KR20210158693A - 항 pcsk9 항체 및 이의 용도 - Google Patents
항 pcsk9 항체 및 이의 용도 Download PDFInfo
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- KR20210158693A KR20210158693A KR1020200077370A KR20200077370A KR20210158693A KR 20210158693 A KR20210158693 A KR 20210158693A KR 1020200077370 A KR1020200077370 A KR 1020200077370A KR 20200077370 A KR20200077370 A KR 20200077370A KR 20210158693 A KR20210158693 A KR 20210158693A
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Abstract
본 발명의 항 PCSK9 항체는 종래의 항 PCSK9 항체와 상이한 에피토프에 결합함에도 PCSK9과 특이적으로 결합한다. 특히, PCSK9과의 결합력이 매우 우수하다. 따라서, 항기 항 PCSK9 항체는 LDLR과 혈장 PCSK9의 결합을 효과적으로 차단할 수 있다. 그러므로, 이에 의해 LDLR의 흡수 및 분해를 방지할 수 있다. 따라서, 상기 항 PCSK 항체는 고콜레스테롤혈증, 고지혈증, 죽상경화성 심혈관질환(ACVD), 급성관상동맥증후군(ACS), 고혈압, 당뇨병, 뇌졸중, 알츠하이머 및 이상지질혈증을 치료 또는 예방하는데 유용하게 사용될 수 있다.
Description
본 발명은 항체 의약품 분야에 관한 것이며, 구체적으로는 전구단백질 전환효소 서브틸리신/켁신 타입 9(PCSK9)에 특이적으로 결합하는 항체, 이의 용도 및 이의 제조 방법에 관한 것이다.
고지혈증(Hyperlipidaemia)은 필요 이상의 지방성분 물질인 저밀도 지단백질 콜레스테롤(LDL), 고밀도 지단백질 콜레스테롤(HDL), 초저밀도 지단백질 콜레스테롤(VLDL), 중성지방(Triglyceride)이 혈액에 존재하여 염증을 일으키는 상태를 말한다. 또한, 고지혈증은 그 자체로 특별한 증상이 나타나지는 않지만, 고혈압, 동맥경화, 뇌졸중 등의 위험요인으로서 심혈관계 질환에 의한 사망률을 유의하게 증가시킨다. 지질의 농도가 관리되지 않는 환자들은 스타틴을 비롯한 약을 이용하여 혈중 지질을 조절하여 심혈관계 질환의 위험성을 낮출 필요가 있다.
1990년대부터 사용된 스타틴은 혈중 LDL 콜레스테롤의 조절과 심혈관질환 발생 및 사망률 저하에 효력이 있지만 간 독성과 근육독성과 같은 부작용이 있다. 또한, 스타틴을 복용했는데도 LDL 콜레스테롤 수준이 충분히 조절되지 않는 유전성 콜레스테롤 과다증에 해당하는 환자들이 존재한다. 전구단백질 전환효소 서브틸리신/켁신 타입 9(이하, PCSK9)가 LDL 콜레스테롤을 조절하는 핵심적인 역할을 한다는 것이 2003년 전후에 보고되었다(Maxwell, K.N, et.al. Novel putative SREP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res. 44,2109-2119, 2003).
2006년에 유전자 돌연변이 때문에 생기는 Autosomal dominant hypercholesterolemia(ADH)가 보고되었다. 구체적으로, LDLR, APOB, PCSK9, LDLRAP1 유전자에 이상이 있는 경우에 혈중 LDL 콜레스테롤이 심하게 증가한다고 보고되었다. 높은 농도의 LDL 콜레스테롤이 혈중에서 오랜 시간 지속되면 관상동맥질환이 발생한다. 주로 유럽, 미국에서 연구가 되었으며, heterozygous ADH는 500명 중에 한명 꼴로, homozygous ADH는 백만 중에 한명 정도 있을 것으로 예상된다. ADH 환자들은 관상동맥질환 발생의 교차비(Odds ratio)가 10배 가까이 된다고 알려져 있다. ADH는 가족력에 있는 유전질환이며, 상염색체 우성 유전방식을 따른다. 이는 부모 중에서 한 명만 ADH이면 50%의 확률로 자식도 같은 질환일 가능성이 있다는 것을 의미한다.
2013년 발표된 미국심장학회(ACC) 및 심장협회(AHA)의 지질 가이드라인에 따르면, 죽상동맥경화성 심혈관질환(ASCVD) 환자에 PCSK9 억제제인 단일클론항체를 사용할 경우, LDL 콜레스테롤 순환율을 높일 수 있으며, LDLR의 수를 증가시킬 수 있다는 점이 보고되었다. 그리고 PCSK9 억제제 처방이 필요한 환자군으로 우선 LDL 콜레스테롤 목표치에 도달하지 못하는 ASCVD, 급성관상동맥증후군(ACS), 계획되지 않은 관상동맥중재술, 5년내 허혈성 뇌졸중 재발, 고콜레스테롤혈증, 고혈압이 포함될 수 있다는 점이 보고되었다. 또한 ASCVD가 없는 가족성 고콜레스테롤혈증, 스타틴 내인성이 없는 환자에게도 PCSK9 억제제를 투여할 수 있다고 권고했다.
따라서, PCSK9 억제제인 모노클로날 항체가 요구되는 상황이며, 특히 안전성과 유효성을 갖는 항체는 산업적으로 널리 응용될 수 있다.
Maxwell, K.N, et.al. Novel putative SREP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res. 44, 2109-2119, 2003].
본 발명은 PCSK9과 특이적으로 결합하는 항 PCSK9 항체에 관한 것이다. Human PCSK9 단백질 서열을 기반으로 기능에 영향을 주지 않는 범위 내의 특정 부위의 아미노산을 제거한 PCSK9 단백질을 원핵세포를 사용하여 발현 정제하여 면역원으로 사용하였다. 이를 이용하여 PCSK9과 특이적으로 결합하는 항 PCSK9 항체를 제조하였다. 제조된 항체는 LDLR과 PCSK9의 결합을 억제시켜 세포안으로 LDL의 흡수를 증가시킬 수 있다.
상기 목적을 달성하기 위해, 본 발명의 일 측면은, 인간 PCSK9의 209번째 내지 218번째 아미노산에 특이적으로 결합하는 항체를 유효성분으로 포함하는 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물을 제공한다.
