KR20160055789A - Glp-1r에 특이적으로 결합하는 항체 및 그 glp-1과의 융합 단백질 - Google Patents
Glp-1r에 특이적으로 결합하는 항체 및 그 glp-1과의 융합 단백질 Download PDFInfo
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Abstract
본 발명에서는 GLP-1R에 특이적으로 결합하는 항체 및 그 GLP-1과의 융합 단백질이 개시된다. 융합 단백질은 효율적으로 인간 GLP-1R 수용체와 결합하고 수용체 시그널 전달 경로를 활성화할 수 있어, 당뇨병, 과체중, 비만 및 그와 관련된 질병의 치료에 유용하다.
Description
본 발명은 항체의 기술 분야에 관한 것이며, 특히 GLP-1R과 특이적으로 결합 가능한 항체 및 그 GLP-1과의 융합 단백질에 관한 것이다.
2형 당뇨병의 전형적인 증상은 다음의 3가지 측면을 포함한다: 1) 말초의 인슐린 저항성, 주로 인슐린에 대한 골격 및 근육의 감수성이 저하되고, 이들 조직으로의 글루코스의 수송이 영향을 받음(비특허문헌 1, 비특허문헌 2); 2) 과도한 간 글루코스 생산, 인슐린의 조절에 대한 간세포의 감수성 저하(비특허문헌 1, 비특허문헌 3) 및 글루카곤의 과도한 분비(비특허분헌 4); 3) 랑게르한스섬 β세포 실조, 질환 초기에 β세포의 증식 및 인슐린 분비량의 증가에 따라 혈당에 대한 인슐린 저항성의 영향이 대상적으로 보상되나(비특허문헌 5), 시간의 경과 및 인슐린 저항성 정도의 증가에 따라 β세포가 피폐해지고, 그에 따라 인슐린 분비가 저하되어 2형 당뇨병의 진정한 시작에 이른다(비특허문헌 6, 비특허문헌 7).
글루카곤 유사 펩티드-1(GLP-1)은, 30개의 아미노산을 포함하는 펩티드 세그먼트이다. 장 내의 L세포로부터 분비되어 글로코스의 흡수를 자극한다(비특허문헌 8, 비특허문헌 9). 분비를 자극한 후, GLP-1이 췌장의 GLR-1R(글루카곤 유사 펩티드-1 수용체)과 결합하고, 하류의 아데닐산 시클라아제 시그널 전달 경로를 활성화하여 인슐린의 합성 및 분비를 촉진한다. GLP-1의 분비는 또한 위 배출을 감소시키고, 이로 인해 음식의 소화 후에 순환계로 들어가는 글루코스의 양을 감소시킨다(비특허문헌 10). 마우스 및 1형 및 2형 당뇨병 환자에 있어서, GLP-1은 인슐린의 분비를 증가시키며, 혈당치를 저하시켰다(비특허문헌 11, 비특허문헌 12). 일부 연구에서는, GLP-1은, 또한 췌장 β세포의 사멸을 억제하고 그 증식을 촉진한다는 것이 나타나 있다(비특허문헌 13, 비특허문헌 14). 임상에서는 GLP-1에 의한 당뇨병 환자의 치료의 실현 가능성 및 효과가 이미 실증되어 있으며(비특허문헌 15), GLP-1 및 그 유도체를 사용하여 당뇨병을 치료하는 방법을 기재한 특허도 이미 존재한다(특허문헌 1, 특허문헌 2). 그러나 GLP-1의 생물학적 반감기는 비교적 짧으며, 치료 효과는 양호하지 않다.
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본 발명의 목적 중 하나는, GLP-1R과 특이적으로 결합 가능한 항체를 제공하는 것이다.
본 발명의 또 하나의 목적은, GLP-1의 생물학적 반감기를 연장시키고 GLP-1의 분자 생물학적 활성을 유지할 수 있는 GLP-1R과 특이적으로 결합 가능한 항체가 GLP-1과 형성하는 융합 단백질을 제공하는 것이다. 또한, GLP-1 및 GLP-1R과 특이적으로 결합 가능한 항체에 의해 형성되는 융합 단백질은 항체에 의해 제공되는 분자 표적성을 가지며, 또한 항체의 면역원성도 다른 융합 파트너 단백질보다 낮다.
본 발명에서 그 기술적 과제를 해결하기 위해 이용하는 기법은 다음과 같다.
다음의 방식:
a. 다음의 배열 중 임의의 것으로부터 선택되는 경쇄 CDR3 배열:
L1~L13의 경쇄 CDR3 배열: 배열 번호 46~배열 번호 53으로부터 선택되는 어떠한 것과의 차가 합계 3개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR3 배열, 바람직하게는, L1~L13의 경쇄 CDR3 배열: 배열 번호 46~배열 번호 53으로부터 선택되는 어떠한 것과의 차가 합계 2개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR3 배열, 보다 바람직하게는, L1~L13의 경쇄 CDR3 배열: 배열 번호 46~배열 번호 53으로부터 선택되는 어떠한 것과의 차가 1개인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR3 배열,
b. 다음의 배열 중 임의의 것으로부터 선택되는 중쇄 CDR3 배열:
H1~H13의 중쇄 CDR3 배열: 배열 번호 20~배열 번호 27로부터 선택되는 어떠한 것과의 차가 합계 4개 이하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR3 배열, 바람직하게는, H1~H13의 중쇄 CDR3 배열: 배열 번호 20~배열 번호 27로부터 선택되는 어떠한 것과의 차가 합계 3개 이하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR3 배열, 보다 바람직하게는, H1~H13의 중쇄 CDR3 배열: 배열 번호 20~배열 번호 27로부터 선택되는 어떠한 것과의 차가 합계 2개 이하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR3 배열, 더욱 바람직하게는, H1~H13의 중쇄 CDR3 배열: 배열 번호 20~배열 번호 27로부터 선택되는 어떠한 것과의 차가 1개인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR3 배열,
c. (a)의 경쇄 CDR3 배열 및 (b)의 중쇄 CDR3 배열
중 임의의의 아미노산 배열을 포함하는 GLP-1R과 특이적으로 결합 가능한 항체.
바람직하게는, 상기 항체는, 다음의 방식:
a. 다음 중 임의의 것으로부터 선택되는 경쇄 CDR1 배열:
L1~L13의 경쇄 CDR1 배열: 배열 번호 28~배열 번호 37로부터 선택되는 어떠한 것과의 차가 3개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR1, 바람직하게는, L1~L13의 경쇄 CDR1 배열: 배열 번호 28~배열 번호 37로부터 선택되는 어떠한 것과의 차가 합계 2개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR1 배열, 보다 바람직하게는, L1~L13의 경쇄 CDR1 배열: 배열 번호 28~배열 번호 37로부터 선택되는 어떠한 것과의 차가 1개인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR1 배열,
b. 다음 중 임의의 것으로부터 선택되는 경쇄 CDR2 배열:
L1~L13의 경쇄 CDR2 배열: 배열 번호 38~배열 번호 45로부터 선택되는 어떠한 것과의 차가 2개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR2, 바람직하게는, L1~L13의 경쇄 CDR2 배열: 배열 번호 38~배열 번호 45로부터 선택되는 어떠한 것과의 차가 1개인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR2 배열,
c. 다음 중 임의의 것으로부터 선택된 중쇄 CDR1 배열:
H1~H13의 중쇄 CDR1 배열: 배열 번호 6~배열 번호 12로부터 선택되는 어떠한 것과의 차가 2개 이하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR1, 바람직하게는, H1~H13의 중쇄 CDR1 배열: 배열 번호 6~배열 번호 12로부터 선택되는 어떠한 것과의 차가 1개인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR1 배열,
d. 다음 중 임의의 것으로부터 선택된 중쇄 CDR2 배열:
H1~H13의 중쇄 CDR2 배열: 배열 번호 13~배열 번호 19로부터 선택되는 어떠한 것과의 차가 3개 이하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 배열, 바람직하게는, H1~H13의 중쇄 CDR2 배열: 배열 번호 13~배열 번호 19로부터 선택되는 어떠한 것과의 차가 합계 2개 이하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR2 배열, 보다 바람직하게는, H1~H13의 중쇄 CDR2 배열: 배열 번호 13~배열 번호 19로부터 선택되는 어떠한 것과의 차가 1개인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR2 배열
중 1종 또는 2종 이상을 조합한 아미노산 배열을 포함한다.
다음의 방식:
a. 다음의 방식 중 1종 또는 2종 이상을 포함하는 경쇄 가변 영역:
ⅰ. 배열 번호 28~배열 번호 37 중 임의의 것으로부터 선택되는 경쇄 CDR1 배열,
ⅱ. 배열 번호 38~배열 번호 45 중 임의의 것으로부터 선택되는 경쇄 CDR2 배열,
ⅲ. 배열 번호 46~배열 번호 53 중 임의의 것으로부터 선택되는 경쇄 CDR3 배열,
b. 다음의 방식 중 1종 또는 2종 이상을 포함하는 중쇄 가변 영역:
ⅰ. 배열 번호 6~배열 번호 12 중 임의의 것으로부터 선택되는 중쇄 CDR1 배열,
ⅱ. 배열 번호 13~배열 번호 19 중 임의의 것으로부터 선택되는 중쇄 CDR2 배열,
ⅲ. 배열 번호 20~배열 번호 27 중 임의의 것으로부터 선택되는 중쇄 CDR3 배열,
c. (a)의 경쇄 가변 영역 배열 및 (b)의 중쇄 가변 영역 배열
중 임의의 것을 포함하는 GLP-1R과 특이적으로 결합 가능한 항체.
다음의 방식:
a. 다음의 방식 중 임의의 것으로부터 선택되는 경쇄 가변 영역 배열:
ⅰ. L1~L13의 경쇄 가변 영역 배열: 배열 번호 81, 배열 번호 83, 배열 번호 85, 배열 번호 87, 배열 번호 89, 배열 번호 91, 배열 번호 93, 배열 번호 95, 배열 번호 97, 배열 번호 99, 배열 번호 101, 배열 번호 103, 배열 번호 105로부터 선택되는 임의의 것과 적어도 80%가 동일한 배열을 가지는 아미노산,
ⅱ. L1~L13의 경쇄 가변 영역 배열을 코드하는 폴리뉴클레오티드 배열: 배열 번호 80, 배열 번호 82, 배열 번호 84, 배열 번호 86, 배열 번호 88, 배열 번호 90, 배열 번호 92, 배열 번호 94, 배열 번호 96, 배열 번호 98, 배열 번호 100, 배열 번호 102, 배열 번호 104 중 임의의 것과 적어도 80%가 동일한 폴리뉴클레오티드 배열로 코드된 아미노산 배열,
b. 다음의 방식 중 임의의 것으로부터 선택되는 중쇄 가변 영역 배열:
ⅰ. H1~H13의 중쇄 가변 영역 배열: 배열 번호 55, 배열 번호 57, 배열 번호 59, 배열 번호 61, 배열 번호 63, 배열 번호 65, 배열 번호 67, 배열 번호 69, 배열 번호 71, 배열 번호 73, 배열 번호 75, 배열 번호 77, 배열 번호 79 중 임의의 것과 적어도 80%가 동일한 아미노산 배열,
ⅱ. H1~H13의 중쇄 가변 영역 배열을 코드하는 폴리뉴클레오티드 배열: 배열 번호 54, 배열 번호 56, 배열 번호 58, 배열 번호 60, 배열 번호 62, 배열 번호 64, 배열 번호 66, 배열 번호 68, 배열 번호 70, 배열 번호 72, 배열 번호 74, 배열 번호 76, 배열 번호 78 중 임의의 것과 적어도 80%가 동일한 폴리뉴클레오티드 배열로 코드된 아미노산 배열,
c. (a)의 경쇄 가변 영역 배열 및 (b)의 중쇄 가변 영역 배열
중 임의의 것의 아미노산 배열을 포함하는 GLP-1R과 특이적으로 결합 가능한 항체.
바람직하게는, 상기 항체는, 다음의 방식:
a. L1~L13의 경쇄 가변 영역 배열: 배열 번호 81, 배열 번호 83, 배열 번호 85, 배열 번호 87, 배열 번호 89, 배열 번호 91, 배열 번호 93, 배열 번호 95, 배열 번호 97, 배열 번호 99, 배열 번호 101, 배열 번호 103, 배열 번호 105로부터 선택되는 임의의 경쇄 가변 영역 배열,
b. H1~H13의 중쇄 가변 영역 배열: 배열 번호 55, 배열 번호 57, 배열 번호 59, 배열 번호 61, 배열 번호 63, 배열 번호 65, 배열 번호 67, 배열 번호 69, 배열 번호 71, 배열 번호 73, 배열 번호 75, 배열 번호 77, 배열 번호 79로부터 선택되는 임의의 중쇄 가변 영역 배열,
c. (a)의 경쇄 가변 영역 배열 및 (b)의 중쇄 가변 영역 배열
중 임의의 아미노산 배열을 포함한다.
바람직하게는, 방식 (c)에서의 (a)의 경쇄 가변 영역 배열과 (b)의 중쇄 가변 영역 배열의 조합은, L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13 중 임의의 것으로부터 선택된다.
바람직하게는, 상기 항체는, 다음의 방식:
a. 배열 번호 106의 경쇄 정상 영역 아미노산 배열,
b. 배열 번호 107의 경쇄 정상 영역 아미노산 배열,
c. 배열 번호 108의 중쇄 정상 영역 아미노산 배열,
d. 배열 번호 109의 중쇄 정상 영역 아미노산 배열,
e. 배열 번호 106의 경쇄 정상 영역 아미노산 배열 및 배열 번호 108의 중쇄 정상 영역 아미노산 배열,
f. 배열 번호 107의 경쇄 정상 영역 아미노산 배열 및 배열 번호 108의 중쇄 정상 영역 아미노산 배열,
g. 배열 번호 106의 경쇄 정상 영역 아미노산 배열 및 배열 번호 109의 중쇄 정상 영역 아미노산 배열,
h. 배열 번호 107의 경쇄 정상 영역 아미노산 배열 및 배열 번호 109의 중쇄 정상 영역 아미노산 배열,
중 임의의 아미노산 배열을 포함한다.
바람직하게는, 상기 항체는 마우스 항체, 인간 항체, 인간화 항체, 키메라 항체, 모노클로날 항체, 폴리클로날 항체, 재조합 항체, 항원 결합 항체 단편, 외가닥 항체, 2중 가닥 항체, 3중 가닥 항체, 4중 가닥 항체, Fab 단편, F(f'a)x 단편, 도메인 항체, IgD 항체, IgE 항체, IgM 항체, IgG1 항체, IgG2 항체. IgG3 항체, IgG4 항체로부터 선택된다.
