KR101030612B1 - 폴리펩타이드의 재조합 발현 방법 - Google Patents
폴리펩타이드의 재조합 발현 방법 Download PDFInfo
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- KR101030612B1 KR101030612B1 KR1020087009355A KR20087009355A KR101030612B1 KR 101030612 B1 KR101030612 B1 KR 101030612B1 KR 1020087009355 A KR1020087009355 A KR 1020087009355A KR 20087009355 A KR20087009355 A KR 20087009355A KR 101030612 B1 KR101030612 B1 KR 101030612B1
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Abstract
본 발명은 진핵 생물 숙주 세포에서 이종 폴리펩타이드를 재조합 생성시키는 방법에 관한 것이다. 숙주 세포는 발현 플라스미드를 포함하고, 발현 플라스미드는 5'에서 3' 방향으로 (a) 프로모터; (b) 아미노산 서열이 제 2 폴리펩타이드의 처음 두 아미노산에 따라 표 1로부터 선택되는 제 1 폴리펩타이드를 코딩하는 핵산; (c) 이종 폴리펩타이드를 코딩하는 핵산, 연결자를 코딩하는 핵산 및 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산, 및 (d) 폴리아데닐화 신호를 포함하는 3' 미번역 영역을 포함한다. 또한, 플라스미도 및 키트도 기재되어 있다.
이종 폴리펩타이드의 재조합 발현, 면역 글로불린.
Description
본 발명은 진핵 생물 세포에서의 폴리펩타이드의 재조합 발현 방법에 관한 것이다.
재조합 폴리펩타이드를 생성시키기 위한 발현 시스템은 당해 분야에 널리 알려져 있고, 예를 들어 마리노(Marino, M.H.)의 문헌[Biopharm. 2 (1989) 18-33]; 괴델(Goeddel, D.V.) 등의 문헌[Methods Enzymol. 185 (1990) 3-7]; 웜(Wurm, F.) 및 버나드(Bernard, A.)의 문헌[Curr. Opin. Biotechnol. 10 (1999) 156-159]에 기재되어 있다. 약학 용도에 사용하기 위한 폴리펩타이드는 바람직하게는 CHO 세포, NS0 세포, Sp2/0 세포, COS 세포, HEK 세포, BHK 세포 등과 같은 포유동물 세포에서 생성된다. 발현 플라스미드의 필수적인 요소는 복제 원점 및 선택 마커를 포함하는 예컨대 대장균(E. coli)용 원핵 생물 플라스미드 전파 단위, 진핵 생물 선택 마커, 및 각각 프로모터, 구조 유전자 및 폴리아데닐화 신호를 포함하는 전사 종결자를 포함하는 관심 있는 구조 유전자의 발현을 위한 하나 이상의 발현 카셋트이 다. 포유동물 세포에서의 일시적인 발현을 위하여 SV40 Ori 또는 OriP 같은 포유동물 복제 원점이 포함될 수 있다. 프로모터로서는 구성(constitutive) 또는 유도(inducible) 프로모터가 선택될 수 있다. 최적화된 전사를 위하여, 5' 미번역 영역에 코작(Kozak) 서열이 포함될 수 있다. mRNA 처리, 특히 mRNA 스플라이싱 및 전사 종결을 위하여, 폴리아데닐화 신호뿐만 아니라 구조 유전자의 구성(엑손/인트론 구성)에 따라 mRNA 스플라이싱 신호가 포함될 수 있다.
유전자의 발현은 일시적인 또는 영구적인 발현으로서 수행된다. 관심 있는 폴리펩타이드는 일반적으로 분비된 폴리펩타이드이고, 따라서 세포를 통해 세포외 매질 내로 폴리펩타이드를 수송/분비하는데 필요한 N-말단 연장부(신호 서열로서도 알려져 있음)를 함유한다.
일반적으로, 신호 서열은 분비된 폴리펩타이드를 코딩하는 임의의 유전자로부터 유래될 수 있다. 이종 신호 서열이 사용되는 경우, 이는 바람직하게는 숙주 세포에 의해 인식 및 처리되는(즉, 신호 펩티다제에 의해 절단되는) 것이다. 효모에서의 분비를 위하여, 예를 들어 발현되어야 하는 이종 유전자의 천연적인 신호 서열이 분비된 유전자로부터 유래되는 동종 효모 신호 서열, 예컨대 효모 인버타제 신호 서열, 알파-인자 리더[사카로마이세스(Saccharomyces), 클루이베로마이세스(Kluyveromyces), 피치아(Pichia) 및 한세눌라(Hansenula) α-인자 리더, 두번째 것은 US 5,010,182 호에 기재되어 있음], 산 포스파타제 신호 서열 또는 씨. 알비칸스(C. albicans) 글루코아밀라제 신호 서열(EP 0 362 179 호)로 치환될 수 있다. 포유동물 세포 발현에서는, 관심 있는 단백질의 천연적인 신호 서열의 발현이 만족 스럽기는 하지만, 다른 포유동물 신호 서열, 예를 들어 동일하거나 관련이 있는 종의 분비된 폴리펩타이드, 예컨대 인간 또는 쥣과 기원의 면역 글로불린의 신호 서열뿐만 아니라 바이러스성 분비 신호 서열, 예를 들어 단순 헤르페스 당단백 D 신호 서열이 적합할 수 있다. 이러한 프리세그먼트(presegment)를 코딩하는 DNA 단편을 프레임 내에서 관심 있는 폴리펩타이드를 코딩하는 DNA 단편에 결찰시킨다.
WO 98/28427 호에는, Fc 면역 글로불린 영역, OB 단백질의 N-말단 부위에 융합된 유도체 또는 유사체를 포함하는 유전공학적으로 또는 화학적으로 제조된 융합 단백질이 보고되어 있다. 키메라 분자, 즉 카복시 말단 단백질 내수송 서열 및 아미노 말단 선적 영역을 포함하는 항체 융합 또는 융합 단백질이 WO 03/035892 호에 기재된다.
US 2003/0049227 호에는, 아미노-말단 면역 글로불린 부분 및 카복시-말단 사이토카인 부분을 포함하는 융합 단백질인 면역 사이토카인을 투여함으로써 포유동물의 암에 대항하는 살세포성 면역 응답을 유도하는 방법이 보고되어 있다.
WO 91/16437 호는 표적 분자에 대한 인식 부위, 예컨대 상보 수용체 부위를 함유하고 면역 글로불린 쇄의 N-종결 말단에 연결되는 폴리펩타이드를 포함하는 포유동물 순환 시스템에서 안정한 가용성의 재조합 융합 단백질을 보고한다. 생물학적 활성을 갖는 펩타이드 및 항체로 제조된 융합 단백질이 US 2003/0103984 호에 보고되어 있다.
US 2004/0033511 호에는 항체-사이토카인 융합 단백질이, US 2004/0180035 호에는 항체-사이토카인 면역 접합체(immunoconjugate)가 보고되어 있다. 겔로 닌(Gelonin) 및 항체를 포함하는 면역 독소가 WO 94/26910 호에 보고되어 있다.
발명의 개요
본 발명은 발현 플라스미드를 포함하는 진핵 생물 숙주 세포에서 이종 폴리펩타이드를 재조합 생성시키는 방법을 포함하는데, 이 때 발현 플라스미드는 5'에서 3' 방향으로 (a) 프로모터; (b) 아미노산 서열이 제 2 폴리펩타이드의 첫 두 아미노산에 따라 표 1로부터 선택되는 제 1 폴리펩타이드를 코딩하는 핵산; (c) 이종 폴리펩타이드를 코딩하는 핵산, 연결자를 코딩하는 핵산, 및 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산; 및 (d) 폴리아데닐화 신호를 포함하는 3' 미번역 영역을 포함한다. 본 방법은 제 2 폴리펩타이드의 발현에 적합한 조건하에서 배양되는 진핵 생물 숙주 세포 내로 발현 플라스미드를 도입함을 추가로 포함하며, 제 2 폴리펩타이드를 배지로부터 회수한다.
본 발명의 한 실시양태에서, 제 2 폴리펩타이드를 코딩하는 핵산은 5' 위치에 이종 폴리펩타이드를 코딩하는 핵산 및 단일 아미노산 또는 다이펩타이드 또는 아미노산 서열 QIWNN(서열 번호: 472)의 펩타이드 또는 그의 단편을 코딩하는 추가적인 핵산을 함유한다.
다른 실시양태에서는, IgG 또는 IgE로부터 면역 글로불린 단편을 수득한다.
추가의 실시양태에서, 진핵 생물 세포는 포유동물 세포, 특히 CHO 세포, NS0 세포, Sp2/0 세포, COS 세포, K562 세포, BHK 세포, PER.C6 세포 또는 HEK 세포이다.
또 다른 실시양태에서, 연결자는 서열 번호: 06, 07, 08, 09, 10, 139, 140, 554, 555, 556 및 557로 이루어진 군으로부터 선택되는 펩타이드 또는 폴리펩타이드이다.
다른 실시양태에서, 면역 글로불린 단편은 천연 발생 또는 합성 면역 글로불린의 중질 또는 경질 쇄의 카복시-말단 불변 도메인, 즉 중질 쇄의 CH1-, 경첩 부위(hinge region), CH2-, CH3-도메인 또는 경질 쇄의 CL-도메인을 포함한다. 또한, 면역 글로불린 단편은 가변 도메인 단편을 포함한다.
다른 실시양태에서, 가변 도메인 단편은 가변 도메인의 1 내지 6개의 아미노산이 결실된 면역 글로불린 중질 또는 경질 쇄의 가변 도메인이다.
다른 실시양태에서는, 가변 도메인의 1 내지 6개의 영역(FR1, FR2, FR3, CDR1, CDR2, CDR3)이 결실된다.
추가적인 실시양태에서는, 가변 도메인이 결실된다.
다른 실시양태에서, 면역 글로불린 단편은 천연 발생 면역 글로불린 또는 그의 변이체로부터 유래된다.
추가의 실시양태에서, 면역 글로불린 단편은 적어도 부분적으로 합성 면역 글로불린으로부터 유래된다.
본 발명의 또 다른 실시양태에서, 이종 폴리펩타이드의 아미노산 서열은 5 내지 500개의 아미노산 잔기, 더욱 바람직하게는 10 내지 350개의 아미노산 잔기, 가장 바람직하게는 15 내지 150개의 아미노산 잔기이다.
본 발명은 5'에서 3' 방향으로 (a) 프로모터; (b) 아미노산 서열이 제 2 폴리펩타이드의 처음 두 아미노산에 따라 표 1로부터 결정되는 제 1 폴리펩타이드를 코딩하는 핵산; (c) 이종 폴리펩타이드를 코딩하는 핵산, 연결자를 코딩하는 핵산 및 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산; 및 (d) 폴리아데닐화 신호를 포함하는 3'-미번역 영역을 포함하는 플라스미드를 추가로 포함한다.
본 발명은 또한 5'에서 3' 방향으로 (a) 프로모터; (b) 아미노산 서열이 서열 번호: 36, 37, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328 및 329로 이루어진 군으로부터 선택되는 제 1 폴리펩타이드를 코딩하는 핵산; (c) (i) 아미노산 서열 QIWNN(서열 번호: 472)의 펩타이드 또는 그의 N-말단 일부를 코딩하는 핵산, (ii) 이종 폴리펩타이드를 코딩하는 핵산을 삽입하는데 적합한 하나 이상의 제한 절단 부위를 포함하는 클로닝 부위, (iii) 서열 번호: 06, 07, 08, 09, 10, 139, 140, 554, 555, 556 및 557로 이루어진 군으로부터 선택되는 연결자를 코딩하는 핵산, 및 (iv) 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산; 및 (d) 폴리아데닐화 신호를 포함하는 3'-미번역 영역을 포함하는 플라스미드를 포함하는 진핵 생물 세포에서 이종 폴리펩타이드를 발현시키는 플라스미드를 제조하기 위한 키트를 추가로 포함한다.
본 발명은 적합한 프로모터, 전사 종결자, 선택될 수 있는 마커, 폴리펩타이드를 코딩하는 핵산 서열 및 신호 서열을 코딩하는 핵산 서열을 함유하는 발현 벡터를 포함하는, 진핵 생물 숙주 세포에서 관심 있는 이종 폴리펩타이드를 재조합 발현시키는 방법을 포함하며, 이 때 신호 서열을 코딩하는 핵산 서열은 후속 폴리펩타이드의 처음 두 아미노산에 따라 표 1로부터 선택된다. 이종 폴리펩타이드를 코딩하는 핵산 서열은, 신호 서열을 코딩하는 핵산 서열 다음의 뉴클레오타이드 15개 내에서 시작된다. 이종 폴리펩타이드를 코딩하는 핵산 서열은 면역 글로불린의 FR1-영역 내에, 면역 글로불린의 VL-영역 내에 또는 면역 글로불린의 첫 불변 도메인 내에 삽입될 수 있거나, 또는 이는 면역 글로불린의 FR1-영역, 면역 글로불린의 VL-영역 또는 면역 글로불린의 첫 불변 도메인 전부 또는 일부를 대체할 수 있다.
본 발명의 영역 내에서, 사용되는 용어중 일부는 다음과 같이 정의된다:
본원에 사용되는 "핵산 분자"는 재조합에 의해 생성될 수 있는 폴리펩타이드를 코딩하는 천연 발생, 또는 부분적으로 또는 완전히 비-천연 발생 핵산을 말한다. 핵산 분자는 화학적 수단에 의해 단리 또는 합성되는 DNA-단편으로 구성될 수 있다. 핵산 분자는 예를 들어 발현 플라스미드 또는 진핵 생물 숙주 세포의 게놈/염색체 내의 다른 핵산 내로 일체화될 수 있다. 플라스미드는 셔틀 및 발현 벡터를 포함한다. 전형적으로, 플라스미드는 또한 세균 내에서 각각 벡터의 복제 및 선택을 위하여 복제 원점(예컨대, ColE1 복제 원점) 및 선택가능한 마커(예를 들어, 암피실린 또는 테트라사이클린 내성 유전자)를 포함하는 원핵 생물 전파 단위도 포함한다.
"발현 카셋트"는 세포 내에서 하나 이상의 제한된 구조 유전자를 발현 및 분비시키는데 필요한 요소를 함유하는 핵산 서열을 일컫는다.
핵산 분자는 마찬가지로 개별적인 뉴클레오타이드로 이루어진 그의 핵산 서열 및/또는 핵산 분자에 의해 코딩되는 아미노산 서열을 그 특징으로 한다.
"유전자"는 펩타이드, 폴리펩타이드 또는 단백질의 발현에 필요한 예컨대 염색체 또는 플라스미드 상의 분절을 가리킨다. 코딩 영역 외에, 유전자는 프로모터, 인트론 및 종결자를 포함하는 다른 기능성 요소를 포함한다.
"구조 유전자"는 신호 서열이 없는 유전자의 코딩 영역을 가리킨다.
본원에서 호환성 있게 사용되는 "내성 유전자" 또는 "선택가능한 마커"는 상응하는 선택 약제의 존재하에서 유전자를 갖는 세포가 그를 위해 또는 그에 대항하여 특이적으로 선택되도록 하는 유전자이다. 유용한 양성의 선택가능한 마커는 항생제 내성 유전자이다. 이 선택가능한 마커는 유전자로 형질전환된 숙주 세포가 상응하는 항생제의 존재하에서 긍정적으로 선택되도록 하고; 형질전화되지 않은 숙주 세포는 선택적인 배양 조건하에서 생육 또는 생존할 수 없다. 선택가능한 마커는 양성, 음성 또는 이작용성일 수 있다. 양성의 선택가능한 마커는 마커를 갖는 세포를 선택하도록 하는 반면, 음성의 선택가능한 마커는 마커를 갖는 세포가 선택적으로 제거되도록 한다. 전형적으로, 선택가능한 마커는 숙주 세포에서 약물에 대한 내성을 부여하거나 대사 또는 이화 결함을 보충한다. 진핵 생물 세포에서 유용한 내성 유전자는 예를 들어 하이그로마이신 포스포트랜스퍼라제(hyg) 같은 아미노글라이코사이드 포스포트랜스퍼라제(APH), 네오마이신 및 G418 APH, 다이하이드로폴레이트 리덕타제(DHFR), 티미딘 키나제(tk), 글루타민 신테타제(GS), 아스파라긴 신테타제, 트립토판 신테타제(인돌), 히스티딘올 데하이드로게나제(히스티딘올 D)의 유전자, 및 퓨로마이신, 블레오마이신, 플레오마이신, 클로르암페니콜, 제오신 및 마이코페놀산에 대한 내성을 코딩하는 유전자를 포함한다. 추가적인 마커 유전자는 WO 92/08796 호 및 WO 94/28143 호에 기재되어 있다.
본원에 사용되는 "조절 요소"는 관심 있는 폴리펩타이드를 코딩하는 핵산 서열을 포함하는 유전자의 전사 및/또는 번역에 필요한 시스로 존재하는 뉴클레오타이드 서열을 지칭한다. 전사 조절 요소는 통상 발현되어야 하는 구조 유전자 서열 상류의 프로모터, 전사 개시 및 종결 부위, 및 폴리아데닐화 신호 서열을 포함한다. 용어 "전사 개시 부위"는 제 1 전사물, 즉 mRNA 전구체 내로 혼입되는 제 1 핵산에 상응하는 유전자의 핵산 염기를 말하고; 전사 개시 부위는 프로모터 서열과 중첩될 수 있다. 용어 "전사 종결 부위"는 RNA 폴리머라제가 전사를 종결하도록 하는, 전사되어야 하는 관심 있는 유전자의 3' 말단에서 통상적으로 표시되는 뉴클레오타이드 서열을 말한다. 폴리아데닐화 신호 서열 또는 폴리-A 부가 신호는 진핵 생물 mRNA의 3' 말단에 있는 특이적인 부위에서의 절단 및 절단된 3' 말단으로의 약 100 내지 200 아데닌 뉴클레오타이드(폴리A 꼬리)의 서열의 핵에서의 전사후 부가를 위한 신호를 제공한다. 폴리아데닐화 신호 서열은 절단 부위로부터 뉴클레오타이드 약 10 내지 30개의 상류에 위치하는 공통 염기 서열 AATAAA를 포함할 수 있다.
분비되는 폴리펩타이드를 생성시키기 위하여, 관심 있는 구조 유전자는 신호 서열/리더 펩타이드를 코딩하는 DNA 분절을 포함한다. 신호 서열은 새로 합성된 폴리펩타이드를 ER 막 쪽으로 또한 ER 막을 통해 유도하는데, ER 막에서는 폴리펩타이드가 분비를 위해 송달될 수 있다. 신호 서열은 단백질이 ER 막을 가로지르는 동안 신호 펩티다제에 의해 절단된다. 신호 서열의 기능에 있어서는, 숙주 세포의 분비 기구에 의한 인식이 필수적이다. 따라서, 사용되는 신호 서열은 숙주 세포의 단백질 및 분비 기구의 효소에 의해 인식되어야 한다.
번역 조절 요소는 번역 개시 코돈(AUG) 및 중지 코돈(TAA, TAG 또는 TGA)을 포함한다. 내부 리보좀 진입 부위(internal ribosome entry site; IRES)가 몇몇 구조물에 포함될 수 있다.
"프로모터"는 이것이 작동가능하게 연결되는 유전자/구조 유전자 또는 핵산 서열의 전사를 제어하는 폴리뉴클레오타이드 서열을 일컫는다. 프로모터는 RNA 폴리머라제 결합 및 전사 개시의 신호를 포함한다. 사용되는 프로모터는 선택된 서열의 발현이 고려되는 숙주 세포의 세포 유형에서 기능성이다. 다양하고 상이한 공급원으로부터의 구성, 유도 및 억제 프로모터를 비롯한 다수의 프로모터가 당해 분야에 널리 공지되어 있고[젠뱅크(GenBank) 같은 데이터베이스에서 확인되며] 클로닝된 폴리뉴클레오타이드로서 또는 클로닝된 폴리뉴클레오타이드 내에서 입수될 수 있다(예를 들어, ATCC 같은 수탁 기관 및 다른 상업적 또는 개인적 공급원으로부터). "프로모터"는 구조 유전자의 전사를 명령하는 뉴클레오타이드 서열을 포함한다. 전형적으로, 프로모터는 구조 유전자의 전사 개시 부위에 인접한 유전자의 5' 비-코딩 또는 비번역 영역에 위치한다. 전사 개시에서 기능을 발휘하는 프로모터 내의 서열 요소는 흔히 뉴클레오타이드 공통 염기 서열을 그 특징으로 한다. 이들 프로모터 요소는 RNA 폴리머라제 결합 부위, TATA 서열, CAAT 서열, 분화-특이적 요소[DSE; 맥기히(McGehee, R.E.) 등, Mol. Endocrinol. 7 (1993) 551], 환상 AMP 응답 요소(CRE), 혈청 응답 요소[SRE; 트레이스맨(Treisman, R.) Seminars in Cancer Biol. 1 (1990) 47], 글루코코르티코이드 응답 요소(GRE) 및 CRE/ATF[오라일리(O'Reilly, M.A.) 등, J. Biol. Chem. 267 (1992) 19938], AP2[예(Ye, J.) 등, J. Biol. Chem. 269 (1994) 25728], SP1, cAMP 응답 요소 결합 단백질[CREB; 뢰켄(Leoken, M.R.), Gene Expr. 3 (1993) 253] 및 옥타머 인자[일반적으로는 와트슨(Watson) 등 편집, Molecular Biology of the Gene, 제4판 (The Benjamin/Cummings Publishing Company, Inc. 1987) 참조, 및 르마이그리(Lemaigre, F.P.) 및 루소(Rousseau, G.G.), Biochem. J. 303 (1994) 1-14 참조] 같은 다른 전사 인자의 결합 부위를 포함한다. 프로모터가 유도 프로모터인 경우, 전사 속도는 유도제에 응답하여 증가한다. 대조적으로, 프로모터가 구성 프로모터인 경우에는 전사 속도가 유도제에 의해 조절되지 않는다. 억제 프로모터 또한 공지되어 있다. 예를 들어, c-fos 프로모터는 성장 호르몬이 세포 표면 상에서 그의 수용체에 결합할 때 특이적으로 활성화된다. 예컨대 CMV 프로모터에 후속하는 2개의 Tet-작동자 부위로 이루어진 인공적인 하이브리드 프로모터에 의해 테트라사이클린(tet) 조절되는 발현이 달성될 수 있다. Tet-억제자는 2개의 Tet-작동자 부위에 결합하고 전사를 차단한다. 유도제인 테트라사이클린을 첨가하면, Tet-억제자가 Tet-작동자 부위로부터 방출되고 전사가 진행된다[고센(gossen, M.) 및 부자드(Bujard, H.), PNAS 89 (1992) 5547-5551]. 메탈로티오네인 및 열 쇼크 프로모터를 포함하는 다른 유도 프로모터에 대해서는, 예를 들어 샘브룩 등의 상기 문헌 및 고센 등의 문헌[Curr. Opin. Biotech. 5 (1994) 516-520]을 참조한다. 높은 수준의 발현을 위한 강한 프로모터로서 확인된 진핵 생물 프로모터로는 SV40 초기 프로모터, 아데노바이러스 주요 말기 프로모터, 마우스 메날로티오네인-I 프로모터, 라우스(Rous) 육종 바이러스 장기 말단 반복부, 차이니즈 햄스터 신장 인자 1 알파(CHEF-1, 예컨대 US 5,888,809 호 참조), 인간 EF-1 알파, 유비퀴틴 및 인간 사이토메갈로바이러스 중간 초기 프로모터(CMV IE)가 있다.