본 발명의 또 다른 측면은, 서열번호 1의 LCDR1, 서열번호 2의 LCDR2, 및 서열번호 3의 LCDR3을 포함하는 경쇄가변영역; 및 서열번호 4의 HCDR1, 서열번호 5의 HCDR2, 및 서열번호 6의 HCDR3을 포함하는 중쇄가변영역을 포함하는 PCSK9에 특이적인 항체 및 이의 약학적 조성물을 제공한다.
본 발명인 항 PCSK9 항체는 PCSK9과 특이적으로 결합할 뿐 아니라, 종래 알려진 에피토프와 상이한 에피토프에 결합한다. 또한, PCSK9과의 결합력이 매우 우수하다. 따라서, 상기 항 PCSK9 항체는 LDLR과 혈장 PCSK9의 결합을 차단할 수 있고, 이에 의해 LDLR의 흡수 및 분해를 방지할 수 있다. 뿐만 아니라, 세포 표면 상에서 LDLR 발현 수준 및 양을 증가시키고, LDLR에 의한 LDL 재흡수를 증가시킬 수 있다. 따라서, 상기 항 PCSK9 항체는 고콜레스테롤혈증, 고지혈증, 죽상경화성 심혈관질환(ACVD), 급성관상동맥증후군(ACS) 및 고혈압을 치료 또는 예방하는데 유용하게 사용될 수 있다.
도 1a는 pGEX 4T-1 vector와 결합된 BST PM1의 DNA 서열을 나타낸 것이다(서열번호 58).
도 1b는 pGEX 4T-1 vector와 결합된 BST PM1의 아미노산 서열을 나타낸 것이다(서열번호 57).
도 1c는 PCSK9 original과 BST PM1 sequence alignment를 수행한 것이다.
도 2는 BST PM1 Ag과 PCSK9 다클론항체의 웨스턴블롯 결과를 나타낸 것이다: M: 사이즈 마커, Lane 1 : PCSK9 original antigen, coomassie staining, Lane 2 : BST PM1 Ag, coomasie staining, Lane 3 : PCSK9 original antigen과 PCSK9 Pab(다클론항체)를 이용한 western blot 밴드, Lane 4 : BST PM1 Ag과 PCSK9 Pab(다클론항체)를 이용한 western blot 밴드.
도 3a는 단일클론항체 선별을 위한 1차 스크리닝의 ELISA 결과값을 나타낸 것이다.
도 3b는 단일클론항체 선별을 위한 2차 스크리닝의 ELISA 결과값을 나타낸 것이다.
도 4a는 선별된 8종의 항 PCSK9 항체의 FACS 결과값을 나타낸 것이다.
도 4b는 선별된 8종의 항 PCSK9 항체의 Isotype을 확인한 것이다.
도 5는 9G8, 4B10, 7D1 Mab 정제 후 SDS PAGE 결과를 나타낸다: M: 사이즈 마커, Lane 1 : 9G8 Mab(단클론항체), Lane 2 : 4B10 Mab, Lane 3 : 7D1 Mab.
도 6은 정제된 9G8, 4B10, 7D1 Mab와 PCSK9 Ag의 웨스턴 블롯 결과를 나타낸 것이다.
도 7은 정제된 9G8, 4B10, 7D1 Mab와 PCSK9 Ag의 ELISA 결과를 나타낸 것이다.
도 8은 PCSK9 Ag과 LDLR 결합을 억제하기 위한 항 PCSK9 항체의 효능 ELISA 결과를 나타낸다.
도 9는 항 PCSK9 항체의 HepG2 세포의 LDL 흡수 영향을 나타낸 것이다.
도 10은 m7D1 항 PCSK9 항체의 에피토프 매핑 결과를 나타낸 것이다.
도 11은 7D1 항 PCSK9 항체의 Humanization 가변 영역 서열 정보를 나타낸 것이다.
도 12는 ch7D1, hz7D1.11 및 hz7D1.22 3종의 IgG를 생산 및 정제 후, SDS-PAGE로 확인한 결과를 나타낸 것이다.
도 13은 ch7D1과 2 종의 hz7D1 IgG 생산 정제 후, 항원 PCSK9 Ag에 대한 EC 50 analysis 결과를 나타낸 것이다.
도 14a 내지 도 14d는 ch7D1과 2 종의 hz7D1 IgG 생산 정제 후, 항원 PCSK9 Ag에 대한 Octet analysis 결과를 나타낸 것이다.
도 1b는 pGEX 4T-1 vector와 결합된 BST PM1의 아미노산 서열을 나타낸 것이다(서열번호 57).
도 1c는 PCSK9 original과 BST PM1 sequence alignment를 수행한 것이다.
도 2는 BST PM1 Ag과 PCSK9 다클론항체의 웨스턴블롯 결과를 나타낸 것이다: M: 사이즈 마커, Lane 1 : PCSK9 original antigen, coomassie staining, Lane 2 : BST PM1 Ag, coomasie staining, Lane 3 : PCSK9 original antigen과 PCSK9 Pab(다클론항체)를 이용한 western blot 밴드, Lane 4 : BST PM1 Ag과 PCSK9 Pab(다클론항체)를 이용한 western blot 밴드.
도 3a는 단일클론항체 선별을 위한 1차 스크리닝의 ELISA 결과값을 나타낸 것이다.
도 3b는 단일클론항체 선별을 위한 2차 스크리닝의 ELISA 결과값을 나타낸 것이다.
도 4a는 선별된 8종의 항 PCSK9 항체의 FACS 결과값을 나타낸 것이다.
도 4b는 선별된 8종의 항 PCSK9 항체의 Isotype을 확인한 것이다.
도 5는 9G8, 4B10, 7D1 Mab 정제 후 SDS PAGE 결과를 나타낸다: M: 사이즈 마커, Lane 1 : 9G8 Mab(단클론항체), Lane 2 : 4B10 Mab, Lane 3 : 7D1 Mab.
도 6은 정제된 9G8, 4B10, 7D1 Mab와 PCSK9 Ag의 웨스턴 블롯 결과를 나타낸 것이다.
도 7은 정제된 9G8, 4B10, 7D1 Mab와 PCSK9 Ag의 ELISA 결과를 나타낸 것이다.
도 8은 PCSK9 Ag과 LDLR 결합을 억제하기 위한 항 PCSK9 항체의 효능 ELISA 결과를 나타낸다.
도 9는 항 PCSK9 항체의 HepG2 세포의 LDL 흡수 영향을 나타낸 것이다.
도 10은 m7D1 항 PCSK9 항체의 에피토프 매핑 결과를 나타낸 것이다.