배열 번호 1, 배열 번호 2, 배열 번호 3, 배열 번호 4, 배열 번호 5, 배열 번호 127로부터 선택되는 임의의 아미노산 배열을 포함하는 GLP-1과 본 발명의 항체를 융합하여 형성되는 GLP-1 융합 단백질.
바람직하게는, GLP-1은 N'-R1-L-R2-C', N'-R2-L-R1-C' 또는 N'-R2-L-R1r-C'
(식 중 L은 LK1~LK3의 아미노산 배열: 배열 번호 110, 배열 번호 111, 배열 번호 112로부터 선택되는 임의의 전장의, 부분적인 또는 반복되는 아미노산 배열을 포함하는 펩티드 링커 배열이고,
R1은 GLP-1의 아미노산 배열이며,
R1r은 GLP-1의 역방향 아미노산 배열이고,
R2는 청구항 1 또는 3 또는 4에 기재된 항체의 경쇄 또는 중쇄 아미노산 배열이며,
C'는 GLP-1 융합 단백질 폴리펩티드쇄의 카복실 말단을 나타내고,
N'는 GLP-1 융합 단백질 폴리펩티드쇄의 아미노 말단을 나타낸다)
의 결합 방식에 의해 청구항 1 또는 3 또는 4에 기재된 항체의 경쇄 및/또는 중쇄와 융합된다.
본 발명의 GLP-1 융합 단백질을 코드하는 폴리뉴클레오티드.
본 발명의 폴리뉴클레오티드를 포함하는 벡터.
본 발명의 벡터를 포함하는 숙주 세포.
의약적으로 허용되는 벡터와 혼합된 본 발명의 GLP-1 융합 단백질을 포함하는 의약 조성물.
인슐린 비의존성 당뇨병의 예방 또는 치료에 이용하는 의약품을 제조하는, 본 발명의 항체 또는 GLP-1 융합 단백질을 포함하거나 또는 그에 근거하는 의약 조성물의 용도.
인슐린 유사 펩티드-1을 이용하여 2형 당뇨병 환자의 혈당치를 제어하는 방법에 있어서, GLP-1R이 하는 중요한 작용 및 GLP-1R의 치료의 현저한 특징이 인슐린 분비를 자극하지만 저혈당과 관련된 위험을 수반하지 않는다는 능력이라는 것을 고려한다. 본 발명은 GLP-1을 GLP-1R과 특이적으로 결합 가능한 항체와 융합하고, GLP-1의 생물학적 반감기를 연장시키며, GLP-1의 분자 생물학적 활성을 유지한다. 또한 GLP-1 및 GLP-1R과 특이적으로 결합 가능한 항체에 의해 형성되는 융합 단백질은 항체에 의해 제공되는 분자 표적성을 가지며, 또한 항체의 면역원성도 다른 융합 파트너 단백질보다 낮다.
본 발명의 유익한 효과는 다음과 같다. GLP-1을 GLP-1R과 특이적으로 결합 가능한 항체와 융합하고, GLP-1의 생물학적 반감기를 연장시키며, GLP-1의 분자 생물학적 활성을 유지한다. 또한 GLP-1 및 GLP-1R과 특이적으로 결합 가능한 항체에 의해 형성되는 융합 단백질은 항체에 의해 제공되는 분자 표적성을 가지며, 또한 항체의 면역원성도 다른 융합 파트너 단백질보다 낮다.
본 발명은, GLP-1이 체내에 있어서 디펩티딜펩티다아제(DPP-Ⅳ)에 의해 신속히 제거되지만 유효성이 불충분하다는 결점에 대하여, GLP-1R의 항체를 이용하여 그것과 융합시킴으로써 그 반감기 및 생물학적 활성을 증강한다. 융합에 이용되는 항체는 GLP-1과 수용체의 결합을 저해하지 않는다는 전제 하에서 GLP-1R의 생물학적 활성을 특이적으로 식별하고, 자신의 수용체와의 고친화력 및 안정성에 의해 수용체 주위에서의 GLP-1의 국소적인 농도를 지속적으로 증강시키며, 수용체와 결합하는 작용 시간 및 역가를 대폭으로 증가시킬 수 있다. 또한, 항체와의 융합에 의해 GLP-1이 DPP-Ⅳ에 의해 식별 또는 포획되는 입체 장애를 증가시키고, 체내에서 제거될 확률은 감소시키며, GLP-1의 작용 시간을 증가시킨다. 문헌의 보고에 따르면, GLP-1R의 N말단 세포 외 도메인 및 그 막 관통 도메인의 부분적 교합 상태의 해방은 GLP-1이 GLP-1R과의 결합 개소에 들어가 그 생물 활성을 행사하는 중요한 단계이다. 본 발명에 기재된 항체와 GLP-1R의 결합은 수용체의 N말단 세포 외 도메인에 상당히 관련되며, 수용체와의 결합은 상기 교합 상태의 해방에 도움이 되고 GLP-1의 진입에 유리하다. 그 때문에 GLP-1은 GLP-1R에 대한 항체와 융합한 후에 자신의 반감기 및 친화력가를 증가시키고, 나아가 강한 생물학적 활성을 가지게 되어, GLP-1 요법보다 더 뛰어난 중요한 쇄신이다. 더욱 중요한 것은, 본 발명에서 이용하는 부분 항체 자체가 GLP-1이 존재하는 상황 하에서 GLP-1R에 의한 GLP-1의 작용을 증강하는 생물학적 특정을 가진다는 것이다. 이상의 몇 가지 이유에 의해 본 발명에 기재된 GLP-1 융합 단백질은 GLP-1보다 유효한 GLP-1R 작동약이다.
융합 단백질을 장기간 반복적으로 이용했을 때의 항원성에는 보편적인 우려가 존재한다. GLP-1 융합물 요법에 대해서는, 당뇨병 환자가 이 질환이라고 진단을 받으면 치료를 평생 받을 필요가 있기 때문에 특히 우려된다. 또한 면역 글로블린의 Fc 부분에 불필요한 이펙터 기능이 남아 Fc 융합 단백질 요법이 우려될 가능성이 있다. 컴퓨터 지원에 의한 면역 글로블린의 3차원 구조의 예측 및 항체 배열의 최적화 및 인간화에 의해, 나아가 반복적 및 장기적으로 이용한 후에 면역 반응을 유도하는 리스크가 저하되고, 이펙터 기능을 가지지 않게 되는 특정 GLP-1 융합 단백질을 동정하며, 본 발명에 있어서 고려되는 GLP-1 부분의 아미노산은, 바람직하게는 글리신 및 세린을 풍부하게 포함하는 펩티드 링커에 의해 항체의 경쇄 및 중쇄를 융합한다. 글리신 및 세린은 비교적 작은 측쇄를 가지고, 펩티드 링커의 배열은 상당한 유연성을 가지며, GLP-1과 항체 사이의 상대 위치의 강성을 감소시켜 GLP-1이 자유롭게 GLP-1R과 상호 작용할 수 있도록 한다. 또한 펩티드 링커의 존재는 GLP-1과 항체를 격리하고, 양자의 도메인의 상호 작용을 회피한다. 글리신 및 세린이 번갈아 나타나고 불필요한 면역원성을 융합 단백질에 과도하게 반복적으로 도입하는 것을 회피하나, 펩티드 링커는 융합 단백질의 체내 면역원성, 바람직하게는 펩티드 링커의 길이를 불가피하게 증가시키고, 평형 구조 유연도 및 면역원성은 중요하기 때문에, 본 발명은 길이가 서로 다른 세 개의 펩티드 링커를 제공하여 융합에 이용한다. 또한 본 발명에서는 GLP-1과 항체를 펩티드 링커에서 서로 다른 결합 방식을 이용하여 융합을 형성하는 것을 제공하며, 이에 따라 형성되는 GLP-1 융합 단백질의 형식은 다음을 포함한다.
1) GLP-1을 가지고, N'-R1-L-R2-C'의 방식으로 경쇄와 결합하는 융합 단백질.
2) GLP-1을 가지고, N'-R2-L-R1-C'의 방식으로 경쇄와 결합하는 융합 단백질.
3) GLP-1을 가지고, N'-R2-L-R1r-C'의 방식으로 경쇄와 결합하는 융합 단백질.
4) GLP-1을 가지고, N'-R1-L-R2-C'의 방식으로 중쇄와 결합하는 융합 단백질.
5) 1) 및 4)를 동시에 가지는 융합 단백질.
6) 2) 및 4)를 동시에 가지는 융합 단백질.
7) 3) 및 4)를 동시에 가지는 융합 단백질.
본 발명에 있어서, GLP-1을 코드하는 DNA와 상기 항체의 전장/가변 영역/단편 경쇄 또는 전장/가변 영역/전장 중쇄 DNA는 펩티드 링커 배열을 코드하는 DNA에 의해 융합 경쇄 또는 융합 중쇄 DNA로서 결합함과 동시에, 경쇄 DNA의 5'말단은 나아가 시그널 리더 펩티드를 코드하는 DNA를 도입하여 유전자를 형성하고, 이 유전자를 기초로 변이/야생형 GLP-1 및 항체 배열을 결합할 수 있다. 본 발명은 유전자 합성 방법에 의해 GLP-1의 배열을 얻고, PCR의 방식에 의해 펩티드 링커 배열 및 항체 경쇄 또는 중쇄 DNA와 결합시킨다. GLP-1R의 항체 경쇄 또는 중쇄 가변 영역 배열에 대하여, 특정한 하이브리도마 세포로부터 PCR의 방법에 의해 추출하고, 특정한 항체 아형의 정상 영역 DNA와 결합하여 조성할 수 있다. 야생형 항체 아형의 정상 영역 DNA는 특정 라이브러리로부터 클로닝하여 얻어지며, 배열 최적화의 기초로 삼을 수 있다. 여기서 말하는 융합 단백질의 발현에 이용하는 유전자는 클로닝 방식에 의해 발현 백터에 삽입되어 융합 단백질의 생성 및 발현에 이용된다. 발현 프로세스에 있어서, 경쇄 및 중쇄 발현 벡터를 합친 후 동시 전이(cotransfection) 또는 형질 전환 방식으로 그 유전자를 가지는 DNA를 숙주 세포 내로 도입하고, 최적화 적응 유도 프로모터를 이용하여 형질 전환체 또는 원하는 배열을 코드하는 유전자를 증폭하는 배지를 선택하고 적절한 pH, 온도에서 배양한다. DNA 도입 방식은 일반적으로 이용되는 CaPO4, 전기 천공법(electroporation) 및 PEI 등의 방식을 선정한다.
여기서 발하는 벡터에서의 핵산의 발현에 적합한 적절한 숙주 세포로는 고등 진핵 세포 등이 있으며, 포유류 동물 숙주 세포계 발현의 실례로는 차이니즈 햄스터 난소 세포(CHO) 및 인간 태아 신장 세포(HEK 293 또는 현탁 배양한 HEK 293 세포계) 등이 있으며, 경쇄 N말단에 위치하는 시그널 리더 펩티드가 포유류 동물 숙주 세포계로부터의 재조합 융합 단백질의 분비를 지시한다. 발현 및 클로닝에 이용하는 벡터 상에 융합 단백질을 코드하는 핵산을 흡수하는 능력을 가지는 세포를 선별하기 위해 이용하는 벡터를 숙주 세포에 있어서 항상 복제시킬 수 있는 선택 마커를 가지며, 또한 융합 단백질 코드 배열과 유효하게 결합하고 mRNA의 합성을 지시하는 프로모터를 가진다. 그 중 하나의 실례는 항생 물질 저항성 및 B형 간염 바이러스 및 유인원 바이러스 프로모터(SV 40)를 가지는 벡터를 이용하는 것이며, 융합 단백질을 발현하는 CHO 숙주 세포를 안정화시키는 것이 바람직하다.
본 발명은, 숙주 세포계가 융합 단백질을 발현한 후 친화 크로마토그래피(affinity chromatography) 방법을 이용하여 세포 배양 상청액에 분비한 부분을 정제한다. 본 발명에서의 실례는, 프로틴G의 친화 컬럼을 이용하여 전장 항체가 융합된 융합 단백질을 포획하고, 이어서 낮은 pH로 컬럼의 충전제로부터 용출한 후 수집하는 것을 포함한다. 온화한 용출 조건은 프로틴의 변성 방지에 도움이 된다.
1종 또는 2종 이상의 부형제를 이용하여 본 발명의 융합 단백질을 조제할 수도 있다. 본 발명의 융합 단백질은 의약용 완충액, 조절을 거쳐 허용 가능한 안정성을 제공하는 pH 및 투여(예를 들면 비경구투여) 가능한 pH와 조합할 수도 있다. 임의 선택적으로 1종 또는 2종 이상의 의약용 항균제를 부가할 수도 있다. m-크레졸 및 페놀이 바람직한 의약용 항균제이다. 1종 또는 2종 이상의 의약용 염용액을 부가하여 이온 강도 또는 장력을 조절할 수도 있다. 1종 또는 2종 이상의 부형제를 부가하여 제제의 등장성을 더욱 조절할 수도 있다. 글리세린은 등장성 조절 부형제의 실례이다. 의약용이란, 인간 또는 그 밖의 동물에 대한 투여에 적합하기 때문에 독성 성분 또는 바람직하지 않은 오염물을 포함하지 않으며 또한 활성 화합물의 활성에 간섭하지 않는 것을 의미한다.
용액 제제 또는 적절한 희석제를 이용하여 재구성 가능한 동결 건조 분말로 본 발명의 융합 단백질을 조제할 수도 있다. 동결 건조 제형은 융합 단백질을 안정화시키는 제형이며, 재구성 제품의 예상되는 사용 저장 기간 내에 pH를 유지하는 완충 능력을 가지거나 또는 가지지 않는다. 여기서 고찰되는 융합 단백질을 포함하는 용액은 동결 건조 전에 바람직하게는 등장성을 가지며, 이를 재구성한 후에 등장성 용액을 형성할 수 있다.
본 발명의 융합 단백질의 의약용 염용액의 형식은 본 발명의 범위 내에 있다. 산부가염의 형성에 상용되는 산은, 예를 들면 염산, 브롬화수소산, 요오드화수소산, 황산, 인산 등의 무기산, 및 예를 들면 p-톨루엔술폰산, 메탄술폰산, 옥살산, p-브로모벤젠술폰산, 탄산, 숙신산, 구연산, 벤조산, 아세트산 등의 유기산이다. 바람직한 산부가염은, 예를 들면 염산 및 브롬화수소산 등의 무기산으로 형성된 염이다.