"프로모터"는 구성 또는 유도성일 수 있다. 프로모터와 함께 증강자(즉, 프로모터 상에서 전사를 증가시키도록 작용하는 시스-작용 DNA 요소)를 작용시켜 프로모터 단독의 경우에 수득되는 발현 수준을 증가시킬 필요가 있을 수 있고, 증강자는 전사 조절 요소로서 포함될 수 있다. 흔히, 프로모터를 함유하는 폴리뉴클레오타이드 분절은 증강자 서열도 포함한다(예컨대, CMV 또는 SV40).
본원에 사용되는 "증강자"는 그가 작동가능하게 연결된 유전자 또는 코딩 서열의 전사를 증강시키는 폴리뉴클레오타이드 서열을 지칭한다. 프로모터와는 달리, 증강자는 비교적 배향 및 위치에 대해 의존적이지 않고 인트론 내에서[배너지(Banerji, J.) 등, Cell 33 (1983) 729] 및 코딩 서열 자체 내에서[오스본(Osborne, T.F.) 등, Mol. Cell Bio. 4 (1984) 1293] 전사 단위에 대해 5' 또는 3'[러스키(Lusky, M.) 등, Mol. Cell Bio. 3 (1983) 1108]에서 발견되었다. 그러므로, 증강자는 전사 개시 부위로부터 상류 또는 하류에, 또는 프로모터로부터 상당한 거리에 위치할 수 있으나, 실제로 증강자는 프로모터와 물리적으로 또한 기능적으로 중첩될 수 있다. 다양하고 상이한 공급원으로부터의 다수의 증강자가 당해 분야에 널리 공지되어 있고(젠뱅크 같은 데이터베이스에서 확인되며) 클로닝된 폴리뉴클레오타이드 서열로서 또는 클로닝된 폴리뉴클레오타이드 서열 내에서 입수될 수 있다(예컨대, ATCC 같은 수탁 기관 및 다른 상업적 또는 개인적 공급원으로부터). 프로모터 서열(통상적으로 사용되는 CMV 프로모터 같은)을 포함하는 다수의 폴리뉴클레오타이드는 또한 증강자 서열을 포함한다. 예를 들어, 상기 나열된 강한 프로모터는 모두 강한 증강자도 함유할 수 있다[예컨대, 벤디히(Bendig, M.M.), Genetic Engineering 7 (1988) 91-127 참조].
"내부 리보좀 진입 부위" 또는 "IRES"는 IRES의 유전자 5'과는 독립적인 번역 개시를 기능적으로 촉진시키고 두 시스트론(개방 판독 프레임)이 동물 세포에서 단일 전사물로부터 번역되도록 하는 서열을 기재한다. IRES는 그의 바로 하류(하류는 본원에서 3'과 호환성 있게 사용됨)에 개방 판독 프레임의 번역을 위한 독립적인 리보좀 진입 부위를 제공한다. 다시스트론성(polycistronic)일 수 있는(즉, mRNA로부터 연속적으로 번역되는 수개의 상이한 폴리펩타이드를 코딩할 수 있는) 세균 mRNA와는 달리, 동물 세포의 대부분의 mRNA는 모노시스트론성이고, 한 단백질의 합성만 코딩한다. 진핵 생물 세포에서 다시스트론성 전사물을 사용하면, 번역이 가장 5'인 번역 개시 부위로부터 개시되고 첫번째 중지 코돈에서 종결되며, 전사물이 리보좀으로부터 방출되어 mRNA의 최초 코딩된 폴리펩타이드만 번역된다. 진핵 생물 세포에서, 전사물의 제 2의 또는 후속 개방 판독 프레임에 작동가능하게 연결된 IRES를 갖는 다시스트론성 전사물은 이 하류 개방 판독 프레임의 연속적인 번역이 동일한 전사물에 의해 코딩되는 둘 이상의 폴리펩타이드를 생성시키도록 한다. 벡터 구성에서의 IRES 요소의 사용은 이미 기재된 바 있으며, 예를 들어 펠레티어(Pelletier, J.) 등의 문헌[Nature 334 (1988) 320-325]; 장(Jang, S.K.) 등의 문헌[J. Virol. 63 (1989) 1651-1660]; 데이비즈(Davies, M.V.) 등의 문헌[J. Virol. 66 (1992) 1924-1932]; 아담(Adam, M.A.) 등의 문헌[J. Virol. 65 (1991) 4985-4990]; 모건(Morgan, R.A.) 등의 문헌[Nucl. Acids Res. 20 (1992) 1293-1299]; 스기모토(Sugimoto, Y.) 등의 문헌[Biotechnology 12 (1994) 694-698]; 라메쉬(Ramesh, N.) 등의 문헌[Nucl. Acids Res. 24 (1996) 2697-2700]; 및 모서(Mosser, D.D.) 등의 문헌[Biotechniques 22 (1997) 150-152]을 참조한다.
"작동하게 연결되는"이란, 이렇게 기재되는 구성요소가 이들이 의도되는 방식으로 기능을 발휘하도록 하는 관계에 있는, 둘 이상의 구성요소의 병렬을 일컫는다. 예를 들어, 프로모터 및/또는 증강자는 코딩 서열이 연결된 서열의 전사를 조절 또는 조정하도록 시스로 작용한다면 코딩 서열에 작동가능하게 연결된 것이다. 일반적으로(반드시는 아님), "작동가능하게 연결된" DNA 서열은 인접하고, 분비 리더/신호 서열 및 폴리펩타이드 같은 2개의 단백질 코딩 영역을 연결시켜야 하는 경우 인접하고 판독 프레임 내에 있다. 그러나, 작동가능하게 연결된 프로모터가 일반적으로 코딩 서열의 상류에 위치한다고 하더라도, 반드시 코딩 서열과 인접해야 하는 것은 아니다.
증강자는 인접할 필요가 없다. 증강자가 코딩 서열의 전사를 증가시킨다면, 증강자는 코딩 서열에 작동가능하게 연결된 것이다. 작동가능하게 연결된 증강자는 코딩 서열의 상류에, 내에 또는 하류에 위치할 수 있으며, 프로모터로부터 상당한 거리에 위치할 수 있다. 전사가 코딩 서열을 통해 폴리아데닐화 서열 내로 진행되도록 폴리아데닐화 부위가 코딩 서열의 하류 말단에 위치하는 경우, 폴리아데닐화 부위는 코딩 서열에 작동가능하게 연결된 것이다. 당해 분야에 공지되어 있는 재조합 방법에 의해, 예컨대 PCR 방법을 이용하여 및/또는 편리한 제한 부위에서의 결찰에 의해 연결시킨다. 편리한 제한 부위가 존재하지 않으면, 종래의 관행에 따라 합성 올리고뉴클레오타이드 어댑터 또는 연결자를 사용한다.
본원에 사용되는 용어 "발현"은 숙주 세포 내에서 전사 및/또는 번역이 이루어짐을 말한다. 숙주 세포에서의 목적하는 생성물의 전사 수준은 세포에 존재하는 상응하는 mRNA의 양에 기초하여 결정될 수 있다. 예를 들어, 선택된 서열로부터 전사되는 mRNA는 PCR에 의해 또는 노던(Northern) 하이브리드 형성에 의해 정량될 수 있다[샘브룩 등, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989) 참조]. 선택된 서열에 의해 코딩되는 단백질은 다양한 방법에 의해, 예를 들어 ELISA에 의해, 단백질의 생물학적 활성의 분석에 의해, 또는 단백질을 인식하고 단백질에 결합하는 항체를 사용하는 웨스턴 블롯팅(Western blotting) 또는 방사성 면역 분석 같은 이러한 활성에 무관한 분석을 이용함으로써 정량될 수 있다[샘브룩 등의 상기 문헌 (1989) 참조].
"숙주 세포"는 본 발명의 폴리펩타이드를 코딩하는 유전자가 도입되는 세포를 일컫는다. 숙주 세포는 플라스미드/벡터의 전파에 사용되는 원핵 생물 세포, 및 구조 유전자의 발현을 위한 진핵 생물 세포 둘 다를 포함한다. 전형적으로, 진색 생물 세포는 포유동물 세포이다.
"폴리펩타이드"는 천연적으로 생성되는지 합성에 의해 생성되는지에 관계 없이 펩타이드 결합에 의해 연결된 아미노산 잔기의 중합체이다. 약 20개 미만의 아미노산 잔기를 갖는 폴리펩타이드를 "펩타이드"라고 칭할 수 있다. 하나 이상의 폴리펩타이드 쇄를 포함하거나 또는 100개 이상의 아미노산 길이의 아미노산 쇄를 포함하는 폴리펩타이드를 "단백질"로 일컬을 수 있다.
"단백질"은 하나 이상의 폴리펩타이드 쇄를 포함하는 거대분자이며, 이 때 하나 이상의 쇄는 아미노산 100개 이상의 아미노산 길이를 갖는다. 단백질은 또한 탄수화물 기 같은 비-펩타이드 성분도 포함할 수 있다. 탄수화물 및 다른 비-펩타이드 치환기는 단백질이 생성되는 세포에 의해 단백질에 첨가될 수 있으며, 세포의 유형에 따라 달라질 수 있다. 단백질은 본원에서 그들의 아미노산 주쇄 구조 면에서 정의되며; 탄수화물 기 같은 부가분은 통상적으로 명시되지 않지만 그럼에도 불구하고 존재할 수 있다.
"이종 DNA" 또는 "이종 폴리펩타이드"는 주어진 숙주 세포 내에서 천연적으로 존재하지 않는 DNA 분자 또는 폴리펩타이드, 또는 DNA 분자의 개체군 또는 폴리펩타이드의 개체군을 지칭한다. 특정 숙주 세포에 대해 이종인 DNA 분자는 숙주 DNA가 비-숙주 DNA(즉, 외래 DNA)와 조합되는 한 숙주 세포 종으로부터 유래되는 DNA(즉, 내인성 DNA)를 함유할 수 있다. 예를 들어, 프로모터를 포함하는 숙주 DNA 분절에 작동가능하게 연결된 폴리펩타이드를 코딩하는 비-숙주 DNA 분절을 함유하는 DNA 분자는 이종 DNA 분자인 것으로 생각된다. 반대로, 이종 DNA 분자는 외래 프로모터와 작동가능하게 연결된 내인성 구조 유전자를 포함할 수 있다.
비-숙주 DNA 분자에 의해 코딩되는 펩타이드 또는 폴리펩타이드는 "이종" 펩타이드 또는 폴리펩타이드이다.
"클로닝 벡터"는 숙주 세포에서 자발적으로 복제하는 능력을 갖는, 플라스미드, 코스미드, 파지미드 또는 세균 인공 염색체(BAC) 같은 핵산 분자이다. 클로닝 벡터는 전형적으로 벡터의 본질적인 생물학적 기능을 상실하지 않으면서 결정가능한 방식으로 핵산 분자의 삽입을 허용할 수 있는 하나의 또는 소수의 제한 엔도뉴클레아제 인식 부위, 및 클로닝 벡터로 형질 전환되는 세포의 확인 및 선택에 사용하기 적합한 내성 유전자를 코딩하는 뉴클레오타이드 서열을 함유한다. 내성 유전자는 전형적으로 테트라사이클린 내성 또는 암피실린 내성을 제공하는 유전자를 포함한다.
"발현 플라스미드"는 숙주 세포에서 발현되는 단백질을 코딩하는 핵산 분자이다. 전형적으로, 발현 플라스미드는 복제 원점 및 선택 마커를 포함하는 예컨대 대장균의 원핵 생물 플라스미드 전파 단위, 진핵 생물 선택 마커, 및 프로모터, 구조 유전자 및 폴리아데닐화 신호를 포함하는 전사 종결자를 포함하는 관심 있는 구조 유전자의 발현을 위한 하나 이상의 발현 카셋트를 포함한다. 유전자 발현은 통상 프로모터의 제어하에 이루어지며, 이러한 구조 유전자는 프로모터에 "작동가능하게 연결되었다"라고 말해진다. 유사하게, 조절 요소 및 코어 프로모터는 조절 요소가 코어 프로모터의 활성을 조정하는 경우 작동가능하게 연결된 것이다.
"다시스트론성 전사 단위"는 하나보다 많은 구조 유전자가 동일한 프로모터의 제어하에 있는 전사 단위이다.
"단리된 폴리펩타이드"는 탄수화물, 지질 또는 천연에서 폴리펩타이드에 수반되는 다른 단백질성 불순물 같은 오염성 세포 성분을 본질적으로 함유하지 않는 폴리펩타이드이다. 전형적으로, 단리된 폴리펩타이드 제제는 고도로 정제된 형태, 즉 약 80% 이상 순수하거나, 약 90% 이상 순수하거나, 약 95% 이상 순수하거나, 95%보다 더 높게 순수하거나 또는 99%보다 더 높게 순수한 형태의 폴리펩타이드를 함유한다. 특정 단백질 제제가 단리된 폴리펩타이드를 함유함을 보여주는 한 방법은 단백질 제제의 소듐 도데실 설페이트(SDS)-폴리아크릴아마이드 겔 전기 영동 후의 단일 밴드의 출현 및 겔의 쿠마지 브릴리언트 블루(Coomassie Brilliant Blue) 염색에 의해서이다. 그러나, 용어 "단리된"은 이량체 또는 달리 글라이코실화 또는 유도체화된 형태 같은 다른 물리적 형태의 동일한 폴리펩타이드의 존재를 배제하지는 않는다.
용어 "면역 글로불린"은 면역 글로불린 유전자에 의해 실질적으로 코딩되는 하나 이상의 폴리펩타이드로 이루어진 단백질을 일컫는다. 인식된 면역 글로불린 유전자는 상이한 불변 도메인(영역) 유전자 및 무수한 면역 글로불린 가변 영역 유전자를 포함한다. 면역 글로불린은 예를 들어 Fv, Fab 및 F(ab)2뿐만 아니라 단일 쇄(scFv)를 비롯한 다양한 포맷으로 존재할 수 있다[예를 들어, 휴스턴(Houston, J.S.) 등, PNAS USA 85 (1988) 5879-5883; 버드(Bird, R.E.) 등, Science 242 (1988) 423-426; 일반적으로는 후드(Hood) 등, Immunology, Benjamin N.Y., 제2판 (1984); 및 헝커필러(Hunkapiller, T.) 및 후드(Hood, L.), Nature 323 (1986) 15-16].
일반적으로 면역 글로불린은 둘 이상의 경질 쇄 폴리펩타이드 및 2개의 중질 쇄 폴리펩타이드를 포함한다. 중질 및 경질 폴리펩타이드 쇄는 각각 항원과 상호작용할 수 있는 결합 영역(도메인)을 함유하는 가변 도메인(영역)(일반적으로는 폴리펩타이드 쇄의 아미노 말단 부위)을 함유할 수 있다. 중질 및 경질 폴리펩타이드 쇄는 각각 불변 영역(일반적으로는 카복실 말단 부위)을 포함한다. 중질 쇄의 불변 영역은 (i) 식세포 같은 Fc 감마 수용체(FcγR)를 갖는 세포, 또는 (ii) 브람벨(Brambell) 수용체로도 알려져 있는 신생아 Fc 수용체(FcRn)를 갖는 세포로의 항원의 결합을 매개한다. 이는 또한 구성요소(C1q) 같은 고전적인 상보 시스템의 인자를 비롯한 일부 인자로의 결합도 매개한다.
면역 글로불린의 경질 또는 중질 쇄의 가변 도메인은 다시 상이한 분절, 즉 4개의 골격 영역(FR) 및 3개의 다변이 영역(CDR)을 포함한다.
"면역 글로불린 단편"은 면역 글로불린의 쇄의 적어도 불변 도메인, 즉 면역 글로불린의 중질 쇄의 CH1, 경첩 부위, CH2 및 CH3 및 임의적으로는 CH4 또는 면역 글로불린의 경질 쇄의 CL을 포함하는 폴리펩타이드를 가리킨다. 또한, 이들의 유도체 및 변이체도 포함된다. 또한, 하나 이상의 아미노산 또는 아미노산 영역이 결실된 가변 도메인도 존재할 수 있다. 바람직한 실시양태에서는, 가변 도메인이 면역 글로불린 단편에서 결실된다.
본원 내에서 지칭되는 "전사 종결자"는 RNA 폴리머라제에게 mRNA 합성 종결 신호를 제공하는 길이 50 내지 750 염기 쌍의 DNA 서열이다. 특히 강한 프로모터를 사용하는 경우 RNA 폴리머라제가 판독하지 못하도록 하기 위해서는 발현 카셋트의 3' 말단에서의 매우 효율적인 (강한) 종결자가 권할 만하다. 비효율적인 전사 종결자는 오페론-유사 mRNA를 형성시킬 수 있으며, 이는 바람직하지 못한, 예컨대 플라스미드-코딩된 유전자 발현의 이유가 될 수 있다.
본원에서 사용되는 용어 "연결자"는 천연 또는 합성 기원의 펩타이드 연결자를 가리킨다. 이들은 선형 아미노산 쇄를 구성한다. 쇄는 1 내지 50개, 바람직하게는 3 내지 25개의 아미노산의 길이를 갖는다. 연결자는 반복 아미노산 서열 또는 천연 발생 폴리펩타이드(예컨대, 경첩-기능을 갖는 폴리펩타이드)의 일부를 함유할 수 있다.
"합성 연결자"는 글리신, 글루타민 및 세린 잔기가 풍부한 것으로 표시된다. 이들 잔기는 5개 이하의 아미노산의 작은 펩타이드 단위(예컨대, GGGGS, QQQQG 또는 SSSSG)로 배열된다. 작은 펩타이드 단위가 2 내지 5회 반복되어 다중체 단위를 형성한다. 다중체 단위의 각 아미노- 및/또는 카복시-말단에 6개 이하의 추가적인 아미노산을 부가할 수 있다.
본원에 사용되는 용어 "생물학적 활성 분자"는 세포주 및 바이러스를 사용하는 생물학적 정량 같은 인공의 생물학적 시스템 내에 또는 상기 시스템으로 투여되거나 또는 조류 및 포유동물(인간 포함)을 포함하지만 이들로 한정되지는 않는 동물에게 생체내 투여될 때 생물학적 효과를 야기하는 유기 분자, 예를 들어 펩타이드, 단백질, 당단백, 핵단백, 점액 단백질, 지단백, 합성 폴리펩타이드 또는 단백질 같은 생물학적 거대분자를 일컫는다. 이 생물학적 효과는 효소 저해 또는 활성화, 결합 부위에서의 또는 주위에서의 수용체 또는 리간드로의 결합, 신호 촉발 또는 신호 조정일 수 있으나, 이들로 국한되지는 않는다.
생물학적 활성 분자는 예컨대 호르몬, 사이토카인, 성장 인자, 수용체 리간드, 작용제 또는 길항제, 세포 독성제, 항바이러스제, 조영제, 효소 저해제, 효소 활성화제 또는 효소 활성 조정제(예컨대, 입체성 성분)이지만, 이들로 한정되지는 않는다.
본원에 사용되는 용어 "아미노산"은 알라닌(3문자 코드: ala, 1문자 코드: A), 아르기닌(arg, R), 아스파라긴(asn, N), 아스파르트산(asp, D), 시스테인(cys, C), 글루타민(gln, Q), 글루탐산(glu, E), 글리신(gly, G), 히스티딘(his, H), 아이소류신(ile, I), 류신(leu, L), 리신(lys, K), 메티오닌(met, M), 페닐알라닌(phe, F), 프롤린(pro, P), 세린(ser, S), 트레오닌(thr, T), 트립토판(trp, W), 티로신(tyr, Y) 및 발린(val, V)을 포함한다.
본 발명을 수행하는데 유용한, 당해 분야의 숙련자에게 공지되어 있는 방법 및 기법은 예를 들어 오스벨(Ausubel, F.M.)이 편집한 문헌[Current Protocols in Molecular Biology, Volumes I to III (1997), Wiley and Sons]; 샘브룩 등의 문헌[Molecular Cloning: A Laboratory Manual, 제2판, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)]에 기재되어 있다.
본 발명은 진핵 생물 숙주 세포에서 이종 폴리펩타이드를 재조합 생성시키는 방법을 포함한다. 숙주 세포는 5'에서 3' 방향으로 (a) 프로모터; (b) 아미노산 서열이 제 2 폴리펩타이드의 처음 두 아미노산에 따라 표 1로부터 선택되는 제 1 폴리펩타이드를 코딩하는 핵산; (c) 생물학적 활성을 갖는 이종 폴리펩타이드를 코딩하는 핵산, 서열 번호: 06 내지 10, 139, 140 및 554 내지 557로 이루어진 군으로부터 선택되는 펩타이드 또는 폴리펩타이드를 코딩하는 핵산, 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산; 및 (d) 3' 미번역 영역을 포함하는 발현 플라스미드를 포함한다. 제 2 폴리펩타이드의 발현에 적합한 조건하에서 배양되는 숙주 세포 내로 이 발현 플라스미드를 도입한다. 분비된 제 2 폴리펩타이드를 배지로부터 회수한다.
제 1 폴리펩타이드는 소위 신호 서열이다. 신호 서열은 부착된/후속하는/작동가능하게 연결된 폴리펩타이드의 분비를 담당한다. 효과적이기 위하여, 신호 서열은 폴리펩타이드를 발현하는 세포 내에서 단백질 및 효소에 의해 인식 및 처리되어야 한다. 진핵 생물 숙주 세포의 경우, 신호 서열은 바람직하게는 진핵 생물 신호 서열이다. 본 발명에 따른 제 2 폴리펩타이드의 올바른 분비를 보장하기 위하여, 신호 서열을 인간 및 쥣과의 면역 글로불린 신호 서열로부터 선택한다. 신호 서열의 집계가 표 1이 기재된다.
어떤 신호 서열이 선택되는지는 후속하는 아미노산에 따라 달라진다. 분비 과정 후에 신호 서열을 절단하는 신호 펩티다제가 분비된 폴리펩타이드의 신호 서열을 인식하고 이를 제거함이 보장되어야 한다. 신호 서열로부터 이종 폴리펩타이드로의 "자연스러운" 전이를 제공하기 위하여, 신호 서열은 이종 폴리펩타이드의 처음 두 아미노산이 자연적으로 후속하는 면역 글로불린 FR1-영역의 아미노산 서열의 처음 두 아미노산과 동일하도록 하는 방식으로 선택되어야 한다.
제 2 폴리펩타이드의 처음 두 아미노산의 다이펩타이드가 표 1에 명시적으로 기재되지 않거나 표 1의 마지막 행에 기재된 서열을 사용하지 않고자 하는 경우에는, 제 1 폴리펩타이드와 제 2 폴리펩타이드를 직접 함께 배열시키지 않는 것이 바람직하다. 이러한 경우, 아미노산 5개 이하의 짧은 서열을 삽입하여 자연적으로 제 1 폴리펩타이드에 후속하는 면역 글로불린 FR1 영역 서열의 시작을 모방하는 것이 바람직하다. 이 서열은 자연적으로 면역 글로불린 FR1 영역에 후속하는 처음 두 아미노산과 유사한 단일 아미노산 또는 다이펩타이드, 펩타이드 QIWNN(서열 번호: 472) 또는 그의 단편일 수 있다. 한 실시양태에서, 이 서열은 펩타이드 QIWNN(서열 번호: 472) 또는 적어도 다이펩타이드 QI를 포함하는 그의 N-말단 단편이다.
