KR20160050773A - AMFR-Fc 융합 단백질 및 이의 항암 용도 - Google Patents
AMFR-Fc 융합 단백질 및 이의 항암 용도 Download PDFInfo
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- KR20160050773A KR20160050773A KR1020140149772A KR20140149772A KR20160050773A KR 20160050773 A KR20160050773 A KR 20160050773A KR 1020140149772 A KR1020140149772 A KR 1020140149772A KR 20140149772 A KR20140149772 A KR 20140149772A KR 20160050773 A KR20160050773 A KR 20160050773A
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Abstract
본 발명은 AMFR (Autocrine motility factor receptor) 단백질과 인간 면역글로불린 Fc 영역이 융합된 AMFR-Fc 융합 단백질 및 이의 암 예방 또는 치료 용도에 관한 것이다. 본 발명에 따른 AMFR-Fc 융합 단백질은 위암, 유방암 등 각종 암조직에서 AMF의 과발현에 의해 유도되는 암세포의 증식을 효과적으로 억제함으로써, 각종 암에 대하여 우수한 암 예방 또는 치료 효과를 나타낸다.
Description
본 발명은 AMFR (Autocrine motility factor receptor) 단백질과 인간 면역글로불린 Fc 영역이 융합된 AMFR-Fc 융합 단백질 및 이의 암 예방 또는 치료 용도에 관한 것이다.
암은 세계적으로 감염성 질환 및 심혈관계 질환과 더불어 3대 사망원인중 하나로서 환경문제, 수명연장, 식문화의 서구화 등으로 인해 향후 암 발생인구가 급격하게 증가할 것으로 예상되는 주요 질환의 한가지이다. 보다 더 효과적인 항암제의 개발을 위해 암에 대한 많은 연구가 진행되고 있음에도 불구하고 암에 대한 발병기전의 다양화로 인해 부작용이 적고 내성을 극복할 수 있는 새로운 항암제의 개발이 여전히 절실한 상황이다.
최근 세포독성 항암제가 갖는 안전성과 유효성 문제를 극복하기 위한 방법으로 표적치료제의 개념이 도입되었고, 현재 개발되는 항암제의 주류를 이루고 있다.
표적 치료제 개발을 위한 암세포의 정보전달 차단 전략은 크게 두 가지로 나눌 수 있는데, 첫번째는 이마티닙(imatinib)과 같이 세포 내 키나아제의 활성화를 조절하는 방법이고, 두번째는 트라스트주맙(trastuzumab)이나 베바시주맙(bevacizumab)과 같이 단백질과 단백질의 상호작용을 차단하는 것이다. 일반적으로 첫번째 방법에 의한 항암 치료제의 개발은 저분자 화합물을 이용한 치료제의 개발 시 주요 전략으로 이용되는 반면, 두번째 방법은 저분자 화합물을 비롯해서 항체나 융합 단백질과 같은 단백질 치료제를 이용한 항암제 개발 시 주로 이용된다.
AMF는 하우스키핑(housekeeping) 단백질로서 세포내에서 에너지 대사와 관련하여 해당작용(glycolysis)의 두 번째 과정의 글루코오스-6-포스페이트(glucose-6-phosphate)와 프락토오스-6-포스페이트(fructose-6-phosphate)를 상호전환(interconversion)하는 역할을 하는 것으로 알려졌으며 이러한 기능으로 인해 글루코오스-6-포스페이트 이성질화제(glucose-6-phosphate isomerase)라고 불리기도 한다.
위암과 간암을 비롯한 다양한 암조직에서 세포내의 에너지대사와 관련된 AMF가 세포 밖으로 분비되어 암세포에 존재하는 수용체에 자가분비(autocrine) 방식으로 결합함으로서 암세포의 증식, 침윤 및 전이를 촉진하고, 암세포 주변의 혈관 내피세포의 수용체에 측분비(paracrine) 방식으로 결합함으로서 혈관신생(angiogenesis)을 촉진하는 것으로 보고되어 있으나, 세포 내부의 AMF가 세포 밖으로 분비되는 매커니즘은 현재까지 알려져 있지 않다(Torimura T et al., Hepatology, 2001, 34(1): 62-71; Yu FL et al., Biochem Biophys Res Commun. 2004, 314(1): 76-82; Shin WL et al., Cancer Lett. 2008, 270(2): 202-17). 특히 AMF는 위암, 유방암, 간암, 난소암, 폐암, 골수종, 신장암, 대장암, 식도암, 췌장암, 직장암, 흑색종 등 각종 암에서 과발현되는 것으로 보고되어 있다 (Haga A et al., Biochim Biophys Acta., 2000, 1480(1-2): 235-44; Yanagawa T et al., Endocr Relat Cancer, 2004, 11(4): 749-59; Torimura T et al., Hepatology, 2001, 34(1): 62-71; Niizeki H et al., Br J Cancer, 2002, 86(12): 1914-9) 등.
이러한 AMF에 대한 수용체로는 AMFR(autocrine motility factor receptor)이 알려져 있다 (Nabi IR et al ., Cancer Res. 1990, 50(2): 409-14). AMFR은 암세포 특이적인 AMF와는 달리 암세포 뿐만 아니라 정상세포에서도 발현되는 단백질이며, 원래의 기능은 ER(endoplasmic reticulum) 막단백질로서 아포리포단백질(apolipoprotein), CD3D(cluster of differentiation 3 molecule, delta), CYP3A4(cytocrhome P450), CFTR(cystic fibrosis transmembrane conductance regulator)의 ER 연관된 분해(ER associated degradation)를 위해, 각 단백질에 유비퀴틴화(ubiquitylation)를 시켜주는 E3 유비퀴틴 리가아제로서의 기능을 갖는 것으로 보고되어 있다 (Fang S et al., Proc Natl Acad Sci USA. 2001, 98(25): 14422-7).
암세포 표면에 발현된 AMFR과 AMF의 상호작용은 세포 내부의 티로신 키나아제(tyrosine kinase) 나 세린/트레오닌 키나아제와 같은 인산화 효소에 의한 신호의 전달을 촉진하며 그 결과 암세포의 이동, 증식, 항-세포자멸사 효과 등의 효과를 유발하는 것으로 알려져 있다 (Funasaka T and Raz A, Cancer Metastasis Rev. 2007, 26(3-4): 725-35).
따라서 AMF을 타깃으로 하는 항암제의 개발에 대한 기대가 있으나, 아직까지 AMF와 관련된 각종 암에서 효과적으로 암세포 증식을 억제하는 재조합 단백질에 대해서는 많이 보고되어 있지 않으며, 이를 타깃으로 한 새로운 암 치료제의 개발에 대한 필요성이 있다.
본 발명자들은 위암, 유방암, 간암, 신장암, 대장암 등 각종 암조직에서 과발현되어 암 치료의 중요한 타깃이 될 수 있는 AMF에 대해 연구하던 중, AMF 수용체인 AMFR(autocrine motility factor receptor)의 특정 도메인을 포함하는 서열을 갖는 단백질이 우수한 암 증식 억제, 항암 효과를 갖는 것을 발견하고 본 발명을 완성하였다.
따라서 본 발명의 목적은 서열번호 3의 아미노산 서열로 표시되는 AMFR (Autocrine motility factor receptor) 단백질과 인간 면역글로불린 Fc 영역이 융합된 AMFR-Fc 융합 단백질을 제공하는 것이다.
또한 본 발명의 목적은 AMFR-Fc 융합 단백질을 암호화하는 폴리뉴클레오티드를 제공하는 것이다.
또한 본 발명의 목적은 상기 폴리뉴클레오티드를 포함하는 벡터를 제공하는 것이다.
또한 본 발명의 목적은 상기 벡터로 형질전환된 세포를 제공하는 것이다.
또한 본 발명의 목적은 상기 형질전환 세포를 배양하는 단계; 및 상기 배양액으로부터 AMFR-Fc 융합 단백질을 분리하는 단계;를 포함하는 AMFR-Fc 융합 단백질의 제조방법을 제공하는 것이다.
또한 본 발명의 목적은 서열번호 3의 아미노산 서열로 표시되는 AMFR(Autocrine motility factor receptor) 단백질을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공하는 것이다.
상기 목적을 달성하기 위하여, 본 발명은 서열번호 3의 아미노산 서열로 표시되는 AMFR(Autocrine motility factor receptor) 단백질과 인간 면역글로불린 Fc 영역이 융합된 AMFR-Fc 융합 단백질을 제공한다.
또한 본 발명은 상기 AMFR-Fc 융합 단백질이 서열번호 23의 아미노산 서열로 표시되는, AMFR-Fc 융합 단백질을 제공한다.
또한 본 발명은 상기 AMFR-Fc 융합 단백질을 암호화하는 폴리뉴클레오티드를 제공한다.
또한 본 발명은 상기 폴리뉴클레오티드가 서열번호 22로 표시되는 것인, 폴리뉴클레오티드를 제공한다.
또한 본 발명은 상기 폴리뉴클레오티드를 포함하는 벡터를 제공한다.
또한 본 발명은 상기 벡터로 형질전환된 세포를 제공한다.
또한 본 발명은 상기 형질전환 세포를 배양하는 단계; 및 상기 배양액으로부터 AMFR-Fc 융합 단백질을 분리하는 단계;를 포함하는 AMFR-Fc 융합 단백질의 제조방법을 제공한다.
또한 본 발명은 서열번호 3의 아미노산 서열로 표시되는 AMFR(Autocrine motility factor receptor) 단백질을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.
또한 본 발명은 상기 AMFR 단백질에 인간 면역글로불린 Fc 영역이 융합된, 암 예방 또는 치료용 약학적 조성물을 제공한다.
또한 본 발명은 상기 암이 위암, 유방암, 간암, 난소암, 폐암, 골수종, 신장암, 대장암, 식도암, 췌장암, 흑색종 및 직장암으로 이루어진 군에서 선택된 1종 이상인, 암 예방 또는 치료용 약학적 조성물을 제공한다.
본 발명에 따른 AMFR-Fc 융합 단백질은 위암, 유방암 등 각종 암조직에서 AMF의 과발현에 의해 유도되는 암세포의 증식을 효과적으로 억제함으로써, 각종 암에 대하여 우수한 암 예방 또는 치료 효과를 나타낸다.
도 1은 인간 AMF(전사체 변이체 2(transcript variant 2)) DNA와 아미노산 서열을 나타낸 도이다.
도 2는 재조합 사람 AMF 발현 벡터를 나타낸 도이다.
도 3은 TMHMM 데이터베이스를 이용하여 AMFR의 7개의 막관통 도메인을 확인한 결과를 나타낸 도이다.