염기 부가염은, 예를 들면 암모늄, 염기 또는 알칼리토류 금속 수산화물 등의 무기 염기 유래의 염, 탄산염, 탄산수소염 등을 포함한다. 따라서 본 발명의 염용액의 조제에 유용한 이들 염기는 수산화나트륨, 수산화칼륨, 수산화암모늄, 탄산칼륨 등을 포함한다.
본 발명의 융합 단백질은 생물학적 활성을 가진다. 생물학적 활성이랑 이 융합 단백질이 체내에서 결합하고 GLP-1R을 작동하여 세포 스트레스 응답을 일으키는 것을 말한다. 응답은 인슐린 분비의 상승, 글루카곤 분비의 억제, 식욕 억제, 체중 감소, 배부름 유도, 아폽토시스 억제, 췌장 β세포 증식 및 췌장 β세포 분화의 유도를 포함하나 이에 한정되지 않는다. 대표적인 GLP-1 융합 단백질에 대하여, in vitro 및 in vivo 활성을 측정하였다. 먼저 4 단계(도 1)는 이 융합 단백질과 GLP-1R의 상호 작용의 형광 검출 데이터를 제공한다. 이어서 5 단계는 이 융합 단백질과 인간 GLP-1R의 상호 작용 후에 활성화시킨 in vitro 활성의 측정을 제공한다. 실험에 있어서, 인간 GLP-1R을 발현하는 CHO 세포를 이용하였다. 이들 세포에 있어서, GLP-1R의 활성화에 의해 아데닐산 시클라아제의 활성화가 일어나며, 이 효소의 활성화는 또한 cAMP의 응답 배열(CRE)에 의해 구동되는 리포터 유전자의 발현을 유도하였다. 12 단계(도 2)는 리포터 유전자가 루시페라아제인 데이터를 제공한다. in vitro의 실험 데이터는 융합 단백질이 GLP-1R을 결합하고 활성화할 수 있으며, in vitro의 결과는 GLP-1-Gly8(7-37)OH보다 유효하다는 것을 공동으로 나타내고 있다. 13 단계(도 3)는 절식시키고 본 발명의 융합 단백질 중 임의의 것을 복강 내 주사한 16시간 후에 글루코스를 마우스에 경구 투여한 후의 혈당치의 변화 데이터를 제공한다. 13 단계의 마우스에 있어서 생성된 데이터는, 이 융합 단백질이 체내에서 활성을 가지며 또한 천연 GLP-1보다 긴 반감기를 가진다는 것을 나타내었다.
통상의 기능을 가지는 내과의가 유효하다는 것을 이미 알고 있는 임의의 경로로 이들 융합 단백질을 투여할 수 있다. 말초 비경구는 이러한 방법에 속한다. 의약 문헌에 있어서, 통상적으로 비경구 투여는 소독 주사기 또는 예를 들면 시린지 펌프 등의 그 밖의 기계 장치에 의해 개체에 제형을 주사하는 것으로 이해되고 있다. 말초 비경구는 경정맥, 근육 내, 피하 및 복강 내의 투여 경로를 포함할 수 있다.
본 발명의 융합 단백질은 경구, 직장, 경비 또는 하기도의 경로로 투여할 수 있으며, 이들은 비경구 이외의 경로이다. 이러한 비경구 이외의 경로 중 하기도 경로 및 경구 경로가 바람직하다.
본 발명의 융합 단백질은 복수의 질환 및 질병의 치료에 이용할 수 있다. 본 발명의 융합 단백질은 먼저 GLP-1R에 작용함으로써 그 생물학적 작용을 발휘한다. 그 때문에, 본 발명의 GLP-1 융합 단백질을 이용하여 GLP-1R 자극에 대하여 또는 GLP-1 화합물의 투여에 대하여 응답이 있는 질환 및/또는 질병의 피험자를 치료할 수 있다. 이들 피험자를 "GLP-1 화합물 치료가 필요" 또는 "GLP-1R 자극이 필요"한 피험자라 한다. 인슐린 비의존성 당뇨병, 인슐린 의존성 당뇨병, 뇌경색(특허문헌 3을 참조), 심근경색(특허문헌 4를 참조), 비만(특허문헌 5를 참조), 수술 후 이화 변화(특허문헌 6 참조), 기능성 위장병 및 과민성 장 증후군(특허문헌 7을 참조)을 포함한다. 예를 들면, 인슐린 비의존성 당뇨병으로 발전할 위험이 있는 피험자(특허문헌 8을 참조) 등, GLP-1 화합물에서의 예방적 치료가 요구되는 피험자도 포함한다. 내당능 이상 또는 공복 시 혈당 이상인 피험자, 체중이 피험자의 신장 및 체액에 대하여 정상 체중을 약 25% 초과하는 피험자, 췌장의 일부를 절제한 피험자, 양친 중 어느 한 명 또는 모두가 인슐린 비의존성 당뇨병인 피험자, 임신성 당뇨병이 된 적이 있는 피험자 및 급성 또는 만성 췌염이 된 적이 있는 피험자는 모두 인슐린 비의존성 당뇨병으로 발전할 위험이 있다. 본 특허에 기재된 융합 단백질의 유효량은, 원하는 치료 및/또는 예방 효과가 얻어지고 허용할 수 없는 부작용이 없을 때의 GLP-1 수용체 자극이 필요한 피험자에게 투여하는 용량이다. "원하는 치료 효과"는 다음의 하나 또는 둘 이상을 포함한다. 질환 또는 질병에 관련된 증상의 개선, 질환 또는 질병에 관련된 증상 발작의 지연, 치료하고 있지 않은 경우와 비교했을 때의 수명 연장, 치료하고 있지 않은 경우와 비교했을 때의 삶의 질(quality of life)의 향상. 당뇨병을 치료하는 GLP-1 융합 단백질의 "유효량"은 치료하고 있지 않은 경우에 비해 혈당치를 보다 좋게 제어할 수 있으며, 이로 인해 당뇨병의 합병증(예를 들면 망막증, 신경 장애 또는 신증)의 발작 지연을 초래하는 양이다. 당뇨병을 예방하는 GLP-1 융합 단백질의 "유효량"은 치료하지 않은 경우에 비해 혈당치 상승 발작을 지연시키는 양이며, 상기 발작은 예를 들면 술포닐우레아계, 티아졸리딘디온, 인슐린 및/또는 비구아니드계 등의 혈당 강하약 치료를 필요로 한다. 환자의 혈당치를 유효하게 정상화하는 융합 단백질의 용량은 많은 요소에 의해 결정되며, 피험자의 성별, 체중 및 연령, 혈당 조절 이상의 중증성, 투여 경로 및 생물학적 이용능을 포함하나 이것들에 한정되지 않는다. 융합 단백질의 약물 동태 프로필, 잠재 능력 및 제형. 용량은 0.01~1mg/kg체중으로 할 수 있으며, 바람직하게는 0.05~0.5mg/kg체중이다. 바람직하게는 주 1회 또는 2회 본 발명의 융합 단백질을 투여한다. 치료하는 질환에 따라 결정되며, 이 융합 단백질을 예를 들면 주3회 이상 등, 보다 빈번하게 투여할 필요가 있을 가능성이 있다.
도 1은, 재조합으로 발현한 GLP-1 융합 단백질(GLP-1(A8G)-LK-L13H13)과 인간 GLP-1R(hGLP-1R)의 발현을 안정화하는 차이니즈 햄스터 난소 세포주(*로 나타낸 실선 피크) 및 차이니즈 햄스터 난소 세포주 자체(점선 피크)의 특이적 결합을 유세포분석기(FACS)로 검출한 비교이다.
도 2는, 리포터 유전자법으로 얻어진 GLP-1 야생형(원형) 및 GLP-1(A8G)-LK-L13H13(삼각형)의 hGLP-1R의 발현을 안정화하는 차이니즈 햄스터 난소 세포주의 작동 곡선이다.
도 3은, 마우스(ICR) 내당능 실험으로, GLP-1(A8G)-LK-L13H13을 5mg/마리(사각형) 및 15mg/마리(삼각형), 1회 복강 내(i.p.) 주사한 16시간 후의 절식 상태의 마우스의 내당능에 대한 영향을 조사하였다.
도 4는, 마우스(C57BL) 내당능 실험으로, GLP-1(A8G)-LK-L13H13을 15mg/마리(삼각형), 1회 복강 내(i.p.) 주사한 40시간 후의 절식 상태의 마우스의 내당능에 대한 영향을 조사하였다.
도 5는, 2형 당뇨병 마우스(db/db 마우스) 혈당치 시간 당곡선으로, GLP-1(A8G)-LK-L13H13을 10nmol/kg의 농도로(역삼각형) 2형 당뇨병 마우스에 1회 복강 내(i.p.) 주사한 후의 마우스의 혈당치 변화의 시간 곡선이다.
도 6은, 2형 당뇨병 마우스(db/db 마우스)의 일일 섭식량 시간 곡선으로, GLP-1(A8G)-LK-L13H13을 10nmol/kg의 농도로(역삼각형) 1회, 2형 당뇨병 마우스에 복강 내(i.p.) 주사하기 3일 전부터 주사 후 5일째까지의 기간 내의 마우스의 일일 섭식량의 변화를 기록한 시간 곡선이다. 도 6 및 도 5는 병행하여 수행한 실험의 결과이다.
도 2는, 리포터 유전자법으로 얻어진 GLP-1 야생형(원형) 및 GLP-1(A8G)-LK-L13H13(삼각형)의 hGLP-1R의 발현을 안정화하는 차이니즈 햄스터 난소 세포주의 작동 곡선이다.
도 3은, 마우스(ICR) 내당능 실험으로, GLP-1(A8G)-LK-L13H13을 5mg/마리(사각형) 및 15mg/마리(삼각형), 1회 복강 내(i.p.) 주사한 16시간 후의 절식 상태의 마우스의 내당능에 대한 영향을 조사하였다.
도 4는, 마우스(C57BL) 내당능 실험으로, GLP-1(A8G)-LK-L13H13을 15mg/마리(삼각형), 1회 복강 내(i.p.) 주사한 40시간 후의 절식 상태의 마우스의 내당능에 대한 영향을 조사하였다.
도 5는, 2형 당뇨병 마우스(db/db 마우스) 혈당치 시간 당곡선으로, GLP-1(A8G)-LK-L13H13을 10nmol/kg의 농도로(역삼각형) 2형 당뇨병 마우스에 1회 복강 내(i.p.) 주사한 후의 마우스의 혈당치 변화의 시간 곡선이다.
도 6은, 2형 당뇨병 마우스(db/db 마우스)의 일일 섭식량 시간 곡선으로, GLP-1(A8G)-LK-L13H13을 10nmol/kg의 농도로(역삼각형) 1회, 2형 당뇨병 마우스에 복강 내(i.p.) 주사하기 3일 전부터 주사 후 5일째까지의 기간 내의 마우스의 일일 섭식량의 변화를 기록한 시간 곡선이다. 도 6 및 도 5는 병행하여 수행한 실험의 결과이다.
이어서, 구체적인 실시예에 따라 도면에 맞추어 본 발명의 기법에 대하여 더 구체적으로 설명한다.
본 발명에 있어서, 특별히 지정되지 않은 경우, 이용되는 원료 및 설비 등은 모두 시판되고 있는 것이거나 혹은 해당 기술 분야에서 상용되고 있는 것이다. 하기 실시예에서의 방법은 특별한 설명이 없는 경우 모두 해당 기술 분야의 통상적인 방법이다.
[실시예]
1 단계: 면역용 항원 세포 안정주의 제작
CHO-DHFR세포를 6웰 플레이트에 접종하고, 24시간 배양한 후 hGLP-1R 유전자(뉴클레오티드 배열은 배열 번호 113을 참조, 아미노산 배열은 배열 번호 114를 참조)를 포함하는 pYS 플라스미드를 6웰 플레이트 내의 세포에 형질 주입(transfection)하였다. 형질 주입 전에 배양액을 교환하고, Invitrogen사가 추천하는 Lipofectamine 2000의 형질 주입 조건에 근거하여 형질 주입을 수행하였다. 48시간 후에 10nM의 MTX를 함유하는 완전 배지로 다시 교환하고, 3일마다 배양액을 교환하여, 2주 정도를 기다려 안정적으로 성장한 클론이 나타났다. 콜로니를 소화 분산시키고 50%의 유합도로 성장할 때까지 기다리고, MTX의 농도를 서서히 높여 MTX의 농도가 10μM이 될 때까지 가압 선별을 수행하였다. 제작한 안정 세포주에 대하여 각각 FACS 검출을 수행하고, 항 hGLP-1R의 항체(Abcam)를 이용하여 가압 후의 세포 집단을 동정하여, 10μM의 MTX 선별 후의 CHO-DHFR-hGLP-1R 세포막 상에서 hGLP-1R이 대량으로 발현하였다. 마지막으로 서브 클로닝, 동정을 거쳐 hGLP-1R 고발현 세포 안정주 6주를 얻었다.
2 단계: 항체의 조제
프로인트 항원 보강제(Freund's adjuvant) 속에서 유화한 CHO-DHFR-hGLP-1R 전 세포를 2×106개의 세포/마리의 용량으로 BLAB/c마우스(6~8주령)에 피하 주사하였다. 2주 후에 불완전 프로인트 항원 보강제 유화 면역원을 이용하여 면역 마우스를 증강하고, 그 후 주 1회 증강하였다. 꼬리를 절단하는 방식에 의해 채혈하여, 혈청을 원심 분리하고 FACS를 수행하여 혈청 역가를 측정하였다. 적절한 항체가에 달했을 때 단두에 의해 마우스를 안락사시키고, 무균 상태에서 비장 세포를 얻었다. 성장 상태가 대수 증식기에 있는 SP2/O 세포를 수집하여 2000rpm으로 3회분 동안 원심분리하고, 침전을 무혈청 배양으로 재현탁하고, 다시 원심-재현탁하여 계수를 수행하였다. 비장 세포 및 SP2/O 세포를 혼합하여 SP2/O:비장 세포≥1:1을 보증하고 "세정-원심"을 총 3회 수행하였다. 마지막 1회의 원심 후의 침전을 진탕하고, 37℃까지 예열한 PEG-1350 1mL에 한 방울씩 첨가하고(30초 이내에 적하를 완료한다), 1분간 상하로 불어서 빨아들이고 37℃까지 예열한 무혈청 배지(Invitrogen) 30mL에 천천히 첨가하며, PEG의 융합 작용을 종료하고 1500rpm으로 5분간 원심하고, 세포 침전을 진탕하고, HAT(히포크산틴, 메토트렉세이트 및 티미딘: Invitrogen), 20% FBS(Bioind)를 부가한 RPMI 1640(Invitrogen)을 융합 배지로 하고, 각 웰에 비장 세포 20000개 및 피더 세포 5000개를 96웰 플레이트 속에 넣고 각 웰을 100μl로 하였다. 융합한 하이브리도마 세포 및 피더 세포를 모두 96웰 플레이트 속에서 배양하고, HAT 선별을 수행하여 융합되지 않은 세포를 제거하였다. 10일 후에 배양 플레이트 속의 하이브리도마 세포 상등에 대하여 ELISA 검출을 수행하였다.