도 11은 7D1 항 PCSK9 항체의 Humanization 가변 영역 서열 정보를 나타낸 것이다.
도 12는 ch7D1, hz7D1.11 및 hz7D1.22 3종의 IgG를 생산 및 정제 후, SDS-PAGE로 확인한 결과를 나타낸 것이다.
도 13은 ch7D1과 2 종의 hz7D1 IgG 생산 정제 후, 항원 PCSK9 Ag에 대한 EC 50 analysis 결과를 나타낸 것이다.
도 14a 내지 도 14d는 ch7D1과 2 종의 hz7D1 IgG 생산 정제 후, 항원 PCSK9 Ag에 대한 Octet analysis 결과를 나타낸 것이다.
PCSK9의 209번째 내지 218번째 아미노산에 특이적으로 결합하는 항체
본 발명의 일 측면은, 인간 PCSK9의 209번째 내지 218번째 아미노산에 특이적으로 결합하는 항체를 유효성분으로 포함하는 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물을 제공한다.
본 명세서에서 사용하는 용어, "PCSK9" 또는 "서브틸리신/켁신 타입 9"은 염색체 1에서 인간의 PCSK9 유전자에 의해 암호화된 효소를 의미한다. PCSK9은 다른 단백질을 활성화시키는 단백질의 프로 단백질 전환 효소 패밀리의 9번째 구성원이다. 상기 효소는 692개의 아미노산 잔기로 구성되어 있다. 주로 간장, 신장, 및 소장 등에 존재하며, 간질세포, 간엽세포 및 결장표피세포 등에서 발현되어 혈액 중에 존재한다. 이때, 상기 PCSK9은 서열번호 49의 아미노산 서열을 가질 수 있다. 또한, 인간 PCSK9의 209번째 내지 218번째 아미노산 서열은 서열번호 27의 아미노산 서열일 수 수 있다.
PCSK9은 간세포의 원형질막의 표면에 존재하는 LDLR(LDL receptor)의 분해를 매개할 수 있다. PCSK9은 LDLR 구조에서 성장인자-유사 반복 상동성 도메인-A(EGF-A)에 결합할 수 있다. 한편, LDLR/PCSK9 복합체는 간세포에 흡수된다. 흡수된 LDLR/PCSK9 복합체는 간세포의 엔도좀에서 LDLR의 형태 변화를 저해하여, LDLR의 해리 및 재순환을 방지한다. 또한, LDLR/PCSK9 복합체가 형성될 경우, 상기 복합체는 단백질을 분해하는 리보솜으로 수송되게 된다.
또한, 상기 콜레스테롤 관련 질환은 고콜레스테롤혈증, 고지혈증, 죽상경화성 심혈관질환(ACVD), 급성관상동맥증후군(ACS), 고혈압, 당뇨병, 뇌졸중, 알츠하이머 및 이상지질혈증으로 이루어진 군에서 선택되는 어느 하나인 것일 수 있다.
또한, 상기 항체를 수득하기 위한 항원으로 PCSK9의 일부가 제거된 "BST PM1 Ag"을 사용할 수 있다. 본 명세서에서 사용하는 용어, "BST PM1 Ag"은 면역에 사용한 PCSK9 단백질 단편을 지칭한다. 또한, 상기 항원은 "BST PM1"으로 지칭되기도 한다. 이때, "BST PM1 Ag"은 상기 PCSK9 단백질에서 항원의 활성에 영향을 주지 않는 범위 내에서 암젠 특허(출원번호 10-2010-7006252)의 결합 부위에 대응하는 영역의 아미노산이 제거된 PCSK9의 변이체이다.
구체적으로, 상기 "BST PM1 Ag"은 Human PCSK9 단백질에서 서열번호 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 및 38의 아미노산이 제거된 형태를 의미한다. 이는 암젠의 항 PCSK9 항체 특허의 항-PCSK9 항체가 PCSK9의 단편 내의 에피토프에 결합하는 부위를 제거한 형태이다. Human PCSK9과 BST PM1 Ag의 서열 비교는 Multiple sequence alignment by Florence Corpet로 비교하여 결실된 아미노산의 위치를 비교하였다(도 1c).
항
PCSK9 항체
본 발명의 또 다른 측면은, 서열번호 1의 LCDR1, 서열번호 2의 LCDR2, 및 서열번호 3의 LCDR3을 포함하는 경쇄가변영역; 및 서열번호 4의 HCDR1, 서열번호 5의 HCDR2, 및 서열번호 6의 HCDR3을 포함하는 중쇄가변영역을 포함하는 PCSK9에 특이적인 항체 또는 이의 단편을 제공한다. 이때, 상기 항체는 인간화 항체 또는 인간 항체 일 수 있다.
구체적으로, 상기 항체는 PCSK9의 서열번호 27, 서열번호 49, 및/또는 서열번호 50의 아미노산 서열을 갖는 폴리펩티드 또는 단백질에 특이적으로 결합할 수 있다. 바람직하게, 서열번호 50의 아미노산 서열을 가지는 항원에 특이적으로 결합할 수 있다.
또한, 상기 항체의 중쇄영역은 서열번호 19 또는 서열번호 23의 아미노산 서열을 가지는 것일 수 있다. 또한, 상기 항체의 중쇄영역은 서열번호 19 또는 서열번호 23의 아미노산 서열과 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 또는 99% 동일성 또는 100% 동일성을 갖는 아미노산 서열을 포함하거나 이들로 이루어질 수 있다.
또한, 상기 항체의 경쇄영역은 서열번호 21 또는 서열번호 25의 아미노산 서열을 가지는 것일 수 있다. 또한, 상기 항체의 경쇄영역은 서열번호 21 또는 서열번호 25의 아미노산 서열과 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 또는 99% 동일성 또는 100% 동일성을 갖는 아미노산 서열을 포함하거나 이들로 이루어질 수 있다.
본 명세서에서 사용하는 용어, "항체 단편"은 항원-결합 활성을 갖는 Fab 단편, Fab' 단편, F(ab')2 단편뿐만 아니라, Human PCSK9에 결합하는 Fv 단편인 scFv 단편을 지칭하며; 서열번호 1 내지 서열번호 6으로 이루어지는 군으로부터 선택된, 본 발명에 기술된 항체의 하나 이상의 CDR 영역을 포함한다. Fv 단편은 불변 영역 없이, 중쇄가변영역 및 경쇄가변영역을 포함하며, 모든 항원-결합 자리를 보유하는 최소 항체 단편이다.