제 1 폴리펩타이드 또는 임의적으로는 삽입된 짧은 서열 후의 제 2 폴리펩타이드는 이종 폴리펩타이드를 포함한다. 이 이종 폴리펩타이드는 5 내지 500개의 아미노산 잔기의 아미노산 서열을 갖는다. 본 발명의 바람직한 실시양태에서, 아미노산 서열은 10 내지 350개의 아미노산 잔기를 갖고, 더욱 바람직한 실시양태에서는 15 내지 150개의 아미노산 잔기를 갖는다. 면역 글로불린으로 접합되는 이종 폴리펩타이드는 생물학적 활성 분자를 포함하는 군으로부터 선택된다. 이들 분자는 인공적인 생물학적 시스템 또는 살아 있는 세포(예컨대 정량-시스템에서의)에, 또는 살아 있는 생물체(예를 들어, 조류, 또는 인간을 비롯한 포유동물)에 투여될 때 생물학적 효과를 나타낸다. 이들 생물학적 활성 화합물은 수용체의 작용제 및 길항제, 효소의 저해제 및 활성화제 등, 또한 세포 독성, 항바이러스, 항균 또는 항암 활성을 나타내는 펩타이드, 폴리펩타이드 및 단백질뿐만 아니라 항원을 포함하지만, 이들로 국한되는 것은 아니다. 생물학적 효과는 효소 저해, 결합 부위에서의 또는 주위에서의 수용체로의 결합, 및 신호 촉발일 수 있으나, 이들로 한정되지는 않는다. 이들 생물학적 활성 화합물은 예를 들어 약학, 치료 또는 진단 용도에 유용하다.
제 2 폴리펩타이드는 이종 폴리펩타이드 후에 연결자를 추가로 포함한다. 본 발명에서 바람직하게 사용될 수 있는 연결자가 표 2에 기재된다.
연결자 후에는, 제 2 폴리펩타이드의 카복시-말단 부분으로서 면역 글로불린 단편이 뒤따른다.
제 2 폴리펩타이드는 이종 폴리펩타이드, 그에 후속하는 연결자 및 그에 후속하는 카복시-말단 부분으로서의 면역 글로불린 단편을 포함한다. 즉, 제 2 폴리펩타이드를 코딩하는 핵산은 5'에서 3' 방향으로 이종 폴리펩타이드, 연결자 및 면역 글로불린 단편을 코딩하는 핵산을 포함한다.
면역 글로불린 분자는 5개의 상이한 부류로 지정된다: IgA(면역 글로불린 A), IgD, IgE, IgG 및 IgM. 이들 중에서 IgG 및 IgE가 약학 및 진단 용도에서 보다 흔히 사용된다. 이들 부류 내에서, 면역 글로불린은 전체적인 구조가 상이하지만 구성 블록은 유사하다. 모든 면역 글로불린은 둘 이하의 상이한 폴리펩타이드 쇄, 즉 경질 쇄 및 중질 쇄로 구성된다.
면역 글로불린 단편은 면역 글로불린 경질 또는 중질 쇄의 카복시-말단 불변 도메인을 포함한다. 예를 들어, 이는 적어도 면역 글로불린 중질 쇄의 CH1-, CH2-, CH3-도메인 및 경첩 부위 및 임의적으로는 CH4-도메인, 또는 면역 글로불린 경질 쇄의 CL-도메인을 포함한다. 단편이 유래되는 면역 글로불린은 천연적으로 발생될 수 있거나 합성 면역 글로불린일 수 있다. 본 발명의 한 실시양태에서, 면역 글로불린 단편은 또한 중질 또는 경질 쇄 가변 도메인 또는 그의 변이체의 단편을 함유한다. 가변 도메인 다편에서는, 아미노산 또는 영역이 결실된다. 한 실시양태에서는, 가변 도메인의 1 내지 6개의 아미노산이 결실된다. 다른 실시양태에서는, 가변 도메인의 1 내지 6개의 영역이 결실된다. 추가의 실시양태에서는, 가변 도메인이 결실된다. 면역 글로불린 단편에서의 기능성(즉, 항원 인식) 가변 도메인의 존재는 본 발명에서 필수적이지 않다. 본 발명에 따른 비-기능성 면역 글로불린은 항원 인식 가변 도메인을 갖지 않는 면역 글로불린이다. 한 실시양태에서, 면역 글로불린 단편은 비-기능성 면역 글로불린이다. 한 실시양태에서, 면역 글로불린 단편에 포함되는 가변 및 불변 도메인은 동일한 항체로부터 유래된다(즉, 동일한 항체에 속한다).
상이한 핵산 서열을 발현 플라스미드 상에서 작동가능하게 연결한다. 발현을 위해, 플라스미드를 숙주 세포 내로 도입한다. CHO 세포, NS0 세포, Sp2/0 세포, COS 세포, HEK 세포, K562 세포, BHK 세포, PER.C6 세포 등과 같은 포유동물 세포에서 단백질을 바람직하게 생성시킨다.
하기 실시예, 서열 목록 및 도면은 본 발명의 이해를 돕기 위해 제공되며, 본 발명의 진정한 영역은 첨부된 청구의 범위에 기재된다. 본 발명의 원리로부터 벗어나지 않으면서 기재된 절차에 변형을 가할 수 있는 것으로 생각된다.
도 1은 IgG 부류의 면역 글로불린의 통상적인 구조이다.
도 2는 항-IGF-1R γ1-중질 쇄 발현 벡터 4818의 플라스미드 맵이다.
도 3은 항-IGF-1R κ-경질 쇄 발현 벡터의 플라스미드 맵이다.
도 4는 γ1-중질 쇄 불변 영역 유전자 벡터 4962의 플라스미드 맵이다.
도 5는 개질된 항-IGF-1R κ-경질 쇄 발현 벡터 4964의 플라스미드 맵이다.
도 6은 개질된 항-IGF-1R 경질 쇄 발현 벡터 4963의 플라스미드 맵이다.
도 7은 친화력 정제된 면역 글로불린 접합체의 쿠마지 블루 염색된 SDS-PAGE 겔을 도시한다(샘플 배열은 표 6에 따름).
도 8은 HEK293 EBNA 세포에서의 일시적인 발현 후 세포 배양 상청액중 경질 쇄의 면역 검출을 도시한다(샘플 배열은 표 6에 따름).
도 9는 HEK293 EBNA 세포에서의 일시적인 발현 후 세포 배양 상청액중 중질 쇄의 면역 검출을 도시한다(샘플 배열은 표 6에 따름).
물질 및 방법
인간 면역 글로불린 경질 및 중질 쇄의 뉴클레오타이드 서열에 관한 전반적 인 정보는 캐뱃(Kabat, E.A.) 등의 문헌[(1991) Sequences of Proteins of Immunological Interest, 제5판, NIH Publication No 91-3242]에 기재되어 있다.
항체 쇄의 아미노산은 EU 번호 기재 규정[에델맨(Edelman, G.M.) 등, PNAS 63 (1969) 78-85; 캐뱃 등, (1991) Sequences of Proteins of Immunological Interest, 제5판, NIH Publication No 91-3242]에 따라 번호가 매겨진다.
재조합
DNA
기법
샘브룩 등의 문헌[Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989]에 기재된 바와 같은 표준 방법을 이용하여 DNA를 조작하였다. 제조업체의 지시에 따라 분자 생물학적 시약을 사용하였다.
단백질 결정
아미노산 서열에 기초하여 계산된 몰 흡광 계수를 이용하여, 280nm에서의 광학 밀도(OD)를 결정함으로써 단백질 농도를 결정하였다.
DNA
서열 결정
메디게노믹스 게엠베하(MediGenomix GmbH; Martinsried, 독일)에서 수행된 이중 가닥 서열 결정에 의해 DNA 서열을 결정하였다.
DNA
및 단백질 서열 분석 및 서열 데이터 처리
서열 생성, 맵핑, 분석, 주석 및 도시를 위해 GCG(Genetics Computer Group; Madison, Wisconsin)의 소프트웨어 패키지 버전 10.2 및 인포맥스(Infomax)의 벡터 NTI Advance suite 버전 8.0을 사용하였다.
유전자 합성
화학적 합성에 의해 제조된 올리고뉴클레오타이드로부터 메디게노믹스 게엠베하(Martinsried, 독일)에 의해 목적하는 유전자 분절을 제조하였다. PCR 증폭을 비롯한 올리고뉴클레오타이드의 어닐링 및 결찰에 의해 단일 제한 엔도뉴클레아제 절단 부위에 인접한 100 내지 600bp 길이의 유전자 분절을 조합한 후, A-돌출부를 통해 pCR2.1-TOPO-TA 클로닝 벡터[인비트로젠 코포레이션(Invitrogen Corp.), 미국] 내로 클로닝시켰다. DNA 서열 결정에 의해, 서브클로닝된 유전자 단편의 DNA 서열을 확인하였다.
면역 글로불린 접합체
의
친화력 정제
공지 방법에 따라 단백질 A-세파로즈(Protein A-Sepharose™) CL-4B[지이 헬쓰케어 포머 애머샴 바이오사이언스(GE Healthcare former Amersham Bioscience), 스웨덴]를 사용하는 친화력 크로마토그래피에 의해 발현 및 분비된 면역 글로불린 접합체를 정제시켰다. 간략히, 원심분리(10,000g에서 10분간) 및 0.45㎛ 필터를 통한 여과 후, 면역 글로불린 접합체를 함유하는 정제된 배양 상청액을 PBS 완충액(10mM Na2HPO4, 1mM KH2PO4, 137mM NaCl 및 2.7mM KCl, pH 7.4)으로 평형화된 단백질 A-세파로즈™ CL-4B 칼럼에 걸어주었다. 결합되지 않은 단백질은 PBS 평형화 완충액 및 0.1M 시트레이트 완충액(pH 5.5)으로 세척해내었다. 면역 글로불린 접합체를 0.1M 시트레이트 완충액(pH 3.0)으로 용리시키고, 면역 글로불린 접합체를 함유하는 분획을 1M 트리스-염기로 중화시켰다. 이어, 면역 글로불린 접합체를 4 ℃에서 PBS 완충액에 대해 광범위하게 투석하고, 바이오맥스-SK(Biomax-Sk) 막[밀리포어 코포레이션(Millipore Corp.), 미국]이 설치된 울트라프리(ultrafree) 원심 분리 필터 장치로 농축시키고, 0℃의 빙수욕에 저장하였다.
실시예
1
발현 플라스미드의 제조
항-인슐린-유사 성장 인자 I 수용체(IGF-1R) 항체 경질 쇄 가변 도메인(영역)(VL) 및 인간 카파-경질 쇄 불변 도메인(영역)(CL)을 코딩하는 유전자 분절을, 항-IGF-1R 중질 쇄 가변 도메인(영역)(VH) 및 인간 감마1-중질 쇄 불변 영역(CH1-경첩-CH2-CH3)의 유전자 분절과 같이 연결하였다.
(a) 벡터 4818
벡터 4818은 HEK293 EBNA 세포에서 항-IGF-1R 항체(이후, 항-IGF-1R로도 표시됨) 중질 쇄(게놈 구성된 발현 카셋트; 엑손-인트론 구성)를 일시적으로 발현시키기 위한 발현 플라스미드이다(서열에 대해서는 US 2005/0008642 호 참조). 이는 하기 기능성 요소를 포함한다:
항-IGF-1R γ1-중질 쇄 발현 카셋트 외에 이 벡터는 하기를 함유한다:
- 선택가능한 마커로서의 하이그로마이신 내성 유전자,
- 엡스타인-바르(Epstein-Barr) 바이러스(EBV)의 복제 원점(oriP),
- 이 플라스미드가 대장균에서 복제될 수 있도록 하는 벡터 pUC18로부터의 복제 원점, 및
- 대장균에 암피실린 내성을 부여하는 베타-락타마제 유전자.
항-IGF-1R 감마1-중질 유전자의 전사 단위는 하기 요소로 구성된다:
- 인간 사이토메갈로바이러스(HCMV)로부터의 인접한 초기 증강자 및 프로모터,
- 합성 5'-미번역 영역(UT),
- 신호 서열 인트론을 포함하는 쥣과의 면역 글로불린 중질 쇄 신호 서열(신호 서열 1, 인트론, 신호 서열 2[L1-인트론-L2]),
- 5'-말단(L2 신호 서열)에 독특한 BsmI 제한 부위 및 3'-말단에 스플라이스 도너 부위 및 독특한 NotI 제한 부위를 갖도록 배열된 클로닝된 항-IGF-1R 가변 중질 쇄 코딩 분절,
- 마우스 중질 쇄 증강자 요소를 포함하는 마우스/인간 중질 쇄 하이브리드 인트론 2(JH3, JH4 부분)[노이버거(Neuberger, M.S.), EMBO J. 2 (1983) 1373-1378],
- 게놈 인간 γ1-중질 유전자 불변 영역,
- 인간 γ1-면역 글로불린 폴리아데닐화("poly A") 신호 서열, 및
- 각각 5'-말단 및 3'-말단에서의 독특한 제한 부위 AscI 및 SgrAI.
항-IGF-1R γ1-중질 쇄 발현 벡터 4818의 플라스미드 맵은 도 2에 도시되어 있다.
(b) 벡터 4802
벡터 4802는 HEK293 EBNA 세포에서 항-IGF-1R 항체 경질 쇄(cDNA)를 일시적으로 발현시키기 위한 발현 플라스미드이다. 이는 하기 기능성 요소를 포함한다.
항-IGF-1R 카파-경질 쇄 발현 카셋트 외에, 이 벡터는 하기를 함유한다:
- 선택가능한 마커로서의 하이그로마이신 내성 유전자,
- 엡스타인-바르 바이러스(EBV)의 복제 원점(oriP),
- 이 플라스미드가 대장균에서 복제될 수 있도록 하는 벡터 pUC18로부터의 복제 원점, 및
- 대장균에 암피실린 내성을 부여하는 β-락타마제 유전자.
항-IGF-1R κ-경질 쇄 유전자의 전사 단위는 하기 요소로 구성된다:
- 인간 사이토메갈로바이러스(HCMV)로부터의 인접한 초기 증강자 및 프로모터,
- 클로닝된 항-IGF-1R 가변 경질 쇄 cDNA,
- 천연 5'-UT,
- 5'-말단에 독특한 BglII 제한 부위를 갖도록 배열된 인간 면역 글로불린 생식 계열 유전자의 천연 경질 쇄 신호 서열,
- 인간 κ-경질 쇄 유전자 불변 영역,
- 인간 면역 글로불린 κ-폴리아데닐화("poly A") 신호 서열, 및
- 각각 5'-말단 및 3'-말단에서의 독특한 제한 부위 AscI 및 FseI.
항-IGF-1R κ-경질 쇄 발현 벡터 4802의 플라스미드 맵은 도 3에 도시되어 있다.
(c) 플라스미드 4962
벡터 4962는 발현 플라스미드 4965, 4966 및 4967의 조합을 위한 기본 구조체로서의 역할을 하였다. 이들 플라스미드는 HEK 293 EBNA 세포에서 개질된 항체 중질 쇄(가변 도메인이 없는 N-말단 접합, cDNA 구성)의 일시적인 발현을 가능케 하였다. 플라스미드 4962는 하기 기능성 요소를 포함한다.
감마1-중질 쇄 불변 영역을 위한 발현 카셋트 외에, 이 벡터는 하기를 함유한다:
- 선택가능한 마커로서의 하이그로마이신 내성 유전자,
- 엡스타인-바르 바이러스(EBV)의 복제 원점(oriP),
- 이 플라스미드가 대장균에서 복제될 수 있도록 하는 벡터 pUC18로부터의 복제 원점, 및
- 대장균에 암피실린 내성을 부여하는 베타-락타마제 유전자.
γ1-중질 쇄 불변 영역 유전자(CH1-경첩-CH2-CH3)의 전사 단위는 하기 요소로 구성된다:
- 인간 사이토메갈로바이러스(HCMV)로부터의 인접한 초기 증강자 및 프로모터,
- 5'-말단에 단일 BglII 제한 부위 및 3'-말단에 단일 NheI 제한 부위(CH1 N-말단 내의 NheI 부위)를 포함하는 합성 연결자(서열 번호: 01)
- 인간 γ1-중질 쇄 유전자 불변 도메인(영역)(CH1-경첩-CH2-CH3, cDNA 구성),
- 인간 γ1-면역 글로불린 폴리아데닐화("poly A") 신호 서열, 및
- 각각 5'-말단 및 3'-말단에 독특한 제한 부위 AscI 및 FseI.
γ1-중질 쇄 불변 도메인/영역 유전자 벡터 4962의 플라스미드 맵은 도 4에 도시되어 있다.
(d) 플라스미드 4964
벡터 4964는 발현 플라스미드 4976 및 4977을 조합하기 위한 기본 구조체로서의 역할을 하였다. 이들 플라스미드는 HEK 293 EBNA 세포에서 개질된 항-IGF-1R 항체 경질 쇄(N-말단 접합)의 일시적인 발현을 가능케 하였다.
플라스미드 4964는 발현 플라스미드 4802의 변이체이다.
항-IGF-1R κ-경질 유전자의 전사 단위를 아래 표시되는 바와 같이 개질시켰다:
천연 경질 쇄 신호 서열을, VL-IGF-1R 가변 도메인(영역)(서열 번호: 03)에 직접 연결되는 5'-말단에서의 독특한 BglII 제한 부위 및 3'-말단에서의 독특한 NheI 제한 부위를 갖도록 배열된 합성 연결자로 대체한다.
개질된 항-IGF-1R κ-경질 쇄 발현 벡터 4964의 플라스미드 맵이 도 5에 도시되어 있다.
(e) 플라스미드 4969
발현 플라스미드 4969는 항-IGF-1R 항체 경질 쇄의 발현 플라스미드인 플라스미드 4802로부터 유도된다. 이 플라스미드는 개질된 항체 경질 쇄 단편(가변 도메인이 없는 N-말단 접합; 폴리펩타이드-연결자-카파 쇄의 불변 영역)을 코딩한다.
플라스미드 4969를 구성하기 위하여, CMV-프로모터의 3'-말단에 독특한 BglII 제한 부위를 도입하고, 항-IGF-1R 항체 경질 쇄(서열 번호: 04)의 불변 영역의 내부에 독특한 BbsI 제한 부위를 도입하였다.
(f) 플라스미드 4963
이 플라스미드는 HEK 293 EBNA 세포에서 항-IGF-1R 항체 경질 쇄의 일시적인 발현을 가능케 하였다.
플라스미드 4963은 발현 플라스미드 4802의 변이체이다.
항-IGF-1R κ-경질 유전자의 전사 단위는 아래 표시된 바와 같이 개질되었다:
- 인간 κ-경질 쇄 불변 유전자 영역을 C-카파-Ig-카파 pA 연결 영역에서 약간 개질시켰다(독특한 HindIII 및 KasI 제한 부위의 삽입, 서열 번호: 558).
개질된 항-IGF-1R 경질 쇄 발현 벡터 4963의 플라스미드 맵은 도 6에 도시된다.
실시예
2
최종 발현 플라스미드의 제조
면역 글로불린 유전자 분절, 연결자 유전자 분절 및 폴리펩타이드 유전자 분절을 포함하는 면역 글로불린 융합 유전자(중질 및 경질 쇄)를, 유전자 분절(핵산)의 연결에 의해 공지 재조합 방법 및 기법으로 조합하였다.
펩타이드 연결자 및 폴리펩타이드를 코딩하는 핵산 서열을 각각 화학적 합성에 의해 합성한 다음, 대장균 플라스미드 내로 결찰시켰다. 서브클로닝된 핵산 서열을 DNA 서열 결정에 의해 입증하였다.
사용된 면역 글로불린 폴리펩타이드 쇄, 면역 글로불린 단편, 폴리펩타이드 접합(N-말단)의 위치, 사용된 연결자 및 사용된 폴리펩타이드가 표 2(39쪽), 표 3 및 표 3a에 기재된다.
| 단백질 및 폴리펩타이드 | 서열 번호: |
| HIV-1 gp41(BH8 gp 160의 위치 507-851) | 11 |
| T-651(예컨대, US 6,656,906 호 참조) | 12 |
| HIV-1 gp41 엑토도메인 변이체 단일 변이주: I568P | 13 |
| HIV-1 gp41 엑토도메인 변이체 4종 변이주: I568P, L550E, L566E, I580E | 14 |
| 삽입체 | 서열 번호: |
| 삽입체 4964 (독특한 제한 부위의 도입) | 15 |
| 신호 서열(MDTLCSTLLLLTIPSWVLS), 삽입된 짧은 서열(QIWNN), 이종 폴리펩타이드(MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL), 연결자(GGGGSGGGGSGGGGSG)를 포함하는 삽입체 4965(T-651과 함께) | 16 |
| 신호 서열(MDTLCSTLLLLTIPSWVLS), 삽입된 짧은 서열(QIWNN), 이종 폴리펩타이드(MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL), 연결자(GGGGSGGGGSGGGGSGGGGSGGGGSG)를 포함하는 삽입체 4966(T-651과 함께) | 17 |
| 신호 서열(MDTLCSTLLLLTIPSWVLS), 삽입된 짧은 서열(QIWNN), 이종 폴리펩타이드(MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL), 연결자(GSSSSSSSSSSSSSSSG)를 포함하는 삽입체 4967(T-651과 함께) | 18 |
| 신호 펩타이드(MEFGLSWVFLVALLRGVQC), 삽입된 짧은 서열(Q), 이종 폴리펩타이드(VQARQLLSGIVQQQNNLLRAIEGQQHLLQLTVWGPKQLQARILAVERYLKDQQLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL), 연결자(GGGGSGGGGSGGGGSG)를 포함하는 삽입체 4969(gp41 단일 변이주) | 19 |
개질된 면역 글로불린 폴리펩타이드 경질 및 중질 쇄(발현 카셋트)의 일시적인 발현을 위한 최종 발현 플라스미드의 구성에 사용되는 구성요소가 사용된 기본 플라스미드, 클로닝 부위 및 접합된 면역 글로불린 폴리펩타이드를 코딩하는 삽입된 핵산 서열과 관련하여 표 4에 기재된다.
| 발현 플라스미드 | 기본 벡터 | 삽입된 DNA 유전자 분절 | 클로닝 부위 |
| N-말단 접합: 중질 쇄(가변 도메인 없음) | |||
| 4965 | 4962 | 삽입체 4965(249Bp) | BglII/NheI |
| 4966 | 4962 | 삽입체 4966(279Bp) | BglII/NheI |
| 4967 | 4962 | 삽입체 4967(252Bp) | BglII/NheI |
| N-말단 접합: 경질 쇄(가변 도메인 없음) | |||
| 4969 | 4802 | 삽입체 4969(589Bp) | BglII/BbsI |
| N-말단 접합: 경질 쇄(가변 도메인 포함) | |||
| 4976 | 4964 | 삽입체 4965(249Bp) | HindIII/KasI |
| 4977 | 4964 | 삽입체 4967(252Bp) | HindIII/KasI |
표 5에는 HIV-1 억제 특성을 갖는 사용된 폴리펩타이드(T-651 및 HIV-1 gp41 엑토도메인 변이체), 면역 글로불린 경질 또는 중질 쇄를 폴리펩타이드와 연결시키는데 사용된 연결자 및 코딩된 아미노산 서열로부터 유추되는 개질된 항체 쇄의 유추된 분자량이 기재되어 있다.
| 발현 플라스미드 | 폴리펩타이드 | 분자량[Da] | 연결자 서열 번호: |
| 기준 플라스미드 | |||
| 4818 | 항-IGF-1R 중질 쇄 | 49263.5 | 연결자 없음 |
| 4802 | 항-IGF-1R 경질 쇄 | 23572.2 | 연결자 없음 |
| N-말단 융합: 중질 쇄(가변 도메인 없음) | |||
| 4965 | T-651 | 42227.3 | 554 |
| 4966 | T-651 | 42857.9 | 555 |
| 4967 | T-651 | 42644.7 | 09 |
| N-말단 융합; 경질 쇄(가변 도메인 없음) | |||
| 4969 | Gp41 단일 변이주 | 27247.3 | 554 |
| N-말단 융합: 경질 쇄(가변 도메인 포함) | |||
| 4976 | T-651 | 29851.9 | 139 |
| 4977 | T-651 | 30269.2 | 140 |
실시예
3
HEK
293
EBNA
세포에서의 면역 글로불린
변이체의
일시적인 발현
10% 초저 IgG FCS[태아 송아지 혈청, 깁코(Gibco), 인비트로젠 코포레이션, 미국], 2mM 글루타민(깁코, 인비트로젠 코포레이션, 미국), 1%(v/v) 비-필수 아미노산(깁코, 인비트로젠 코포레이션, 미국) 및 250㎍/ml G418[로슈 몰레큘라 바이오케미칼즈(Roche Molecular Biochemicals), 로슈 다이아그노스틱스 게엠베하(Roche Diagnostics GmbH), 독일]로 보충된 DMEM[덜베코 개질된 이글 배지(Dulbecco's modified Eagle's medium), 깁코, 인비트로젠 코포레이션, 미국]에서 배양된 착생 생육중인 HEK293-EBNA 세포[엡스타인-바르-바이러스 핵 항원을 발현하는 인간 배아 신장 세포주 293; 어메리칸 타입 컬쳐 콜렉션(American type culture collection) 수탁 번호 ATCC # CRL-10852]를 일시적으로 형질 감염시킴으로써 재조합 면역 글로불린 변이체를 발생시켰다. 형질 감염을 위해서는, 퓨젠(Fugene™) 6 형질 감염 시약(로슈 몰레큘라 바이오케미칼즈, 로슈 다이아그노스틱스 게엠베하, 독일)을 3:1 내지 6:1의 시약(㎕) 대 DNA(㎍)의 비로 사용하였다.