3 단계: 전세포 ELISA 선별
CHO-DHFR-hGLP-1R의 hGLP-1R을 발현한 세포 및 hGLP-1R을 발현하지 않은 CHO-DHFR-블랭크 세포를 각각 96웰 플레이트에 접종하고, 90%의 유합도까지 성장시켰다. 세포 배양 상등을 제거하고 PBS로 2회 세정하고, 100%의 메탄올 100μl를 첨가하여 4℃에서 10분간 고정하였다. 새롭게 제조한 0.6%의 H2O2-PBS 100μl를 더 첨가하고, 실온에서 20분간 처리하고 PBS로 2회 세정하였다. PBS-1%의 BSA로 밀봉한 후 하이브리도마 세포 상등을 첨가하여 4℃에서 90분간 배양하였다. 복수 회 세정한 후, 5000배로 희석한 GxM-HRP-Fc 2차 항체(Sigma-Aldrich) 100μl를 각 웰에 첨가하고 37℃에서 0.5시간 배양하였다. 5회 세정한 후 각 웰에 TMB 발색 기질 100μl를 첨가하고, 37℃에서 15분간 반응시키고 2M의 H2SO4에서 종료하여 OD 450값을 판독하였다. 양성 대조는 면역 마우스의 혈정으로 하고 음성 대조는 세포 배양 상등으로 하였다. 항 hGLP-1R 항체를 분비하는 하이브리도마주를 선택하고 클론화를 수행하여, hGLP-1R에 대한 분비를 안정화할 수 있는 세포주를 얻었다. 마지막으로 하이브리도마 세포가 분비한 항체 상등을 선택하고 FACS 검증을 수행하였다.
4 단계: 양성 하이브리도마 세포 상등 플로우 분석 동정(FACS)
10mM의 EDTA를 포함하는 PBS로 소화하고, CHO-DHFR-hGLP-1R 세포 105개를 수집하고 각각 1.5ml의 EP튜브에 첨가하여 원심 후에 상등을 버리며, 음성 대조 시료는 플로우식 샘플 로딩 버퍼(PBS, 2% FBS)로 재현탁하였다. 양성 처리군 세포는 각 튜브에 항체 상등 200μl를 첨가하고 실온에서 배양하며, 1500rpm으로 원심하고 상등을 버리고, 플로우식 샘플 로딩 버퍼로 1회 세정하고 더 원심하고 재현탁하며, 각 웰에 1:50으로 희석한 FITC 마커의 양 항 마우스 형광 항체(BD Pharmingen) 200μl를 첨가하여 실온에서 빛을 피해 30분간 배양하고 원심하여 상등을 버리고, 나아가 플로우식 샘플 로딩 버퍼로 1회 세정하고 원심하며, 마지막으로 플로우식 샘플 로딩 버퍼로 재현탁하고 기계로 검출하였다. 하이브리도마 세포 상등 및 hGLP-1R이 발현한 CHO-DHFR 세포는 특이적 결합을 가지며, 회색 피크와 점선 피크는 음성 대조이고, 하이브리도마 세포 상등이 대응하는 실선 피크(*로 기재되어 있다)는 현저하게 오른쪽으로 치우쳐 있었다(도 1).
5 단계: 항체 유전자의 클로닝 및 서브 클로닝
항체를 분비하는 하이브리도마 세포를 수집하고, QIAGEN의 mRNA 추출 시약 키트의 조작 절차서에 근거하여 하이브리도마 세포의 mRNA를 추출하였다. 이어서 추출한 mRNA를 cDNA에 역전사하고, 역전사 프라이머는 마우스의 경, 중쇄 정상 영역의 특이성 프라이머이며, 중쇄 역전사 프라이머는(5'-TTTGGRGGGAAGATGAAGAC-3')(배열 번호 115)이고, 경쇄 역전사 프라이머는(5'-TTAACACTCTCCCCTGTTGAA-3')(배열 번호 116) 및 (5'-TTAACACTCATTCCTGTTGAA-3')(배열번호 117)이었다. RT-PCR의 반응 조건은 25℃에서 5분, 50℃에서 60분, 70℃에서 15분으로 하였다. 역전사한 cDNA를 0.1mM의 TE에서 500μl까지 희석하고, 한외 여과 원심관(Amicon Ultra-0.5) 속에 첨가하여 2000g으로 10분 원심하고 여과액을 버리며, 다시 0.1mM의 TE 500μl를 첨가하여 2000g로 10분간 원심 분리하고 여과액을 버리며, 조제 튜브를 새로운 원심 튜브 속에 반대로 놓고 2000g으로 10분간 원심하여 정제한 cDNA를 얻으며, 정제한 cDNA 10μl를 주형(template)으로 하고, 5배의 테일링 버퍼(tailing buffer) 4μl, dATP(1mM) 4μl 및 10U의 터미널 트랜스퍼라아제(Promega)를 첨가한 후 균일하게 섞고 37℃에서 5분간 배양한 후 65℃에서 5분간 배양하며, 이어서 폴리 A 테일을 첨가한 cDNA를 주형으로 하고 PCR에서 항체의 경, 중쇄 가변 영역 유전자를 증폭하였다. 상류 프라이머는 모두 OligodT이고, 중쇄 하류 프라이머는 (5'-TGGACAGGGATCCAGAGTTCC-3')(배열 번호 118) 및 (5'-TGGACAGGGCTCCATAGTTCC-3')(배열 번호 119)이며, 경쇄 하류 프라이머는 (5'-ACTCGTCCTTGGTCAACGTG-3')(배열 번호 120)이다. PCR 반응 조건: 95℃에서 5분간, 95℃에서 30초간, 56℃에서 30초간, 72℃에서 1분간을 40사이클, 72℃에서 7분간. PCR 생성물을 PMD 18-T 벡터에 결합한 후 시퀀싱을 수행하였다. 시퀀싱으로 얻어진 항체 경쇄 및 중쇄 가변 영역 배열은 부록의 배열표를 참조.
이전에 시퀀싱하여 얻어진 항체의 DNA 배열에 근거하여 PCR 프라이머를 설계하고, 이에 따라 완전한 경쇄, 중쇄 시그널 펩티드 및 가변 영역 및 마우스 IgG1 정상 영역을 발현 벡터 pTM5와 결합하였다.
6 단계: 현탁 HEK 293 숙주 세포계에서의 항 GLP-1R 항체의 일과성 발현
현탁 HEK 293 또는 CHO 발현 세포계를 스피너 플라스크에 접종하고, 37℃에서 24시간 회전 배양한 후 형질 주입에 이용하였다. 형질 주입 과정에 있어서, 폴리에틸렌이민(PEI)를 형질 주입 매체로 하고 DNA와 혼합한 후 세포 배양에 첨가하였다. PEI와 DNA의 혼합의 바람직한 배합비는 1:1부터 5:1이다. 세포는 PEI와 DNA의 혼합물을 수용한 후 37℃의 회전 배양을 96시간 이상 계속하여 항원 결합 단백질을 발현하고, 그 동안에 0.5%의 카세인펩톤을 발현에 필요한 아미노산원으로서 세포 배양에 첨가하며, 마지막으로 세포 상등을 수집하여 항원 결합 단백질의 정제 분리에 이용하였다.
7 단계: 항체 인간화 및 최적화
먼저, 얻어진 마우스 항체 경, 중쇄 가변 영역 배열을 선별하고, NCBI의 온라인 항체 가변 영역 배열 대조 툴 Ig Blast를 이용하여 도입한 항체 가변 영역 배열과 상동인 인간 항체 생식 세포계 유전자 배열(Ig Germline Gene sequence)를 검색하고, CDR 배열을 제거하고 상동성이 가장 높은 인간 유전자 배열을 주형 배열로 하고 CDR 그라프팅을 수행하여 인간 항체 가변 영역 배열을 얻어, 인간화 항체 경, 중쇄 유전자를 외부 주입하고 합성하였다. 배열에 근거하여 PCR 프라이머를 설계하고, 합성 배열의 5'말단 및 3'말단에 적절한 제한 효소 절단 부위를 도입하며, PCR증식 후에 인간 IgG2 또는 IgG4 정상 영역 배열과 그라프팅한 후, 완전한 재조합 인간화 항체 배열을 얻었다. 재조합 항체는 6 단계에 근거하여 발현을 수행하고, 4 단계에서의 FACS 기술에 의해 GLP-1R에 대한 친화력을 검증하였다. GLP-1R에 대한 친화력을 남긴 인간화 항체군으로부터 친화력이 가장 뛰어난 항체를 골라내고, 부위 특이적 변이 도입에 의해 가변 영역 배열을 더 개조하여 GLP-1R에 대한 친화력을 더욱 향상시켰다.
8 단계: GLP-1 인간화 융합 단백질의 유전자 클로닝과 서브 클로닝
최적화한 인간화 항체를 경쇄의 N말단 또는 C말단에 있어서 GLP-1 및 그 유도체 배열과 융합하여 GLP-1 융합 단백질을 만들었다. 양자의 배열은 펩티드 링커 배열(LK)을 가교로 하여 결합하였다. 시그널 펩티드-GLP-1-펩티드 링커의 뉴클레오티드 배열은 GenScript (Nanjing) Co., Ltd가 합성하고, 합성 유전자를 주형으로 하여 "시그널 펩티드-GLP1-링커" 부분의 배열을 PCR 증폭하였다. PCR 상류 프라이머는 (5'-CCACCATGGACTTTGGGCTGAGC-3')(배열 번호 121)이고, PCR 하류 프라이머는 (5'-AGAGCCGGTGGCAGGAGCCAG-3')(배열 번호 122)이며, PCR 반응 조건은 95℃에서 5분간, 95℃에서 30초간, 56℃에서 30초간, 72℃에서 30초간을 35사이클, 72℃에서 7분으로 하였다. 또한 인간화 항체의 뉴클레오티드 배열을 주형으로 하여 융합 단백질의 항체 부분의 배열을 증폭하였다.
PCR 상류 프라이머는 (5'-CTGGCTCTGCCACCGGCTCTCTGCCATCCAGATGACCCACTCTCC-3')(배열 번호 123)이고, PCR 하류 프라이머는 (5'-ACACTCTCCCCTGTTGAAGCTC-3')(배열 번호 124)이며, PCR 반응 조건은 95℃에서 5분간, 95℃에서 30초간, 56℃에서 30초간, 72℃에서 1분간을 35사이클, 72℃에서 7분으로 하였다. 이어서 오버랩 PCR(overlapping PCR)에 의해 융합 단백질 핵산 배열의 "시그널 펩티드- GLP-1-펩티드 링커"부분을 항체 부분과 결합하고, 프라이머 양단에 Nhe1 및 Not1의 효소 절단 부위를 부가하여, 이에 의해 완전한 융합 단백질 배열을 발현 벡터 pTM5와 결합하였다. 오버랩 PCR의 상류 프라이머는 (5'-CCGGCTAGCCACCATGGACTTTGGGCTGAGC-3')(배열 번호 125)이고, 하류 프라이머는 (5'-AGTGCGGCCGCTCAACACTCTCCCCTGTTGAAGCTC-3')(배열 번호 126)이었다. PCR 반응 조건: 95℃에서 5분간, 95℃에서 30초간, 56℃에서 30초간, 72℃에서 1분간을 35사이클, 72℃에서 7분간. PCR 생성물을 PTM5 벡터에 결합한 후 시퀀싱을 수행하였다.
9 단계: 현탁 HEK 293 숙주 세포계에서의 GLP-1 융합 단백질의 일과성 발현
HEK 293 현탁 세포를 스피너 플라스크 속에 접종하고, 형질 주입 전에 배지를 바꾸었다. 융합 단백질 경/중쇄 유전자를 포함하는 벡터를 DNA 총량의 0.5~1.5㎍/ml의 농도로 1.5~7.5㎍/ml의 폴리에틸렌이민(PEI)과 혼합하고, 15~25분간 정치한 후 세포 배양에 첨가하였다. 24시간 후에 다시 세포 배양에 0.5~1%의 Trypton N1을 첨가하였다. 5~10일간 배양한 후에 수집한 상등 속에 분비 발현한 GLP-1 융합 단백질을 함유하였다.
10 단계: 현탁 CHO 숙주 세포계에서의 GLP-1 융합 단백질의 안정 발현
현탁 CHO 세포를 6웰 플레이트에 접종하고, 1 단계에서의 형질 주입 조건에서 융합 단백질의 발현 벡터를 형질 주입하였다. 48시간 후에 300mg/ml의 히그로마이신(중쇄) 및 6mg/ml의 퓨로마이신(경쇄)를 첨가하고 공동 선별을 수행하였다. 세포에 대량의 아폽토시스가 나타난 후(사망률>90%), 항생 물질 농도를 서서히 낮추고 잉여 세포의 성장을 회복하며, 그 후 스피너 플라스크 확대 배양으로 바꾸고 이어서 상등 속의 항체 발현을 확인하였다. 그 후의 배지에 있어서, 절반의 항생 물질 농도를 유지하고 GLP-1 융합 단백질에 대한 세포의 안정 발현을 유지하였다.
11 단계: GLP-1 융합 단백질의 세포 배양 상등으로부터의 정제 및 조제
세포 배양을 원심하고 그 속의 세포를 제거하며, 그 상등이 공역 단백 G 리간드의 친화 컬럼을 거친 후, pH 2.5~3.5의 용출액에서 발현한 GLP-1 융합 단백질을 컬럼 상으로부터 용출하였다. 용출 튜브 속에 미리 중화 완충액을 넣어 두고 용출액의 저pH값을 재빨리 중화하였다. 용출 후에 수집한 단백질 용액을 PBS에 대하여 투석하였다.
12 단계: 리포터 유전자 실험에서의 GLP-1 융합 단백질의 in vitro에서의 GLP-1 수용체의 작동 기능 검출(도 2를 참조)
각 웰에 20000개의 공발현 hGLP1R-CRE-루시페라아제의 CHO-DHFR-세포를 96웰의 세포 배양 플레이트에 접종하고, 37℃에서 하룻밤 배양하였다. 이틀째에 배지 상등을 제거하고 무혈청 배지에서 세포 표면을 2회 세정하여 잔액을 제거하고, 다시 100μl를 첨가하여 무혈청 배지에서 정제 항체 또는 GLP-1을 희석하고 37℃에서 4시간 배양하였다. 자극 종료 후 Promega의 Bright Glo 화학 발현 기질 100μl를 첨가하고, 마지막으로 세포 분해물을 백색 96웰 플레이트로 옮겨 Molecular Devices의 SpecraMax L 루미노메터로 상대 발광 강도를 판독하였다.