도 4는 단백질 모델링 포탈 데이터베이스를 이용하여, AMFR의 가용성 영역에 존재하는 3개의 기능적 도메인을 확인한 결과를 나타낸 도이다.
도 5는 AMFR 결실 돌연변이를 도식화한 것이다.
도 6은 ZnCUE2-Fc의 DNA 및 아미노산 서열을 나타낸 도이다 (아미노산 기준 1~20 : 쥣과 IgG 카파 쇄 신호 펩타이드(murine IgG kappa chain signal peptide), 21~358 : AMFR의 ZnCUE2 도메인, 359~590 : IgG1 Fc).
도 7은 CUE2-Fc의 DNA 및 아미노산 서열을 나타낸 도이다 (아미노산 기준 1~20 : 쥣과 IgG 카파 쇄 신호 펩타이드, 21~237 : AMFR의 CUE2 도메인, 239~469 : IgG1 Fc).
도 8은 E2-Fc의 DNA 및 아미노산 서열을 나타낸 도이다 (아미노산 기준 1~20 : 쥣과 IgG 카파 쇄 신호 펩타이드, 21~160 : AMFR의 E2 도메인, 161~392 : IgG1 Fc).
도 9는 제조된 3종의 AMFR-Fc 융합 단백질 발현벡터를 나타낸 도이다.
도 10은 비환원 및 환원 조건에서 SDS-PAGE로 확인한 CUE2-Fc 및 E2-Fc 구조물을 확인한 결과를 나타낸 도이다((A) CUE2-Fc(비환원조건), (B) CUE2-Fc(환원조건), (C) E2-Fc(비환원조건), (D) E2-Fc (환원조건)).
도 11은 AMF에 대한 AMFR-Fc 융합단백질의 반응성을 확인한 결과를 나타낸 도이다.
도 12는 유방암 및 위암 암세포에서의 암 세포 증식억제능을 확인한 결과를 나타낸 도이다.
도 13은 종양 접종 후 투여 약물에 따른 체중변화를 관찰하여 독성여부를 확인한 결과를 나타낸 도이다.
도 14는 종양 접종 후 투여 약물에 따른 종양 무게를 확인한 결과를 나타낸 도이다.
도 15는 종양 접종 후 투여 약물에 따른 종양 부피를 확인한 결과를 나타낸 도이다.
도 2는 재조합 사람 AMF 발현 벡터를 나타낸 도이다.
도 3은 TMHMM 데이터베이스를 이용하여 AMFR의 7개의 막관통 도메인을 확인한 결과를 나타낸 도이다.
도 4는 단백질 모델링 포탈 데이터베이스를 이용하여, AMFR의 가용성 영역에 존재하는 3개의 기능적 도메인을 확인한 결과를 나타낸 도이다.
도 5는 AMFR 결실 돌연변이를 도식화한 것이다.
도 6은 ZnCUE2-Fc의 DNA 및 아미노산 서열을 나타낸 도이다 (아미노산 기준 1~20 : 쥣과 IgG 카파 쇄 신호 펩타이드(murine IgG kappa chain signal peptide), 21~358 : AMFR의 ZnCUE2 도메인, 359~590 : IgG1 Fc).
도 7은 CUE2-Fc의 DNA 및 아미노산 서열을 나타낸 도이다 (아미노산 기준 1~20 : 쥣과 IgG 카파 쇄 신호 펩타이드, 21~237 : AMFR의 CUE2 도메인, 239~469 : IgG1 Fc).
도 8은 E2-Fc의 DNA 및 아미노산 서열을 나타낸 도이다 (아미노산 기준 1~20 : 쥣과 IgG 카파 쇄 신호 펩타이드, 21~160 : AMFR의 E2 도메인, 161~392 : IgG1 Fc).
도 9는 제조된 3종의 AMFR-Fc 융합 단백질 발현벡터를 나타낸 도이다.
도 10은 비환원 및 환원 조건에서 SDS-PAGE로 확인한 CUE2-Fc 및 E2-Fc 구조물을 확인한 결과를 나타낸 도이다((A) CUE2-Fc(비환원조건), (B) CUE2-Fc(환원조건), (C) E2-Fc(비환원조건), (D) E2-Fc (환원조건)).
도 11은 AMF에 대한 AMFR-Fc 융합단백질의 반응성을 확인한 결과를 나타낸 도이다.
도 12는 유방암 및 위암 암세포에서의 암 세포 증식억제능을 확인한 결과를 나타낸 도이다.
도 13은 종양 접종 후 투여 약물에 따른 체중변화를 관찰하여 독성여부를 확인한 결과를 나타낸 도이다.
도 14는 종양 접종 후 투여 약물에 따른 종양 무게를 확인한 결과를 나타낸 도이다.
도 15는 종양 접종 후 투여 약물에 따른 종양 부피를 확인한 결과를 나타낸 도이다.
본 발명은 서열번호 3의 아미노산 서열로 표시되는 AMFR(Autocrine motility factor receptor) 단백질과 인간 면역글로불린 Fc 영역이 융합된 AMFR-Fc 융합 단백질을 제공한다.
상기 AMFR-Fc 융합 단백질은 위암, 유방암 등 각종 암 조직에서 AMF의 과발현에 의해 유도되는 암세포의 증식을 효과적으로 억제함으로써, 각종 암에 대하여 우수한 암 예방 또는 치료 효과를 나타낸다.
본 발명의 AMFR은 AMF와는 달리 암세포 뿐만 아니라 정상세포에서도 발현되는 단백질로 알려진 AMF(Autoocrine motility factor)의 수용체 단백질 중 AMF와 반응성이 있을 것으로 예상되는 가용성 영역으로 이루어진 단백질이며, AMF와 결합하는 결합 활성을 제외하고 다른 부가적인 기능을 갖지 않는 것이 바람직하다. 또한 상기 AMFR은 전장 AMFR의 599번 위치의 Arg을 반드시 포함하는 것이 바람직하며, 가장 바람직하게는 서열번호 19의 AMFR의 아미노산 서열 중 427 내지 643의 아미노산 서열을 포함하는 것이 바람직하다.
특히 본 발명의 AMFR-Fc 융합단백질의 AMFR은 서열번호 3으로 표시되는 아미노산 서열을 갖는 것이 가장 바람직하나, 이와 동일한 정도의 암 세포 증식 억제 효과를 보유하는 한 서열번호 3의 아미노산 서열과 80 내지 99% 상동성, 바람직하게는 85 내지 99% 상동성, 더욱 바람직하게는 90 내지 99%의 상동성, 가장 바람직하게는 95 내지 99%의 상동성을 갖는 아미노산 서열로 이루어지는 AMFR 단백질을 갖는 AMFR-Fc 융합 단백질도 본 발명의 AMFR-Fc 융합 단백질에 포함될 수 있다.
또한 본 발명의 "인간 면역글로불린 Fc(fragment crystallizable) 영역"은 면역글로불린 연쇄 불변 영역의 카복실 말단 부분, 바람직하게는 면역글로불린 중쇄 불변 영역, 또는 이의 일부를 의미한다. 예를 들면, 면역글로불린 Fc 영역은 (1) CH1 도메인, CH2 도메인 및 CH3 도메인, (2) CH1 도메인 및 CH2 도메인, (3) CH1 도메인 및 CH3 도메인, (4) CH2 도메인 및 CH3 도메인, 또는 (5) 2 이상의 도메인과 면역글로불린 힌지 영역의 조합을 포함할 수 있다. 바람직한 실시형태에서, 면역글로불린 Fc 영역은 적어도 면역글로불린 힌지 영역, CH2 도메인 및 CH3 도메인을 포함하고, CH1 도메인이 결여되어 있는 것이 바람직하다.
용도에 따라서, 사람 외의 다른 종(예컨대, 마우스 또는 래트) 유래의 불변 영역 유전자를 사용할 수 있다. DNA 구성물에서 융합 파트너로 사용되는 면역글로불린 Fc 영역은 일반적으로 임의의 포유동물 종으로부터 얻을 수 있다. 숙주세포 또는 동물에서 Fc 영역에 대한 면역 반응을 유발시키는 것이 바람직하지 않을 경우, Fc 영역은 숙주 세포 또는 동물과 동일한 종에서 유래된 것일 수 있다. 예를 들면, 숙주 동물 또는 세포가 사람인 경우 사람 면역글로불린 Fc 영역을 사용하는 것이 바람직하며, 마찬가지로 숙주 동물 또는 세포가 마우스인 경우, 쥐과 면역글로불린 Fc 영역을 사용할 수 있다.
또한, 면역글로불린 중쇄 불변 영역 내의 아미노산의 치환 또는 결실이 본 발명의 실시에 유용할 수 있다. 일예로는 Fc 수용체에 대한 친화력이 감소된 Fc 변이체를 생성하기 위해 상부 CH2 영역에 아미노산 치환을 도입하는 것을 들 수 있고, 당업자라면 잘 알려진 분자생물학 기술을 이용하여 이러한 구성물을 제조할 수 있다.
본 발명에서는 본 발명의 실시에 유용한 Fc가 융합된 재조합 단백질을 생성하기 위한 통상적인 재조합 DNA 기술을 이용한다. Fc가 융합된 재조합 단백질은 바람직하게는 DNA 수준에서 생성되며, 이렇게 생성된 DNA를 발현 벡터로 삽입시키고, 이를 발현시켜서 본 발명의 융합단백질을 생산한다.
또한 본 발명은 상기 AMFR-Fc 융합 단백질이 서열번호 23의 아미노산 서열로 표시되는, AMFR-Fc 융합 단백질을 제공한다.
따라서 본 발명에서 바람직한 AMFR-Fc 융합 단백질은 서열번호 23의 아미노산 서열로 표시되는 AMFR-Fc 융합 단백질일 수 있으며, 이와 동일한 암 예방 또는 치료 효과를 보유하는 한 서열번호 23의 아미노산 서열과 80 내지 99% 상동성, 바람직하게는 85 내지 99% 상동성, 더욱 바람직하게는 90 내지 99%의 상동성, 가장 바람직하게는 95 내지 99%의 상동성을 갖는 아미노산 서열로 표시되는 AMFR-Fc 융합 단백질도 본 발명의 AMFR-Fc 융합 단백질에 포함될 수 있다.
또한 본 발명에서는 AMFR-Fc 융합 단백질을 암호화하는 폴리뉴클레오티드를 제공한다. 상기 폴리뉴클레오티드는 전사, 번역 과정을 거쳐 암 예방 또는 치료 효과를 갖는 본 발명의 AMFR-Fc 융합 단백질을 암호화하는 것이라면 제한없이 포함될 수 있으며, 바람직하게는 서열번호 22로 표시되는 폴리뉴클레오티드 및 이와 80 내지 99% 상동성, 바람직하게는 85 내지 99% 상동성, 더욱 바람직하게는 90 내지 99%의 상동성, 가장 바람직하게는 95 내지 99%의 상동성을 갖는 폴리뉴클레오티드, 특히 염기의 종류가 다르더라도 전사 후 번역을 통해 동일한 아미노산으로 번역되는 폴리뉴클레오티드라면 바람직한 예로서 본 발명의 폴리뉴클레오티드에 포함된다.