1:2 내지 2:1의 경질 쇄 코딩 플라스미드 대 중질 쇄 코딩 플라스미드의 몰비를 사용하여 두 상이한 플라스미드로부터 면역 글로불린 폴리펩타이드 경질 및 중질 쇄를 발현시켰다. 면역 글로불린 변이체를 함유하는 세포 배양 상청액을 형질 감염시킨 후 4일째 내지 11일째에 수획하였다. 상청액을 정제할 때까지 빙수욕에서 0℃에서 저장하였다.
예컨대 HEK293 세포에서의 인간 면역 글로불린의 재조합 발현에 관한 일반적인 정보는 메이스너(Meissner, P.) 등의 문헌[Biotechnol. Bioeng. 75 (2001) 197-203]에 기재되어 있다.
실시예
4
면역 글로불린 특이적 항체 접합체
를
사용하는
SDS
PAGE
,
웨스턴
블롯팅
전달 및 검출을 이용한 발현 분석
소듐 도데실 설페이트(SDS) 폴리아크릴아마이드 겔 전기영동(SDS-PAGE)에 의해, 발현 및 분비된 폴리펩타이드를 처리하였고, 분리된 폴리펩타이드를 겔로부터 막으로 전달한 다음, 면역학적 방법에 의해 검출하였다.
SDS
-
PAGE
LDS 샘플 완충액, 4배 농축액(4x): 글라이세롤 4g, 트리스-염기 0.682g, 트리스-하이드로클로라이드 0.666g, LDS(리튬 도데실 설페이트) 0.8g, EDTA(에틸렌 다이아민 테트라 산) 0.006g, 물중 서바 블루(Serva Blue) G250의 1중량%(w/v) 용액 0.75ml, 페놀 레드의 1중량%(w/v) 용액 0.75ml, 총 부피가 10ml가 되도록 물을 첨가함.
분비된 폴리펩타이드를 함유하는 배양액을 원심분리하여 세포 및 세포 찌꺼기를 제거하였다. 정제된 상청액의 분취량을 4xLDS 샘플 완충액 1/4부피(v/v) 및 0.5M 1,4-다이티오트레이톨(DTT) 1/10부피(v/v)와 혼합하였다. 이어, 샘플을 70℃에서 10분간 배양하고, SDS-PAGE에 의해 단백질을 분리하였다. 제조업체의 지시에 따라 누페이지(NuPAGE; 등록상표) 프리-캐스트(Pre-Cast) 겔 시스템(인비트로젠 코포레이션, 미국)을 사용하였다. 구체적으로는, 10% 누페이지(등록상표) 노벡스(Novex; 등록상표) 비스-트리스 프리-캐스트 겔(pH 6.4) 및 누페이지(등록상표) MOPS 실행 완충액을 사용하였다.
웨스턴
블롯
전달 완충액: 39mM 글리신, 48mM 트리스-하이드로클로라이드, 0.04중량%(w/v) SDS, 및 20부피% 메탄올(v/v).
SDS-PAGE 후, 분리된 면역 글로불린 접합체 폴리펩타이드 쇄를 버넷(Burnette)의 "세미드라이-블롯팅-방법"[버넷, Anal. Biochem. 112 (1981) 195-203]에 따라 전기 영동에 의해 나이트로셀룰로즈 필터 막(공극 크기: 0.45㎛)으로 옮겼다.
면역학적 검출
TBS-완충액: 50mM 트리스-하이드로클로라이드, 150mM NaCl, pH 7.5로 조정됨.
차단 용액: TBS-완충액중 1% (w/v) 웨스턴 블로킹 시약(로슈 몰레큘라 바이오케미칼즈, 로슈 다이아그노스틱스 게엠베하, 독일).
TBST-완충액: 트윈(Tween)-20 0.05부피%(v/v)를 갖는 1xTBS-완충액.
면역학적 검출을 위해, 웨스턴 블롯팅 막을 실온에서 5분간 TBS-완충액중에서 2회, 또한 차단 용액중에서 90분간 1회, 진탕하면서 배양하였다.
면역 글로불린 접합체
폴리펩타이드
쇄의 검출
중질 쇄: 중질 쇄 또는 중질 쇄 단편을 함유하는 폴리펩타이드를 검출하기 위하여, 퍼옥시다제에 접합된 정제된 토끼 항-인간 IgG 항체를 사용하였다(코드 번호: P 0214, DAKO, 덴마크).
경질 쇄: 경질 쇄 또는 경질 쇄 단편을 함유하는 폴리펩타이드를, 정제된 퍼옥시다제 접합된 토끼 항-인간 카파 경질 쇄 항체(DAKO, 덴마크, 코드 번호: P 0129)로 검출하였다.
항체 경질 및 중질 쇄 또는 이들의 단편을 가시화하기 위하여, 세척 및 차단된 웨스턴 블롯 막을 먼저, 4℃에서 진탕하면서 하룻밤동안 10ml의 차단 용액 중에서 1:10,000의 희석비로, 중질 쇄의 경우 퍼옥시다제에 접합된 정제된 토끼 항-인간 IgG 항체로, 또는 경질 쇄의 경우 정제된 퍼옥시다제 접합된 토끼 항-인간 카파 경질 쇄 항체로 배양하였다. 실온에서 막을 TBTS-완충액으로 3회, 또한 TBS 완충액으로 1회 10분간 세척한 다음, 웨스턴-블롯 막을 루미놀/퍼옥사이드-용액 발생 화학 발광법으로 전개시켰다[루미-라이트플러스(Lumi-LightPLUS) 웨스턴 블롯팅 기질, 로슈 몰레큘라 바이오케미칼즈, 로슈 다이아그노스틱스 게엠베하, 독일]. 따라서, 막을 루미놀/퍼옥사이드-용액 10ml 중에서 10초 내지 5분간 배양하고, 그 후 루미-이미저(Lumi-Imager) F1 어낼러세이터(Analysator)(로슈 몰레큘라 바이오케미칼즈, 로슈 다이아그노스틱스 게엠베하, 독일)로 방출된 광을 검출하고/하거나, x-선-필름으로 기록하였다.
반점의 세기를 루미애널리스트(LumiAnalyst) 소프트웨어(버전 3.1)로 정량하였다.
면역
블롯(immunoblot)의
다중-염색
10mM 베타-머캅토에탄올 및 20%(w/v) SDS를 함유하는 1M 트리스-하이드로클로라이드-완충액(pH 6.7) 중에서 70℃에서 1시간동안 막을 배양함으로써, 염색된 블롯으로부터, 검출에 사용된 2차 퍼옥시다제-라벨링된 항체 접합체를 제거할 수 있다. 이 처리 후, 블롯을 다른 2차 항체로 두번째로 염색할 수 있다. 제 2 검출 전에, 블롯을 실온에서 TBS-완충액 중에서 진탕하면서 각각 10분동안 3회 세척한다.
샘플 배열은 표 6에 기재된다.
| 샘플 | 발현 플라스미드 | 주 |
|
| 경질 쇄 | 중질 쇄 | ||
| MW 마커 | |||
| 항-IGF-1R(기준 항체), 50ng | |||
| 항-IGF-1R(기준 항체), 150ng | |||
| 항-IGF-1R(기준 항체), 500ng | |||
| HEK 293 배지 | |||
| 3 | 4802(중량) | 4818(중량) | 항-IGF-1R(기준 항체) 대조용 |
| 4 | 4802(중량) | 4961(중량) | 항-IGF-1R(기준 항체) 대조용 |
| 5 | 4963(중량) | 4818(중량) | 항-IGF-1R(기준 항체) 대조용 |
| 6 | 4802(중량) | 4965 | N-말단; 중질; VH 없음 |
| 7 | 4802(중량) | 4966 | N-말단; 중질; VH 없음 |
| 8 | 4802(중량) | 4967 | N-말단; 중질; VH 없음 |
| 9 | 4969 | 4818(중량) | N-말단; 경질; VL 없음 |
| 10 | 4976 | 4818(중량) | N-말단; 경질 |
| 11 | 4977 | 4918(중량) | N-말단; 경질 |
| 12 | 4969 | 4966 | N-말단; 경질; VL 없음 N-말단; 중질; VH 없음 |
| 13 | 4976 | 4966 | N-말단; 경질 N-말단; 중질; VH 없음 |
| 14 | 4977 | 4967 | N-말단; 경질 N-말단; 중질; VH 없음 |
실시예
5
조합된 면역 글로불린
폴리펩타이드의
검출
단백질 A
세파로즈
™
CL
-4B로의 친화력 결합에 의한 면역 글로불린
폴리펩타이드의
정제 및 농도
하나 이상의 플라스미드를 함유하는 HEK 293 EBNA 세포를, 플라스미드 상에 위치하는 폴리펩타이드 유전자의 일시적인 발현에 적합한 조건하에서 6 내지 10일간 배양하였다. 1.8ml들이 에펜도르프(Eppendorf) 컵 내의 정제된 배양 상청액 1ml에, 단백질 A 세파로즈™ CL-4B(지이 헬쓰케어 포머 애머샴 바이오사이언시즈, 스웨덴) 현탁액[PBS 완충액(10mM Na2HPO4, 1mM KH2PO4, 137mM NaCl 및 2.7mM KCl, pH 7.4)중 단백질 A 세파로즈의 1:1 (v/v) 현탁액] 0.1ml를 첨가하였다. 현탁액을 실온에서 진탕하면서 1시간 내지 16시간동안 배양하였다. 그 후, 세파로즈 비드를 원심분리(30초, 5000rpm)에 의해 침강시키고, 상청액을 폐기하였다. 이어, 세파로즈 펠렛을 각각 PBS 완충액 1.6ml, 0.1M 시트레이트 완충액(pH 5.0) 1.6ml 및 증류수 1.6ml로 세척하였다. 단백질 A 결합된 면역 글로불린을 70℃에서 5 내지 10분동안 1xLDS-PAGE 샘플 완충액 0.1ml로 세파로즈 비드로부터 추출하였다. 실시예 4에 기재된 바와 같이 SDS-PAGE 분리 및 쿠마지 브릴리언트 블루를 사용한 염색에 의해 분석을 수행하였다.
결과:
일시적인 발현 후 중질 및/또는 경질 쇄 단편을 함유하는 폴리펩타이드의 발현/분비-분석:
도 7a 내지 7c: 친화력 정제된 폴리펩타이드의 쿠마지 블루 염색된 SDS-PAGE-겔; 표 6에 따른 샘플 배열
면역 글로불린을 함유하는
폴리펩타이드의
면역 검출:
도 8a 내지 8c: HEK 293 EBNA 세포에서 일시적으로 발현시킨 후 세포 배양 상청액중 경질 쇄 단편을 함유하는 폴리펩타이드의 면역 검출
도 9a 내지 9c: HEK 293 EBNA 세포에서 일시적으로 발현시킨 후 세포 배양 상청액중 중질 쇄 단편을 함유하는 폴리펩타이드의 면역 검출
도 7a 내지 7c, 도 8a 내지 8c 및 도 9a 내지 9c로부터, 폴리펩타이드가 일시적으로 발현되고 배지중으로 분비되는 것으로 유추될 수 있다. 면역 글로불린을 함유하는 폴리펩타이드가 하나 또는 수개의 글라이코실화 부위를 갖는 경우, 최종 폴리펩타이드는 정확하게 한정되는 분자량을 갖지 않고, 글라이코실화도에 따른 분자량 분포를 갖는다. 이는 SDS-PAGE에서 하나의 폴리펩타이드를 나타내는 모든 종이 균질하게 이동하지 않아서 밴드가 넓어지도록 한다.
실시예
6
인간
IgG
ELISA
를 사용한, 발현된 중질 쇄 함유
폴리펩타이드의
정량
캡쳐 시약으로서 바이오틴일화된 항-인간 IgG F(ab')2 단편을 사용하는, 퍼옥시다제-접합된 항-인간 IgG F(ab')2 항체 단편을 검출하기 위한 샌드위치 ELISA에 의해, 세포 배양 상청액중 면역 글로불린 중질 쇄 단편 함유 폴리펩타이드 농도를 결정하였다.
스트펩타비딘이 코팅된 96개-웰 플레이트[피어스 리액티-바인드(Pierce Reacti-Bind™) 스트렙타비딘 코팅된 폴리스타이렌 스트립 플레이트, 코드 번호: 15121, 피어스 케미칼 캄파니(Pierce Chemical Company), 미국]를 진탕 하에 실온(RT)에서 1시간동안 배양함으로써 희석 완충액[희석 완충액: 0.5%(w/v) 소 혈청 알부민을 함유하는 PBS 완충액]중 0.5㎍/ml의 바이오틴일화된 염소 다클론 항-인간 IgG F(ab')2 항체 단편[F(ab')2<h-Fcγ>Bi; 다이아노바(Dianova), 독일, 코드 번호: 109-066-098] 캡쳐 항체(0.1ml/웰)로 코팅하였다. 그 후, 플레이트를 0.3ml보다 많은 세척 완충액[세척 완충액: 1%(w/v) 트윈 20을 함유하는 PBS]으로 3회 세척하였다. IgG 면역 글로불린 접합체를 함유하는 세포 배양 상청액(샘플)을 희석 완충액 중에서 0.5 내지 20ng/ml의 농도까지 연속적으로(2배) 희석시키고, 플레이트에 첨가한 다음, 진탕하면서 실온에서 1시간동안 배양하였다. IgG 단백질 기준 곡선을 생성시키는데, 희석 완충액중 정제된 항-IGF-1R 기준 항체(0.5 내지 20ng/ml)를 사용하였다. 플레이트를 0.3ml/웰의 세척 완충액으로 3회 세척한 다음, 인간 Fc감마에 결합한 착체를 염소 다클론 항-인간 F(ab')2-특이적 IgG[F(ab')2<h-Fcγ>POD; 다이아노바, 코드 번호: 109-036-098]의 퍼옥시다제-접합된 F(ab')2 단편으로 검출하였다. 플레이트를 0.3ml/웰의 세척 완충액으로 3회 세척한 다음, 플레이트를 ABTS(등록상표)(2,2'-아지노-비스(3-에틸벤즈티아졸린-6-설폰산) 퍼옥시다제 기질 용액(로슈 몰레큘라 바이오케미칼즈, 코드 번호: 1684302, 로슈 다이아그노스틱스 게엠베하, 독일)으로 전개시켰다. 10 내지 30분 후, 테칸 스펙트라플루오르플러스(Tecan Spectrafluorplus) 플레이트 판독기[테칸 도이칠란트 게엠베하(Tecan Deutschland GmbH), 독일] 상에서 시약 블랭크[배양 완충액+ABTS(등록상표) 용액]에 대해 405nm 및 490nm에서의 흡광도를 측정하였다. 배경 보정을 위하여, 하기 수학식 I에 따라 490nm에서의 흡광도를 405nm에서의 흡광도에서 뺐다. 모든 샘플을 최소 2회 분석하였고, 2회 또는 3회 흡광도 측정 값의 평균을 구하였다. 샘플의 IgG 함량을 표준 곡선으로부터 계산하였다.