13 단계: 마우스(ICR) 절식 상태에서의 내당능 시험
마우스의 정맥 내 포도당 부하를 측정하여 본 특허의 GLP-1 융합 단백질(바람직하게는 항체 GLP-1(A8G)-LK-L13H13))의 효과를 평가하였다. 4군에서는 각 군에 적어도 3에서 5마리의 마우스를 포함하였다. Ⅰ군은 동 체적 PBS 대조 복강 내 주사를 맞았다. Ⅱ군은 15㎍/마리의 1회 복강 내 주사를 맞았다. Ⅲ군은 5㎍/마리의 1회 복강 내 주사를 맞았다. 주사 후에 그 기초 혈당치를 측정하였다. 이어서 농도 1.5g/kg의 글루코스 위 존데 경구 투여를 수행하였다. 글루코스 위 존제 경구 투여 후 15분, 30분, 60분 및 90분 후에 그 혈액 시료를 채취하여 혈당치를 측정하였다(도 3을 참조).
14 단계: 내당능 시험에 의한 GLP-1 융합 단백질의 마우스(G57BL) 체내 지속성(40분간)의 검출
마우스의 정맥 내 포도당 부하를 측정하여 본 특허의 GLP-1 융합 단백질(바람직하게는 항체 GLP-1(A8G)-LK-L13H13))의 마우스 체내에서의 지속성을 평가하였다. 양군에서는 적어도 3에서 5마리의 마우스를 포함하였다. Ⅰ군은 동 체적 PBS 대조 복강 내 주사를 맞았다. Ⅱ군은 15㎍/마리의 1회 복강 내 주사를 맞았다. 주사 24시간 후에 마우스에 16시간의 절식 처치를 수행하고, 절식 완료 후 마우스의 혈액 시료를 채취하여 그 기초 혈당치를 측정하였다. 이어서 농도 1.5g/kg의 글루코스 위 존데 경구 투여를 수행하였다. 글루코스 위 존제 경구 투여 후 15분, 30분, 60분 및 90분 후에 그 혈액 시료를 채취하여 혈당치를 측정하였다(도 4를 참조).
15 단계: GLP-1 융합 단백질에 의한 2형 당뇨병 마우스(db/db 마우스)의 혈당치 저하의 지속성 연구(72시간)
서로 다른 시점에서 2형 당뇨병 마우스의 혈당치를 측정하여 본 특허의 GLP-1 융합 단백질(바람직하게는 항체 GLP-1(A8G)-LK-L13H13))에 의한 2형 당뇨병 마우스 체내에서의 그 혈당치 저하의 지속성을 평가하였다. 양군에서는 각 군에 적어도 6마리의 마우스를 포함하였다. 주사 개시 전에 마우스 혈액 시료를 채취하고 그 기초 혈당치를 측정하였다. 그 후, Ⅰ군은 동 체적 PBS 대조 복강 내 주사를 맞고 Ⅱ군은 10nmol/kg 농도의 1회 복강 내 주사를 맞았다. 주사 후 1, 4, 6, 24, 48, 72시간 후에 각각 그 혈액 시료를 채취하여 양군의 마우스 혈당치를 측정하였다(도 5를 참조).
16 단계: GLP-1 융합 단백질에 의한 2형 당뇨병 마우스(db/db 마우스)의 일일 섭식량 감소의 지속성 연구(120시간)
2형 당뇨병 마우스의 일일 섭식량 변화를 측정하여 본 특허의 GLP-1 융합 단백질(바람직하게는 항체 GLP-1(A8G)-LK-L13H13))에 의한 2형 당뇨병 마우스의 섭식 레벨면 저하의 지속성을 평가하였다. 이 단계 및 15 단계는 같은 로트의 마우스로 동시에 수행하였다. 양군에서는 각 군에 적어도 6마리의 마우스를 포함하였다. 15 단계의 주사 3일 전부터 주사 5일 (120시간) 후까지, 매일 아침 같은 시간에 각 군의 마우스의 일일 섭식량을 칭량하였다(도 6을 참조).
이상에 기재된 실시예는 본 발명의 바람직한 방법에 불과하고, 본 발명에 대한 어떠한 형식의 한정을 수행하는 것도 아니며, 특허 청구의 범위에 기재된 기술 수법을 넘지 않는다는 전제 하에서 또 다른 변경 및 수정이 있다.
SEQUENCE LISTING
<110> GMAX BIOPHARM LLC.
<120> GLP-1R 특이적 결합이 가능한 항체 및 그 GLP-1과의 융합 단백질
<130> 2014
<160> 127
<170> PatentIn version 3.5
<210> 1
<211> 31
<212> PRT
<213> 호모 사피엔스
<400> 1
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210> 2
<211> 31
<212> PRT
<213> 호모 사피엔스
<400> 2
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210> 3
<211> 22
<212> PRT
<213> 호모 사피엔스
<400> 3
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe
20
<210> 4
<211> 23
<212> PRT
<213> 호모 사피엔스
<400> 4
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile
20
<210> 5
<211> 24
<212> PRT
<213> 호모 사피엔스
<400> 5
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala
20
<210> 6
<211> 10
<212> PRT
<213> 쥐
<400> 6
Gly Phe Ser Leu Thr Gly Tyr Gly Val Asn
1 5 10
<210> 7
<211> 10
<212> PRT
<213> 쥐
<400> 7
Gly Phe Thr Phe Ser Asp Asn Gly Met Ala
1 5 10
<210> 8
<211> 10
<212> PRT
<213> 쥐
<400> 8
Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala
1 5 10
<210> 9
<211> 10
<212> PRT
<213> 쥐
<400> 9
Gly Tyr Lys Phe Thr Asp Tyr Ala Met Tyr
1 5 10
<210> 10
<211> 10
<212> PRT
<213> 쥐
<400> 10
Gly Tyr Lys Phe Thr Asp Tyr Ala Met His
1 5 10
<210> 11
<211> 12
<212> PRT
<213> 쥐
<400> 11
Gly Phe Ser Leu Ser Thr Phe Gly Met Gly Val Gly
1 5 10
<210> 12
<211> 10
<212> PRT
<213> 쥐
<400> 12
Gly Phe Thr Leu Ser Ser Tyr Gly Met His
1 5 10
<210> 13
<211> 17
<212> PRT
<213> 쥐
<400> 13
Gly Met Ile Trp Gly Gly Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys
1 5 10 15
Ser
<210> 14
<211> 17
<212> PRT
<213> 쥐
<400> 14
Phe Ile Ser Asn Leu Ser Tyr Arg Ile Tyr Tyr Ala Asp Thr Val Thr
1 5 10 15
Gly
<210> 15
<211> 17
<212> PRT
<213> 쥐
<400> 15
Phe Ile Ser Asn Leu Ala Tyr Arg Ile Tyr Tyr Ala Asp Thr Val Thr
1 5 10 15
Gly
<210> 16
<211> 17
<212> PRT
<213> 쥐
<400> 16
Val Ile Ser Ile Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 17
<211> 17
<212> PRT
<213> 쥐
<400> 17
Val Ile Asn Ile Tyr Tyr Gly Asn Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 18
<211> 16
<212> PRT
<213> 쥐
<400> 18
His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala Leu Lys Ser
1 5 10 15
<210> 19
<211> 17
<212> PRT
<213> 쥐
<400> 19
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 20
<211> 6
<212> PRT
<213> 쥐
<400> 20
Gly Leu Pro Gly Asp Tyr
1 5
<210> 21
<211> 11
<212> PRT
<213> 쥐
<400> 21
Gly Thr Met Ala Pro Asn Trp Tyr Phe Asp Val
1 5 10
<210> 22
<211> 11
<212> PRT
<213> 쥐
<400> 22
Gly Thr Thr Ala Pro Asn Trp Tyr Phe Asp Val
1 5 10
<210> 23
<211> 9
<212> PRT
<213> 쥐
<400> 23
Gly Ile Thr Thr Ala Ala Phe Asp Tyr
1 5
<210> 24
<211> 9
<212> PRT
<213> 쥐
<400> 24
Gly Ile Thr Met Ala Ala Phe Asp Tyr
1 5
<210> 25
<211> 9
<212> PRT
<213> 쥐
<400> 25
Gly Val Thr Phe Tyr Ala Met Asp His
1 5
<210> 26
<211> 9
<212> PRT
<213> 쥐
<400> 26
Lys Gly Asn Phe Ala Trp Phe Thr Tyr
1 5
<210> 27
<211> 16
<212> PRT
<213> 쥐
<400> 27
Gly Gly Gly Ser Gly Ser Tyr Arg Tyr Tyr Tyr Tyr Gly Leu Asp Val
1 5 10 15
<210> 28
<211> 16
<212> PRT
<213> 쥐
<400> 28
Lys Ser Thr Lys Ser Leu Leu Asn Ser Asp Gly Phe Thr Tyr Leu Asp
1 5 10 15
<210> 29
<211> 10
<212> PRT
<213> 쥐
<400> 29
Arg Ala Ser Ser Ser Val Thr Tyr Ile His
1 5 10
<210> 30
<211> 10
<212> PRT
<213> 쥐
<400> 30
Arg Ala Ser Ser Ser Val Ser Tyr Met Tyr
1 5 10
<210> 31
<211> 8
<212> PRT
<213> 쥐
<400> 31
Gln Gly Ile Ser Asn Tyr Leu Asn
1 5
<210> 32
<211> 17
<212> PRT
<213> 쥐
<400> 32
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 33
<211> 10
<212> PRT
<213> 쥐
<400> 33
Arg Ala Ser Ser Ser Val Thr Tyr Ile His
1 5 10
<210> 34
<211> 16
<212> PRT
<213> 쥐
<400> 34
Arg Ser Ser Lys Ser Leu Leu Asp Arg Asn Gly Asn Thr Tyr Leu Tyr
1 5 10 15
<210> 35
<211> 16
<212> PRT
<213> 쥐
<400> 35
Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr
1 5 10 15
<210> 36
<211> 17
<212> PRT
<213> 쥐
<400> 36
Lys Ser Ser Gln Ser Leu Leu Asn Ser Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 37
<211> 11
<212> PRT
<213> 쥐
<400> 37
Arg Ala Ser Gln Asn Ile Asn Asn Leu Leu Ala
1 5 10
<210> 38
<211> 7
<212> PRT
<213> 쥐
<400> 38
Leu Val Ser Asn Arg Phe Ser
1 5
<210> 39
<211> 7
<212> PRT
<213> 쥐
<400> 39
Gly Thr Ser Asn Leu Ala Ser
1 5
<210> 40
<211> 7
<212> PRT
<213> 쥐
<400> 40
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 41
<211> 7
<212> PRT
<213> 쥐
<400> 41
Tyr Thr Ser Ser Leu His Ser
1 5
<210> 42
<211> 7
<212> PRT
<213> 쥐
<400> 42
Gly Ala Ser Thr Arg Glu Ser
1 5
<210> 43
<211> 7
<212> PRT
<213> 쥐
<400> 43
Arg Met Ser Asn Leu Ala Ser
1 5
<210> 44
<211> 7
<212> PRT
<213> 쥐
<400> 44
Phe Ala Ser Thr Arg Glu Ser
1 5
<210> 45
<211> 7
<212> PRT
<213> 쥐
<400> 45
Thr Ala Ser Ser Leu Gln Ser
1 5
<210> 46
<211> 9
<212> PRT
<213> 쥐
<400> 46
Phe Gln Ser Asn Tyr Leu Pro Phe Thr
1 5
<210> 47
<211> 9
<212> PRT
<213> 쥐
<400> 47
Gln Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 48
<211> 9
<212> PRT
<213> 쥐
<400> 48
Gln Gln Trp Thr Ser Asn Pro Pro Thr
1 5
<210> 49
<211> 9
<212> PRT
<213> 쥐
<400> 49
Gln Gln Tyr Ser Lys Leu Pro Tyr Thr
1 5
<210> 50
<211> 9
<212> PRT
<213> 쥐
<400> 50
Gln Asn Asp His Ser Tyr Pro Phe Thr
1 5
<210> 51
<211> 9
<212> PRT
<213> 쥐
<400> 51
Met Gln His Leu Glu Tyr Pro Tyr Thr
1 5
<210> 52
<211> 9
<212> PRT
<213> 쥐
<400> 52
Gln Gln His Tyr Tyr Thr Pro Tyr Thr
1 5
<210> 53
<211> 9
<212> PRT
<213> 쥐
<400> 53
Gln Gln Ala His Arg Phe Pro Pro Thr
1 5
<210> 54
<211> 342
<212> DNA
<213> 쥐
<400> 54
caggtgcaac tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccatc 60
acatgcaccg tctcaggatt ctcattaacc ggctatggtg taaactgggt tcgccagcct 120
ccaggaaagg gtctggagtg gctgggaatg atatggggtg gtggaagcac agactataat 180
tcagctctca aatccagact gagcatcagc aaggacaact ccaagagcca agttttctta 240
aaaatgaaca gtctgcaaag tgatgacaca gccaggtact actgtgccag aggactaccg 300
ggggactact ggggtcgagg aacctcagtc accgtctcct ca 342
<210> 55
<211> 114
<212> PRT
<213> 쥐
<400> 55
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr
20 25 30
Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Gly Gly Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asp Asp Thr Ala Arg Tyr Tyr Cys Ala
85 90 95
Arg Gly Leu Pro Gly Asp Tyr Trp Gly Arg Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 56
<211> 360
<212> DNA
<213> 쥐
<400> 56
gaggtgaagc tggtggagtc tgggggcggc atagtgcagc ctggagggtc ccggaaactc 60
tcctgtgcag cctctggatt cactttcagt gacaacggaa tggcgtgggt tcgacaggct 120
ccagggaagg ggcctgagtg ggtagcattc attagtaatt tgtcatatag gatctactat 180
gcagacactg tgacgggccg attcaccgtc tctagagaga atgccaagaa caccctgtac 240
ctggaaatga gcagtctgcg gtctgaggac acagcctttt actactgtgc acggggcact 300
atggctccta actggtactt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360
<210> 57
<211> 120
<212> PRT
<213> 쥐
<400> 57
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Ile Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asn
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Leu Ser Tyr Arg Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Val Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Met Ala Pro Asn Trp Tyr Phe Asp Val Trp Gly Ala
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 58
<211> 360
<212> DNA
<213> 쥐
<400> 58
gaggtgaagg tggtggagtc tgggggaggc ttagtgcagc ctggagggtc ccggaaactc 60
tcctgtgcag cctctggatt cactttcagt gactacggaa tggcgtgggt tcgacaggct 120
ccagggaagg ggcctgagtg ggtagcattc attagtaatt tggcatatag aatctactat 180
gcagacactg tgacgggccg attcaccatc tctagagaga atgccaagaa caccctgtac 240
ctggaaatga gcagtctgag gtctgaggac acagccatgt attactgtgc aaggggcact 300
acggctccta actggtactt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360
<210> 59
<211> 120
<212> PRT
<213> 쥐
<400> 59
Glu Val Lys Val Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Leu Ala Tyr Arg Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Thr Ala Pro Asn Trp Tyr Phe Asp Val Trp Gly Ala
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 60
<211> 354
<212> DNA
<213> 쥐
<400> 60
caggtccagc tgcagcagtc tgggcctgag ctggtgaggc ctggggtctc agtgaagatt 60
tcctgcaagg gttccggcta caaattcact gattatgcta tgtactgggt gaagcagagt 120
catgcaaaga gtctagagtg gattggagtt attagtattt actatggtaa tacaaactac 180
aaccagaagt ttaaggacaa ggccacaatg actgtagaca aatcctccag cacagcctat 240
atggaacttg ccagattgac atctgaggat tctgccatct attactgtgc aagggggatt 300
actacggccg cttttgacta ctggggccaa ggcaccactc tcacagtctc ctca 354
<210> 61
<211> 118
<212> PRT
<213> 쥐
<400> 61
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Lys Phe Thr Asp Tyr
20 25 30
Ala Met Tyr Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Ile Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Thr Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 62
