되고 활성화 IX 인자(FIXa)와 함께 X 인자를 활성화하여 활성화 X 인자(FXa)로 전환시킨다.

또한, 본원에 따른 연결체에 포함될 수 있는 효소절단부위는 트롬빈 외에 coagulant cascade에 있는 FVIIa, FXa, 또는 FXIa에 의해 잘릴 수 있는 부위도 포함될 수 있으며, 이러한 부위는 ASKPQGRIVGG (서열번호 39), IDGR (서열번호 40), IEGR (서열번호 41), SKLTRAETVF (서열번호 42)로 표시될 수 있다.

본원에 따른 일 구현예에서 효소절단 부위는 링커의 N-말단 방향 쪽에 포함되며, 트롬빈과 같은 효소에 의해 이 부위가 잘리면 연결체와 D'D3 도메인이 FVIII으로부터 분리된다.

본원에 따른 다른 구현예에서는 효소절단 부위는 링커의 C-말단 방향에 포함되며, 트롬빈에 의해 이 부위가 잘리어 연결체와 D’D3 도메인이 FVIII으로부터 분리된다.

도 2b를 참조하면, 앞서 언급한 바와 같이 본원에 따른 키메라 단백질은 중쇄 및 경쇄 각각이 별개의 폴리펩타이드로 발현되는 이쇄 또는 제 1 및 제 2의 두 개의 폴리펩타이드의 형태로 구현되며, 이 경우, 경쇄와 중쇄는 금속 이온 매개 비공유 결합에 의해 회합될 수 있다.

본원에 따른 키메라 단백질이 이쇄로 구현되는 경우, 제 1 폴리펩타이드는 FVIII의 중쇄 A1, A2 및 B 도메인의 전부 또는 일부를 포함하고, 제2 폴리펩타이드는 FVIII의 경쇄 A3, C1, C2 및/또는 B 도메인의 일부를 포함한다.

본원에 따른 단백질이 이쇄로 구현되는 경우 제 1 폴리펩타이드에 포함되는 B 도메인은 앞서 언급한 바 및 후술하는 바를 참조할 수 있다.

본원에 따른 단백질이 이쇄로 구현되는 경우 제 2 폴리펩타이드에는 B 도메인이 포함되지 않을 수 있거나 또는 B 도메인의 일부가 사용될 수 있다. 후자의 경우, 예를 들면 B 도메인 C-말단 잔기부터 N-말단 방향으로 86개의 잔기를 포함한다. 제 2 폴리펩타이드로 발현된 B 도메인 일부는 세포외로 분비될 때 떨어져 나간다.

본원에 따른 키메라 단백질이 이쇄로 구현되는 경우, vWF D’D3 도메인은 제 1 폴리펩타이드의 C 말단 방향에 연결된다. 이 경우 B 도메인이 일종의 연결체로서 작용할 수 있다. 또한 본원에 따른 단백질이 이쇄로 구현되는 경우, 단쇄로 발현되는 경우와 비교하여 동일하거나 또는 긴 길이의 B 도메인이 사용될 수 있다.

본원에 따른 일 구현예에서 단쇄의 경우 서열번호 1의 서열을 기준으로 741-902 및 1654-1689 잔기의 B 도메인이 사용되고, 이쇄의 경우 서열번호 01을 기준으로 741-936의 196개 잔기 길이의 B 도메인이 사용된다. 이쇄로 발현되는 경우 B 도메인에 D’도메인이 연결될 수 있고, 본 이론으로 제한되는 것은 아니나, 융합되는 단백질간의 연결이 구조적으로 보다 자연스럽게 이어주기 위함이다. 구체적으로 일 구현예에서 본원에 채용된 196개 B 도메인의 C-말단의 아미노산 잔기 서열은 - SGGPLSLS이다. D’도메인의 N-말단의 아미노산 서열은 SLSCR PPMVKLVCPA- 로 시작한다. 따라서 상기 SLS의 3개의 아미노산 잔기가 겹쳐지도록 하기 위해 196개의 B 도메인이 사용되었다. 196개의 B 도메인은 -SGGPLSLS 중에 SGGPL 잔기까지만을 포함하여 계산한 것이다.

본원에 따른 키메라 단백질은 vWF D’D3를 하나 이상 포함할 수 있다.

D’D3는 vWF의 N-말단에 위치한 2개의 도메인으로, D3 도메인은 실제 다른 분자의 vWF와 D3 도메인을 통해 이량체를 형성한다. 따라서 본원에서는 D’D3를 단량체 또는 이량체 형태로 FVIII에 융합될 수 있다.

복수개의 vWF D’D3를 포함하는 경우, 예를 들면 두 개를 포함하는 경우, 제 1 D’D3는 FVIII에 연결되고, 제 2 D’D3는 제 1 D’D3에 연결되는 방식으로 구현될 수 있다.

복수개의 vWF D’D3를 포함하는 경우, 제 1 및 제 2 D’D3는 연결체를 통해서 연결될 수 있거나, 또는 제 2 D’D3는 별개로 발현되어, 키메라 단백질과 복합체(complex)를 형성하도록 할 수 있다. 예를 들면 scFVIII/D’D3/D’D3-120 키메라 단백질에서와 같이 연결체를 이용하여 연결되는 경우, 상기 연결체는 앞서 언급한 바를 참조할 수 있으나 효소절단 부위는 포함하지 않는다.

또한 D’D3를 dimer 형태로 사용하는 경우 D’D3는 D3 도메인에 있는 S-S bond를 통해 이량체가 형성될 수 있다. 복수개의 D’D3를 예를 들면 이쇄의 경우와 같이 별개의 벡터에서 발현하는 경우, FVIII-D’D3의 DNA와 D’D3 DNA를 하나의 세포에서 동시 발현시켜, 세포내에서 D’D3끼리 이량체가 만들어 지고, 세포 밖으로 분비되게 한 후, 이를 분리 정제하여 사용할 수 있다.

나아가 본원에 따른 키메라 단백질은 하나 이상의 Fc 단백질을 추가로 포함할 수 있다. Fc를 추가로 D’D3와 함께 FVIII에 융합하게 되면, D’D3에 의해 혈중 vWF가 결합하지 못 하는 효과와 함께 Fc에 의해 FcRn 리사이클링을 통한 반감기 증가 효과를 추가로 기대 할 수 있다. 일 구현예에서는 특히 약 50 kDa 정도 되는 Fc가 융합되며, Fc에 의한 입체적 방해(steric hindrance)에 의해 혈중 vWF가 이 물질에 결합하는 것을 더욱 어렵게 할 수 있다.

따라서, 위와 같은 기능을 본원에 따른 목적을 달성하는 한 다양한 길이 및 유래의 Fc가 포함될 수 있다. 본원에 따른 일 구현예에서는 서열번호 22로 표시되는 Fc, 인간 기원의 IgG 유래의 Fc가 사용된다.

본원에 따른 키메라 단백질이 단쇄로 구현되는 경우, Fc는 vWF D’D3에 연결될 수 있다. 이 경우 연결체를 이용하여 연결될 수 있으며, 상기 연결체는 앞서 언급한 바를 참조할 수 있으나 효소절단 부위는 포함하지 않는다.

본원에 따른 키메라 단백질이 이쇄로 구현되는 경우, Fc는 중쇄의 일부로 발현되는 vWF D’D3에 및/또는 경쇄의 C 말단 방향에 연결될 수 있다. 이 경우 연결체를 이용하여 연결될 수 있으며, 상기 연결체는 앞서 언급한 바를 참조할 수 있으며, 특히 경쇄에 연결되는 경우에는 효소절단 부위를 포함하며, D’D3에 연결되는 경우에는 효소절단 부위는 포함하지 않는다.

본원에 따른 키메라 단백질에 두 개 이상의 Fc가 포함될 수 있다.

복수개의 Fc를 포함하는 경우, 예를 들면 두 개를 포함하는 경우, 일 구현예에서 제 1 Fc는 키메라 FVIII에 연결되고, 제 2 Fc는 제 1 Fc에 연결되는 방식으로 구현될 수 있다. 다른 구현예에서 제 1 Fc는 이쇄로 발현되는 키메라 FVIII의 중쇄에 연결되고, 제 2 Fc는 경쇄에(그 역순도 가능) 연결되는 방식으로 구현될 수 있으며, 이 경우 복수의 Fc 간에 이량체와 같은 복합체가 형성될 수 있다.

복수개의 Fc를 포함하는 경우, 제 1 및 제 2 Fc는 연결체를 통해서 연결될 수 있거나, 또는 제 2 Fc는 하나의 세포에서 별개의 벡터로 발현되고, 세포 내에서 Fc 간에 이량체가 만들어지고, 이후 세포 외로 분비된 것을 정제하여 사용할 수 있다.

앞서 언급한 바와 같이 본원에 따른 키메라 단백질은 단쇄 또는 이쇄로 구현될 수 있다.

일 구현예에서 본원에 따른 단쇄의 키메라 단백질은 서열번호 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21 또는 25로 표시될 수 있다. 상기 단백질은 별개의 D’D3 및/또는 Fc와 복합체를 형성할 수 있으며, 일 구현예에서 서열번호 19의 키메라 단백질은 서열번호 20으로 표시되는 하나 이상의 D’D3와 복합체를 형성할 수 있으며, 또는 서열번호 21의 키메라 단백질은 서열번호 22로 표시되는 하나 이상의 Fc와 복합체를 형성할 수 있다.

일 구현예에서 본원에 따른 이쇄의 키메라 단백질은 서열번호 4 및 5 (각각 중쇄 및 경쇄), 서열번호 23 및 24 (각각 중쇄 및 경쇄), 서열번호 26 및 27 (각각 중쇄 및 경쇄), 서열번호 28 및 29 (각각 중쇄 및 경쇄), 서열번호 30 및 31 (각각 중쇄 및 경쇄), 서열번호 32 및 33 (각각 중쇄 및 경쇄), 또는 서열번호 34 및 35 (각각 중쇄 및 경쇄)로 표시될 수 있다. 상기 단백질은 별개의 D’D3 및/또는 Fc와 복합체를 형성할 수 있으며, 일 구현예에서 서열번호 28 및 29 (각각 중쇄 및 경쇄) 또는 서열번호 32 및 33 (각각 중쇄 및 경쇄)의 키메라 단백질은 서열번호 22로 표시되는 하나 이상의 Fc와 복합체를 형성할 수 있다.

본원에는 상술한 서열번호 04 내지 35로 표시되는 아미노산 서열은 물론 이와 90% 이상 상동성 또는 실질적으로 동일한 서열의 단백질도 포함된다.

이러한 실질적 동일성 또는 상동성은 당업계에 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 서열을 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. BLSAT는 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 키메라 단백질은 반감기 측면에서 야생형의 FVIII와 비교하여 최소 1.5배, 최소 2배, 최소 3배 이상의 반감기가 향상된 것이다. 반감기를 측정하는 방법은 개시되어 있으며, 당업자라면 본원의 기재, 당업계의 기술 및 참고문헌의 기재를 고려하여 적절한 방법을 선택하여 반감기 및 활성을 측정하고 이에 기반하여 본원의 범위에 포함되는 키메라단백질을 결정할 수 있을 것이다.

다른 양태에서 본원은 또한 본원에 개시된 키메라 단백질을 코딩하는 핵산분자 또는 폴리뉴클레오타이드, 상기 폴리뉴클레오타이드를 포함하는 벡터 또는 상기 벡터로 형질전환된 세포(주)에 관한 것이다.

본원에 따른 핵산분자는, 본원에 따른 키메라 단백질이 발현되는 세포의 종류에 맞추어 코돈최적화(Codon optimized) 된 것을 포함하는 것이다. 본원에 따른 일 구현예에서는 CHO 코돈에 최적화되며, 이러한 핵산 서열은 서열번호 58, 59, 60, 62, 63, 64, 65, 또는 66의 서열로 표시될 수 있다.

본원에 따른 키메라 단백질을 코딩하는 핵산분자는 또한 상술한 바와 같이 실질적으로 동일한 생물학적 균등물에 해당하는 FVIII을 코딩하는 것을 또한 포함하는 것이다.

또한 본원에 따른 키메라단백질을 코딩하는 핵산분자는 다양한 목적을 위해 다양한 발현 벡터에 클로닝되어 사용될 수 있다. 발현 벡터의 구체적 구성은 본원에 따른 키메라단백질을 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 키메라 단백질을 코딩하는 핵산분자를 포함하는 벡터는 당업계에 공지된 방법을 통하여 제조될 수 있으며, 예를 들면 본원에 따른 키메라 단백질을 코딩하는 핵산분자를 벡터의 프로모터 및/또는 인핸서에 작동 가능하게 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. 본원에 따른 일 구현예에서는 도 3에 기재된 것이 사용된다. 본원에 따른 키메라단백질은 상술한 바와 같이 단일 폴리펩타이드 또는 두 개의 폴리펩타이드로 발현될 수 있다.

또한, 본원에 따른 키메라 단백질을 코딩하는 핵산분자를 포함하는 상기 재조합 발현 벡터는 다양한 목적을 위해 적절한 숙주세포에 형질 전환될 수 있다. 숙주세포는 본원에 따른 벡터의 증폭 및/또는 벡터에 포함된 핵산분자가 발현될 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 발현할 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 또는 CHO-K1 세포주 또는 CHO-DG44 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 전기천공법등 당업계의 공지된 방법을 이용하여 수행될 수 있으나, 이로 제한하는 것은 아니다.

다른 양태에서 본원은 또한 상술한 본원에 따른 벡터를 진핵세포에 전달이입하는 단계; 상기 세포를 배양액 중에서 배양하는 단계; 상기 배양액을 수집하여 시스테인(cysteine) 도입된 키메라 단백질을 정제하는 단계; 및 상기 정제된 시스테인(cysteine) 도입된 단백질을 페길화 완충액으로 처리하는 단계; 도입된 시스테인(cysteine)의 자유 티올기를 환원 과정을 통해 복원하는 단계; 환원 과정 중 분리된 키메라 단백질 내부의 이황화 결합을 복원하기 위하여 산화시키는 단계; 환원형의 티올기로 복원된 키메라 단백질 시스테인(cysteine)에 특이적으로 페길화시키는 단계 및 페길화 키메라 단백질을 분리하는 단계를 포함하는, 키메라 단백질의 생산방법에 관한 것이다.

본원에 따른 방법에 사용되는 구체적인 벡터, 세포 및 각 단계의 처리 과정은 본원 실시예에 기재된 것을 참고할 수 있다.

본원에 따른 키메라 단백질은 혈액응고가 필요한 질환, 혈우병, 특히 혈우병 A 환자의 혈액응고 또는 혈우병 A의 치료에 유용하게 사용될 수 있다.

이에 다른 양태에서 본원은 또한 상술한 바와 같은 본원에 따른 키메라 단백질, 이를 코딩하는 핵산 분자, 이를 포함하는 벡터, 또는 상기 핵산분자 또는 벡터를 포함하는 세포, 또는 상기 구성에 및 약학적으로 허용 가능한 담체를 포함하는 약학적 조성물을 혈우병 환자 특히 A형 환자 또는 혈액의 응고가 필요한 환자에게 치료적으로 유효한 양으로 투여하는 단계를 포함하는 혈우병, 특히 A형 혈우병의 치료 방법 또는 혈액응고 방법에 관한 것이다.

본원에 따른 키메라 단백질 또는 이를 코딩하는 핵산 분자 또는 이를 코딩하는 벡터는 약학적으로 허용 가능한 담체를 함께 포함하는 혈우병, 특히 A형 혈우병의 치료용 약학 조성물의 형태로 제공될 수 있다.

또한 본원의 약학 조성물은 단독으로, 또는 기타 약물치료 및 생물학적 반응조절제를 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 허용 가능한 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 들어 폴리비닐피롤리돈, 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 만니톨또는 소르비톨, 염 형성 카운터 이온, 예를 들어 나트륨, 및(또는) 비 이온계 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. 본원의 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.

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.

본원에 따른 재조합 키메라 단백질은 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.

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. 키메라 FVIII 구축

실시예 1-1. scFVIII (single-chain FVIII) 제작

단쇄 형태로 발현되는 FVIII의 구축을 위해, furin 절단 위치인 1648 잔기(전장 FVIII 아미노산 서열을 나타내는 서열번호 01의 아미노산 서열기준)를 포함하는 B 도메인의 일부가 결실된 FVIII를 구축하였다. 구축된 각각의 scFVIII은 B 도메인의 N-말단(서열번호 01의 741번째 아미노산 잔기)로부터 특정 길이의 B 도메인을 포함하고 포함된 B 도메인은 원래 보유하고 있는 당쇄를 그대로 포함하도록 제작되었으며, 위치 특이적 페길화(site-specific PEGylation)를 위해 B 도메인에 위치한 782번 아이소루이신 잔기를 시스테인으로 개질하였다.

제조 방법은 다음과 같다.

하기 표 1의 B 도메인이 결실된 각 scFVIII은 인간 FVIII 핵산서열 (NM000132)을 기준으로 합성하였다. 먼저 scFVIII 유전자 발현벡터를 제조하기 위하여 인간 FVIII 핵산서열(NM000132)을 기준으로 CSL 형태(Leader-중쇄-B 도메인 (741-764, 1653-1689)-경쇄)를 5’에 NotI-AsisI과 3’에 PacI-XhoI 효소절단 부위를 포함하도록 GeneArt 사를 통해 유전자 전체를 합성하였다. 합성된 유전자를 pcDSW 벡터의 NotI/XhoI site에 클로닝하여 pcDSW-CSL 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 AsisI/PacI 효소를 이용하여 절단 후 절단된 밴드 크기 비교를 통해 확인하였다. 이후 B 도메인이 결실된 각 scFVIII는 FVIII 중쇄의 A2 도메인 내에 존재하는 BamHI site (GGATCC) 부터 경쇄 3’에 PacI 효소절단 부위를 포함하도록 GeneArt 사를 통해 유전자를 합성한 후 기존에 완성된 pcDSW-CSL 발현벡터를 효소 BamHI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 BamHI/PacI site로 자르고 pcDSW-CSL 발현벡터의 BamHI/PacI site에 클로닝하여 pcDSW-scFVIII 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 BamHI/PacI 효소를 이용하여 절단 후 크기 비교를 통해 확인하였다.

[표 1] scFVIII constructed in the present disclosure

Cysteine이 도입된 scFVIII G4 (B3, 서열번호 3)은 cysteine 치환 부위 및 FVIII 중쇄 A2 도메인 내에 존재하는 BamHI site (GGATCC) 부터 경쇄 말단 3’에 PacI 효소절단 부위가 포함되도록 GeneArt 사를 통해 유전자를 합성한 후, 앞에서 제작한 발현벡터 pcDSW-scFVIII G4에 효소 BamHI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후, 합성된 유전자를 BamHI/PacI site에 클로닝하여 cysteine이 치환된 pcDSW-scFVIII G4 (B3) 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 서열분석을 통해 확인하였다.

실시예 1-2. dcFVIII (dual-chain FVIII) 제작

D’D3를 포함하는 이량체 형태로 발현되는 FVIII 구축을 위해 D’D3를 포함하는 중쇄와 경쇄를 각각 다른 벡터를 이용하여 하나의 세포에서 발현시켰다. D’D3를 포함하는 중쇄에는 실시예 1-1에서 사용한 B3에 해당하는 B 도메인이 포함되어 있으며, 경쇄는 대한민국 특허 제251286호에 기재된 경쇄를 발현하는 벡터를 참고하여 만들었다.

실시예 1-3. 키메라 FVIII 제작

키메라 FVIII은 실시예 1-1과 1-2에서 만든 단쇄 FVIII과 이량체 FVIII을 기본으로 하여 D’D3를 1개 또는 2개를 융합 하였으며, 융합한 D’D3가 FVIII에 적절히 결합할 수 있게 링커를 사용하였다. 링커는 FVIII의 B 도메인 일부를 사용하거나 [G₄S]_n 를 이용하였다. 또한 일부는 상기에 명시한 구성에 Fc까지 포함하였다 (도 2, 도 3, 표 2).

[표 2] 본원에서 제작한 키메라 FVIII

키메라 FVIII의 클로닝은 특허 실시예 1-1에서 기술한 scFVIII G4 (B3)를 이용하여 진행하였다. 서열번호 04의 FVIII 중쇄는 FVIII의 A2 도메인에 존재하는 KpnI 효소절단 부위부터 말단 3’에 PacI 효소절단 부위가 포함하도록 GeneArt 사를 통해 유전자를 합성한 후, 실시예 1-1에서 제작한 scFVIII G4 (B3) 발현벡터 pcDSW-scFVIII G4 (B3)에 효소 KpnI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 KpnI/PacI에 클로닝하여 서열번호 04의 중쇄에 해당하는 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석을 통해 확인하였다. 서열번호 05 경쇄는 5’에 AsisI-Leader 서열과 FVIII 경쇄 C1 도메인에 존재하는 BspEI 효소절단 부위까지 포함하도록 GeneArt 사를 통해 유전자를 합성한 후 실시예 1-1에 제작한 scFVIII G4 (B3) 발현벡터 pcDSW-scFVIII G4 (B3)에 효소 AsiSI/BspEI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 AsiSI/BspEI site에 클로닝하여 서열번호 05의 경쇄에 해당하는 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석을 통해 확인하였다. 서열번호 06, 07, 08, 09, 10, 11, 12, 13, 14, 15, 16은 FVIII 경쇄의 C1 도메인에 존재하는 BspEI 효소 부위 서열부터 말단 3’에 PacI 효소절단 부위가 포함되도록 GeneArt 사를 통해 유전자를 합성한 후 실시예 1-1에서 제작한 scFVIII G4 (B3) 발현벡터 pcDSW-scFVIII G4 (B3)에 효소 BspEI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 BspEI/PacI site에 클로닝하여 서열번호 06, 07, 08, 09, 10, 11, 12, 13, 14, 15, 16에 해당하는 키메라 FVIII 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석 및 서열분석을 통해 확인하였다. 서열번호 14와 비교하여 서열번호 15로 표시되는 펩타이드는 링커에 있는 트롬빈 절단부위의 위치가 상이하고, 서열번호 16으로 표시되는 펩타이드는 트롬빈 절단부위의 위치 및 링커의 서열자체가 상이하며, 이를 각각 TH1 및 TH2로 표시하였다.

서열번호 17, 18, 21은 FVIII 경쇄 C1 도메인에 존재하는 BspEI 효소 부위 서열부터 말단 3’에 PacI 효소절단 부위가 포함되도록 코스모진텍사를 통해 CHO 코돈 최적화 및 유전자를 합성한 후 실시예 1-1에서 제작한 scFVIII G4 (B3) 발현벡터 pcDSW-scFVIII G4 (B3)에 효소 BspEI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 BspEI/PacI site에 클로닝하여 서열번호 17, 18, 21에 해당하는 키메라 FVIII 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석을 통해 확인하였다.

서열번호 19는 5’에 NotI-AsiSI 효소절단 부위를 추가하고 FVIII 중쇄 A1 도메인에 존재하는 AflII 효소절단 부위까지 포함되도록 코스모진텍사를 통해 CHO 코돈 최적화 및 유전자를 합성한 후, 실시예 1-1에서 제작한 scFVIII G4 (B3) 발현벡터 pcDSW-scFVIII G4 (B3)에 효소 AsiSI/AflII을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 AsiSI/AflII site에 클로닝하여 서열번호 19에 해당하는 키메라 FVIII 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석을 통해 확인하였다.

서열번호 20은 코스모진텍에서 합성된 서열번호 64로 표시되는 유전자를 효소 MfeI/XbaI을 이용하여 기존 해당 부위 유전자를 제거하고 합성된 서열번호 63으로 표시되는 유전자로부터 효소 MfeI/XbaI을 처리하고 인서트를 확보하여 MfeI/XbaI site에 일차 클로닝 하였다. 일차 클로닝 된 유전자를 발현 벡터로 옮기기 위하여 기 제작된 scFVIII G4 (B3) 발현벡터 pcDSW-scFVIII G4 (B3)에 효소 NotI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 일차 클로닝 된 유전자를 효소 NotI/PacI으로 인서트를 절단하고 발현 벡터의 NotI/PacI site에 클로닝하여 서열번호 20에 해당하는 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석을 통해 확인하였다.

서열번호 22는 5’에는 AsisI, 3’에는 PacI 효소절단 부위가 각 각 포함되도록 GeneArt 사를 통해 유전자를 합성한 후, 실시예 1-1에서 제작한 scFVIII G4 (B3) 발현벡터 pcDSW-scFVIII G4 (B3)에 효소 AsisI/PacI을 이용하여 기존 FVIII의 해당 부위를 제거한 후 합성된 유전자를 AsisI/PacI site에 클로닝하여 서열번호 22에 해당하는 발현 벡터를 구축하였고, 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석을 통해 확인하였다.

이외에 서열번호 15는 CHO 형질전환 세포주를 제작하기 위하여 추가로 CHO 발현벡터를 제작하였다. 서열번호 15의 5’에는 AatII-AscI, 3’에는 BsiWI-PacI 효소절단 부위가 각각 포함되도록 본 유전자를 합성하거나 Biobasics 사, GeneArt 사 그리고 Genscript 사를 통해 CHO 발현에 최적화되도록 유전자를 합성하였다. CHO 발현벡터 pMSID2의 AscI/PacI site에 합성된 유전자를 클로닝하여 서열번호 15에 해당하는 CHO 발현 벡터를 구축하였다. 발현 벡터 구축의 정확성은 효소 절단을 통한 길이 분석을 통해 확인하였다.

실시예 2. 키메라 FVIII 발현

실시예 1에서 구축한 키메라 FVIII을 세포에서 발현하였으며, 발현된 세포는 세포배양배지로 배양된다. 우선 발현을 위해 실시예 1에서 구축한 발현 벡터를 Expi293F™ 세포에 Expi293F™ Expression System Kit (Thermofisher 사, Catalog Number A14635)을 사용하여 전달 이입하였다. 형질전환 방법 및 배양은 30mL scale 기준으로 아래와 같이 실시하였으며, 단백 필요량에 따라 실제 배양 부피는 조절하였다. 형질전환 수행 24시간 전에 Expi293F™ 세포를 2.0 X 10⁶ cells/mL로 Expi293 배양배지를 이용하여 예상 필요량에 맞추어 계대배양 하였다. 형질전환 수행 당일, 세포 수와 세포 생존율(viability)을 측정하여 세포 생존율이 95% 이상일 경우 형질전환을 진행하였다. 125mL 플라스크에 7.5 X 10⁷ cell 되도록 Expi293 배양배지를 첨가하여 25.5mL로 맞춰주었다. 실시예 1에서 구축한 발현 벡터 30μg를 Opti-MEM을 이용하여 총 볼륨이 1.5mL이 되도록 섞어주었다. 80μL transfection reagent 를 Opti-MEM을 이용하여 총 볼륨이 1.5mL이 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) 한 방울씩 떨어뜨려주고 37℃, 5% CO₂ shaking incubator에서 125 rpm으로 배양하였다. 16 ~ 20시간 후에 Enhancer 1과 Enhancer 2를 각각 150μL, 1.5mL을 넣어주고 34℃, 5% CO₂ shaking incubator에서 125 rpm으로 배양하였다. 배양 2일째 세포를 모두 원심분리하여 기존의 배양배지를 완전히 제거하고 30mL의 새로운 배양배지에 세포를 모두 풀어준 후 34℃, 5% CO₂ shaking incubator에서 125 rpm으로 배양하였다. 도입 3일차에 키메라 FVIII을 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 키메라 FVIII의 활성 분석 및 정제를 진행하였다. 위와 유사한 방법으로 CHO-DG44 세포에서 FVIII 발현을 진행하였다.

이외에 CHO 형질전환 세포주를 제작 및 키메라 FVIII을 발현하였다. 형질전환 수행 24시간 전에 CHO DG44 세포를 CDM4CHO 배지 (Hyclone 사, Catalog Number, SH30557.02)에서 5~6 x 10⁵ cells/mL의 양으로 필요량에 맞추어 계대하였다. 형질전환 당일 125mL 플라스크에 1 x 10⁷ cells/mL로 OptiPro 배지 (Thermo fisher 사, Catalog Number 12309-019)를 이용하여 3mL로 분주하였다. 실시 예 1에서 구축한 30μg의 CHO 발현 벡터를 OptiPro을 이용하여 총 볼륨이 1.5mL이 되도록 섞어주었다. 90μL PEI MAX(1 μg/μL)와 OptiPro을 이용하여 총 볼륨이 1.5mL이 되도록 섞어주었다. 5분 뒤에 PEI MAX가 포함된 1.5mL OptiPro을 DNA가 들어있는 1.5mL OptiPro에 넣어주고 부드럽게 섞어주어 30분간 상온에서 반응시켰다. DNA:PEI 복합체 3mL을 미리 준비한 CHO DG44세포에 한 방울씩 떨어뜨려 주었다. 37℃, 5% CO₂ shaking incubator에서 140 rpm으로 4시간 동안 배양하였다. 24mL의 CDM4CHO 배지를 첨가하여 140 rpm으로 배양하고 48시간 후에 세포 선별을 수행하였다.

형질전환된 CHO DG44 세포를 20nM MTX가 포함된 CDM4CHO 배양 배지를 이용하여 T-175 플라스크에 5 x 10⁶ cells/mL로 50mL 되도록 현탁하고 37℃, 5% CO₂ incubator에서 7일간 정치 배양하였다. 만약, 세포수가 모자라면 총 볼륨을 줄이고 진행하였다. 선별 수행 7일 후 세포수를 측정하여 125mL 플라스크에 5 x 10⁵ cells/mL로 20nM MTX가 포함된 배양 배지를 이용하여 계대하고 37℃, 5% CO₂ shaking incubator에서 140 rpm으로 배양하였다. 3 ~ 4일 간격으로 125mL 플라스크에 계대 배양을 실시하고 세포 농도가 1 x 10⁶ cells/mL, 생존율이 90% 이상일 경우 선별이 완료된 것으로 판단하였다.

키메라 FVIII 발현을 위하여 CHO 형질전환 세포주를 3 x 10⁵ cells/mL로 접종하여 37℃, 5% CO₂ shaking incubator에서 140 rpm으로 배양하였다. 배양 4일째 세포를 모두 원심 분리하여 기존의 배양 배지를 완전히 제거하고 동일 부피의 새로운 배양배지에 세포를 모두 풀어준 후 31℃, 5% CO₂ shaking incubator에서 140 rpm 으로 1일간 배양하였다. 본 배지교환 및 배양과정을 배양 8일차까지 반복하고 6일, 7일 그리고 8일 배양액을 회수하여 키메라 FVIII의 활성 분석 및 정제를 진행하였다.

실시예 3. 키메라 FVIII 발현 확인

실시예 3-1. 키메라 FVIII 발현량 측정

많이 사용하는 FVIII 활성 측정 시험 방법은 one-stage clotting method와 chromogenic method 두 가지이다. 그 중 키메라 FVIII 발현량 측정은 chromogenic method를 이용하여 측정하였다. Chromogenic method는 FIXa, FX, thrombin, calcium, phospholipids와 FVIII 시료를 섞어 준 후, FVIII 시료에 의해 활성화 된 FXa의 양을 측정하기 위해 FXa에 의해 잘리면서 발색하는 chromogenic substrate를 넣어주고, chromogenic substrate의 발색 정도에 따라 FVIII의 활성을 측정하는 방법이다.

Chromogenic method의 실험 방법은 CHROMOGENIX(社)에서 판매하고 있는 chromogenic assay kit를 endpoint 방법으로 사용하였고, 제조사가 제공한 시험방법을 본 시험에 적합하게 변형하여 시험을 진행하였다. 시료를 1× 희석버퍼를 사용하여 standard range (0.25-1 IU/mL)에 들어 오도록 희석한다. 표준품 (calibration plasma)을 0, 0.25, 0.5, 1 IU/mL 농도가 되게 1× 희석버퍼를 이용하여 준비하였다. 이렇게 준비한 시료와 표준품 10μL를 1× 희석버퍼 790μL로 희석한 후, 96 well plate에 50μL씩 분주하고, 37℃에서 5분간 정치시켰다. Automatic dispenser pipette을 사용하여 factor reagent를 50μL씩 각 well에 분주한 후 2분간 37℃에서 2분간 반응 시켰다. 50μL substrate를 각 well에 분주한 후 2분간 37℃에서 2분간 정치하여 발색 시켰다. 발색된 시료에 50μL 2% citric acid를 넣어주어 반응을 정지 시켰다. 405nm 파장에서 흡광도를 측정하여 선형 calibration curve를 그린 후, 샘플의 흡광도를 calibration curve에 대입하여 시료의 활성을 측정하였다.

[표 3] 키메라 FVIII 발현량

D’D3를 융합 하기 전인 scFVIII-B3의 발현량은 1.6에서 8.0 IU/mL 사이로 측정되었었다. D’D3를 융합한 키메라 FVIII 중 단쇄 형태로 발현되는 경우 expression level이 D’D3를 융합하기 전인 scFVIII-B3와 유사한 것을 확인하였다. 하지만, 이량체로 발현되는 경우 expression level이 0.1 IU/mL로 기존 scFVIII-B3 보다 10배 이상 낮은 것을 확인하였으며, 측정된 결과는 표 3에 기재되었다.

실시예 3-2. 발현 패턴 분석

본원에 구축된 키메라 FVIII을 실시예 4에 따라 정제한 후, 정제 시료를 웨스턴블랏 분석을 통해 발현 패턴을 확인하였다.

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 러닝한다. 러닝이 완료된 젤을 nitrocellulose (NC) membrane에 transfer한 후, blocking 버퍼 (Thermo Scientific)에 한 시간 정치하였다. 제 8인자의 중쇄 (GMA-012, Green Mountain Antibodies), 경쇄 (ab41188, Abcam) 및 D’D3 (96340, Abcam)을 인식하는 primary 항체를 TBST 버퍼에 희석하여 제조한 후, blocking이 완료된 NC membrane과 1시간 반응시켰다. TBST 버퍼를 사용하여 5분 간격으로 3회 washing을 진행한다. Secondary 항체 (Goat anti-mouse IgG-HRP conjugate)는 TBST 버퍼로 희석하여 제조한 후, NC membrane과 10분간 반응시킨다. TBST 버퍼를 사용하여 5분 간격으로 5회 세척하였다. ECL Prime Western Blotting Detection Reagent을 뿌려주어 NC membrane을 발색시킨 후, 암실에서 Hyperfilm ECL (GE healthcare)에 membrane을 노출하여 현상하였다.

그 결과 단쇄로 발현되는 키메라 FVIII은 모두 본원에서 디자인 한 형태로 발현되는 것을 확인하였고, 링커 길이에 따른 발현 패턴 변화는 없는 것으로 나타났다 (도 5).

실시예 4. 키메라 FVIII 생산

키메라 FVIII의 생산 공정은 크게 5단계로 구성되어 있으며, 실시예 2에서 배양한 배양액을 이용하여 정제를 진행하였다.

첫 번째 단계에서는 배양액에서 키메라 FVIII을 분리정제 하는 공정으로 FVIII 정제용으로 GE에서 개발한 VIIISelect resin을 이용하였다. VIIISelect resin을 컬럼에 패킹한 후, 2% citric acid로 컬럼을 세척하였다. 평형 버퍼 (20 mM Histidine, 5 mM CaCl₂, 1 M NaCl, 0.02% Tween® 80, pH 7.0)를 흘려주어 평형을 잡는다. 배양액에 최종 1 M NaCl 농도가 되도록 5 M NaCl 버퍼를 넣어주고, pH를 7.0으로 적정한 후, 컬럼에 로딩하였다. 배양액 로딩 후, 평형 버퍼를 UV가 baseline으로 떨어질 때까지 흘려주어 평형을 잡았다. 용출 버퍼 (20 mM Histidine, 5 mM CaCl₂, 0.9 M Arginine, 45% propylene glycol, 0.02% Tween® 80, pH 6.5)를 흘려주어 키메라 FVIII을 용출하였다.

두 번째 단계에서는 첫 번째 단계의 용출액에 섞여 있는 propylene glycol을 제거해주고, 일부 섞여 있는 분순물을 제거해주는 공정으로 GE사의 Q fast flow resin을 이용하였다. Q fast flow resin을 컬럼에 패킹한 후, 세척 버퍼 (0.5 M NaOH, 1 M NaCl)를 흘려주어 컬럼을 세척하였다. 평형 버퍼 (20 mM Histidine, 5 mM 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 (20 mM Histidine, 5 mM CaCl₂, 500 mM NaCl, 0.02% Tween® 80, pH 7.0)를 흘려주어 키메라 FVIII을 용출하였다.