SEQUENCE LISTING
<110> F. Hoffmann-La Roche AG
<120> METHOD FOR THE RECOMBINANT EXPRESSION OF A POLYPEPTIDE
<130> 23215 FT
<150> EP 05023003
<151> 2005-10-21
<150> EP 06010665
<151> 2006-05-24
<160> 558
<170> PatentIn version 3.2
<210> 1
<211> 21
<212> DNA
<213> Artificial
<220>
<223> synthetic linker comprising a BglII restriction site at the
5'-end and a NheI restriction site at the 3'-end (NheI site
within the CH1 N-terminus)
<400> 1
agatcttttg ccaccgctag c 21
<210> 2
<211> 15
<212> PRT
<213> Mus musculus
<400> 2
Met Asp Phe Gly Leu Ser Leu Val Phe Leu Val Leu Ile Leu Lys
1 5 10 15
<210> 3
<211> 24
<212> DNA
<213> Artificial
<220>
<223> synthetic linker arranged with a BglII restriction site at the
5'- and a NheI restriction site at the 3'-end directly joined to
the VL-IR variable region
<400> 3
agatctatat atatatatgc tagc 24
<210> 4
<211> 27
<212> DNA
<213> Artificial
<220>
<223> BglII restriction site at the 3'-end of CMV-promoter and BbsI
restriction site inside the constant region of <IGF-IR>HuMab
antibody light chain
<400> 4
cgaactgtgg ctgcaccatc tgtcttc 27
<210> 5
<211> 15
<212> PRT
<213> Mus musculus
<400> 5
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr
1 5 10 15
<210> 6
<211> 15
<212> PRT
<213> Artificial
<220>
<223> linker 1
<400> 6
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
<210> 7
<211> 25
<212> PRT
<213> Artificial
<220>
<223> linker 2
<400> 7
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25
<210> 8
<211> 15
<212> PRT
<213> Artificial
<220>
<223> linker 3
<400> 8
Gly Gln Gln Gln Gln Gly Gln Gln Gln Gln Gly Gln Gln Gln Gln
1 5 10 15
<210> 9
<211> 17
<212> PRT
<213> Artificial
<220>
<223> linker 4
<400> 9
Gly Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser
1 5 10 15
Gly
<210> 10
<211> 3
<212> PRT
<213> Artificial
<220>
<223> linker 5
<400> 10
Gly Ser Thr
1
<210> 11
<211> 345
<212> PRT
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> Natural amino acid sequence derived from the HIV-1 gp41
glycoprotein of HN-1 isolate LAI/IIIB clone BH8 (locus HIVH3BH8)
(bp-position: 507-851)
<400> 11
Ala Val Gly Ile Gly Ala Leu Phe Leu Gly Phe Leu Gly Ala Ala Gly
1 5 10 15
Ser Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val Gln Ala Arg Gln
20 25 30
Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile
35 40 45
Glu Gly Gln Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys Gln
50 55 60
Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln
65 70 75 80
Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala
85 90 95
Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile Trp
100 105 110
Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr
115 120 125
Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys
130 135 140
Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn
145 150 155 160
Trp Phe Asn Ile Thr Asn Trp Leu Trp Tyr Ile Lys Leu Phe Ile Met
165 170 175
Ile Val Gly Gly Leu Val Gly Leu Arg Ile Val Phe Ala Val Leu Ser
180 185 190
Ile Val Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser Phe Gln Thr
195 200 205
His Leu Pro Asn Pro Arg Gly Pro Asp Arg Pro Glu Gly Ile Glu Glu
210 215 220
Glu Gly Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Gly
225 230 235 240
Ser Leu Ala Leu Ile Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser
245 250 255
Tyr His Arg Leu Arg Asp Leu Leu Leu Ile Val Thr Arg Ile Val Glu
260 265 270
Leu Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu
275 280 285
Leu Gln Tyr Trp Ser Gln Glu Leu Lys Asn Ser Ala Val Asn Leu Leu
290 295 300
Asn Ala Thr Ala Ile Ala Val Ala Glu Gly Thr Asp Arg Val Ile Glu
305 310 315 320
Leu Val Gln Ala Ala Tyr Arg Ala Ile Arg His Ile Pro Arg Arg Ile
325 330 335
Arg Gln Gly Leu Glu Arg Ile Leu Leu
340 345
<210> 12
<211> 36
<212> PRT
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> Natural amino acid sequence derived from the HIV-1 gp41
ectodomain (bp-position: 621-656)
<400> 12
Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu
1 5 10 15
Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu
20 25 30
Gln Glu Leu Leu
35
<210> 13
<211> 123
<212> PRT
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> HIV-1 gp41 ectodomain variant I568P (single mutant), pb-position
534-656
<400> 13
Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn
1 5 10 15
Leu Leu Arg Ala Ile Glu Gly Gln Gln His Leu Leu Gln Leu Thr Val
20 25 30
Trp Gly Pro Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr
35 40 45
Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu
50 55 60
Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser
65 70 75 80
Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu
85 90 95
Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln
100 105 110
Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu
115 120
<210> 14
<211> 135
<212> PRT
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> HIV-1 gp41 ectodomain variant I568P, L550E, L566E, I580E
(quadruple mutant), bp-position 522-656
<400> 14
Gly Ser Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val Gln Ala Arg
1 5 10 15
Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Glu Leu Arg Ala
20 25 30
Ile Glu Gly Gln Gln His Leu Glu Gln Leu Thr Val Trp Gly Pro Lys
35 40 45
Gln Leu Gln Ala Arg Glu Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln
50 55 60
Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr
65 70 75 80
Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile
85 90 95
Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr
100 105 110
Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu
115 120 125
Lys Asn Glu Gln Glu Leu Leu
130 135
<210> 15
<211> 133
<212> DNA
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> Insert 4964
<400> 15
agatctatat atatatatgc tagcgaaatt gtgttgacac agtctccagc caccctgtct 60
ttgtctccag gggaaagagc caccctctcc tgcagggcca gtcagagtgt tagtagctac 120
ttagcctggt acc 133
<210> 16
<211> 249
<212> DNA
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> Insert 4965
<400> 16
agatcttttg ccaccatgga caccctgtgc agcaccctgc tcctgctgac catccccagc 60
tgggtgctct cccaaatctg gaacaacatg acctggatgg agtgggaccg cgagatcaat 120
aactacacaa gcttgatcca ctctctgatc gaggaaagcc agaaccagca ggagaagaac 180
gagcaggagc tcctgggcgg gggtggatcc ggcggcgggg gcagcggcgg gggaggctcc 240
ggcgctagc 249
<210> 17
<211> 279
<212> DNA
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> Insert 4966
<400> 17
agatcttttg ccaccatgga caccctgtgc agcaccctgc tcctgctgac catccccagc 60
tgggtgctct cccaaatctg gaacaacatg acctggatgg agtgggaccg cgagatcaat 120
aactacacaa gcttgatcca ctctctgatc gaggaaagcc agaaccagca ggagaagaac 180
gagcaggagc tcctgggcgg gggtggctcc ggcggcgggg gcagcggcgg gggaggctcc 240
ggcgggggcg gatccggggg cggtggcagc ggcgctagc 279
<210> 18
<211> 252
<212> DNA
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> Insert 4967
<400> 18
agatcttttg ccaccatgga caccctgtgc agcaccctgc tcctgctgac catccccagc 60
tgggtgctct cccaaatctg gaacaacatg acctggatgg agtgggaccg cgagatcaat 120
aactacacaa gcttgatcca ctccctgatc gaggaaagcc agaaccagca ggagaagaac 180
gagcaggagc tcctgggatc cagctccagc tccagctcca gctccagcag tagctccagc 240
tctggcgcta gc 252
<210> 19
<211> 589
<212> DNA
<213> Human immunodeficiency virus
<220>
<221> misc_feature
<223> Insert 4969
<400> 19
agatctagct ctgggagagg agcccagcac tagaagtcgg cggtgtttcc attcggtgat 60
cagcactgaa cacagaggac tcaccatgga gtttgggctg agctgggtgt tcctcgtggc 120
actgctcagg ggtgtacagt gtcaggtgca ggcccgccag ctgctctccg gcatcgtcca 180
gcagcaaaac aatctgctgc gggcgatcga ggggcagcag cacctcctgc agctgacggt 240
gtggggtccc aagcagctgc aggcccgcat tctggccgtg gaacggtacc tgaaggacca 300
gcagctgctc ggcatctggg gatgctctgg caagcttatc tgcaccacag ccgtcccctg 360
gaacgctagc tggagtaaca aaagcctgga gcaaatttgg aacaacatga cctggatgga 420
gtgggatcgc gagatcaata attacacaag cctgatccac tccctgatcg aggaaagcca 480
gaaccagcag gagaagaacg agcaggagct cctgggcggg ggcggatccg gcggcggggg 540
cagcggtggg ggcggctccg gccgaactgt ggctgcacca tctgtcttc 589
<210> 20
<211> 15
<212> PRT
<213> Mus musculus
<400> 20
Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys
1 5 10 15
<210> 21
<211> 15
<212> PRT
<213> Mus musculus
<400> 21
Met Asn Phe Gly Leu Ser Leu Ile Phe Leu Val Leu Ile Leu Lys
1 5 10 15
<210> 22
<211> 13
<212> PRT
<213> Mus musculus
<400> 22
Met Gly Val Pro Thr Gln Leu Leu Leu Leu Trp Leu Thr
1 5 10
<210> 23
<211> 16
<212> PRT
<213> Mus musculus
<400> 23
Met Arg Val Leu Ala Glu Leu Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
<210> 24
<211> 16
<212> PRT
<213> Mus musculus
<400> 24
Met Arg Val Leu Pro Glu Phe Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
<210> 25
<211> 16
<212> PRT
<213> Mus musculus
<400> 25
Met Arg Cys Ser Leu Gln Phe Leu Gly Val Leu Met Phe Trp Ile Ser
1 5 10 15
<210> 26
<211> 15
<212> PRT
<213> Mus musculus
<400> 26
Arg Glu Trp Ser Trp Asn Phe Leu Phe Leu Leu Ser Gly Thr Thr
1 5 10 15
<210> 27
<211> 15
<212> PRT
<213> Mus musculus
<400> 27
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210> 28
<211> 19
<212> PRT
<213> Homo sapiens
<400> 28
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 29
<211> 19
<212> PRT
<213> Homo sapiens
<400> 29
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 30
<211> 19
<212> PRT
<213> Homo sapiens
<400> 30
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Ser
1 5 10 15
Ala His Ser
<210> 31
<211> 19
<212> PRT
<213> Homo sapiens
<400> 31
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Pro Thr Gly
1 5 10 15
Ala His Ser
<210> 32
<211> 19
<212> PRT
<213> Homo sapiens
<400> 32
Met Asp Cys Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Thr His Ala
<210> 33
<211> 19
<212> PRT
<213> Homo sapiens
<400> 33
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Asp
1 5 10 15
Ala Tyr Ser
<210> 34
<211> 19
<212> PRT
<213> Homo sapiens
<400> 34
Met Asp Trp Thr Trp Arg Val Phe Cys Leu Leu Ala Val Ala Pro Gly
1 5 10 15
Ala His Ser
<210> 35
<211> 19
<212> PRT
<213> Homo sapiens
<400> 35
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 36
<211> 19
<212> PRT
<213> Homo sapiens
<400> 36
Met Asp Thr Leu Cys Ser Thr Leu Leu Leu Leu Thr Ile Pro Ser Trp
1 5 10 15
Val Leu Ser
<210> 37
<211> 19
<212> PRT
<213> Homo sapiens
<400> 37
Met Asp Thr Leu Cys Tyr Thr Leu Leu Leu Leu Thr Thr Pro Ser Trp
1 5 10 15
Val Leu Ser
<210> 38
<211> 19
<212> PRT
<213> Homo sapiens
<400> 38
Met Glu Leu Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys
<210> 39
<211> 19
<212> PRT
<213> Homo sapiens
<400> 39
Met Glu Leu Gly Leu Ser Trp Ile Phe Leu Leu Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 40
<211> 19
<212> PRT
<213> Homo sapiens
<400> 40
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly
1 5 10 15
Val Gln Cys
<210> 41
<211> 19
<212> PRT
<213> Homo sapiens
<400> 41
Met Glu Leu Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys
<210> 42
<211> 19
<212> PRT
<213> Homo sapiens
<400> 42
Met Glu Phe Gly Leu Ser Trp Ile Phe Leu Ala Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 43
<211> 19
<212> PRT
<213> Homo sapiens
<400> 43
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 44
<211> 19
<212> PRT
<213> Homo sapiens
<400> 44
Met Glu Leu Gly Leu Arg Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys
<210> 45
<211> 19
<212> PRT
<213> Homo sapiens
<400> 45
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 46
<211> 19
<212> PRT
<213> Homo sapiens
<400> 46
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys
<210> 47
<211> 19
<212> PRT
<213> Homo sapiens
<400> 47
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys
<210> 48
<211> 19
<212> PRT
<213> Homo sapiens
<400> 48
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 49
<211> 19
<212> PRT
<213> Homo sapiens
<400> 49
Met Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys
<210> 50
<211> 19
<212> PRT
<213> Homo sapiens
<400> 50
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 51
<211> 19
<212> PRT
<213> Homo sapiens
<400> 51
Met Glu Phe Trp Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 52
<211> 20
<212> PRT
<213> human germline sequence
<400> 52
Met Thr Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Phe Lys
1 5 10 15
Gly Val Gln Cys
20
<210> 53
<211> 19
<212> PRT
<213> Homo sapiens
<400> 53
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 54
<211> 19
<212> PRT
<213> Homo sapiens
<400> 54
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Val Ile Leu Gln Gly
1 5 10 15
Val Gln Cys
<210> 55
<211> 19
<212> PRT
<213> Homo sapiens
<400> 55
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 56
<211> 19
<212> PRT
<213> Homo sapiens
<400> 56
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210> 57
<211> 19
<212> PRT
<213> Homo sapiens
<400> 57
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210> 58
<211> 19
<212> PRT
<213> Homo sapiens
<400> 58
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Pro
<210> 59
<211> 19
<212> PRT
<213> Homo sapiens
<400> 59
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210> 60
<211> 19
<212> PRT
<213> Homo sapiens
<400> 60
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210> 61
<211> 19
<212> PRT
<213> Homo sapiens
<400> 61
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210> 62
<211> 19
<212> PRT
<213> Homo sapiens
<400> 62
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210> 63
<211> 19
<212> PRT
<213> Homo sapiens
<400> 63
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210> 64
<211> 19
<212> PRT
<213> Homo sapiens
<400> 64
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ser
<210> 65
<211> 19
<212> PRT
<213> human germline sequence
<400> 65
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala
<210> 66
<211> 20
<212> PRT
<213> Homo sapiens
<400> 66
Met Ser Val Ser Phe Leu Ile Phe Leu Pro Val Leu Gly Leu Pro Trp
1 5 10 15
Gly Val Leu Ser
20
<210> 67
<211> 19
<212> PRT
<213> Homo sapiens
<400> 67
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 68
<211> 22
<212> PRT
<213> Homo sapiens
<400> 68
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys
20
<210> 69
<211> 22
<212> PRT
<213> human germline sequence
<400> 69
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys
20
<210> 70
<211> 22
<212> PRT
<213> Homo sapiens
<400> 70
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Gln Leu Trp
1 5 10 15
Leu Ser Gly Ala Arg Cys
20
<210> 71
<211> 22
<212> PRT
<213> Homo sapiens
<400> 71
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Ser Gly Ala Arg Cys
20
<210> 72
<211> 22
<212> PRT
<213> Homo sapiens
<400> 72
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Asp Thr Arg Cys
20
<210> 73
<211> 22
<212> PRT
<213> Homo sapiens
<400> 73
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210> 74
<211> 22
<212> PRT
<213> Homo sapiens
<400> 74
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210> 75
<211> 22
<212> PRT
<213> Homo sapiens
<400> 75
Met Asp Met Arg Val Leu Ala Gln Leu Leu Gly Leu Leu Leu Leu Cys
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210> 76
<211> 22
<212> PRT
<213> Homo sapiens
<400> 76
Met Asp Met Arg Val Leu Ala Gln Leu Leu Gly Leu Leu Leu Leu Cys
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210> 77
<211> 22
<212> PRT
<213> Homo sapiens
<400> 77
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210> 78
<211> 22
<212> PRT
<213> Homo sapiens
<400> 78
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210> 79
<211> 22
<212> PRT
<213> Homo sapiens
<400> 79
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys
20
<210> 80
<211> 22
<212> PRT
<213> Homo sapiens
<400> 80
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys
20
<210> 81
<211> 22
<212> PRT
<213> Homo sapiens
<400> 81
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210> 82
<211> 22
<212> PRT
<213> Homo sapiens
<400> 82
Met Asp Met Arg Val Pro Ala Gln Arg Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210> 83
<211> 20
<212> PRT
<213> Homo sapiens
<400> 83
Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Gly Ala Arg Cys
20
<210> 84
<211> 22
<212> PRT
<213> Homo sapiens
<400> 84
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210> 85
<211> 22
<212> PRT
<213> human germline sequence
<400> 85
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210> 86
<211> 22
<212> PRT
<213> Homo sapiens
<400> 86
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Lys Cys
20
<210> 87
<211> 20
<212> PRT
<213> Homo sapiens
<400> 87
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Glu
20
<210> 88
<211> 20
<212> PRT
<213> Homo sapiens
<400> 88
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Glu
20
<210> 89
<211> 20
<212> PRT
<213> Homo sapiens
<400> 89
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly
20
<210> 90
<211> 20
<212> PRT
<213> Homo sapiens
<400> 90
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly
20
<210> 91
<211> 20
<212> PRT
<213> Homo sapiens
<400> 91
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Ile Pro
1 5 10 15
Gly Ser Ser Ala
20
<210> 92
<211> 20
<212> PRT
<213> Homo sapiens
<400> 92
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Ile Pro
1 5 10 15
Gly Ser Ser Ala
20
<210> 93
<211> 20
<212> PRT
<213> Homo sapiens
<400> 93
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Ser
1 5 10 15
Gly Ser Ser Gly
20
<210> 94
<211> 20
<212> PRT
<213> Homo sapiens
<400> 94
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Ser
1 5 10 15
Gly Ser Ser Gly
20
<210> 95
<211> 20
<212> PRT
<213> Homo sapiens
<400> 95
Met Arg Leu Leu Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly
20
<210> 96
<211> 20
<212> PRT
<213> Homo sapiens
<400> 96
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210> 97
<211> 20
<212> PRT
<213> Homo sapiens
<400> 97
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210> 98
<211> 20
<212> PRT
<213> Homo sapiens
<400> 98
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210> 99
<211> 20
<212> PRT
<213> Homo sapiens
<400> 99
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210> 100
<211> 20
<212> PRT
<213> Homo sapiens
<400> 100
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210> 101
<211> 20
<212> PRT
<213> Homo sapiens
<400> 101
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Thr Thr Gly
20
<210> 102
<211> 23
<212> PRT
<213> Homo sapiens
<400> 102
Met Glu Pro Trp Lys Pro Gln His Ser Phe Phe Phe Leu Leu Leu Leu
1 5 10 15
Trp Leu Pro Asp Thr Thr Gly
20
<210> 103
<211> 20
<212> PRT
<213> Homo sapiens
<400> 103
Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15
Gly Ala Tyr Gly
20
<210> 104
<211> 20
<212> PRT
<213> Homo sapiens
<400> 104
Met Gly Ser Gln Val His Leu Leu Ser Phe Leu Leu Leu Trp Ile Ser
1 5 10 15
Asp Thr Arg Ala
20
<210> 105
<211> 19
<212> PRT
<213> Homo sapiens
<400> 105
Met Leu Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala
1 5 10 15
Ser Arg Gly
<210> 106
<211> 19
<212> PRT
<213> Homo sapiens
<400> 106
Met Leu Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala
1 5 10 15
Ser Arg Gly
<210> 107
<211> 20
<212> PRT
<213> Homo sapiens
<400> 107
Met Val Ser Pro Leu Gln Phe Leu Arg Leu Leu Leu Leu Trp Val Pro
1 5 10 15
Ala Ser Arg Gly
20
<210> 108
<211> 19
<212> PRT
<213> Homo sapiens
<400> 108
Met Ala Trp Ser Pro Leu Phe Leu Thr Leu Ile Thr His Cys Ala Gly
1 5 10 15
Ser Trp Ala
<210> 109
<211> 19
<212> PRT
<213> Homo sapiens
<400> 109
Met Ala Trp Ser Pro Leu Leu Leu Thr Leu Leu Ala His Cys Thr Gly
1 5 10 15
Ser Trp Ala
<210> 110
<211> 19
<212> PRT
<213> Homo sapiens
<400> 110
Met Ala Ser Phe Pro Leu Leu Leu Thr Leu Leu Thr His Cys Ala Gly
1 5 10 15
Ser Trp Ala
<210> 111
<211> 19
<212> PRT
<213> Homo sapiens
<400> 111
Met Ala Gly Phe Pro Leu Leu Leu Thr Leu Leu Thr His Cys Ala Gly
1 5 10 15
Ser Trp Ala
<210> 112
<211> 19
<212> PRT
<213> Homo sapiens
<400> 112
Met Thr Cys Ser Pro Leu Leu Leu Thr Leu Leu Ile His Cys Thr Gly
1 5 10 15
Ser Trp Ala
<210> 113
<211> 19
<212> PRT
<213> Homo sapiens
<400> 113
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210> 114
<211> 19
<212> PRT
<213> Homo sapiens
<400> 114
Met Ala Trp Ala Leu Leu Leu Leu Ser Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210> 115
<211> 19
<212> PRT
<213> Homo sapiens
<400> 115
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210> 116
<211> 19
<212> PRT
<213> Homo sapiens
<400> 116
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210> 117
<211> 19
<212> PRT
<213> Homo sapiens
<400> 117
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Asp Thr Gly
1 5 10 15
Ser Trp Ala
<210> 118
<211> 19
<212> PRT
<213> Homo sapiens
<400> 118
Met Ala Trp Ile Pro Leu Phe Leu Gly Val Leu Ala Tyr Cys Thr Gly
1 5 10 15
Ser Val Ala
<210> 119
<211> 19
<212> PRT
<213> Homo sapiens
<400> 119
Met Ala Trp Thr Ala Leu Leu Leu Ser Leu Leu Ala His Phe Thr Gly
1 5 10 15
Ser Val Ala
<210> 120
<211> 19
<212> PRT
<213> Homo sapiens
<400> 120
Met Ala Trp Thr Pro Leu Leu Leu Pro Leu Leu Thr Phe Cys Thr Val
1 5 10 15
Ser Glu Ala
<210> 121
<211> 19
<212> PRT
<213> Homo sapiens
<400> 121
Met Ala Trp Ile Pro Leu Leu Leu Pro Leu Leu Thr Leu Cys Thr Gly
1 5 10 15
Ser Glu Ala
<210> 122
<211> 19
<212> PRT
<213> Homo sapiens
<400> 122
Met Ala Trp Thr Pro Leu Trp Leu Thr Leu Leu Thr Leu Cys Ile Gly
1 5 10 15
Ser Val Val
<210> 123
<211> 19
<212> PRT
<213> Homo sapiens
<400> 123
Met Ala Trp Thr Val Leu Leu Leu Gly Leu Leu Ser His Cys Thr Gly