<211> 354
<212> DNA
<213> 쥐
<400> 62
caggtccagc tgcagcagtc tgggcctgag ctggtgaggc ctggggtctc agtgaagatt 60
tcctgcaagg gttccggcta caaattcact gattatgcta tgtattgggt gaagcagagt 120
catgcaaaga gtctagagtg gattggagtt attagtattt attatggtaa tacaaactac 180
aaccagaagt ttaagggcaa ggccacaatg actgtagaca aatcctccaa cacagcctat 240
atggaacttg ccagattgac atctgaggat tctgccatct attactgtgc aagggggatt 300
actatggccg cttttgacta ctggggccaa ggcaccactc tcacagtctc ctca 354
<210> 63
<211> 118
<212> PRT
<213> 쥐
<400> 63
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Lys Phe Thr Asp Tyr
20 25 30
Ala Met Tyr Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Ile Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Met Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 64
<211> 360
<212> DNA
<213> 쥐
<400> 64
gaggtgaagc tggtggagtc tgggggcggc atagtgcagc ctggagggtc ccggaaactc 60
tcctgtgcag cctctggatt cactttcagt gacaacggaa tggcgtgggt tcgacaggct 120
ccagggaagg ggcctgagtg ggtagcattc attagtaatt tgtcatatag gatctactat 180
gcagacactg tgacgggccg attcaccgtc tctagagaga atgccaagaa caccctgtac 240
ctggaaatga gcagtctgcg gtctgaggac acagcctttt actactgtgc acggggcact 300
atggctccta actggtactt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360
<210> 65
<211> 120
<212> PRT
<213> 쥐
<400> 65
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Ile Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asn
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Leu Ser Tyr Arg Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Val Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Met Ala Pro Asn Trp Tyr Phe Asp Val Trp Gly Ala
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 66
<211> 354
<212> DNA
<213> 쥐
<400> 66
caggtccagc tgcagcagtc tggggctgag atggtgaggc ctggggtctc agtgaagatt 60
tcctgcaagg gttctggcta caaattcact gattacgcta tgcactgggt gaagcagagt 120
catgcaaaga gtctagagtg gattggagtt attaatattt attatggtaa taccagttac 180
aaccagaagt tcaagggcaa ggccacaatg actattgaca gatcctccag cacagcctat 240
atggaacttg ccagactgac atctgacgat tctgccatct attattgtgc aagaggggtt 300
accttttatg ctatggacca ctggggtcaa ggaacctcag tcaccgtctc ctca 354
<210> 67
<211> 118
<212> PRT
<213> 쥐
<400> 67
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Met Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Lys Phe Thr Asp Tyr
20 25 30
Ala Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Ile Tyr Tyr Gly Asn Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Ile Asp Arg Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Asp Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Val Thr Phe Tyr Ala Met Asp His Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 68
<211> 354
<212> DNA
<213> 쥐
<400> 68
caggtccagc tgcagcagtc tgggcctgag ctggtgaggc ctggggtctc agtgaagatt 60
tcctgcaagg gttccggcta caaattcact gattatgcta tgtattgggt gaagcagagt 120
catgcaaaga gtctagagtg gattggagtt attagtattt attatggtaa tacaaactac 180
aaccagaagt ttaagggcaa ggccacaatg actgtagaca aatcctccaa cacagcctat 240
atggaacttg ccagattgac atctgaggat tctgccatct attactgtgc aagggggatt 300
actatggccg cttttgacta ctggggccaa ggcaccactc tcacagtctc ctca 354
<210> 69
<211> 118
<212> PRT
<213> 쥐
<400> 69
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Lys Phe Thr Asp Tyr
20 25 30
Ala Met Tyr Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Ile Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Met Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 70
<211> 357
<212> DNA
<213> 쥐
<400> 70
caggttactc tgaaagagtc tggccctggg atattgcagc cctcccagac cctcagtctg 60
acttgttctt tctctgggtt ttcactgagc acttttggta tgggtgtagg ctggattcgt 120
cagccttcag ggaagggtct ggagtggctg gcacacattt ggtgggatga tgataagtac 180
tataacccag ccctgaagag tcggctcaca atctccaagg atacctccaa aaaccaggta 240
ttcctcaaga tcgccaatgt ggacactgca gatactgcca catactactg tgctcgaaag 300
ggcaacttcg cctggttcac ctactggggc caagggactc tggtcactgt ctctagt 357
<210> 71
<211> 119
<212> PRT
<213> 쥐
<400> 71
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Lys Gly Asn Phe Ala Trp Phe Thr Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 72
<211> 354
<212> DNA
<213> 쥐
<400> 72
caggtccagc tgcagcagtc tgggcctgag ctggtgaggc ctggggtctc agtgaagatt 60
tcctgcaagg gttccggcta caaattcact gattatgcta tgcactgggt gaagcaaagt 120
catgcaaaga gtctagagtg gattggagtt attagtattt actatggtaa tacaaactac 180
aaccagaagt ttaaggacaa ggccacaatg actgtagaca agtcctccag cacagcctat 240
atggaacttg ccagattgac atctgaggat tctgccatct attactgtgc aagggggatt 300
actacggccg cttttgacta ctggggccaa ggcaccactc tcacagtctc ctca 354
<210> 73
<211> 118
<212> PRT
<213> 쥐
<400> 73
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Lys Phe Thr Asp Tyr
20 25 30
Ala Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Ile Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Thr Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 74
<211> 375
<212> DNA
<213> 쥐
<400> 74
caggtgcagc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt caccttaagt agctatggca tgcactgggt tcgtcaggct 120
ccagagaagg ggctggagtg ggttgcagtc atatggtatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca atgccaagaa caccctgttc 240
ctgcaaatga ccagtctgag gtctgaggac acggccatgt attactgtgc aagagggggt 300
ggttcgggga gttatcggta ctactactac ggtctggacg tctggggcac agggaccacg 360
gtcaccgtct ctagt 375
<210> 75
<211> 125
<212> PRT
<213> 쥐
<400> 75
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Gly Ser Gly Ser Tyr Arg Tyr Tyr Tyr Tyr Gly Leu
100 105 110
Asp Val Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 76
<211> 357
<212> DNA
<213> 호모 사피엔스
<400> 76
caggtcaccc tgaaagagtc cggccctgcc ctggtgaagc ctacccagac cctgaccctg 60
acatgcacct tcagcggctt cagcctgagc accttcggca tgggcgtggg ctggatcaga 120
cagcctcccg gcaaggccct ggaatggctg gcccacattt ggtgggacga cgacaagtac 180
tacaaccccg ccctgaagtc ccggctgacc atcagcaagg acaccagcaa gaaccaggtg 240
gtgctgacca tgaccaacat ggaccccgtg gacaccgcca cctactactg cgcccggaag 300
ggcaacttcg cctggttcac ctactggggc cagggcaccc tggtgaccgt ctctagt 357
<210> 77
<211> 119
<212> PRT
<213> 호모 사피엔스
<400> 77
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Lys Gly Asn Phe Ala Trp Phe Thr Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 78
<211> 375
<212> DNA
<213> 호모 사피엔스
<400> 78
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttaagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtc atatggtatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagggggt 300
ggttcgggga gttatcggta ctactactac ggtctggacg tctggggcca agggaccacg 360
gtcaccgtct ctagt 375
<210> 79
<211> 125
<212> PRT
<213> 호모 사피엔스
<400> 79
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Gly Ser Gly Ser Tyr Arg Tyr Tyr Tyr Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 80
<211> 336
<212> DNA
<213> 쥐
<400> 80
gatgttgttc tgacccaaac tccactctct ctgcctgtca atattggaga tcaagcctct 60
atctcttgca agtctactaa gagtcttctg aatagtgatg gattcactta tttggactgg 120
tacctgcaga agccaggcca gtctccacag ctcctaatat atttggtttc taatcgattt 180
tctggagttc cagacaggtt cagtggcagt gggtcaggaa cagatttcac actcaagatc 240
agcagagtgg aggctgatga tttgggagtt tattattgct tccagagtaa ctatcttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaa 336
<210> 81
<211> 112
<212> PRT
<213> 쥐
<400> 81
Asp Val Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Ile Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Lys Ser Thr Lys Ser Leu Leu Asn Ser
20 25 30
Asp Gly Phe Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Asp Asp Leu Gly Val Tyr Tyr Cys Phe Gln Ser
85 90 95
Asn Tyr Leu Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 82
<211> 318
<212> DNA
<213> 쥐
<400> 82
caaattgttc tctcccagtc tccagcaatc ctgtctgcat ctccagggga gaaggtcaca 60
atgacttgca gggccagctc aagtgttact tacatacact ggtaccagca gaagccagga 120
tcctccccca aaccctggat ttatggcaca tccaatctgg cttctggagt ccctgttcgc 180
ttcagtggca gtgggtctgg gacctctttc tctctcacaa tcaccagagt ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg agtagtaacc cacccacgtt cggtactggg 300
accaagctgg agctgaaa 318
<210> 83
<211> 106
<212> PRT
<213> 쥐
<400> 83
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Thr Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile Thr Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr
85 90 95
Phe Gly Thr Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 84
<211> 318
<212> DNA
<213> 쥐
<400> 84
caaattgttc tctcccagtc tccagcaatc ctgtctgcat ctccagggga gaaggtcaca 60
atgacttgca gggccagctc aagtgtaagt tacatgtact ggtaccagca gaagccagga 120
tcctccccca aaccctggat ttatgccaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagagt ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg actagtaacc cacccacgtt cggtgctggg 300
tccaagctgg agctgaga 318
<210> 85
<211> 106
<212> PRT
<213> 쥐
<400> 85
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Ala Gly Ser Lys Leu Glu Leu Arg
100 105
<210> 86
<211> 324
<212> DNA
<213> 쥐
<400> 86
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gtgcaagtca gggcattagc aattatttaa actggtatca gcagaaaccg 120
gatggaactg ttaaactcct gatctattac acatcaagtt tacactcagg agtcccatca 180
aggttcagtg gcagtgggtc tgggacagat tattctctca ccatcagcaa cctggaacct 240
gaagatgttg ccacttacta ttgtcagcag tatagtaagc ttccgtacac gttcggaggg 300
gggaccaagc tggaaataag acgg 324
<210> 87
<211> 108
<212> PRT
<213> 쥐
<400> 87
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Lys Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg
100 105
<210> 88
<211> 339
<212> DNA
<213> 쥐
<400> 88
gacattgtga tgacacagtc tccatcctcc ctgagtgtgt cagcaggaga gaaggtcact 60
atgagctgca agtccagtca gagtctgtta aacagtggaa atcaaaagaa ctacttggcc 120
tggtaccagc agaaaccagg gcagcctcct aaactgttga tctacggggc atccactagg 180
gaatctgggg tccctgatcg cttcacaggc agtggatctg gaactgattt cactcttacc 240
atcagcagtg tgcaggctga agacctggca gtttattact gtcagaatga tcatagttat 300
ccattcacgt tcggctcggg gacaaagttg gaaataaaa 339
<210> 89
<211> 113
<212> PRT
<213> 쥐
<400> 89
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp His Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 90
<211> 318
<212> DNA
<213> 쥐
<400> 90
caaattgttc tctcccagtc tccagcaatc ctgtctgcat ctccagggga gaaggtcaca 60
atgacttgca gggccagctc aagtgttact tacatacact ggtaccagca gaagccagga 120