본 명세서에서 사용하는 용어, "항체"는 두 개의 동일한 중쇄와 두 개의 동일한 경쇄 사이의 이황화 결합에 의해 서로 연결된 네 개의 펩티드 사슬 구조인 면역글로불린을 지칭한다. 상이한 면역글로불린 중쇄 불변 영역은 상이한 아미노산 조성 및 순서를 나타내므로, 상이한 유형의 항원성을 보유한다. 따라서, 면역글로불린은 다섯 가지 카테고리로 분류될 수 있거나, 면역글로불린 이소형, 즉, IgM, IgD, IgG, IgA 및 IgE로 지칭될 수 있고, 상응하는 중쇄는 각각 μ 사슬, δ 사슬, γ 사슬, α 사슬 및 ε 사슬이다. 힌지 영역의 아미노산 조성 및 중쇄 이황화 결합의 수와 위치에 따라, 동일한 유형의 Ig는 상이한 하위 유형으로 분류될 수 있다. 예를 들어, IgG는 IgG1, IgG2, IgG3, 및 IgG4로 분류될 수 있다. 경쇄는 상이한 불변 영역에 따라 κ 또는 λ 사슬로 분류될 수 있다. 다섯 가지 유형의 IgG 각각은 κ 또는 λ 사슬을 가질 수 있다. 바람직하게는, 상기 항체는 κ 사슬을 가질 수 있다.
일 실시예에 따르면, 본 발명의 항 PCSK9 항체 또는 이의 항원-결합 단편은 경쇄가변영역(LCVR)을 포함하고, 여기서 상기 LCVR는 상보성 결정 영역(CDR) LCRD1, LCDR2 및 LCDR3을 포함하고, LCRD1, LCDR2 및 LCDR3은 각각 서열번호 1, 2 및 3로 이루어진 그룹으로부터 선택된 아미노산 서열과 적어도 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 또는 99% 동일성 또는 100% 동일성을 갖는 아미노산 서열을 포함하거나 이들로 이루어질 수 있다. 바람직하게, 상기 LCRD1, LCDR2 및 LCDR3은 각각 서열번호 1, 2 및 3의 아미노산 서열을 가질 수 있다.
일 실시예에 따르면, 본 발명의 항 PCSK9 항체 또는 이의 항원-결합 단편은 중쇄가변영역(HCVR)을 포함하고, 여기서 상기 HCVR는 상보성 결정 영역(CDR) HCRD1, HCDR2 및 HCDR3을 포함하고, HCRD1, HCDR2 및 HCDR3은 각각 서열번호 4, 5 및 6으로 이루어진 그룹으로부터 선택된 아미노산 서열과 적어도 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 또는 99% 동일성 또는 100% 동일성을 갖는 아미노산 서열을 포함하거나 이들로 이루어질 수 있다. 바람직하게, 상기 HCRD1, HCDR2 및 HCDR3은 각각 서열번호 4, 5 및 6의 아미노산 서열을 가질 수 있다.
본 발명에서 사용하는 용어, "인간화 항체"는 비-인간 초가변영역(HVR)로부터의 아미노산 잔기 및 인간 프레임워크(FR)로부터의 아미노산 잔기를 포함하는 키메라 항체를 지칭한다. 특정 실시양태에서, 인간화 항체는 적어도 1개, 전형적으로 2개의 가변 도메인을 실질적으로 모두 포함하고, 여기서 실질적으로 모든 초가변영역(예를 들어, CDR)은 비-인간 항체의 것에 상응하고, 실질적으로 모든 프레임 워크 영역(FR)은 인간 항체의 것에 상응한다. 인간화 항체는 임의로 인간 항체로부터 유래된 항체 불변 영역의 적어도 일부를 포함할 수 있다. 예를 들어 비-인간 항체의 "인간화 형태"는 인간화를 겪은 항체를 지칭한다.
항
PCSK9 항체의 용도
본 발명의 또 다른 측면은, 상기 항체를 유효성분으로 포함하는 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물을 제공하는 것이다.
이때, 상기 콜레스테롤 관련 질환은 고콜레스테롤혈증, 고지혈증, 죽상경화성 심혈관질환(ACVD), 급성관상동맥증후군(ACS), 고혈압, 당뇨병, 뇌졸중, 알츠하이머 및 이상지질혈증으로 이루어진 군에서 선택되는 어느 하나인 것일 수 있다.
본 발명의 약학 조성물은 유효성분으로서 상기 항체를 조성물의 총 중량을 기준으로 약 0.1 중량% 내지 약 90 중량%, 구체적으로 약 0.5 중량% 내지 약 75 중량%, 보다 구체적으로 약 1 중량% 내지 약 50 중량%로 함유할 수 있다.
본 발명의 약학 조성물은, 통상적인 방법에 따라 제제로 배합되는 통상적이고 무독성인 약학적으로 허용가능한 첨가제를 포함할 수 있다. 예를 들어, 상기 약학 조성물은 약학적으로 허용되는 담체, 희석제 또는 부형제를 추가로 포함할 수 있다.
본 발명의 조성물에 사용되는 첨가제의 예는 감미제, 결합제, 용매, 용해 보조제, 습윤제, 유화제, 등장화제, 흡수제, 붕해제, 산화방지제, 보존제, 윤활제, 활택제, 충전제 등을 포함할 수 있다.
본 발명의 조성물은 비경구 투여(예컨대, 근육내, 정맥내 또는 피하 주사)를 위한 다양한 제제 형태로 배합될 수 있다.
또한, 비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61. 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.
본 발명의 항체 또는 조성물은 치료학적으로 유효한 양 또는 약학적으로 유효한 양으로 환자에 투여될 수 있다.
여기서 "치료학적으로 유효한 양" 또는 "약학적으로 유효한 양"이란 대상 질환을 예방 또는 치료하는데 유효한 항체 또는 조성물의 양으로서, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미한다. 상기 유효량의 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.
본 발명의 항체 또는 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 최소한의 부작용으로 또는 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
구체적으로, 본 발명의 조성물에서 항체의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 kg 당 약 0.1 mg 내지 약 1,000 mg, 또는 약 5 mg 내지 약 200 mg을 매일 또는 격일 투여하거나 1일 1회 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로, 본 발명의 범위는 이에 한정되지 않는다.