1 5 10 15
Ser Val Thr
<210> 124
<211> 19
<212> PRT
<213> Homo sapiens
<400> 124
Met Ala Trp Ala Thr Leu Leu Leu Pro Leu Leu Asn Leu Tyr Thr Gly
1 5 10 15
Ser Ile Ala
<210> 125
<211> 19
<212> PRT
<213> Homo sapiens
<400> 125
Met Ala Trp Ile Pro Leu Leu Leu Pro Leu Leu Thr Leu Cys Thr Gly
1 5 10 15
Ser Glu Ala
<210> 126
<211> 19
<212> PRT
<213> Homo sapiens
<400> 126
Met Ala Trp Ile Pro Leu Leu Leu Pro Leu Leu Ile Leu Cys Thr Val
1 5 10 15
Ser Val Ala
<210> 127
<211> 19
<212> PRT
<213> Homo sapiens
<400> 127
Met Ala Trp Val Ser Phe Tyr Leu Leu Pro Phe Ile Phe Ser Thr Gly
1 5 10 15
Leu Cys Ala
<210> 128
<211> 21
<212> PRT
<213> Homo sapiens
<400> 128
Met Ala Trp Thr Gln Leu Leu Leu Leu Phe Pro Leu Leu Leu His Trp
1 5 10 15
Thr Gly Ser Leu Ser
20
<210> 129
<211> 20
<212> PRT
<213> Homo sapiens
<400> 129
Met Ala Trp Thr Pro Leu Leu Phe Leu Thr Leu Leu Leu His Cys Thr
1 5 10 15
Gly Ser Leu Ser
20
<210> 130
<211> 19
<212> PRT
<213> Homo sapiens
<400> 130
Met Ala Trp Thr Pro Leu Leu Leu Leu Leu Leu Ser His Cys Thr Gly
1 5 10 15
Ser Leu Ser
<210> 131
<211> 19
<212> PRT
<213> Homo sapiens
<400> 131
Met Ala Trp Thr Pro Leu Leu Leu Leu Phe Leu Ser His Cys Thr Gly
1 5 10 15
Ser Leu Ser
<210> 132
<211> 19
<212> PRT
<213> Homo sapiens
<400> 132
Met Ala Trp Thr Leu Leu Leu Leu Val Leu Leu Ser His Cys Thr Gly
1 5 10 15
Ser Leu Ser
<210> 133
<211> 19
<212> PRT
<213> Homo sapiens
<400> 133
Met Ala Trp Ala Pro Leu Leu Leu Thr Leu Leu Ala His Cys Thr Gly
1 5 10 15
Ser Trp Ala
<210> 134
<211> 19
<212> PRT
<213> Homo sapiens
<400> 134
Met Ala Trp Thr Pro Leu Phe Leu Phe Leu Leu Thr Cys Cys Pro Gly
1 5 10 15
Ser Asn Ser
<210> 135
<211> 19
<212> PRT
<213> Homo sapiens
<400> 135
Met Ala Trp Thr Pro Leu Phe Leu Phe Leu Leu Thr Cys Cys Pro Gly
1 5 10 15
Ser Asn Ser
<210> 136
<211> 19
<212> PRT
<213> Homo sapiens
<400> 136
Met Ala Trp Met Met Leu Leu Leu Gly Leu Leu Ala Tyr Gly Ser Gly
1 5 10 15
Val Asp Ser
<210> 137
<211> 19
<212> PRT
<213> Homo sapiens
<400> 137
Met Ala Trp Ala Pro Leu Leu Leu Thr Leu Leu Ser Leu Leu Thr Gly
1 5 10 15
Ser Leu Ser
<210> 138
<211> 19
<212> PRT
<213> Homo sapiens
<400> 138
Met Pro Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr His Ser Ala Val
1 5 10 15
Ser Val Val
<210> 139
<211> 18
<212> PRT
<213> Artificial
<220>
<223> linker 6
<400> 139
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Ala Ser
<210> 140
<211> 19
<212> PRT
<213> Artificial
<220>
<223> linker 7
<400> 140
Gly Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser
1 5 10 15
Gly Ala Ser
<210> 141
<211> 14
<212> PRT
<213> Mus musculus
<400> 141
Met Asp Phe Gly Leu Ile Phe Phe Ile Val Ala Leu Leu Lys
1 5 10
<210> 142
<211> 10
<212> PRT
<213> Mus musculus
<400> 142
Glu Leu Trp Val Leu Met Val Trp Val Pro
1 5 10
<210> 143
<211> 13
<212> PRT
<213> Mus musculus
<400> 143
Glu Leu Trp Val Leu Met Val Trp Val Pro Ser Thr Ser
1 5 10
<210> 144
<211> 18
<212> PRT
<213> Mus musculus
<400> 144
His Asp His Ala Leu Thr Ser Ser Ser Pro Gln Pro Ser Ser Pro Leu
1 5 10 15
Cys Leu
<210> 145
<211> 16
<212> PRT
<213> Mus musculus
<400> 145
Leu Ala Val Ile Thr Ser Asn Ile Trp Phe Pro Met Val Cys Met Ser
1 5 10 15
<210> 146
<211> 21
<212> PRT
<213> Mus musculus
<400> 146
Met Asp Met Trp Thr Ser Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Leu Ala Arg Cys
20
<210> 147
<211> 18
<212> PRT
<213> Mus musculus
<400> 147
Met Asp Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Val
1 5 10 15
Leu Ser
<210> 148
<211> 16
<212> PRT
<213> Mus musculus
<400> 148
Met Leu Arg Ala Ile Lys Ala Ala Pro Phe Ser Arg Phe Gly Cys Ser
1 5 10 15
<210> 149
<211> 19
<212> PRT
<213> Mus musculus
<400> 149
Met Arg Ala Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
Ala Arg Cys
<210> 150
<211> 16
<212> PRT
<213> Mus musculus
<400> 150
Met Arg Cys Ser Pro His Phe Leu Glu Leu Leu Val Phe Trp Ile Leu
1 5 10 15
<210> 151
<211> 19
<212> PRT
<213> Mus musculus
<400> 151
Met Arg Pro Thr Leu Ser Phe Leu Gly Ser Cys Cys Ser Ser Leu Ile
1 5 10 15
Leu Arg Cys
<210> 152
<211> 19
<212> PRT
<213> Mus musculus
<400> 152
Met Arg Thr Pro Ala His Phe Leu Gly Leu Leu Leu Leu Cys Phe Leu
1 5 10 15
Gly Arg Cys
<210> 153
<211> 19
<212> PRT
<213> Mus musculus
<400> 153
Met Arg Thr Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Ser
1 5 10 15
Ala Arg Cys
<210> 154
<211> 19
<212> PRT
<213> Mus musculus
<400> 154
Met Ser Leu Leu Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Arg Cys
<210> 155
<211> 19
<212> PRT
<213> Mus musculus
<400> 155
Met Ser Leu Pro Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210> 156
<211> 18
<212> PRT
<213> Mus musculus
<400> 156
Met Thr Met Leu Ser Leu Ala Pro Leu Leu Ser Leu Leu Leu Leu Cys
1 5 10 15
Val Ser
<210> 157
<211> 16
<212> PRT
<213> Mus musculus
<400> 157
Met Thr Ser Leu Ser Gln Leu Leu Gly Met Leu Met Leu Gln Ser Leu
1 5 10 15
<210> 158
<211> 16
<212> PRT
<213> Mus musculus
<400> 158
Met Val Phe Ala Pro Gln Ile Leu Gly Phe Leu Leu Leu Trp Ile Ser
1 5 10 15
<210> 159
<211> 16
<212> PRT
<213> Mus musculus
<400> 159
Met Val Phe Thr Pro His Ile Leu Gly Leu Leu Leu Phe Trp Ile Ser
1 5 10 15
<210> 160
<211> 19
<212> PRT
<213> Mus musculus
<400> 160
Gln His Gly His Glu Gly Leu Cys Ser Val Ser Trp Val Pro Val Ala
1 5 10 15
Thr Asn Ser
<210> 161
<211> 18
<212> PRT
<213> Mus musculus
<400> 161
Arg Glu Trp Ser Trp Asn Phe Leu Phe Leu Leu Ser Gly Thr Thr Val
1 5 10 15
Ser Ser
<210> 162
<211> 19
<212> PRT
<213> Mus musculus
<400> 162
Thr Asp Phe His Met Gln Ile Phe Ser Phe Met Leu Ile Ser Phe Thr
1 5 10 15
Ala Arg Cys
<210> 163
<211> 16
<212> PRT
<213> Mus musculus
<400> 163
Met Glu Phe Gln Thr Gln Val Leu Met Ser Leu Leu Leu Cys Met Ser
1 5 10 15
<210> 164
<211> 16
<212> PRT
<213> Mus musculus
<400> 164
Met Glu Ser Gln Thr Gln Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 165
<211> 16
<212> PRT
<213> Mus musculus
<400> 165
Met Val Ser Thr Pro Gln Phe Leu Val Phe Leu Leu Phe Trp Ile Pro
1 5 10 15
<210> 166
<211> 16
<212> PRT
<213> Mus musculus
<400> 166
Met Val Ser Thr Pro Gln Phe Leu Val Phe Leu Leu Phe Trp Ile Pro
1 5 10 15
<210> 167
<211> 16
<212> PRT
<213> Mus musculus
<400> 167
Met Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 168
<211> 16
<212> PRT
<213> Mus musculus
<400> 168
Met Lys Ser Gln Thr Gln Val Phe Ile Phe Leu Leu Leu Cys Val Ser
1 5 10 15
<210> 169
<211> 16
<212> PRT
<213> Mus musculus
<400> 169
Met Lys Ser Gln Thr Gln Val Phe Val Phe Leu Leu Leu Cys Val Ser
1 5 10 15
<210> 170
<211> 15
<212> PRT
<213> Mus musculus
<400> 170
Met Ala Trp Ile Ser Leu Ile Leu Ser Leu Leu Ala Leu Ser Ser
1 5 10 15
<210> 171
<211> 15
<212> PRT
<213> Mus musculus
<400> 171
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser
1 5 10 15
<210> 172
<211> 16
<212> PRT
<213> Mus musculus
<400> 172
Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
<210> 173
<211> 15
<212> PRT
<213> Mus musculus
<400> 173
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr
1 5 10 15
<210> 174
<211> 16
<212> PRT
<213> Mus musculus
<400> 174
Met Arg Phe Gln Val Gln Val Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
<210> 175
<211> 16
<212> PRT
<213> Mus musculus
<400> 175
Met Arg Pro Ser Ile Gln Phe Leu Gly Leu Leu Leu Phe Trp Leu His
1 5 10 15
<210> 176
<211> 18
<212> PRT
<213> Mus musculus
<400> 176
Met Asp Ile Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 177
<211> 18
<212> PRT
<213> Mus musculus
<400> 177
Met Asp Met Met Val Leu Ala Gln Phe Leu Ala Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 178
<211> 18
<212> PRT
<213> Mus musculus
<400> 178
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 179
<211> 18
<212> PRT
<213> Mus musculus
<400> 179
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 180
<211> 18
<212> PRT
<213> Mus musculus
<400> 180
Met Asp Met Arg Ala Pro Ala Gln Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 181
<211> 18
<212> PRT
<213> Mus musculus
<400> 181
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 182
<211> 18
<212> PRT
<213> Mus musculus
<400> 182
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 183
<211> 18
<212> PRT
<213> Mus musculus
<400> 183
Met Asp Met Trp Thr Ser Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Leu
<210> 184
<211> 18
<212> PRT
<213> Mus musculus
<400> 184
Met Asn Thr Arg Ala Pro Ala Glu Phe Leu Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Leu
<210> 185
<211> 16
<212> PRT
<213> Mus musculus
<400> 185
Met Arg Ala Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
<210> 186
<211> 16
<212> PRT
<213> Mus musculus
<400> 186
Met Arg Thr Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Ser
1 5 10 15
<210> 187
<211> 16
<212> PRT
<213> Mus musculus
<400> 187
Met Ser Ile Ser Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 188
<211> 16
<212> PRT
<213> Mus musculus
<400> 188
Met Ser Leu Pro Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 189
<211> 16
<212> PRT
<213> Mus musculus
<400> 189
Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 190
<211> 16
<212> PRT
<213> Mus musculus
<400> 190
Met Ser Val Pro Thr Gln Leu Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 191
<211> 16
<212> PRT
<213> Mus musculus
<400> 191
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 192
<211> 16
<212> PRT
<213> Mus musculus
<400> 192
Thr Asp Phe His Met Gln Ile Phe Ser Phe Met Leu Ile Ser Phe Thr
1 5 10 15
<210> 193
<211> 15
<212> PRT
<213> Mus musculus
<400> 193
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser
1 5 10 15
<210> 194
<211> 16
<212> PRT
<213> Mus musculus
<400> 194
Met Arg Cys Leu Ala Glu Phe Leu Arg Leu Leu Val Leu Trp Ile Pro
1 5 10 15
<210> 195
<211> 18
<212> PRT
<213> Mus musculus
<400> 195
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ser
1 5 10 15
Ser Ser
<210> 196
<211> 21
<212> PRT
<213> Mus musculus
<400> 196
Met Asp Ile Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210> 197
<211> 21
<212> PRT
<213> Mus musculus
<400> 197
Met Asp Met Met Val Leu Ala Gln Phe Leu Ala Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210> 198
<211> 21
<212> PRT
<213> Mus musculus
<400> 198
Met Asp Met Arg Ala Pro Ala Gln Phe Phe Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ile Arg Cys
20
<210> 199
<211> 21
<212> PRT
<213> Mus musculus
<400> 199
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210> 200
<211> 21
<212> PRT
<213> Mus musculus
<400> 200
Met Asp Met Arg Ala Pro Ala Gln Ile Phe Gly Phe Leu Leu Leu Leu
1 5 10 15
Phe Gln Thr Arg Cys
20
<210> 201
<211> 21
<212> PRT
<213> Mus musculus
<400> 201
Met Asp Met Arg Ala Pro Ala Gln Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210> 202
<211> 18
<212> PRT
<213> Mus musculus
<400> 202
Met Asp Met Arg Ala Ser Ala Gln Phe Leu Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 203
<211> 18
<212> PRT
<213> Mus musculus
<400> 203
Met Asp Met Arg Asp Pro Pro Gln Phe Leu Ala Phe Leu Leu Leu Trp
1 5 10 15
Ile Pro
<210> 204
<211> 21
<212> PRT
<213> Mus musculus
<400> 204
Met Asp Met Arg Thr Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ile Lys Cys
20
<210> 205
<211> 21
<212> PRT
<213> Mus musculus
<400> 205
Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro Thr Arg Cys
20
<210> 206
<211> 19
<212> PRT
<213> Mus musculus
<400> 206
Met Asp Ser Gln Ala Gln Val Leu Ile Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 207
<211> 19
<212> PRT
<213> Mus musculus
<400> 207
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Ser Val Ser
1 5 10 15
Thr Cys Gly
<210> 208
<211> 19
<212> PRT
<213> Mus musculus
<400> 208
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 209
<211> 19
<212> PRT
<213> Mus musculus
<400> 209
Met Asp Ser Gln Ala Arg Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 210
<211> 19
<212> PRT
<213> Mus musculus
<400> 210
Met Glu Phe Gln Thr Gln Val Phe Val Phe Val Leu Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210> 211
<211> 19
<212> PRT
<213> Mus musculus
<400> 211
Met Glu Phe Gln Thr Gln Val Leu Met Ser Leu Leu Leu Cys Met Ser
1 5 10 15
Ala Cys Ala
<210> 212
<211> 19
<212> PRT
<213> Mus musculus
<400> 212
Met Glu Lys Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210> 213
<211> 19
<212> PRT
<213> Mus musculus
<400> 213
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210> 214
<211> 19
<212> PRT
<213> Mus musculus
<400> 214
Met Glu Ser Gln Ile Gln Ala Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210> 215
<211> 19
<212> PRT
<213> Mus musculus
<400> 215
Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210> 216
<211> 16
<212> PRT
<213> Mus musculus
<400> 216
Met Ser Leu Leu Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 217
<211> 7
<212> PRT
<213> Mus musculus
<400> 217
Leu Ile Leu Lys Val Gln Cys
1 5
<210> 218
<211> 7
<212> PRT
<213> Mus musculus
<400> 218
Leu Val Leu Lys Val Leu Cys
1 5
<210> 219
<211> 21
<212> PRT
<213> Mus musculus
<400> 219
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210> 220
<211> 19
<212> PRT
<213> Mus musculus
<400> 220
Met Lys Leu Pro Val Leu Leu Val Val Leu Leu Leu Phe Thr Ser Pro
1 5 10 15
Ser Ser Ser
<210> 221
<211> 18
<212> PRT
<213> Mus musculus
<400> 221
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ser
1 5 10 15
Ser Ser
<210> 222
<211> 19
<212> PRT
<213> Mus musculus
<400> 222
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln
1 5 10 15
Thr Asn Gly
<210> 223
<211> 19
<212> PRT
<213> Mus musculus
<400> 223
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg
1 5 10 15
Thr Asn Gly
<210> 224
<211> 19
<212> PRT
<213> Mus musculus
<400> 224
Met Met Ser Pro Val His Ser Ile Phe Ile Leu Leu Leu Trp Ile Val
1 5 10 15
Ile Ser Gly
<210> 225
<211> 19
<212> PRT
<213> Mus musculus
<400> 225
Met Met Ser Pro Val Gln Phe Leu Phe Leu Leu Met Leu Trp Ile Gln
1 5 10 15
Thr Asn Gly
<210> 226
<211> 18
<212> PRT
<213> Mus musculus
<400> 226
Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Val
1 5 10 15
Gln Cys
<210> 227
<211> 19
<212> PRT
<213> Mus musculus
<400> 227
Met Asn Leu Pro Val His Leu Leu Val Leu Leu Leu Phe Trp Ile Pro
1 5 10 15
Ser Arg Gly
<210> 228
<211> 21
<212> PRT
<213> Mus musculus
<400> 228
Met Asn Thr Arg Ala Pro Ala Glu Phe Leu Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Leu Ala Arg Cys
20
<210> 229
<211> 19
<212> PRT
<213> Mus musculus
<400> 229
Met Arg Phe Gln Val Gln Val Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
Ala Gln Cys
<210> 230
<211> 18
<212> PRT
<213> Mus musculus
<400> 230
Met Arg Val Leu Ser Leu Leu Tyr Leu Leu Thr Ala Ile Pro Gly Ile
1 5 10 15
Leu Ser
<210> 231
<211> 21
<212> PRT
<213> Mus musculus
<400> 231
Met Asp Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
Ile Leu Ser Ser Gly
20
<210> 232
<211> 21
<212> PRT
<213> Mus musculus
<400> 232
Met Asp Phe Gln Met Gln Ile Ile Ser Leu Leu Leu Ile Ser Val Thr
1 5 10 15
Ile Val Ser Asn Gly
20
<210> 233
<211> 21
<212> PRT
<213> Mus musculus
<400> 233
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Thr
1 5 10 15
Ile Leu Thr Asn Gly
20
<210> 234
<211> 21
<212> PRT
<213> Mus musculus
<400> 234
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210> 235
<211> 21
<212> PRT
<213> Mus musculus
<400> 235
Met Asn Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
Ile Gly Ser Ser Gly
20
<210> 236
<211> 19
<212> PRT
<213> Mus musculus
<400> 236
Met Thr Met Leu Ser Leu Val Leu Leu Leu Ser Phe Leu Leu Leu Cys
1 5 10 15
Ser Arg Ala
<210> 237
<211> 19
<212> PRT
<213> Mus musculus
<400> 237
Met Val Ser Thr Pro Gln Phe Leu Val Phe Leu Leu Phe Trp Ile Pro
1 5 10 15
Ala Cys Gly
<210> 238
<211> 20
<212> PRT
<213> Mus musculus
<400> 238
Thr Glu Leu Ile Cys Val Phe Leu Phe Leu Leu Ser Val Thr Ala Ile
1 5 10 15
Leu Ser Ser Gly
20
<210> 239
<211> 17
<212> PRT
<213> Mus musculus
<400> 239
Met Asp Cys Gly Ile Ser Leu Val Phe Leu Val Leu Ile Leu Lys Val
1 5 10 15
Cys
<210> 240
<211> 19
<212> PRT
<213> Mus musculus
<400> 240
Met Asp Met Trp Val Gln Ile Phe Ser Leu Leu Leu Ile Cys Val Thr
1 5 10 15
Ser Lys Gly
<210> 241
<211> 11
<212> PRT
<213> Mus musculus
<400> 241
Leu Leu Ile Ser Val Thr Ile Met Ser Arg Gly
1 5 10
<210> 242
<211> 21
<212> PRT
<213> Mus musculus
<400> 242
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210> 243
<211> 21
<212> PRT
<213> Mus musculus
<400> 243
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ile Ser
1 5 10 15
Val Met Ser Arg Gly
20
<210> 244
<211> 21
<212> PRT
<213> Mus musculus
<400> 244
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210> 245
<211> 21
<212> PRT
<213> Mus musculus
<400> 245
Met Asp Leu Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ile Val Thr
1 5 10 15
Ile Met Ser Arg Gly
20
<210> 246
<211> 19
<212> PRT
<213> Mus musculus
<400> 246
Met Gly Glu Gln Arg Ile Arg Ser Cys His Ala Thr Ser Gly Ala Glu
1 5 10 15
Ser Ala Arg
<210> 247
<211> 20
<212> PRT
<213> Mus musculus
<400> 247
Met Gly Ser Gln Val His Leu Leu Ser Phe Leu Leu Leu Trp Ile Ser
1 5 10 15
Asp Thr Arg Ala
20
<210> 248
<211> 21
<212> PRT
<213> Mus musculus
<400> 248
Met Thr Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys
1 5 10 15
Val Ser Ser Arg Ala
20
<210> 249
<211> 18
<212> PRT
<213> Mus musculus
<400> 249
Met Thr Met Leu Ser Leu Ala Pro Leu Leu Ser Leu Leu Leu Leu Ser
1 5 10 15
Arg Ala
<210> 250
<211> 22
<212> PRT
<213> Mus musculus
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa can be any naturally occurring amino acid
<400> 250
Met Xaa Thr Met Asp Glu His Glu Ser Gly Ala Val Thr Pro His Gln
1 5 10 15
Val Leu Lys Ser Arg Ala
20
<210> 251
<211> 18
<212> PRT
<213> Mus musculus
<400> 251
Ile Lys Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210> 252
<211> 18
<212> PRT
<213> Mus musculus
<400> 252
Ile Lys Trp Ser Trp Ile Ser Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210> 253
<211> 7
<212> PRT
<213> Mus musculus
<400> 253
Leu Ile Leu Lys Val Gln Cys
1 5
<210> 254
<211> 7
<212> PRT
<213> Mus musculus
<400> 254
Leu Val Leu Lys Val Gln Cys
1 5
<210> 255
<211> 18
<212> PRT
<213> Mus musculus
<400> 255
Met Ala Val Val Thr Gly Lys Gly Leu Pro Ser Pro Lys Leu Glu Val
1 5 10 15
Asn Ser
<210> 256
<211> 17
<212> PRT
<213> Mus musculus
<400> 256
Met Asp Phe Gly Leu Ile Phe Phe Ile Val Ala Leu Leu Lys Val Gln
1 5 10 15
Cys
<210> 257
<211> 18
<212> PRT
<213> Mus musculus
<400> 257
Met Asp Phe Gly Leu Ser Leu Val Phe Leu Val Leu Ile Leu Lys Val
1 5 10 15
Gln Cys
<210> 258
<211> 21
<212> PRT
<213> Mus musculus
<400> 258
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210> 259
<211> 19
<212> PRT
<213> Mus musculus
<400> 259
Met Glu Trp Glu Leu Ser Leu Ile Phe Ile Phe Ala Leu Leu Lys Asp
1 5 10 15
Val Gln Cys
<210> 260
<211> 18
<212> PRT
<213> Mus musculus
<400> 260
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
His Ser
<210> 261
<211> 18
<212> PRT
<213> Mus musculus
<400> 261
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala Ile
1 5 10 15
His Ser
<210> 262
<211> 18
<212> PRT
<213> Mus musculus
<400> 262
Met Glu Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 263
<211> 18
<212> PRT
<213> Mus musculus
<400> 263
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr Ala
1 5 10 15
Leu Ser
<210> 264
<211> 18
<212> PRT
<213> Mus musculus
<400> 264
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 265
<211> 18
<212> PRT
<213> Mus musculus
<400> 265
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr Val
1 5 10 15
His Ser
<210> 266
<211> 18
<212> PRT
<213> Mus musculus
<400> 266
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 267
<211> 18
<212> PRT
<213> Mus musculus
<400> 267
Met Gly Trp Ser Trp Ile Phe Phe Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 268
<211> 18
<212> PRT
<213> Mus musculus
<400> 268
Met Gly Trp Ser Trp Ile Phe Leu Phe Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 269
<211> 18
<212> PRT
<213> Mus musculus
<400> 269
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala Val
1 5 10 15
Leu Ser
<210> 270
<211> 18
<212> PRT
<213> Mus musculus
<400> 270
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala Val
1 5 10 15
His Ser
<210> 271
<211> 18
<212> PRT
<213> Mus musculus
<400> 271
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210> 272
<211> 15
<212> PRT
<213> Mus musculus
<400> 272
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 273
<211> 19
<212> PRT
<213> Mus musculus
<400> 273
Ile Asp Ile Asn Val Gln Ile Phe Arg Phe Leu Leu Ile Ser Val Thr
1 5 10 15
Ser Ser Gly
<210> 274
<211> 16
<212> PRT
<213> Mus musculus
<400> 274
Met Asn Met Leu Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Phe Ala
1 5 10 15
<210> 275
<211> 16
<212> PRT
<213> Mus musculus
<400> 275
Met Arg Thr Pro Ala His Phe Leu Gly Leu Leu Leu Leu Cys Phe Leu
1 5 10 15
<210> 276
<211> 18
<212> PRT
<213> Mus musculus
<400> 276
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 277
<211> 16
<212> PRT
<213> Mus musculus
<400> 277
Met Asn Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
<210> 278
<211> 15
<212> PRT
<213> Mus musculus
<400> 278
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210> 279
<211> 16
<212> PRT
<213> Mus musculus
<400> 279
Met Asp Phe Gln Val Gln Ile Phe Gln Ile Pro Val Lys Gln Cys Leu
1 5 10 15
<210> 280
<211> 16
<212> PRT
<213> Mus musculus
<400> 280
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210> 281
<211> 16
<212> PRT