세 번째 단계에서는 정제한 키메라 FVIII에 PEG를 접합시켜 주는 공정이다. 정제된 키메라 FVIII 용액에 최종농도가 0.1 mM이 되도록 TCEP를 첨가한 후 4℃에서 1시간 정치시켜 삽입한 cysteine을 환원시켰다. 페길화 버퍼 (20 mM Histidine, 5 mM CaCl₂, 200 mM NaCl, 0.02% Tween® 80, pH 7.0)로 평형이 잡힌 PD-10 컬럼 (GE healthcare)을 사용하여 잔존 TCEP를 제거하였다. 환원된 키메라 FVIII 자체의 이황화 결합을 산화시켜주기 위하여 4℃에서 2시간 정치 시켰다. PEG 접합은 DMSO에 녹인 PEG 용액(50 mg/mL)을 단백질 당 PEG 비율을 1:20이 되도록 넣어준 후 4℃에서 12-16시간 정치시켰다.

네 번째 단계에서는 PEGylation 과정 중에 생긴 impurity인 PEG가 붙지 않은 키메라 FVIII과 PEG가 2개 이상 붙은 키메라 FVIII을 제거하는 공정으로 GE사의 Superdex 200 resin을 이용하였다. Pre-packing 된 superdex 200 컬럼에 평형 버퍼 (20 mM Histidine, 5 mM CaCl₂, 200 mM NaCl, 0.02% Tween® 80, pH 7.0)를 흘려주어 평형을 잡았다. PEGylation 공정 시료를 sample loop를 이용하여 컬럼에 로딩하였다. 로딩 후, 평형 버퍼를 흘려주며 peak을 수집하고, SDS-PAGE로 분석하여 적절한 fraction을 풀링(pooling) 하였다.

다섯 번째 단계에서는 네 번째 단계에서 풀링한 페길화 키메라 FVIII을 농축하는 공정이다. 이를 위해 Millipore사의 amicon 30kDa를 이용하여 25 IU/mL 농도가 되게 농축을 하였다.

정제 정도와 페길화 정도를 분석하기 위하여 공정 중간 시료와 최종 시료에 대한 SDS-PAGE를 수행하였다 (도 4, 도 6). scFVIII/D’D3의 경우 linker 길이에 따른 정제 패턴은 거의 유사한 것을 확인할 수 있다. 첫 번째 공정인 VIIISelect 공정에서 대부분의 HCP가 제거 되는 것을 볼 수 있으며, 두 번째 공정인 Q FF 공정에서 monomer 형태인 scFVIII/D’D3만 정제 되는 것을 확인하였다. 그 후, PEGylation 공정을 진행 한 후, 정제한 결과 PEG-scFVIII/D’D3만 정제 된 것을 확인하였다.

실시예 5. 키메라 FVIII 물질 비역가(specific activity) 확인

키메라 FVIII의 비역가를 확인하기 위해 chromogenic method로 키메라 FVIII의 activity를 측정하였고, BSA를 standard로 사용하여 BCA 방법으로 키메라 FVIII의 단백정량을 측정하였다. 이렇게 측정한 activity 결과 값을 단백정량 값으로 나누어 주어 specific activity를 측정하였으며, 그 결과는 표 4와 같다.

[표 4] 키메라 FVIII 비역가(specific activity)

scFVIII/D’D3의 경우 linker 길이를 바꾸어 주어도 specific activity 값은 큰 차이가 없는 것을 확인하였으며, 본 실시예에서 측정한 specific activity는 다른 recombinant FVIII의 specific activity 값들과 유사한 것을 확인하였다.

실시예 6. 키메라 FVIII의 LRP, vWF binding affinity 측정 실험

키메라 FVIII과 LRP 또는 vWF와의 binding affinity를 ELISA 방법을 이용하여 측정하였다. vWF (HCVWF-0191, Haemtech, 200 μg/mL) 또는 LRP (#04-03, Biomac, 260 μg/mL)를 사용하여 96 well plate에 well 당 100μL씩 coating한 후, 상온에서 2시간 동안 정치한다. 2시간 incubation 후, PBS에 0.1% Tween® 20을 첨가한 washing buffer로 washing을 수행한다. PBS에 1% BSA를 첨가한 blocking buffer를 well 당 200μL씩 넣고, 상온에서 1시간 동안 incubation하여 blocking을 수행한다. 1시간 incubation 후, PBS에 0.1% Tween® 20을 첨가한 washing buffer로 washing을 수행한다. FVIII sample을 blocking buffer로 적절한 농도로 희석한 후, well 당 100μL씩 loading 후, 상온에서 1시간 동안 incubation 한다. PBS에 0.1% Tween® 20을 첨가한 washing buffer로 washing을 수행한다. Anti-Factor VIII biotin (SAF8C-APBIO, Affinity Biologicals, 100 μg/mL)을 blocking buffer로 1/2000 희석하여 well 당 100μL씩 loading 하고, 상온에서 1시간 동안 정치한다. PBS에 0.1% Tween® 20을 첨가한 washing buffer로 washing을 수행한다. Streptavidin-HRP (S2438, Sigma-Aldrich)를 blocking buffer로 1/3000 희석하여 well 당 100μL씩 loading 하고 상온에서 45분 동안 incubation 한다. PBS에 0.1% Tween® 20을 첨가한 washing buffer로 washing을 수행한다. TMB substrate (52-00-03, KPL)를 well 당 100μL씩 처리 후, 10분 동안 incubation 한다. Stop solution (1 N 황산)을 well 당 100μL씩 넣어주어 반응 정지시킨 후, 490 nm 흡광도를 측정한다.

실험 결과, 키메라 FVIII의 LRP, vWF에 대한 결합이 ADVATE® 보다 현저히 감소되는 것을 확인하였다. 또한, 키메라 FVIII이 페길화 되면 LRP, vWF 결합은 더 감소되는 것을 확인하였다 (도 7, 도 8).

실시예 7. 동물 PK 시험: PEG-scFVIII/D’D3-120

페길화 키메라 FVIII의 체내 반감기를 측정하기 위해 혈우병 A형 마우스 모델 (HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화 하였다 (n = 3 / time point). 대조 물질인 Advate®와 페길화 키메라 FVIII (본 실시예에서는 PEG-scFVIII/D’D3-120을 이용하였음)을 125 IU/kg 용량을 정맥으로 단 회 투여 하였다. PK 혈액 샘플은 Advate® 투여군에서는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, PEG-scFVIII/D’D3-120 투여군에서는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 PEG-scFVIII/D’D3-120의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다. PK 분석 결과(도 9) Advate®의 반감기는 약 7.86시간으로 측정되었고, PEG-scFVIII/D’D3-120의 반감기는 Advate® 보다 3.3배 긴 약 26.12시간으로 측정되었다. PEG-scFVIII/D’D3-120의 평균 머무름시간(MRT)도 Advate®에 비해 3.6배 증가하였다. 또한 PEG-scFVIII/D’D3-120의 소실속도(CL)는 Advate®보다 약 2배 감소하였고, 농도곡선하면적(AUC)은 약 2배 증가하는 것으로 나타났다.

[표 5] 페길화 키메라 FVIII 약동학적 파라미터

실제 예방적 요법으로 FVIII의 투여 시, 혈중 FVIII의 농도가 1% 또는 3% 이상으로 유지되도록 하기 때문에 반감기가 긴 지속형 FVIII을 사용할 경우 혈중 FVIII의 농도가 1% 또는 3% 이하로 떨어지는 시간을 지연시킬 수 있고 이는 투여 횟수의 감소로 이어질 수 있다. 지금까지 개발된 지속형 FVIII의 경우 HA mice에서 반감기의 증가폭은 대조군 대비 2배 이하 수준이었다. 이는 상기에서 언급한 것처럼 FVIII이 혈중에서 vWF와 강한 비공유 결합을 한 상태로 돌아다니기 때문에 vWF의 반감기보다 더 길어지지 못했던 것으로 판단된다. 본원에서 개발한 키메라 FVIII은 혈중 vWF와의 결합을 저해하는 것과 동시에 키메라 FVIII이 LRP에 의한 소실도 막아주기 때문에 지금까지 개발 된 지속형 FVIII이 넘지 못 했던 대조군 대비 반감기가 2배 이상 증가한 것으로 판단되며, 이는 매우 의미 있는 결과라고 판단한다.

실시예 8. 동물 PK 시험: 다양한 크기의PEG 접합된 scFVIII/D’D3-120

실시예 7과 유사하게 혈우병 A형 마우스 모델(HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화하였다 (n = 3 / time point). 이 후 대조 물질인 Advate®와 페길화 키메라 FVIII을 125 IU/kg 용량을 정맥으로 단 회 투여 하였다. 본 실시예에서는 scFVIII/D’D3-120에 서로 다른 size의 PEG를 접합시켜 PK 시험을 진행하였다. 대조 물질인 Advate® 투여군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, 시험군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72, 96 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 페길화 키메라 FVIII의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다.

PK 분석 결과 Advate®의 반감기는 약 7.88시간으로 측정되었고, 40kDa PEG-scFVIII/D’D3-120의 반감기는 약 20.93시간으로 측정되었고, 60kDa PEG-scFVIII/D’D3-120의 반감기는 약 28.09시간으로 측정되었다. 약동학적 프로파일 및 약동학적 파라미터는 도 10 및 표 6과 같다.

[표 6] 페길화 키메라 FVIII 약동학적 파라미터

실시예 9. 동물 PK 시험: PEG-scFVIII/D’D3-60과 Fc가 융합된 scFVIII/D’D3-120에 PEG 접합

혈우병 A형 마우스 모델(HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화 하였다 (n = 3 / time point). 대조 물질인 Advate®와 페길화 키메라 FVIII을 125 IU/kg 용량을 정맥으로 단 회 투여 하였다. 본 실시예에서는 PEG-scFVIII/D’D3-60과 Fc가 융합된 scFVIII/D’D3-120에 PEG를 접합시킨 물질을 이용하여 PK 시험을 진행하였다. 대조 물질인 Advate® 투여군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, 시험군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72, 96 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 페길화 키메라 FVIII의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다.

PK 분석 결과 Advate®의 반감기는 약 7.08시간으로 측정되었고, PEG-scFVIII/D’D3-60의 반감기는 약 16.53시간으로 측정되었고, PEG-scFVIII/D’D3/Fc-120, Fc의 반감기는 약 18.89시간으로 측정되었다. 약동학적 프로파일 및 약동학적 파라미터는 도 11 및 표 7과 같다.

[표 7] 페길화 키메라 FVIII 약동학적 파라미터

실시예 10. 동물 PK 시험: PEG-scFVIII/D’D3-300과 D’D3를 이량체 형태로 FVIII의 c-말단에 융합한 scFVIII/D’D3-120에 PEG 접합

혈우병 A형 마우스 모델(HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화하였다 (n = 3 / time point). 대조 물질인 Advate®와 페길화 키메라 FVIII을 125 IU/kg 용량을 정맥으로 단 회 투여 하였다. 본 실시예에서는 PEG-scFVIII/D’D3-300과 D’D3를 이량체 형태로 FVIII의 c-말단에 융합한 scFVIII/D’D3-120에 PEG를 접합시킨 물질을 이용하여 PK 시험을 진행하였다. 대조 물질인 Advate® 투여군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, 시험군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72, 96 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 페길화 키메라 FVIII의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다.

PK 분석 결과 Advate®의 반감기는 약 9.02시간으로 측정되었고, PEG-scFVIII/D’D3-300의 반감기는 약 15.76시간으로 측정되었고, PEG-scFVIII/D’D3/D’D3-120의 반감기는 약 18.00시간으로 측정되었다. 약동학적 프로파일 및 약동학적 파라미터는 도 12 및 표 8과 같다.

[표 8] 페길화 키메라 FVIII 약동학적 파라미터

실시예 11. 동물 PK 시험: PEG-scFVIII/D’D3-60, PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-300

혈우병 A형 마우스 모델(HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화하였다 (n = 3 / time point). 대조 물질인 Advate®와 페길화 키메라 FVIII을 125 IU/kg 용량을 정맥으로 단 회 투여 하였다. 본 실시예에서는 PEG-scFVIII/D’D3-60, PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-300을 이용하여 PK 시험을 진행하였다. 대조 물질인 Advate® 투여군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, 시험군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72, 96 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 페길화 키메라 FVIII의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다.

PK 분석 결과 Advate®의 반감기는 약 6.99시간으로 측정되었고, PEG-scFVIII/D’D3-60, PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-300의 반감기는 각각 약 20.07, 24.48, 17.13시간으로 측정되었다. 약동학적 프로파일 및 약동학적 파라미터는 도 13 및 표 9와 같다.

[표 9] 페길화 키메라 FVIII 약동학적 파라미터

실시예 12. 동물 PK 시험: PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-120-TH1, PEG-scFVIII/D’D3-120-TH2

혈우병 A형 마우스 모델(HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화 하였다 (n = 3 / time point). 대조 물질인 Advate®와 페길화 키메라 FVIII을 125 IU/kg 용량을 정맥으로 단 회 투여 하였다. 본 실시예에서는 PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-120-TH1, PEG-scFVIII/D’D3-120-TH2를 이용하여 PK 시험을 진행하였다. 대조 물질인 Advate® 투여군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, 시험군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72, 96 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 페길화 키메라 FVIII의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다.

PK 분석 결과 Advate®의 반감기는 약 6.26시간으로 측정되었고, PEG-scFVIII/D’D3-120, PEG-scFVIII/D’D3-120-TH1, PEG-scFVIII/D’D3-120-TH2의 반감기는 각각 약 21.28, 24.19, 25.28시간으로 측정되었다. 약동학적 프로파일 및 약동학적 파라미터는 도 14 및 표 10과 같다.

[표 10] 페길화 키메라 FVIII 약동학적 파라미터

실시예 13. 동물 PK 시험: 다양한 크기 및 형태의 PEG 접합된 scFVIII/D’D3-120-TH1

혈우병 A형 마우스 모델(HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화 하였다 (n = 3 / time point). 대조 물질인 Advate®와 페길화 키메라 FVIII을 125 IU/kg 용량으로 정맥으로 단 회 투여 하였다. 본 실시예에서는 scFVIII/D’D3-120-TH1에 여러 가지 PEG를 접합시킨 물질을 이용하여 PK 시험을 진행하였다. 대조 물질인 Advate® 투여군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, 시험군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72, 96 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 페길화 키메라 FVIII의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다.

PK 분석 결과 Advate®의 반감기는 약 7.66시간으로 측정되었고, 20kDa linear PEG-scFVIII/D’D3-120-TH1, 20kDa branch PEG-scFVIII/D’D3-120-TH1, 40kDa branch PEG-scFVIII/D’D3-120-TH1의 반감기는 각각 약 22.98, 16.10, 27.33시간으로 측정되었다. 약동학적 프로파일 및 약동학적 파라미터는 도 15 및 표 11과 같다.

[표 11] 페길화 키메라 FVIII 약동학적 파라미터

실시예 14. Thrombin generation assay

페길화 키메라 FVIII의 thrombin generation profile을 확인하기 위해 thrombin generation assay를 진행하였다. Fluoroskan Ascent™ FL microplate fluorometer and luminometer (5210460, Thermofisher) 기기를 미리 37℃로 warming 해 놓고, 37℃ pre-warmed D.W로 기계의 line을 washing 하였다. FVIII deficient plasma (OTXW17, Siemens), Calibrator (TS20.00, Thrombinoscope), PPP-low-reagent (TS31.00, Thrombinoscope)를 상온에서 15분 이상 방치하여 warming 시킨 후, 37℃ pre-warmed D.W 1mL로 reconstitution 하였다. 96 well plate에 Calibrator와 PPP-low-reagent를 20μL씩 넣어주고, 앞에서 준비한 Fluoroskan 기기에 plate를 넣어 37℃로 가온해 놓았다. Sample dilution은 앞에서 준비한 FVIII deficient plasma를 이용하여 적절한 농도로 희석하였다. FluCa-Kit (TS50.00, Thrombinoscope)안의 Fluo-buffer를 37℃로 warming 해 놓았다. 준비한 sample을 Fluoroskan 기기 안에 들어있는 plate에 80μL씩 넣고, 37℃로 warming 된 Fluo-buffer 1 vial에 40μL의 Fluo-substrate를 넣어 준비하였다. 준비된 Flu-Ca를 기계에 넣은 후, 미리 짜놓은 software를 실행하면 각 well 당 20μL의 Flu-Ca가 분주 되고, thrombin generation을 진행하였다.

Thrombin generation assay 결과 FVIII deficient plasma에서는 thrombin generation profile이 현저히 낮은 반면, 키메라 FVIII에서는 thrombin generation profile이 농도 의존적으로 점차 높아지는 것을 확인하였다. 키메라 FVIII 1 IU/mL의 thrombin generation profile은 normal plasma의 thrombin generation profile과 유사한 것을 확인할 수 있었다 (도 16).

실시예 15. 동물 급성 효능(acute efficacy) 시험

키메라 FVIII의 효력을 확인하기 위해 혈우병 A형 마우스(HA mice)의 tail clip model에서 acute efficacy 시험을 진행하였다. Wild type mice (WT)는 19 - 25 g 중량의 수컷 C57BL/6 mouse를 오리엔트 바이오에서 공급받은 개체를 이용하였고, HA mice는 녹십자에서 breeding한 개체로 19 - 25 g 중량의 수컷 mouse를 선별하여 이용하였다. 시험 당일, 15mL conical tube (1개/마리)에 saline을 14mL까지 채운 후, 가열된 water bath에 담가서 saline의 온도가 37℃가 되도록 유지시켰고, 투여 전 mouse의 체중을 측정하였다. Pentobarbital sodium을 IP로 60 mg/kg dose로 투여하여 마취시킨 후, 음성 대조물질은 0.9% 생리 식염수를, 양성대조 물질인 Advate®와 페길화 키메라 FVIII은 100 IU/kg dose로 jugular vein으로 5 mL/kg의 볼륨으로 단 회 투여하였다. 5분 후, HA mice 꼬리의 말단에서 4mm 되는 지점을 절단하고, 꼬리를 saline buffer에 넣어 30분 동안 혈액을 모았다. 30분 동안 모은 혈액 시료를 1,500g 에서 5분간 원심 분리하여 상층액을 제거한 후, 10mL pipet을 이용하여 conical tube에 3차 증류수를 10mL까지 넣고, vortex를 이용하여 혈액을 완전히 용혈 시켰다. Blood loss를 측정하기 위해 용혈 된 샘플을 hemoglobin assay kit (MAK115-1KT, Sigma-Aldrich)의 방법으로 분석하였다.

Wild type mice (WT)의 경우 hemoglobin의 농도가 약 100 nM 인 것을 확인하였고, HA mice (KO)에서 음성대조군인 경우 hemoglobin의 농도가 약 1,000 nM 인 것을 확인하였다. Advate®와 페길화 키메라 FVIII의 경우 hemoglobin의 농도가 약 140 - 450 nM 인 것을 확인하였으며, 이는 음성대조군에 비해 약 55% 감소한 수치이다. Advate®와 페길화 키메라 FVIII 간에는 통계적으로 차이가 없는 것을 확인하였다 (도 17).

실시예 16. 동물 PK 시험: CHO 세포에서 발현한 scFVIII/D’D3-120-TH1에 다양한 크기 및 형태의 PEG 접합

혈우병 A형 마우스 모델(HA mice)을 이용한 PK 시험을 진행하였다. HA mice는 8주령의 쥐(20 ± 2 g)를 이용하였고, 투여 전 개체 별 무게 측정 후, 그룹화 하였다 (n = 3 / time point). 대조 물질인 Advate®와 페길화 키메라 FVIII을 125 IU/kg 용량으로 정맥으로 단 회 투여 하였다. 본 실시예에서는 CHO 세포에서 발현한 scFVIII/D’D3-120-TH1에 여러 가지 PEG를 접합시킨 물질을 이용하여 PK 시험을 진행하였다. 대조 물질인 Advate® 투여군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 9, 16, 22, 30 hr에, 시험군의 혈액 시료는 투여 후 0, 0.083, 2, 6, 16, 30, 40, 48, 64, 72, 96 hr에 200μL sampling 하였다. 채혈 직후 샘플을 항응고제 (sodium citrate 3.2% buffer)와 1:9 부피로 섞은 후 원심분리로 혈장을 분리하였다. Advate®와 페길화 키메라 FVIII의 역가는 Chromogenic method를 사용하여 측정하였고, 약동학적 파라미터는 WinNonLin software(version 6.4)의 non-compartmental (NCA) model을 적용하여 산출하였다.

PK 분석 결과 Advate®의 반감기는 약 8.22시간으로 측정되었고, 20kDa linear PEG-scFVIII/D’D3-120-TH1, 40kDa linear PEG-scFVIII/D’D3-120-TH1의 반감기는 각각 약 25.01, 26.88시간으로 측정되었다. 약동학적 프로파일 및 약동학적 파라미터는 도 18 및 표 12와 같다.