본 발명의 항원은 BST PM1 Ag을 코딩하는 DNA를 합성한 후 발현 벡터 pGEX 4T1에 클로닝 완료하였다. 또한, 상기 벡터를 대장균에 형질전환 한 후, IPTG를 넣어주어 BST PM1 Ag의 발현을 유도하였다. GST tag이 같이 융합된 형태로 발현된 BST PM1 Ag을 GST affinity chromatography로 일차로 정제하였다. 그 후, 2차적으로 Ion chromatography(DEAE)에서 목적 단백질을 용출하였다. 마지막으로 Size exclusion chromatography(SEC)를 진행하여 최종적으로 면역에 사용할 단백질을 준비하였다.
본 발명의 하이브리도마 생산을 위해, 마우스 면역 동물을 이용하여 면역을 실시하였다. 그 후, 상기 동물에서 얻은 세포 및 NS0 세포와 결합시켜 하이브리도마 세포를 제조하였다. Human PCSK9, BST PM1 Ag, GST 단백질을 사용하여 ELISA 스크리닝으로 Human PCSK9, BST PM1 Ag에는 잘 결합하지만 GST 단백질에 결합하지 않는 하이브리도마 세포를 선택적으로 분류하였다. 그 후, 선택된 3종의 하이브리도마 세포를 무혈청 배지 조건으로 적응시킨 후 적정 세포를 넣어주어 배양을 완료하였다. 항체 정제는 Protein G column을 사용하였고 산성의 용출 용액으로 용출 후 PBS로 투석하여 항체 준비를 완료하였다. 준비된 항체의 기능적인 효과를 입증하고자 LDLR와 PCSK9의 결합을 억제시켜 세포가 LDL의 흡수를 증가시키는 실험을 통해 항 PCSK9 항체를 선별하였다.
본 발명은 최종후보 항 PCSK9 항체 3종 9G8, 4B10, 7D1 Mab를 사용하여 실험을 진행하였다. Human PCSK9, BST PM1 Ag으로 결합력을 측정 결과 4B10이 가장 높았으며 9G8 그리고 7D1 순이였다. 하지만 항체의 기능적인 효과 실험을 진행한 결과 7D1 Mab이 LDLR과 PCSK9의 결합을 억제하는 정도가 가장 높아 최종적으로 선택하였다. 선택된 항 PCSK9 항체인 7D1 Mab이 PCSK9의 단편 내의 에피토프에 결합하는 부위를 Linear Epitope Mapping 방법을 사용하여 7D1 Mab와 Human PCSK9 항원의 결합부위를 확인하였다.
또한, 스크리닝을 통해 7D1 Mab의 경쇄/중쇄 상보 결정 영역을 확인하였고, 인간화가 완료된 가변영역서열을 확인하였다. 상기 특이적으로 PCSK9에 결합하는 단일클론 항체는 HCDR1, HCDR2 및 HCDR3 시퀀스의 중쇄가변영역 및 LCDR1, LCDR2 및 LCDR3 시퀀스를 함유한 경쇄가변영역을 포함하고, 상기 경쇄가변영역의 LCDR1 시퀀스는 KSSQSLLDSDGKTYLN(서열번호 1), LCDR2 시퀀스는 LVSKLDS(서열번호 2), LCDR3 시퀀스는 WQGTHFPQT(서열번호 3)의 아미노산 서열을 가진다. 또한, 상기 중쇄가변영역의 HCDR1 시퀀스는 DYYMH(서열번호 4), HCDR2 시퀀스는 YIDPENGDTEYAPKFQG(서열번호 5), HCDR3 시퀀스는 SPFTY(서열번호 6)의 아미노산 서열을 가진다(표 1).
LCDR1 | LCDR2 | LCDR3 |
서열번호 1 | 서열번호 2 | 서열번호 3 |
KSSQSLLDSDGKTYLN | LVSKLDS | WQGTHFPQT |
HCDR1 | HCDR1 | HCDR1 |
서열번호 4 | 서열번호 5 | 서열번호 6 |
DYYMH | YIDPENGDTEYAPKFQG | SPFTY |
PCSK9 Ag 에피토프 서열 위치 | 아미노산 서열 | |
서열번호 27 | 209 - 218 | PEEDGTRFHR |
PCSK9 아미노산 서열 위치 | 아미노산 서열 | ||
1 | 서열번호 28 | 68 - 82 | AKDPWRLPGTYVVVL |
2 | 서열번호 29 | 150 - 152 | FAQ |
3 | 서열번호 30 | 255 - 258 | CQGK |
4 | 서열번호 31 | 317 - 318 | NF |
5 | 서열번호 32 | 348 - 353 | LGTLGT |
6 | 서열번호 33 | 380 - 384 | VSQSG |
7 | 서열번호 34 | 431 - 440 | EDQRVLTPNL |
8 | 서열번호 35 | 457 - 463 | CRTVWSA |
9 | 서열번호 36 | 477 - 480 | CAPD |
10 | 서열번호 37 | 574 - 582 | HKPPVLRPR |
11 | 서열번호 38 | 662 - 673 | STTGSTSEGAVT |
서열번호 49: PCSK9 아미노산 서열
MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGTTATFHRC AKDPWRLPGTYVVVL KEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLPGFLVKMSGDLLELALKLPHVDYIEEDSSV FAQ SIPWNLERITPPRYRADEYQPPDGGSLVEVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAGVAKGASMRSLRVLN CQGK GTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAACQRLARAGVVLVTAAG NF RDDACLYSPASAPEVITVGATNAQDQPVT LGTLGT NFGRCVDLFAPGEDIIGASSDCSTCF VSQSG TSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSAKDVINEAWFP EDQRVLTPNL VAALPPSTHGAGWQLF CRTVWSA HSGPTRMATAVARCAPDEELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAPPAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGT HKPPVLRPR GQPNQCVGHREASIHASCCHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRDV STTGSTSEGAVT AVAICCRSRHLAQASQELQA
서열번호 50: PCSK9 단편
MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGTTATFHRCKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLPGFLVKMSGDLLELALKLPHVDYIEEDSSVSIPWNLERITPPRYRADEYQPPDGGSLVEVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAGVAKGASMRSLRVLNGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAACQRLARAGVVLVTAAGRDDACLYSPASAPEVITVGATNAQDQPVTNFGRCVDLFAPGEDIIGASSDCSTCFTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSAKDVINEAWFPVAALPPSTHGAGWQLFHSGPTRMATAVAREELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAPPAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTGQPNQCVGHREASIHASCCHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRDVAVAICCRSRHLAQASQELQA
서열번호 57: GST-PCSK9 amino acid sequence
MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRGSQEDEDGDYEELVLALRSEEDGLAEAPEHGTTATFHRCKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLPGFLVKMSGDLLELALKLPHVDYIEEDSSVSIPWNLERITPPRYRADEYQPPDGGSLVEVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAGVAKGASMRSLRVLNGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAACQRLARAGVVLVTAAGRDDACLYSPASAPEVITVGATNAQDQPVTNFGRCVDLFAPGIIGASSDCSTCFTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSAKDVINEAWFPVAALPPSTHGAGWQLFHSGPT RMATAIAREELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAPPAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTGQPNQCVGHREASIHASCCHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRDVAVAICCRSRHLAQASQELQ
GST-PCSK9 -> pI/Mw: 5.94 / 90 kDa
PCSK9 -> pI/Mw: 5.89 / 62.6kDa
서열번호 58: GST-PCSK9 DNA sequence
atgtcccctatactaggttattggaaaattaagggccttgtgcaacccactcgacttcttttggaatatcttgaagaaaaatatgaagagcatttgtatgagcgcgatgaaggtgataaatggcgaaacaaaaagtttgaattgggtttggagtttcccaatcttccttattatattgatggtgatgttaaattaacacagtctatggccatcatacgttatatagctgacaagcacaacatgttgggtggttgtccaaaagagcgtgcagagatttcaatgcttgaaggagcggttttggatattagatacggtgtttcgagaattgcatatagtaaagactttgaaactctcaaagttgattttcttagcaagctacctgaaatgctgaaaatgttcgaagatcgtttatgtcataaaacatatttaaatggtgatcatgtaacccatcctgacttcatgttgtatgacgctcttgatgttgttttatacatggacccaatgtgcctggatgcgttcccaaaattagtttgttttaaaaaacgtattgaagctatcccacaaattgataagtacttgaaatccagcaagtatatagcatggcctttgc agggctggcaagccacgtttggtggtggcgaccatcctccaaaatcggatctggttccgcgtggatcccaagaagatgaagatggtgattatgaggaactggtgctggcgctgcgtagcgaagaggacggtctggcggaggcgccggaacacggtaccaccgcgaccttccaccgttgcaaagaggaaacccacctgagccagagcgaacgtaccgcgcgtcgtctgcaagcgcaagcggcgcgtcgtggctacctgaccaaaatcctgcacgtgttccacggtctgctgccgggctttctggttaagatgagcggtgacctgctggagctggcgctgaaactgccgcacgtggactatattgaggaagatagcagcgttagcatcccgtggaacctggagcgtattaccccgccgcgttaccgtgcggacgaatatcagccgccggatggtggtagcctggttgaggtgtacctgctggacaccagcatccaaagcgatcaccgtgagattgaaggtcgtgtgatggttaccgacttcgaaaacgtgccggaggaagatggcacccgttttcaccgtcaggcgagcaaatgcgacagccacggcacccatctggcgggtgtggttagcggccgtgatgcgggtgttgcgaaaggcgcgagcatgcgtagcctgcgtgtgctgaacggcaccgtgagcggcaccctgatcggtctggagttcattcgtaagagccagctggtgcaaccggttggtccgctggttgtgctgctgccgctggcgggtggctacagccgtgtgctgaacgcggcgtgccagcgtctggcgcgtgcgggcgtggttctggttaccgcggcgggtcgtgatgatgcgtgcctgtatagcccggcgagcgcgccggaagtgatcaccgttggtgcgaccaacgcgcaggaccaaccggtgaccaactttggtcgttgcgtggacctgttcgcgccgggtatcattggcgcgagcagcgactgcagcacctgctttaccagccaagctgcggcgcatgttgcgggtattgcggcgatgatgctgagcgcggagccggaactgaccctggcggaactgcgtcaacgtctgatccacttcagcgcgaaagatgtgattaacgaggcgtggtttccggttgcggcgctgccgccgagcacccacggtgcgggttggcagctgtttcatagcggtccgacccgtatggcgaccgcgattgcgcgtgaggaactgctgagctgcagcagctttagccgtagcggcaagcgtcgtggtgagcgtatggaagcgcagggtggcaaactggtgtgccgtgcgcacaacgcgtttggtggcgaaggcgtttacgcgattgcgcgttgctgcctgctgccgcaagcgaactgcagcgtgcacaccgctccgccggcggaggcgagcatgggcacccgtgtgcactgccaccagcaaggccacgttctgaccggttgcagcagccactgggaagtggaagatctgggcaccggccagccgaaccaatg cgttggtcaccgtgaagcgagcattcatgcgagctgctgccatgcgccgggcctggagtgcaaggttaaagaacacggtattccggcgccgcaggagcaagtgaccgttgcgtgcgaggaaggctggaccctgaccggttgcagcgcgctgccgggcaccagccacgtgctgggtgcgtatgcggttgacaacacctgcgtggttcgtagccgtgatgtggcggtggcgatctgctgccgtagccgtcatctggcgcaagcgagccaagaactgcaa
Amino acid sequence | |
IGHV1-2*02/IGHJ4*03 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARYFDYWGQGTLVTVSS (서열번호 39) |
IGKV2-30*01/IGKJ4*2 | DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPLTFGGGTKVEIK (서열번호 40) |
구분 | Amino acid sequence |
ch7D1 VH
(서열번호 15) |
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
ch7D1 VL
(서열번호 17) |
DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
hz7D1.11 VH
(서열번호 19) |
QVQLVQSGAEVKKPGASVKVSCKASGFNIKDYYMHWVRQAPGQGLEWIGYIDPENGDTEYAPKFQGRATMTADTSISTAYMELSRLRSDDTAVYYCRSSPFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
hz7D11.11 VL
(서열번호 21) |
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPQTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
hz7D1.22 VH
(서열번호 23) |
QVQLVQSGAEVKKPGASVKVSCKASGYTFKDYYMHWVRQAPGQGLEWMGYIDPENGDTEYAPKFQGRVTMTADTSISTAYMELSRLRSDDTAVYYCRSSPFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
hz7D11.22 VL
(서열번호 25) |
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWFQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPQTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
* Under bar: CDRs defined by Kabat numbering
이하, 본원 발명을 하기 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예는 본원 발명을 예시하기 위한 것일 뿐, 본원 발명의 범위가 이들만으로 한정되는 것은 아니다.