또한 본 발명의 폴리뉴클레오티드는 추가적으로 발현될 단백질의 분비를 위한 신호 펩타이드를 암호화하는 서열을 포함할 수 있다. 신호 펩타이드 서열은 마우스 IgG 카파 체인의 신호 펩타이드를 사용할 수 있으나, 이에 제한되지 않으며 단백질의 발현 및 정제 과정 후에는 절단되어 제거되는 것이 바람직하다.
또한 본 발명은 상기 폴리뉴클레오티드를 포함하는 벡터를 제공한다.
본 발명의 벡터는 숙주 세포에 삽입되어 숙주 세포 게놈과 재조합되고 이에 삽입되거나, 또는 에피좀으로서 자발적으로 복제하는 컴피턴트 뉴클레오티드 서열을 포함하는 임의의 핵산을 의미한다. 이러한 벡터로는 선형 핵산, 플라스미드, 파지미드, 코스미드, RNA 벡터, 바이러스 벡터 등이 있으며, 바이러스 벡터의 예로는 레트로바이러스, 아데노바이러스 및 아데노 관련 바이러스가 있으나 이에 제한되는 것은 아니다.
본 발명에서 사용되는 유전자 발현 또는 표적 단백질의 발현이란 용어는 DNA 서열의 전사, mRNA 전사체의 번역 및 Fc 융합 단백질 생성물의 분비를 의미하는 것이다.
적절한 숙주 세포를 이용하여 본 발명의 재조합 AMFR-Fc 단백질을 발현시킬 수 있다. 따라서 본 발명은 상기 벡터로 형질전환된 세포를 제공한다. 보다 구체적으로 폴리뉴클레오티드 서열로 숙주세포를 형질전환 또는 형질감염시키고, 이를 표적 단백질을 발현 및/또는 분비시키는 데 이용할 수 있다. 본 발명에 사용하기에 바람직한 숙주 세포로는 불멸화된 하이브리도마 세포, NS/O 골수종 세포, 293 세포, 차이니즈 햄스터 난소 세포(CHO), HELA 세포, HEK293F 세포 및 COS 세포 등이 있으나, 이에 제한되는 것은 아니다.
또한 본 발명은 형질전환 세포를 배양하는 단계; 및 상기 배양액으로부터 AMFR-Fc 융합 단백질을 분리하는 단계;를 포함하는 AMFR-Fc 융합 단백질의 제조방법을 제공한다.
본 발명의 AMFR-Fc 융합 단백질의 제조방법에 있어서, 세포의 배양, 융합 단백질의 분리 방법은 당 분야에 속하는 통상의 기술자들의 통상의 기술적 범위 내에 있는 것이며, 당 분야에 널리 공지되어 있는 재조합 단백질 생산 방법을 제한없이 이용할 수 있다.
또한 본 발명은 서열번호 3의 아미노산 서열로 표시되는 AMFR (Autocrine motility factor receptor) 단백질을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.
상기 약학적 조성물은 AMFR 단백질을 포함함으로써, AMF가 과발현된 각종 암 조직에서 암세포의 증식을 효과적으로 억제하여 우수한 암 예방 및 치료 효과를 나타낼 수 있다.
또한 본 발명은 상기 AMFR 단백질에 인간 면역글로불린 Fc 영역이 융합된 것을 특징으로 하는 암 예방 또는 치료용 약학적 조성물을 제공한다.
본 발명에 있어서, 암은 AMF이 과발현되는 것으로 알려진 각종 암을 제한없이 포함할 수 있으나, 바람직하게는 위암, 유방암, 간암, 난소암, 폐암, 골수종, 신장암, 대장암, 식도암, 췌장암, 흑색종 및 직장암으로 이루어진 군에서 선택된 1종 이상일 수 있다.
본 발명에서, 용어 "예방"은 질환 또는 질병을 보유하고 있다고 진단된 적은 없으나, 이러한 질환 또는 질병에 걸리기 쉬운 경향이 있는 개체에서 질환 또는 질병의 발생을 억제하는 것을 의미한다.
본 발명에서, 용어 "치료"는 개체에서 (a) 질환 또는 질병의 발전의 억제 (b) 질환 또는 질병의 경감 및 (c) 질환 또는 질환의 제거를 의미한다.
본 발명의 약학적 조성물은 질병 예방 또는 치료용 제형으로 제형화될 수 있으며, 목적에 따라 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 제형화 되어 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제 및 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.
특히 본 발명의 약학적 조성물을 경구용 제제 또는 주사용 제제인 것이 바람직하다.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제 및 캡슐제 등이 포함되며, 이러한 고형 제제는 본 발명의 약학적 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스, 락토오스 및 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘, 스티레이드, 탈크 같은 윤활제도 사용될 수 있다.
경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 및 보존제 등이 포함될 수 있다.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제가 포함된다. 비수성용제와 현탁용제로는 프로필레글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 61, 카카오지, 라우린지, 글리세롤 및 젤라틴 등이 사용될 수 있다. 본 발명의 약학적 조성물은 비경구 투여시 피하주사, 정맥주사 또는 근육내 주사를 통하여 투여될 수 있다.
본 발명의 약학 조성물은 약학적으로 허용되는 담체를 첨가하여 제제화할 수 있으며, 제제화에 관한 내용은 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA의 문헌을 참조할 수 있다. 상기 약학적으로 허용 가능한 담체는 의약 발명 부분에 속하는 통상의 기술자에게 의약 조성물 제조시 통상적으로 사용되는 것을 의미한다. 예를 들어, 락토오즈, 덱스트로오즈, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오즈, 메틸 셀룰로오즈, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다. 또한, 약학적으로 허용되는 담체는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함한다.
그러나, 상기 열거된 약제학적으로 허용되는 담체 등으로 본 발명이 한정되는 것은 아니며, 이들은 단지 예시에 불과하다.
본 발명에 따른 약학적 조성물의 투여량은 약제학적으로 유효한 양이어야 한다. "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 예방 또는 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 제제화 방법, 환자의 상태 및 체중, 환자의 성별, 연령, 질환의 정도, 약물형태, 투여경로 및 기간, 배설 속도, 반응 감응성 등과 같은 요인들에 따라 당업자에 의해 다양하게 선택될 수 있다. 유효량은 당업자에게 인식되어 있듯이 처리의 경로, 부형제의 사용 및 다른 약제와 함께 사용할 수 있는 가능성에 따라 변할 수 있다.
따라서 상기 약학적 조성물에 함유되는 AMFR-Fc 재조합 단백질의 적용량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 경우에 따라 적절하게 선택될 수 있다. 예를 들면, AMFR-Fc 재조합 단백질은 1일 1 내지 80 mg/kg으로, 바람직하게는 2 내지 20mg/kg의 용량으로 비경구 투여될 수 있으며, 상기 적용은 하루에 한번 또는 수회 나누어 적용할 수도 있다. 상기 약학적 조성물은 인간 등의 포유동물에 다양한 경로로, 예를 들면, 경구, 정맥, 근육, 또는 피하 주사에 의해 적용될 수 있으며, 바람직하게는 비경구투여, 더욱 바람직하게는 정맥 투여에 의해 적용될 수 있다.
또한 본 발명의 AMFR-Fc 재조합 단백질 외에 암 예방 또는 치료 효과를 나타내는 유효성분을 1종 이상 함유할 수 있다.
또한 본 발명의 약학적 조성물은 암의 개선, 완화, 치료 또는 예방을 위하여 단독으로, 또는 수술, 호르몬 치료, 약물 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.
이상 본 명세서에 기재된 수치값은 달리 명시되어 있지 않은 한 균등범위까지 포함하는 것으로 해석되어야 한다.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예 및 제제예를 제시한다. 그러나 하기의 실시예 및 제제예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예 및 제제예에 의해 본 발명의 내용이 한정되는 것은 아니다.
실시예
1. 재조합
AMF
의 생산
AMF의 전사체 변이체 중 암세포 특이적인 AMF로 보고된 변이체 2(accession number NM_000175.3)를 AMFR-Fc 융합 단백질의 AMF 반응성 확인을 위하여 클로닝하였다. 사람 AMF(전사체 변이체 2)의 DNA 서열 및 아미노산 서열을 각각 서열번호 1과 서열번호 2에 나타내었으며, 이를 도 1에 나타내었다.
정제용이성을 위하여 AMF의 C 말단에 6x 히스티딘으로 표지하였으며, AMF 발현벡터를 HEK293 세포에 형질감염 시약(Attractene, invitrogen)를 이용하여 형질전환 시키고, 형질전환된 HEK293 세포를 무혈청 DMEM에서 5% CO2, 37℃ 조건으로 48시간 동안 배양하였다. 세포배양이 완료된 후 배양액을 회수하고 Ni2+ 친화도 크로마토그래피를 이용하여 재조합 AMF를 정제하였다. 확립된 인간 재조합 AMF 발현벡터를 도 2에 나타내었다. 정제된 재조합 AMF 활성을 글루코오스-6-포스페이트 이성질화제 활성 어세이 키트(abcam)를 이용하여 약 3000unit/mg 정도의 활성을 갖는 것을 확인하였다.
실시예
2 :
AMFR
-
Fc
컨스트럭트
(
construct
) 제작
2-1.
domain
분석
2-1-1.
막관통
도메인(
transmembrane
domain
) 예측
세포 표면에 발현된 AMFR은 7개의 막관통 도메인을 갖는 GPCR(G-protein coupled receptor)로서 AMF와의 결합을 위한 가용성 영역(soluble region)이 C-말단의 일부에 국한되는 것으로 알려져 있다. AMFR의 아미노산 서열(accession number: AAH69197.1)을 기반으로 막관통 영역(transmembrane region)과 가용성 영역의 예측을 위해 TMHMM 데이터베이스를 이용하였으며, 그 결과를 도 3에 나타내었다.
도 3에 나타낸 바와 같이, N-말단으로부터 302번 아미노산 사이에 총 7개의 막관통 도메인이 있는 것으로 확인되었으며, AMF와 반응성이 있을 것으로 예상되는 가용성 영역은 303번 아미노산 이후인 것으로 확인되었다.