[표 12] 페길화 키메라 FVIII 약동학적 파라미터

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> Chimeric protein of Factor VIII and Von Willebrand Factor and its use <130> PCT201705004P <150> US 62/354,255 <151> 2016-06-24 <160> 80 <170> KoPatentIn 3.0 <210> 1 <211> 2332 <212> PRT <213> Homo sapiens <220> <221> PEPTIDE <222> (1)..(2332) <223> Full length Factor VIII <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 Xaa 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> 2791 <212> PRT <213> Homo sapiens <220> <221> PEPTIDE <222> (1)..(2791) <223> Full length vWF <400> 2 Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr Ala Arg Cys Ser Leu Phe 1 5 10 15 Gly Ser Asp Phe Val Asn Thr Phe Asp Gly Ser Met Tyr Ser Phe Ala 20 25 30 Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly Cys Gln Lys Arg Ser Phe 35 40 45 Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys Arg Val Ser Leu Ser Val 50 55 60 Tyr Leu Gly Glu Phe Phe Asp Ile His Leu Phe Val Asn Gly Thr Val 65 70 75 80 Thr Gln Gly Asp Gln Arg Val Ser Met Pro Tyr Ala Ser Lys Gly Leu 85 90 95 Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys Leu Ser Gly Glu Ala Tyr 100 105 110 Gly Phe Val Ala Arg Ile Asp Gly Ser Gly Asn Phe Gln Val Leu Leu 115 120 125 Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly Leu Cys Gly Asn Phe Asn 130 135 140 Ile Phe Ala Glu Asp Asp Phe Met Thr Gln Glu Gly Thr Leu Thr Ser 145 150 155 160 Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala Leu Ser Ser Gly Glu Gln 165 170 175 Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser Ser Cys Asn Ile Ser Ser 180 185 190 Gly Glu Met Gln Lys Gly Leu Trp Glu Gln Cys Gln Leu Leu Lys Ser 195 200 205 Thr Ser Val Phe Ala Arg Cys His Pro Leu Val Asp Pro Glu Pro Phe 210 215 220 Val Ala Leu Cys Glu Lys Thr Leu Cys Glu Cys Ala Gly Gly Leu Glu 225 230 235 240 Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala Arg Thr Cys Ala Gln Glu 245 250 255 Gly Met Val Leu Tyr Gly Trp Thr Asp His Ser Ala Cys Ser Pro Val 260 265 270 Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys Val Ser Pro Cys Ala Arg 275 280 285 Thr Cys Gln Ser Leu His Ile Asn Glu Met Cys Gln Glu Arg Cys Val 290 295 300 Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu Leu Asp Glu Gly Leu Cys 305 310 315 320 Val Glu Ser Thr Glu Cys Pro Cys Val His Ser Gly Lys Arg Tyr Pro 325 330 335 Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn Thr Cys Ile Cys Arg Asn 340 345 350 Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys Pro Gly Glu Cys Leu Val 355 360 365 Thr Gly Gln Ser His Phe Lys Ser Phe Asp Asn Arg Tyr Phe Thr Phe 370 375 380 Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg Asp Cys Gln Asp His Ser 385 390 395 400 Phe Ser Ile Val Ile Glu Thr Val Gln Cys Ala Asp Asp Arg Asp Ala 405 410 415 Val Cys Thr Arg Ser Val Thr Val Arg Leu Pro Gly Leu His Asn Ser 420 425 430 Leu Val Lys Leu Lys His Gly Ala Gly Val Ala Met Asp Gly Gln Asp 435 440 445 Val Gln Leu Pro Leu Leu Lys Gly Asp Leu Arg Ile Gln His Thr Val 450 455 460 Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu Asp Leu Gln Met Asp Trp 465 470 475 480 Asp Gly Arg Gly Arg Leu Leu Val Lys Leu Ser Pro Val Tyr Ala Gly 485 490 495 Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn Gly Asn Gln Gly Asp Asp 500 505 510 Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro Arg Val Glu Asp Phe Gly 515 520 525 Asn Ala Trp Lys Leu His Gly Asp Cys Gln Asp Leu Gln Lys Gln His 530 535 540 Ser Asp Pro Cys Ala Leu Asn Pro Arg Met Thr Arg Phe Ser Glu Glu 545 550 555 560 Ala Cys Ala Val Leu Thr Ser Pro Thr Phe Glu Ala Cys His Arg Ala 565 570 575 Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys Arg Tyr Asp Val Cys Ser 580 585 590 Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly Ala Leu Ala Ser Tyr Ala 595 600 605 Ala Ala Cys Ala Gly Arg Gly Val Arg Val Ala Trp Arg Glu Pro Gly 610 615 620 Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln Val Tyr Leu Gln Cys Gly 625 630 635 640 Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu Ser Tyr Pro Asp Glu Glu 645 650 655 Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe Cys Pro Pro Gly Leu Tyr 660 665 670 Met Asp Glu Arg Gly Asp Cys Val Pro Lys Ala Gln Cys Pro Cys Tyr 675 680 685 Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp Ile Phe Ser Asp His His 690 695 700 Thr Met Cys Tyr Cys Glu Asp Gly Phe Met His Cys Thr Met Ser Gly 705 710 715 720 Val Pro Gly Ser Leu Leu Pro Asp Ala Val Leu Ser Ser Pro Leu Ser 725 730 735 His Arg Ser Lys Arg Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 740 745 750 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 755 760 765 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 770 775 780 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 785 790 795 800 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 805 810 815 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 820 825 830 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 835 840 845 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 850 855 860 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 865 870 875 880 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 885 890 895 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 900 905 910 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 915 920 925 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 930 935 940 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 945 950 955 960 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 965 970 975 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 980 985 990 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 995 1000 1005 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1010 1015 1020 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1025 1030 1035 1040 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 1045 1050 1055 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 1060 1065 1070 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 1075 1080 1085 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 1090 1095 1100 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 1105 1110 1115 1120 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 1125 1130 1135 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 1140 1145 1150 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 1155 1160 1165 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 1170 1175 1180 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 1185 1190 1195 1200 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 1205 1210 1215 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 1220 1225 1230 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 1235 1240 1245 Tyr Cys Ser Arg Leu Leu Asp Leu Val Phe Leu Leu Asp Gly Ser Ser 1250 1255 1260 Arg Leu Ser Glu Ala Glu Phe Glu Val Leu Lys Ala Phe Val Val Asp 1265 1270 1275 1280 Met Met Glu Arg Leu Arg Ile Ser Gln Lys Trp Val Arg Val Ala Val 1285 1290 1295 Val Glu Tyr His Asp Gly Ser His Ala Tyr Ile Gly Leu Lys Asp Arg 1300 1305 1310 Lys Arg Pro Ser Glu Leu Arg Arg Ile Ala Ser Gln Val Lys Tyr Ala 1315 1320 1325 Gly Ser Gln Val Ala Ser Thr Ser Glu Val Leu Lys Tyr Thr Leu Phe 1330 1335 1340 Gln Ile Phe Ser Lys Ile Asp Arg Pro Glu Ala Ser Arg Ile Thr Leu 1345 1350 1355 1360 Leu Leu Met Ala Ser Gln Glu Pro Gln Arg Met Ser Arg Asn Phe Val 1365 1370 1375 Arg Tyr Val Gln Gly Leu Lys Lys Lys Lys Val Ile Val Ile Pro Val 1380 1385 1390 Gly Ile Gly Pro His Ala Asn Leu Lys Gln Ile Arg Leu Ile Glu Lys 1395 1400 1405 Gln Ala Pro Glu Asn Lys Ala Phe Val Leu Ser Ser Val Asp Glu Leu 1410 1415 1420 Glu Gln Gln Arg Asp Glu Ile Val Ser Tyr Leu Cys Asp Leu Ala Pro 1425 1430 1435 1440 Glu Ala Pro Pro Pro Thr Leu Pro Pro Asp Met Ala Gln Val Thr Val 1445 1450 1455 Gly Pro Gly Leu Leu Gly Val Ser Thr Leu Gly Pro Lys Arg Asn Ser 1460 1465 1470 Met Val Leu Asp Val Ala Phe Val Leu Glu Gly Ser Asp Lys Ile Gly 1475 1480 1485 Glu Ala Asp Phe Asn Arg Ser Lys Glu Phe Met Glu Glu Val Ile Gln 1490 1495 1500 Arg Met Asp Val Gly Gln Asp Ser Ile His Val Thr Val Leu Gln Tyr 1505 1510 1515 1520 Ser Tyr Met Val Thr Val Glu Tyr Pro Phe Ser Glu Ala Gln Ser Lys 1525 1530 1535 Gly Asp Ile Leu Gln Arg Val Arg Glu Ile Arg Tyr Gln Gly Gly Asn 1540 1545 1550 Arg Thr Asn Thr Gly Leu Ala Leu Arg Tyr Leu Ser Asp His Ser Phe 1555 1560 1565 Leu Val Ser Gln Gly Asp Arg Glu Gln Ala Pro Asn Leu Val Tyr Met 1570 1575 1580 Val Thr Gly Asn Pro Ala Ser Asp Glu Ile Lys Arg Leu Pro Gly Asp 1585 1590 1595 1600 Ile Gln Val Val Pro Ile Gly Val Gly Pro Asn Ala Asn Val Gln Glu 1605 1610 1615 Leu Glu Arg Ile Gly Trp Pro Asn Ala Pro Ile Leu Ile Gln Asp Phe 1620 1625 1630 Glu Thr Leu Pro Arg Glu Ala Pro Asp Leu Val Leu Gln Arg Cys Cys 1635 1640 1645 Ser Gly Glu Gly Leu Gln Ile Pro Thr Leu Ser Pro Ala Pro Asp Cys 1650 1655 1660 Ser Gln Pro Leu Asp Val Ile Leu Leu Leu Asp Gly Ser Ser Ser Phe 1665 1670 1675 1680 Pro Ala Ser Tyr Phe Asp Glu Met Lys Ser Phe Ala Lys Ala Phe Ile 1685 1690 1695 Ser Lys Ala Asn Ile Gly Pro Arg Leu Thr Gln Val Ser Val Leu Gln 1700 1705 1710 Tyr Gly Ser Ile Thr Thr Ile Asp Val Pro Trp Asn Val Val Pro Glu 1715 1720 1725 Lys Ala His Leu Leu Ser Leu Val Asp Val Met Gln Arg Glu Gly Gly 1730 1735 1740 Pro Ser Gln Ile Gly Asp Ala Leu Gly Phe Ala Val Arg Tyr Leu Thr 1745 1750 1755 1760 Ser Glu Met His Gly Ala Arg Pro Gly Ala Ser Lys Ala Val Val Ile 1765 1770 1775 Leu Val Thr Asp Val Ser Val Asp Ser Val Asp Ala Ala Ala Asp Ala 1780 1785 1790 Ala Arg Ser Asn Arg Val Thr Val Phe Pro Ile Gly Ile Gly Asp Arg 1795 1800 1805 Tyr Asp Ala Ala Gln Leu Arg Ile Leu Ala Gly Pro Ala Gly Asp Ser 1810 1815 1820 Asn Val Val Lys Leu Gln Arg Ile Glu Asp Leu Pro Thr Met Val Thr 1825 1830 1835 1840 Leu Gly Asn Ser Phe Leu His Lys Leu Cys Ser Gly Phe Val Arg Ile 1845 1850 1855 Cys Met Asp Glu Asp Gly Asn Glu Lys Arg Pro Gly Asp Val Trp Thr 1860 1865 1870 Leu Pro Asp Gln Cys His Thr Val Thr Cys Gln Pro Asp Gly Gln Thr 1875 1880 1885 Leu Leu Lys Ser His Arg Val Asn Cys Asp Arg Gly Leu Arg Pro Ser 1890 1895 1900 Cys Pro Asn Ser Gln Ser Pro Val Lys Val Glu Glu Thr Cys Gly Cys 1905 1910 1915 1920 Arg Trp Thr Cys Pro Cys Val Cys Thr Gly Ser Ser Thr Arg His Ile 1925 1930 1935 Val Thr Phe Asp Gly Gln Asn Phe Lys Leu Thr Gly Ser Cys Ser Tyr 1940 1945 1950 Val Leu Phe Gln Asn Lys Glu Gln Asp Leu Glu Val Ile Leu His Asn 1955 1960 1965 Gly Ala Cys Ser Pro Gly Ala Arg Gln Gly Cys Met Lys Ser Ile Glu 1970 1975 1980 Val Lys His Ser Ala Leu Ser Val Glu Leu His Ser Asp Met Glu Val 1985 1990 1995 2000 Thr Val Asn Gly Arg Leu Val Ser Val Pro Tyr Val Gly Gly Asn Met 2005 2010 2015 Glu Val Asn Val Tyr Gly Ala Ile Met His Glu Val Arg Phe Asn His 2020 2025 2030 Leu Gly His Ile Phe Thr Phe Thr Pro Gln Asn Asn Glu Phe Gln Leu 2035 2040 2045 Gln Leu Ser Pro Lys Thr Phe Ala Ser Lys Thr Tyr Gly Leu Cys Gly 2050 2055 2060 Ile Cys Asp Glu Asn Gly Ala Asn Asp Phe Met Leu Arg Asp Gly Thr 2065 2070 2075 2080 Val Thr Thr Asp Trp Lys Thr Leu Val Gln Glu Trp Thr Val Gln Arg 2085 2090 2095 Pro Gly Gln Thr Cys Gln Pro Ile Leu Glu Glu Gln Cys Leu Val Pro 2100 2105 2110 Asp Ser Ser His Cys Gln Val Leu Leu Leu Pro Leu Phe Ala Glu Cys 2115 2120 2125 His Lys Val Leu Ala Pro Ala Thr Phe Tyr Ala Ile Cys Gln Gln Asp 2130 2135 2140 Ser Cys His Gln Glu Gln Val Cys Glu Val Ile Ala Ser Tyr Ala His 2145 2150 2155 2160 Leu Cys Arg Thr Asn Gly Val Cys Val Asp Trp Arg Thr Pro Asp Phe 2165 2170 2175 Cys Ala Met Ser Cys Pro Pro Ser Leu Val Tyr Asn His Cys Glu His 2180 2185 2190 Gly Cys Pro Arg His Cys Asp Gly Asn Val Ser Ser Cys Gly Asp His 2195 2200 2205 Pro Ser Glu Gly Cys Phe Cys Pro Pro Asp Lys Val Met Leu Glu Gly 2210 2215 2220 Ser Cys Val Pro Glu Glu Ala Cys Thr Gln Cys Ile Gly Glu Asp Gly 2225 2230 2235 2240 Val Gln His Gln Phe Leu Glu Ala Trp Val Pro Asp His Gln Pro Cys 2245 2250 2255 Gln Ile Cys Thr Cys Leu Ser Gly Arg Lys Val Asn Cys Thr Thr Gln 2260 2265 2270 Pro Cys Pro Thr Ala Lys Ala Pro Thr Cys Gly Leu Cys Glu Val Ala 2275 2280 2285 Arg Leu Arg Gln Asn Ala Asp Gln Cys Cys Pro Glu Tyr Glu Cys Val 2290 2295 2300 Cys Asp Pro Val Ser Cys Asp Leu Pro Pro Val Pro His Cys Glu Arg 2305 2310 2315 2320 Gly Leu Gln Pro Thr Leu Thr Asn Pro Gly Glu Cys Arg Pro Asn Phe 2325 2330 2335 Thr Cys Ala Cys Arg Lys Glu Glu Cys Lys Arg Val Ser Pro Pro Ser 2340 2345 2350 Cys Pro Pro His Arg Leu Pro Thr Leu Arg Lys Thr Gln Cys Cys Asp 2355 2360 2365 Glu Tyr Glu Cys Ala Cys Asn Cys Val Asn Ser Thr Val Ser Cys Pro 2370 2375 2380 Leu Gly Tyr Leu Ala Ser Thr Ala Thr Asn Asp Cys Gly Cys Thr Thr 2385 2390 2395 2400 Thr Thr Cys Leu Pro Asp Lys Val Cys Val His Arg Ser Thr Ile Tyr 2405 2410 2415 Pro Val Gly Gln Phe Trp Glu Glu Gly Cys Asp Val Cys Thr Cys Thr 2420 2425 2430 Asp Met Glu Asp Ala Val Met Gly Leu Arg Val Ala Gln Cys Ser Gln 2435 2440 2445 Lys Pro Cys Glu Asp Ser Cys Arg Ser Gly Phe Thr Tyr Val Leu His 2450 2455 2460 Glu Gly Glu Cys Cys Gly Arg Cys Leu Pro Ser Ala Cys Glu Val Val 2465 2470 2475 2480 Thr Gly Ser Pro Arg Gly Asp Ser Gln Ser Ser Trp Lys Ser Val Gly 2485 2490 2495 Ser Gln Trp Ala Ser Pro Glu Asn Pro Cys Leu Ile Asn Glu Cys Val 2500 2505 2510 Arg Val Lys Glu Glu Val Phe Ile Gln Gln Arg Asn Val Ser Cys Pro 2515 2520 2525 Gln Leu Glu Val Pro Val Cys Pro Ser Gly Phe Gln Leu Ser Cys Lys 2530 2535 2540 Thr Ser Ala Cys Cys Pro Ser Cys Arg Cys Glu Arg Met Glu Ala Cys 2545 2550 2555 2560 Met Leu Asn Gly Thr Val Ile Gly Pro Gly Lys Thr Val Met Ile Asp 2565 2570 2575 Val Cys Thr Thr Cys Arg Cys Met Val Gln Val Gly Val Ile Ser Gly 2580 2585 2590 Phe Lys Leu Glu Cys Arg Lys Thr Thr Cys Asn Pro Cys Pro Leu Gly 2595 2600 2605 Tyr Lys Glu Glu Asn Asn Thr Gly Glu Cys Cys Gly Arg Cys Leu Pro 2610 2615 2620 Thr Ala Cys Thr Ile Gln Leu Arg Gly Gly Gln Ile Met Thr Leu Lys 2625 2630 2635 2640 Arg Asp Glu Thr Leu Gln Asp Gly Cys Asp Thr His Phe Cys Lys Val 2645 2650 2655 Asn Glu Arg Gly Glu Tyr Phe Trp Glu Lys Arg Val Thr Gly Cys Pro 2660 2665 2670 Pro Phe Asp Glu His Lys Cys Leu Ala Glu Gly Gly Lys Ile Met Lys 2675 2680 2685 Ile Pro Gly Thr Cys Cys Asp Thr Cys Glu Glu Pro Glu Cys Asn Asp 2690 2695 2700 Ile Thr Ala Arg Leu Gln Tyr Val Lys Val Gly Ser Cys Lys Ser Glu 2705 2710 2715 2720 Val Glu Val Asp Ile His Tyr Cys Gln Gly Lys Cys Ala Ser Lys Ala 2725 2730 2735 Met Tyr Ser Ile Asp Ile Asn Asp Val Gln Asp Gln Cys Ser Cys Cys 2740 2745 2750 Ser Pro Thr Arg Thr Glu Pro Met Gln Val Ala Leu His Cys Thr Asn 2755 2760 2765 Gly Ser Val Val Tyr His Glu Val Leu Asn Ala Met Glu Cys Lys Cys 2770 2775 2780 Ser Pro Arg Lys Cys Ser Lys 2785 2790 <210> 3 <211> 1581 <212> PRT <213> Artificial Sequence <220> <223> Single chain FVIII with partial B domain <220> <221> MISC_FEATURE <222> (782) <223> Xaa = Isoleucine or Cysteine <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 Xaa 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> 4 <211> 1443 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC Heavy chain <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 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 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 Cys Arg Pro Pro Met 930 935 940 Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu 945 950 955 960 Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly 965 970 975 Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn 980 985 990 Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu 995 1000 1005 Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys 1010 1015 1020 Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys 1025 1030 1035 1040 Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr 1045 1050 1055 Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly 1060 1065 1070 Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser 1075 1080 1085 His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly 1090 1095 1100 Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met 1105 1110 1115 1120 Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile 1125 1130 1135 Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser 1140 1145 1150 Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu 1155 1160 1165 Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn 1170 1175 1180 Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val 1185 1190 1195 1200 Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro 1205 1210 1215 Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser 1220 1225 1230 Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val 1235 1240 1245 Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys 1250 1255 1260 Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr 1265 1270 1275 1280 Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala 1285 1290 1295 Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly 1300 1305 1310 Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val 1315 1320 1325 Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu 1330 1335 1340 Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu 1345 1350 1355 1360 Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly 1365 1370 1375 Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro 1380 1385 1390 Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu 1395 1400 1405 Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro 1410 1415 1420 Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu 1425 1430 1435 1440 His Asp Phe <210> 5 <211> 772 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC Light chain <400> 5 Ala Thr Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro 1 5 10 15 Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe 20 25 30 Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His 35 40 45 Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val 50 55 60 Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro 65 70 75 80 Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln 85 90 95 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 100 105 110 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 115 120 125 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 130 135 140 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 145 150 155 160 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 165 170 175 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 180 185 190 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 195 200 205 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 210 215 220 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 225 230 235 240 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 245 250 255 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 260 265 270 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 275 280 285 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 290 295 300 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 305 310 315 320 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 325 330 335 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 340 345 350 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 355 360 365 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 370 375 380 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 385 390 395 400 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 405 410 415 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 420 425 430 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 435 440 445 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 450 455 460 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 465 470 475 480 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 485 490 495 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 500 505 510 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 515 520 525 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 530 535 540 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 545 550 555 560 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 565 570 575 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 580 585 590 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 595 600 605 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 610 615 620 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 625 630 635 640 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 645 650 655 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 660 665 670 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 675 680 685 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 690 695 700 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 705 710 715 720 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 725 730 735 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 740 745 750 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 755 760 765 Gln Asp Leu Tyr 770 <210> 6 <211> 2094 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-6 <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 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu Val Cys 1585 1590 1595 1600 Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys Thr Cys 1605 1610 1615 Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser Gly Cys 1620 1625 1630 Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val Ala Leu 1635 1640 1645 Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro Gly Glu 1650 1655 1660 Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg Lys Trp 1665 1670 1675 1680 Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile Gly Met 1685 1690 1695 Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro Gly Glu 1700 1705 1710 Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro Gly Thr 1715 1720 1725 Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser Val Lys 1730 1735 1740 Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile Glu Leu 1745 1750 1755 1760 Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu Thr His 1765 1770 1775 Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu Gly Lys 1780 1785 1790 Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val Val Leu 1795 1800 1805 Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn Phe Asp 1810 1815 1820 Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val Glu Glu 1825 1830 1835 1840 Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln Cys Ala 1845 1850 1855 Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys His Asn 1860 1865 1870 Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr 1875 1880 1885 Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr 1890 1895 1900 Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp 1905 1910 1915 1920 Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala 1925 1930 1935 Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln 1940 1945 1950 Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu Trp 1955 1960 1965 Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln His Pro 1970 1975 1980 Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His Ala His 1985 1990 1995 2000 Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys Val Asp 2005 2010 2015 Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe Ala Ser 2020 2025 2030 Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys Gln Ile 2035 2040 2045 Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln Glu Pro 2050 2055 2060 Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr 2065 2070 2075 2080 Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2085 2090 <210> 7 <211> 2098 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-10 <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 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val 1585 1590 1595 1600 Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys 1605 1610 1615 Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys 1620 1625 1630 Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg 1635 1640 1645 Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr 1650 1655 1660 Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg 1665 1670 1675 1680 Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser 1685 1690 1695 Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu 1700 1705 1710 Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser 1715 1720 1725 Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His 1730 1735 1740 Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly 1745 1750 1755 1760 Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys 1765 1770 1775 Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu 1780 1785 1790 Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile 1795 1800 1805 Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys 1810 1815 1820 Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu 1825 1830 1835 1840 Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser 1845 1850 1855 Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala 1860 1865 1870 Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys 1875 1880 1885 Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp 1890 1895 1900 Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu 1905 1910 1915 1920 Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala 1925 1930 1935 His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr 1940 1945 1950 Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr 1955 1960 1965 Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr 1970 1975 1980 Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly 1985 1990 1995 2000 Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln 2005 2010 2015 Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg 2020 2025 2030 Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu 2035 2040 2045 His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala 2050 2055 2060 Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val 2065 2070 2075 2080 Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His 2085 2090 2095 Asp Phe <210> 8 <211> 2108 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-20 <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 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu Val Cys Pro Ala 1605 1610 1615 Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn 1620 1625 1630 Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser Gly Cys Leu Cys 1635 1640 1645 Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val Ala Leu Glu Arg 1650 1655 1660 Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val 1665 1670 1675 1680 Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg Lys Trp Asn Cys 1685 1690 1695 Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile Gly Met Ala His 1700 1705 1710 Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln 1715 1720 1725 Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg 1730 1735 1740 Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser Val Lys Cys Lys 1745 1750 1755 1760 Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile Glu Leu Phe Asp 1765 1770 1775 Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu Thr His Phe Glu 1780 1785 1790 Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu 1795 1800 1805 Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val Val Leu Lys Gln 1810 1815 1820 Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile 1825 1830 1835 1840 Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val Glu Glu Asp Pro 1845 1850 1855 Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr 1860 1865 1870 Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile 1875 1880 1885 Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp 1890 1895 1900 Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp 1905 1910 1915 1920 Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala 1925 1930 1935 Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln His 1940 1945 1950 Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln Ser Cys 1955 1960 1965 Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu Trp Arg Tyr 1970 1975 1980 Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln His Pro Glu Pro 1985 1990 1995 2000 Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His Ala His Cys Pro 2005 2010 2015 Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys Val Asp Pro Glu 2020 2025 2030 Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe Ala Ser Gly Lys 2035 2040 2045 Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys Gln Ile Cys His 2050 2055 2060 Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln Glu Pro Gly Gly 2065 2070 2075 2080 Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr 2085 2090 2095 Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2100 2105 <210> 9 <211> 2118 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-30 <400> 9 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg 1605 1610 1615 Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu 1620 1625 1630 Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met 1635 1640 1645 Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg 1650 1655 1660 His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln 1665 1670 1675 1680 Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr 1685 1690 1695 Cys Val Cys Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp 1700 1705 1710 Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly 1715 1720 1725 Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp 1730 1735 1740 Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys 1745 1750 1755 1760 Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu 1765 1770 1775 Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys 1780 1785 1790 Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg 1795 1800 1805 Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg 1810 1815 1820 His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val 1825 1830 1835 1840 Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr 1845 1850 1855 Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser 1860 1865 1870 Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp 1875 1880 1885 Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val 1890 1895 1900 Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn 1905 1910 1915 1920 Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr 1925 1930 1935 Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile 1940 1945 1950 Ala Ala Tyr Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp 1955 1960 1965 Arg Thr Ala Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg 1970 1975 1980 Glu Asn Gly Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala 1985 1990 1995 2000 Cys Gln Val Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln 2005 2010 2015 Cys Val Glu Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp 2020 2025 2030 Glu Leu Leu Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu 2035 2040 2045 Val Ala Gly Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro 2050 2055 2060 Ser Asp Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu 2065 2070 2075 2080 Thr Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr 2085 2090 2095 Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu 2100 2105 2110 Pro Pro Leu His Asp Phe 2115 <210> 10 <211> 2128 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-40 <400> 10 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 1620 1625 1630 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 1635 1640 1645 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 1650 1655 1660 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 1665 1670 1675 1680 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 1685 1690 1695 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 1700 1705 1710 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 1715 1720 1725 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 1730 1735 1740 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 1745 1750 1755 1760 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 1765 1770 1775 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 1780 1785 1790 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 1795 1800 1805 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 1810 1815 1820 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 1825 1830 1835 1840 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 1845 1850 1855 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 1860 1865 1870 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 1875 1880 1885 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1890 1895 1900 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1905 1910 1915 1920 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 1925 1930 1935 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 1940 1945 1950 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 1955 1960 1965 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 1970 1975 1980 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 1985 1990 1995 2000 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 2005 2010 2015 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 2020 2025 2030 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 2035 2040 2045 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 2050 2055 2060 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 2065 2070 2075 2080 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 2085 2090 2095 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 2100 2105 2110 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2115 2120 2125 <210> 11 <211> 2138 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-50 <400> 11 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Leu Ser Cys Arg Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn 1635 1640 1645 Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp 1650 1655 1660 Leu Glu Cys Met Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro 1665 1670 1675 1680 Gly Met Val Arg His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro 1685 1690 1695 Cys Phe His Gln Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile 1700 1705 1710 Gly Cys Asn Thr Cys Val Cys Arg Asp Arg Lys Trp Asn Cys Thr Asp 1715 1720 1725 His Val Cys Asp Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu 1730 1735 1740 Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val 1745 1750 1755 1760 Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu 1765 1770 1775 Val Gly Asn Lys Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg 1780 1785 1790 Val Thr Ile Leu Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu 1795 1800 1805 Val Asn Val Lys Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val 1810 1815 1820 Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val 1825 1830 1835 1840 Val Trp Asp Arg His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr 1845 1850 1855 Gln Glu Lys Val Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn 1860 1865 1870 Asn Asp Leu Thr Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp 1875 1880 1885 Phe Gly Asn Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys 1890 1895 1900 Val Pro Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys 1905 1910 1915 1920 Gln Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe 1925 1930 1935 Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val Cys 1940 1945 1950 Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala Cys Phe 1955 1960 1965 Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln His Gly Lys 1970 1975 1980 Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln Ser Cys Glu Glu 1985 1990 1995 2000 Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu Trp Arg Tyr Asn Ser 2005 2010 2015 Cys Ala Pro Ala Cys Gln Val Thr Cys Gln His Pro Glu Pro Leu Ala 2020 2025 2030 Cys Pro Val Gln Cys Val Glu Gly Cys His Ala His Cys Pro Pro Gly 2035 2040 2045 Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys Val Asp Pro Glu Asp Cys 2050 2055 2060 Pro Val Cys Glu Val Ala Gly Arg Arg Phe Ala Ser Gly Lys Lys Val 2065 2070 2075 2080 Thr Leu Asn Pro Ser Asp Pro Glu His Cys Gln Ile Cys His Cys Asp 2085 2090 2095 Val Val Asn Leu Thr Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val 2100 2105 2110 Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu 2115 2120 2125 Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2130 2135 <210> 12 <211> 2148 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-60 <400> 12 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro 1635 1640 1645 Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu 1650 1655 1660 Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met 1665 1670 1675 1680 Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu 1685 1690 1695 Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys 1700 1705 1710 Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val 1715 1720 1725 Cys Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr 1730 1735 1740 Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys 1745 1750 1755 1760 Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys 1765 1770 1775 Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys 1780 1785 1790 Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu 1795 1800 1805 Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro 1810 1815 1820 Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile 1825 1830 1835 1840 Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu 1845 1850 1855 Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly 1860 1865 1870 Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser 1875 1880 1885 Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys 1890 1895 1900 Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser 1905 1910 1915 1920 Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser 1925 1930 1935 Ser Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu 1940 1945 1950 Val Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser 1955 1960 1965 Cys Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala 1970 1975 1980 Tyr Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr 1985 1990 1995 2000 Ala Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn 2005 2010 2015 Gly Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln 2020 2025 2030 Val Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val 2035 2040 2045 Glu Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu 2050 2055 2060 Leu Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala 2065 2070 2075 2080 Gly Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp 2085 2090 2095 Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys 2100 2105 2110 Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala 2115 2120 2125 Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro 2130 2135 2140 Leu His Asp Phe 2145 <210> 13 <211> 2178 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-90 <400> 13 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1635 1640 1645 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1650 1655 1660 Gly Gly Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val 1665 1670 1675 1680 Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys 1685 1690 1695 Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys 1700 1705 1710 Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg 1715 1720 1725 Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr 1730 1735 1740 Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg 1745 1750 1755 1760 Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser 1765 1770 1775 Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu 1780 1785 1790 Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser 1795 1800 1805 Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His 1810 1815 1820 Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly 1825 1830 1835 1840 Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys 1845 1850 1855 Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu 1860 1865 1870 Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile 1875 1880 1885 Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys 1890 1895 1900 Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu 1905 1910 1915 1920 Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser 1925 1930 1935 Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala 1940 1945 1950 Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys 1955 1960 1965 Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp 1970 1975 1980 Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu 1985 1990 1995 2000 Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala 2005 2010 2015 His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr 2020 2025 2030 Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr 2035 2040 2045 Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr 2050 2055 2060 Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly 2065 2070 2075 2080 Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln 2085 2090 2095 Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg 2100 2105 2110 Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu 2115 2120 2125 His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala 2130 2135 2140 Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val 2145 2150 2155 2160 Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His 2165 2170 2175 Asp Phe <210> 14 <211> 2208 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-120 <400> 14 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1635 1640 1645 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1650 1655 1660 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1665 1670 1675 1680 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1685 1690 1695 Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 1700 1705 1710 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 1715 1720 1725 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 1730 1735 1740 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 1745 1750 1755 1760 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 1765 1770 1775 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 1780 1785 1790 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 1795 1800 1805 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 1810 1815 1820 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 1825 1830 1835 1840 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 1845 1850 1855 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 1860 1865 1870 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 1875 1880 1885 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 1890 1895 1900 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 1905 1910 1915 1920 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 1925 1930 1935 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 1940 1945 1950 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 1955 1960 1965 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1970 1975 1980 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1985 1990 1995 2000 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 2005 2010 2015 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 2020 2025 2030 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 2035 2040 2045 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 2050 2055 2060 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 2065 2070 2075 2080 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 2085 2090 2095 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 2100 2105 2110 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 2115 2120 2125 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 2130 2135 2140 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 2145 2150 2155 2160 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 2165 2170 2175 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 2180 2185 2190 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2195 2200 2205 <210> 15 <211> 2208 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-120-TH1 <400> 15 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 Gly Gly Gly 1570 1575 1580 Ser Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1585 1590 1595 1600 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1605 1610 1615 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1620 1625 1630 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1635 1640 1645 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1650 1655 1660 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1665 1670 1675 1680 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1685 1690 1695 Gly Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 1700 1705 1710 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 1715 1720 1725 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 1730 1735 1740 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 1745 1750 1755 1760 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 1765 1770 1775 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 1780 1785 1790 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 1795 1800 1805 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 1810 1815 1820 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 1825 1830 1835 1840 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 1845 1850 1855 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 1860 1865 1870 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 1875 1880 1885 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 1890 1895 1900 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 1905 1910 1915 1920 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 1925 1930 1935 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 1940 1945 1950 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 1955 1960 1965 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1970 1975 1980 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1985 1990 1995 2000 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 2005 2010 2015 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 2020 2025 2030 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 2035 2040 2045 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 2050 2055 2060 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 2065 2070 2075 2080 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 2085 2090 2095 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 2100 2105 2110 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 2115 2120 2125 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 2130 2135 2140 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 2145 2150 2155 2160 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 2165 2170 2175 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 2180 2185 2190 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2195 2200 2205 <210> 16 <211> 2208 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-120-TH2 <400> 16 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 Leu Ser Lys 1570 1575 1580 Asn Asn Ala Ile Glu Pro Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly 1585 1590 1595 1600 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1605 1610 1615 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1620 1625 1630 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1635 1640 1645 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1650 1655 1660 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1665 1670 1675 1680 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1685 1690 1695 Gly Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 1700 1705 1710 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 1715 1720 1725 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 1730 1735 1740 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 1745 1750 1755 1760 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 1765 1770 1775 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 1780 1785 1790 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 1795 1800 1805 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 1810 1815 1820 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 1825 1830 1835 1840 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 1845 1850 1855 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 1860 1865 1870 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 1875 1880 1885 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 1890 1895 1900 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 1905 1910 1915 1920 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 1925 1930 1935 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 1940 1945 1950 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 1955 1960 1965 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1970 1975 1980 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1985 1990 1995 2000 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 2005 2010 2015 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 2020 2025 2030 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 2035 2040 2045 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 2050 2055 2060 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 2065 2070 2075 2080 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 2085 2090 2095 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 2100 2105 2110 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 2115 2120 2125 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 2130 2135 2140 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 2145 2150 2155 2160 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 2165 2170 2175 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 2180 2185 2190 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2195 2200 2205 <210> 17 <211> 2388 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3-300 <400> 17 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1635 1640 1645 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1650 1655 1660 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1665 1670 1675 1680 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1685 1690 1695 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1700 1705 1710 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1715 1720 1725 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1730 1735 1740 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1745 1750 1755 1760 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1765 1770 1775 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1780 1785 1790 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1795 1800 1805 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1810 1815 1820 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1825 1830 1835 1840 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1845 1850 1855 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1860 1865 1870 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro 1875 1880 1885 Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu 1890 1895 1900 Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met 1905 1910 1915 1920 Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu 1925 1930 1935 Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys 1940 1945 1950 Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val 1955 1960 1965 Cys Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr 1970 1975 1980 Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys 1985 1990 1995 2000 Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys 2005 2010 2015 Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys 2020 2025 2030 Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu 2035 2040 2045 Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro 2050 2055 2060 Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile 2065 2070 2075 2080 Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu 2085 2090 2095 Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly 2100 2105 2110 Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser 2115 2120 2125 Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys 2130 2135 2140 Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser 2145 2150 2155 2160 Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser 2165 2170 2175 Ser Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu 2180 2185 2190 Val Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser 2195 2200 2205 Cys Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala 2210 2215 2220 Tyr Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr 2225 2230 2235 2240 Ala Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn 2245 2250 2255 Gly Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln 2260 2265 2270 Val Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val 2275 2280 2285 Glu Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu 2290 2295 2300 Leu Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala 2305 2310 2315 2320 Gly Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp 2325 2330 2335 Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys 2340 2345 2350 Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala 2355 2360 2365 Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro 2370 2375 2380 Leu His Asp Phe 2385 <210> 18 <211> 2745 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3/D'D3-120 <400> 18 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1635 1640 1645 