실시예 1. 원핵세포를 이용한 BST PM1 Ag의 클로닝 및 단백질 정제
실시예 1.1. BST PM1 유전자의 PCR 산물의 pGEX4T-1 vector 클로닝
Genescript에서 합성한 BST PM1 유전자와 pGEX4T-1 vector를 절단(Ligation) 하기 위해 동일한 2가지 제한 효소(BamH1 및 EcoR1)로 각각 37℃, 14시간 절단을 진행하였다. 1% 아가로스 젤(Agarose gel)에 제한 효소로 절단된 벡터(Vector)와 절단된 BST PM1 유전자를 로딩하여 밴드를 확인한 후 Gel extraction을 진행하여 제한 효소 처리 완료된 Vector와 절단된 BST PM1 유전자를 준비하였다. pGEX4T-1 vector 2 ul, BST PM1 6 ul, 10X buffer 1 ul, T4 DNA ligase(Biofact, korea) 1 ul를 혼합하여 4℃, 12시간동안 라이게이션(Ligation)을 실시하였다.
라이게이션 후 대장균 DH5α에 형질 전환하였고 Ampicillin(100 ug/ml)이 포함된 Luria-Bertani(LB) agar배지에 도말하여 콜로니를 선별하였다. 그 후, 유전자가 제대로 삽입되었는지 확인하기 위해 콜로니를 LB 배지에 접종하여 배양 후 원심분리기를 사용하여 셀을 수확하였다. HiGene plasmid MiniPrpep kit(Biofact, korea)를 이용하여 재조합 플라스미드를 분리하였고, 제한 효소(BamH1/EcoR1)로 처리한 결과 BST PM1 유전자의 DNA 밴드와 pGEX4T-1 vector 밴드가 확인되었다. PCSK9 original antigen과 BST PM1 antigen은 서열의 차이가 있고 그 차이를 Sequence alignment로 비교하였으며, 그 결과를 도 1c에 나타내었다(도 1c).
실시예 1.2. 재조합 단백질 발현 및 정제
BST PM1의 발현을 확인하기 위해서 E.coli BL21(DE3) 세포에 형질전환 후 Ampicillin(100 ug/ml) 포함된 Luria-Bertani(LB) agar 배지에 도말하여 콜로니를 생성하였다. 그 후, 콜로니에서 세포를 수득하여 50 ml Luria-Bertani(LB) 배지에 접종한 후, 37℃, 12시간 배양하였다. Ampicillin(100 ug/ml)이 포함된 LB 배지 5 L에 접종한 셀 배양액 50 ml을 넣고 OD600 값이 0.5 ~ 0.6 사이가 될 때까지 배양한 후 IPTG(Isopropyl-β-D-thio-galactoside)를 0.5 mM 농도로 배지에 첨가한 후, 18℃에서 16시간 추가로 배양하였다.
발현된 세포를 원심분리(6,000 rpm, 30분, 4℃)하여 세포를 수확한 후, 용해 완충액 lysis buffer PBS(Phosphate Buffered Saline), 0.2 mM PMSF, 0.1% Triton X 100 pH 7.4] 50 ml에 풀어준 후 초음파 분쇄를 15회(60초/1회) 실시하였다. 파쇄한 세포는 원심분리(13,000 rpm, 30분, 4℃)를 실시하여 수용성 세포 용해액과 불용성 세포 펠렛으로 분리하였다. 그 후, 수용성 세포 용해액(50 ml)을 0.45 μm syringe 필터기로 필터를 진행 후, lysis buffer로 평형화를 마친 5 ml GST Trap FF affinity column(GE Healthcare)에 1 ml/min이 되도록 로딩하였다.
비특이적으로 결합한 단백질을 제거하기 위해 컬럼 부피의 10 CV(column volume)의 lysis buffer를 2 ml/min으로 수행하여 충분히 세척한 후 단백질 샘플은 용출(Elution buffer) 버퍼(PBS, 10 mM Glutathione, pH 7.4)를 사용하여 선형 구배(linear gradient) 1 ml/min으로 용출 시켰다. DEAE column을 진행하기 위해 Lysis buffer(20 mM sodium phosphate, pH 7.4)로 dialysis 후 1 ml HighTrap DEAE FF column(GE Healthcare)에 1 ml/min로 로딩하였다.
목적 단백질은 DEAE flow-through에서 확인되었고 SEC(Size exclusion chromatography)를 통해 다시 분리하였다. 완충액 PBS(Phosphate Buffered Saline), pH 7.4, 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM KH2PO4로 평형화된 Hiprep 26/60 Sephacryl S-200 HR(GE Healthcare)에 0.5 ml/min으로 로딩하였다. 3 단계의 column work을 진행하였고 분리 과정 동안의 FPLC chromatography와 BST PM1 Ag은 12% SDS PAGE gel을 사용하여 확인하였다.
실시예 2. BST PM1 Ag 및 PCSK9 다클론항체을 이용한 웨스턴 블롯
정제된 BST PM1 Ag이 PCSK9 다클론 항체와 결합하는지 확인하기 위해, BST PM1 Ag 1 ug과 control Ag(PCSK9 (Human) recombinant protein, abnova사 Cat No: H00255738-P01) 1 ug을 10% SDS PAGE에 로딩 후 0.45 μm PVDF membrane에 transfer를 진행하였다. 5% skim milk in PBST(pH 7.4)에 옮긴 후 2시간 동안 실온에서 차단시킨 후, 세척 용액(PBST)으로 3회 세척 진행하였고, PCSK9 polyclonal antibody(Abnova사, Cat No: PAB17045)를 1 : 1,000으로 희석 후 1시간 동안 실온에서 웨스턴 블롯을 진행하였다.
세척 용액으로 3회 세척 후 Goat anti Rabbit IgG HRP(산타 크루즈 바이오테크놀러지)를 1 : 2,500 희석 후, 실온에서 1시간 인큐베이션 하고, 세척 용액으로 3회 세척 후 ECL 플러스 키트를 사용하여 BST PM1 Ag, PCSK9 control antigen의 밴드를 확인하였다(도 2).
실시예 3. 항-PCSK9 마우스 항체 및 하이브리도마 생성
BST PM1 항원을 마우스(BALB/c)에 Adjuvant(Sigma, Cat No: T2684)와 혼합하여 주사하고 생쥐의 혈액을 채취하여 항체 생성 여부를 ELISA로 확인하였다. 2회 면역 후 항체의 역가(1:5,000)가 적정하게 증가하여 면역된 생쥐에서 비장을 떼어내어 B 림프구를 분리하였다. 그 후, 배양한 골수종(Myeloma) 세포(sp2/0)와 융합시킨 후 융합된 세포를 hypoxanthin, Aminopterine 및 Thymidine이 첨가되어 있는 배지(HAT medium)에서 배양하여 골수종(Myeloma)과 B 림프구만이 융합된 세포(Hybridoma)를 선택적으로 선별하여 배양하였다.