2-1-2. 기능적 도메인(
functional
domain
) 예측
AMFR의 가용성 영역은 소포체막(Endoplasmic Reticulum membrane)에서 유비퀴틴화(ubiquitinylation)와 관련된 도메인을 포함하는 것으로 알려져 있다 (S. Fang et al., PNAS, 2001, vol 98(25), 14422-14427). 따라서 AMFR-Fc 융합 단백질을 설계하는 데 있어서, AMF와 결합 활성을 제외하고는 어떠한 부가 기능도 갖지 않도록 만들어 주는 것이 중요하다. 게다가 세포 표면에 발현된 AMFR이 AMF 와 결합하는데 있어서는 AMFR의 599번 Arg의 N-글리코실화(N-glycosylation)가 필수적인 역할을 하는 것으로 보고되어 있다 (A. Haga et al., JMB, 2006, vol 358(3), 741-753). 따라서 599번 아미노산을 포함하면서 동시에 부가적인 기능을 갖지 못하도록 최소한의 크기를 갖는 AMFR 영역의 선정을 위해 단백질 모델링 포탈 데이터베이스(http://www.proteinmodelportal.org)를 이용하여 기능적 도메인에 대한 분석을 수행하였으며, 그 결과를 도 4에 나타내었다.
도 4에 나타낸 바와 같이, AMFR 의 기능적 도메인에 대한 분석을 수행한 결과, 막관통 도메인이 밀집되어 있는 부분은 앵커(anchor)로서의 역할을 하는 것으로 예측되었고, 가용성 영역인 303번 아미노산 이후로는 크게 3가지의 기능적 도메인을 가지고 있을 것으로 예측되었다.
첫번째 도메인은, E3 유비퀴틴 리가아제(E3 ubiquitin ligase) 활성을 갖는 징크 핑거 도메인(Zinc finger domain)으로서, AMFR 아미노산 서열의 329 내지 385 아미노산 사이에 위치하는 것으로 예측되었다. 두번째 도메인은, CUE(coupling of Ub conjugation to ERAD) 도메인으로서, AMFR 아미노산 서열의 448 내지 502 아미노산 사이에 위치하는 것으로 예측되었다. 세번째 도메인은, AMF의 결합에 필수적인 599번 N-글리코실레이션 부위(N-glycosylation site)를 포함하는 E2 결합 도메인(E2 binding domain)으로서, AMFR 아미노산 서열의 574 내지 600 아미노산 사이에 위치하며, Ube2g2 E2 효소 결합 부위에 해당되는 것으로 예측되었다.
2-2. 도메인 결실
AMFR
컨스트럭트
(
domain
deleted
AMFR
construct
) 구축
상기 2-1-2에서의 기능적 도메인에 대한 예측 결과를 바탕으로 하여, 각 기능적 도메인을 N-말단으로부터 순차적으로 결실시키면서 Fc와 융합시킨 컨스트럭트를 설계하였으며, 이들 도메인 결실 AMFR 컨스트럭트를 도 5에 도식화 하였다.
도 5에 나타낸 바와 같이, 총 3개의 기능적 도메인 모두를 포함하는 서열을 ZnCuE2(아미노산 306-643)로 하였으며, 첫번째 도메인인 징크핑거 도메인을 결실시킨 컨스트럭트를 CUE2(아미노산 427-643, 서열번호 3), 마지막으로 징크핑거 도메인과 CUE 도메인을 모두 결실시키고 E2 결합 도메인만을 포함하는 서열을 E2(아미노산 604-643)로 명명하였다. 아미노산 서열에서 확인할 수 있는 바와 같이, 상기 결실 컨스트럭트들은 모두 AMF 결합에 필수적인 599 아미노산 위치를 포함하고 있다.
실시예
3.
AMFR
-
Fc
융합단백질
발현벡터 확립
상기 실시예 2에서 구축한 AMFR의 순차적 도메인 결실 컨스트럭트들과 Fc가 융합된 AMFR-Fc 융합단백질을 생산하기 위한 발현벡터를 확립하였다.
구체적으로, AMFR(autocrine motility factor receptor)와 면역글로불린 Fc(Immunoglobulin Fc)의 융합을 위한 결실 AMFR 컨스트럭트는 NCBI 데이터베이스에 등록된 accession number BC069197 의 염기서열을 참고하고, 각 컨스트럭트의 증폭을 위한 프라이머를 이용하여 제조하였다. 각 프라이머의 서열을 하기 표 1에 나타내었다.
[표 1]
컨스트럭트의 증폭을 위한 AMFR 주형 cDNA는 Origene의 AMFR cDNA 클론을 구입하여 사용하였다. AMFR DNA와 아미노산 서열을 각각 서열번호 18 및 서열번호 19에 나타내었다.
AMFR 도메인 분석을 통해 얻어진 결과를 토대로 가용성 영역(306aa 내지 643 aa)을 기준으로 3종(ZnCUE2, CUE2, E2)의 AMFR-Fc 융합 단백질을 설계하였다.
ZnCUE2-Fc의 DNA 및 아미노산 서열을 각각 서열번호 20, 21에, CUE2-Fc의 DNA 및 아미노산 서열을 각각 서열번호 22, 23에, E2-Fc의 DNA 및 아미노산 서열을 각각 서열번호 24, 25에 기재하였다.
융합 파트너인 Fc는 인간 IgG1의 힌지 부분이 포함된 99번 아미노산부터 마지막 아미노산까지 모두 발현될 수 있도록 설계하였다. 발현된 단백질의 분비를 위한 신호 펩타이드(signal peptide)를 추가로 포함하도록 하였으며, 이는 마우스 IgG 카파 체인의 신호 펩타이드를 사용하였다. 각 AMFR 컨스트럭트들과 IgG1 Fc는 중첩 PCR(overlapping PCR) 방법을 통해 cDNA 수준에서 융합을 진행하였고 동물세포용 발현 벡터인 pcDNA3.1(invitrogen)에 서브클로닝하였다. 서브클로닝의 용이성을 위해 삽입 DNA의 5'에는 HindIII 부위를 3' 말단에는 NotI 부위를 포함하였다. 신호서열까지 포함된 3종의 AMFR-Fc 재조합 단백질을 도 6 내지 8에 나타내었으며, 제조된 3종의 AMFR-Fc 융합 단백질 발현벡터를 도 9에 나타내었다.
클로닝에 앞서 AMFR과 Fc가 융합된 가상의 DNA 서열(ZnCuE2-Fc, CuE2-Fc, E2-Fc)을 바탕으로 in silico translation tool(www.vivo.colostate.edu/molkit/index.html)을 이용하여 아미노산으로 번역하였고, 각 컨스트럭트가 DNA수준에서의 삽입(insertion)이나 결실(deletion)과 같은 변이(mutation)없이 제대로 발현될 수 있음을 확인하였다. 또한 단백질의 분비를 위해 융합시킨 신호 펩타이드가 세포내에서 발현 후 분비되는 과정에서 제대로 제거되는지를 확인하기 위해 signalP 4.1 데이터베이스(www.cbs.dtu.dk/services/signalP)를 이용하여 각 컨스트럭트들의 아미노산 서열을 토대로 신호 펩타이드의 절단 부위를 예측하였다. 또한 단백질 발현 및 정제 후 N-말단 서열 분석을 통하여 신호 펩타이드가 제대로 절단되어 제거되었음을 확인하였다.
실시예
4.
AMFR
-
Fc
융합단백질
생산 및
AMF
와의 반응성 분석
실시예 3에서 확립한 발현벡터 및 HEK293F transient 시스템(Roseanne Tom et al ., Transfection of HEK293-EBNA1 Cells in Suspension with Linear PEI for Production of Recombinant Proteins, Cold Spring Harbor protocols 참조)을 이용하여 각각의 AMFR-Fc 융합단백질을 생산하였다. 형질감염(transfection)을 위해 HEK293F 세포를 Expi 293 media(invitrogen)에 2.5x106/ml이 되도록 준비하고, 각 발현벡터를 50ug/ml, PEI(polyethyleneimine, MW 25,000, polyscience Inc)를 125ug/ml로 섞어서 Expi 293 미디어에 녹인 후 10분간 인큐베이션(incubation)하고 준비된 세포에 형질감염시켰다. 형질감염된 세포는 삼각플라스크에서 110rpm, 7.5% CO2 조건에서 배양하였다.
상기 transient 시스템을 통해 생산된 AMFR-Fc의 정제를 위해 Mabselect sure column(GE)을 이용한 단백질 A 친화도 크로마토그래피 (protein A affinity chromatography)를 실시하였다. 세포를 제거한 배양액을 결합완충액(binding buffer) (20mM sodium phosphate buffer, pH7.0)과 동량으로 혼합하여 Mabselect sure column을 결합한 AKTA FPLC purifier system(GE healthcare bioscience)에 로딩(loading)하고, 로딩이 완료된 후 0.1M 글리신-HCl(pH3.0) 완충액으로 용출(elution)한 후 바로 1M Tris-base buffer(pH9.0)로 중성 pH가 되도록 적정하였다. 정제된 시료는 증류수와 PBS로 한외여과(30K MWCO)하고 농축하였다.
이 후, 10% SDS-PAGE 겔에 5ug/well로 로딩하고 전기영동한 후 쿠마시블루(Coomassie brilliant blue) R-250 용액으로 염색하고 분자량을 확인하였으며, 그 결과를 도 10에 나타내었다.
또한, ELISA를 이용하여 AMFR-Fc 융합단백질의 AMF에 대한 반응성을 확인하였다. 96웰 플레이트의 각 웰당 250ng의 AMF를 코팅한 후 BSA용액를 이용하여 상온에서 2시간 동안 블로킹(blocking)하였다. AMFR-Fc 융합단백질은 25ug/ml부터 2배씩 희석해서 최종 24ng/ml까지 준비하여 각 웰에 로딩하고 인큐베이션한 후 HRP-컨쥬게이트된(HRP-conjugated) 항-인간 IgG mAb를 1:5000으로 희석하여 반응시켰다. TMB(3,3',5,5'-tetramethylbenzidine)으로 발색후 450nm에서 흡광도를 측정하여, 그 결과를 도 11에 나타내었다.
3개의 도메인을 모두 포함하는 ZnCUE2-Fc 컨스트럭트는 HEK 세포를 이용한 발현 단계 중 세포 내부에서부터 자가-유비퀴틴화(self-ubiquitinylation)에 의하여 분해되므로 온전한 형태의 단백질로 발현되지 않았다. 반면, 온전하게 발현된 CUE2-Fc 컨스트럭트 및 E2-Fc 컨스트럭트를 SDS-PAGE 상에서 도 10과 같이 비환원 및 환원 조건에서 확인할 수 있었다.
또한 도 11에서 나타낸 바와 같이, CUE2-Fc는 AMF 농도를 증가시킴에 따라 450nm에서의 흡광도가 뚜렷하게 증가하는 경향을 나타내어, AMF 농도 증가에 따른 반응성 증가 경향이 확인되었다. 반면 E2-Fc는 AMF의 농도 증가에도 불구하고 반응성이 거의 없는 것으로 확인되었다.