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1650 1655 1660 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1665 1670 1675 1680 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1685 1690 1695 Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 1700 1705 1710 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 1715 1720 1725 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 1730 1735 1740 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 1745 1750 1755 1760 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 1765 1770 1775 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 1780 1785 1790 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 1795 1800 1805 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 1810 1815 1820 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 1825 1830 1835 1840 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 1845 1850 1855 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 1860 1865 1870 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 1875 1880 1885 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 1890 1895 1900 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 1905 1910 1915 1920 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 1925 1930 1935 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 1940 1945 1950 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 1955 1960 1965 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1970 1975 1980 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1985 1990 1995 2000 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 2005 2010 2015 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 2020 2025 2030 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 2035 2040 2045 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 2050 2055 2060 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 2065 2070 2075 2080 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 2085 2090 2095 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 2100 2105 2110 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 2115 2120 2125 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 2130 2135 2140 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 2145 2150 2155 2160 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 2165 2170 2175 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 2180 2185 2190 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2195 2200 2205 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 2210 2215 2220 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Leu 2225 2230 2235 2240 Ser Cys Arg Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu 2245 2250 2255 Arg Ala Glu Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu 2260 2265 2270 Glu Cys Met Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly 2275 2280 2285 Met Val Arg His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys 2290 2295 2300 Phe His Gln Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly 2305 2310 2315 2320 Cys Asn Thr Cys Val Cys Arg Asp Arg Lys Trp Asn Cys Thr Asp His 2325 2330 2335 Val Cys Asp Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr 2340 2345 2350 Phe Asp Gly Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu 2355 2360 2365 Val Gln Asp Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val 2370 2375 2380 Gly Asn Lys Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg Val 2385 2390 2395 2400 Thr Ile Leu Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val 2405 2410 2415 Asn Val Lys Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val Glu 2420 2425 2430 Ser Gly Arg Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val 2435 2440 2445 Trp Asp Arg His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln 2450 2455 2460 Glu Lys Val Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn 2465 2470 2475 2480 Asp Leu Thr Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe 2485 2490 2495 Gly Asn Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val 2500 2505 2510 Pro Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln 2515 2520 2525 Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe Gln 2530 2535 2540 Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile 2545 2550 2555 2560 Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys 2565 2570 2575 Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln His Gly Lys Val 2580 2585 2590 Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg 2595 2600 2605 Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys 2610 2615 2620 Ala Pro Ala Cys Gln Val Thr Cys Gln His Pro Glu Pro Leu Ala Cys 2625 2630 2635 2640 Pro Val Gln Cys Val Glu Gly Cys His Ala His Cys Pro Pro Gly Lys 2645 2650 2655 Ile Leu Asp Glu Leu Leu Gln Thr Cys Val Asp Pro Glu Asp Cys Pro 2660 2665 2670 Val Cys Glu Val Ala Gly Arg Arg Phe Ala Ser Gly Lys Lys Val Thr 2675 2680 2685 Leu Asn Pro Ser Asp Pro Glu His Cys Gln Ile Cys His Cys Asp Val 2690 2695 2700 Val Asn Leu Thr Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val 2705 2710 2715 2720 Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp 2725 2730 2735 Ile Ser Glu Pro Pro Leu His Asp Phe 2740 2745 <210> 19 <211> 2949 <212> PRT <213> Artificial Sequence <220> <223> D'D3/scFVIII-120 of the complex of D'D3/scFVIII-120 and D'D3 <400> 19 Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr Ala Arg Cys Ser Leu Phe 1 5 10 15 Gly Ser Asp Phe Val Asn Thr Phe Asp Gly Ser Met Tyr Ser Phe Ala 20 25 30 Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly Cys Gln Lys Arg Ser Phe 35 40 45 Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys Arg Val Ser Leu Ser Val 50 55 60 Tyr Leu Gly Glu Phe Phe Asp Ile His Leu Phe Val Asn Gly Thr Val 65 70 75 80 Thr Gln Gly Asp Gln Arg Val Ser Met Pro Tyr Ala Ser Lys Gly Leu 85 90 95 Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys Leu Ser Gly Glu Ala Tyr 100 105 110 Gly Phe Val Ala Arg Ile Asp Gly Ser Gly Asn Phe Gln Val Leu Leu 115 120 125 Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly Leu Cys Gly Asn Phe Asn 130 135 140 Ile Phe Ala Glu Asp Asp Phe Met Thr Gln Glu Gly Thr Leu Thr Ser 145 150 155 160 Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala Leu Ser Ser Gly Glu Gln 165 170 175 Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser Ser Cys Asn Ile Ser Ser 180 185 190 Gly Glu Met Gln Lys Gly Leu Trp Glu Gln Cys Gln Leu Leu Lys Ser 195 200 205 Thr Ser Val Phe Ala Arg Cys His Pro Leu Val Asp Pro Glu Pro Phe 210 215 220 Val Ala Leu Cys Glu Lys Thr Leu Cys Glu Cys Ala Gly Gly Leu Glu 225 230 235 240 Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala Arg Thr Cys Ala Gln Glu 245 250 255 Gly Met Val Leu Tyr Gly Trp Thr Asp His Ser Ala Cys Ser Pro Val 260 265 270 Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys Val Ser Pro Cys Ala Arg 275 280 285 Thr Cys Gln Ser Leu His Ile Asn Glu Met Cys Gln Glu Arg Cys Val 290 295 300 Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu Leu Asp Glu Gly Leu Cys 305 310 315 320 Val Glu Ser Thr Glu Cys Pro Cys Val His Ser Gly Lys Arg Tyr Pro 325 330 335 Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn Thr Cys Ile Cys Arg Asn 340 345 350 Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys Pro Gly Glu Cys Leu Val 355 360 365 Thr Gly Gln Ser His Phe Lys Ser Phe Asp Asn Arg Tyr Phe Thr Phe 370 375 380 Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg Asp Cys Gln Asp His Ser 385 390 395 400 Phe Ser Ile Val Ile Glu Thr Val Gln Cys Ala Asp Asp Arg Asp Ala 405 410 415 Val Cys Thr Arg Ser Val Thr Val Arg Leu Pro Gly Leu His Asn Ser 420 425 430 Leu Val Lys Leu Lys His Gly Ala Gly Val Ala Met Asp Gly Gln Asp 435 440 445 Val Gln Leu Pro Leu Leu Lys Gly Asp Leu Arg Ile Gln His Thr Val 450 455 460 Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu Asp Leu Gln Met Asp Trp 465 470 475 480 Asp Gly Arg Gly Arg Leu Leu Val Lys Leu Ser Pro Val Tyr Ala Gly 485 490 495 Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn Gly Asn Gln Gly Asp Asp 500 505 510 Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro Arg Val Glu Asp Phe Gly 515 520 525 Asn Ala Trp Lys Leu His Gly Asp Cys Gln Asp Leu Gln Lys Gln His 530 535 540 Ser Asp Pro Cys Ala Leu Asn Pro Arg Met Thr Arg Phe Ser Glu Glu 545 550 555 560 Ala Cys Ala Val Leu Thr Ser Pro Thr Phe Glu Ala Cys His Arg Ala 565 570 575 Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys Arg Tyr Asp Val Cys Ser 580 585 590 Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly Ala Leu Ala Ser Tyr Ala 595 600 605 Ala Ala Cys Ala Gly Arg Gly Val Arg Val Ala Trp Arg Glu Pro Gly 610 615 620 Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln Val Tyr Leu Gln Cys Gly 625 630 635 640 Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu Ser Tyr Pro Asp Glu Glu 645 650 655 Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe Cys Pro Pro Gly Leu Tyr 660 665 670 Met Asp Glu Arg Gly Asp Cys Val Pro Lys Ala Gln Cys Pro Cys Tyr 675 680 685 Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp Ile Phe Ser Asp His His 690 695 700 Thr Met Cys Tyr Cys Glu Asp Gly Phe Met His Cys Thr Met Ser Gly 705 710 715 720 Val Pro Gly Ser Leu Leu Pro Asp Ala Val Leu Ser Ser Pro Leu Ser 725 730 735 His Arg Ser Lys Arg Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 740 745 750 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 755 760 765 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 770 775 780 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 785 790 795 800 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 805 810 815 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 820 825 830 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 835 840 845 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 850 855 860 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 865 870 875 880 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 885 890 895 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 900 905 910 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 915 920 925 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 930 935 940 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 945 950 955 960 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 965 970 975 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 980 985 990 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 995 1000 1005 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1010 1015 1020 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1025 1030 1035 1040 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 1045 1050 1055 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 1060 1065 1070 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 1075 1080 1085 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 1090 1095 1100 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 1105 1110 1115 1120 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 1125 1130 1135 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 1140 1145 1150 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 1155 1160 1165 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 1170 1175 1180 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 1185 1190 1195 1200 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 1205 1210 1215 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 1220 1225 1230 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 1235 1240 1245 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1250 1255 1260 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1265 1270 1275 1280 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1285 1290 1295 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1300 1305 1310 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1315 1320 1325 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1330 1335 1340 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1345 1350 1355 1360 Gly Ser Leu Val Pro Arg Gly Ser Ala Thr Arg Arg Tyr Tyr Leu Gly 1365 1370 1375 Ala Val Glu Leu Ser Trp Asp Tyr Met Gln Ser Asp Leu Gly Glu Leu 1380 1385 1390 Pro Val Asp Ala Arg Phe Pro Pro Arg Val Pro Lys Ser Phe Pro Phe 1395 1400 1405 Asn Thr Ser Val Val Tyr Lys Lys Thr Leu Phe Val Glu Phe Thr Asp 1410 1415 1420 His Leu Phe Asn Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu 1425 1430 1435 1440 Gly Pro Thr Ile Gln Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu 1445 1450 1455 Lys Asn Met Ala Ser His Pro Val Ser Leu His Ala Val Gly Val Ser 1460 1465 1470 Tyr Trp Lys Ala Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln 1475 1480 1485 Arg Glu Lys Glu Asp Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr 1490 1495 1500 Val Trp Gln Val Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Leu 1505 1510 1515 1520 Cys Leu Thr Tyr Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu 1525 1530 1535 Asn Ser Gly Leu Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu 1540 1545 1550 Ala Lys Glu Lys Thr Gln Thr Leu His Lys Phe Ile Leu Leu Phe Ala 1555 1560 1565 Val Phe Asp Glu Gly Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu 1570 1575 1580 Met Gln Asp Arg Asp Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His 1585 1590 1595 1600 Thr Val Asn Gly Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys 1605 1610 1615 His Arg Lys Ser Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro 1620 1625 1630 Glu Val His Ser Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn 1635 1640 1645 His Arg Gln Ala Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala 1650 1655 1660 Gln Thr Leu Leu Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile 1665 1670 1675 1680 Ser Ser His Gln His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser 1685 1690 1695 Cys Pro Glu Glu Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu 1700 1705 1710 Asp Tyr Asp Asp Asp Leu Thr Asp Ser Glu Met Asp Val Val Arg Phe 1715 1720 1725 Asp Asp Asp Asn Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys 1730 1735 1740 Lys His Pro Lys Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp 1745 1750 1755 1760 Trp Asp Tyr Ala Pro Leu Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys 1765 1770 1775 Ser Gln Tyr Leu Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys 1780 1785 1790 Lys Val Arg Phe Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu 1795 1800 1805 Ala Ile Gln His Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu 1810 1815 1820 Val Gly Asp Thr Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro 1825 1830 1835 1840 Tyr Asn Ile Tyr Pro His Gly Ile Thr Asp Val Arg Pro Leu Tyr Ser 1845 1850 1855 Arg Arg Leu Pro Lys Gly Val Lys His Leu Lys Asp Phe Pro Ile Leu 1860 1865 1870 Pro Gly Glu Ile Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly 1875 1880 1885 Pro Thr Lys Ser Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe 1890 1895 1900 Val Asn Met Glu Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu 1905 1910 1915 1920 Ile Cys Tyr Lys Glu Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser 1925 1930 1935 Asp Lys Arg Asn Val Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser 1940 1945 1950 Trp Tyr Leu Thr Glu Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly 1955 1960 1965 Val Gln Leu Glu Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser 1970 1975 1980 Ile Asn Gly Tyr Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His 1985 1990 1995 2000 Glu Val Ala Tyr Trp Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe 2005 2010 2015 Leu Ser Val Phe Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr 2020 2025 2030 Glu Asp Thr Leu Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met 2035 2040 2045 Ser Met Glu Asn Pro Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp 2050 2055 2060 Phe Arg Asn Arg Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp 2065 2070 2075 2080 Lys Asn Thr Gly Asp Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Ala 2085 2090 2095 Tyr Leu Leu Ser Lys Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln 2100 2105 2110 Asn Ser Arg His Pro Ser Thr Arg Gln Lys Gln Phe Asn Ala Thr Thr 2115 2120 2125 Ile Pro Glu Asn Asp Ile Glu Lys Thr Asp Pro Trp Phe Ala His Arg 2130 2135 2140 Thr Pro Met Pro Lys Cys Gln Asn Val Ser Ser Ser Asp Leu Leu Met 2145 2150 2155 2160 Leu Leu Arg Gln Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu 2165 2170 2175 Gln Glu Ala Lys Tyr Glu Thr Phe Ser Asp Asp Pro Ser Pro Gly Ala 2180 2185 2190 Ile Asp Ser Asn Asn Ser Leu Ser Glu Met Thr His Phe Arg Pro Gln 2195 2200 2205 Leu His His Ser Gly Asp Met Val Phe Thr Pro Glu Ser Gly Leu Gln 2210 2215 2220 Leu Arg Leu Asn Glu Lys Leu Gly Thr Thr Ala Ala Thr Glu Leu Lys 2225 2230 2235 2240 Lys Leu Asp Phe Lys Val Ser Ser Thr Ser Asn Asn Leu Ile Ser Thr 2245 2250 2255 Ile Pro Ser Asp Asn Leu Ala Ala Gly Thr Asp Asn Thr Ser Thr Leu 2260 2265 2270 Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu 2275 2280 2285 Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser 2290 2295 2300 Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val 2305 2310 2315 2320 Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg 2325 2330 2335 Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe 2340 2345 2350 Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu 2355 2360 2365 Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val 2370 2375 2380 Glu Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr 2385 2390 2395 2400 Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly 2405 2410 2415 Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr 2420 2425 2430 Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp 2435 2440 2445 Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val 2450 2455 2460 His Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu 2465 2470 2475 2480 Asn Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe 2485 2490 2495 Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met 2500 2505 2510 Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr 2515 2520 2525 Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp 2530 2535 2540 Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr 2545 2550 2555 2560 Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser 2565 2570 2575 Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu 2580 2585 2590 Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser 2595 2600 2605 Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His 2610 2615 2620 Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr 2625 2630 2635 2640 Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala 2645 2650 2655 Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr 2660 2665 2670 Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile 2675 2680 2685 Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln 2690 2695 2700 Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile 2705 2710 2715 2720 Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser 2725 2730 2735 Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile 2740 2745 2750 Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu 2755 2760 2765 His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met 2770 2775 2780 Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys 2785 2790 2795 2800 Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met 2805 2810 2815 Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg 2820 2825 2830 Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln 2835 2840 2845 Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly 2850 2855 2860 Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser 2865 2870 2875 2880 Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys 2885 2890 2895 Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn 2900 2905 2910 Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln 2915 2920 2925 Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu 2930 2935 2940 Ala Gln Asp Leu Tyr 2945 <210> 20 <211> 1248 <212> PRT <213> Artificial Sequence <220> <223> D'D3 of the complex of D'D3/scFVIII-120 and D'D3 <400> 20 Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr Ala Arg Cys Ser Leu Phe 1 5 10 15 Gly Ser Asp Phe Val Asn Thr Phe Asp Gly Ser Met Tyr Ser Phe Ala 20 25 30 Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly Cys Gln Lys Arg Ser Phe 35 40 45 Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys Arg Val Ser Leu Ser Val 50 55 60 Tyr Leu Gly Glu Phe Phe Asp Ile His Leu Phe Val Asn Gly Thr Val 65 70 75 80 Thr Gln Gly Asp Gln Arg Val Ser Met Pro Tyr Ala Ser Lys Gly Leu 85 90 95 Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys Leu Ser Gly Glu Ala Tyr 100 105 110 Gly Phe Val Ala Arg Ile Asp Gly Ser Gly Asn Phe Gln Val Leu Leu 115 120 125 Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly Leu Cys Gly Asn Phe Asn 130 135 140 Ile Phe Ala Glu Asp Asp Phe Met Thr Gln Glu Gly Thr Leu Thr Ser 145 150 155 160 Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala Leu Ser Ser Gly Glu Gln 165 170 175 Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser Ser Cys Asn Ile Ser Ser 180 185 190 Gly Glu Met Gln Lys Gly Leu Trp Glu Gln Cys Gln Leu Leu Lys Ser 195 200 205 Thr Ser Val Phe Ala Arg Cys His Pro Leu Val Asp Pro Glu Pro Phe 210 215 220 Val Ala Leu Cys Glu Lys Thr Leu Cys Glu Cys Ala Gly Gly Leu Glu 225 230 235 240 Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala Arg Thr Cys Ala Gln Glu 245 250 255 Gly Met Val Leu Tyr Gly Trp Thr Asp His Ser Ala Cys Ser Pro Val 260 265 270 Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys Val Ser Pro Cys Ala Arg 275 280 285 Thr Cys Gln Ser Leu His Ile Asn Glu Met Cys Gln Glu Arg Cys Val 290 295 300 Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu Leu Asp Glu Gly Leu Cys 305 310 315 320 Val Glu Ser Thr Glu Cys Pro Cys Val His Ser Gly Lys Arg Tyr Pro 325 330 335 Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn Thr Cys Ile Cys Arg Asn 340 345 350 Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys Pro Gly Glu Cys Leu Val 355 360 365 Thr Gly Gln Ser His Phe Lys Ser Phe Asp Asn Arg Tyr Phe Thr Phe 370 375 380 Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg Asp Cys Gln Asp His Ser 385 390 395 400 Phe Ser Ile Val Ile Glu Thr Val Gln Cys Ala Asp Asp Arg Asp Ala 405 410 415 Val Cys Thr Arg Ser Val Thr Val Arg Leu Pro Gly Leu His Asn Ser 420 425 430 Leu Val Lys Leu Lys His Gly Ala Gly Val Ala Met Asp Gly Gln Asp 435 440 445 Val Gln Leu Pro Leu Leu Lys Gly Asp Leu Arg Ile Gln His Thr Val 450 455 460 Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu Asp Leu Gln Met Asp Trp 465 470 475 480 Asp Gly Arg Gly Arg Leu Leu Val Lys Leu Ser Pro Val Tyr Ala Gly 485 490 495 Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn Gly Asn Gln Gly Asp Asp 500 505 510 Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro Arg Val Glu Asp Phe Gly 515 520 525 Asn Ala Trp Lys Leu His Gly Asp Cys Gln Asp Leu Gln Lys Gln His 530 535 540 Ser Asp Pro Cys Ala Leu Asn Pro Arg Met Thr Arg Phe Ser Glu Glu 545 550 555 560 Ala Cys Ala Val Leu Thr Ser Pro Thr Phe Glu Ala Cys His Arg Ala 565 570 575 Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys Arg Tyr Asp Val Cys Ser 580 585 590 Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly Ala Leu Ala Ser Tyr Ala 595 600 605 Ala Ala Cys Ala Gly Arg Gly Val Arg Val Ala Trp Arg Glu Pro Gly 610 615 620 Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln Val Tyr Leu Gln Cys Gly 625 630 635 640 Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu Ser Tyr Pro Asp Glu Glu 645 650 655 Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe Cys Pro Pro Gly Leu Tyr 660 665 670 Met Asp Glu Arg Gly Asp Cys Val Pro Lys Ala Gln Cys Pro Cys Tyr 675 680 685 Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp Ile Phe Ser Asp His His 690 695 700 Thr Met Cys Tyr Cys Glu Asp Gly Phe Met His Cys Thr Met Ser Gly 705 710 715 720 Val Pro Gly Ser Leu Leu Pro Asp Ala Val Leu Ser Ser Pro Leu Ser 725 730 735 His Arg Ser Lys Arg Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 740 745 750 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 755 760 765 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 770 775 780 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 785 790 795 800 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 805 810 815 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 820 825 830 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 835 840 845 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 850 855 860 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 865 870 875 880 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 885 890 895 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 900 905 910 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 915 920 925 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 930 935 940 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 945 950 955 960 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 965 970 975 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 980 985 990 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 995 1000 1005 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1010 1015 1020 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1025 1030 1035 1040 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 1045 1050 1055 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 1060 1065 1070 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 1075 1080 1085 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 1090 1095 1100 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 1105 1110 1115 1120 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 1125 1130 1135 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 1140 1145 1150 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 1155 1160 1165 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 1170 1175 1180 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 1185 1190 1195 1200 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 1205 1210 1215 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 1220 1225 1230 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 1235 1240 1245 <210> 21 <211> 2465 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3/Fc-120 of the complex of scFVIII/D'D3/Fc-120Fc and Fc <400> 21 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1635 1640 1645 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1650 1655 1660 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1665 1670 1675 1680 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1685 1690 1695 Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 1700 1705 1710 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 1715 1720 1725 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 1730 1735 1740 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 1745 1750 1755 1760 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 1765 1770 1775 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 1780 1785 1790 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 1795 1800 1805 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 1810 1815 1820 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 1825 1830 1835 1840 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 1845 1850 1855 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 1860 1865 1870 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 1875 1880 1885 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 1890 1895 1900 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 1905 1910 1915 1920 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 1925 1930 1935 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 1940 1945 1950 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 1955 1960 1965 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1970 1975 1980 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1985 1990 1995 2000 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 2005 2010 2015 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 2020 2025 2030 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 2035 2040 2045 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 2050 2055 2060 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 2065 2070 2075 2080 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 2085 2090 2095 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 2100 2105 2110 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 2115 2120 2125 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 2130 2135 2140 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 2145 2150 2155 2160 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 2165 2170 2175 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 2180 2185 2190 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2195 2200 2205 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 2210 2215 2220 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys 2225 2230 2235 2240 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 2245 2250 2255 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 2260 2265 2270 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 2275 2280 2285 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 2290 2295 2300 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 2305 2310 2315 2320 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 2325 2330 2335 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 2340 2345 2350 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 2355 2360 2365 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 2370 2375 2380 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 2385 2390 2395 2400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 2405 2410 2415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 2420 2425 2430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 2435 2440 2445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 2450 2455 2460 Lys 246 <210> 22 <211> 227 <212> PRT <213> Artificial Sequence <220> <223> Fc of the complex of scFVIII/D'D3/Fc-120 and Fc <400> 22 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 23 <211> 1980 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/D'D3-HC Heavy chain <400> 23 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 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 Cys Arg Pro Pro Met 930 935 940 Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu 945 950 955 960 Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly 965 970 975 Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn 980 985 990 Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu 995 1000 1005 Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys 1010 1015 1020 Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys 1025 1030 1035 1040 Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr 1045 1050 1055 Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly 1060 1065 1070 Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser 1075 1080 1085 His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly 1090 1095 1100 Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met 1105 1110 1115 1120 Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile 1125 1130 1135 Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser 1140 1145 1150 Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu 1155 1160 1165 Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn 1170 1175 1180 Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val 1185 1190 1195 1200 Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro 1205 1210 1215 Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser 1220 1225 1230 Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val 1235 1240 1245 Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys 1250 1255 1260 Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr 1265 1270 1275 1280 Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala 1285 1290 1295 Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly 1300 1305 1310 Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val 1315 1320 1325 Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu 1330 1335 1340 Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu 1345 1350 1355 1360 Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly 1365 1370 1375 Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro 1380 1385 1390 Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu 1395 1400 1405 Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro 1410 1415 1420 Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu 1425 1430 1435 1440 His Asp Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1445 1450 1455 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1460 1465 1470 Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu Val Cys Pro Ala 1475 1480 1485 Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn 1490 1495 1500 Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser Gly Cys Leu Cys 1505 1510 1515 1520 Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val Ala Leu Glu Arg 1525 1530 1535 Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val 1540 1545 1550 Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg Lys Trp Asn Cys 1555 1560 1565 Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile Gly Met Ala His 1570 1575 1580 Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln 1585 1590 1595 1600 Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg 1605 1610 1615 Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser Val Lys Cys Lys 1620 1625 1630 Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile Glu Leu Phe Asp 1635 1640 1645 Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu Thr His Phe Glu 1650 1655 1660 Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu 1665 1670 1675 1680 Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val Val Leu Lys Gln 1685 1690 1695 Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile 1700 1705 1710 Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val Glu Glu Asp Pro 1715 1720 1725 Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr 1730 1735 1740 Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile 1745 1750 1755 1760 Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp 1765 1770 1775 Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp 1780 1785 1790 Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala 1795 1800 1805 Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln His 1810 1815 1820 Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln Ser Cys 1825 1830 1835 1840 Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu Trp Arg Tyr 1845 1850 1855 Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln His Pro Glu Pro 1860 1865 1870 Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His Ala His Cys Pro 1875 1880 1885 Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys Val Asp Pro Glu 1890 1895 1900 Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe Ala Ser Gly Lys 1905 1910 1915 1920 Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys Gln Ile Cys His 1925 1930 1935 Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln Glu Pro Gly Gly 1940 1945 1950 Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr 1955 1960 1965 Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 1970 1975 1980 <210> 24 <211> 772 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/D'D3-HC Light chain <400> 24 Ala Thr Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro 1 5 10 15 Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe 20 25 30 Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His 35 40 45 Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val 50 55 60 Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro 65 70 75 80 Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln 85 90 95 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 100 105 110 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 115 120 125 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 130 135 140 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 145 150 155 160 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 165 170 175 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 180 185 190 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 195 200 205 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 210 215 220 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 225 230 235 240 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 245 250 255 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 260 265 270 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 275 280 285 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 290 295 300 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 305 310 315 320 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 325 330 335 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 340 345 350 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 355 360 365 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 370 375 380 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 385 390 395 400 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 405 410 415 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 420 425 430 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 435 440 445 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 450 455 460 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 465 470 475 480 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 485 490 495 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 500 505 510 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 515 520 525 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 530 535 540 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 545 550 555 560 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 565 570 575 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 580 585 590 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 595 600 605 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 610 615 620 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 625 630 635 640 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 645 650 655 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 660 665 670 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 675 680 685 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 690 695 700 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 705 710 715 720 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 725 730 735 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 740 745 750 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 755 760 765 Gln Asp Leu Tyr 770 <210> 25 <211> 2722 <212> PRT <213> Artificial Sequence <220> <223> scFVIII/D'D3/Fc/Fc-120 <400> 25 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 Leu Val Pro 1570 1575 1580 Arg Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1585 1590 1595 1600 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1605 1610 1615 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1620 1625 1630 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1635 1640 1645 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1650 1655 1660 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1665 1670 1675 1680 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1685 1690 1695 Ser Gly Gly Gly Gly Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu 1700 1705 1710 Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys 1715 1720 1725 Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser 1730 1735 1740 Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys Val 1745 1750 1755 1760 Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro 1765 1770 1775 Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Arg Asp Arg 1780 1785 1790 Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile 1795 1800 1805 Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro 1810 1815 1820 Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro 1825 1830 1835 1840 Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser 1845 1850 1855 Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile 1860 1865 1870 Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu 1875 1880 1885 Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu 1890 1895 1900 Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser Val 1905 1910 1915 1920 Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn 1925 1930 1935 Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val 1940 1945 1950 Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln 1955 1960 1965 Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys 1970 1975 1980 His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile 1985 1990 1995 2000 Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu 2005 2010 2015 Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile 2020 2025 2030 Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val 2035 2040 2045 Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys 2050 2055 2060 Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys 2065 2070 2075 2080 Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln 2085 2090 2095 His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys His 2100 2105 2110 Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys 2115 2120 2125 Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg Phe 2130 2135 2140 Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys 2145 2150 2155 2160 Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln 2165 2170 2175 Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro 2180 2185 2190 Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Asp Phe 2195 2200 2205 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 2210 2215 2220 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys 2225 2230 2235 2240 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 2245 2250 2255 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 2260 2265 2270 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 2275 2280 2285 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 2290 2295 2300 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 2305 2310 2315 2320 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 2325 2330 2335 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 2340 2345 2350 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 2355 2360 2365 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 2370 2375 2380 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 2385 2390 2395 2400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 2405 2410 2415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 2420 2425 2430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 2435 2440 2445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 2450 2455 2460 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 2465 2470 2475 2480 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 2485 2490 2495 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 2500 2505 2510 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 2515 2520 2525 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 2530 2535 2540 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 2545 2550 2555 2560 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 2565 2570 2575 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 2580 2585 2590 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 2595 2600 2605 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 2610 2615 2620 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 2625 2630 2635 2640 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 2645 2650 2655 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 2660 2665 2670 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 2675 2680 2685 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 2690 2695 2700 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 2705 2710 2715 2720 Gly Lys <210> 26 <211> 1700 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC/Fc-LC Heavy chain <400> 26 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 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 Cys Arg Pro Pro Met 930 935 940 Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu 945 950 955 960 Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly 965 970 975 Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn 980 985 990 Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu 995 1000 1005 Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys 1010 1015 1020 Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys 1025 1030 1035 1040 Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr 1045 1050 1055 Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly 1060 1065 1070 Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser 1075 1080 1085 His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly 1090 1095 1100 Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met 1105 1110 1115 1120 Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile 1125 1130 1135 Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser 1140 1145 1150 Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu 1155 1160 1165 Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn 1170 1175 1180 Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val 1185 1190 1195 1200 Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro 1205 1210 1215 Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser 1220 1225 1230 Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val 1235 1240 1245 Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys 1250 1255 1260 Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr 1265 1270 1275 1280 Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala 1285 1290 1295 Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly 1300 1305 1310 Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val 1315 1320 1325 Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu 1330 1335 1340 Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu 1345 1350 1355 1360 Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly 1365 1370 1375 Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro 1380 1385 1390 Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu 1395 1400 1405 Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro 1410 1415 1420 Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu 1425 1430 1435 1440 His Asp Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1445 1450 1455 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1460 1465 1470 Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 1475 1480 1485 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 1490 1495 1500 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 1505 1510 1515 1520 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 1525 1530 1535 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 1540 1545 1550 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 1555 1560 1565 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 1570 1575 1580 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 1585 1590 1595 1600 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 1605 1610 1615 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 1620 1625 1630 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 1635 1640 1645 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 1650 1655 1660 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 1665 1670 1675 1680 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 1685 1690 1695 Ser Pro Gly Lys 1700 <210> 27 <211> 1029 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC/Fc-LC Light chain <400> 27 Ala Thr Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro 1 5 10 15 Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe 20 25 30 Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His 35 40 45 Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val 50 55 60 Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro 65 70 75 80 Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln 85 90 95 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 100 105 110 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 115 120 125 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 130 135 140 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 145 150 155 160 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 165 170 175 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 180 185 190 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 195 200 205 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 210 215 220 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 225 230 235 240 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 245 250 255 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 260 265 270 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 275 280 285 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 290 295 300 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 305 310 315 320 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 325 330 335 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 340 345 350 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 355 360 365 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 370 375 380 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 385 390 395 400 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 405 410 415 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 420 425 430 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 435 440 445 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 450 455 460 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 465 470 475 480 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 485 490 495 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 500 505 510 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 515 520 525 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 530 535 540 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 545 550 555 560 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 565 570 575 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 580 585 590 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 595 600 605 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 610 615 620 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 625 630 635 640 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 645 650 655 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 660 665 670 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 675 680 685 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 690 695 700 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 705 710 715 720 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 725 730 735 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 740 745 750 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 755 760 765 Gln Asp Leu Tyr Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gly 770 775 780 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 785 790 795 800 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 805 810 815 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 820 825 830 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 835 840 845 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 850 855 860 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 865 870 875 880 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 885 890 895 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 900 905 910 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 915 920 925 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 930 935 940 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 945 950 955 960 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 965 970 975 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 980 985 990 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 995 1000 1005 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 1010 1015 1020 Leu Ser Pro Gly Lys 1025 <210> 28 <211> 1700 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC, Fc Heavy chain <400> 28 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 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 Cys Arg Pro Pro Met 930 935 940 Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu 945 950 955 960 Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly 965 970 975 Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn 980 985 990 Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu 995 1000 1005 Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys 1010 1015 1020 Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys 1025 1030 1035 1040 Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr 1045 1050 1055 Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly 1060 1065 1070 Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser 1075 1080 1085 His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly 1090 1095 1100 Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met 1105 1110 1115 1120 Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile 1125 1130 1135 Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser 1140 1145 1150 Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu 1155 1160 1165 Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn 1170 1175 1180 Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val 1185 1190 1195 1200 Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro 1205 1210 1215 Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser 1220 1225 1230 Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val 1235 1240 1245 Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys 1250 1255 1260 Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr 1265 1270 1275 1280 Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala 1285 1290 1295 Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly 1300 1305 1310 Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val 1315 1320 1325 Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu 1330 1335 1340 Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu 1345 1350 1355 1360 Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly 1365 1370 1375 Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro 1380 1385 1390 Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu 1395 1400 1405 Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro 1410 1415 1420 Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu 1425 1430 1435 1440 His Asp Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1445 1450 1455 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1460 1465 1470 Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 1475 1480 1485 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 1490 1495 1500 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 1505 1510 1515 1520 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 1525 1530 1535 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 1540 1545 1550 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 1555 1560 1565 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 1570 1575 1580 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 1585 1590 1595 1600 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 1605 1610 1615 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 1620 1625 1630 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 1635 1640 1645 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 1650 1655 1660 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 1665 1670 1675 1680 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 1685 1690 1695 Ser Pro Gly Lys 1700 <210> 29 <211> 772 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC, Fc Light chain <400> 29 Ala Thr Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro 1 5 10 15 Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe 20 25 30 Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His 35 40 45 Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val 50 55 60 Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro 65 70 75 80 Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln 85 90 95 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 100 105 110 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 115 120 125 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 130 135 140 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 145 150 155 160 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 165 170 175 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 180 185 190 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 195 200 205 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 210 215 220 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 225 230 235 240 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 245 250 255 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 260 265 270 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 275 280 285 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 290 295 300 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 305 310 315 320 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 325 330 335 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 340 345 350 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 355 360 365 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 370 375 380 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 385 390 395 400 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 405 410 415 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 420 425 430 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 435 440 445 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 450 455 460 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 465 470 475 480 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 485 490 495 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 500 505 510 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 515 520 525 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 530 535 540 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 545 550 555 560 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 565 570 575 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 580 585 590 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 595 600 605 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 610 615 620 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 625 630 635 640 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 645 650 655 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 660 665 670 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 675 680 685 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 690 695 700 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 705 710 715 720 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 725 730 735 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 740 745 750 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 755 760 765 Gln Asp Leu Tyr 770 <210> 30 <211> 1957 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc/Fc-HC Heavy chain <400> 30 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 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 Cys Arg Pro Pro Met 930 935 940 Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu 945 950 955 960 Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly 965 970 975 Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn 980 985 990 Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu 995 1000 1005 Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys 1010 1015 1020 Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys 1025 1030 1035 1040 Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr 1045 1050 1055 Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly 1060 1065 1070 Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser 1075 1080 1085 His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly 1090 1095 1100 Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met 1105 1110 1115 1120 Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile 1125 1130 1135 Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser 1140 1145 1150 Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu 1155 1160 1165 Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn 1170 1175 1180 Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val 1185 1190 1195 1200 Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro 1205 1210 1215 Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser 1220 1225 1230 Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val 1235 1240 1245 Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys 1250 1255 1260 Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr 1265 1270 1275 1280 Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala 1285 1290 1295 Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly 1300 1305 1310 Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val 1315 1320 1325 Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu 1330 1335 1340 Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu 1345 1350 1355 1360 Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly 1365 1370 1375 Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro 1380 1385 1390 Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu 1395 1400 1405 Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro 1410 1415 1420 Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu 1425 1430 1435 1440 His Asp Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1445 1450 1455 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1460 1465 1470 Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 1475 1480 1485 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 1490 1495 1500 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 1505 1510 1515 1520 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 1525 1530 1535 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 1540 1545 1550 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 1555 1560 1565 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 1570 1575 1580 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 1585 1590 1595 1600 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 1605 1610 1615 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 1620 1625 1630 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 1635 1640 1645 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 1650 1655 1660 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 1665 1670 1675 1680 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 1685 1690 1695 Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1700 1705 1710 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1715 1720 1725 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 1730 1735 1740 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 1745 1750 1755 1760 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 1765 1770 1775 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 1780 1785 1790 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 1795 1800 1805 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 1810 1815 1820 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 1825 1830 1835 1840 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 1845 1850 1855 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 1860 1865 1870 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 1875 1880 1885 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 1890 1895 1900 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 1905 1910 1915 1920 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 1925 1930 1935 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 1940 1945 1950 Leu Ser Pro Gly Lys 1955 <210> 31 <211> 772 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc/Fc-HC Light chain <400> 31 Ala Thr Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro 1 5 10 15 Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe 20 25 30 Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His 35 40 45 Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val 50 55 60 Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro 65 70 75 80 Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln 85 90 95 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 100 105 110 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 115 120 125 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 130 135 140 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 145 150 155 160 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 165 170 175 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 180 185 190 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 195 200 205 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 210 215 220 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 225 230 235 240 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 245 250 255 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 260 265 270 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 275 280 285 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 290 295 300 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 305 310 315 320 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 325 330 335 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 340 345 350 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 355 360 365 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 370 375 380 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 385 390 395 400 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 405 410 415 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 420 425 430 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 435 440 445 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 450 455 460 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 465 470 475 480 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 485 490 495 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 500 505 510 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 515 520 525 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 530 535 540 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 545 550 555 560 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 565 570 575 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 580 585 590 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 595 600 605 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 610 615 620 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 625 630 635 640 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 645 650 655 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 660 665 670 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 675 680 685 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 690 695 700 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 705 710 715 720 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 725 730 735 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 740 745 750 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 755 760 765 Gln Asp Leu Tyr 770 <210> 32 <211> 1443 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc-LC, Fc Heavy chain <400> 32 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 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 Cys Arg Pro Pro Met 930 935 940 Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu 945 950 955 960 Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly 965 970 975 Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn 980 985 990 Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu 995 1000 1005 Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys 1010 1015 1020 Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys 1025 1030 1035 1040 Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr 1045 1050 1055 Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly 1060 1065 1070 Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser 1075 1080 1085 His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly 1090 1095 1100 Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met 1105 1110 1115 1120 Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile 1125 1130 1135 Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser 1140 1145 1150 Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu 1155 1160 1165 Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn 1170 1175 1180 Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val 1185 1190 1195 1200 Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro 1205 1210 1215 Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser 1220 1225 1230 Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val 1235 1240 1245 Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys 1250 1255 1260 Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr 1265 1270 1275 1280 Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala 1285 1290 1295 Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly 1300 1305 1310 Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val 1315 1320 1325 Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu 1330 1335 1340 Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu 1345 1350 1355 1360 Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly 1365 1370 1375 Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro 1380 1385 1390 Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu 1395 1400 1405 Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro 1410 1415 1420 Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu 1425 1430 1435 1440 His Asp Phe <210> 33 <211> 1029 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc-LC, Fc Light chain <400> 33 Ala Thr Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro 1 5 10 15 Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe 20 25 30 Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His 35 40 45 Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val 50 55 60 Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro 65 70 75 80 Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln 85 90 95 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 100 105 110 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 115 120 125 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 130 135 140 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 145 150 155 160 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 165 170 175 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 180 185 190 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 195 200 205 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 210 215 220 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 225 230 235 240 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 245 250 255 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 260 265 270 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 275 280 285 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 290 295 300 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 305 310 315 320 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 325 330 335 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 340 345 350 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 355 360 365 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 370 375 380 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 385 390 395 400 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 405 410 415 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 420 425 430 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 435 440 445 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 450 455 460 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 465 470 475 480 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 485 490 495 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 500 505 510 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 515 520 525 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 530 535 540 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 545 550 555 560 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 565 570 575 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 580 585 590 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 595 600 605 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 610 615 620 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 625 630 635 640 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 645 650 655 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 660 665 670 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 675 680 685 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 690 695 700 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 705 710 715 720 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 725 730 735 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 740 745 750 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 755 760 765 Gln Asp Leu Tyr Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gly 770 775 780 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 785 790 795 800 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 805 810 815 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 820 825 830 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 835 840 845 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 850 855 860 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 865 870 875 880 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 885 890 895 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 900 905 910 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 915 920 925 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 930 935 940 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 945 950 955 960 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 965 970 975 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 980 985 990 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 995 1000 1005 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 1010 1015 1020 Leu Ser Pro Gly Lys 1025 <210> 34 <211> 1443 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc/Fc-LC Heavy chain <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 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 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 Cys Arg Pro Pro Met 930 935 940 Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu 945 950 955 960 Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly 965 970 975 Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn 980 985 990 Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu 995 1000 1005 Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys 1010 1015 1020 Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys 1025 1030 1035 1040 Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr 1045 1050 1055 Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly 1060 1065 1070 Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser 1075 1080 1085 His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly 1090 1095 1100 Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met 1105 1110 1115 1120 Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile 1125 1130 1135 Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser 1140 1145 1150 Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu 1155 1160 1165 Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn 1170 1175 1180 Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val 1185 1190 1195 1200 Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro 1205 1210 1215 Ala Thr Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser 1220 1225 1230 Cys Arg Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val 1235 1240 1245 Asp Pro Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys 1250 1255 1260 Glu Ser Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr 1265 1270 1275 1280 Ala His Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala 1285 1290 1295 Thr Leu Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly 1300 1305 1310 Tyr Glu Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val 1315 1320 1325 Thr Cys Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu 1330 1335 1340 Gly Cys His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu 1345 1350 1355 1360 Gln Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly 1365 1370 1375 Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro 1380 1385 1390 Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu 1395 1400 1405 Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro 1410 1415 1420 Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu 1425 1430 1435 1440 His Asp Phe <210> 35 <211> 1286 <212> PRT <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc/Fc-LC Light chain <400> 35 Ala Thr Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro 1 5 10 15 Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe 20 25 30 Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His 35 40 45 Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val 50 55 60 Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro 65 70 75 80 Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln 85 90 95 Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met 100 105 110 Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro 115 120 125 Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu 130 135 140 Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn 145 150 155 160 Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln 165 170 175 Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu 180 185 190 Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu 195 200 205 Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser 210 215 220 Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala 225 230 235 240 Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe 245 250 255 Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys 260 265 270 Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His 275 280 285 Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn 290 295 300 Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe 305 310 315 320 Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu 325 330 335 Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe 340 345 350 Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr 355 360 365 Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu 370 375 380 Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly 385 390 395 400 His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr 405 410 415 Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys 420 425 430 Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala 435 440 445 Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro 450 455 460 Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser 465 470 475 480 Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser 485 490 495 Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys 500 505 510 Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly 515 520 525 Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met 530 535 540 Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr 545 550 555 560 Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys 565 570 575 His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His 580 585 590 Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly 595 600 605 Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala 610 615 620 Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe 625 630 635 640 Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser 645 650 655 Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val 660 665 670 Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val 675 680 685 Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser 690 695 700 Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val 705 710 715 720 Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser 725 730 735 Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser 740 745 750 Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala 755 760 765 Gln Asp Leu Tyr Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gly 770 775 780 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 785 790 795 800 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 805 810 815 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 820 825 830 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 835 840 845 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 850 855 860 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 865 870 875 880 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 885 890 895 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 900 905 910 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 915 920 925 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 930 935 940 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 945 950 955 960 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 965 970 975 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 980 985 990 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 995 1000 1005 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 1010 1015 1020 Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1025 1030 1035 1040 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1045 1050 1055 Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 1060 1065 1070 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 1075 1080 1085 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 1090 1095 1100 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 1105 1110 1115 1120 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 1125 1130 1135 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 1140 1145 1150 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 1155 1160 1165 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 1170 1175 1180 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 1185 1190 1195 1200 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 1205 1210 1215 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 1220 1225 1230 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 1235 1240 1245 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 1250 1255 1260 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 1265 1270 1275 1280 Ser Leu Ser Pro Gly Lys 1285 <210> 36 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Thrombin site <400> 36 Asp Phe Leu Ala Glu Gly Gly Gly Val Arg 1 5 10 <210> 37 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Thrombin site <400> 37 Thr Thr Lys Ile Lys Pro Arg 1 5 <210> 38 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Thrombin site <400> 38 Leu Val Pro Arg Gly Ser 1 5 <210> 39 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> FVIIa site <400> 39 Ala Ser Lys Pro Gln Gly Arg Ile Val Gly Gly 1 5 10 <210> 40 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> FXa site <400> 40 Ile Asp Gly Arg 1 <210> 41 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> FXa site <400> 41 Ile Glu Gly Arg 1 <210> 42 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> FXa site <400> 42 Ser Lys Leu Thr Arg Ala Glu Thr Val Phe 1 5 10 <210> 43 <211> 6999 <212> DNA <213> Homo sapiens <220> <221> gene <222> (1)..(6999) <223> mature FVIII <400> 43 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> 44 <211> 8376 <212> DNA <213> Homo sapiens <220> <221> gene <222> (1)..(8376) <223> full length vWF <400> 44 gcagaaggaa ctcgcggcag gtcatccacg gcccgatgca gccttttcgg aagtgacttc 60 gtcaacacct ttgatgggag catgtacagc tttgcgggat actgcagtta cctcctggca 120 gggggctgcc agaaacgctc cttctcgatt attggggact tccagaatgg caagagagtg 180 agcctctccg tgtatcttgg ggaatttttt gacatccatt tgtttgtcaa tggtaccgtg 240 acacaggggg accaaagagt ctccatgccc tatgcctcca aagggctgta tctagaaact 300 gaggctgggt actacaagct gtccggtgag gcctatggct ttgtggccag gatcgatggc 360 agcggcaact ttcaagtcct gctgtcagac agatacttca acaagacctg cgggctgtgt 420 ggcaacttta acatctttgc tgaagatgac tttatgaccc aagaagggac cttgacctcg 480 gacccttatg actttgccaa ctcatgggct ctgagcagtg gagaacagtg gtgtgaacgg 540 gcatctcctc ccagcagctc atgcaacatc tcctctgggg aaatgcagaa gggcctgtgg 600 gagcagtgcc agcttctgaa gagcacctcg gtgtttgccc gctgccaccc tctggtggac 660 cccgagcctt ttgtggccct gtgtgagaag actttgtgtg agtgtgctgg ggggctggag 720 tgcgcctgcc ctgccctcct ggagtacgcc cggacctgtg cccaggaggg aatggtgctg 780 tacggctgga ccgaccacag cgcgtgcagc ccagtgtgcc ctgctggtat ggagtatagg 840 cagtgtgtgt ccccttgcgc caggacctgc cagagcctgc acatcaatga aatgtgtcag 900 gagcgatgcg tggatggctg cagctgccct gagggacagc tcctggatga aggcctctgc 960 gtggagagca ccgagtgtcc ctgcgtgcat tccggaaagc gctaccctcc cggcacctcc 1020 ctctctcgag actgcaacac ctgcatttgc cgaaacagcc agtggatctg cagcaatgaa 1080 gaatgtccag gggagtgcct tgtcacaggt caatcacact tcaagagctt tgacaacaga 1140 tacttcacct tcagtgggat ctgccagtac ctgctggccc gggattgcca ggaccactcc 1200 ttctccattg tcattgagac tgtccagtgt gctgatgacc gcgacgctgt gtgcacccgc 1260 tccgtcaccg tccggctgcc tggcctgcac aacagccttg tgaaactgaa gcatggggca 1320 ggagttgcca tggatggcca ggacgtccag ctccccctcc tgaaaggtga cctccgcatc 1380 cagcatacag tgacggcctc cgtgcgcctc agctacgggg aggacctgca gatggactgg 1440 gatggccgcg ggaggctgct ggtgaagctg tcccccgtct atgccgggaa gacctgcggc 1500 ctgtgtggga attacaatgg caaccagggc gacgacttcc ttaccccctc tgggctggcg 1560 gagccccggg tggaggactt cgggaacgcc tggaagctgc acggggactg ccaggacctg 1620 cagaagcagc acagcgatcc ctgcgccctc aacccgcgca tgaccaggtt ctccgaggag 1680 gcgtgcgcgg tcctgacgtc ccccacattc gaggcctgcc atcgtgccgt cagcccgctg 1740 ccctacctgc ggaactgccg ctacgacgtg tgctcctgct cggacggccg cgagtgcctg 1800 tgcggcgccc tggccagcta tgccgcggcc tgcgcgggga gaggcgtgcg cgtcgcgtgg 1860 cgcgagccag gccgctgtga gctgaactgc ccgaaaggcc aggtgtacct gcagtgcggg 1920 accccctgca acctgacctg ccgctctctc tcttacccgg atgaggaatg caatgaggcc 1980 tgcctggagg gctgcttctg ccccccaggg ctctacatgg atgagagggg ggactgcgtg 2040 cccaaggccc agtgcccctg ttactatgac ggtgagatct tccagccaga agacatcttc 2100 tcagaccatc acaccatgtg ctactgtgag gatggcttca tgcactgtac catgagtgga 2160 gtccccggaa gcttgctgcc tgacgctgtc ctcagcagtc ccctgtctca tcgcagcaaa 2220 aggagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 2280 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 2340 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 2400 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 2460 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 2520 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 2580 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 2640 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 2700 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 2760 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 2820 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 2880 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 2940 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 3000 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 3060 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 3120 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 3180 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 3240 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 3300 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 3360 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 3420 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 3480 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 3540 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 3600 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 3660 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 3720 tcggaaccgc cgttgcacga tttctactgc agcaggctac tggacctggt cttcctgctg 3780 gatggctcct ccaggctgtc cgaggctgag tttgaagtgc tgaaggcctt tgtggtggac 3840 atgatggagc ggctgcgcat ctcccagaag tgggtccgcg tggccgtggt ggagtaccac 3900 gacggctccc acgcctacat cgggctcaag gaccggaagc gaccgtcaga gctgcggcgc 3960 attgccagcc aggtgaagta tgcgggcagc caggtggcct ccaccagcga ggtcttgaaa 4020 tacacactgt tccaaatctt cagcaagatc gaccgccctg aagcctcccg catcaccctg 4080 ctcctgatgg ccagccagga gccccaacgg atgtcccgga actttgtccg ctacgtccag 4140 ggcctgaaga agaagaaggt cattgtgatc ccggtgggca ttgggcccca tgccaacctc 4200 aagcagatcc gcctcatcga gaagcaggcc cctgagaaca aggccttcgt gctgagcagt 4260 gtggatgagc tggagcagca aagggacgag atcgttagct acctctgtga ccttgcccct 4320 gaagcccctc ctcctactct gccccccgac atggcacaag tcactgtggg cccggggctc 4380 ttgggggttt cgaccctggg gcccaagagg aactccatgg ttctggatgt ggcgttcgtc 4440 ctggaaggat cggacaaaat tggtgaagcc gacttcaaca ggagcaagga gttcatggag 4500 gaggtgattc agcggatgga tgtgggccag gacagcatcc acgtcacggt gctgcagtac 4560 tcctacatgg tgactgtgga gtaccccttc agcgaggcac agtccaaagg ggacatcctg 4620 cagcgggtgc gagagatccg ctaccagggc ggcaacagga ccaacactgg gctggccctg 4680 cggtacctct ctgaccacag cttcttggtc agccagggtg accgggagca ggcgcccaac 4740 ctggtctaca tggtcaccgg aaatcctgcc tctgatgaga tcaagaggct gcctggagac 4800 atccaggtgg tgcccattgg agtgggccct aatgccaacg tgcaggagct ggagaggatt 4860 ggctggccca atgcccctat cctcatccag gactttgaga cgctcccccg agaggctcct 4920 gacctggtgc tgcagaggtg ctgctccgga gaggggctgc agatccccac cctctcccct 4980 gcacctgact gcagccagcc cctggacgtg atccttctcc tggatggctc ctccagtttc 5040 ccagcttctt attttgatga aatgaagagt ttcgccaagg ctttcatttc aaaagccaat 5100 atagggcctc gtctcactca ggtgtcagtg ctgcagtatg gaagcatcac caccattgac 5160 gtgccatgga acgtggtccc ggagaaagcc catttgctga gccttgtgga cgtcatgcag 5220 cgggagggag gccccagcca aatcggggat gccttgggct ttgctgtgcg atacttgact 5280 tcagaaatgc atggtgccag gccgggagcc tcaaaggcgg tggtcatcct ggtcacggac 5340 gtctctgtgg attcagtgga tgcagcagct gatgccgcca ggtccaacag agtgacagtg 5400 ttccctattg gaattggaga tcgctacgat gcagcccagc tacggatctt ggcaggccca 5460 gcaggcgact ccaacgtggt gaagctccag cgaatcgaag acctccctac catggtcacc 5520 ttgggcaatt ccttcctcca caaactgtgc tctggatttg ttaggatttg catggatgag 5580 gatgggaatg agaagaggcc cggggacgtc tggaccttgc cagaccagtg ccacaccgtg 5640 acttgccagc cagatggcca gaccttgctg aagagtcatc gggtcaactg tgaccggggg 5700 ctgaggcctt cgtgccctaa cagccagtcc cctgttaaag tggaagagac ctgtggctgc 5760 cgctggacct gcccctgcgt gtgcacaggc agctccactc ggcacatcgt gacctttgat 5820 gggcagaatt tcaagctgac tggcagctgt tcttatgtcc tatttcaaaa caaggagcag 5880 gacctggagg tgattctcca taatggtgcc tgcagccctg gagcaaggca gggctgcatg 5940 aaatccatcg aggtgaagca cagtgccctc tccgtcgagc tgcacagtga catggaggtg 6000 acggtgaatg ggagactggt ctctgttcct tacgtgggtg ggaacatgga agtcaacgtt 6060 tatggtgcca tcatgcatga ggtcagattc aatcaccttg gtcacatctt cacattcact 6120 ccacaaaaca atgagttcca actgcagctc agccccaaga cttttgcttc aaagacgtat 6180 ggtctgtgtg ggatctgtga tgagaacgga gccaatgact tcatgctgag ggatggcaca 6240 gtcaccacag actggaaaac acttgttcag gaatggactg tgcagcggcc agggcagacg 6300 tgccagccca tcctggagga gcagtgtctt gtccccgaca gctcccactg ccaggtcctc 6360 ctcttaccac tgtttgctga atgccacaag gtcctggctc cagccacatt ctatgccatc 6420 tgccagcagg acagttgcca ccaggagcaa gtgtgtgagg tgatcgcctc ttatgcccac 6480 ctctgtcgga ccaacggggt ctgcgttgac tggaggacac ctgatttctg tgctatgtca 6540 tgcccaccat ctctggtcta caaccactgt gagcatggct gtccccggca ctgtgatggc 6600 aacgtgagct cctgtgggga ccatccctcc gaaggctgtt tctgccctcc agataaagtc 6660 atgttggaag gcagctgtgt ccctgaagag gcctgcactc agtgcattgg tgaggatgga 6720 gtccagcacc agttcctgga agcctgggtc ccggaccacc agccctgtca gatctgcaca 6780 tgcctcagcg ggcggaaggt caactgcaca acgcagccct gccccacggc caaagctccc 6840 acgtgtggcc tgtgtgaagt agcccgcctc cgccagaatg cagaccagtg ctgccccgag 6900 tatgagtgtg tgtgtgaccc agtgagctgt gacctgcccc cagtgcctca ctgtgaacgt 6960 ggcctccagc ccacactgac caaccctggc gagtgcagac ccaacttcac ctgcgcctgc 7020 aggaaggagg agtgcaaaag agtgtcccca ccctcctgcc ccccgcaccg tttgcccacc 7080 cttcggaaga cccagtgctg tgatgagtat gagtgtgcct gcaactgtgt caactccaca 7140 gtgagctgtc cccttgggta cttggcctca actgccacca atgactgtgg ctgtaccaca 7200 accacctgcc ttcccgacaa ggtgtgtgtc caccgaagca ccatctaccc tgtgggccag 7260 ttctgggagg agggctgcga tgtgtgcacc tgcaccgaca tggaggatgc cgtgatgggc 7320 ctccgcgtgg cccagtgctc ccagaagccc tgtgaggaca gctgtcggtc gggcttcact 7380 tacgttctgc atgaaggcga gtgctgtgga aggtgcctgc catctgcctg tgaggtggtg 7440 actggctcac cgcgggggga ctcccagtct tcctggaaga gtgtcggctc ccagtgggcc 7500 tccccggaga acccctgcct catcaatgag tgtgtccgag tgaaggagga ggtctttata 7560 caacaaagga acgtctcctg cccccagctg gaggtccctg tctgcccctc gggctttcag 7620 ctgagctgta agacctcagc gtgctgccca agctgtcgct gtgagcgcat ggaggcctgc 7680 atgctcaatg gcactgtcat tgggcccggg aagactgtga tgatcgatgt gtgcacgacc 7740 tgccgctgca tggtgcaggt gggggtcatc tctggattca agctggagtg caggaagacc 7800 acctgcaacc cctgccccct gggttacaag gaagaaaata acacaggtga atgttgtggg 7860 agatgtttgc ctacggcttg caccattcag ctaagaggag gacagatcat gacactgaag 7920 cgtgatgaga cgctccagga tggctgtgat actcacttct gcaaggtcaa tgagagagga 7980 gagtacttct gggagaagag ggtcacaggc tgcccaccct ttgatgaaca caagtgtctg 8040 gctgagggag gtaaaattat gaaaattcca ggcacctgct gtgacacatg tgaggagcct 8100 gagtgcaacg acatcactgc caggctgcag tatgtcaagg tgggaagctg taagtctgaa 8160 gtagaggtgg atatccacta ctgccagggc aaatgtgcca gcaaagccat gtactccatt 8220 gacatcaacg atgtgcagga ccagtgctcc tgctgctctc cgacacggac ggagcccatg 8280 caggtggccc tgcactgcac caatggctct gttgtgtacc atgaggttct caatgccatg 8340 gagtgcaaat gctcccccag gaagtgcagc aagtga 8376 <210> 45 <211> 4749 <212> DNA <213> Artificial Sequence <220> <223> Single chain FVIII with partial B domain <220> <221> misc_feature <222> (2344) <223> W= A or T <220> <221> misc_feature <222> (2345) <223> K= T or G <220> <221> misc_feature <222> (2346) <223> W= A or T <220> <221> misc_feature <222> (2344)..(2346) <223> encoding Isoleucine or Cysteine <400> 45 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 aaawkwcaaa 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 tactgataa 4749 <210> 46 <211> 4335 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC Heavy chain <400> 46 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 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cctatcctgt 2820 cggcccccca tggtcaagct ggtgtgtccc gctgacaacc tgcgggctga agggctcgag 2880 tgtaccaaaa cgtgccagaa ctatgacctg gagtgcatga gcatgggctg tgtctctggc 2940 tgcctctgcc ccccgggcat ggtccggcat gagaacagat gtgtggccct ggaaaggtgt 3000 ccctgcttcc atcagggcaa ggagtatgcc cctggagaaa cagtgaagat tggctgcaac 3060 acttgtgtct gtcgggaccg gaagtggaac tgcacagacc atgtgtgtga tgccacgtgc 3120 tccacgatcg gcatggccca ctacctcacc ttcgacgggc tcaaatacct gttccccggg 3180 gagtgccagt acgttctggt gcaggattac tgcggcagta accctgggac ctttcggatc 3240 ctagtgggga ataagggatg cagccacccc tcagtgaaat gcaagaaacg ggtcaccatc 3300 ctggtggagg gaggagagat tgagctgttt gacggggagg tgaatgtgaa gaggcccatg 3360 aaggatgaga ctcactttga ggtggtggag tctggccggt acatcattct gctgctgggc 3420 aaagccctct ccgtggtctg ggaccgccac ctgagcatct ccgtggtcct gaagcagaca 3480 taccaggaga aagtgtgtgg cctgtgtggg aattttgatg gcatccagaa caatgacctc 3540 accagcagca acctccaagt ggaggaagac cctgtggact ttgggaactc ctggaaagtg 3600 agctcgcagt gtgctgacac cagaaaagtg cctctggact catcccctgc cacctgccat 3660 aacaacatca tgaagcagac gatggtggat tcctcctgta gaatccttac cagtgacgtc 3720 ttccaggact gcaacaagct ggtggacccc gagccatatc tggatgtctg catttacgac 3780 acctgctcct gtgagtccat tggggactgc gcctgcttct gcgacaccat tgctgcctat 3840 gcccacgtgt gtgcccagca tggcaaggtg gtgacctgga ggacggccac attgtgcccc 3900 cagagctgcg aggagaggaa tctccgggag aacgggtatg agtgtgagtg gcgctataac 3960 agctgtgcac ctgcctgtca agtcacgtgt cagcaccctg agccactggc ctgccctgtg 4020 cagtgtgtgg agggctgcca tgcccactgc cctccaggga aaatcctgga tgagcttttg 4080 cagacctgcg ttgaccctga agactgtcca gtgtgtgagg tggctggccg gcgttttgcc 4140 tcaggaaaga aagtcacctt gaatcccagt gaccctgagc actgccagat ttgccactgt 4200 gatgttgtca acctcacctg tgaagcctgc caggagccgg gaggcctggt ggtgcctccc 4260 acagatgccc cggtgagccc caccactctg tatgtggagg acatctcgga accgccgttg 4320 cacgatttct gataa 4335 <210> 47 <211> 2322 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC light chain <400> 47 gccaccgatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 60 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 120 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 180 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 240 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 300 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 360 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 420 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 480 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 540 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 600 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 660 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 720 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 780 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 840 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 900 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 960 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 1020 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 1080 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 1140 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 1200 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 1260 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 1320 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 1380 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 1440 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 1500 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 1560 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 1620 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 1680 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 1740 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 1800 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 1860 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 1920 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 1980 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 2040 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 2100 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 2160 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 2220 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 2280 atggaggttc tgggctgcga ggcacaggac ctctactgat aa 2322 <210> 48 <211> 6288 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-6 <400> 48 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 tacctggttc cgcgtggatc cagcctatcc tgtcggcccc ccatggtcaa gctggtgtgt 4800 cccgctgaca acctgcgggc tgaagggctc gagtgtacca aaacgtgcca gaactatgac 4860 ctggagtgca tgagcatggg ctgtgtctct ggctgcctct gccccccggg catggtccgg 4920 catgagaaca gatgtgtggc cctggaaagg tgtccctgct tccatcaggg caaggagtat 4980 gcccctggag aaacagtgaa gattggctgc aacacttgtg tctgtcggga ccggaagtgg 5040 aactgcacag accatgtgtg tgatgccacg tgctccacga tcggcatggc ccactacctc 5100 accttcgacg ggctcaaata cctgttcccc ggggagtgcc agtacgttct ggtgcaggat 5160 tactgcggca gtaaccctgg gacctttcgg atcctagtgg ggaataaggg atgcagccac 5220 ccctcagtga aatgcaagaa acgggtcacc atcctggtgg agggaggaga gattgagctg 5280 tttgacgggg aggtgaatgt gaagaggccc atgaaggatg agactcactt tgaggtggtg 5340 gagtctggcc ggtacatcat tctgctgctg ggcaaagccc tctccgtggt ctgggaccgc 5400 cacctgagca tctccgtggt cctgaagcag acataccagg agaaagtgtg tggcctgtgt 5460 gggaattttg atggcatcca gaacaatgac ctcaccagca gcaacctcca agtggaggaa 5520 gaccctgtgg actttgggaa ctcctggaaa gtgagctcgc agtgtgctga caccagaaaa 5580 gtgcctctgg actcatcccc tgccacctgc cataacaaca tcatgaagca gacgatggtg 5640 gattcctcct gtagaatcct taccagtgac gtcttccagg actgcaacaa gctggtggac 5700 cccgagccat atctggatgt ctgcatttac gacacctgct cctgtgagtc cattggggac 5760 tgcgcctgct tctgcgacac cattgctgcc tatgcccacg tgtgtgccca gcatggcaag 5820 gtggtgacct ggaggacggc cacattgtgc ccccagagct gcgaggagag gaatctccgg 5880 gagaacgggt atgagtgtga gtggcgctat aacagctgtg cacctgcctg tcaagtcacg 5940 tgtcagcacc ctgagccact ggcctgccct gtgcagtgtg tggagggctg ccatgcccac 6000 tgccctccag ggaaaatcct ggatgagctt ttgcagacct gcgttgaccc tgaagactgt 6060 ccagtgtgtg aggtggctgg ccggcgtttt gcctcaggaa agaaagtcac cttgaatccc 6120 agtgaccctg agcactgcca gatttgccac tgtgatgttg tcaacctcac ctgtgaagcc 6180 tgccaggagc cgggaggcct ggtggtgcct cccacagatg ccccggtgag ccccaccact 6240 ctgtatgtgg aggacatctc ggaaccgccg ttgcacgatt tctgataa 6288 <210> 49 <211> 6300 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-10 <400> 49 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 tacctggttc cgcgtggatc cgggggtgga ggtagcctat cctgtcggcc ccccatggtc 4800 aagctggtgt gtcccgctga caacctgcgg gctgaagggc tcgagtgtac caaaacgtgc 4860 cagaactatg acctggagtg catgagcatg ggctgtgtct ctggctgcct ctgccccccg 4920 ggcatggtcc ggcatgagaa cagatgtgtg gccctggaaa ggtgtccctg cttccatcag 4980 ggcaaggagt atgcccctgg agaaacagtg aagattggct gcaacacttg tgtctgtcgg 5040 gaccggaagt ggaactgcac agaccatgtg tgtgatgcca cgtgctccac gatcggcatg 5100 gcccactacc tcaccttcga cgggctcaaa tacctgttcc ccggggagtg ccagtacgtt 5160 ctggtgcagg attactgcgg cagtaaccct gggacctttc ggatcctagt ggggaataag 5220 ggatgcagcc acccctcagt gaaatgcaag aaacgggtca ccatcctggt ggagggagga 5280 gagattgagc tgtttgacgg ggaggtgaat gtgaagaggc ccatgaagga tgagactcac 5340 tttgaggtgg tggagtctgg ccggtacatc attctgctgc tgggcaaagc cctctccgtg 5400 gtctgggacc gccacctgag catctccgtg gtcctgaagc agacatacca ggagaaagtg 5460 tgtggcctgt gtgggaattt tgatggcatc cagaacaatg acctcaccag cagcaacctc 5520 caagtggagg aagaccctgt ggactttggg aactcctgga aagtgagctc gcagtgtgct 5580 gacaccagaa aagtgcctct ggactcatcc cctgccacct gccataacaa catcatgaag 5640 cagacgatgg tggattcctc ctgtagaatc cttaccagtg acgtcttcca ggactgcaac 5700 aagctggtgg accccgagcc atatctggat gtctgcattt acgacacctg ctcctgtgag 5760 tccattgggg actgcgcctg cttctgcgac accattgctg cctatgccca cgtgtgtgcc 5820 cagcatggca aggtggtgac ctggaggacg gccacattgt gcccccagag ctgcgaggag 5880 aggaatctcc gggagaacgg gtatgagtgt gagtggcgct ataacagctg tgcacctgcc 5940 tgtcaagtca cgtgtcagca ccctgagcca ctggcctgcc ctgtgcagtg tgtggagggc 6000 tgccatgccc actgccctcc agggaaaatc ctggatgagc ttttgcagac ctgcgttgac 6060 cctgaagact gtccagtgtg tgaggtggct ggccggcgtt ttgcctcagg aaagaaagtc 6120 accttgaatc ccagtgaccc tgagcactgc cagatttgcc actgtgatgt tgtcaacctc 6180 acctgtgaag cctgccagga gccgggaggc ctggtggtgc ctcccacaga tgccccggtg 6240 agccccacca ctctgtatgt ggaggacatc tcggaaccgc cgttgcacga tttctgataa 6300 6300 <210> 50 <211> 6330 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-20 <400> 50 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 tacctggttc cgcgtggatc cgggggtgga ggttcaggag gtggaggttc aggaggtgga 4800 ggtagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 4860 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 4920 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 4980 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 5040 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 5100 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 5160 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 5220 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 5280 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 5340 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 5400 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 5460 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 5520 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 5580 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 5640 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 5700 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 5760 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 5820 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 5880 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 5940 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 6000 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 6060 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 6120 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 6180 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 6240 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 6300 tcggaaccgc cgttgcacga tttctgataa 6330 <210> 51 <211> 6360 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-30 <400> 51 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 tacctggttc cgcgtggatc cgggggtgga ggttcaggag gtggaggttc aggaggtgga 4800 ggttcaggag gtggaggttc aggaggtgga ggtagcctat cctgtcggcc ccccatggtc 4860 aagctggtgt gtcccgctga caacctgcgg gctgaagggc tcgagtgtac caaaacgtgc 4920 cagaactatg acctggagtg catgagcatg ggctgtgtct ctggctgcct ctgccccccg 4980 ggcatggtcc ggcatgagaa cagatgtgtg gccctggaaa ggtgtccctg cttccatcag 5040 ggcaaggagt atgcccctgg agaaacagtg aagattggct gcaacacttg tgtctgtcgg 5100 gaccggaagt ggaactgcac agaccatgtg tgtgatgcca cgtgctccac gatcggcatg 5160 gcccactacc tcaccttcga cgggctcaaa tacctgttcc ccggggagtg ccagtacgtt 5220 ctggtgcagg attactgcgg cagtaaccct gggacctttc ggatcctagt ggggaataag 5280 ggatgcagcc acccctcagt gaaatgcaag aaacgggtca ccatcctggt ggagggagga 5340 gagattgagc tgtttgacgg ggaggtgaat gtgaagaggc ccatgaagga tgagactcac 5400 tttgaggtgg tggagtctgg ccggtacatc attctgctgc tgggcaaagc cctctccgtg 5460 gtctgggacc gccacctgag catctccgtg gtcctgaagc agacatacca ggagaaagtg 5520 tgtggcctgt gtgggaattt tgatggcatc cagaacaatg acctcaccag cagcaacctc 5580 caagtggagg aagaccctgt ggactttggg aactcctgga aagtgagctc gcagtgtgct 5640 gacaccagaa aagtgcctct ggactcatcc cctgccacct gccataacaa catcatgaag 5700 cagacgatgg tggattcctc ctgtagaatc cttaccagtg acgtcttcca ggactgcaac 5760 aagctggtgg accccgagcc atatctggat gtctgcattt acgacacctg ctcctgtgag 5820 tccattgggg actgcgcctg cttctgcgac accattgctg cctatgccca cgtgtgtgcc 5880 cagcatggca aggtggtgac ctggaggacg gccacattgt gcccccagag ctgcgaggag 5940 aggaatctcc gggagaacgg gtatgagtgt gagtggcgct ataacagctg tgcacctgcc 6000 tgtcaagtca cgtgtcagca ccctgagcca ctggcctgcc ctgtgcagtg tgtggagggc 6060 tgccatgccc actgccctcc agggaaaatc ctggatgagc ttttgcagac ctgcgttgac 6120 cctgaagact gtccagtgtg tgaggtggct ggccggcgtt ttgcctcagg aaagaaagtc 6180 accttgaatc ccagtgaccc tgagcactgc cagatttgcc actgtgatgt tgtcaacctc 6240 acctgtgaag cctgccagga gccgggaggc ctggtggtgc ctcccacaga tgccccggtg 6300 agccccacca ctctgtatgt ggaggacatc tcggaaccgc cgttgcacga tttctgataa 6360 6360 <210> 52 <211> 6390 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-40 <400> 52 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 tacctggttc cgcgtggatc cgggggtgga ggttcaggag gtggaggttc aggaggtgga 4800 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4860 ggtagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 4920 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 4980 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 5040 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 5100 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 5160 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 5220 