tcctccccca aaccctggat ttatggcaca tccaatctgg cttctggagt ccctgttcgc 180
ttcagtggca gtgggtctgg gacctctttc tctctcacaa tcaccagagt ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg agtagtaacc cacccacgtt cggtactggg 300
accaagctgg agctgaaa 318
<210> 91
<211> 106
<212> PRT
<213> 쥐
<400> 91
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Thr Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Phe Ser Leu Thr Ile Thr Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr
85 90 95
Phe Gly Thr Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 92
<211> 339
<212> DNA
<213> 쥐
<400> 92
gatattgtga tgactcaggc tgcaccctct gtacctgtca cttctggaga gtcagtatcc 60
atctcctgca ggtctagtaa gagtctcctg gatcgtaatg gcaacactta tttatattgg 120
ttcctgcaga ggccaggcca gtctcctcag ctcctgatat atcggatgtc caaccttgcc 180
tcaggagtcc cagacaggtt cagtggaagt gggtcgggaa gtgctttcac actgagaatc 240
agtagagtgg aggctgagga tgtgggtgtt tattactgta tgcaacatct agaatatccg 300
tacacgttcg gaggggggac caagctggaa ataaaacgg 339
<210> 93
<211> 113
<212> PRT
<213> 쥐
<400> 93
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Ser Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asp Arg
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Ser Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 94
<211> 339
<212> DNA
<213> 쥐
<400> 94
gatattgtga tgactcaggc tgcaccctct gtacctgtca ctcctggagc gtcagtatcc 60
atctcctgca ggtctagtaa gagtctcctg catagtaatg gcaacactta tttgtattgg 120
ttcctgcaga ggccaggcca gtctcctcac ctcctgatat atcggatgtc caaccttgcc 180
tcgggagtcc cagacaggtt cagtggcagt gggtcaggaa ctgctttcac actgagaatc 240
agtagagtgg aggctgagga tgtgggtgtt tattactgta tgcaacatct agaatatccg 300
tacacgttcg gaggggggac caagctggaa ataaaacgg 339
<210> 95
<211> 113
<212> PRT
<213> 쥐
<400> 95
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Ala Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro His Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 96
<211> 339
<212> DNA
<213> 쥐
<400> 96
gacattgtga tgacacagtc tccatcctcc ctggctatgt cagtaggaca gaaggtcact 60
atgagctgca agtccagtca gagcctttta aatagtagca atcaaaagaa ctatttggcc 120
tggtaccagc agaaaccagg acagtctcct aaacttctga tatactttgc atccactagg 180
gaatctgggg tccctgatcg cttcataggc agtggatctg ggacagattt cactcttacc 240
atcagcagtg tgcaggctga agacctggca gattacttct gtcagcaaca ttattacact 300
ccttacacgt tcggaggggg gaccaagctg gaaataaaa 339
<210> 97
<211> 113
<212> PRT
<213> 쥐
<400> 97
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Met Ser Val Gly
1 5 10 15
Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln
85 90 95
His Tyr Tyr Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 98
<211> 339
<212> DNA
<213> 쥐
<400> 98
gatattgtga tgactcaggc tgcaccctct gtacctgtca ctcctggaga gtcagtatcc 60
atctcctgca ggtctagtaa gagtctcctg catagtaatg gcaacactta cttgtattgg 120
ttcctgcaga ggccaggcca gtctcctcag ctcctgattt atcggatgtc caaccttgcc 180
tcaggagtcc cagacaggtt cagtggcagt gggtcaggaa ctgctttcac actgagaatc 240
agtagagtgg aggctgagga tgtgggtatt tattactgta tgcaacatct agaatatccg 300
tacacgttcg gaggggggac caagctggaa ataaaacgg 339
<210> 99
<211> 113
<212> PRT
<213> 쥐
<400> 99
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 100
<211> 324
<212> DNA
<213> 쥐
<400> 100
gccatcaaga tgacccagtc tccatcttcc atgtatgcat ctctaggaga gagagtcact 60
atcacttgcc gggcgagtca aaatattaac aacttattag cctggttcca gcagaaacca 120
gggaaatctc ctaagaccct gatctatact gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggcaagat tattctctca ccatcagcag cctggagtat 240
gaagatatgg gaatttatta ttgtcaacag gctcatagat tccctccgac gttcggtgga 300
ggcaccaagc tggaaatcag acgt 324
<210> 101
<211> 108
<212> PRT
<213> 쥐
<400> 101
Ala Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Asn Asn Leu
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr
65 70 75 80
Glu Asp Met Gly Ile Tyr Tyr Cys Gln Gln Ala His Arg Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg
100 105
<210> 102
<211> 339
<212> DNA
<213> 호모 사피엔스
<400> 102
gacatcgtga tgacccagag ccccgatagc ctggccgtgt ctctgggcga gcgggccacc 60
atcaactgca agagcagcca gagcctgctg aacagcagca accagaagaa ctacctggcc 120
tggtatcagc agaagcccgg ccagcccccc aagctgctga tctacttcgc cagcaccaga 180
gaaagcggcg tgcccgacag attttctggc agcggcagcg gcaccgactt taccctgaca 240
atcagctctc tgcaggccga ggacgtggcc gtgtacttct gccagcagca ctactacacc 300
ccctacacct tcggcggagg caccaaggtg gagatcaag 339
<210> 103
<211> 113
<212> PRT
<213> 호모 사피엔스
<400> 103
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln
85 90 95
His Tyr Tyr Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 104
<211> 324
<212> DNA
<213> 호모 사피엔스
<400> 104
gccatccaga tgacccagtc tccatcttcc gtgtctgctt ctataggaga cagagtcacc 60
atcacttgtc gggcgagtca aaatattaac aacttattag cctggtatca gcagaaacca 120
gggaaagccc ccaaactcct gatctatact gcatccagtt tgcaaagtga ggtcccatca 180
aggttcagcg gcagtgggtc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caatttactg ttgccaacag gctcatagat tccctccgac gttcggccaa 300
gggaccaagg tggaaatcag acgt 324
<210> 105
<211> 108
<212> PRT
<213> 호모 사피엔스
<400> 105
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Ile Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Asn Asn Leu
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Glu Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ile Tyr Cys Cys Gln Gln Ala His Arg Phe Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg
100 105
<210> 106
<211> 106
<212> PRT
<213> 쥐
<400> 106
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
1 5 10 15
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
20 25 30
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
35 40 45
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
50 55 60
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
65 70 75 80
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
85 90 95
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
<210> 107
<211> 105
<212> PRT
<213> 쥐
<400> 107
Gly Gln Pro Lys Ser Thr Pro Thr Leu Thr Val Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Lys Glu Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asn
20 25 30
Phe Ser Pro Ser Gly Val Thr Val Ala Trp Lys Ala Asn Gly Thr Pro
35 40 45
Ile Thr Gln Gly Val Asp Thr Ser Asn Pro Thr Lys Glu Gly Asn Lys
50 55 60
Phe Met Ala Ser Ser Phe Leu His Leu Thr Ser Asp Gln Trp Arg Ser
65 70 75 80
His Asn Ser Phe Thr Cys Gln Val Thr His Glu Gly Asp Thr Val Glu
85 90 95
Lys Ser Leu Ser Pro Ala Glu Cys Leu
100 105
<210> 108
<211> 325
<212> PRT
<213> 쥐
<400> 108
Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly
1 5 10 15
Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
100 105 110
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
115 120 125
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly Lys Gly
325
<210> 109
<211> 326
<212> PRT
<213> 호모 사피엔스
<400> 109
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 110
<211> 16
<212> PRT
<213> 인공 순서
<400> 110
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
<210> 111
<211> 23
<212> PRT
<213> 인공 순서
<400> 111
Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly Ser Gly Ala Ser Ser Gly
1 5 10 15
Ser Gly Ser Ala Thr Gly Ser
20
<210> 112
<211> 12
<212> PRT
<213> 인공 순서
<400> 112
Lys Asp Ile Asp Arg Lys Cys Cys Val Glu Cys Pro
1 5 10
<210> 113
<211> 3123
<212> DNA
<213> 호모 사피엔스
<400> 113
atcagtctcc gcacgcggtt ccgcaggtgg cagcgatggc ccagtcctga actccccgcc 60
atggccggcg cccccggccc gctgcgcctt gcgctgctgc tgctcgggat ggtgggcagg 120
gccggccccc gcccccaggg tgccactgtg tccctctggg agacggtgca gaaatggcga 180
gaataccgac gccagtgcca gcgctccctg actgaggatc cacctcctgc cacagacttg 240
ttctgcaacc ggaccttcga tgaatacgcc tgctggccag atggggagcc aggctcgttc 300
gtgaatgtca gctgcccctg gtacctgccc tgggccagca gtgtgccgca gggccacgtg 360
taccggttct gcacagctga aggcctctgg ctgcagaagg acaactccag cctgccctgg 420
agggacttgt cggagtgcga ggagtccaag cgaggggaaa gaagctcccc ggaggagcag 480
ctcctgttcc tctacatcat ctacacggtg ggctacgcac tctccttctc tgctctggtt 540
atcgcctctg cgatcctcct cggcttcaga cacctgcact gcaccaggaa ctacatccac 600
ctgaacctgt ttgcatcctt catcctgcga gcattgtccg tcttcatcaa ggacgcagcc 660
ctgaagtgga tgtatagcac agccgcccag cagcaccagt gggatgggct cctctcctac 720
caggactctc tgagctgccg cctggtgttt ctgctcatgc agtactgtgt ggcggccaat 780
tactactggc tcttggtgga gggcgtgtac ctgtacacac tgctggcctt ctcggtctta 840
tctgagcaat ggatcttcag gctctacgtg agcataggct ggggtgttcc cctgctgttt 900
gttgtcccct ggggcattgt caagtacctc tatgaggacg agggctgctg gaccaggaac 960
tccaacatga actactggct cattatccgg ctgcccattc tctttgccat tggggtgaac 1020
ttcctcatct ttgttcgggt catctgcatc gtggtatcca aactgaaggc caatctcatg 1080
tgcaagacag acatcaaatg cagacttgcc aagtccacgc tgacactcat ccccctgctg 1140
gggactcatg aggtcatctt tgcctttgtg atggacgagc acgcccgggg gaccctgcgc 1200
ttcatcaagc tgtttacaga gctctccttc acctccttcc aggggctgat ggtggccata 1260
ttatactgct ttgtcaacaa tgaggtccag ctggaatttc ggaagagctg ggagcgctgg 1320
cggcttgagc acttgcacat ccagagggac agcagcatga agcccctcaa gtgtcccacc 1380
agcagcctga gcagtggagc cacggcgggc agcagcatgt acacagccac ttgccaggcc 1440
tcctgcagct gagactccag cgcctgccct ccctggggtc cttgctgcag gccgggtggc 1500
caatccaggt gggagagaca ctcccaggga caagggaagg aagggacaca cacacacaca 1560
cacacacaca cacacacaca cacatacatc ctgctttccc tccccaaacc catcagacag 1620
gtaaatgggc agtgcctcct gggaccatgg acacattttc tcctaggaga agcagcctcc 1680
taatttgatc acagtggcga gaggagagga aaaacgatcg ctgtgaaaat gaggaggatt 1740
gcttcttgtg aaaccacagg cccttggggt tcccccagac agagccgcaa atcaacccca 1800
gactcaaact caaggtcaac ggcttattag tgaaactggg gcttgcaaga ggaggtggtt 1860
ctgaaagtgg ctcttctaac ctcagccaaa cacagagcgg gagtgacggg agcctcctct 1920
gcttgcatca cttggggtca ccaccctccc ctgtcttctc tcaaagggaa gctgtttgtg 1980
tgtctgggtt gcttatttcc ctcatcttgc cccctcatct cactgcccag tttctttttg 2040
aggggctttg tttgggccac tgccagcagc tgtttctgga aatggctgta ggtggtgttg 2100
agaaagaatg agcattgaga cggtgctcgc ttctcctcca ggtatttgag ttgttttggt 2160
gcctgcctct gccatgccca gagaatcagg gcaggcttgc caccggggaa cccagccctg 2220
gggtatgagc tgccaagtct attttaaaga cgctcaagaa tcctctgggg ttcatctagg 2280
gacacgttag gaatgtccag actgtgggtg tagattacct gccacttcca ggagcccaga 2340
gggccaagag agacattgcc tccacctctc cttggaaata ctttatctgt gaccacacgc 2400
tgtctcttga gaatttggat acactctcta gctttagggg accatgaaga gactctctta 2460