상기와 같이, 총 3종류의 AMFR-Fc 컨스트럭트 중 CUE2-Fc 컨스트럭트가 온전한 형태로 발현됨과 동시에 AMF와의 반응성이 가장 우수한 것으로 나타났다.
실시예
5:
AMFR
-
Fc 의
암세포 증식
억제능
재조합 사람 AMF(rhAMF)에 의한 암세포의 증식 촉진능과 AMFR-Fc에 의한 암세포 증식 저해능을 BT474(유방암)과 NCI-N87(위암) 세포주에서 확인하였다. 각 세포는 10% FBS를 함유한 RPMI1640 배지에서 배양하였다.
구체적으로 Day 0에 96웰 플레이트에 상기 암세포주를 5x103/well로 접종하고, Day 1에 상기 암세포에 5ug/ml(0.9uM)의 재조합 사람 AMF를 처리하고 3일간 배양한 후, Day 4에 대조군과 비교하여 암세포가 얼마나 증식되었는지를 MTS를 이용하여 확인하였다. 또한, 재조합 사람 AMF에 의해 촉진된 암세포 성장을 상기 실시예 4에서 정제된 AMFR-Fc가 효과적으로 저해할 수 있는지 확인하기 위해, Day 0에 96웰 플레이트에 상기 암세포주를 5x103/well로 접종한 후 5ug/ml의 재조합 사람 AMF를 처리하고, Day 1에 AMFR-Fc 융합단백질 중 210ug/ml의 CUE2-Fc(1.8uM)와 176ug/ml의 E2-Fc(1.8uM)를 처리하여 3일간 배양한 후, Day 4에 암세포 증식능 억제 정도를 확인하였다.
암세포의 증식 촉진능 및 저해능 확인은 세포의 생존도를 간접적으로 측정할 수 있는 formazan assay를 통해 수행하였다. 2mg/ml로 제조된 MTS tetrazolium 화합물과 0.92mg/ml로 제조된 PES(phenazine ethosulfate)(전자 커플링 시약)를 20:1의 비율로 섞어준 뒤, 세포가 배양된 96 웰 플레이트에 20ul/웰씩 처리하였으며, 2시간 동안 37℃, 5% CO2 인큐베이터에서 인큐베이션한 후 마이크로플레이트 리더를 이용하여 490nm에서 흡광도를 측정하였다. 상기 실험 결과를 도 12에 나타내었다.
도 12에 나타낸 바와 같이, 재조합 사람 AMF만을 처리한 실험군은 아무것도 처리하지 않은 대조군과 비교하여 유방암 세포(BT474) 및 위암 세포(NCI-N87) 모두에서 50% 이상 세포증식이 증가하여, AMF가 암세포의 증식을 증가시키는 것을 확인할 수 있었다. 그러나 이와 같은 재조합 인간 AMF에 의한 암세포 증식 촉진은 유방암세포 및 위암세포 모두에서 CUE2-Fc 처리에 의하여 뚜렷하게 완화되어 CUE2-Fc가 AMF를 중화함으로서 암세포 증식에 대한 저해능이 있는 물질임을 확인하였다.
반면 E2-Fc 의 경우, 암세포 증식 억제 효과가 거의 없는 것으로 확인되었다.
실시예
6. 위암 동물 모델에서의 암세포 증식 억제 효과
in vitro에서 암세포 증식 억제능이 확인된 AMFR-Fc를 동물 모델에 적용하여 in vivo 활성을 추가적으로 확인하였다.
보다 구체적으로, in vivo 이종이식(in vivo xenograft) 효력시험을 위하여 NCI-N87(사람 위암세포주) 세포를 계수하여 1x109 cell/ml의 양으로 준비하였다.
Balb/c 누드 마우스에 준비된 세포를 마우스 당 0.1ml(1x107 cells/mouse) 씩 마우스 상복부 피하에 주입하였다. 이식 후 7일차에 각 마우스에 이식된 종양의 부피를 측정하여 그룹화(grouping)하였다.
대조 물질로는 위암치료제로 사용되는 허셉틴(herceptin)을 이용하였다. 허셉틴과 시험물질인 CUE2-Fc, E2-Fc을 각 군별 종양크기가 100mm3 도달한 이후부터, 주 2회로 총 2주에 걸쳐서 15mg/kg의 용량으로 피하(sc) 투여하였다.
투여 후 시간에 따라 마우스의 체중이 변화하는 지 여부를 관찰하여 AMFR-Fc가 독성이 있는지 여부를 확인하였으며, 측정된 종양의 무게 및 부피 감소 정도에 따라 암세포 증식 억제 효과를 비교하였다.
종양의 무게는 투여 개시일로부터 시험 종료 시까지 주 2회 측정하였으며, 종양의 부피는 장축, 단축의 순으로 버니어 캘리퍼를 이용하여 계산하였다. 종양의 부피 측정을 위한 계산식은 (장축)x(단축)2/2(mm3)을 사용하였다.
결과를 도 13 내지 도 15에 나타내었다.
도 13에 나타낸 바와 같이, 실험군 모두에서 약물에 따른 체중의 감소가 나타나지 않았으며, 이에 따라 현재 암 치료제로 사용되고 있는 허셉틴과 동일하게 AMFR-Fc인 CUE2-Fc와 E2-Fc 역시 독성없이 치료제로 사용하기에 적합한 물질임을 확인하였다.
또한 도 14 에 나타낸 바와 같이, 종양을 적출한 뒤 적출된 종양의 무게를 측정한 결과 허셉틴은 대조군과 비교하여 34%의 무게감소가 확인되었으며, CUE2-Fc와 E2-Fc는 각각 26%와 7%의 감소효과를 갖는 것으로 확인되었다.
또한 각 약물의 투여에 따른 종양의 부피를 날짜별로 측정한 결과, 도 15에 나타낸 바와 같이, 허셉틴 투여군은 대조군과 비교하여 종양의 무게 감소효과가 39%로 확인이 되었으며, CUE2-Fc와 E2-Fc의 경우 각각 45% 와 34%로 확인되었다.
상기와 같은 결과에 따르면, AMFR-Fc 중 CUE2-Fc은 종양의 부피와 무게를 모두 감소시키는 효과가 있음을 알 수 있으며, 이는 AMF와의 반응성 확인 결과와도 일치하는 것으로, 암세포를 이식한 누드 마우스의 혈중에서 CUE2-Fc 가 AMF를 효과적으로 중화함으로서 나타나는 효과인 것으로 판단된다. 반면 E2-Fc의 경우 종양 부피를 측정한 결과에서는 효력이 있는 것처럼 보이지만, 종양 무게를 측정한 결과에서는 대조군과 유사한 결과를 나타내었고, 이는 AMF 반응성 확인 결과에서 예측되었던 대로 E2-Fc가 AMF에 대한 중화능이 거의 없음을 나타내는 결과인 것으로 판단된다.
따라서 뛰어난 AMF 중화능을 나타내고 이에 따라 암세포 증식을 억제할 수 있는 물질은 AMFR-Fc 중에서도 특정 도메인 영역을 포함하는 서열을 필수 구성으로 해야하며, 모든 AMFR 서열과 Fc 융합 단백질이 이와 같은 암세포 증식 억제능을 나타내는 것을 아니라는 것을 분명하게 확인하였다.
제제예
1. 의약품의 제조
1.1 산제의 제조
AMFR-Fc 융합 단백질 100mg
유당 100mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
1.2 정제의 제조
AMFR-Fc 융합 단백질 100mg
옥수수전분 100mg
유당 100mg
스테아린산 마그네슘 2mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
1.3 캡슐제의 제조
AMFR-Fc 융합 단백질 100mg
옥수수전분 100mg
유당 100mg
스테아린산 마그네슘 2mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 정제를 제조한다.
1.4 주사제의 제조
AMFR-Fc 융합 단백질 100mg
주사용 멸균 증류수 적량
pH 조절제 적량
통상의 주사제의 제조방법에 따라 1 앰플당(2ml) 상기의 성분 함량으로 제조한다.
1.5 액제의 제조
AMFR-Fc 융합 단백질 100mg
설탕 20g
이성화당 20g
레몬향 적량
정제수를 가하여 전체 1,00ml로 맞추었다. 통상의 액제의 제조방법에 따라 상기의 성분을 혼합한 다음, 갈색병에 충전하고 멸균시켜 액제를 제조한다.