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 5280 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 5340 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 5400 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 5460 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 5520 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 5580 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 5640 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 5700 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 5760 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 5820 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 5880 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 5940 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 6000 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 6060 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 6120 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 6180 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 6240 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 6300 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 6360 tcggaaccgc cgttgcacga tttctgataa 6390 <210> 53 <211> 6420 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-50 <400> 53 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 tacctggttc cgcgtggatc cgggggtgga ggttcaggag gtggaggttc aggaggtgga 4800 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4860 ggttcaggag gtggaggttc aggaggtgga ggtagcctat cctgtcggcc ccccatggtc 4920 aagctggtgt gtcccgctga caacctgcgg gctgaagggc tcgagtgtac caaaacgtgc 4980 cagaactatg acctggagtg catgagcatg ggctgtgtct ctggctgcct ctgccccccg 5040 ggcatggtcc ggcatgagaa cagatgtgtg gccctggaaa ggtgtccctg cttccatcag 5100 ggcaaggagt atgcccctgg agaaacagtg aagattggct gcaacacttg tgtctgtcgg 5160 gaccggaagt ggaactgcac agaccatgtg tgtgatgcca cgtgctccac gatcggcatg 5220 gcccactacc tcaccttcga cgggctcaaa tacctgttcc ccggggagtg ccagtacgtt 5280 ctggtgcagg attactgcgg cagtaaccct gggacctttc ggatcctagt ggggaataag 5340 ggatgcagcc acccctcagt gaaatgcaag aaacgggtca ccatcctggt ggagggagga 5400 gagattgagc tgtttgacgg ggaggtgaat gtgaagaggc ccatgaagga tgagactcac 5460 tttgaggtgg tggagtctgg ccggtacatc attctgctgc tgggcaaagc cctctccgtg 5520 gtctgggacc gccacctgag catctccgtg gtcctgaagc agacatacca ggagaaagtg 5580 tgtggcctgt gtgggaattt tgatggcatc cagaacaatg acctcaccag cagcaacctc 5640 caagtggagg aagaccctgt ggactttggg aactcctgga aagtgagctc gcagtgtgct 5700 gacaccagaa aagtgcctct ggactcatcc cctgccacct gccataacaa catcatgaag 5760 cagacgatgg tggattcctc ctgtagaatc cttaccagtg acgtcttcca ggactgcaac 5820 aagctggtgg accccgagcc atatctggat gtctgcattt acgacacctg ctcctgtgag 5880 tccattgggg actgcgcctg cttctgcgac accattgctg cctatgccca cgtgtgtgcc 5940 cagcatggca aggtggtgac ctggaggacg gccacattgt gcccccagag ctgcgaggag 6000 aggaatctcc gggagaacgg gtatgagtgt gagtggcgct ataacagctg tgcacctgcc 6060 tgtcaagtca cgtgtcagca ccctgagcca ctggcctgcc ctgtgcagtg tgtggagggc 6120 tgccatgccc actgccctcc agggaaaatc ctggatgagc ttttgcagac ctgcgttgac 6180 cctgaagact gtccagtgtg tgaggtggct ggccggcgtt ttgcctcagg aaagaaagtc 6240 accttgaatc ccagtgaccc tgagcactgc cagatttgcc actgtgatgt tgtcaacctc 6300 acctgtgaag cctgccagga gccgggaggc ctggtggtgc ctcccacaga tgccccggtg 6360 agccccacca ctctgtatgt ggaggacatc tcggaaccgc cgttgcacga tttctgataa 6420 6420 <210> 54 <211> 6450 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-60 <400> 54 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 tacctggttc cgcgtggatc cgggggtgga ggttcaggag gtggaggttc aggaggtgga 4800 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4860 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4920 ggtagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 4980 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 5040 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 5100 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 5160 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 5220 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 5280 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 5340 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 5400 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 5460 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 5520 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 5580 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 5640 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 5700 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 5760 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 5820 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 5880 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 5940 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 6000 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 6060 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 6120 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 6180 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 6240 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 6300 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 6360 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 6420 tcggaaccgc cgttgcacga tttctgataa 6450 <210> 55 <211> 6540 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-90 <400> 55 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 tacctggttc cgcgtggatc cgggggtgga ggttcaggag gtggaggttc aggaggtgga 4800 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4860 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4920 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4980 ggttcaggag gtggaggttc aggaggtgga ggtagcctat cctgtcggcc ccccatggtc 5040 aagctggtgt gtcccgctga caacctgcgg gctgaagggc tcgagtgtac caaaacgtgc 5100 cagaactatg acctggagtg catgagcatg ggctgtgtct ctggctgcct ctgccccccg 5160 ggcatggtcc ggcatgagaa cagatgtgtg gccctggaaa ggtgtccctg cttccatcag 5220 ggcaaggagt atgcccctgg agaaacagtg aagattggct gcaacacttg tgtctgtcgg 5280 gaccggaagt ggaactgcac agaccatgtg tgtgatgcca cgtgctccac gatcggcatg 5340 gcccactacc tcaccttcga cgggctcaaa tacctgttcc ccggggagtg ccagtacgtt 5400 ctggtgcagg attactgcgg cagtaaccct gggacctttc ggatcctagt ggggaataag 5460 ggatgcagcc acccctcagt gaaatgcaag aaacgggtca ccatcctggt ggagggagga 5520 gagattgagc tgtttgacgg ggaggtgaat gtgaagaggc ccatgaagga tgagactcac 5580 tttgaggtgg tggagtctgg ccggtacatc attctgctgc tgggcaaagc cctctccgtg 5640 gtctgggacc gccacctgag catctccgtg gtcctgaagc agacatacca ggagaaagtg 5700 tgtggcctgt gtgggaattt tgatggcatc cagaacaatg acctcaccag cagcaacctc 5760 caagtggagg aagaccctgt ggactttggg aactcctgga aagtgagctc gcagtgtgct 5820 gacaccagaa aagtgcctct ggactcatcc cctgccacct gccataacaa catcatgaag 5880 cagacgatgg tggattcctc ctgtagaatc cttaccagtg acgtcttcca ggactgcaac 5940 aagctggtgg accccgagcc atatctggat gtctgcattt acgacacctg ctcctgtgag 6000 tccattgggg actgcgcctg cttctgcgac accattgctg cctatgccca cgtgtgtgcc 6060 cagcatggca aggtggtgac ctggaggacg gccacattgt gcccccagag ctgcgaggag 6120 aggaatctcc gggagaacgg gtatgagtgt gagtggcgct ataacagctg tgcacctgcc 6180 tgtcaagtca cgtgtcagca ccctgagcca ctggcctgcc ctgtgcagtg tgtggagggc 6240 tgccatgccc actgccctcc agggaaaatc ctggatgagc ttttgcagac ctgcgttgac 6300 cctgaagact gtccagtgtg tgaggtggct ggccggcgtt ttgcctcagg aaagaaagtc 6360 accttgaatc ccagtgaccc tgagcactgc cagatttgcc actgtgatgt tgtcaacctc 6420 acctgtgaag cctgccagga gccgggaggc ctggtggtgc ctcccacaga tgccccggtg 6480 agccccacca ctctgtatgt ggaggacatc tcggaaccgc cgttgcacga tttctgataa 6540 6540 <210> 56 <211> 6630 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-120 <400> 56 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 tacctggttc cgcgtggatc cgggggtgga ggttcaggag gtggaggttc aggaggtgga 4800 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4860 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4920 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 4980 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 5040 ggttcaggag gtggaggttc aggaggtgga ggttcaggag gtggaggttc aggaggtgga 5100 ggtagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 5160 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 5220 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 5280 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 5340 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 5400 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 5460 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 5520 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 5580 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 5640 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 5700 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 5760 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 5820 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 5880 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 5940 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 6000 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 6060 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 6120 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 6180 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 6240 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 6300 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 6360 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 6420 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 6480 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 6540 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 6600 tcggaaccgc cgttgcacga tttctgataa 6630 <210> 57 <211> 6630 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-120-TH1 <400> 57 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 tacggtggag gttcactggt tccgcgtgga tccgggggtg gaggttcagg aggtggaggt 4800 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 4860 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 4920 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 4980 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 5040 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 5100 ggtagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 5160 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 5220 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 5280 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 5340 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 5400 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 5460 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 5520 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 5580 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 5640 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 5700 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 5760 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 5820 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 5880 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 5940 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 6000 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 6060 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 6120 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 6180 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 6240 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 6300 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 6360 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 6420 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 6480 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 6540 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 6600 tcggaaccgc cgttgcacga tttctgataa 6630 <210> 58 <211> 6630 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-120-TH1 <400> 58 gccactagaa ggtactacct gggggctgtg gagctgtcct gggattacat gcagtccgac 60 ctgggagagc tgcccgttga tgctagattc ccacctaggg tgcccaaatc tttccccttt 120 aatacatctg tggtgtacaa aaagacactg tttgtggagt ttaccgatca cctcttcaat 180 attgccaagc ctcgaccacc ctggatgggt ctccttggcc ctacaattca ggccgaggtc 240 tacgacaccg tggtaatcac cctgaagaac atggcatcac accccgtgag cctgcacgct 300 gtgggcgtgt cttactggaa ggccagtgaa ggcgccgaat atgatgacca gacaagccag 360 agagaaaagg aggacgataa ggtgttccct ggcggatctc acacatatgt gtggcaggtg 420 ctgaaggaga atggacccat ggcatctgac cccctttgcc taacttatag ttatctttcc 480 catgtggacc ttgtcaagga cctgaattct gggcttatcg gagcactgct cgtgtgtaga 540 gagggttcat tggctaagga gaagactcag acactgcaca agttcatcct gctgttcgct 600 gtcttcgatg aggggaagtc ttggcacagc gaaaccaaga attccctgat gcaagatcgc 660 gatgccgcat ccgctcgcgc atggcctaag atgcatacag tgaatgggta cgtcaataga 720 tccttgcctg gcctgattgg ctgtcacaga aaatctgtgt actggcacgt gattggtatg 780 gggaccaccc cagaagtgca tagtatcttt ttggaagggc atacctttct ggtgcggaac 840 cacagacagg cctccctgga aattagtcca atcacattcc tgacagccca gacactgctg 900 atggatctgg ggcagtttct cctgttctgt catatctcta gccaccagca tgacgggatg 960 gaggcctatg tgaaggtgga tagttgtcca gaagagcctc agttgagaat gaagaacaac 1020 gaggaggctg aagactatga tgatgatttg accgactctg aaatggatgt tgtcagattt 1080 gacgacgata atagcccaag ctttatccag atcagatcag tggcaaagaa gcaccctaag 1140 acctgggtgc attatatcgc tgccgaagag gaggactggg actacgcccc tcttgtgctg 1200 gcccctgacg ataggagcta taagtcacag tacctcaaca acggacctca gcgaattggc 1260 cggaagtata aaaaggttcg gtttatggct tacaccgatg aaaccttcaa gactagggag 1320 gccattcaac acgagtccgg tattctcggc cccctcctgt atggcgaagt gggggacaca 1380 ctgctgatca tctttaagaa ccaggcttcc cgcccctaca acatctaccc tcacggtatt 1440 accgatgtgc ggccactgta ttctaggaga ctccctaaag gagtgaagca cctcaaagat 1500 ttccctattc tgcctggtga gatctttaaa tacaaatgga ccgtcaccgt ggaggatggg 1560 cccacaaaat ccgaccccag gtgtctgacc aggtattata gtagctttgt taatatggag 1620 agggatctcg ccagcggact gatcggaccc ctgctgattt gctacaagga atctgttgat 1680 cagagaggta accagatcat gagtgataag agaaacgtga tactgttttc agtgttcgat 1740 gaaaacagat catggtactt gactgaaaat attcagcggt ttctgccaaa ccccgctgga 1800 gttcagcttg aggaccctga atttcaagct agtaacatca tgcacagcat taatggatat 1860 gtttttgatt cattgcagct gtctgtttgc ctgcacgagg tggcctattg gtatattctt 1920 agcattggtg ctcagactga cttcctgtcc gtgttcttta gcgggtacac cttcaagcac 1980 aagatggtct atgaggacac attgactctc tttccattct ccggtgagac tgtctttatg 2040 tctatggaga acccagggtt gtggattctg ggctgccata actctgattt tagaaacaga 2100 ggcatgacag ctctgctaaa ggtgagttct tgcgataaga acacaggaga ctattatgag 2160 gacagttacg aagacatctc agcgtacctt ctaagtaaga ataatgccat tgaaccaaga 2220 agtttctctc agaattcccg ccatccctcc acaaggcaga aacagttcaa cgccacaact 2280 atccctgaga atgatattga aaagacagac ccttggttcg ctcacagaac tccaatgcct 2340 aaatgccaga atgtctcctc aagcgacctg ctgatgctgc tgagacagag ccccacccct 2400 cacgggttgt ccctctctga cctgcaggaa gcaaagtatg agacttttag cgatgatccc 2460 tccccaggag caattgactc taacaattcc ctgagtgaga tgacccactt cagaccacag 2520 ttgcaccata gcggcgacat ggttttcaca cctgaaagcg gcctgcagct tcgtctgaat 2580 gagaagctcg gcacaacagc tgcaactgaa cttaagaaac tcgattttaa agtgagctcc 2640 accagtaata atctgatctc caccatccct agcgataact tggccgccgg gacagataat 2700 acttctactc tgcagagtga ccaggaggaa atcgactatg acgatactat tagcgtggag 2760 atgaagaagg aagattttga tatctatgac gaagatgaga atcagagccc caggtctttt 2820 cagaaaaaga ccagacacta tttcatcgca gctgtcgagc ggttgtggga ctacggcatg 2880 tctagttctc cccatgtgct caggaacagg gcccagtctg gcagcgtccc tcagttcaag 2940 aaggtcgtgt tccaggaatt cactgacggc tcttttacac agccactgta tcgtggagag 3000 ctcaatgaac atctgggtct gctgggtccc tacattcgcg cagaagtgga ggataacatc 3060 atggtgactt tcagaaatca ggcaagtaga ccttacagct tctactcaag cttaattagt 3120 tacgaggagg accagagaca aggcgctgag cctaggaaga actttgttaa acctaatgag 3180 acaaagacct acttctggaa ggtgcagcat catatggctc ctacaaagga tgagttcgac 3240 tgtaaagcat gggcttactt ttcagatgtg gatctggaaa aggacgttca ttcgggtctg 3300 atcggacctc tactggtgtg ccacaccaac accctaaacc cagctcatgg acgacaggtg 3360 acagtgcagg aattcgctct gttctttacc atcttcgatg agactaagtc atggtacttc 3420 actgaaaata tggagcgtaa ttgtcgagct ccatgtaaca ttcagatgga ggatcctact 3480 ttcaaagaga attacagatt tcatgccatt aatggctata ttatggatac tctgccaggc 3540 ctggtcatgg cccaggatca gaggattcga tggtacctgc tcagtatggg tagcaatgaa 3600 aacattcatt caatccattt ttctggtcat gtgttcactg tgagaaagaa agaggagtat 3660 aaaatggctc tgtataatct gtatcctgga gtgtttgaga cagttgaaat gctgccctca 3720 aaagcaggta tctggagagt ggaatgcttg atcggtgagc atctgcatgc cggtatgagc 3780 accctgttct tggtctactc caataagtgt cagacgcctc tggggatggc cagcgggcac 3840 atccgagatt tccagatcac cgccagcgga cagtacggac agtgggcacc aaagctggcc 3900 aggctccact atagcggctc tatcaacgcg tggtccacta aagaaccctt tagctggatc 3960 aaagtcgatc tgttggcccc aatgatcatc catgggatta agactcaggg tgctaggcag 4020 aaattcagca gcctgtacat atcccagttc atcattatgt atagcttgga cggaaagaaa 4080 tggcagacat atagagggaa ctctaccggc accttaatgg tgttcttcgg aaacgtcgac 4140 agcagcggca ttaagcataa tatctttaat cccccaatca ttgctcgtta tattaggctc 4200 caccctaccc attattctat ccggagtacc ctgcgaatgg aactgatggg ctgtgacctt 4260 aatagctgct ctatgcctct cggcatggaa tctaaagcaa tttccgacgc ccagatcaca 4320 gcctcttcct actttacaaa catgttcgca acctggtctc catctaaggc aagactgcac 4380 ttgcagggcc ggagtaatgc ttggaggcct caggtgaaca atcccaaaga gtggctgcag 4440 gttgattttc agaagacaat gaaggtgact ggggtgacca cacaaggtgt taagagcctg 4500 ttaacatcta tgtacgtgaa ggagtttctg atcagctctt ctcaggatgg ccatcaatgg 4560 accctatttt tccagaacgg aaaagttaag gtgttccagg gaaaccagga cagctttacc 4620 cccgtggtga atagtttgga ccctccactc ctgacacgtt atcttaggat ccacccacaa 4680 agctgggttc atcagattgc cctgagaatg gaagtcctgg ggtgcgaggc acaggacctg 4740 tacgggggag gttctctcgt gccaagaggt agtggagggg gcggatccgg aggaggtggc 4800 agcggcggag gaggatctgg agggggcggg tcaggggggg gcggctccgg cggtggtgga 4860 agcggaggcg ggggaagcgg cggcggaggg agcggaggtg gcggatccgg cgggggcggc 4920 agcggcggag gtggtagcgg ggggggtggc tctggtggag ggggatctgg cggtggcggc 4980 agtggagggg gaggttctgg aggcggcgga tctggaggag gaggatcagg cggcggaggt 5040 agtggaggag ggggaagcgg cggcggaggc agcggtggcg gtggctcagg cggcggagga 5100 ggttcactca gttgcaggcc tcccatggtg aaactggtgt gtcccgctga taacctgagg 5160 gccgagggac tggagtgcac taagacatgc caaaactacg atctggagtg tatgagcatg 5220 ggatgtgtga gtggctgtct atgtcctcct ggcatggtgc ggcacgagaa tcggtgcgtc 5280 gctctagagc gttgtccatg cttccaccag ggcaaggagt acgctcctgg cgagacagta 5340 aaaatcggtt gtaacacttg tgtttgcaga gataggaagt ggaactgtac agatcacgtc 5400 tgcgacgcca catgttccac tattggcatg gctcactacc tgaccttcga cggtctgaag 5460 tatctgttcc ctggcgaatg tcagtatgtg ctggtacagg attactgcgg gagtaatccc 5520 ggtactttta ggatcctggt cggaaataag ggttgtagtc acccttccgt aaagtgtaag 5580 aaacgggtga ccatccttgt cgaggggggg gaaatcgagc tgtttgacgg cgaggtgaat 5640 gtgaagaggc ctatgaagga tgagactcat tttgaggtgg tggagtctgg ccgctatatt 5700 attctgctgc tcggcaaagc actctctgtt gtgtgggatc ggcacctgtc aatcagcgtg 5760 gtgcttaagc agacatacca ggagaaagtg tgcggcctct gtggaaactt cgacgggatc 5820 cagaacaatg atctgaccag ctctaatctc caggtggagg aggatccagt ggactttgga 5880 aattcctgga aagtgagttc ccagtgtgca gacaccagaa aggtccctct ggactctagc 5940 cccgctacct gtcacaataa catcatgaag cagacaatgg ttgacagctc ttgtcgcatt 6000 ttgactagtg atgtgttcca ggattgtaat aagctggttg acccagaacc ctatttggat 6060 gtgtgtatct atgacacatg ctcttgtgag tctatcggtg actgtgcctg tttctgcgat 6120 acaatcgccg cttacgcgca tgtttgcgca cagcacggta aagtggtaac ttggcgaacg 6180 gcaacacttt gtccccagtc ctgtgaggaa cgtaatcttc gtgaaaacgg ctatgagtgt 6240 gagtggcgat ataatagctg cgcgccagca tgtcaagtga catgccagca tcctgagcct 6300 ctagcttgtc cagtgcagtg cgttgagggt tgccatgctc actgtccacc cggcaagatt 6360 ctggatgaac ttctgcagac atgcgtggat ccagaggatt gtccagtttg tgaagtggcc 6420 ggccgtaggt ttgctagtgg taaaaaggtg accctgaatc ccagtgaccc agagcattgc 6480 cagatctgcc actgcgacgt ggtgaacctg acatgtgaag cttgccagga acctggaggg 6540 ctggttgtgc ctcctaccga cgcaccagtg tctcccacta cactgtatgt ggaggatatc 6600 agtgagccac ctctgcatga tttctgataa 6630 <210> 59 <211> 6630 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-120-TH1 <400> 59 gccaccagaa gatattacct gggcgccgtg gaactgtcct gggactacat gcagtctgat 60 ctgggcgagc tgcccgtgga tgccagattt cctccaagag tgcccaagag cttccccttc 120 aacacctccg tggtgtacaa gaaaaccctg ttcgtggaat tcaccgacca cctgttcaat 180 atcgccaagc ctagacctcc ttggatgggc ctgctgggac ctacaattca ggccgaggtg 240 tacgacaccg tggtcatcac cctgaagaac atggcttctc accccgtgtc tctgcacgcc 300 gtgggagtgt cttattggaa ggcttctgag ggcgccgagt acgacgatca gaccagccag 360 agagagaaag aggacgacaa ggttttccct ggcggctccc acacctatgt gtggcaggtc 420 ctgaaagaaa acggccccat ggcctctgat cctctgtgcc tgacctactc ctacctgtct 480 cacgtggacc tggtcaagga cctgaattct ggactgatcg gcgctctgct cgtgtgcaga 540 gagggaagcc tggccaaaga aaagacccag acactgcaca agttcatcct gctgttcgcc 600 gtgttcgacg agggcaagtc ctggcactcc gagacaaaga actctctgat gcaggacagg 660 gacgccgcct ctgctagagc ttggcctaag atgcacaccg tgaacggcta cgtgaacaga 720 tccctgcctg gcctgatcgg atgccacaga aagtctgtgt actggcacgt gatcggcatg 780 ggcacaacac ctgaggtgca ctccatcttt ctggaaggcc acaccttcct cgtgcggaac 840 catagacagg ccagcctgga aatctcccct atcacctttc tgaccgctca gaccctgctg 900 atggatctgg gccagtttct gctgttctgt cacatctcca gccaccagca cgacggcatg 960 gaagcttacg tgaaggtgga cagctgcccc gaggaacccc agctgagaat gaagaacaac 1020 gaggaagccg aggactacga cgacgacctg accgactctg agatggatgt cgtcagattc 1080 gacgacgata actcccctag cttcatccag attcggagcg tggccaagaa gcaccctaag 1140 acttgggtgc actatatcgc cgccgaggaa gaggattggg attacgctcc tctggtgctg 1200 gcccctgacg acagatccta caagtcccag tacctgaaca acggccctca gcggatcggc 1260 cggaagtata agaaagtgcg gttcatggcc tacaccgacg agacattcaa gaccagagag 1320 gctatccagc acgagtccgg aattctggga cctctgctgt atggcgaagt gggcgacaca 1380 ctgctgatca tcttcaagaa ccaggcctct cggccctaca acatctaccc tcatggcatc 1440 acagacgtgc ggcctctgta ctctagaagg ctgcctaagg gcgtgaagca cctgaaggac 1500 ttccctattc tgcccggcga gatcttcaag tacaagtgga ccgtgaccgt ggaagatggc 1560 cccaccaagt ctgaccctag atgtctgacc cggtactact cctccttcgt gaacatggaa 1620 agagatctgg cctccggcct gattggccct ctgctgatct gctacaaaga atccgtggac 1680 cagcggggca accagatcat gtccgacaag cggaacgtga tcctgttctc tgtgttcgat 1740 gagaaccggt cctggtatct gaccgagaac atccagcggt ttctgcccaa tcctgctggc 1800 gtgcagctgg aagatcctga gttccaggcc tccaacatca tgcacagcat caacggctat 1860 gtgttcgact ccctgcagct gtctgtgtgt ctgcacgagg tggcctactg gtacatcctg 1920 tctatcggag cccagaccga cttcctgtcc gtgttcttct ccggctacac cttcaagcac 1980 aagatggtgt acgaggacac cctgacactg ttccctttct ccggcgaaac cgtgttcatg 2040 tccatggaaa accccggcct gtggatcctg ggctgccaca actctgactt ccggaacaga 2100 ggcatgaccg ctctgctgaa ggtgtcctcc tgtgacaaga acaccggcga ctactacgag 2160 gactcttacg aggatatctc cgcctacctg ctgtccaaga acaatgccat cgagccccgg 2220 tccttcagcc agaactctag acacccttcc accagacaga agcagttcaa cgccaccacc 2280 attccagaga acgacatcga aaagaccgat ccttggtttg cccacagaac ccctatgcct 2340 aagtgccaga acgtgtcctc cagcgacctg ctcatgctgc tgagacagtc tccaacacct 2400 cacggcctgt ctctgtctga cctgcaagag gctaagtacg agactttcag cgacgaccct 2460 tctcctggcg ccatcgactc taacaactcc ctgtccgaga tgacccactt cagacctcag 2520 ctgcaccact ccggcgatat ggtgtttacc cctgagtctg gcctgcagct cagactgaat 2580 gagaagctgg gcaccaccgc tgccaccgag ctgaagaaac tggacttcaa ggtgtccagc 2640 acctccaaca acctgatcag cacaatccct tccgacaacc tggccgctgg caccgataat 2700 acctctacac tgcagtccga ccaagaggaa atcgattacg acgacaccat cagcgtcgag 2760 atgaagaaag aagatttcga catctacgac gaggacgaga accagtctcc tcggagcttc 2820 cagaagaaaa ccagacacta ctttatcgcc gctgtggaac ggctgtggga ctacggaatg 2880 tcctcttctc ctcacgtgct gcggaataga gcccagtctg gctccgtgcc tcagttcaag 2940 aaagtggtgt tccaagagtt caccgacggc agcttcaccc agcctctgta tagaggcgag 3000 ctgaacgagc atctgggact gctgggccct tatatcagag ccgaggtcga ggataacatc 3060 atggtcacct tcagaaacca ggccagcaga ccctactcct tctactccag cctgatctcc 3120 tacgaagagg accagagaca aggcgccgag cctcggaaga acttcgtgaa gcctaacgag 3180 actaagacct acttttggaa ggtgcagcac cacatggctc ctaccaagga cgagttcgat 3240 tgcaaggcct gggcctactt ctccgatgtg gatctggaaa aggacgtgca ctccgggctg 3300 atcggaccac tgcttgtgtg tcacaccaac acactgaacc ctgctcacgg caggcaagtg 3360 acagtgcaag agttcgccct gttcttcacc atcttcgacg aaacaaagtc ctggtacttc 3420 accgaaaaca tggaacggaa ctgcagagcc ccttgcaaca tccagatgga agatcccacc 3480 ttcaaagaga actaccggtt ccacgccatc aatggctaca tcatggatac cctgccaggc 3540 ctcgtgatgg ctcaggatca gcgcatcaga tggtatctgc tgagcatggg ctccaacgag 3600 aatatccact ccatccactt cagcggccac gtgttcaccg tgcggaaaaa agaagagtac 3660 aagatggctc tgtacaatct gtaccccggc gtgttcgaga cagtggaaat gctgccttct 3720 aaggccggca tctggcgcgt ggaatgtctg atcggagagc atctgcatgc cggaatgtct 3780 accctgttcc tggtgtactc caacaagtgt cagacccctc tcggcatggc ttccggccat 3840 atcagagact tccagatcac cgcttccgga cagtatggcc agtgggctcc taagctggcc 3900 agactgcact actctggctc catcaacgcc tggtctacca aagagccctt cagctggatc 3960 aaggtggacc tgctggctcc catgatcatc cacggcatca agacacaggg cgctagacag 4020 aagttcagct ccctgtacat ctcccagttc atcatcatgt actccctgga cggcaagaag 4080 tggcagacct acagaggcaa ctccaccggc acactcatgg tgttcttcgg caacgtggac 4140 tcctccggca ttaagcacaa catcttcaac cctccaatca ttgcccggta catccggctg 4200 caccccacac actactccat cagatctacc ctgagaatgg aactgatggg ctgcgacctg 4260 aactcctgtt ctatgcccct cggaatggaa tccaaggcca tcagcgacgc ccagattacc 4320 gcctcctcct acttcaccaa catgttcgcc acttggagcc cctctaaggc caggctgcat 4380 ctgcagggca gatctaatgc ttggcggcct caagtgaaca accccaaaga gtggctgcag 4440 gtcgactttc agaaaaccat gaaggtcaca ggcgtgacaa cccagggcgt caagtccctg 4500 ctgacctcta tgtacgtgaa agagttcctg atctctagca gccaggacgg ccaccagtgg 4560 accctgtttt tccagaacgg caaagtgaag gtgttccagg gcaatcagga ttctttcacc 4620 cctgtggtca acagcctgga tcctccactg ctgaccagat acctgcggat ccatcctcag 4680 tcctgggtgc accagattgc tctgcgaatg gaagtgctgg gatgtgaagc ccaagatctg 4740 tacggcggag gctctctggt tcctagagga tctggcggtg gtggttctgg cggcggagga 4800 agcggaggcg gaggtagtgg tggcggtgga agtggcggtg gcggatccgg tggcggcgga 4860 tctggcggag gcggcagcgg cggtggtggt agcggcggag gcggctcagg tggcggaggc 4920 agtggcggcg gaggttcagg cggtggtgga agtggcggcg gtggctctgg cggtggcggc 4980 tcaggcggtg gtggctccgg cggaggcgga agcggcggag gcggcagcgg aggcggaggc 5040 tctggtggcg gaggttccgg tggcggaggc agcggcggag gcggctctgg cggaggtggt 5100 ggatctttgt cttgtcggcc tcctatggtc aagctcgtgt gtcccgccga taatctgaga 5160 gccgaaggac tggaatgcac caagacctgc cagaactacg acctcgagtg catgtctatg 5220 ggctgtgtgt ccggatgtct gtgccctcct ggcatggtcc gacacgagaa tagatgcgtg 5280 gccctggaaa gatgcccctg cttccaccaa ggcaaagagt acgctcctgg cgagactgtg 5340 aagatcggct gcaacacctg tgtgtgtcgg gacagaaagt ggaactgcac agaccacgtg 5400 tgcgacgcca catgctctac catcggaatg gcccactacc tgaccttcga cggcctgaag 5460 tacctgtttc caggcgagtg ccagtatgtg ctggtgcagg actactgtgg cagcaacccc 5520 ggcaccttta gaatcctcgt gggcaacaag ggctgctctc acccctccgt gaaatgcaag 5580 aagcgggtca caatcctggt cgaaggcgga gagatcgagc tgttcgacgg cgaagtgaac 5640 gtgaagcggc ccatgaagga cgagacacac ttcgaggttg tggaatccgg ccggtacatt 5700 atcctgctgc tgggcaaagc tctgtccgtc gtgtgggata gacacctgtc catttccgtg 5760 gtgctgaagc agacctatca agagaaagtg tgcggcctgt gcggcaactt tgacggcatc 5820 cagaacaatg acctgacctc cagcaatctc caggtcgaag aggatcccgt ggatttcggc 5880 aactcctgga aagtgtccag ccagtgcgcc gacacaagaa aggtgccact ggattctagc 5940 cctgccacct gtcacaacaa tatcatgaag caaaccatgg tggactccag ctgccggatc 6000 ctgacatccg atgtgtttca ggactgcaac aagctggtgg accccgagcc ttacctggac 6060 gtgtgtatct acgatacctg ctcctgcgag tctatcggcg actgcgcctg cttttgcgac 6120 acaatcgctg cttacgccca tgtgtgcgct cagcatggaa aggtggtcac ttggagaacc 6180 gccacactgt gtccccagtc ctgcgaggaa agaaacctgc gcgagaatgg ctatgagtgc 6240 gagtggcggt acaactcttg tgcccctgcc tgtcaagtga cctgtcagca tcctgaacca 6300 ctggcttgtc ccgtgcagtg cgtggaaggc tgtcatgctc attgcccacc aggcaagatc 6360 ctggatgagc tgctgcagac ctgtgtggat ccagaggatt gtcctgtgtg cgaagtggcc 6420 ggcagaagat tcgcctccgg aaagaaagtg accctgaatc ctagcgaccc tgagcactgc 6480 cagatctgcc actgtgatgt cgtgaacctg acctgcgagg cttgtcaaga acctggcgga 6540 ctggtggtgc ctcctacaga tgctcctgtg tctcccacca cactgtacgt cgaggacatc 6600 tctgagccac ctctgcacga tttctgatag 6630 <210> 60 <211> 6630 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-120-TH1 <400> 60 gctactcgtc gttactacct gggagctgtc gagctgagct gggattacat gcagtctgac 60 ctgggagagc tgcctgtgga cgctaggttt ccacctcggg tgcctaagtc cttccccttc 120 aacaccagcg tggtgtataa gaagaccctg ttcgtggagt ttacagatca cctgttcaac 180 atcgctaagc ctagaccacc ctggatgggc ctgctgggcc caacaatcca ggccgaggtg 240 tacgacaccg tggtcatcac cctgaagaac atggcttccc accctgtgag cctgcatgct 300 gtgggcgtgt cctactggaa ggccagcgag ggcgctgagt atgacgatca gacctctcag 360 cgcgagaagg aggacgataa ggtgtttcca ggcggctccc atacctacgt gtggcaggtg 420 ctgaaggaga atggcccaat ggcttctgat cccctgtgcc tgacctactc ttatctgtcc 480 cacgtggacc tggtgaagga tctgaacagc ggcctgatcg gcgctctgct ggtgtgcagg 540 gagggctctc tggccaagga gaagacccag acactgcata agttcatcct gctgttcgcc 600 gtgtttgacg agggcaagag ctggcactct gagacaaaga attctctgat gcaggacaga 660 gatgctgctt ccgccagggc ttggccaaag atgcatacag tgaacggcta cgtgaataga 720 tccctgcctg gcctgatcgg atgccacagg aagagcgtgt attggcatgt gatcggcatg 780 ggcaccacac cagaggtgca ctctatcttc ctggagggcc atacctttct ggtgaggaat 840 caccggcagg cttctctgga gatctccccc atcaccttcc tgacagccca gaccctgctg 900 atggatctgg gccagttcct gctgttttgc cacatctcca gccaccagca tgatggcatg 960 gaggcttacg tgaaggtgga ctcctgtcct gaggagccac agctgaggat gaagaacaat 1020 gaggaggccg aggactatga cgatgacctg accgactctg agatggatgt ggtgaggttc 1080 gatgacgata actcccccag ctttatccag atccggtccg tggccaagaa gcaccctaag 1140 acatgggtgc attacatcgc cgctgaggag gaggactggg attatgctcc tctggtgctg 1200 gccccagacg atcggtccta caagagccag tatctgaaca atggccccca gagaatcggc 1260 cgcaagtaca agaaggtgag attcatggct tatacagatg agacattcaa gacacgcgag 1320 gccatccagc acgagagcgg aatcctggga cctctgctgt acggagaagt gggcgacacc 1380 ctgctgatca tctttaagaa ccaggccagc agaccctaca atatctatcc tcatggcatc 1440 acagatgtgc gcccactgta ctctaggcgg ctgcccaagg gcgtgaagca cctgaaggac 1500 ttccccatcc tgcctggcga gatctttaag tataagtgga ccgtgacagt ggaggatggc 1560 ccaaccaaga gcgaccccag atgcctgaca cgctactatt cttccttcgt gaatatggag 1620 cgggatctgg cttctggcct gatcggacca ctgctgatct gttacaagga gtctgtggat 1680 cagaggggca accagatcat gtccgacaag cggaatgtga tcctgttcag cgtgtttgac 1740 gagaacaggt cttggtatct gactgagaac atccagcggt tcctgcctaa tccagctggc 1800 gtgcagctgg aggatcctga gtttcaggcc tctaacatca tgcattccat caatggctac 1860 gtgttcgaca gcctgcagct gtccgtgtgc ctgcacgagg tggcttactg gtatatcctg 1920 tccatcggcg cccagaccga tttcctgtcc gtgttcttta gcggctacac cttcaagcat 1980 aagatggtgt atgaggacac cctgacactg ttcccatttt ccggcgagac agtgttcatg 2040 agcatggaga atcccggcct gtggatcctg ggctgccaca acagcgattt caggaatcgg 2100 ggcatgaccg ccctgctgaa ggtgagctct tgtgacaaga acacaggcga ctactatgag 2160 gatagctacg aggacatctc tgcttatctg ctgtccaaga acaatgccat cgagcccaga 2220 tctttttccc agaattctag gcatccttcc acccggcaga agcagttcaa cgctaccaca 2280 atcccagaga atgatatcga gaagaccgac ccctggtttg cccataggac acccatgcct 2340 aagtgtcaga acgtgtccag ctctgatctg ctgatgctgc tgaggcagtc tccaacccca 2400 cacggcctga gcctgtctga cctgcaggag gctaagtacg agacattcag cgacgatcct 2460 tctccaggcg ccatcgattc caacaattcc ctgagcgaga tgacccactt caggcctcag 2520 ctgcaccata gcggcgacat ggtgtttaca ccagagtctg gcctgcagct gcggctgaac 2580 gagaagctgg gcaccacagc cgctaccgag ctgaagaagc tggactttaa ggtgtccagc 2640 acctccaaca atctgatctc cacaatccct agcgataacc tggccgctgg caccgacaat 2700 acctctacac tgcagtccga tcaggaggag atcgactacg acgatacaat cagcgtggag 2760 atgaagaagg aggacttcga tatctatgac gaggatgaga accagtctcc aagatccttc 2820 cagaagaaga cccgccatta ctttatcgcc gctgtggaga ggctgtggga ttatggcatg 2880 tcttccagcc ctcacgtgct gagaaatcgc gcccagtctg gctccgtgcc acagttcaag 2940 aaggtggtgt tccaggagtt taccgacggc agctttacac agccactgta cagaggcgag 3000 ctgaacgagc acctgggcct gctgggacca tatatcaggg ctgaggtgga ggataacatc 3060 atggtgacct tcagaaatca ggccagccgc ccatactctt tttattcttc cctgatctct 3120 tacgaggagg accagaggca gggagctgag cctcggaaga acttcgtgaa gccaaatgag 3180 acaaagacat acttttggaa ggtgcagcac catatggccc ccaccaagga cgagttcgat 3240 tgcaaggcct gggcttactt ctccgacgtg gatctggaga aggacgtgca ctccggcctg 3300 attggaccac tgctggtgtg ccataccaac acactgaatc ctgctcacgg caggcaggtg 3360 accgtgcagg agttcgccct gttctttacc atctttgatg agacaaagtc ctggtacttc 3420 acagagaaca tggagaggaa ttgtcgggct ccctgcaata tccagatgga ggaccctacc 3480 ttcaaggaga actaccggtt tcatgctatc aatggctata tcatggatac actgccaggc 3540 ctggtcatgg cccaggacca gaggatccgg tggtacctgc tgagcatggg ctctaacgag 3600 aatatccact ccatccattt cagcggccac gtgtttaccg tgagaaagaa ggaggagtat 3660 aagatggccc tgtacaacct gtatccaggc gtgttcgaga cagtggagat gctgcccagc 3720 aaggctggca tctggagggt ggagtgcctg atcggagagc acctgcatgc cggcatgtct 3780 accctgtttc tggtgtactc caataagtgt cagacacctc tgggcatggc ttctggccat 3840 atcagagatt tccagatcac cgcttccgga cagtacggac agtgggctcc aaagctggct 3900 cgcctgcact atagcggctc tatcaacgcc tggtctacca aggagccatt ttcctggatc 3960 aaggtggacc tgctggctcc catgatcatc catggcatca agacacaggg cgccagacag 4020 aagttcagct ctctgtacat cagccagttt atcatcatgt attctctgga tggcaagaag 4080 tggcagacct accgcggcaa tagcaccggc acactgatgg tgttctttgg caacgtggac 4140 tccagcggca tcaagcacaa catcttcaat cctccaatca tcgctagata catccgcctg 4200 caccccaccc attattccat caggagcaca ctgcggatgg agctgatggg ctgcgatctg 4260 aactcctgta gcatgcctct gggcatggag tctaaggcca tctccgacgc tcagatcacc 4320 gcctcttcct acttcaccaa tatgtttgct acatggtccc cctccaaggc ccggctgcat 4380 ctgcagggca ggtctaacgc ctggcggcct caggtgaaca atccaaagga gtggctgcag 4440 gtggattttc agaagaccat gaaggtgaca ggcgtgacca cacagggcgt gaagagcctg 4500 ctgacctcta tgtatgtgaa ggagttcctg atcagctctt cccaggacgg ccaccagtgg 4560 acactgttct ttcagaacgg caaggtgaag gtgttccagg gcaatcagga ttcctttacc 4620 ccagtggtga acagcctgga cccccctctg ctgacaaggt acctgcggat ccacccccag 4680 tcctgggtgc atcagatcgc tctgagaatg gaggtgctgg gatgcgaggc tcaggacctg 4740 tatggaggcg gcagcctggt gccccgcggc agtggcggcg gcggcagcgg cggcggcggc 4800 tccggcggcg gtggttctgg tggtggtggt tccggtggtg gcggctccgg cggcggaggt 4860 tctggtggtg gtggatccgg tggaggcggc tccggcggcg ggggttctgg tggtggtggg 4920 tccggtgggg gcggctccgg cggcggcggt tctggtggtg gtggctccgg tggcggtggc 4980 tccggcggcg gtggatctgg tggtggtggt agcggtggcg gaggctccgg cggcggtggg 5040 tctggtggtg gtggttcagg cggcggcggc tccggaggag gaggaagcgg cggaggagga 5100 ggcagcctgt cttgcaggcc acccatggtg aagctggtgt gccctgctga taatctgcgg 5160 gccgagggcc tggagtgtac caagacatgc cagaactacg acctggagtg catgtctatg 5220 ggatgcgtgt ccggatgcct gtgccctcca ggcatggtga gacatgagaa ccgctgcgtg 5280 gctctggaga gatgcccttg ttttcaccag ggcaaggagt atgccccagg cgagacagtg 5340 aagatcggct gcaatacatg cgtgtgcagg gacaggaagt ggaactgtac cgatcacgtg 5400 tgcgacgcta cctgcagcac aatcggcatg gcccactacc tgacattcga tggcctgaag 5460 tatctgtttc caggcgagtg ccagtacgtg ctggtgcagg actattgtgg ctctaatcct 5520 ggcaccttca gaatcctggt gggcaacaag ggctgctctc acccatccgt gaagtgtaag 5580 aagcgcgtga caatcctggt ggagggcggc gagatcgagc tgtttgatgg cgaagtgaat 5640 gtgaagaggc ccatgaagga cgagacacat ttcgaggtgg tggagtccgg ccggtacatc 5700 atcctgctgc tgggcaaggc cctgagcgtg gtgtgggaca ggcacctgtc catcagcgtg 5760 gtgctgaagc agacctatca ggagaaggtg tgcggcctgt gcggcaactt tgatggcatc 5820 cagaacaatg acctgacaag ctctaatctg caggtggagg aggaccctgt ggatttcggc 5880 aactcttgga aggtgtccag ccagtgcgct gataccagga aggtgcccct ggactcttcc 5940 cctgccacct gtcacaacaa tatcatgaag cagacaatgg tggatagctc ttgccggatc 6000 ctgacatccg acgtgttcca ggactgtaac aagctggtgg accccgagcc ttacctggac 6060 gtgtgcatct atgacacctg cagctgtgag tctatcggcg attgcgcttg tttctgcgac 6120 acaatcgccg cttacgctca cgtgtgcgcc cagcatggca aggtggtgac ctggaggacc 6180 gccaccctgt gcccacagtc ctgcgaggag agaaacctgc gcgagaatgg ctacgagtgc 6240 gagtggcggt ataacagctg tgcccccgct tgccaggtga cctgtcagca cccagagccc 6300 ctggcttgcc ctgtgcagtg cgtggaggga tgccacgctc attgtccacc tggcaagatc 6360 ctggatgagc tgctgcagac ctgcgtggac cccgaggatt gtcccgtgtg cgaggtggct 6420 ggcagacgct tcgcttccgg caagaaggtg acactgaatc caagcgatcc cgagcactgt 6480 cagatctgtc attgcgacgt ggtgaacctg acctgtgagg cttgccagga gcctggaggc 6540 ctggtggtgc cacccacaga cgcccctgtc agcccaacta ccctgtatgt ggaagatatt 6600 tcagagcccc ccctgcacga tttctgataa 6630 <210> 61 <211> 6630 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-120-TH2 <400> 61 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 tacctgagta aaaacaatgc cattgaacca agagggggtg gaggttcagg aggtggaggt 4800 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 4860 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 4920 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 4980 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 5040 tcaggaggtg gaggttcagg aggtggaggt tcaggaggtg gaggttcagg aggtggaggt 5100 ggtagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 5160 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 5220 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 5280 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 5340 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 5400 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 5460 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 5520 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 5580 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 5640 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 5700 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 5760 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 5820 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 5880 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 5940 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 6000 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 6060 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 6120 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 6180 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 6240 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 6300 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 6360 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 6420 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 6480 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 6540 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 6600 tcggaaccgc cgttgcacga tttctgataa 6630 <210> 62 <211> 7170 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3-300 <400> 62 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 catcaacgca tggtccacca aggagccatt cagctggatc 3960 aaggtggacc tcctcgcacc tatgatcatc cacggcatca agacccaggg cgcaaggcag 4020 aagttctcca gcctctacat ctcccagttc atcatcatgt actccctgga cggcaagaag 4080 tggcagacct accgcggcaa ctccaccggc accctcatgg tcttcttcgg caacgtcgac 4140 tcctccggca tcaagcacaa catcttcaac cctcctatca tcgccaggta catccgtctc 4200 caccccaccc actactccat ccgaagcacc ctgcgaatgg agctcatggg ctgcgacctc 4260 aactcctgct ccatgcccct gggcatggag agcaaggcaa tctccgacgc tcagatcacc 4320 gcatcctcct acttcaccaa catgttcgct acctggagcc ctagcaaggc ccggctccac 4380 cttcagggca ggtccaacgc atggcgtcca caggtcaaca accctaagga gtggctgcag 4440 gtcgacttcc agaagactat gaaggtcacc ggcgtgacca cccagggagt caagtccctc 4500 ctcacctcca tgtacgtcaa ggagttcctc atctcctcca gccaggacgg ccaccagtgg 4560 accctcttct tccagaacgg aaaggtgaag gtgttccagg gaaaccagga ctccttcacc 4620 cccgtcgtca actccctcga ccccccactc ctgacccgtt acctgcgtat ccatccacag 4680 agctgggtcc atcagatagc cctgagaatg gaggtgctgg gatgcgaggc tcaggacctg 4740 tacctggtcc caagaggatc tggaggtgga ggcagcggcg gagggggatc aggcggaggc 4800 ggatcaggcg gcggtggctc tggaggtggc ggatctggag gaggtggttc aggaggaggt 4860 ggaagcggtg gtggaggttc aggtggagga ggttcaggag gtggtgggtc aggtgggggg 4920 ggatcaggag gtgggggaag tggtggtgga ggatctgggg gtggtggaag tggtggaggt 4980 ggtagtggtg gaggaggctc aggtggtggg ggttctggag gaggaggttc tggtggggga 5040 ggttcaggcg gaggtggaag tgggggtgga ggtagtggag gcggtggtag tggcggtggt 5100 ggcagcggag gaggggggtc tggaggaggc ggttcaggag gcggagggtc tggaggcgga 5160 ggaagtgggg ggggtggatc aggaggggga ggaagtggcg gtggagggag tggaggaggg 5220 ggaagtggag gcggcggttc tggagggggc ggatctgggg gaggaggctc tggaggcggg 5280 ggttcaggag gggggggaag cggcggcgga ggcagtggtg ggggcggcag tggcgggggc 5340 gggagtggtg gcggggggtc agggggcggg gggagtgggg gagggggctc aggcggcggg 5400 gggagcgggg gaggtggttc tgggggcggg ggctcaggtg ggggcgggag cggaggcggt 5460 gggtcaggcg gaggagggtc aggcgggggg ggcagtggcg gtggggggtc tggtggcggt 5520 gggagtgggg gcggtggtag cggcggtggt ggatcagggg ggggcggctc tggcggcggg 5580 ggctctggcg gaggtggttc cgggggcggc gggagcggcg gcggtgggtc cggcgggggc 5640 ggcagccttt cttgtcgacc acctatggta aaacttgttt gtcctgctga taatcttaga 5700 gcagaaggct tggaatgtac aaaaacttgt caaaattatg atttggaatg tatgagtatg 5760 ggctgtgtaa gtgggtgttt gtgtcctcca ggcatggttc gacatgaaaa tcgatgtgta 5820 gctcttgaaa gatgtccatg ttttcatcaa ggcaaagaat atgctcctgg cgaaactgta 5880 aaaattggct gtaatacatg tgtatgtaga gatagaaaat ggaattgtac agatcatgta 5940 tgtgatgcaa cttgttctac aattgggatg gcacattatt tgacatttga tggcttgaaa 6000 tatttgtttc caggcgaatg tcaatatgta ttggttcaag attattgtgg ctctaatcca 6060 ggcactttta ggatacttgt tggcaataaa ggctgttctc atccaagtgt taaatgtaaa 6120 aaaagggtta ctattcttgt tgaaggcggc gaaattgaac tttttgatgg cgaagttaac 6180 gttaaaaggc caatgaaaga tgaaacacat tttgaggttg ttgaaagtgg ccgctatatt 6240 attcttttgt tggggaaagc tctttctgtg gtgtgggatc ggcatctttc tatatctgtg 6300 gtgttgaaac aaacatatca agaaaaggtg tgtggcctgt gtggcaactt tgacgggatt 6360 cagaacaacg acctgaccag cagcaacctg caagtggagg aggaccctgt ggactttggc 6420 aacagctgga aggtgagctc ccagtgcgcc gacacccgca aggtgccttt ggactcttct 6480 ccagctacat gccacaataa tattatgaag cagacaatgg tggacagcag ctgccgcatt 6540 ctgacaagcg acgtgtttca ggactgcaat aagctggtgg accccgagcc ttacctggac 6600 gtctgcatat acgacacttg ctcctgcgag agcattggcg attgcgcctg cttttgcgat 6660 acaattgccg cctacgccca cgtctgcgcc cagcacggca aggtggtgac atggcgcaca 6720 gccactctgt gccctcagag ctgcgaggag cggaatctgc gggagaatgg ctacgagtgc 6780 gagtggcgct ataattcctg cgctcccgcc tgccaggtca cttgccagca ccccgagcct 6840 ctggcttgcc cagtgcagtg cgtggaaggc tgtcatgctc attgccctcc aggcaagatt 6900 ctggatgagc tgctgcagac atgcgtcgat cccgaggatt gccctgtatg cgaggtggct 6960 gggcggcggt ttgcctctgg gaaaaaggtg actctgaatc cctctgatcc cgagcactgt 7020 caaatatgcc actgcgatgt ggtgaatctg acttgcgagg cctgtcaaga gcccggcggc 7080 ctggtggtgc cccccacaga tgcccccgtg tctcccacta ctctgtatgt ggaagatatt 7140 agcgagcccc ccctgcacga tttttgataa 7170 <210> 63 <211> 8241 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3/D'D3-120 <400> 63 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 attccggaag catcaacgca tggtccacca aggagccttt ctcctggatc 3960 aaggtggacc tgcttgcacc tatgatcatc cacggaatca agacccaggg cgctcgtcaa 4020 aagttctcct ccctgtacat ctcccagttc atcatcatgt actccctgga cggaaagaag 4080 tggcagacct acaggggaaa ctccaccggc accctgatgg tcttcttcgg aaacgtggac 4140 tccagcggaa tcaagcacaa catcttcaac cctcccatca tcgcccgtta catccgtctc 4200 caccctaccc actactccat ccgttccacc cttcgtatgg agctgatggg atgcgatctc 4260 aacagctgct ccatgcccct cggaatggaa agcaaggcaa tctccgacgc tcaaatcacc 4320 gcttcctcct acttcaccaa catgttcgcc acctggtccc catcaaaggc acgacttcac 4380 ctgcaaggac gttccaacgc atggcgacct caagtaaaca accctaagga gtggctgcaa 4440 gtggacttcc agaagaccat gaaggtgacc ggagtgacca cccaaggagt aaagtccctc 4500 ctcacctcca tgtacgtcaa ggagttcctg atctcctcat cacaagacgg acatcagtgg 4560 acccttttct tccagaacgg caaggtgaag gtcttccagg gcaaccagga ctccttcacc 4620 cctgtagtca actccctcga ccctccattg ctcacccgat acttgcgaat ccatccacag 4680 tcctgggttc atcagatcgc actccgaatg gaagtcctgg gctgtgaggc acaagacctt 4740 tacctggtgc ctagaggaag cggaggcgga ggaagtggag gcggtggatc tggtggcggg 4800 ggatctggtg gtggaggtag tggtggagga ggttcaggtg gaggtggttc tggaggtggt 4860 ggttctggtg gcggaggttc aggaggtgga ggttcagggg gtggtggatc aggaggtggc 4920 ggttctggtg ggggaggatc tggaggagga ggcagtggtg gtggcggtag tggaggaggt 4980 ggtagtggtg gtgggggttc aggagggggt ggttcaggag gaggcggatc tggaggtggg 5040 gggagtggcg gaggaggtag tggcggaggg ggatcaggag gagggggatc tggcggtggt 5100 gggtcacttt cttgtcgacc tccaatggta aaacttgtat gtccagctga taatcttaga 5160 gcagaaggcc ttgaatgtac aaaaacatgt caaaattatg atcttgaatg tatgtctatg 5220 ggttgtgtat caggttgtct ttgtccacct ggaatggtac gacatgaaaa tagatgtgta 5280 gcacttgaaa gatgtccttg ttttcatcaa gggaaagaat atgctccagg ggaaactgta 5340 aaaatagggt gtaatacttg tgtatgcagg gatagaaagt ggaactgcac cgaccacgtg 5400 tgtgacgcta cctgttccac catcggcatg gctcattacc tgaccttcga cgggcttaaa 5460 tacctgttcc ccggggagtg tcaatacgtg cttgtgcaag actactgcgg ctcaaaccca 5520 gggacattca gaatcctcgt cggcaacaag gggtgttccc atccttccgt taagtgcaag 5580 aagagggtga ccatcctggt ggaaggcggg gaaatcgaac ttttcgacgg ggaagttaac 5640 gtgaagcgcc caatgaagga cgagacccat ttcgaggtgg tcgaaagcgg gagatacatc 5700 atcctgctgc tcgggaaggc tttgtccgtt gtttgggaca gacacctctc catctcagtg 5760 gtcctcaagc agacctacca ggaaaaggtg tgcggcttgt gtgggaactt cgacggcata 5820 cagaacaacg acctcacctc atcaaatctc caggtcgagg aagaccctgt cgactttggg 5880 aacagctgga aggtgagcag ccagtgcgca gataccagaa aggttccact cgacagcagc 5940 ccagcaactt gtcataacaa catcatgaag cagaccatgg tggacagcag ctgcaggatt 6000 ctgaccagcg acgtctttca ggactgcaac aagctggtcg acccagagcc atacctcgac 6060 gtttgcattt acgacacatg cagctgcgag agcattgggg actgcgcatg cttttgcgac 6120 accattgctg cttacgccca tgtgtgcgct cagcatggga aggttgttac atggaggaca 6180 gctacactgt gcccacagag ctgcgaagaa agaaacctca gggagaacgg gtacgaatgc 6240 gagtggaggt acaacagctg cgctccagca tgtcaggtaa cttgccagca cccagaacct 6300 cttgcttgcc cagttcaatg cgttgaaggg tgccatgctc attgcccacc aggcaaaatt 6360 ctggacgaac tgctccagac ttgcgtcgat ccagaagact gcccagtatg cgaggttgct 6420 ggcaggaggt ttgcaagtgg gaaaaaggtt acactcaacc caagcgaccc agaacactgc 6480 cagatatgcc actgcgacgt tgttaacctg acttgcgagg catgccagga acctggcggc 6540 cttgttgttc ctccaacaga tgctccagtt agcccaacaa cattgtatgt ggaggacatt 6600 agcgagcccc ctttgcacga ctttggcggg ggaggcagtg ggggcggggg cagtggcggg 6660 ggcggctctg gggggggcgg ctcagggggc ggtggtagtg gcggcggggg cgggagtttg 6720 tcttgtaggc ctcctatggt aaaattggtt tgtcctgctg ataatttgag ggctgaaggg 6780 ttggagtgta caaaaacttg tcagaattat gatttggaat gcatgtctat gggctgtgtt 6840 agtggctgtt tgtgtcctcc tggcatggtc cggcatgaaa atcggtgtgt ggctttggaa 6900 cggtgtccct gttttcatca gggcaaagag tatgcccctg gcgagacagt caaaattggc 6960 tgtaatacat gtgtgtgtcg ggatcggaaa tggaattgta cagatcatgt gtgtgatgcc 7020 acttgttcta ctattggcat ggcccactat ttgacttttg acggcctgaa gtatctgttt 7080 cccggcgagt gccagtatgt gctggtgcag gactattgcg gcagcaaccc tggcacattt 7140 cgcatactgg tggggaataa gggctgcagt caccctagtg tgaagtgcaa gaaacgcgtg 7200 actattctgg tggagggggg cgaaattgag ttgtttgacg gcgaggtgaa tgtgaagcgg 7260 cctatgaagg atgagactca ctttgaggtg gtggagagcg gccggtatat tatactcctg 7320 ctgggcaaag ccctgagcgt cgtgtgggat cgccacttgt ctattagcgt ggtgttgaaa 7380 cagacttatc aggagaaagt ctgcgggctg tgcggcaatt ttgatgggat tcagaataat 7440 gatctgacta gcagcaatct gcaggtggaa gaagatcccg tcgattttgg caatagttgg 7500 aaagtgtctt ctcagtgcgc cgatacacgg aaagtgcccc tggatagtag tcccgccaca 7560 tgccacaata atattatgaa acagacaatg gtggatagtt cttgccgcat tctgacttct 7620 gatgtgtttc aggattgcaa taaactggtc gatcccgagc cctatctgga tgtgtgcata 7680 tatgatactt gctcttgcga gtctattggc gattgcgcct gcttttgcga tacaattgcc 7740 gcctatgccc acgtgtgcgc ccagcacggc aaagtcgtca cttggcggac tgccactctg 7800 tgcccccagt cttgcgagga gcgcaatctc cgcgagaatg gctatgagtg cgagtggcgc 7860 tataattctt gcgcccccgc ctgccaggtg acttgtcagc accccgagcc cctggcctgt 7920 cccgtgcagt gtgtggaggg ctgtcacgcc cactgtcccc ccggcaaaat tctcgatgag 7980 ctgctgcaga catgtgtgga ccccgaggat tgtcccgtct gtgaggtggc cggccggcgc 8040 tttgcctctg gcaaaaaagt cacactgaat ccctctgatc ccgagcactg tcagatatgt 8100 cattgtgatg tcgtcaatct cacttgtgag gcctgtcagg agcccggcgg cctggtggtg 8160 cctcccacag atgcccccgt gtctcccaca actttgtatg tcgaggatat ttctgagccc 8220 cccctgcatg atttttgata a 8241 <210> 64 <211> 8853 <212> DNA <213> Artificial Sequence <220> <223> D'D3/scFVIII-120 <400> 64 gcagaaggaa cccgtgggag atcctccaca gcacgttgtt cccttttcgg ctccgacttc 60 gtcaacacct tcgacggctc catgtactcc ttcgccggat actgctcata cctgctcgca 120 ggagggtgcc agaagcgttc tttctccatc atcggagact tccagaacgg aaagcgtgtc 180 tccctgtccg tctacctggg ggaattcttc gacatccacc tcttcgtcaa cggaaccgtc 240 acccagggag accagcgtgt cagtatgcct tacgcatcca agggacttta cctggagacc 300 gaggcaggat actacaagct cagcggagag gcatacggct tcgtcgcaag aatcgacggc 360 tccggcaact tccaggtgct gctctccgac cgttacttca acaagacctg cggtctttgc 420 ggtaacttca acatcttcgc cgaggacgac ttcatgaccc aggagggcac ccttacctca 480 gacccatacg acttcgcaaa cagctgggct ctttcctccg gagagcagtg gtgtgagcga 540 gcatctcctc ctagttcttc ctgtaacatc tccagcggtg agatgcagaa gggtctgtgg 600 gagcagtgtc agctcttgaa gtcaacctcc gtcttcgcac gatgccaccc attggtcgat 660 cctgagccat tcgtagctct ttgcgagaag accctctgcg aatgcgcagg aggtcttgaa 720 tgcgcatgtc cagcattgct cgagtacgca cgaacttgcg cacaagaggg tatggtactc 780 tacggttgga ccgaccattc agcatgctcc ccagtatgcc cagcaggaat ggaataccga 840 cagtgtgtat ccccatgtgc tcgaacctgt cagtccctcc acatcaacga gatgtgccag 900 gagcgatgtg tcgacggttg ttcatgccct gagggacaac ttctcgacga gggtttgtgt 960 gtcgagagta ccgagtgtcc atgcgtacac tcaggaaagc gatacccacc aggtacctcc 1020 ctttcaagag actgcaacac ctgcatctgc aggaacagcc agtggatctg ctccaacgag 1080 gagtgccctg gtgaatgtct tgtcaccggt cagtcacact tcaaaagctt cgacaaccgc 1140 tacttcacct tctccggcat ctgccagtac ctgctcgctc gagactgcca ggatcactca 1200 ttctccatcg tgatcgagac cgtgcagtgc gctgatgaca gagacgctgt ctgtacccga 1260 tcagtaaccg tcagactgcc aggtctccat aactcccttg tcaagctcaa gcacggtgct 1320 ggtgtagcta tggacggtca ggacgtacag ctccctttgc tcaagggaga ccttagaatc 1380 cagcacaccg taaccgcttc agtgagactc agctacggtg aggaccttca gatggactgg 1440 gacggtagag gtagactgct cgtcaagctc tcaccagtat acgccggtaa gacctgcgga 1500 ctttgcggta attacaacgg gaaccagggt gacgacttcc tgaccccatc aggtcttgct 1560 gagcctagag tcgaagactt cggtaacgct tggaagctgc acggagactg ccaagacctc 1620 cagaagcagc actcagaccc atgtgctttg aaccctagaa tgaccaggtt tagcgaggag 1680 gcctgcgctg tcttgacctc cccaactttt gaggcttgcc acagagctgt aagcccattg 1740 ccatacctga gaaactgcag gtacgacgtc tgcagctgta gcgacggtag ggagtgtctt 1800 tgcggagctt tggcttccta cgctgcagca tgtgctggaa ggggagttag ggtagcttgg 1860 agggaaccag gaaggtgtga attgaactgc ccaaagggac aggtctactt gcagtgcgga 1920 actccttgca acttgacttg caggtccctg agctacccag acgaggagtg taacgaggct 1980 tgcttggagg gatgtttttg cccaccagga ttgtacatgg acgagcgggg agactgcgtt 2040 ccaaaggctc agtgtccatg ctattatgac ggcgagatct ttcagcccga ggacatcttt 2100 agcgaccacc acactatgtg ctattgcgag gacggcttta tgcactgcac aatgagcggg 2160 gtgcctggca gcctgttgcc agacgccgtt ttgagcagcc ctttgagcca taggagcaag 2220 aggagcttga gctgcaggcc tcctatggtt aagttggtgt gccctgccga taacttgagg 2280 gccgaaggat tggagtgtac aaagacttgc cagaactatg atctggagtg catgagcatg 2340 ggctgcgtga gcgggtgcct gtgccctccc ggaatggtta ggcatgaaaa ccgctgtgtt 2400 gccctggaac ggtgtccttg ttttcaccaa ggaaaggagt atgcccctgg agagacagtt 2460 aagatcgggt gcaatacttg cgtgtgccgc gatcggaagt ggaattgcac agatcacgtg 2520 tgcgatgcca catgcagcac aatcgggatg gcccactatc tgacatttga tggcctgaag 2580 tatctgtttc ccggcgagtg ccagtatgtg ctggtgcagg attattgcgg cagcaatccc 2640 gggacttttc ggatactggt gggcaataag ggctgcagtc accccagcgt gaagtgcaag 2700 aagcgcgtga caattctggt cgagggcgga gagattgagc tgtttgatgg cgaggtgaat 2760 gtcaaacggc ccatgaaaga tgagactcac tttgaggtgg tggagagtgg gcggtatata 2820 atactgcttc ttgggaaagc cctgagtgtg gtgtgggatc gccatctgtc tatatctgtg 2880 gtgctgaaac agacttatca ggagaaagtg tgcgggctgt gcgggaattt tgatggcatt 2940 cagaataatg atctgactag tagtaatctg caggtggaag aagatcccgt ggattttggc 3000 aattcttgga aagtgtcttc tcagtgtgcc gacacacgga aagtgcccct ggattcttct 3060 cccgccactt gtcataataa tataatgaaa cagactatgg tggattctag ttgtcgcatt 3120 ctgactagtg atgtgtttca ggattgtaat aaactggttg atcccgagcc ctatctggat 3180 gtgtgtattt atgatacatg tagttgtgaa agtattggcg attgtgcctg tttttgtgat 3240 acaattgccg cctatgccca tgtgtgtgcc cagcatggca aagtggtgac atggcgcaca 3300 gccacactct gtccccaaag ctgtgaagaa cgcaatctgc gggaaaatgg ctatgaatgt 3360 gaatggcgct ataattcttg tgcccccgcc tgtcaagtga catgtcaaca tcccgaaccc 3420 ctggcctgtc ctgtgcaatg tgtggaaggc tgtcatgctc attgtccccc tgggaaaatt 3480 ctcgacgaac tcctgcaaac atgtgttgat cccgaagatt gtcccgtgtg tgaagtggcc 3540 gggcgccgct ttgccagtgg caaaaaagtg actctgaatc ccagtgatcc cgaacattgt 3600 caaatttgtc attgtgatgt ggtgaatctg acatgtgaag cttgtcaaga accaggcggg 3660 ctcgtggtgc ctcccacaga tgcccccgtg tctcccacaa ctctgtatgt ggaagatatt 3720 tctgaacccc ctctgcatga ttttggaggc ggcggaagtg gcggcggagg cagcggaggc 3780 ggggggtctg ggggtggtgg atctggcggg ggcgggagtg gcggaggagg gtctggcggc 3840 gggggcagcg gcggtggtgg gagtggaggc gggggctcag ggggcggggg atcaggcggg 3900 ggcggctcag gcggaggtgg ttcagggggt ggtggcagtg gggggggcgg gtctgggggc 3960 ggaggaagtg ggggcggcgg gtctggcgga gggggatctg gaggcggtgg ctctggtgga 4020 gggggctctg gcggtggtgg ctctgggggc ggggggagtg gcggcggtgg ctcaggcggt 4080 ggtagtctcg ttcctcgggg ctctgccaca cggcggtatt atctgggcgc cgttgaactc 4140 tcttgggatt atatgcaatc tgatctcggc gaactgcctg ttgatgcccg ctttcctcct 4200 cgggttccta aatcttttcc ctttaataca tctgttgttt ataaaaaaac tctgtttgtt 4260 gaatttactg atcatctgtt taatattgcc aaaccccggc ccccctggat gggcctgctg 4320 ggccccacaa ttcaagccga agtttatgat actgttgtga ttactcttaa gaacatggct 4380 tcccatcctg tcagtcttca tgctgttggt gtatcctact ggaaagcttc tgagggagct 4440 gaatatgatg atcagaccag tcaaagggag aaagaagatg ataaagtctt ccctggtgga 4500 agccatacat atgtctggca ggtcctgaaa gagaatggtc caatggcctc tgacccactg 4560 tgccttacct actcatatct ttctcatgtg gacctggtaa aagacttgaa ttcaggcctc 4620 attggagccc tactagtatg tagagaaggg agtctggcca aggaaaagac acagaccttg 4680 cacaaattta tactactttt tgctgtattt gatgaaggga aaagttggca ctcagaaaca 4740 aagaactcct tgatgcagga tagggatgct gcatctgctc gggcctggcc taaaatgcac 4800 acagtcaatg gttatgtaaa caggtctctg ccaggtctga ttggatgcca caggaaatca 4860 gtctattggc atgtgattgg aatgggcacc actcctgaag tgcactcaat attcctcgaa 4920 ggtcacacat ttcttgtgag gaaccatcgc caggcgtcct tggaaatctc gccaataact 4980 ttccttactg ctcaaacact cttgatggac cttggacagt ttctactgtt ttgtcatatc 5040 tcttcccacc aacatgatgg catggaagct tatgtcaaag tagacagctg tccagaggaa 5100 ccccaactac gaatgaaaaa taatgaagaa gcggaagact atgatgatga tcttactgat 5160 tctgaaatgg atgtggtcag gtttgatgat gacaactctc cttcctttat ccaaattcgc 5220 tcagttgcca agaagcatcc taaaacttgg gtacattaca ttgctgctga agaggaggac 5280 tgggactatg ctcccttagt cctcgccccc gatgacagaa gttataaaag tcaatatttg 5340 aacaatggcc ctcagcggat tggtaggaag