<213> Mus musculus
<400> 281
Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
1 5 10 15
<210> 282
<211> 18
<212> PRT
<213> Mus musculus
<400> 282
Met Asp Met Arg Thr Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 283
<211> 15
<212> PRT
<213> Mus musculus
<400> 283
Met Ala Val Leu Ala Leu Leu Phe Cys Leu Val Thr Phe Pro Ser
1 5 10 15
<210> 284
<211> 16
<212> PRT
<213> Mus musculus
<400> 284
Met Asp Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
<210> 285
<211> 16
<212> PRT
<213> Mus musculus
<400> 285
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210> 286
<211> 15
<212> PRT
<213> Mus musculus
<400> 286
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Arg
1 5 10 15
<210> 287
<211> 16
<212> PRT
<213> Mus musculus
<400> 287
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Thr
1 5 10 15
<210> 288
<211> 15
<212> PRT
<213> Mus musculus
<400> 288
Thr Glu Leu Ile Cys Val Phe Leu Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210> 289
<211> 6
<212> PRT
<213> Mus musculus
<400> 289
Leu Leu Ile Ser Val Thr
1 5
<210> 290
<211> 16
<212> PRT
<213> Mus musculus
<400> 290
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210> 291
<211> 16
<212> PRT
<213> Mus musculus
<400> 291
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
<210> 292
<211> 16
<212> PRT
<213> Mus musculus
<400> 292
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
<210> 293
<211> 16
<212> PRT
<213> Mus musculus
<400> 293
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Met Ser Ala Ser
1 5 10 15
<210> 294
<211> 16
<212> PRT
<213> Mus musculus
<400> 294
Met Asp Leu Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ile Val Thr
1 5 10 15
<210> 295
<211> 16
<212> PRT
<213> Mus musculus
<400> 295
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210> 296
<211> 15
<212> PRT
<213> Mus musculus
<400> 296
Met Lys Cys Ser Trp Val Ile Phe Phe Leu Met Ala Val Val Ile
1 5 10 15
<210> 297
<211> 15
<212> PRT
<213> Mus musculus
<400> 297
Met Lys Leu Trp Leu Asn Trp Ile Leu Leu Val Ala Leu Leu Asn
1 5 10 15
<210> 298
<211> 18
<212> PRT
<213> Mus musculus
<400> 298
Met Asp Met Arg Ala Pro Ala Gln Phe Phe Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 299
<211> 16
<212> PRT
<213> Mus musculus
<400> 299
Met Ile Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
<210> 300
<211> 16
<212> PRT
<213> Mus musculus
<400> 300
Met Met Ser Pro Val His Ser Ile Phe Ile Leu Leu Leu Trp Ile Val
1 5 10 15
<210> 301
<211> 16
<212> PRT
<213> Mus musculus
<400> 301
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
<210> 302
<211> 16
<212> PRT
<213> Mus musculus
<400> 302
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
<210> 303
<211> 16
<212> PRT
<213> Mus musculus
<400> 303
Met Asp Phe Gln Met Gln Ile Ile Ser Leu Leu Leu Ile Ser Val Thr
1 5 10 15
<210> 304
<211> 21
<212> PRT
<213> Mus musculus
<400> 304
Met Asp Phe Gln Val Gln Ile Phe Gln Ile Pro Val Lys Gln Cys Leu
1 5 10 15
Ile Ile Ser Arg Gly
20
<210> 305
<211> 16
<212> PRT
<213> Mus musculus
<400> 305
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210> 306
<211> 16
<212> PRT
<213> Mus musculus
<400> 306
Met Arg Pro Thr Leu Ser Phe Leu Gly Ser Cys Cys Ser Ser Leu Ile
1 5 10 15
<210> 307
<211> 16
<212> PRT
<213> Mus musculus
<400> 307
Met Lys Phe Pro Ser Gln Leu Leu Leu Leu Leu Leu Phe Gly Ile Pro
1 5 10 15
<210> 308
<211> 19
<212> PRT
<213> Mus musculus
<400> 308
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Ser
<210> 309
<211> 19
<212> PRT
<213> Mus musculus
<400> 309
Met Glu Ser Gln Thr Leu Val Phe Ile Ser Ile Leu Leu Trp Leu Tyr
1 5 10 15
Ala Asp Gly
<210> 310
<211> 19
<212> PRT
<213> Mus musculus
<400> 310
Met Glu Ser Gln Thr Gln Val Phe Leu Ser Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 311
<211> 19
<212> PRT
<213> Mus musculus
<400> 311
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210> 312
<211> 18
<212> PRT
<213> Mus musculus
<400> 312
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 313
<211> 19
<212> PRT
<213> Mus musculus
<400> 313
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 314
<211> 18
<212> PRT
<213> Mus musculus
<400> 314
Met Ala Trp Ile Ser Leu Ile Leu Ser Leu Leu Ala Leu Ser Ser Ala
1 5 10 15
Ile Ser
<210> 315
<211> 18
<212> PRT
<213> Mus musculus
<400> 315
Ile Gly Trp Ser Tyr Ile Ile Leu Leu Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 316
<211> 18
<212> PRT
<213> Mus musculus
<400> 316
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser Ala
1 5 10 15
Ser Ser
<210> 317
<211> 18
<212> PRT
<213> Mus musculus
<400> 317
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser Ala
1 5 10 15
Ile Ser
<210> 318
<211> 18
<212> PRT
<213> Mus musculus
<400> 318
Met Gly Trp Ser Cys Val Leu Leu Phe Leu Val Ser Gly Thr Ala Val
1 5 10 15
Leu Cys
<210> 319
<211> 21
<212> PRT
<213> Mus musculus
<400> 319
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Ile Ser Arg Gly
20
<210> 320
<211> 21
<212> PRT
<213> Mus musculus
<400> 320
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Leu Phe Arg Gly
20
<210> 321
<211> 21
<212> PRT
<213> Mus musculus
<400> 321
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Leu Ser Arg Gly
20
<210> 322
<211> 21
<212> PRT
<213> Mus musculus
<400> 322
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210> 323
<211> 21
<212> PRT
<213> Mus musculus
<400> 323
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Leu Met Ser Arg Gly
20
<210> 324
<211> 20
<212> PRT
<213> Mus musculus
<400> 324
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Arg Ile
1 5 10 15
Leu Ser Arg Gly
20
<210> 325
<211> 21
<212> PRT
<213> Mus musculus
<400> 325
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210> 326
<211> 21
<212> PRT
<213> Mus musculus
<400> 326
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Met Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210> 327
<211> 19
<212> PRT
<213> Mus musculus
<400> 327
Met Asp Thr Leu Cys Ser Thr Leu Leu Leu Leu Thr Ile Pro Ser Trp
1 5 10 15
Val Leu Ser
<210> 328
<211> 18
<212> PRT
<213> Mus musculus
<400> 328
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Cys
<210> 329
<211> 21
<212> PRT
<213> Mus musculus
<400> 329
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210> 330
<211> 18
<212> PRT
<213> Mus musculus
<400> 330
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Val Leu His Cys Ser Ser
1 5 10 15
Phe Ser
<210> 331
<211> 18
<212> PRT
<213> Mus musculus
<400> 331
Met Arg Val Leu Gly Phe Leu Cys Leu Val Thr Val Leu Pro Gly Ser
1 5 10 15
Leu Ser
<210> 332
<211> 18
<212> PRT
<213> Mus musculus
<400> 332
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Leu Leu His Cys Ser Ser
1 5 10 15
Phe Ser
<210> 333
<211> 13
<212> PRT
<213> Mus musculus
<400> 333
Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala Val His Cys
1 5 10
<210> 334
<211> 18
<212> PRT
<213> Mus musculus
<400> 334
Lys Gly Gly Ser Cys Val Ser Leu Phe Leu Val Ala Thr Ala Asn Val
1 5 10 15
His Phe
<210> 335
<211> 18
<212> PRT
<213> Mus musculus
<400> 335
Met Ala Val Leu Ala Leu Leu Phe Cys Leu Val Thr Phe Pro Ser Ile
1 5 10 15
Leu Ser
<210> 336
<211> 18
<212> PRT
<213> Mus musculus
<400> 336
Met Ala Val Leu Gly Leu Leu Phe Cys Leu Val Thr Phe Pro Ser Val
1 5 10 15
Leu Ser
<210> 337
<211> 18
<212> PRT
<213> Mus musculus
<400> 337
Met Ala Val Leu Gly Leu Leu Leu Cys Leu Val Thr Phe Pro Ser Val
1 5 10 15
Leu Ser
<210> 338
<211> 18
<212> PRT
<213> Mus musculus
<400> 338
Met Ala Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Val
1 5 10 15
His Ser
<210> 339
<211> 18
<212> PRT
<213> Mus musculus
<400> 339
Met Asp Trp Ile Trp Ile Met Leu His Leu Leu Ala Ala Thr Gly Ile
1 5 10 15
Gln Ser
<210> 340
<211> 18
<212> PRT
<213> Mus musculus
<400> 340
Met Glu Cys Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ala Val
1 5 10 15
His Cys
<210> 341
<211> 19
<212> PRT
<213> Mus musculus
<400> 341
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys
<210> 342
<211> 18
<212> PRT
<213> Mus musculus
<220>
<221> misc_feature
<222> (5)..(6)
<223> Xaa can be any naturally occurring amino acid
<400> 342
Met Glu Trp Leu Xaa Xaa Phe Leu Leu Phe Leu Ser Leu Thr Ala Val
1 5 10 15
His Cys
<210> 343
<211> 18
<212> PRT
<213> Mus musculus
<400> 343
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
His Ser
<210> 344
<211> 16
<212> PRT
<213> Mus musculus
<400> 344
Met Glu Thr Pro Ala Ser Phe Leu Cys Leu Leu Leu Leu Trp Thr Thr
1 5 10 15
<210> 345
<211> 15
<212> PRT
<213> Mus musculus
<400> 345
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Leu Leu His Cys Ser
1 5 10 15
<210> 346
<211> 15
<212> PRT
<213> Mus musculus
<400> 346
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Val Leu His Cys Ser
1 5 10 15
<210> 347
<211> 19
<212> PRT
<213> Mus musculus
<400> 347
Met Lys Ser Gln Thr Gln Val Phe Ile Phe Leu Leu Leu Cys Val Ser
1 5 10 15
Ala His Gly
<210> 348
<211> 19
<212> PRT
<213> Mus musculus
<400> 348
Met Lys Ser Gln Thr Gln Val Phe Val Phe Leu Leu Leu Cys Val Ser
1 5 10 15
Ala His Gly
<210> 349
<211> 16
<212> PRT
<213> Mus musculus
<400> 349
Met Asp Met Trp Val Gln Ile Phe Ser Leu Leu Leu Ile Cys Val Thr
1 5 10 15
<210> 350
<211> 19
<212> PRT
<213> Mus musculus
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa can be any naturally occurring amino acid
<400> 350
Met Xaa Thr Met Asp Glu His Glu Ser Gly Ala Val Thr Pro His Gln
1 5 10 15
Val Leu Lys
<210> 351
<211> 16
<212> PRT
<213> Mus musculus
<400> 351
Met Gly Glu Gln Arg Ile Arg Ser Cys His Ala Thr Ser Gly Ala Glu
1 5 10 15
<210> 352
<211> 16
<212> PRT
<213> Mus musculus
<400> 352
Met Asn Leu Pro Val His Leu Leu Val Leu Leu Leu Phe Trp Ile Pro
1 5 10 15
<210> 353
<211> 18
<212> PRT
<213> Mus musculus
<400> 353
Met Thr Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys
1 5 10 15
Val Ser
<210> 354
<211> 15
<212> PRT
<213> Mus musculus
<400> 354
Met Thr Met Leu Ser Leu Ala Pro Leu Leu Ser Leu Leu Leu Leu
1 5 10 15
<210> 355
<211> 16
<212> PRT
<213> Mus musculus
<400> 355
Met Thr Met Leu Ser Leu Val Leu Leu Leu Ser Phe Leu Leu Leu Cys
1 5 10 15
<210> 356
<211> 16
<212> PRT
<213> Mus musculus
<400> 356
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
<210> 357
<211> 15
<212> PRT
<213> Mus musculus
<400> 357
Met Val Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln
1 5 10 15
<210> 358
<211> 16
<212> PRT
<213> Mus musculus
<400> 358
Met Val Ser Thr Ser Gln Leu Leu Gly Leu Leu Leu Phe Trp Thr Ser
1 5 10 15
<210> 359
<211> 13
<212> PRT
<213> Mus musculus
<400> 359
Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln
1 5 10
<210> 360
<211> 16
<212> PRT
<213> Mus musculus
<400> 360
Ile Asp Ile Asn Val Gln Ile Phe Arg Phe Leu Leu Ile Ser Val Thr
1 5 10 15
<210> 361
<211> 16
<212> PRT
<213> Mus musculus
<400> 361
Met Lys Leu Pro Val Leu Leu Val Val Leu Leu Leu Phe Thr Ser Pro
1 5 10 15
<210> 362
<211> 15
<212> PRT
<213> Mus musculus
<400> 362
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro
1 5 10 15
<210> 363
<211> 15
<212> PRT
<213> Mus musculus
<400> 363
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro
1 5 10 15
<210> 364
<211> 16
<212> PRT
<213> Mus musculus
<400> 364
Met Glu Lys Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 365
<211> 16
<212> PRT
<213> Mus musculus
<400> 365
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 366
<211> 16
<212> PRT
<213> Mus musculus
<400> 366
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 367
<211> 16
<212> PRT
<213> Mus musculus
<400> 367
Met Glu Thr Asp Pro Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 368
<211> 16
<212> PRT
<213> Mus musculus
<400> 368
Met Glu Thr Asp Thr Ile Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 369
<211> 16
<212> PRT
<213> Mus musculus
<400> 369
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 370
<211> 16
<212> PRT
<213> Mus musculus
<400> 370
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 371
<211> 16
<212> PRT
<213> Mus musculus
<400> 371
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210> 372
<211> 16
<212> PRT
<213> Mus musculus
<400> 372
Met Arg Phe Ser Ala Gln Leu Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
<210> 373
<211> 16
<212> PRT
<213> Mus musculus
<400> 373
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
<210> 374
<211> 16
<212> PRT
<213> Mus musculus
<400> 374
Met Asp Ser Gln Ala Gln Val Leu Ile Leu Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 375
<211> 16
<212> PRT
<213> Mus musculus
<400> 375
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Ser Val Ser
1 5 10 15
<210> 376
<211> 16
<212> PRT
<213> Mus musculus
<400> 376
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 377
<211> 16
<212> PRT
<213> Mus musculus
<400> 377
Met Asp Ser Gln Ala Arg Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 378
<211> 16
<212> PRT
<213> Mus musculus
<400> 378
Met Glu Ser Gln Asn His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 379
<211> 16
<212> PRT
<213> Mus musculus
<400> 379
Met Glu Ser Gln Thr His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 380
<211> 16
<212> PRT
<213> Mus musculus
<400> 380
Met Glu Ser Gln Thr Gln Val Phe Leu Ser Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 381
<211> 16
<212> PRT
<213> Mus musculus
<400> 381
Met Glu Ser Gln Thr Gln Val Leu Ile Ser Leu Leu Phe Trp Val Ser
1 5 10 15
<210> 382
<211> 16
<212> PRT
<213> Mus musculus
<400> 382
Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser
1 5 10 15
<210> 383
<211> 19
<212> PRT
<213> Mus musculus
<400> 383
Met Glu Thr Pro Ala Ser Phe Leu Cys Leu Leu Leu Leu Trp Thr Thr
1 5 10 15
Ser Ala Val
<210> 384
<211> 16
<212> PRT
<213> Mus musculus
<400> 384
Gln His Gly His Glu Gly Leu Cys Ser Val Ser Trp Val Pro Val Ala
1 5 10 15
<210> 385
<211> 16
<212> PRT
<213> Mus musculus
<400> 385
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln
1 5 10 15
<210> 386
<211> 16
<212> PRT
<213> Mus musculus
<400> 386
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg
1 5 10 15
<210> 387
<211> 16
<212> PRT
<213> Mus musculus
<400> 387
Met Met Ser Pro Val Gln Phe Leu Phe Leu Leu Met Leu Trp Ile Gln
1 5 10 15
<210> 388
<211> 16
<212> PRT
<213> Mus musculus
<400> 388
Met Ile Ala Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
<210> 389
<211> 16
<212> PRT
<213> Mus musculus
<400> 389
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
<210> 390
<211> 16
<212> PRT
<213> Mus musculus
<400> 390
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
<210> 391
<211> 18
<212> PRT
<213> Mus musculus
<400> 391
Met Asp Met Arg Ala Pro Ala Gln Ile Phe Gly Phe Leu Leu Leu Leu
1 5 10 15
Phe Gln
<210> 392
<211> 18
<212> PRT
<213> Mus musculus
<400> 392
Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210> 393
<211> 15
<212> PRT
<213> Mus musculus
<400> 393
Met Asp Cys Gly Ile Ser Leu Val Phe Leu Val Leu Ile Leu Lys
1 5 10 15
<210> 394
<211> 16
<212> PRT
<213> Mus musculus
<400> 394
Met Glu Phe Gln Thr Gln Val Phe Val Phe Val Leu Leu Trp Leu Ser
1 5 10 15
<210> 395
<211> 16
<212> PRT
<213> Mus musculus
<400> 395
Met Glu Ser Gln Ile Gln Ala Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
<210> 396
<211> 16
<212> PRT
<213> Mus musculus
<400> 396
Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
<210> 397
<211> 16
<212> PRT
<213> Mus musculus
<400> 397
Met Glu Ser Gln Thr Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
<210> 398
<211> 20
<212> PRT
<213> Mus musculus
<400> 398
Met Gly Phe Lys Met Glu Ser His Thr Gln Ala Phe Val Phe Ala Phe
1 5 10 15
Leu Trp Leu Ser
20
<210> 399
<211> 16
<212> PRT
<213> Mus musculus
<400> 399
Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
<210> 400
<211> 15
<212> PRT
<213> Mus musculus
<220>
<221> misc_feature
<222> (5)..(6)
<223> Xaa can be any naturally occurring amino acid
<400> 400
Met Glu Trp Leu Xaa Xaa Phe Leu Leu Phe Leu Ser Leu Thr Ala
1 5 10 15
<210> 401
<211> 15
<212> PRT
<213> Mus musculus
<400> 401
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210> 402
<211> 15
<212> PRT
<213> Mus musculus
<400> 402
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210> 403
<211> 15
<212> PRT
<213> Mus musculus
<400> 403
Met Glu Trp Ser Arg Val Phe Ile Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210> 404
<211> 15
<212> PRT
<213> Mus musculus
<400> 404
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr
1 5 10 15
<210> 405
<211> 15
<212> PRT
<213> Mus musculus
<400> 405
Met Glu Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ser
1 5 10 15
<210> 406
<211> 15
<212> PRT
<213> Mus musculus
<400> 406
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr
1 5 10 15
<210> 407
<211> 15
<212> PRT
<213> Mus musculus
<400> 407
Met Gly Trp Ser Cys Ile Ile Phe Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 408
<211> 15
<212> PRT
<213> Mus musculus
<400> 408
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Asn
1 5 10 15
<210> 409
<211> 15
<212> PRT
<213> Mus musculus
<400> 409
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Thr
1 5 10 15
<210> 410
<211> 15
<212> PRT
<213> Mus musculus
<400> 410
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 411
<211> 15
<212> PRT
<213> Mus musculus
<400> 411
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 412
<211> 15
<212> PRT
<213> Mus musculus
<400> 412
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 413
<211> 15
<212> PRT
<213> Mus musculus
<400> 413
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ser Thr Ala Thr
1 5 10 15
<210> 414
<211> 15
<212> PRT
<213> Mus musculus
<400> 414
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr
1 5 10 15
<210> 415
<211> 15
<212> PRT
<213> Mus musculus
<400> 415
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr
1 5 10 15
<210> 416
<211> 15
<212> PRT
<213> Mus musculus
<400> 416
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Arg Ala Thr
1 5 10 15
<210> 417
<211> 15
<212> PRT
<213> Mus musculus
<400> 417
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210> 418
<211> 15
<212> PRT
<213> Mus musculus
<400> 418
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210> 419
<211> 15
<212> PRT
<213> Mus musculus
<400> 419
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210> 420
<211> 15
<212> PRT
<213> Mus musculus
<400> 420
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210> 421
<211> 15
<212> PRT
<213> Mus musculus
<400> 421
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210> 422
<211> 15
<212> PRT
<213> Mus musculus
<400> 422
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210> 423
<211> 15
<212> PRT
<213> Mus musculus
<400> 423
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210> 424
<211> 15
<212> PRT
<213> Mus musculus
<400> 424
Met Gly Trp Ser Arg Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala
1 5 10 15
<210> 425
<211> 15
<212> PRT
<213> Mus musculus
<400> 425
Met Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 426
<211> 15
<212> PRT
<213> Mus musculus
<400> 426
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala
1 5 10 15
<210> 427
<211> 15
<212> PRT
<213> Mus musculus
<400> 427
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 428
<211> 15
<212> PRT
<213> Mus musculus
<400> 428
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 429
<211> 15
<212> PRT
<213> Mus musculus
<400> 429
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala
1 5 10 15
<210> 430
<211> 15
<212> PRT
<213> Mus musculus
<400> 430
Met Gly Trp Ser Trp Ile Phe Pro Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 431
<211> 15
<212> PRT
<213> Mus musculus
<400> 431
Met Gly Trp Ser Trp Ile Phe Pro Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 432
<211> 15
<212> PRT
<213> Mus musculus
<400> 432
Met Gly Trp Ser Tyr Ile Ile Phe Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 433
<211> 15
<212> PRT
<213> Mus musculus
<400> 433
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 434
<211> 15
<212> PRT
<213> Mus musculus
<400> 434
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 435
<211> 15
<212> PRT
<213> Mus musculus
<400> 435
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 436
<211> 15
<212> PRT
<213> Mus musculus
<400> 436
Met Leu Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln
1 5 10 15
<210> 437
<211> 15
<212> PRT
<213> Mus musculus
<400> 437
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 438
<211> 15
<212> PRT
<213> Mus musculus
<400> 438
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 439
<211> 16
<212> PRT
<213> Mus musculus
<400> 439
Met Val Ser Glu Thr His Val Leu Ile Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210> 440
<211> 10
<212> PRT
<213> Mus musculus
<400> 440
Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala
1 5 10
<210> 441
<211> 15
<212> PRT
<213> Mus musculus
<400> 441
Ile Gly Trp Ser Tyr Ile Ile Leu Leu Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 442
<211> 15
<212> PRT
<213> Mus musculus
<400> 442
Ile Lys Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 443
<211> 15
<212> PRT
<213> Mus musculus
<400> 443
Ile Lys Trp Ser Trp Ile Ser Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 444
<211> 15
<212> PRT
<213> Mus musculus
<400> 444
Lys Gly Gly Ser Cys Val Ser Leu Phe Leu Val Ala Thr Ala Asn
1 5 10 15
<210> 445
<211> 15
<212> PRT