<110> BORYUNG PHARMACEUTICAL CO., LTD
<120> AMFR-Fc fusion protein and anti cancer uses thereof
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atggtagctc tctgcagcct ccaacacctg ggctccagtg atccccgggc tctgcccacc 60
ctccccactg ccacttccgg gcagaggcca gcaaagcggc ggcgcaagag tcccgccatg 120
gccgctctca cccgggaccc ccagttccag aagctgcagc aatggtaccg cgagcaccgc 180
tccgagctga acctgcgccg cctcttcgat gccaacaagg accgcttcaa ccacttcagc 240
ttgaccctca acaccaacca tgggcatatc ctggtggatt actccaagaa cctggtgacg 300
gaggacgtga tgcggatgct ggtggacttg gccaagtcca ggggcgtgga ggccgcccgg 360
gagcggatgt tcaatggtga gaagatcaac tacaccgagg gtcgagccgt gctgcacgtg 420
gctctgcgga accggtcaaa cacacccatc ctggtagacg gcaaggatgt gatgccagag 480
gtcaacaagg ttctggacaa gatgaagtct ttctgccagg gacccctcat ggtgactgaa 540
gcccttaagc catactcttc aggaggtccc cgcgtctggt atgtctccaa cattgatgga 600
actcacattg ccaaaaccct ggcccagctg aaccccgagt cctccctgtt catcattgcc 660
tccaagacct ttactaccca ggagaccatc acgaatgcag agacggcgaa ggagtggttt 720
ctccaggcgg ccaaggatcc ttctgcagtg gcgaagcact ttgttgccct gtctactaac 780
acaaccaaag tgaaggagtt tggaattgac cctcaaaaca tgttcgagtt ctgggattgg 840
gtgggaggac gctactcgct gtggtcggcc atcggactct ccattgccct gcacgtgggt 900
tttgacaact tcgagcagct gctctcgggg gctcactgga tggaccagca cttccgcacg 960
acgcccctgg agaagaacgc ccccgtcttg ctggccctgc tgggtatctg gtacatcaac 1020
tgctttgggt gtgagacaca cgccatgctg ccctatgacc agtacctgca ccgctttgct 1080
gcgtacttcc agcagggcga catggagtcc aatgggaaat acatcaccaa atctggaacc 1140
cgtgtggacc accagacagg ccccattgtg tggggggagc cagggaccaa tggccagcat 1200
gctttttacc agctcatcca ccaaggcacc aagatgatac cctgtgactt cctcatcccg 1260
gtccagaccc agcaccccat acggaagggt ctgcatcaca agatcctcct ggccaacttc 1320
ttggcccaga cagaggccct gatgagggga aaatcgacgg aggaggcccg aaaggagctc 1380
caggctgcgg gcaagagtcc agaggacctt gagaggctgc tgccacataa ggtctttgaa 1440
ggaaatcgcc caaccaactc tattgtgttc accaagctca caccattcat gcttggagcc 1500
ttggtcgcca tgtatgagca caagatcttc gttcagggca tcatctggga catcaacagc 1560
tttgaccagt ggggagtgga gctgggaaag cagctggcta agaaaataga gcctgagctt 1620
gatggcagtg ctcaagtgac ctctcacgac gcttctacca atgggctcat caacttcatc 1680
aagcagcagc gcgaggccag agtccaataa 1710
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Met Val Ala Leu Cys Ser Leu Gln His Leu Gly Ser Ser Asp Pro Arg
1 5 10 15
Ala Leu Pro Thr Leu Pro Thr Ala Thr Ser Gly Gln Arg Pro Ala Lys
20 25 30
Arg Arg Arg Lys Ser Pro Ala Met Ala Ala Leu Thr Arg Asp Pro Gln
35 40 45
Phe Gln Lys Leu Gln Gln Trp Tyr Arg Glu His Arg Ser Glu Leu Asn
50 55 60
Leu Arg Arg Leu Phe Asp Ala Asn Lys Asp Arg Phe Asn His Phe Ser
65 70 75 80
Leu Thr Leu Asn Thr Asn His Gly His Ile Leu Val Asp Tyr Ser Lys
85 90 95
Asn Leu Val Thr Glu Asp Val Met Arg Met Leu Val Asp Leu Ala Lys
100 105 110
Ser Arg Gly Val Glu Ala Ala Arg Glu Arg Met Phe Asn Gly Glu Lys
115 120 125
Ile Asn Tyr Thr Glu Gly Arg Ala Val Leu His Val Ala Leu Arg Asn
130 135 140
Arg Ser Asn Thr Pro Ile Leu Val Asp Gly Lys Asp Val Met Pro Glu
145 150 155 160
Val Asn Lys Val Leu Asp Lys Met Lys Ser Phe Cys Gln Gly Pro Leu
165 170 175
Met Val Thr Glu Ala Leu Lys Pro Tyr Ser Ser Gly Gly Pro Arg Val
180 185 190
Trp Tyr Val Ser Asn Ile Asp Gly Thr His Ile Ala Lys Thr Leu Ala
195 200 205
Gln Leu Asn Pro Glu Ser Ser Leu Phe Ile Ile Ala Ser Lys Thr Phe
210 215 220
Thr Thr Gln Glu Thr Ile Thr Asn Ala Glu Thr Ala Lys Glu Trp Phe
225 230 235 240
Leu Gln Ala Ala Lys Asp Pro Ser Ala Val Ala Lys His Phe Val Ala
245 250 255
Leu Ser Thr Asn Thr Thr Lys Val Lys Glu Phe Gly Ile Asp Pro Gln
260 265 270
Asn Met Phe Glu Phe Trp Asp Trp Val Gly Gly Arg Tyr Ser Leu Trp
275 280 285
Ser Ala Ile Gly Leu Ser Ile Ala Leu His Val Gly Phe Asp Asn Phe
290 295 300
Glu Gln Leu Leu Ser Gly Ala His Trp Met Asp Gln His Phe Arg Thr
305 310 315 320
Thr Pro Leu Glu Lys Asn Ala Pro Val Leu Leu Ala Leu Leu Gly Ile
325 330 335
Trp Tyr Ile Asn Cys Phe Gly Cys Glu Thr His Ala Met Leu Pro Tyr
340 345 350
Asp Gln Tyr Leu His Arg Phe Ala Ala Tyr Phe Gln Gln Gly Asp Met
355 360 365
Glu Ser Asn Gly Lys Tyr Ile Thr Lys Ser Gly Thr Arg Val Asp His
370 375 380
Gln Thr Gly Pro Ile Val Trp Gly Glu Pro Gly Thr Asn Gly Gln His
385 390 395 400
Ala Phe Tyr Gln Leu Ile His Gln Gly Thr Lys Met Ile Pro Cys Asp
405 410 415
Phe Leu Ile Pro Val Gln Thr Gln His Pro Ile Arg Lys Gly Leu His
420 425 430
His Lys Ile Leu Leu Ala Asn Phe Leu Ala Gln Thr Glu Ala Leu Met
435 440 445
Arg Gly Lys Ser Thr Glu Glu Ala Arg Lys Glu Leu Gln Ala Ala Gly
450 455 460
Lys Ser Pro Glu Asp Leu Glu Arg Leu Leu Pro His Lys Val Phe Glu
465 470 475 480
Gly Asn Arg Pro Thr Asn Ser Ile Val Phe Thr Lys Leu Thr Pro Phe
485 490 495
Met Leu Gly Ala Leu Val Ala Met Tyr Glu His Lys Ile Phe Val Gln
500 505 510
Gly Ile Ile Trp Asp Ile Asn Ser Phe Asp Gln Trp Gly Val Glu Leu
515 520 525
Gly Lys Gln Leu Ala Lys Lys Ile Glu Pro Glu Leu Asp Gly Ser Ala
530 535 540
Gln Val Thr Ser His Asp Ala Ser Thr Asn Gly Leu Ile Asn Phe Ile
545 550 555 560
Lys Gln Gln Arg Glu Ala Arg Val Gln
565
<210> 3
<211> 217
<212> PRT
<213> human
<400> 3
Ser Arg Ile Ala Ser Trp Leu Pro Ser Phe Ser Val Glu Val Met His
1 5 10 15
Thr Thr Asn Ile Leu Gly Ile Thr Gln Ala Ser Asn Ser Gln Leu Asn
20 25 30
Ala Met Ala His Gln Ile Gln Glu Met Phe Pro Gln Val Pro Tyr His
35 40 45
Leu Val Leu Gln Asp Leu Gln Leu Thr Arg Ser Val Glu Ile Thr Thr
50 55 60
Asp Asn Ile Leu Glu Gly Arg Ile Gln Val Pro Phe Pro Thr Gln Arg
65 70 75 80
Ser Asp Ser Ile Arg Pro Ala Leu Asn Ser Pro Val Glu Arg Pro Ser
85 90 95
Ser Asp Gln Glu Glu Gly Glu Thr Ser Ala Gln Thr Glu Arg Val Pro
100 105 110
Leu Asp Leu Ser Pro Arg Leu Glu Glu Thr Leu Asp Phe Gly Glu Val
115 120 125
Glu Val Glu Pro Ser Glu Val Glu Asp Phe Glu Ala Arg Gly Ser Arg
130 135 140
Phe Ser Lys Ser Ala Asp Glu Arg Gln Arg Met Leu Val Gln Arg Lys
145 150 155 160
Asp Glu Leu Leu Gln Gln Ala Arg Lys Arg Phe Leu Asn Lys Ser Ser
165 170 175
Glu Asp Asp Ala Ala Ser Glu Ser Phe Leu Pro Ser Glu Gly Ala Ser
180 185 190
Ser Asp Pro Val Thr Leu Arg Arg Arg Met Leu Ala Ala Ala Ala Glu
195 200 205
Arg Arg Leu Gln Lys Gln Gln Thr Ser
210 215
<210> 4
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal-F(HindIII) primer
<400> 4
aagcttatgg agacagacac actc 24
<210> 5
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Fc-R (XbaI) primer
<400> 5
tctagatcat ttacccggag acag 24
<210> 6
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal-ZnCUE2 fusion-F primer
<400> 6
ccaggttcca ctggtcaacg tcgaattcgt 30
<210> 7
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal-ZnCUE2 fusion-R primer
<400> 7
acgaattcga cgttgaccag tggaacctgg 30
<210> 8
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> ZnCUE2-Fc fusion-F primer
<400> 8
cagaagcagc agacctccga gcccaaatct tgtgac 36
<210> 9
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> ZnCUE2-Fc fusion-R primer
<400> 9
gtcacaagat ttgggctcgg aggtctgctg cttctg 36
<210> 10
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal-CUE2 fusion-F primer
<400> 10
ccaggttcca ctggttctcg gattgcgagc 30
<210> 11
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal-CUE2 fusion-R primer
<400> 11
gctcgcaatc cgagaaccag tggaacctgg 30
<210> 12
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> CUE2-Fc fusion-F primer
<400> 12
cagaagcagc agacctccga gcccaaatct tgtgac 36
<210> 13
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> CUE2-Fc fusion-R primer
<400> 13
gtcacaagat ttgggctcgg aggtctgctg cttctg 36
<210> 14
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal-E2-F primer
<400> 14
ccaggttcca ctggtacaca gcggtcagat 30
<210> 15
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal-E2-R primer
<400> 15
atctgaccgc tgtgtaccag tggaacctgg 30
<210> 16
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> E2-Fc fusion-F primer
<400> 16
cagaagcagc agacctccga gcccaaatct tgtgac 36
<210> 17
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> E2-Fc fusion-R primer
<400> 17
gtcacaagat ttgggctcgg aggtctgctg cttctg 36
<210> 18
<211> 1932
<212> DNA
<213> human
<400> 18
atgccgctgc tcttcctcga gcgcttcccc tggcccagcc tccgcaccta cacgggcctc 60
agcggcctgg ccctgctggg caccatcatc agcgcctacc gcgcgctcag ccagcccgag 120
gccggccccg gcgagccgga ccagctaacg gcctcgctgc agcctgagcc gccggcgccc 180
gcccggccga gcgccggggg accccgggcc cgcgatgtgg cccagtacct gctctcagac 240
agcctcttcg tgtgggttct agtaaatacc gcttgctgtg ttttgatgtt ggtggctaag 300