tacaaaaaag tccgatttat ggcatacaca 5400 gatgaaacct ttaagactcg tgaagctatt cagcatgaat caggaatctt gggaccttta 5460 ctttatgggg aagttggaga cacactgttg attatattta agaatcaagc aagcagacca 5520 tataacatct accctcacgg aatcactgat gtccgtcctt tgtattcaag gagattacca 5580 aaaggtgtaa aacatttgaa ggattttcca attctgccag gagaaatatt caaatataaa 5640 tggacagtga ctgtagaaga tgggccaact aaatcagatc ctcggtgcct gacccgctat 5700 tactctagtt tcgttaatat ggagagagat ctagcttcag gactcattgg ccctctcctc 5760 atctgctaca aagaatctgt agatcaaaga ggaaaccaga taatgtcaga caagaggaat 5820 gtcatcctgt tttctgtatt tgatgagaac cgaagctggt acctcacaga gaatatacaa 5880 cgctttctcc ccaatccagc tggagtgcag cttgaggatc cagagttcca agcctccaac 5940 atcatgcaca gcatcaatgg ctatgttttt gatagtttgc agttgtcagt ttgtttgcat 6000 gaggtggcat actggtacat tctaagcatt ggagcacaga ctgacttcct ttctgtcttc 6060 ttctctggat ataccttcaa acacaaaatg gtctatgaag acacactcac cctattccca 6120 ttctcaggag aaactgtctt catgtcgatg gaaaacccag gtctatggat tctggggtgc 6180 cacaactcag actttcggaa cagaggcatg accgccttac tgaaggtttc tagttgtgac 6240 aagaacactg gtgattatta cgaggacagt tatgaagata tttcagcata cttgctgagt 6300 aaaaacaatg ccattgaacc aagaagcttc tcccagaatt caagacaccc tagcactagg 6360 caaaagcaat ttaatgccac cacaattcca gaaaatgaca tagagaagac tgacccttgg 6420 tttgcacaca gaacacctat gcctaaatgt caaaatgtct cctctagtga tttgttgatg 6480 ctcttgcgac agagtcctac tccacatggg ctatccttat ctgatctcca agaagccaaa 6540 tatgagactt tttctgatga tccatcacct ggagcaatag acagtaataa cagcctgtct 6600 gaaatgacac acttcaggcc acagctccat cacagtgggg acatggtatt tacccctgag 6660 tcaggcctcc aattaagatt aaatgagaaa ctggggacaa ctgcagcaac agagttgaag 6720 aaacttgatt tcaaagtttc tagtacatca aataatctga tttcaacaat tccatcagac 6780 aatttggcag caggtactga taatacaagt actcttcagt cagatcaaga ggaaattgac 6840 tatgatgata ccatatcagt tgaaatgaag aaggaagatt ttgacattta tgatgaggat 6900 gaaaatcaga gcccccgcag ctttcaaaag aaaacacgac actattttat tgctgcagtg 6960 gagaggctct gggattatgg gatgagtagc tccccacatg ttctaagaaa cagggctcag 7020 agtggcagtg tccctcagtt caagaaagtt gttttccagg aatttactga tggctccttt 7080 actcagccct tataccgtgg agaactaaat gaacatttgg gactcctggg gccatatata 7140 agagcagaag ttgaagataa tatcatggta actttcagaa atcaggcctc tcgtccctat 7200 tccttctatt ctagccttat ttcttatgag gaagatcaga ggcaaggagc agaacctaga 7260 aaaaactttg tcaagcctaa tgaaaccaaa acttactttt ggaaagtgca acatcatatg 7320 gcacccacta aagatgagtt tgactgcaaa gcctgggctt atttctctga tgttgacctg 7380 gaaaaagatg tgcactcagg cctgattgga ccccttctgg tctgccacac taacacactg 7440 aaccctgctc atgggagaca agtgacagta caggaatttg ctctgttttt caccatcttt 7500 gatgagacca aaagctggta cttcactgaa aatatggaaa gaaactgcag ggctccctgc 7560 aatatccaga tggaagatcc cacttttaaa gagaattatc gcttccatgc aatcaatggc 7620 tacataatgg atacactacc tggcttagta atggctcagg atcaaaggat tcgatggtat 7680 ctgctcagca tgggcagcaa tgaaaacatc cattctattc atttcagtgg acatgtgttc 7740 actgtacgaa aaaaagagga gtataaaatg gcactgtaca atctctatcc aggtgttttt 7800 gagacagtgg aaatgttacc atccaaagct ggaatttggc gggtggaatg ccttattggc 7860 gagcatctac atgctgggat gagcacactt tttctggtgt acagcaataa gtgtcagact 7920 cccctgggaa tggcttctgg acacattaga gattttcaga ttacagcttc aggacaatat 7980 ggacagtggg ccccaaagct ggccagactt cattattccg gatcaatcaa tgcctggagc 8040 accaaggagc ccttttcttg gatcaaggtg gatctgttgg caccaatgat tattcacggc 8100 atcaagaccc agggtgcccg tcagaagttc tccagcctct acatctctca gtttatcatc 8160 atgtatagtc ttgatgggaa gaagtggcag acttatcgag gaaattccac tggaacctta 8220 atggtcttct ttggcaatgt ggattcatct gggataaaac acaatatttt taaccctcca 8280 attattgctc gatacatccg tttgcaccca actcattata gcattcgcag cactcttcgc 8340 atggagttga tgggctgtga tttaaatagt tgcagcatgc cattgggaat ggagagtaaa 8400 gcaatatcag atgcacagat tactgcttca tcctacttta ccaatatgtt tgccacctgg 8460 tctccttcaa aagctcgact tcacctccaa gggaggagta atgcctggag acctcaggtg 8520 aataatccaa aagagtggct gcaagtggac ttccagaaga caatgaaagt cacaggagta 8580 actactcagg gagtaaaatc tctgcttacc agcatgtatg tgaaggagtt cctcatctcc 8640 agcagtcaag atggccatca gtggactctc ttttttcaga atggcaaagt aaaggttttt 8700 cagggaaatc aagactcctt cacacctgtg gtgaactctc tagacccacc gttactgact 8760 cgctaccttc gaattcaccc ccagagttgg gtgcaccaga ttgccctgag gatggaggtt 8820 ctgggctgcg aggcacagga cctctactga taa 8853 <210> 65 <211> 3750 <212> DNA <213> Artificial Sequence <220> <223> D'D3 <400> 65 gcagaaggaa ctcgcggcag gtcatccacg gcccgatgca gccttttcgg aagtgacttc 60 gtcaacacct ttgatgggag catgtacagc tttgcgggat actgcagtta cctcctggca 120 gggggctgcc agaaacgctc cttctcgatt attggggact tccagaatgg caagagagtg 180 agcctctccg tgtatcttgg ggaatttttt gacatccatt tgtttgtcaa tggtaccgtg 240 acacaggggg accaaagagt ctccatgccc tatgcctcca aagggctgta tctagaaact 300 gaggctgggt actacaagct gtccggtgag gcctatggct ttgtggccag gatcgatggc 360 agcggcaact ttcaagtcct gctgtcagac agatacttca acaagacctg cgggctgtgt 420 ggcaacttta acatctttgc tgaagatgac tttatgaccc aagaagggac cttgacctcg 480 gacccttatg actttgccaa ctcatgggct ctgagcagtg gagaacagtg gtgtgaacgg 540 gcatctcctc ccagcagctc atgcaacatc tcctctgggg aaatgcagaa gggcctgtgg 600 gagcagtgcc agcttctgaa gagcacctcg gtgtttgccc gctgccaccc tctggtggac 660 cccgagcctt ttgtggccct gtgtgagaag actttgtgtg agtgtgctgg ggggctggag 720 tgcgcctgcc ctgccctcct ggagtacgcc cggacctgtg cccaggaggg aatggtgctg 780 tacggctgga ccgaccacag cgcgtgcagc ccagtgtgcc ctgctggtat ggagtatagg 840 cagtgtgtgt ccccttgcgc caggacctgc cagagcctgc acatcaatga aatgtgtcag 900 gagcgatgcg tggatggctg cagctgccct gagggacagc tcctggatga aggcctctgc 960 gtggagagca ccgagtgtcc ctgcgtgcat tccggaaagc gctaccctcc cggcacctcc 1020 ctctctcgag actgcaacac ctgcatttgc cgaaacagcc agtggatctg cagcaatgaa 1080 gaatgtccag gggagtgcct tgtcacaggt caatcacact tcaagagctt tgacaacaga 1140 tacttcacct tcagtgggat ctgccagtac ctgctggccc gggattgcca ggaccactcc 1200 ttctccattg tcattgagac tgtccagtgt gctgatgacc gcgacgctgt gtgcacccgc 1260 tccgtcaccg tccggctgcc tggcctgcac aacagccttg tgaaactgaa gcatggggca 1320 ggagttgcca tggatggcca ggacgtccag ctccccctcc tgaaaggtga cctccgcatc 1380 cagcatacag tgacggcctc cgtgcgcctc agctacgggg aggacctgca gatggactgg 1440 gatggccgcg ggaggctgct ggtgaagctg tcccccgtct atgccgggaa gacctgcggc 1500 ctgtgtggga attacaatgg caaccagggc gacgacttcc ttaccccctc tgggctggcg 1560 gagccccggg tggaggactt cgggaacgcc tggaagctgc acggggactg ccaggacctg 1620 cagaagcagc acagcgatcc ctgcgccctc aacccgcgca tgaccaggtt ctccgaggag 1680 gcgtgcgcgg tcctgacgtc ccccacattc gaggcctgcc atcgtgccgt cagcccgctg 1740 ccctacctgc ggaactgccg ctacgacgtg tgctcctgct cggacggccg cgagtgcctg 1800 tgcggcgccc tggccagcta tgccgcggcc tgcgcgggga gaggcgtgcg cgtcgcgtgg 1860 cgcgagccag gccgctgtga gctgaactgc ccgaaaggcc aggtgtacct gcagtgcggg 1920 accccctgca acctgacctg ccgctctctc tcttacccgg atgaggaatg caatgaggcc 1980 tgcctggagg gctgcttctg ccccccaggg ctctacatgg atgagagggg ggactgcgtg 2040 cccaaggccc agtgcccctg ttactatgac ggtgagatct tccagccaga agacatcttc 2100 tcagaccatc acaccatgtg ctactgtgag gatggcttca tgcactgtac catgagtgga 2160 gtccccggaa gcttgctgcc tgacgctgtc ctcagcagtc ccctgtctca tcgcagcaaa 2220 aggagcctat cctgtcggcc ccccatggtc aagctggtgt gtcccgctga caacctgcgg 2280 gctgaagggc tcgagtgtac caaaacgtgc cagaactatg acctggagtg catgagcatg 2340 ggctgtgtct ctggctgcct ctgccccccg ggcatggtcc ggcatgagaa cagatgtgtg 2400 gccctggaaa ggtgtccctg cttccatcag ggcaaggagt atgcccctgg agaaacagtg 2460 aagattggct gcaacacttg tgtctgtcgg gaccggaagt ggaactgcac agaccatgtg 2520 tgtgatgcca cgtgctccac gatcggcatg gcccactacc tcaccttcga cgggctcaaa 2580 tacctgttcc ccggggagtg ccagtacgtt ctggtgcagg attactgcgg cagtaaccct 2640 gggacctttc ggatcctagt ggggaataag ggatgcagcc acccctcagt gaaatgcaag 2700 aaacgggtca ccatcctggt ggagggagga gagattgagc tgtttgacgg ggaggtgaat 2760 gtgaagaggc ccatgaagga tgagactcac tttgaggtgg tggagtctgg ccggtacatc 2820 attctgctgc tgggcaaagc cctctccgtg gtctgggacc gccacctgag catctccgtg 2880 gtcctgaagc agacatacca ggagaaagtg tgtggcctgt gtgggaattt tgatggcatc 2940 cagaacaatg acctcaccag cagcaacctc caagtggagg aagaccctgt ggactttggg 3000 aactcctgga aagtgagctc gcagtgtgct gacaccagaa aagtgcctct ggactcatcc 3060 cctgccacct gccataacaa catcatgaag cagacgatgg tggattcctc ctgtagaatc 3120 cttaccagtg acgtcttcca ggactgcaac aagctggtgg accccgagcc atatctggat 3180 gtctgcattt acgacacctg ctcctgtgag tccattgggg actgcgcctg cttctgcgac 3240 accattgctg cctatgccca cgtgtgtgcc cagcatggca aggtggtgac ctggaggacg 3300 gccacattgt gcccccagag ctgcgaggag aggaatctcc gggagaacgg gtatgagtgt 3360 gagtggcgct ataacagctg tgcacctgcc tgtcaagtca cgtgtcagca ccctgagcca 3420 ctggcctgcc ctgtgcagtg tgtggagggc tgccatgccc actgccctcc agggaaaatc 3480 ctggatgagc ttttgcagac ctgcgttgac cctgaagact gtccagtgtg tgaggtggct 3540 ggccggcgtt ttgcctcagg aaagaaagtc accttgaatc ccagtgaccc tgagcactgc 3600 cagatttgcc actgtgatgt tgtcaacctc acctgtgaag cctgccagga gccgggaggc 3660 ctggtggtgc ctcccacaga tgccccggtg agccccacca ctctgtatgt ggaggacatc 3720 tcggaaccgc cgttgcacga tttctgataa 3750 <210> 66 <211> 7401 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3/Fc-120 <400> 66 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 tatcaacgca tggagcacca aggagccatt ctcctggatc 3960 aaggtggacc tcctcgctcc tatgatcatc cacggcatca agacccaggg cgctagacag 4020 aagttcagca gcctctacat ctcccagttc atcatcatgt actccctgga cggcaagaag 4080 tggcagacct accgcggaaa ctccaccgga accctcatgg tcttcttcgg aaacgtggac 4140 agctccggta tcaagcacaa catcttcaac ccccctatca tcgcacgtta catccgtctg 4200 caccctaccc actactccat caggagcacc ctcagaatgg agctgatggg ttgcgacctc 4260 aactcctgct ccatgccact cggaatggag tcaaaggcaa tctccgacgc acaaatcacc 4320 gcatcctcct acttcaccaa catgttcgcc acctggtcac caagtaaggc aaggctccac 4380 ctccaaggac gttcaaacgc atggcgtcca caagtcaaca acccaaagga gtggctccaa 4440 gtggacttcc agaagacaat gaaggtgacc ggcgtgacca cccaaggagt caagtcactg 4500 ctcacctcca tgtacgtcaa ggagttcctg atctccagct cccaagacgg ccaccaatgg 4560 acccttttct tccagaacgg caaggtgaag gtcttccagg gtaaccagga ctccttcacc 4620 ccagtcgtca actccctcga tccaccactt cttaccagat acctccgaat ccaccctcaa 4680 agctgggtcc accaaatcgc acttcgaatg gaggtcctgg gatgcgaagc acaagatctg 4740 tacctggtcc cacgtggaag tggtggtggg ggaagtggtg gaggtggtag tggaggtgga 4800 ggatctggtg gtggaggttc aggtggaggg ggaagtggag gtggtgggtc tggtggagga 4860 ggtagtggtg gcggaggttc tggaggtggg ggatcaggtg gtggaggatc aggaggaggt 4920 ggatcaggtg ggggaggatc aggcggaggt ggttctggag ggggtgggag tggaggaggc 4980 ggatcaggag gcggtggctc aggaggaggc ggctcaggag gcggaggatc tgggggaggg 5040 ggctcaggag gtgggggttc agggggcggt ggttctgggg gcggggggtc tggcggcgga 5100 ggctctcttt catgtcgacc acctatggtt aaacttgtat gtcctgcaga taatcttaga 5160 gctgaagggc ttgaatgtac aaaaacttgt caaaattatg atcttgaatg tatgtcaatg 5220 gggtgtgtta gtgggtgtct ttgtcctcct gggatggtta gacatgaaaa tcgatgtgta 5280 gctttggaaa gatgtccatg ttttcatcaa ggcaaagaat atgcaccagg cgaaacagta 5340 aaaattgggt gtaatacatg tgtatgtcga gatcgaaaat ggaattgtac tgatcatgtt 5400 tgtgatgcaa cctgtagtac catcggcatg gctcactacc ttaccttcga cgggttgaag 5460 tacctgttcc ctggggaatg ccagtacgta ctcgtccagg attactgcgg gtctaaccct 5520 gggacattta gaattctggt cggcaacaag ggctgctccc acccaagtgt caagtgcaag 5580 aagagggtca ccattctggt cgagggcggc gaaatagaac tgttcgacgg ggaagtaaac 5640 gtgaagaggc caatgaagga cgagacccac ttcgaggtgg tggaatccgg gagatacatt 5700 attctgctcc tcgggaaggc cctgagtgtc gtatgggaca ggcacctttc cattagcgtc 5760 gtcctcaagc agacctacca ggaaaaggtc tgcggccttt gtgggaactt tgacggcata 5820 cagaacaacg acctgacctc cagcaacctg caggtagagg aagacccagt agactttggg 5880 aacagctgga aggtctcctc ccagtgtgct gacaccagga aggtccctct tgactctagt 5940 ccagctacct gtcacaacaa cattatgaag cagaccatgg tggacagcag ctgccggatt 6000 ctcacttccg acgtgtttca ggactgcaac aagctggttg accctgagcc ctacctggac 6060 gtgtgtattt acgacacatg ctcctgcgag agcattggcg actgcgcttg cttttgcgac 6120 acaatagccg cctatgccca cgtgtgtgct cagcacggca aagtggtgac ttggaggaca 6180 gctacactgt gtcctcagag ttgtgaggag aggaacctgc gggaaaatgg ctatgagtgc 6240 gaatggcggt ataatagctg cgccccagct tgtcaggtga cttgtcagca cccagaacca 6300 ctggcttgtc ctgtgcagtg tgttgaaggc tgccatgctc attgcccacc aggcaaaatt 6360 ctggacgaac tgctgcagac atgcgttgat cctgaggatt gccctgtatg cgaagtggct 6420 ggccggcggt ttgcttctgg caaaaaagtt actctgaatc cctccgatcc tgagcactgc 6480 cagatatgcc attgcgatgt ggtgaatctg acttgcgagg cctgccagga acctgggggc 6540 ttggttgttc ctcctacaga tgcccctgtt agtcctacta ctctgtatgt ggaggatatt 6600 agcgagcccc ctctgcatga ttttggcggt ggggggtcag gcggaggcgg cagtggcggc 6660 gggggctctg gcggaggtgg gtccggcggt ggcggttctg gcgggggcgg ctctgacaaa 6720 actcacacat gcccaccgtg cccagcacct gaactccttg ggggaccgtc agtcttcctc 6780 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 6840 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 6900 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 6960 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 7020 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 7080 ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 7140 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 7200 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 7260 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 7320 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 7380 ctgtctccgg gtaaatgata a 7401 <210> 67 <211> 687 <212> DNA <213> Artificial Sequence <220> <223> Fc <400> 67 gacaaaactc acacatgccc accgtgccca gcacctgaac tccttggggg accgtcagtc 60 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccgggtaa atagtaa 687 <210> 68 <211> 5946 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/D'D3-HC Heavy chain <400> 68 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 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cctatcctgt 2820 cggcccccca tggtcaagct ggtgtgtccc gctgacaacc tgcgggctga agggctcgag 2880 tgtaccaaaa cgtgccagaa ctatgacctg gagtgcatga gcatgggctg tgtctctggc 2940 tgcctctgcc ccccgggcat ggtccggcat gagaacagat gtgtggccct ggaaaggtgt 3000 ccctgcttcc atcagggcaa ggagtatgcc cctggagaaa cagtgaagat tggctgcaac 3060 acttgtgtct gtcgggaccg gaagtggaac tgcacagacc atgtgtgtga tgccacgtgc 3120 tccacgatcg gcatggccca ctacctcacc ttcgacgggc tcaaatacct gttccccggg 3180 gagtgccagt acgttctggt gcaggattac tgcggcagta accctgggac ctttcggatc 3240 ctagtgggga ataagggatg cagccacccc tcagtgaaat gcaagaaacg ggtcaccatc 3300 ctggtggagg gaggagagat tgagctgttt gacggggagg tgaatgtgaa gaggcccatg 3360 aaggatgaga ctcactttga ggtggtggag tctggccggt acatcattct gctgctgggc 3420 aaagccctct ccgtggtctg ggaccgccac ctgagcatct ccgtggtcct gaagcagaca 3480 taccaggaga aagtgtgtgg cctgtgtggg aattttgatg gcatccagaa caatgacctc 3540 accagcagca acctccaagt ggaggaagac cctgtggact ttgggaactc ctggaaagtg 3600 agctcgcagt gtgctgacac cagaaaagtg cctctggact catcccctgc cacctgccat 3660 aacaacatca tgaagcagac gatggtggat tcctcctgta gaatccttac cagtgacgtc 3720 ttccaggact gcaacaagct ggtggacccc gagccatatc tggatgtctg catttacgac 3780 acctgctcct gtgagtccat tggggactgc gcctgcttct gcgacaccat tgctgcctat 3840 gcccacgtgt gtgcccagca tggcaaggtg gtgacctgga ggacggccac attgtgcccc 3900 cagagctgcg aggagaggaa tctccgggag aacgggtatg agtgtgagtg gcgctataac 3960 agctgtgcac ctgcctgtca agtcacgtgt cagcaccctg agccactggc ctgccctgtg 4020 cagtgtgtgg agggctgcca tgcccactgc cctccaggga aaatcctgga tgagcttttg 4080 cagacctgcg ttgaccctga agactgtcca gtgtgtgagg tggctggccg gcgttttgcc 4140 tcaggaaaga aagtcacctt gaatcccagt gaccctgagc actgccagat ttgccactgt 4200 gatgttgtca acctcacctg tgaagcctgc caggagccgg gaggcctggt ggtgcctccc 4260 acagatgccc cggtgagccc caccactctg tatgtggagg acatctcgga accgccgttg 4320 cacgatttcg gcggtggggg gtcaggcgga ggcggcagtg gcggcggggg ctctggcgga 4380 ggtgggtccg gcggtggcgg ttctggcggg ggcggcggca gcctatcctg tcggcccccc 4440 atggtcaagc tggtgtgtcc cgctgacaac ctgcgggctg aagggctcga gtgtaccaaa 4500 acgtgccaga actatgacct ggagtgcatg agcatgggct gtgtctctgg ctgcctctgc 4560 cccccgggca tggtccggca tgagaacaga tgtgtggccc tggaaaggtg tccctgcttc 4620 catcagggca aggagtatgc ccctggagaa acagtgaaga ttggctgcaa cacttgtgtc 4680 tgtcgggacc ggaagtggaa ctgcacagac catgtgtgtg atgccacgtg ctccacgatc 4740 ggcatggccc actacctcac cttcgacggg ctcaaatacc tgttccccgg ggagtgccag 4800 tacgttctgg tgcaggatta ctgcggcagt aaccctggga cctttcggat cctagtgggg 4860 aataagggat gcagccaccc ctcagtgaaa tgcaagaaac gggtcaccat cctggtggag 4920 ggaggagaga ttgagctgtt tgacggggag gtgaatgtga agaggcccat gaaggatgag 4980 actcactttg aggtggtgga gtctggccgg tacatcattc tgctgctggg caaagccctc 5040 tccgtggtct gggaccgcca cctgagcatc tccgtggtcc tgaagcagac ataccaggag 5100 aaagtgtgtg gcctgtgtgg gaattttgat ggcatccaga acaatgacct caccagcagc 5160 aacctccaag tggaggaaga ccctgtggac tttgggaact cctggaaagt gagctcgcag 5220 tgtgctgaca ccagaaaagt gcctctggac tcatcccctg ccacctgcca taacaacatc 5280 atgaagcaga cgatggtgga ttcctcctgt agaatcctta ccagtgacgt cttccaggac 5340 tgcaacaagc tggtggaccc cgagccatat ctggatgtct gcatttacga cacctgctcc 5400 tgtgagtcca ttggggactg cgcctgcttc tgcgacacca ttgctgccta tgcccacgtg 5460 tgtgcccagc atggcaaggt ggtgacctgg aggacggcca cattgtgccc ccagagctgc 5520 gaggagagga atctccggga gaacgggtat gagtgtgagt ggcgctataa cagctgtgca 5580 cctgcctgtc aagtcacgtg tcagcaccct gagccactgg cctgccctgt gcagtgtgtg 5640 gagggctgcc atgcccactg ccctccaggg aaaatcctgg atgagctttt gcagacctgc 5700 gttgaccctg aagactgtcc agtgtgtgag gtggctggcc ggcgttttgc ctcaggaaag 5760 aaagtcacct tgaatcccag tgaccctgag cactgccaga tttgccactg tgatgttgtc 5820 aacctcacct gtgaagcctg ccaggagccg ggaggcctgg tggtgcctcc cacagatgcc 5880 ccggtgagcc ccaccactct gtatgtggag gacatctcgg aaccgccgtt gcacgatttc 5940 tgataa 5946 <210> 69 <211> 2322 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/D'D3-HC Light chain <400> 69 gccaccgatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 60 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 120 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 180 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 240 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 300 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 360 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 420 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 480 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 540 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 600 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 660 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 720 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 780 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 840 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 900 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 960 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 1020 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 1080 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 1140 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 1200 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 1260 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 1320 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 1380 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 1440 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 1500 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 1560 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 1620 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 1680 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 1740 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 1800 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 1860 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 1920 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 1980 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 2040 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 2100 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 2160 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 2220 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 2280 atggaggttc tgggctgcga ggcacaggac ctctactgat aa 2322 <210> 70 <211> 8172 <212> DNA <213> Artificial Sequence <220> <223> scFVIII/D'D3/Fc/Fc-120 <400> 70 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 tatcaacgca tggagcacca aggagccatt ctcctggatc 3960 aaggtggacc tcctcgctcc tatgatcatc cacggcatca agacccaggg cgctagacag 4020 aagttcagca gcctctacat ctcccagttc atcatcatgt actccctgga cggcaagaag 4080 tggcagacct accgcggaaa ctccaccgga accctcatgg tcttcttcgg aaacgtggac 4140 agctccggta tcaagcacaa catcttcaac ccccctatca tcgcacgtta catccgtctg 4200 caccctaccc actactccat caggagcacc ctcagaatgg agctgatggg ttgcgacctc 4260 aactcctgct ccatgccact cggaatggag tcaaaggcaa tctccgacgc acaaatcacc 4320 gcatcctcct acttcaccaa catgttcgcc acctggtcac caagtaaggc aaggctccac 4380 ctccaaggac gttcaaacgc atggcgtcca caagtcaaca acccaaagga gtggctccaa 4440 gtggacttcc agaagacaat gaaggtgacc ggcgtgacca cccaaggagt caagtcactg 4500 ctcacctcca tgtacgtcaa ggagttcctg atctccagct cccaagacgg ccaccaatgg 4560 acccttttct tccagaacgg caaggtgaag gtcttccagg gtaaccagga ctccttcacc 4620 ccagtcgtca actccctcga tccaccactt cttaccagat acctccgaat ccaccctcaa 4680 agctgggtcc accaaatcgc acttcgaatg gaggtcctgg gatgcgaagc acaagatctg 4740 tacctggtcc cacgtggaag tggtggtggg ggaagtggtg gaggtggtag tggaggtgga 4800 ggatctggtg gtggaggttc aggtggaggg ggaagtggag gtggtgggtc tggtggagga 4860 ggtagtggtg gcggaggttc tggaggtggg ggatcaggtg gtggaggatc aggaggaggt 4920 ggatcaggtg ggggaggatc aggcggaggt ggttctggag ggggtgggag tggaggaggc 4980 ggatcaggag gcggtggctc aggaggaggc ggctcaggag gcggaggatc tgggggaggg 5040 ggctcaggag gtgggggttc agggggcggt ggttctgggg gcggggggtc tggcggcgga 5100 ggctctcttt catgtcgacc acctatggtt aaacttgtat gtcctgcaga taatcttaga 5160 gctgaagggc ttgaatgtac aaaaacttgt caaaattatg atcttgaatg tatgtcaatg 5220 gggtgtgtta gtgggtgtct ttgtcctcct gggatggtta gacatgaaaa tcgatgtgta 5280 gctttggaaa gatgtccatg ttttcatcaa ggcaaagaat atgcaccagg cgaaacagta 5340 aaaattgggt gtaatacatg tgtatgtcga gatcgaaaat ggaattgtac tgatcatgtt 5400 tgtgatgcaa cctgtagtac catcggcatg gctcactacc ttaccttcga cgggttgaag 5460 tacctgttcc ctggggaatg ccagtacgta ctcgtccagg attactgcgg gtctaaccct 5520 gggacattta gaattctggt cggcaacaag ggctgctccc acccaagtgt caagtgcaag 5580 aagagggtca ccattctggt cgagggcggc gaaatagaac tgttcgacgg ggaagtaaac 5640 gtgaagaggc caatgaagga cgagacccac ttcgaggtgg tggaatccgg gagatacatt 5700 attctgctcc tcgggaaggc cctgagtgtc gtatgggaca ggcacctttc cattagcgtc 5760 gtcctcaagc agacctacca ggaaaaggtc tgcggccttt gtgggaactt tgacggcata 5820 cagaacaacg acctgacctc cagcaacctg caggtagagg aagacccagt agactttggg 5880 aacagctgga aggtctcctc ccagtgtgct gacaccagga aggtccctct tgactctagt 5940 ccagctacct gtcacaacaa cattatgaag cagaccatgg tggacagcag ctgccggatt 6000 ctcacttccg acgtgtttca ggactgcaac aagctggttg accctgagcc ctacctggac 6060 gtgtgtattt acgacacatg ctcctgcgag agcattggcg actgcgcttg cttttgcgac 6120 acaatagccg cctatgccca cgtgtgtgct cagcacggca aagtggtgac ttggaggaca 6180 gctacactgt gtcctcagag ttgtgaggag aggaacctgc gggaaaatgg ctatgagtgc 6240 gaatggcggt ataatagctg cgccccagct tgtcaggtga cttgtcagca cccagaacca 6300 ctggcttgtc ctgtgcagtg tgttgaaggc tgccatgctc attgcccacc aggcaaaatt 6360 ctggacgaac tgctgcagac atgcgttgat cctgaggatt gccctgtatg cgaagtggct 6420 ggccggcggt ttgcttctgg caaaaaagtt actctgaatc cctccgatcc tgagcactgc 6480 cagatatgcc attgcgatgt ggtgaatctg acttgcgagg cctgccagga acctgggggc 6540 ttggttgttc ctcctacaga tgcccctgtt agtcctacta ctctgtatgt ggaggatatt 6600 agcgagcccc ctctgcatga ttttggcggt ggggggtcag gcggaggcgg cagtggcggc 6660 gggggctctg gcggaggtgg gtccggcggt ggcggttctg gcgggggcgg ctctgacaaa 6720 actcacacat gcccaccgtg cccagcacct gaactccttg ggggaccgtc agtcttcctc 6780 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 6840 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 6900 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 6960 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 7020 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 7080 ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 7140 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 7200 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 7260 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 7320 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 7380 ctgtctccgg gtaaaggcgg tggggggtca ggcggaggcg gcagtggcgg cgggggctct 7440 ggcggaggtg ggtccggcgg tggcggttct ggcgggggcg gctctgacaa aactcacaca 7500 tgcccaccgt gcccagcacc tgaactcctt gggggaccgt cagtcttcct cttcccccca 7560 aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 7620 gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 7680 aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 7740 ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 7800 aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 7860 ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 7920 acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 7980 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 8040 ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 8100 tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 8160 ggtaaatgat aa 8172 <210> 71 <211> 5106 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC/Fc-LC Heavy chain <400> 71 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 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cctatcctgt 2820 cggcccccca tggtcaagct ggtgtgtccc gctgacaacc tgcgggctga agggctcgag 2880 tgtaccaaaa cgtgccagaa ctatgacctg gagtgcatga gcatgggctg tgtctctggc 2940 tgcctctgcc ccccgggcat ggtccggcat gagaacagat gtgtggccct ggaaaggtgt 3000 ccctgcttcc atcagggcaa ggagtatgcc cctggagaaa cagtgaagat tggctgcaac 3060 acttgtgtct gtcgggaccg gaagtggaac tgcacagacc atgtgtgtga tgccacgtgc 3120 tccacgatcg gcatggccca ctacctcacc ttcgacgggc tcaaatacct gttccccggg 3180 gagtgccagt acgttctggt gcaggattac tgcggcagta accctgggac ctttcggatc 3240 ctagtgggga ataagggatg cagccacccc tcagtgaaat gcaagaaacg ggtcaccatc 3300 ctggtggagg gaggagagat tgagctgttt gacggggagg tgaatgtgaa gaggcccatg 3360 aaggatgaga ctcactttga ggtggtggag tctggccggt acatcattct gctgctgggc 3420 aaagccctct ccgtggtctg ggaccgccac ctgagcatct ccgtggtcct gaagcagaca 3480 taccaggaga aagtgtgtgg cctgtgtggg aattttgatg gcatccagaa caatgacctc 3540 accagcagca acctccaagt ggaggaagac cctgtggact ttgggaactc ctggaaagtg 3600 agctcgcagt gtgctgacac cagaaaagtg cctctggact catcccctgc cacctgccat 3660 aacaacatca tgaagcagac gatggtggat tcctcctgta gaatccttac cagtgacgtc 3720 ttccaggact gcaacaagct ggtggacccc gagccatatc tggatgtctg catttacgac 3780 acctgctcct gtgagtccat tggggactgc gcctgcttct gcgacaccat tgctgcctat 3840 gcccacgtgt gtgcccagca tggcaaggtg gtgacctgga ggacggccac attgtgcccc 3900 cagagctgcg aggagaggaa tctccgggag aacgggtatg agtgtgagtg gcgctataac 3960 agctgtgcac ctgcctgtca agtcacgtgt cagcaccctg agccactggc ctgccctgtg 4020 cagtgtgtgg agggctgcca tgcccactgc cctccaggga aaatcctgga tgagcttttg 4080 cagacctgcg ttgaccctga agactgtcca gtgtgtgagg tggctggccg gcgttttgcc 4140 tcaggaaaga aagtcacctt gaatcccagt gaccctgagc actgccagat ttgccactgt 4200 gatgttgtca acctcacctg tgaagcctgc caggagccgg gaggcctggt ggtgcctccc 4260 acagatgccc cggtgagccc caccactctg tatgtggagg acatctcgga accgccgttg 4320 cacgatttcg gcggtggggg gtcaggcgga ggcggcagtg gcggcggggg ctctggcgga 4380 ggtgggtccg gcggtggcgg ttctggcggg ggcggctctg acaaaactca cacatgccca 4440 ccgtgcccag cacctgaact ccttggggga ccgtcagtct tcctcttccc cccaaaaccc 4500 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 4560 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 4620 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 4680 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 4740 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 4800 gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 4860 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 4920 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 4980 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 5040 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 5100 tgataa 5106 <210> 72 <211> 3093 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC/Fc-LC light chain <400> 72 gccaccgatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 60 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 120 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 180 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 240 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 300 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 360 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 420 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 480 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 540 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 600 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 660 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 720 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 780 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 840 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 900 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 960 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 1020 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 1080 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 1140 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 1200 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 1260 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 1320 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 1380 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 1440 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 1500 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 1560 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 1620 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 1680 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 1740 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 1800 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 1860 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 1920 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 1980 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 2040 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 2100 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 2160 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 2220 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 2280 atggaggttc tgggctgcga ggcacaggac ctctacctgg tcccacgtgg aagtggcggt 2340 ggggggtcag gcggaggcgg cagtggcggc gggggctctg gcggaggtgg cagtggcggg 2400 ggctctgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct tgggggaccg 2460 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 2520 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 2580 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 2640 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 2700 tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 2760 gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 2820 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 2880 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 2940 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 3000 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 3060 aagagcctct ccctgtctcc gggtaaatga taa 3093 <210> 73 <211> 5106 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC, Fc Heavy chain <400> 73 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 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cctatcctgt 2820 cggcccccca tggtcaagct ggtgtgtccc gctgacaacc tgcgggctga agggctcgag 2880 tgtaccaaaa cgtgccagaa ctatgacctg gagtgcatga gcatgggctg tgtctctggc 2940 tgcctctgcc ccccgggcat ggtccggcat gagaacagat gtgtggccct ggaaaggtgt 3000 ccctgcttcc atcagggcaa ggagtatgcc cctggagaaa cagtgaagat tggctgcaac 3060 acttgtgtct gtcgggaccg gaagtggaac tgcacagacc atgtgtgtga tgccacgtgc 3120 tccacgatcg gcatggccca ctacctcacc ttcgacgggc tcaaatacct gttccccggg 3180 gagtgccagt acgttctggt gcaggattac tgcggcagta accctgggac ctttcggatc 3240 ctagtgggga ataagggatg cagccacccc tcagtgaaat gcaagaaacg ggtcaccatc 3300 ctggtggagg gaggagagat tgagctgttt gacggggagg tgaatgtgaa gaggcccatg 3360 aaggatgaga ctcactttga ggtggtggag tctggccggt acatcattct gctgctgggc 3420 aaagccctct ccgtggtctg ggaccgccac ctgagcatct ccgtggtcct gaagcagaca 3480 taccaggaga aagtgtgtgg cctgtgtggg aattttgatg gcatccagaa caatgacctc 3540 accagcagca acctccaagt ggaggaagac cctgtggact ttgggaactc ctggaaagtg 3600 agctcgcagt gtgctgacac cagaaaagtg cctctggact catcccctgc cacctgccat 3660 aacaacatca tgaagcagac gatggtggat tcctcctgta gaatccttac cagtgacgtc 3720 ttccaggact gcaacaagct ggtggacccc gagccatatc tggatgtctg catttacgac 3780 acctgctcct gtgagtccat tggggactgc gcctgcttct gcgacaccat tgctgcctat 3840 gcccacgtgt gtgcccagca tggcaaggtg gtgacctgga ggacggccac attgtgcccc 3900 cagagctgcg aggagaggaa tctccgggag aacgggtatg agtgtgagtg gcgctataac 3960 agctgtgcac ctgcctgtca agtcacgtgt cagcaccctg agccactggc ctgccctgtg 4020 cagtgtgtgg agggctgcca tgcccactgc cctccaggga aaatcctgga tgagcttttg 4080 cagacctgcg ttgaccctga agactgtcca gtgtgtgagg tggctggccg gcgttttgcc 4140 tcaggaaaga aagtcacctt gaatcccagt gaccctgagc actgccagat ttgccactgt 4200 gatgttgtca acctcacctg tgaagcctgc caggagccgg gaggcctggt ggtgcctccc 4260 acagatgccc cggtgagccc caccactctg tatgtggagg acatctcgga accgccgttg 4320 cacgatttcg gcggtggggg gtcaggcgga ggcggcagtg gcggcggggg ctctggcgga 4380 ggtgggtccg gcggtggcgg ttctggcggg ggcggctctg acaaaactca cacatgccca 4440 ccgtgcccag cacctgaact ccttggggga ccgtcagtct tcctcttccc cccaaaaccc 4500 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 4560 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 4620 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 4680 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 4740 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 4800 gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 4860 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 4920 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 4980 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 5040 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 5100 tgataa 5106 <210> 74 <211> 2322 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc-HC, Fc Light chain <400> 74 gccaccgatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 60 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 120 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 180 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 240 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 300 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 360 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 420 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 480 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 540 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 600 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 660 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 720 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 780 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 840 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 900 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 960 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 1020 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 1080 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 1140 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 1200 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 1260 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 1320 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 1380 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 1440 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 1500 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 1560 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 1620 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 1680 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 1740 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 1800 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 1860 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 1920 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 1980 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 2040 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 2100 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 2160 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 2220 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 2280 atggaggttc tgggctgcga ggcacaggac ctctactgat aa 2322 <210> 75 <211> 5877 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc/Fc-HC Heavy chain <400> 75 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 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cctatcctgt 2820 cggcccccca tggtcaagct ggtgtgtccc gctgacaacc tgcgggctga agggctcgag 2880 tgtaccaaaa cgtgccagaa ctatgacctg gagtgcatga gcatgggctg tgtctctggc 2940 tgcctctgcc ccccgggcat ggtccggcat gagaacagat gtgtggccct ggaaaggtgt 3000 ccctgcttcc atcagggcaa ggagtatgcc cctggagaaa cagtgaagat tggctgcaac 3060 acttgtgtct gtcgggaccg gaagtggaac tgcacagacc atgtgtgtga tgccacgtgc 3120 tccacgatcg gcatggccca ctacctcacc ttcgacgggc tcaaatacct gttccccggg 3180 gagtgccagt acgttctggt gcaggattac tgcggcagta accctgggac ctttcggatc 3240 ctagtgggga ataagggatg cagccacccc tcagtgaaat gcaagaaacg ggtcaccatc 3300 ctggtggagg gaggagagat tgagctgttt gacggggagg tgaatgtgaa gaggcccatg 3360 aaggatgaga ctcactttga ggtggtggag tctggccggt acatcattct gctgctgggc 3420 aaagccctct ccgtggtctg ggaccgccac ctgagcatct ccgtggtcct gaagcagaca 3480 taccaggaga aagtgtgtgg cctgtgtggg aattttgatg gcatccagaa caatgacctc 3540 accagcagca acctccaagt ggaggaagac cctgtggact ttgggaactc ctggaaagtg 3600 agctcgcagt gtgctgacac cagaaaagtg cctctggact catcccctgc cacctgccat 3660 aacaacatca tgaagcagac gatggtggat tcctcctgta gaatccttac cagtgacgtc 3720 ttccaggact gcaacaagct ggtggacccc gagccatatc tggatgtctg catttacgac 3780 acctgctcct gtgagtccat tggggactgc gcctgcttct gcgacaccat tgctgcctat 3840 gcccacgtgt gtgcccagca tggcaaggtg gtgacctgga ggacggccac attgtgcccc 3900 cagagctgcg aggagaggaa tctccgggag aacgggtatg agtgtgagtg gcgctataac 3960 agctgtgcac ctgcctgtca agtcacgtgt cagcaccctg agccactggc ctgccctgtg 4020 cagtgtgtgg agggctgcca tgcccactgc cctccaggga aaatcctgga tgagcttttg 4080 cagacctgcg ttgaccctga agactgtcca gtgtgtgagg tggctggccg gcgttttgcc 4140 tcaggaaaga aagtcacctt gaatcccagt gaccctgagc actgccagat ttgccactgt 4200 gatgttgtca acctcacctg tgaagcctgc caggagccgg gaggcctggt ggtgcctccc 4260 acagatgccc cggtgagccc caccactctg tatgtggagg acatctcgga accgccgttg 4320 cacgatttcg gcggtggggg gtcaggcgga ggcggcagtg gcggcggggg ctctggcgga 4380 ggtgggtccg gcggtggcgg ttctggcggg ggcggctctg acaaaactca cacatgccca 4440 ccgtgcccag cacctgaact ccttggggga ccgtcagtct tcctcttccc cccaaaaccc 4500 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 4560 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 4620 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 4680 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 4740 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 4800 gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 4860 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 4920 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 4980 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 5040 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 5100 ggcggtgggg ggtcaggcgg aggcggcagt ggcggcgggg gctctggcgg aggtgggtcc 5160 ggcggtggcg gttctggcgg gggcggctct gacaaaactc acacatgccc accgtgccca 5220 gcacctgaac tccttggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 5280 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 5340 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 5400 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 5460 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 5520 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 5580 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 5640 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 5700 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 5760 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 5820 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atgataa 5877 <210> 76 <211> 2322 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3/Fc/Fc-HC Light chain <400> 76 gccaccgatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 60 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 120 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 180 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 240 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 300 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 360 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 420 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 480 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 540 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 600 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 660 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 720 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 780 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 840 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 900 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 960 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 1020 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 1080 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 1140 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 1200 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 1260 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 1320 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 1380 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 1440 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 1500 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 1560 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 1620 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 1680 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 1740 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 1800 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 1860 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 1920 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 1980 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 2040 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 2100 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 2160 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 2220 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 2280 atggaggttc tgggctgcga ggcacaggac ctctactgat aa 2322 <210> 77 <211> 4335 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc-LC Heavy chain <400> 77 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 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cctatcctgt 2820 cggcccccca tggtcaagct ggtgtgtccc gctgacaacc tgcgggctga agggctcgag 2880 tgtaccaaaa cgtgccagaa ctatgacctg gagtgcatga gcatgggctg tgtctctggc 2940 tgcctctgcc ccccgggcat ggtccggcat gagaacagat gtgtggccct ggaaaggtgt 3000 ccctgcttcc atcagggcaa ggagtatgcc cctggagaaa cagtgaagat tggctgcaac 3060 acttgtgtct gtcgggaccg gaagtggaac tgcacagacc atgtgtgtga tgccacgtgc 3120 tccacgatcg gcatggccca ctacctcacc ttcgacgggc tcaaatacct gttccccggg 3180 gagtgccagt acgttctggt gcaggattac tgcggcagta accctgggac ctttcggatc 3240 ctagtgggga ataagggatg cagccacccc tcagtgaaat gcaagaaacg ggtcaccatc 3300 ctggtggagg gaggagagat tgagctgttt gacggggagg tgaatgtgaa gaggcccatg 3360 aaggatgaga ctcactttga ggtggtggag tctggccggt acatcattct gctgctgggc 3420 aaagccctct ccgtggtctg ggaccgccac ctgagcatct ccgtggtcct gaagcagaca 3480 taccaggaga aagtgtgtgg cctgtgtggg aattttgatg gcatccagaa caatgacctc 3540 accagcagca acctccaagt ggaggaagac cctgtggact ttgggaactc ctggaaagtg 3600 agctcgcagt gtgctgacac cagaaaagtg cctctggact catcccctgc cacctgccat 3660 aacaacatca tgaagcagac gatggtggat tcctcctgta gaatccttac cagtgacgtc 3720 ttccaggact gcaacaagct ggtggacccc gagccatatc tggatgtctg catttacgac 3780 acctgctcct gtgagtccat tggggactgc gcctgcttct gcgacaccat tgctgcctat 3840 gcccacgtgt gtgcccagca tggcaaggtg gtgacctgga ggacggccac attgtgcccc 3900 cagagctgcg aggagaggaa tctccgggag aacgggtatg agtgtgagtg gcgctataac 3960 agctgtgcac ctgcctgtca agtcacgtgt cagcaccctg agccactggc ctgccctgtg 4020 cagtgtgtgg agggctgcca tgcccactgc cctccaggga aaatcctgga tgagcttttg 4080 cagacctgcg ttgaccctga agactgtcca gtgtgtgagg tggctggccg gcgttttgcc 4140 tcaggaaaga aagtcacctt gaatcccagt gaccctgagc actgccagat ttgccactgt 4200 gatgttgtca acctcacctg tgaagcctgc caggagccgg gaggcctggt ggtgcctccc 4260 acagatgccc cggtgagccc caccactctg tatgtggagg acatctcgga accgccgttg 4320 cacgatttct gataa 4335 <210> 78 <211> 3093 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc-LC Light chain <400> 78 gccaccgatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 60 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 120 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 180 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 240 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 300 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 360 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 420 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 480 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 540 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 600 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 660 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 720 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 780 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 840 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 900 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 960 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 1020 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 1080 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 1140 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 1200 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 1260 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 1320 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 1380 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 1440 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 1500 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 1560 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 1620 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 1680 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 1740 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 1800 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 1860 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 1920 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 1980 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 2040 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 2100 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 2160 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 2220 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 2280 atggaggttc tgggctgcga ggcacaggac ctctacctgg tcccacgtgg aagtggcggt 2340 ggggggtcag gcggaggcgg cagtggcggc gggggctctg gcggaggtgg cagtggcggg 2400 ggctctgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct tgggggaccg 2460 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 2520 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 2580 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 2640 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 2700 tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 2760 gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 2820 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 2880 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 2940 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 3000 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 3060 aagagcctct ccctgtctcc gggtaaatga taa 3093 <210> 79 <211> 4335 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc/Fc-LC Heavy chain <400> 79 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 acaagttcct taggaccccc aagtatgcca gttcattatg atagtcaatt agataccact 2760 ctatttggca aaaagtcatc tccccttact gagtctggtg gacctctgag cctatcctgt 2820 cggcccccca tggtcaagct ggtgtgtccc gctgacaacc tgcgggctga agggctcgag 2880 tgtaccaaaa cgtgccagaa ctatgacctg gagtgcatga gcatgggctg tgtctctggc 2940 tgcctctgcc ccccgggcat ggtccggcat gagaacagat gtgtggccct ggaaaggtgt 3000 ccctgcttcc atcagggcaa ggagtatgcc cctggagaaa cagtgaagat tggctgcaac 3060 acttgtgtct gtcgggaccg gaagtggaac tgcacagacc atgtgtgtga tgccacgtgc 3120 tccacgatcg gcatggccca ctacctcacc ttcgacgggc tcaaatacct gttccccggg 3180 gagtgccagt acgttctggt gcaggattac tgcggcagta accctgggac ctttcggatc 3240 ctagtgggga ataagggatg cagccacccc tcagtgaaat gcaagaaacg ggtcaccatc 3300 ctggtggagg gaggagagat tgagctgttt gacggggagg tgaatgtgaa gaggcccatg 3360 aaggatgaga ctcactttga ggtggtggag tctggccggt acatcattct gctgctgggc 3420 aaagccctct ccgtggtctg ggaccgccac ctgagcatct ccgtggtcct gaagcagaca 3480 taccaggaga aagtgtgtgg cctgtgtggg aattttgatg gcatccagaa caatgacctc 3540 accagcagca acctccaagt ggaggaagac cctgtggact ttgggaactc ctggaaagtg 3600 agctcgcagt gtgctgacac cagaaaagtg cctctggact catcccctgc cacctgccat 3660 aacaacatca tgaagcagac gatggtggat tcctcctgta gaatccttac cagtgacgtc 3720 ttccaggact gcaacaagct ggtggacccc gagccatatc tggatgtctg catttacgac 3780 acctgctcct gtgagtccat tggggactgc gcctgcttct gcgacaccat tgctgcctat 3840 gcccacgtgt gtgcccagca tggcaaggtg gtgacctgga ggacggccac attgtgcccc 3900 cagagctgcg aggagaggaa tctccgggag aacgggtatg agtgtgagtg gcgctataac 3960 agctgtgcac ctgcctgtca agtcacgtgt cagcaccctg agccactggc ctgccctgtg 4020 cagtgtgtgg agggctgcca tgcccactgc cctccaggga aaatcctgga tgagcttttg 4080 cagacctgcg ttgaccctga agactgtcca gtgtgtgagg tggctggccg gcgttttgcc 4140 tcaggaaaga aagtcacctt gaatcccagt gaccctgagc actgccagat ttgccactgt 4200 gatgttgtca acctcacctg tgaagcctgc caggagccgg gaggcctggt ggtgcctccc 4260 acagatgccc cggtgagccc caccactctg tatgtggagg acatctcgga accgccgttg 4320 cacgatttct gataa 4335 <210> 80 <211> 3864 <212> DNA <213> Artificial Sequence <220> <223> dcFVIII/D'D3-HC/Fc/Fc-LC Light chain <400> 80 gccaccgatc ctcttgcttg ggataaccac tatggtactc agataccaaa agaagagtgg 60 aaatcccaag agaagtcacc agaaaaaaca gcttttaaga aaaaggatac cattttgtcc 120 ctgaacgctt gtgaaagcaa tcatgcaata gcagcaataa atgagggaca aaataagccc 180 gaaatagaag tcacctgggc aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca 240 ccagtcttga aacgccatca acgggaaata actcgtacta ctcttcagtc agatcaagag 300 gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 360 gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 420 gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 480 agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 540 ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 600 ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 660 cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 720 gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 780 catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 840 gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 900 aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 960 accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 1020 gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 1080 atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 1140 cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 1200 catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 1260 ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 1320 cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 1380 tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 1440 ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 1500 gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 1560 attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 1620 tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 1680 ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 1740 aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 1800 actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 1860 gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 1920 gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 1980 cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 2040 acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 2100 ctcatctcca gcagtcaaga tggccatcag tggactctct tttttcagaa tggcaaagta 2160 aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 2220 ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 2280 atggaggttc tgggctgcga ggcacaggac ctctacctgg tcccacgtgg aagtggcggt 2340 ggggggtcag gcggaggcgg cagtggcggc gggggctctg gcggaggtgg cagtggcggg 2400 ggctctgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct tgggggaccg 2460 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 2520 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 2580 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 2640 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 2700 tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 2760 gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 2820 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 2880 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 2940 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 3000 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 3060 aagagcctct ccctgtctcc gggtaaaggc ggtggggggt caggcggagg cggcagtggc 3120 ggcgggggct ctggcggagg tgggtccggc ggtggcggtt ctggcggggg cggctctgac 3180 aaaactcaca catgcccacc gtgcccagca cctgaactcc ttgggggacc gtcagtcttc 3240 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 3300 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 3360 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 3420 gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 3480 aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 3540 cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 3600 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 3660 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 3720 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 3780 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 3840 tccctgtctc cgggtaaatg ataa 3864