<213> Mus musculus
<400> 445
Met Ala Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr
1 5 10 15
<210> 446
<211> 15
<212> PRT
<213> Mus musculus
<400> 446
Met Glu Cys Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ala
1 5 10 15
<210> 447
<211> 19
<212> PRT
<213> Mus musculus
<400> 447
Met Ile Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
Ile Ser Lys
<210> 448
<211> 19
<212> PRT
<213> Mus musculus
<400> 448
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
Ile Ser Lys
<210> 449
<211> 19
<212> PRT
<213> Mus musculus
<400> 449
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
Ile Thr Lys
<210> 450
<211> 4
<212> PRT
<213> Mus musculus
<400> 450
Leu Val Leu Lys
1
<210> 451
<211> 15
<212> PRT
<213> Mus musculus
<400> 451
Met Ala Val Leu Gly Leu Leu Phe Cys Leu Val Thr Phe Pro Ser
1 5 10 15
<210> 452
<211> 15
<212> PRT
<213> Mus musculus
<400> 452
Met Ala Val Leu Gly Leu Leu Leu Cys Leu Val Thr Phe Pro Ser
1 5 10 15
<210> 453
<211> 15
<212> PRT
<213> Mus musculus
<400> 453
Met Asp Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala
1 5 10 15
<210> 454
<211> 15
<212> PRT
<213> Mus musculus
<400> 454
Met Glu Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 455
<211> 16
<212> PRT
<213> Mus musculus
<400> 455
Met Gly Arg Leu Thr Phe Ser Phe Leu Leu Leu Leu Pro Val Pro Ala
1 5 10 15
<210> 456
<211> 15
<212> PRT
<213> Mus musculus
<400> 456
Met Gly Trp Ser Cys Val Leu Leu Phe Leu Val Ser Gly Thr Ala
1 5 10 15
<210> 457
<211> 15
<212> PRT
<213> Mus musculus
<400> 457
Met Gly Trp Ser Trp Ile Phe Phe Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 458
<211> 15
<212> PRT
<213> Mus musculus
<400> 458
Met Gly Trp Ser Trp Ile Phe Leu Phe Phe Leu Ser Gly Thr Ala
1 5 10 15
<210> 459
<211> 15
<212> PRT
<213> Mus musculus
<400> 459
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala
1 5 10 15
<210> 460
<211> 15
<212> PRT
<213> Mus musculus
<400> 460
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 461
<211> 15
<212> PRT
<213> Mus musculus
<400> 461
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210> 462
<211> 15
<212> PRT
<213> Mus musculus
<400> 462
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala
1 5 10 15
<210> 463
<211> 15
<212> PRT
<213> Mus musculus
<400> 463
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala
1 5 10 15
<210> 464
<211> 15
<212> PRT
<213> Mus musculus
<400> 464
Met Gly Trp Ser Trp Val Phe Leu Ser Phe Leu Ser Gly Thr Ala
1 5 10 15
<210> 465
<211> 16
<212> PRT
<213> Mus musculus
<400> 465
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ile Ser
1 5 10 15
<210> 466
<211> 15
<212> PRT
<213> Mus musculus
<400> 466
Met Ala Val Val Thr Gly Lys Gly Leu Pro Ser Pro Lys Leu Glu
1 5 10 15
<210> 467
<211> 15
<212> PRT
<213> Mus musculus
<400> 467
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210> 468
<211> 11
<212> PRT
<213> Mus musculus
<400> 468
Met Gln Leu Gly His Leu Leu Pro Asp Gly Ser
1 5 10
<210> 469
<211> 16
<212> PRT
<213> Mus musculus
<400> 469
Arg Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210> 470
<211> 4
<212> PRT
<213> Mus musculus
<400> 470
Leu Ile Leu Lys
1
<210> 471
<211> 4
<212> PRT
<213> Mus musculus
<400> 471
Leu Val Leu Lys
1
<210> 472
<211> 5
<212> PRT
<213> Artificial
<220>
<223> junction peptide
<400> 472
Gln Ile Trp Asn Asn
1 5
<210> 473
<211> 19
<212> PRT
<213> Mus musculus
<400> 473
Met Glu Ser Gln Asn His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 474
<211> 19
<212> PRT
<213> Mus musculus
<400> 474
Met Glu Ser Gln Thr His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 475
<211> 19
<212> PRT
<213> Mus musculus
<400> 475
Met Glu Ser Gln Thr Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210> 476
<211> 19
<212> PRT
<213> Mus musculus
<400> 476
Met Glu Ser Gln Thr Gln Val Leu Ile Ser Leu Leu Phe Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 477
<211> 19
<212> PRT
<213> Mus musculus
<400> 477
Met Glu Ser Gln Thr Gln Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Ala Cys Ala
<210> 478
<211> 19
<212> PRT
<213> Mus musculus
<400> 478
Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser
1 5 10 15
Thr Cys Gly
<210> 479
<211> 19
<212> PRT
<213> Mus musculus
<400> 479
Met Glu Thr Asp Pro Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210> 480
<211> 19
<212> PRT
<213> Mus musculus
<400> 480
Met Glu Thr Asp Thr Ile Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210> 481
<211> 19
<212> PRT
<213> Mus musculus
<400> 481
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210> 482
<211> 19
<212> PRT
<213> Mus musculus
<400> 482
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210> 483
<211> 19
<212> PRT
<213> Mus musculus
<400> 483
Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
Val Glu Gly
<210> 484
<211> 23
<212> PRT
<213> Mus musculus
<400> 484
Met Gly Phe Lys Met Glu Ser His Thr Gln Ala Phe Val Phe Ala Phe
1 5 10 15
Leu Trp Leu Ser Val Asp Gly
20
<210> 485
<211> 16
<212> PRT
<213> Mus musculus
<400> 485
Met Gly Val Pro Thr Gln Leu Leu Leu Leu Trp Leu Thr Val Arg Cys
1 5 10 15
<210> 486
<211> 19
<212> PRT
<213> Mus musculus
<400> 486
Met Ile Ala Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Thr Arg Cys
<210> 487
<211> 19
<212> PRT
<213> Mus musculus
<400> 487
Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
1 5 10 15
Ile Ile Cys
<210> 488
<211> 19
<212> PRT
<213> Mus musculus
<400> 488
Met Lys Phe Pro Ser Gln Leu Leu Leu Leu Leu Leu Phe Gly Ile Pro
1 5 10 15
Met Ile Cys
<210> 489
<211> 19
<212> PRT
<213> Mus musculus
<400> 489
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Thr Arg Cys
<210> 490
<211> 19
<212> PRT
<213> Mus musculus
<400> 490
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Thr Arg Tyr
<210> 491
<211> 19
<212> PRT
<213> Mus musculus
<400> 491
Met Asn Met Leu Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Phe Ala
1 5 10 15
Gly Lys Cys
<210> 492
<211> 19
<212> PRT
<213> Mus musculus
<400> 492
Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Ala Ile Gly
<210> 493
<211> 19
<212> PRT
<213> Mus musculus
<400> 493
Met Arg Cys Leu Ala Glu Phe Leu Arg Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Ala Thr Gly
<210> 494
<211> 19
<212> PRT
<213> Mus musculus
<400> 494
Met Arg Cys Ser Leu Gln Phe Leu Gly Val Leu Met Phe Trp Ile Ser
1 5 10 15
Val Ser Gly
<210> 495
<211> 19
<212> PRT
<213> Mus musculus
<400> 495
Met Arg Phe Ser Ala Gln Leu Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Ser Thr Ala
<210> 496
<211> 19
<212> PRT
<213> Mus musculus
<400> 496
Met Arg Pro Ser Ile Gln Phe Leu Gly Leu Leu Leu Phe Trp Leu His
1 5 10 15
Ala Gln Cys
<210> 497
<211> 19
<212> PRT
<213> Mus musculus
<400> 497
Met Arg Val Leu Ala Glu Leu Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
Val Arg Cys
<210> 498
<211> 19
<212> PRT
<213> Mus musculus
<400> 498
Met Arg Val Leu Pro Glu Phe Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
Val Arg Cys
<210> 499
<211> 19
<212> PRT
<213> Mus musculus
<400> 499
Met Ser Ile Ser Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210> 500
<211> 19
<212> PRT
<213> Mus musculus
<400> 500
Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210> 501
<211> 19
<212> PRT
<213> Mus musculus
<400> 501
Met Ser Val Pro Thr Gln Leu Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210> 502
<211> 19
<212> PRT
<213> Mus musculus
<400> 502
Met Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Gly Cys
<210> 503
<211> 19
<212> PRT
<213> Mus musculus
<400> 503
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210> 504
<211> 19
<212> PRT
<213> Mus musculus
<400> 504
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
Ser Thr Gly
<210> 505
<211> 19
<212> PRT
<213> Mus musculus
<400> 505
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
Ser Arg Gly
<210> 506
<211> 18
<212> PRT
<213> Mus musculus
<400> 506
Met Val Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln Ser
1 5 10 15
Arg Gly
<210> 507
<211> 19
<212> PRT
<213> Mus musculus
<400> 507
Met Val Ser Thr Ser Gln Leu Leu Gly Leu Leu Leu Phe Trp Thr Ser
1 5 10 15
Ser Arg Gly
<210> 508
<211> 16
<212> PRT
<213> Mus musculus
<400> 508
Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln Ser Arg Cys
1 5 10 15
<210> 509
<211> 18
<212> PRT
<213> Mus musculus
<400> 509
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 510
<211> 18
<212> PRT
<213> Mus musculus
<400> 510
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 511
<211> 18
<212> PRT
<213> Mus musculus
<400> 511
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 512
<211> 18
<212> PRT
<213> Mus musculus
<400> 512
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210> 513
<211> 18
<212> PRT
<213> Mus musculus
<400> 513
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 514
<211> 18
<212> PRT
<213> Mus musculus
<400> 514
Met Gly Trp Ser Trp Val Phe Leu Ser Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210> 515
<211> 18
<212> PRT
<213> Mus musculus
<400> 515
Met Lys Cys Ser Trp Val Ile Phe Phe Leu Met Ala Val Val Ile Ile
1 5 10 15
Asn Ser
<210> 516
<211> 18
<212> PRT
<213> Mus musculus
<400> 516
Met Lys Leu Trp Leu Asn Trp Ile Leu Leu Val Ala Leu Leu Asn Ile
1 5 10 15
Gln Cys
<210> 517
<211> 18
<212> PRT
<213> Mus musculus
<400> 517
Met Leu Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln Val
1 5 10 15
His Cys
<210> 518
<211> 19
<212> PRT
<213> Mus musculus
<400> 518
Met Leu Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln Gly
1 5 10 15
Val His Cys
<210> 519
<211> 18
<212> PRT
<213> Mus musculus
<400> 519
Met Met Val Leu Ser Leu Leu Tyr Leu Leu Thr Ala Leu Pro Gly Ile
1 5 10 15
Leu Ser
<210> 520
<211> 18
<212> PRT
<213> Mus musculus
<400> 520
Met Asn Phe Gly Leu Ser Leu Ile Phe Leu Val Leu Ile Leu Lys Val
1 5 10 15
Gln Cys
<210> 521
<211> 14
<212> PRT
<213> Mus musculus
<400> 521
Met Gln Leu Gly His Leu Leu Pro Asp Gly Ser Val Asn Ser
1 5 10
<210> 522
<211> 19
<212> PRT
<213> Mus musculus
<400> 522
Met Val Ser Glu Thr His Val Leu Ile Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Val His Cys
<210> 523
<211> 19
<212> PRT
<213> Mus musculus
<400> 523
Arg Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Val Asn Ser
<210> 524
<211> 18
<212> PRT
<213> Mus musculus
<400> 524
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
Tyr Ser
<210> 525
<211> 18
<212> PRT
<213> Mus musculus
<400> 525
Met Glu Trp Ser Arg Val Phe Ile Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
His Ser
<210> 526
<211> 18
<212> PRT
<213> Mus musculus
<400> 526
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Val
1 5 10 15
His Ser
<210> 527
<211> 18
<212> PRT
<213> Mus musculus
<400> 527
Met Glu Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ser Val
1 5 10 15
His Ser
<210> 528
<211> 19
<212> PRT
<213> Mus musculus
<400> 528
Met Gly Arg Leu Thr Phe Ser Phe Leu Leu Leu Leu Pro Val Pro Ala
1 5 10 15
Val Leu Ser
<210> 529
<211> 18
<212> PRT
<213> Mus musculus
<400> 529
Met Gly Trp Ser Cys Ile Ile Phe Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210> 530
<211> 18
<212> PRT
<213> Mus musculus
<400> 530
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Asn Val
1 5 10 15
His Ser
<210> 531
<211> 18
<212> PRT
<213> Mus musculus
<400> 531
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Thr Val
1 5 10 15
His Ser
<210> 532
<211> 18
<212> PRT
<213> Mus musculus
<400> 532
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 533
<211> 18
<212> PRT
<213> Mus musculus
<400> 533
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 534
<211> 18
<212> PRT
<213> Mus musculus
<400> 534
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ser Thr Ala Thr Val
1 5 10 15
His Ser
<210> 535
<211> 18
<212> PRT
<213> Mus musculus
<400> 535
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr Val
1 5 10 15
His Ser
<210> 536
<211> 18
<212> PRT
<213> Mus musculus
<400> 536
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr Val
1 5 10 15
His Ser
<210> 537
<211> 18
<212> PRT
<213> Mus musculus
<400> 537
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr Val
1 5 10 15
Gln Phe
<210> 538
<211> 18
<212> PRT
<213> Mus musculus
<400> 538
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Arg Ala Thr Val
1 5 10 15
His Ser
<210> 539
<211> 18
<212> PRT
<213> Mus musculus
<400> 539
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210> 540
<211> 18
<212> PRT
<213> Mus musculus
<400> 540
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210> 541
<211> 18
<212> PRT
<213> Mus musculus
<400> 541
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 542
<211> 18
<212> PRT
<213> Mus musculus
<400> 542
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 543
<211> 18
<212> PRT
<213> Mus musculus
<400> 543
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 544
<211> 19
<212> PRT
<213> Mus musculus
<400> 544
Met Gly Trp Ser Phe Leu Pro Leu Phe Leu Ala Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 545
<211> 18
<212> PRT
<213> Mus musculus
<400> 545
Met Gly Trp Ser Arg Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala Val
1 5 10 15
His Cys
<210> 546
<211> 18
<212> PRT
<213> Mus musculus
<400> 546
Met Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 547
<211> 18
<212> PRT
<213> Mus musculus
<400> 547
Met Gly Trp Ser Trp Ile Phe Pro Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Cys
<210> 548
<211> 18
<212> PRT
<213> Mus musculus
<400> 548
Met Gly Trp Ser Tyr Ile Ile Phe Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210> 549
<211> 18
<212> PRT
<213> Mus musculus
<400> 549
Met Gly Trp Ser Tyr Ile Ile Phe Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 550
<211> 18
<212> PRT
<213> Mus musculus
<400> 550
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
His Ser
<210> 551
<211> 18
<212> PRT
<213> Mus musculus
<400> 551
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 552
<211> 18
<212> PRT
<213> Mus musculus
<400> 552
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
Asn Ser
<210> 553
<211> 18
<212> PRT
<213> Mus musculus
<400> 553
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210> 554
<211> 16
<212> PRT
<213> Artificial
<220>
<223> linker 8
<400> 554
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
<210> 555
<211> 26
<212> PRT
<213> Artificial
<220>
<223> linker 9
<400> 555
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
20 25
<210> 556
<211> 17
<212> PRT
<213> Artificial
<220>
<223> linker 10
<400> 556
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly
<210> 557
<211> 27
<212> PRT
<213> Artificial
<220>
<223> linker 11
<400> 557
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25
<210> 558
<211> 38
<212> DNA
<213> Artificial
<220>
<223> insertion of a unique HindIII and KasI restrictino site
<400> 558
aagcttcaac aggggagagt gttgaaggga gaggcgcc 38
Claims (11)
- (a) 발현 플라스미드가 5'에서 3' 방향으로 (aa) 프로모터; (ab) 서열 번호: 46 및 327로부터 선택되는 인간 또는 쥣과의 면역 글로불린의 신호 서열인 제 1 폴리펩타이드를 코딩하는 핵산; (ac) (i) 이종 폴리펩타이드를 코딩하는 핵산, (ii) 연결자를 코딩하는 핵산, 및 (iii) 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산; 및 (ad) 폴리아데닐화 신호를 포함하는 3' 미번역 영역을 포함하고, 상기 제 1 폴리펩타이드를 코딩하는 핵산과 상기 이종 폴리펩타이드를 코딩하는 핵산 사이에 펩타이드 QIWNN(서열 번호: 472) 또는 Q를 코딩하는 핵산이 삽입되고,(b) 상기 발현 플라스미드를 진핵 생물 숙주 세포 내로 도입하고,(c) 상기 숙주 세포를 상기 제 2 폴리펩타이드의 발현에 적합한 조건하에서 배양하고,(d) 상기 제 2 폴리펩타이드를 배지로부터 회수함을 특징으로 하는, 발현 플라스미드를 포함하는 진핵 생물 숙주 세포에서 이종 폴리펩타이드를 재조합 생성시키는 방법.
- 제 1 항에 있어서,제 2 폴리펩타이드가 이종 폴리펩타이드 후에 연결자를 포함하고, 연결자 후에 제 2 폴리펩타이드의 카복시-말단 부분으로서 면역 글로불린 단편이 후속함을 특징으로 하는 방법.
- 삭제
- 제 1 항 또는 제 2 항에 있어서,면역 글로불린 단편을 IgG 또는 IgE로부터 수득함을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서,진핵 생물 세포가 포유동물 세포임을 특징으로 하는 방법.
- 제 5 항에 있어서,포유동물 세포가 CHO 세포, NS0 세포, Sp2/0 세포, COS 세포, K562 세포, BHK 세포, PER.C6 세포 또는 HEK 세포임을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서,연결자가 서열 번호: 06, 07, 08, 09, 10, 139, 140, 554, 555, 556 및 557로 이루어진 군으로부터 선택되는 펩타이드 또는 폴리펩타이드임을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서,면역 글로불린 단편이 (a) 면역 글로불린 중질 쇄의 CH1-, CH2-, CH3-도메인 및 경첩 부위, 또는 면역 글로불린 경질 쇄의 CL-도메인; 및 (b) 가변 면역 글로불린 중질 또는 경질 쇄 도메인의 단편을 포함함을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서,면역 글로불린 단편이 불변 도메인만을 포함함을 특징으로 하는 방법.
- 5'에서 3' 방향으로 (a) 프로모터; (b) 서열 번호: 46 및 327로부터 선택되는 인간 또는 쥣과의 면역 글로불린의 신호 서열인 제 1 폴리펩타이드를 코딩하는 핵산; (c) (i) 이종 폴리펩타이드를 코딩하는 핵산, (ii) 연결자를 코딩하는 핵산, 및 (iii) 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산; 및 (d) 폴리아데닐화 신호를 포함하는 3' 미번역 영역을 포함하고, 상기 제 1 폴리펩타이드를 코딩하는 핵산과 상기 이종 폴리펩타이드를 코딩하는 핵산 사이에 펩타이드 QIWNN(서열 번호: 472) 또는 Q를 코딩하는 핵산이 삽입된 플라스미드.
- 5'에서 3' 방향으로 (a) 프로모터; (b) 서열 번호: 46 및 327로부터 선택되는 인간 또는 쥣과의 면역 글로불린의 신호 서열인 제 1 폴리펩타이드를 코딩하는 핵산; (c) (i) 펩타이드 QIWNN(서열 번호: 472) 또는 Q를 코딩하는 핵산, (ii) 하나 이상의 제한 절단 부위를 포함하는 클로닝 부위, (iii) 서열 번호: 06, 07, 08, 09, 10, 139, 140, 554, 555, 556 및 557로 이루어진 군으로부터 선택되는 연결자를 코딩하는 핵산, 및 (iv) 면역 글로불린 단편을 코딩하는 핵산을 포함하는, 제 2 폴리펩타이드를 코딩하는 핵산; 및 (d) 폴리아데닐화 신호를 포함하는 3' 미번역 영역을 포함하는 플라스미드를 포함하는 진핵 생물 세포에서 이종 폴리펩타이드를 발현시키는 플라스미드를 제조하기 위한 키트.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
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| EP05023003.6 | 2005-10-21 | ||
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| EP (1) | EP1941043B1 (ko) |
| JP (1) | JP4860702B2 (ko) |
| KR (1) | KR101030612B1 (ko) |
| CN (1) | CN101292036B (ko) |
| AR (1) | AR056138A1 (ko) |
| AT (1) | ATE505552T1 (ko) |
| AU (1) | AU2006303440B2 (ko) |
| BR (1) | BRPI0617688A2 (ko) |
| CA (1) | CA2624893C (ko) |
| DE (1) | DE602006021335D1 (ko) |
| IL (1) | IL189420A (ko) |
| TW (1) | TW200732472A (ko) |
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| JP2002511432A (ja) | 1998-04-15 | 2002-04-16 | レキシジェン ファーマシューティカルズ コーポレイション | 新脈管形成インヒビターの同時投与による抗体−サイトカイン融合タンパク質媒介性免疫応答の増強 |
| PT1294401E (pt) | 2000-06-29 | 2007-11-09 | Merck Patent Gmbh | Aumento das respostas imunológicas mediadas por proteínas de fusão anticorpo-citoquina por tratamento combinado com agentes que aumentam a captação de imunocitoquinas |
| DE10045591A1 (de) | 2000-09-15 | 2002-04-04 | Klaus Pfizenmaier | Ortsspezifische, antikörpervermittelte Aktivierung proapoptotischer Zytokine - AMAIZe (Antibody-Mediated Apoptosis Inducing Zytokine) |
| WO2003035892A2 (en) | 2001-10-19 | 2003-05-01 | The Scripps Research Institute | Novel methods for introducing molecules into cells and vectors and compositions for use in such methods |
| AR046071A1 (es) | 2003-07-10 | 2005-11-23 | Hoffmann La Roche | Anticuerpos contra el receptor i del factor de crecimiento de tipo insulinico y los usos de los mismos |
-
2006
- 2006-10-19 AR ARP060104562A patent/AR056138A1/es unknown
- 2006-10-19 CN CN200680039291.9A patent/CN101292036B/zh active Active
- 2006-10-19 EP EP06806380A patent/EP1941043B1/en active Active
- 2006-10-19 AU AU2006303440A patent/AU2006303440B2/en not_active Ceased
- 2006-10-19 KR KR1020087009355A patent/KR101030612B1/ko not_active IP Right Cessation
- 2006-10-19 CA CA2624893A patent/CA2624893C/en not_active Expired - Fee Related
- 2006-10-19 US US11/583,573 patent/US7807409B2/en active Active
- 2006-10-19 TW TW095138577A patent/TW200732472A/zh unknown
- 2006-10-19 AT AT06806380T patent/ATE505552T1/de active
- 2006-10-19 JP JP2008533956A patent/JP4860702B2/ja active Active
- 2006-10-19 WO PCT/EP2006/010067 patent/WO2007045465A1/en active Application Filing
- 2006-10-19 BR BRPI0617688-7A patent/BRPI0617688A2/pt not_active Application Discontinuation
- 2006-10-19 DE DE602006021335T patent/DE602006021335D1/de active Active
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2008
- 2008-02-11 IL IL189420A patent/IL189420A/en not_active IP Right Cessation
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0556111A1 (fr) * | 1992-02-11 | 1993-08-18 | Commissariat A L'energie Atomique | Protéines hybrides complexes, leur procédé de préparation, et leurs applications comme agent de diagnostic, comme agent à visée thérapeutique ou comme reactif utilisable en imagerie medicale |
| WO2000011033A2 (en) * | 1998-08-25 | 2000-03-02 | Lexigen Pharmaceuticals Corp. | Expression and export of angiostatin and endostatin as immunofusins |
| WO2003016501A2 (en) * | 2001-08-21 | 2003-02-27 | Thomas Jefferson University | Recombinant antibodies, and compositions and methods for making and using the same |
| WO2004046306A2 (en) * | 2001-10-05 | 2004-06-03 | Amgen Inc. | Fully human antibody fab fragments with human interferon-gamma neutralizing activity |
Also Published As
| Publication number | Publication date |
|---|---|
| US7807409B2 (en) | 2010-10-05 |
| CN101292036B (zh) | 2016-04-13 |
| JP2009509558A (ja) | 2009-03-12 |
| CN101292036A (zh) | 2008-10-22 |
| JP4860702B2 (ja) | 2012-01-25 |
| AU2006303440B2 (en) | 2011-09-08 |
| CA2624893C (en) | 2015-03-17 |
| EP1941043A1 (en) | 2008-07-09 |
| AR056138A1 (es) | 2007-09-19 |
| IL189420A (en) | 2014-06-30 |
| EP1941043B1 (en) | 2011-04-13 |
| ATE505552T1 (de) | 2011-04-15 |
| BRPI0617688A2 (pt) | 2011-06-07 |
| IL189420A0 (en) | 2008-06-05 |
| WO2007045465A1 (en) | 2007-04-26 |
| CA2624893A1 (en) | 2007-04-26 |
| US20070117185A1 (en) | 2007-05-24 |
| AU2006303440A1 (en) | 2007-04-26 |
| DE602006021335D1 (de) | 2011-05-26 |
| TW200732472A (en) | 2007-09-01 |
| KR20080049115A (ko) | 2008-06-03 |
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