ctcatccagt gtattgtgtt tggccctctt cgagtgagtg agagacagca tctcaaagac 360
aaattttgga attttatttt ctacaagttc attttcatct ttggtgtgct gaatgtccag 420
acagtggaag aggtggtcat gtggtgcctc tggtttgccg gacttgtctt tctgcacctg 480
atggttcagc tctgcaagga tcgatttgaa tatctttcct tctcgcccac cacgccgatg 540
agcagccacg gtcgagtcct gtccctgttg gttgccatgc tgctttcctg ctgtggactg 600
gcggccgtct gctccatcac cggctacacc cacggaatgc acaccttggc tttcatggct 660
gcagagtctc ttcttgtgac agtgaggact gctcatgtga ttttacgata cgtaattcac 720
ctctgggacc tcaaccacga agggacgtgg gaaggaaagg ggacgtatgt ctattacaca 780
gactttgtca tggagctcac tctcctgtcc ctggacctca tgcaccatat tcacatgttg 840
ttatttggca acatctggtt atccatggcc agcctggtca tctttatgca gctgcgttac 900
ctgtttcatg aggtgcaacg tcgaattcgt cggcacaaga actatctacg tgtggttgga 960
aacatggagg ccaggtttgc agttgcaact ccagaggagc tggctgtcaa caatgacgac 1020
tgtgccatct gttgggactc catgcaggct gcgcggaaac tgccctgtgg acatcttttc 1080
cacaactcct gtcttcgttc ctggctagaa caagacacct cctgtccaac atgcagaatg 1140
tctcttaata ttgccgacaa taatcgtgtc agggaagaac atcaaggaga gaacttggat 1200
gagaatttgg ttcctgtagc agcagccgaa gggagacctc gcttaaacca acacaatcac 1260
ttcttccatt tcgatgggtc tcggattgcg agctggctgc cgagtttttc ggttgaagtg 1320
atgcacacca ccaacattct tggcattacg caggccagca actcccagct caatgcaatg 1380
gctcatcaga ttcaagagat gtttccccag gttccatacc atctggtact gcaggacctc 1440
cagctgacac gctcagttga aataacaaca gacaatattt tagaaggacg gattcaagta 1500
ccttttccta cacagcggtc agatagcatc agacctgcat tgaacagtcc tgtggaaagg 1560
ccaagcagtg accaggaaga gggagaaact tctgctcaga ccgagcgtgt gccactggac 1620
ctcagtcctc gcctggagga gacgctggac ttcggcgagg tggaagtgga gcccagtgag 1680
gtggaagact tcgaggctcg tgggagccgc ttctccaagt ctgctgatga gagacagcgc 1740
atgctggtgc agcgtaagga cgaactcctc cagcaagctc gcaaacgttt cttgaacaaa 1800
agttctgaag atgatgcggc ctcagagagc ttcctcccct cggaaggtgc gtcctctgac 1860
cccgtgaccc tgcgtcgaag gatgctggct gccgccgcgg aacggaggct tcagaagcag 1920
cagacctcct ag 1932
<210> 19
<211> 643
<212> PRT
<213> human
<400> 19
Met Pro Leu Leu Phe Leu Glu Arg Phe Pro Trp Pro Ser Leu Arg Thr
1 5 10 15
Tyr Thr Gly Leu Ser Gly Leu Ala Leu Leu Gly Thr Ile Ile Ser Ala
20 25 30
Tyr Arg Ala Leu Ser Gln Pro Glu Ala Gly Pro Gly Glu Pro Asp Gln
35 40 45
Leu Thr Ala Ser Leu Gln Pro Glu Pro Pro Ala Pro Ala Arg Pro Ser
50 55 60
Ala Gly Gly Pro Arg Ala Arg Asp Val Ala Gln Tyr Leu Leu Ser Asp
65 70 75 80
Ser Leu Phe Val Trp Val Leu Val Asn Thr Ala Cys Cys Val Leu Met
85 90 95
Leu Val Ala Lys Leu Ile Gln Cys Ile Val Phe Gly Pro Leu Arg Val
100 105 110
Ser Glu Arg Gln His Leu Lys Asp Lys Phe Trp Asn Phe Ile Phe Tyr
115 120 125
Lys Phe Ile Phe Ile Phe Gly Val Leu Asn Val Gln Thr Val Glu Glu
130 135 140
Val Val Met Trp Cys Leu Trp Phe Ala Gly Leu Val Phe Leu His Leu
145 150 155 160
Met Val Gln Leu Cys Lys Asp Arg Phe Glu Tyr Leu Ser Phe Ser Pro
165 170 175
Thr Thr Pro Met Ser Ser His Gly Arg Val Leu Ser Leu Leu Val Ala
180 185 190
Met Leu Leu Ser Cys Cys Gly Leu Ala Ala Val Cys Ser Ile Thr Gly
195 200 205
Tyr Thr His Gly Met His Thr Leu Ala Phe Met Ala Ala Glu Ser Leu
210 215 220
Leu Val Thr Val Arg Thr Ala His Val Ile Leu Arg Tyr Val Ile His
225 230 235 240
Leu Trp Asp Leu Asn His Glu Gly Thr Trp Glu Gly Lys Gly Thr Tyr
245 250 255
Val Tyr Tyr Thr Asp Phe Val Met Glu Leu Thr Leu Leu Ser Leu Asp
260 265 270
Leu Met His His Ile His Met Leu Leu Phe Gly Asn Ile Trp Leu Ser
275 280 285
Met Ala Ser Leu Val Ile Phe Met Gln Leu Arg Tyr Leu Phe His Glu
290 295 300
Val Gln Arg Arg Ile Arg Arg His Lys Asn Tyr Leu Arg Val Val Gly
305 310 315 320
Asn Met Glu Ala Arg Phe Ala Val Ala Thr Pro Glu Glu Leu Ala Val
325 330 335
Asn Asn Asp Asp Cys Ala Ile Cys Trp Asp Ser Met Gln Ala Ala Arg
340 345 350
Lys Leu Pro Cys Gly His Leu Phe His Asn Ser Cys Leu Arg Ser Trp
355 360 365
Leu Glu Gln Asp Thr Ser Cys Pro Thr Cys Arg Met Ser Leu Asn Ile
370 375 380
Ala Asp Asn Asn Arg Val Arg Glu Glu His Gln Gly Glu Asn Leu Asp
385 390 395 400
Glu Asn Leu Val Pro Val Ala Ala Ala Glu Gly Arg Pro Arg Leu Asn
405 410 415
Gln His Asn His Phe Phe His Phe Asp Gly Ser Arg Ile Ala Ser Trp
420 425 430
Leu Pro Ser Phe Ser Val Glu Val Met His Thr Thr Asn Ile Leu Gly
435 440 445
Ile Thr Gln Ala Ser Asn Ser Gln Leu Asn Ala Met Ala His Gln Ile
450 455 460
Gln Glu Met Phe Pro Gln Val Pro Tyr His Leu Val Leu Gln Asp Leu
465 470 475 480
Gln Leu Thr Arg Ser Val Glu Ile Thr Thr Asp Asn Ile Leu Glu Gly
485 490 495
Arg Ile Gln Val Pro Phe Pro Thr Gln Arg Ser Asp Ser Ile Arg Pro
500 505 510
Ala Leu Asn Ser Pro Val Glu Arg Pro Ser Ser Asp Gln Glu Glu Gly
515 520 525
Glu Thr Ser Ala Gln Thr Glu Arg Val Pro Leu Asp Leu Ser Pro Arg
530 535 540
Leu Glu Glu Thr Leu Asp Phe Gly Glu Val Glu Val Glu Pro Ser Glu
545 550 555 560
Val Glu Asp Phe Glu Ala Arg Gly Ser Arg Phe Ser Lys Ser Ala Asp
565 570 575
Glu Arg Gln Arg Met Leu Val Gln Arg Lys Asp Glu Leu Leu Gln Gln
580 585 590
Ala Arg Lys Arg Phe Leu Asn Lys Ser Ser Glu Asp Asp Ala Ala Ser
595 600 605
Glu Ser Phe Leu Pro Ser Glu Gly Ala Ser Ser Asp Pro Val Thr Leu
610 615 620
Arg Arg Arg Met Leu Ala Ala Ala Ala Glu Arg Arg Leu Gln Lys Gln
625 630 635 640
Gln Thr Ser
<210> 20
<211> 1713
<212> DNA
<213> Artificial Sequence
<220>
<223> ZnCUE2-Fc
<400> 20
caacgtcgaa ttcgtcggca caagaactat ctacgtgtgg ttggaaacat ggaggccagg 60
tttgcagttg caactccaga ggagctggct gtcaacaatg acgactgtgc catctgttgg 120
gactccatgc aggctgcgcg gaaactgccc tgtggacatc ttttccacaa ctcctgtctt 180
cgttcctggc tagaacaaga cacctcctgt ccaacatgca gaatgtctct taatattgcc 240
gacaataatc gtgtcaggga agaacatcaa ggagagaact tggatgagaa tttggttcct 300
gtagcagcag ccgaagggag acctcgctta aaccaacaca atcacttctt ccatttcgat 360
gggtctcgga ttgcgagctg gctgccgagt ttttcggttg aagtgatgca caccaccaac 420
attcttggca ttacgcaggc cagcaactcc cagctcaatg caatggctca tcagattcaa 480
gagatgtttc cccaggttcc ataccatctg gtactgcagg acctccagct gacacgctca 540
gttgaaataa caacagacaa tattttagaa ggacggattc aagtaccttt tcctacacag 600
cggtcagata gcatcagacc tgcattgaac agtcctgtgg aaaggccaag cagtgaccag 660
gaagagggag aaacttctgc tcagaccgag cgtgtgccac tggacctcag tcctcgcctg 720
gaggagacgc tggacttcgg cgaggtggaa gtggagccca gtgaggtgga agacttcgag 780
gctcgtggga gccgcttctc caagtctgct gatgagagac agcgcatgct ggtgcagcgt 840
aaggacgaac tcctccagca agctcgcaaa cgtttcttga acaaaagttc tgaagatgat 900
gcggcctcag agagcttcct cccctcggaa ggtgcgtcct ctgaccccgt gaccctgcgt 960
cgaaggatgc tggctgccgc cgcggaacgg aggcttcaga agcagcagac ctccgagccc 1020
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 1080
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 1140
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 1200
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 1260
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1320
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1380
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1440
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1500
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1560
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1620
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1680
cagaagagcc tctccctgtc tccgggtaaa tga 1713
<210> 21
<211> 570
<212> PRT
<213> Artificial Sequence
<220>
<223> ZnCUE2-Fc
<400> 21
Gln Arg Arg Ile Arg Arg His Lys Asn Tyr Leu Arg Val Val Gly Asn
1 5 10 15
Met Glu Ala Arg Phe Ala Val Ala Thr Pro Glu Glu Leu Ala Val Asn
20 25 30
Asn Asp Asp Cys Ala Ile Cys Trp Asp Ser Met Gln Ala Ala Arg Lys
35 40 45
Leu Pro Cys Gly His Leu Phe His Asn Ser Cys Leu Arg Ser Trp Leu
50 55 60
Glu Gln Asp Thr Ser Cys Pro Thr Cys Arg Met Ser Leu Asn Ile Ala
65 70 75 80
Asp Asn Asn Arg Val Arg Glu Glu His Gln Gly Glu Asn Leu Asp Glu
85 90 95
Asn Leu Val Pro Val Ala Ala Ala Glu Gly Arg Pro Arg Leu Asn Gln
100 105 110
His Asn His Phe Phe His Phe Asp Gly Ser Arg Ile Ala Ser Trp Leu
115 120 125
Pro Ser Phe Ser Val Glu Val Met His Thr Thr Asn Ile Leu Gly Ile
130 135 140
Thr Gln Ala Ser Asn Ser Gln Leu Asn Ala Met Ala His Gln Ile Gln
145 150 155 160
Glu Met Phe Pro Gln Val Pro Tyr His Leu Val Leu Gln Asp Leu Gln
165 170 175
Leu Thr Arg Ser Val Glu Ile Thr Thr Asp Asn Ile Leu Glu Gly Arg
180 185 190
Ile Gln Val Pro Phe Pro Thr Gln Arg Ser Asp Ser Ile Arg Pro Ala
195 200 205
Leu Asn Ser Pro Val Glu Arg Pro Ser Ser Asp Gln Glu Glu Gly Glu
210 215 220
Thr Ser Ala Gln Thr Glu Arg Val Pro Leu Asp Leu Ser Pro Arg Leu