gggaaaccaa tagtccccat cagcaccatg gaggcaggct ccccctgcct ttgaaattcc 2520
cccacttggg agcttgtata tacttcactc acttttcttt attgctgtga atagtctgtg 2580
tgcacaatgg gcaattctga cttctcccat ctagtggaaa tgagcgaaat catggttgta 2640
gtgatgttgt ttgggagagt gcagtagtaa ttgatttgac ccactcacac ttggagctaa 2700
ttaaggtttg ccctgcctgc agcctccccc acaaataatg aacagcagaa agactggacg 2760
gggaaaccta tcaatcctgc ccccagccat ggtgaggaag ccccaagcca tggtgacaca 2820
cagcagcact gcagatagcc agacacatgg ctatcctaga gaggctggca aggagttcgt 2880
ggctgcaaaa gaagtttctg gagcaagaga gagctcgctc ttgggagtca ggacctccgg 2940
ggagagcaga gggttccgac ggattccttt atgagtcagt ctctctctcc cttttaaatg 3000
gtgggaaccc tccccaaaac ctttccccag acacattctc ctgtgcccct cagagaggca 3060
tgtgatgtgc aaggaaaata ataggatata aaacacatca agtagaaaat ttcttatact 3120
tca 3123
<210> 114
<211> 463
<212> PRT
<213> 호모 사피엔스
<400> 114
Met Ala Gly Ala Pro Gly Pro Leu Arg Leu Ala Val Leu Leu Leu Gly
1 5 10 15
Met Val Gly Arg Ala Gly Pro Arg Pro Gln Gly Ala Thr Val Ser Leu
20 25 30
Trp Glu Thr Val Gln Lys Trp Arg Glu Tyr Arg Arg Gln Cys Gln Arg
35 40 45
Ser Leu Thr Glu Asp Pro Pro Pro Ala Thr Asp Leu Phe Cys Asn Arg
50 55 60
Thr Phe Asp Glu Tyr Ala Cys Trp Pro Asp Gly Glu Pro Gly Ser Phe
65 70 75 80
Val Asn Val Ser Cys Pro Trp Tyr Leu Pro Trp Ala Ser Ser Val Pro
85 90 95
Gln Gly His Val Tyr Arg Phe Cys Thr Ala Glu Gly Leu Trp Leu Gln
100 105 110
Lys Asp Asn Ser Ser Leu Pro Trp Arg Asp Leu Ser Glu Cys Glu Glu
115 120 125
Ser Lys Arg Gly Glu Arg Ser Ser Arg Glu Glu Gln Leu Leu Phe Leu
130 135 140
Tyr Ile Ile Tyr Thr Val Gly Tyr Ala Leu Ser Phe Ser Ala Leu Val
145 150 155 160
Ile Ala Ser Ala Ile Leu Leu Gly Phe Arg His Leu His Cys Thr Arg
165 170 175
Asn Tyr Ile His Leu Asn Leu Phe Ala Ser Phe Ile Leu Arg Ala Leu
180 185 190
Ser Val Phe Ile Lys Asp Ala Ala Leu Lys Trp Met Tyr Ser Thr Ala
195 200 205
Ala Gln Gln His Gln Trp Asp Gly Leu Leu Ser Tyr Gln Asp Ser Leu
210 215 220
Ser Cys Arg Leu Val Phe Leu Leu Met Gln Tyr Cys Val Ala Ala Asn
225 230 235 240
Tyr Tyr Trp Leu Leu Val Glu Gly Val Tyr Leu Tyr Thr Leu Leu Ala
245 250 255
Phe Ser Val Phe Ser Glu Gln Trp Ile Phe Arg Leu Tyr Val Ser Ile
260 265 270
Gly Trp Gly Val Pro Leu Leu Phe Val Val Pro Trp Gly Ile Val Lys
275 280 285
Tyr Leu Tyr Glu Asp Glu Gly Cys Trp Thr Arg Asn Ser Asn Met Asn
290 295 300
Tyr Trp Leu Ile Ile Arg Leu Pro Ile Leu Phe Ala Ile Gly Val Asn
305 310 315 320
Phe Leu Ile Phe Val Arg Val Ile Cys Ile Val Val Ser Lys Leu Lys
325 330 335
Ala Asn Leu Met Cys Lys Thr Asp Ile Lys Cys Arg Leu Ala Lys Ser
340 345 350
Thr Leu Thr Leu Ile Pro Leu Leu Gly Thr His Glu Val Ile Phe Ala
355 360 365
Phe Val Met Asp Glu His Ala Arg Gly Thr Leu Arg Phe Ile Lys Leu
370 375 380
Phe Thr Glu Leu Ser Phe Thr Ser Phe Gln Gly Leu Met Val Ala Ile
385 390 395 400
Leu Tyr Cys Phe Val Asn Asn Glu Val Gln Leu Glu Phe Arg Lys Ser
405 410 415
Trp Glu Arg Trp Arg Leu Glu His Leu His Ile Gln Arg Asp Ser Ser
420 425 430
Met Lys Pro Leu Lys Cys Pro Thr Ser Ser Leu Ser Ser Gly Ala Thr
435 440 445
Ala Gly Ser Ser Met Tyr Thr Ala Thr Cys Gln Ala Ser Cys Ser
450 455 460
<210> 115
<211> 20
<212> DNA
<213> 인공 순서
<400> 115
tttggrggga agatgaagac 20
<210> 116
<211> 21
<212> DNA
<213> 인공 순서
<400> 116
ttaacactct cccctgttga a 21
<210> 117
<211> 21
<212> DNA
<213> 인공 순서
<400> 117
ttaacactca ttcctgttga a 21
<210> 118
<211> 21
<212> DNA
<213> 인공 순서
<400> 118
tggacaggga tccagagttc c 21
<210> 119
<211> 21
<212> DNA
<213> 인공 순서
<400> 119
tggacagggc tccatagttc c 21
<210> 120
<211> 20
<212> DNA
<213> 인공 순서
<400> 120
actcgtcctt ggtcaacgtg 20
<210> 121
<211> 23
<212> DNA
<213> 인공 순서
<400> 121
ccaccatgga ctttgggctg agc 23
<210> 122
<211> 20
<212> DNA
<213> 인공 순서
<400> 122
agagccggtg gcagagccag 20
<210> 123
<211> 43
<212> DNA
<213> 인공 순서
<400> 123
ctggctctgc caccggctct gccatccaga tgacccagtc tcc 43
<210> 124
<211> 22
<212> DNA
<213> 인공 순서
<400> 124
acactctccc ctgttgaagc tc 22
<210> 125
<211> 31
<212> DNA
<213> 인공 순서
<400> 125
ccggctagcc accatggact ttgggctgag c 31
<210> 126
<211> 36
<212> DNA
<213> 인공 순서
<400> 126
agtgcggccg ctcaacactc tcccctgttg aagctc 36
<210> 127
<211> 39
<212> PRT
<213> Heloderma의 suspectum
<400> 127
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
Claims (15)
- 다음의 방식:
a. 다음의 배열 중 임의의 것으로부터 선택되는 경쇄 CDR3 배열:
L1~L13의 경쇄 CDR3 배열: 배열 번호 46~배열 번호 53으로부터 선택되는 어떠한 것과의 차가 합계 3개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR3 배열,
b. 다음의 배열 중 임의의 것으로부터 선택되는 중쇄 CDR3 배열:
H1~H13의 중쇄 CDR3 배열: 배열 번호 20~배열 번호 27로부터 선택되는 어떠한 것과의 차가 합계 4개 인하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR3 배열,
c. (a)의 경쇄 CDR3 배열 및 (b)의 중쇄 CDR3 배열
중 임의의 것의 아미노산 배열을 포함하는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 제1항에 있어서,
다음의 방식:
a. 다음 중 임의의 것으로부터 선택되는 경쇄 CDR1 배열:
L1~L13의 경쇄 CDR1 배열: 배열 번호 28~배열 번호 37로부터 선택되는 어떠한 것과의 차가 3개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR1,
b. 다음 중 임의의 것으로부터 선택되는 경쇄 CDR2 배열:
L1~L13의 경쇄 CDR2 배열: 배열 번호 38~배열 번호 45로부터 선택되는 어떠한 것과의 차가 2개 이하인 아미노산이 부가, 치환 및/또는 결실된 경쇄 CDR2,
c. 다음 중 임의의 것으로부터 선택된 중쇄 CDR1 배열:
H1~H13의 중쇄 CDR1 배열: 배열 번호 6~배열 번호 12로부터 선택되는 어떠한 것과의 차가 2개 인하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 CDR1,
d. 다음 중 임의의 것으로부터 선택된 중쇄 CDR2:
H1~H13의 중쇄 CDR2 배열: 배열 번호 13~배열 번호 19로부터 선택되는 어떠한 것과의 차가 3개 인하인 아미노산이 부가, 치환 및/또는 결실된 중쇄 배열,
중 1종 또는 2종 이상을 조합한 아미노산 배열을 더 포함하는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 다음의 방식:
a. 다음의 방식 중 1종 또는 2종 이상을 포함하는 경쇄 가변 영역:
ⅰ. 배열 번호 28~배열 번호 37 중 임의의 것으로부터 선택되는 경쇄 CDR1 배열,
ⅱ. 배열 번호 38~배열 번호 45 중 임의의 것으로부터 선택되는 경쇄 CDR2 배열,
ⅲ. 배열 번호 46~배열 번호 53 중 임의의 것으로부터 선택되는 경쇄 CDR3 배열,
b. 다음의 방식 중 1종 또는 2종 이상을 포함하는 중쇄 가변 영역:
ⅰ. 배열 번호 6~배열 번호 12 중 임의의 것으로부터 선택되는 중쇄 CDR1 배열,
ⅱ. 배열 번호 13~배열 번호 19 중 임의의 것으로부터 선택되는 중쇄 CDR2 배열,
ⅲ. 배열 번호 20~배열 번호 27 중 임의의 것으로부터 선택되는 중쇄 CDR3 배열,
c. (a)의 경쇄 가변 영역 배열 및 (b)의 중쇄 가변 영역 배열
중 임의의 것을 포함하는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 다음의 방식:
a. 다음의 방식 중 임의의 것으로부터 선택되는 경쇄 가변 영역 배열:
ⅰ. L1~L13의 경쇄 가변 영역 배열: 배열 번호 81, 배열 번호 83, 배열 번호 85, 배열 번호 87, 배열 번호 89, 배열 번호 91, 배열 번호 93, 배열 번호 95, 배열 번호 97, 배열 번호 99, 배열 번호 101, 배열 번호 103, 배열 번호 105로부터 선택되는 임의의 것과 적어도 80%가 동일한 배열을 가지는 아미노산,
ⅱ. L1~L13의 경쇄 가변 영역 배열을 코드하는 폴리뉴클레오티드 배열: 배열 번호 80, 배열 번호 82, 배열 번호 84, 배열 번호 86, 배열 번호 88, 배열 번호 90, 배열 번호 92, 배열 번호 94, 배열 번호 96, 배열 번호 98, 배열 번호 100, 배열 번호 102, 배열 번호 104 중 임의의 것과 적어도 80%가 동일한 폴리뉴클레오티드 배열로 코드된 아미노산 배열,
b. 다음의 방식 중 임의의 것으로부터 선택되는 중쇄 가변 영역 배열:
ⅰ. H1~H13의 중쇄 가변 영역 배열: 배열 번호 55, 배열 번호 57, 배열 번호 59, 배열 번호 61, 배열 번호 63, 배열 번호 65, 배열 번호 67, 배열 번호 69, 배열 번호 71, 배열 번호 73, 배열 번호 75, 배열 번호 77, 배열 번호 79 중 임의의 것과 적어도 80%가 동일한 아미노산 배열,
ⅱ. H1~H13의 중쇄 가변 영역 배열을 코드하는 폴리뉴클레오티드 배열: 배열 번호 54, 배열 번호 56, 배열 번호 58, 배열 번호 60, 배열 번호 62, 배열 번호 64, 배열 번호 66, 배열 번호 68, 배열 번호 70, 배열 번호 72, 배열 번호 74, 배열 번호 76, 배열 번호 78 중 임의의 것과 적어도 80%가 동일한 폴리뉴클레오티드 배열로 코드된 아미노산 배열,
c. (a)의 경쇄 가변 영역 배열 및 (b)의 중쇄 가변 영역 배열
중 임의의 것의 아미노산 배열을 포함하는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 제4항에 있어서,
다음의 방식:
a. L1~L13의 경쇄 가변 영역 배열: 배열 번호 81, 배열 번호 83, 배열 번호 85, 배열 번호 87, 배열 번호 89, 배열 번호 91, 배열 번호 93, 배열 번호 95, 배열 번호 97, 배열 번호 99, 배열 번호 101, 배열 번호 103, 배열 번호 105로부터 선택되는 어떠한 경쇄 가변 영역 배열,
b. H1~H13의 중쇄 가변 영역 배열: 배열 번호 55, 배열 번호 57, 배열 번호 59, 배열 번호 61, 배열 번호 63, 배열 번호 65, 배열 번호 67, 배열 번호 69, 배열 번호 71, 배열 번호 73, 배열 번호 75, 배열 번호 77, 배열 번호 79로부터 선택되는 어떠한 중쇄 가변 영역 배열,
c. a의 경쇄 가변 영역 배열 및 b의 중쇄 가변 영역 배열
중 어떠한 아미노산 배열을 더 포함하는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 제5항에 있어서,
방식 c에서의 a의 경쇄 가변 영역 배열과 b의 중쇄 가변 영역 배열의 조합은, L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13 중 임의의 것으로부터 선택되는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 제6항에 있어서,
다음의 방식:
a. 배열 번호 106의 경쇄 정상 영역 아미노산 배열,
b. 배열 번호 107의 경쇄 정상 영역 아미노산 배열,
c. 배열 번호 108의 중쇄 정상 영역 아미노산 배열,
d. 배열 번호 109의 중쇄 정상 영역 아미노산 배열,
e. 배열 번호 106의 경쇄 정상 영역 아미노산 배열 및 배열 번호 108의 중쇄 정상 영역 아미노산 배열,
f. 배열 번호 107의 경쇄 정상 영역 아미노산 배열 및 배열 번호 108의 중쇄 정상 영역 아미노산 배열,
g. 배열 번호 106의 경쇄 정상 영역 아미노산 배열 및 배열 번호 109의 중쇄 정상 영역 아미노산 배열,
h. 배열 번호 107의 경쇄 정상 영역 아미노산 배열 및 배열 번호 109의 중쇄 정상 영역 아미노산 배열,
중 어떠한 아미노산 배열을 더 포함하는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 제1항 또는 제3항 또는 제4항에 있어서,
마우스 항체, 인간 항체, 인간화 항체, 키메라 항체, 모노클로날 항체, 폴리클로날 항체, 재조합 항체, 항원 결합 항체 단편, 외가닥 항체, 2중 가닥 항체, 3중 가닥 항체, 4중 가닥 항체, Fab 단편, F(f'a)x 단편, 도메인 항체, IgD 항체, IgE 항체, IgM 항체, IgG1 항체, IgG2 항체. IgG3 항체, IgG4 항체로부터 선택되는 것을 특징으로 하는 GLP-1R과 특이적으로 결합 가능한 항체. - 배열 번호 1, 배열 번호 2, 배열 번호 3, 배열 번호 4, 배열 번호 5, 배열 번호 127로부터 선택되는 어떠한 아미노산 배열을 포함하는 GLP-1과 제1항 제3항 또는 제4항에 기재된 항체를 융합하여 형성되는 GLP-1 융합 단백질.
- 제9항에 있어서,
GLP-1이 N'-R1-L-R2-C', N'-R2-L-R1-C' 또는 N'-R2-L-R1r-C'
(식 중 L은 LK1~LK3의 아미노산 배열: 배열 번호 110, 배열 번호 111, 배열 번호 112로부터 선택되는 어떠한, 전장의, 부분적인 또는 반복되는 아미노산 배열을 포함하는 펩티드 링커 배열이고,
R1은 GLP-1의 아미노산 배열이며,
R1r은 GLP-1의 역방향 아미노산 배열이고,
R2는 청구항 1 또는 3 또는 4에 기재된 항체의 경쇄 또는 중쇄 아미노산 배열이며,
C'는 GLP-1 융합 단백질 폴리펩티드쇄의 카복실 단말을 나타내고,
N'는 GLP-1 융합 단백질 폴리펩티드쇄의 아미노 단말을 나타낸다)
의 결합 방식에 의해 청구항 1 또는 3 또는 4에 기재된 항체의 경쇄 및/또는 중쇄와 융합되는 것을 특징으로 하는 GLP-1 융합 단백질. - 제9항에 기재된 GLP-1 융합 단백질을 코드하는 것을 특징으로 하는 폴리뉴클레오티드.
- 제11항에 기재된 폴리뉴클레오티드를 포함하는 것을 특징으로 하는 벡터.
- 제12항에 기재된 벡터를 포함하는 것을 특징으로 하는 숙주 세포.
- 의약적으로 허용되는 벡터와 혼합된 제9항에 기재된 GLP-1 융합 단백질을 포함하는 것을 특징으로 하는 의약 조성물.
- 제14항에 있어서,
인슐린 비의존성 당뇨병의 예방 또는 치료에 이용하는 의약품을 제조하는 의약 조성물의 용도.
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WO2015021871A1 (zh) | 2015-02-19 |
JP6749235B2 (ja) | 2020-09-16 |
AU2014308330B2 (en) | 2020-02-13 |
IL243902B (en) | 2020-06-30 |
US20160362498A1 (en) | 2016-12-15 |
RU2016108703A3 (ko) | 2018-03-19 |
EP3034514B1 (en) | 2024-07-17 |
EP3034514A4 (en) | 2017-11-01 |
RU2016108703A (ru) | 2017-09-14 |
US20180346585A1 (en) | 2018-12-06 |
US10059773B2 (en) | 2018-08-28 |
CA2921256A1 (en) | 2015-02-19 |
AU2014308330A1 (en) | 2016-02-25 |
TWI568745B (zh) | 2017-02-01 |
AU2014308330C1 (en) | 2020-05-07 |
HK1226415A1 (zh) | 2017-09-29 |
CN104371019B (zh) | 2019-09-10 |
CA2921256C (en) | 2023-02-21 |
PL3034514T3 (pl) | 2024-10-07 |
CN104371019A (zh) | 2015-02-25 |
KR102285342B1 (ko) | 2021-08-03 |
US10253103B2 (en) | 2019-04-09 |
AU2014308330A2 (en) | 2016-04-28 |
NZ716357A (en) | 2022-03-25 |
RU2681857C2 (ru) | 2019-03-13 |
IL243902A0 (en) | 2016-04-21 |
EP3034514A1 (en) | 2016-06-22 |
TW201514205A (zh) | 2015-04-16 |
JP2016532448A (ja) | 2016-10-20 |
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