Claims

인간 혈액응고 8인자(Factor VIII, FVIII),
하나 이상의 vWF D’D3 도메인, 및
상기 FVIII 및 상기 vWF D’D3 도메인을 연결하는 링커를 포함하는 키메라 단백질로,
상기 FVIII는 서열번호 1의 아미노산 서열에서 B 도메인의 일부가 결실되고, 782번 위치의 아미노산 잔기가 시스테인으로 치환된 것이며,
상기 링커는 효소절단부위를 포함하고,
상기 키메라 단백질은 vWF를 구성하는 도메인 중 D1, D2, A1, A2, A3, D4, C1, C2, C3, C4, C5, C6 및 CK 중 어느 도메인도 포함하지 않는 것인, 키메라 단백질.
제1항에 있어서,
상기 FVIII는 서열번호 1의 아미노산 서열에서 1648번 및 1649번 위치의 아미노산 잔기를 기준으로 상기 잔기를 포함하여 N-말단, C-말단, 또는 N-말단 및 C-말단 방향으로 각각 최소 5개의 아미노산 잔기가 결실된 것인, 키메라 단백질.
제2항에 있어서,
상기 FVIII는 서열번호 1의 아미노산 서열에서 903번 내지 1653번 위치의 아미노산 잔기가 결실된 것인, 키메라 단백질.
제1항에 있어서,
상기 FVIII는 추가적으로 서열번호 1의 아미노산 서열에서 491, 495, 498, 754, 781, 788, 789, 825, 897 및 1806 위치의 아미노산 잔기로 구성된 군으로부터 선택되는 하나 이상의 아미노산 잔기가 시스테인으로 치환된 것인, 키메라 단백질.
제1항에 있어서,
상기 시스테인에 친수성 폴리머가 연결된 것인, 키메라 단백질.
제5항에 있어서,
상기 친수성 폴리머는 폴리에틸렌글리콜(Polyethylene glycol), 폴리에틸렌 옥사이드 또는 덱스트란인 것인, 키메라 단백질.
제6항에 있어서,
상기 친수성 폴리머는 폴리에텔렌글리콜이고,
상기 폴리에틸렌글리콜의 평균 분자량은 20kDa 이상인 것인, 키메라 단백질.
제7항에 있어서,
상기 폴리에틸렌글리콜의 평균 분자량은 40kDa 또는 60kDa인 것인, 키메라 단백질.
제1항에 있어서,
상기 효소절단부위는 트롬빈, FVIIa, FXa 또는 FXIa에 의해 절단될 수 있는 아미노산 서열이고,
상기 링커에서 효소절단부위를 제외한 아미노산 서열은 [G₄S]_n의 아미노산 서열로 표시되고,
상기 식에서 n = 0 내지 100 사이 정수인, 키메라 단백질.
제9항에 있어서,
상기 트롬빈에 의해 절단될 수 있는 아미노산 서열은 DFLAEGGGVR (서열번호 36), TTKIKPR (서열번호 37), 또는 LVPRGS (서열번호 38)이고;
상기 FVIIa에 의해 절단될 수 있는 아미노산 서열은 ASKPQGRIVGG (서열번호 39)이며;
상기 FXa에 의해 절단될 수 있는 서열은 IDGR (서열번호 40) 또는 IEGR (서열번호 41)이고; 또는
상기 FXIa에 의해 절단될 수 있는 서열은 SKLTRAETVF (서열번호 42)인, 키메라 단백질.
제1항에 있어서,
상기 키메라 단백질은 단쇄(single chain) 또는 이쇄(double chain)인 것인, 키메라 단백질.
제11항에 있어서,
상기 이쇄인 키메라 단백질은 제1 폴리펩타이드 및 제2 폴리펩타이드로 구성된 FVIII를 포함하는 것으로서;
상기 제1 폴리펩타이드는 A1 도메인, A2 도메인 및 B 도메인 단편을 포함하며,
상기 제2 폴리펩타이드는 A3 도메인, C1 도메인, C2 도메인 및 B 도메인 단편을 포함하는 것인, 키메라 단백질.
제11항에 있어서,
상기 단쇄인 키메라 단백질은 서열번호 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21 또는 25의 아미노산 서열 또는 이와 90% 이상 상동성이 있는 아미노산 서열로 구성되는 것인, 키메라 단백질.
제12항에 있어서,
상기 이쇄인 키메라 단백질은 서열번호 4 및 5, 서열번호 23 및 24, 서열번호 26 및 27, 서열번호 28 및 29, 서열번호 30 및 31, 서열번호 32 및 33, 또는 서열번호 34 및 35의 아미노산 서열 또는 이와 90% 이상 상동성이 있는 아미노산 서열로 구성되는 것인, 키메라 단백질.
제13항에 기재된 키메라 단백질을 코딩하는 핵산분자.
제14항에 기재된 키메라 단백질을 코딩하는 핵산분자.
제15항에 있어서,
상기 핵산분자는 서열번호 48 내지 64, 66, 또는 70의 염기 서열로 구성되되는 것인, 핵산분자.
제16항에 있어서,
상기 핵산분자는 서열번호 46, 47, 68, 69, 또는 71 내지 80의 염기 서열로 구성되는 것인, 핵산분자.
제15항 내지 제18항 중 어느 한 항에 기재된 핵산분자를 포함하는 벡터.
제19항에 기재된 벡터를 포함하는 세포.
제1항 내지 제14항 중 어느 한 항에 기재된 키메라 단백질, 제15항 내지 제 18항 중 어느 한 항에 기재된 핵산분자, 제19항에 기재된 벡터, 또는 제20항에 기재된 세포 및 약학적으로 허용 가능한 담체를 포함하는 A형 혈우병 치료용 약학적 조성물.
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