225 230 235 240
Glu Glu Thr Leu Asp Phe Gly Glu Val Glu Val Glu Pro Ser Glu Val
245 250 255
Glu Asp Phe Glu Ala Arg Gly Ser Arg Phe Ser Lys Ser Ala Asp Glu
260 265 270
Arg Gln Arg Met Leu Val Gln Arg Lys Asp Glu Leu Leu Gln Gln Ala
275 280 285
Arg Lys Arg Phe Leu Asn Lys Ser Ser Glu Asp Asp Ala Ala Ser Glu
290 295 300
Ser Phe Leu Pro Ser Glu Gly Ala Ser Ser Asp Pro Val Thr Leu Arg
305 310 315 320
Arg Arg Met Leu Ala Ala Ala Ala Glu Arg Arg Leu Gln Lys Gln Gln
325 330 335
Thr Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
340 345 350
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
355 360 365
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
370 375 380
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
385 390 395 400
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
405 410 415
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
420 425 430
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
435 440 445
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
450 455 460
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
465 470 475 480
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
485 490 495
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
500 505 510
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
515 520 525
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
530 535 540
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
545 550 555 560
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
565 570
<210> 22
<211> 1350
<212> DNA
<213> Artificial Sequence
<220>
<223> CUE2-Fc
<400> 22
tctcggattg cgagctggct gccgagtttt tcggttgaag tgatgcacac caccaacatt 60
cttggcatta cgcaggccag caactcccag ctcaatgcaa tggctcatca gattcaagag 120
atgtttcccc aggttccata ccatctggta ctgcaggacc tccagctgac acgctcagtt 180
gaaataacaa cagacaatat tttagaagga cggattcaag taccttttcc tacacagcgg 240
tcagatagca tcagacctgc attgaacagt cctgtggaaa ggccaagcag tgaccaggaa 300
gagggagaaa cttctgctca gaccgagcgt gtgccactgg acctcagtcc tcgcctggag 360
gagacgctgg acttcggcga ggtggaagtg gagcccagtg aggtggaaga cttcgaggct 420
cgtgggagcc gcttctccaa gtctgctgat gagagacagc gcatgctggt gcagcgtaag 480
gacgaactcc tccagcaagc tcgcaaacgt ttcttgaaca aaagttctga agatgatgcg 540
gcctcagaga gcttcctccc ctcggaaggt gcgtcctctg accccgtgac cctgcgtcga 600
aggatgctgg ctgccgccgc ggaacggagg cttcagaagc agcagacctc cgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaatga 1350
<210> 23
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> CUE2-Fc
<400> 23
Ser Arg Ile Ala Ser Trp Leu Pro Ser Phe Ser Val Glu Val Met His
1 5 10 15
Thr Thr Asn Ile Leu Gly Ile Thr Gln Ala Ser Asn Ser Gln Leu Asn
20 25 30
Ala Met Ala His Gln Ile Gln Glu Met Phe Pro Gln Val Pro Tyr His
35 40 45
Leu Val Leu Gln Asp Leu Gln Leu Thr Arg Ser Val Glu Ile Thr Thr
50 55 60
Asp Asn Ile Leu Glu Gly Arg Ile Gln Val Pro Phe Pro Thr Gln Arg
65 70 75 80
Ser Asp Ser Ile Arg Pro Ala Leu Asn Ser Pro Val Glu Arg Pro Ser
85 90 95
Ser Asp Gln Glu Glu Gly Glu Thr Ser Ala Gln Thr Glu Arg Val Pro
100 105 110
Leu Asp Leu Ser Pro Arg Leu Glu Glu Thr Leu Asp Phe Gly Glu Val
115 120 125
Glu Val Glu Pro Ser Glu Val Glu Asp Phe Glu Ala Arg Gly Ser Arg
130 135 140
Phe Ser Lys Ser Ala Asp Glu Arg Gln Arg Met Leu Val Gln Arg Lys
145 150 155 160
Asp Glu Leu Leu Gln Gln Ala Arg Lys Arg Phe Leu Asn Lys Ser Ser
165 170 175
Glu Asp Asp Ala Ala Ser Glu Ser Phe Leu Pro Ser Glu Gly Ala Ser
180 185 190
Ser Asp Pro Val Thr Leu Arg Arg Arg Met Leu Ala Ala Ala Ala Glu
195 200 205
Arg Arg Leu Gln Lys Gln Gln Thr Ser Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 24
<211> 1119
<212> DNA
<213> Artificial Sequence
<220>
<223> E2-Fc
<400> 24
acacagcggt cagatagcat cagacctgca ttgaacagtc ctgtggaaag gccaagcagt 60
gaccaggaag agggagaaac ttctgctcag accgagcgtg tgccactgga cctcagtcct 120
cgcctggagg agacgctgga cttcggcgag gtggaagtgg agcccagtga ggtggaagac 180
ttcgaggctc gtgggagccg cttctccaag tctgctgatg agagacagcg catgctggtg 240
cagcgtaagg acgaactcct ccagcaagct cgcaaacgtt tcttgaacaa aagttctgaa 300
gatgatgcgg cctcagagag cttcctcccc tcggaaggtg cgtcctctga ccccgtgacc 360
ctgcgtcgaa ggatgctggc tgccgccgcg gaacggaggc ttcagaagca gcagacctcc 420
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 480
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 540
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 600
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 660
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 720
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 780
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 840
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 900
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 960
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1020
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1080
tacacgcaga agagcctctc cctgtctccg ggtaaatga 1119
<210> 25
<211> 372
<212> PRT
<213> Artificial Sequence
<220>
<223> E2-Fc
<400> 25
Thr Gln Arg Ser Asp Ser Ile Arg Pro Ala Leu Asn Ser Pro Val Glu
1 5 10 15
Arg Pro Ser Ser Asp Gln Glu Glu Gly Glu Thr Ser Ala Gln Thr Glu
20 25 30
Arg Val Pro Leu Asp Leu Ser Pro Arg Leu Glu Glu Thr Leu Asp Phe
35 40 45
Gly Glu Val Glu Val Glu Pro Ser Glu Val Glu Asp Phe Glu Ala Arg
50 55 60
Gly Ser Arg Phe Ser Lys Ser Ala Asp Glu Arg Gln Arg Met Leu Val
65 70 75 80
Gln Arg Lys Asp Glu Leu Leu Gln Gln Ala Arg Lys Arg Phe Leu Asn
85 90 95
Lys Ser Ser Glu Asp Asp Ala Ala Ser Glu Ser Phe Leu Pro Ser Glu
100 105 110
Gly Ala Ser Ser Asp Pro Val Thr Leu Arg Arg Arg Met Leu Ala Ala
115 120 125
Ala Ala Glu Arg Arg Leu Gln Lys Gln Gln Thr Ser Glu Pro Lys Ser
130 135 140
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
145 150 155 160
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
165 170 175
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
180 185 190
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
195 200 205
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
210 215 220
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
225 230 235 240
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
245 250 255
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
260 265 270
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
275 280 285
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
290 295 300
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
305 310 315 320
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
325 330 335
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
340 345 350
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
355 360 365
Ser Pro Gly Lys
370
Claims (10)
- 서열번호 3의 아미노산 서열로 표시되는 AMFR (Autocrine motility factor receptor) 단백질과 인간 면역글로불린 Fc 영역이 융합된 AMFR-Fc 융합 단백질.
- 제1항에 있어서, 상기 AMFR-Fc 융합 단백질은 서열번호 23의 아미노산 서열로 표시되는, AMFR-Fc 융합 단백질.
- 제1항의 AMFR-Fc 융합 단백질을 암호화하는 폴리뉴클레오티드.
- 제3항에 있어서, 상기 폴리뉴클레오티드는 서열번호 22로 표시되는 것인, 폴리뉴클레오티드.
- 제3항의 폴리뉴클레오티드를 포함하는 벡터.
- 제5항의 벡터로 형질전환된 세포.
- 제6항의 형질전환된 세포를 배양하는 단계; 및
상기 배양액으로부터 AMFR-Fc 융합 단백질을 분리하는 단계;
를 포함하는 AMFR-Fc 융합 단백질의 제조방법. - 서열번호 3의 아미노산 서열로 표시되는 AMFR (Autocrine motility factor receptor) 단백질을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물.
- 제8항에 있어서, 상기 AMFR 단백질에 인간 면역글로불린 Fc 영역이 융합된, 암 예방 또는 치료용 약학적 조성물.
- 제8항 또는 제9항에 있어서, 상기 암은 위암, 유방암, 간암, 난소암, 폐암, 골수종, 신장암, 대장암, 식도암, 췌장암, 흑색종 및 직장암으로 이루어진 군에서 선택된 1종 이상인, 암 예방 또는 치료용 약학적 조성물.
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KR1020140149772A KR20160050773A (ko) | 2014-10-31 | 2014-10-31 | AMFR-Fc 융합 단백질 및 이의 항암 용도 |
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KR1020140149772A KR20160050773A (ko) | 2014-10-31 | 2014-10-31 | AMFR-Fc 융합 단백질 및 이의 항암 용도 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11123402B1 (en) | 2017-06-14 | 2021-09-21 | Daegu Catholic University Industry Academic Cooperation Foundation | Anticancer composition comprising cervical cancer-derived autocrine motility factor as effective component |
-
2014
- 2014-10-31 KR KR1020140149772A patent/KR20160050773A/ko not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11123402B1 (en) | 2017-06-14 | 2021-09-21 | Daegu Catholic University Industry Academic Cooperation Foundation | Anticancer composition comprising cervical cancer-derived autocrine motility factor as effective component |
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