B 림프구는 정상세포이므로 장기간 배양시 죽어나가나, 골수종(Myeloma) 세포는 형질 전환된 세포이므로, 하이브리도마는 HAT에서 선택적으로 선별된다. 수득된 Hybridoma 세포 중에서 항원과 반응하는 항체를 생산하는 세포를 ELISA법을 이용하여 확인하였다. ELISA 양성반응인 세포를 한계희석법(Limiting dilution method)을 이용하였다. 양성세포와 음성세포를 분리하는 과정을 반복하여 항원에 반응하는 항체를 생산하는 단일클론세포를 생산하였다.
실시예 4. 항-PCSK9 항체의 스크리닝
실시예 4.1. 1차 스크리닝
생성된 수많은 단일클론하이브리도마 세포에서 면역에 사용한 BST PM1 Ag과 결합하고 GST tag과 결합하지 않는 클론을 아래의 프로토콜을 사용하여 ELISA 분석을 통해 1차 선별하였다. 96웰 플레이트(코닝 라이프 사이언시스)에 0.2 M sodium carbonate pH 9.5에 희석한 BST PM1 Ag과 GST tag를 100 ng/well로 넣어 후 4℃에서 밤새 인큐베이팅 하여 코팅하였다. 이어서, 플레이트를 세척 용액 PBS pH7.4를 사용하여 3회 세척 후 플레이트를 5% skim milk in PBST(pH 7.4) 200 ul, 1시간 실온에서 인큐베이션 하였다.
플레이트를 3회 세척 후 단일클론하이브리도마 세포 배양액을 50 ul/well 넣어준 후 1시간 실온에서 인큐베이션 후 3회 세척 진행하였다. 1:10,000 농도의 염소 항-마우스 IgG-HRP, 100 ul/well를 플레이트에 첨가하고, 1시간 동안 실온에서 인큐베이션 하였다. 플레이트를 3회 세척 후 TMB 용액을 100 ul/well 첨가하여 20분 실온에서 반응시키고 1N 염산 100 ul/well 넣어주어 10분 후에 실온에서 수행하였다. Perkinelmer Victor X3 플레이트 판독기를 사용하여 450 nm에서 즉시 판독하였다. GST tag에는 결합하지 않고 BST PM1 Ag과 ELISA 결과값을 토대로 69개의 클론을 확인하였고 도 3a에 도식하였다(도 3a).
실시예 4.2. 2차 스크리닝
ELISA 스크리닝을 통해 1차 선별된 단일클론하이브리도마 세포를 96웰 플레이트(코닝 라이프 사이언시스)에 0.2 M sodium carbonate, pH 9.5에 희석한 1) BST PM1 Ag, 2) BST PM1 GST tag 제거, 3) PCSK9 original, 4) GST tag을 100 ng/well로 넣어준 후 4℃에서 밤새 인큐베이션 하여 코팅하였다. 이어서, 플레이트를 세척 용액 PBS pH 7.4를 사용하여 3회 세척 후 플레이트를 5% skim milk in PBST(pH 7.4) 200 ul, 1시간 동안 실온에서 인큐베이션 하였다.
플레이트를 3회 세척 후 단일클론하이브리도마 배양액을 50 ul/well 넣어준 후, 1시간 실온에서 인큐베이션 후 3회 동안 세척을 진행하였다. 1:10,000 농도의 염소 항-마우스 IgG-HRP 100 ul/well를 플레이트에 첨가하고, 1시간 동안 실온에서 인큐베이션 하였다. 플레이트를 3회 세척 후, TMB 용액을 100 ul/well 첨가하여 20분 실온에서 반응시켰다. 그 후, 1N 염산 100 ul/well 넣어주어 10분 후에 실온에서 수행하였다. Perkinelmer Victor X3 플레이트 판독기를 사용하여 450 nm에서 즉시 판독하였다. 1차 선별된 69개의 클론에서 GST tag에 결합하지 않고 나머지 단백질에 모두 결합하는 20개의 클론을 선별한 결과를 도 3b에 도식하였다(도 3b).
실시예 4.3. 유동세포계측법(FACS)을 이용한 선별된 8개 클론의 결합 확인
2차 스크리닝으로 선별된 20개의 하이브리도마 세포 배양액을 사용하여 HepG2 cell을 FACS 분석하였다. Flask에서 배양한 HepG2 세포를 Tripsin-EDTA를 처리하여 떼어낸 다음 1,000 rpm, 3 min 원심분리하여 세포를 수득하였다. 미디어를 제거한 다음 3% FBS가 들어 있는 PBS(3% FBS/PBS)를 처리하여 세포를 세척한 후, 1,000 rpm, 3 min 원심분리하여 세포를 수득하였다. 1x105 세포에 BST-PM1 하이브리도마 세포 배양액 1 mL을 처리한 후 얼음에서 1시간 동안 인큐베이션 하였다.
1,000 rpm, 3 min 원심분리하여 세포를 수득한 다음 3% FBS/PBS를 처리하여 세포를 세척한 후, 1,000 rpm, 3 min 원심분리하여 세포를 수득하였다. Anti-mouse IgG FITC를 3% FBS/PBS에 1:100으로 희석 후 1 mL을 수득한 세포에 처리한 다음 얼음에서 1시간 동안 인큐베이션 하였다. 1,000 rpm, 3 min 원심분리하여 세포를 수득한 다음 3% FBS/PBS를 처리하여 세포를 재현탁한 다음 Beckman Coulter 장비(CYTOMICS FC 500)를 이용하여 FACS 분석을 하였다.
HepG2 세포와 Mouse 2nd control은 MFI 1.0 이하로 유사하게 관찰되었으나 20개의 하이브리도마 배양액을 이용한 분석 결과에서 8개의 클론이 결합한 것을 확인하였고, MFI 값을 비교한 결과 9G8, 4B10의 MFI값이 1.8까지 측정되어 가장 결합력이 높았고 도 4a에 FACS 결과와 MFI 값을 나타내었다. 또한 8종의 항 PCSK9 항체의 Isotype을 확인하였고 각 Type을 도 4b에 나타내었다(도 4a 및 도 4b).
실시예 5. 9G8, 4B10, 7D1 하이브리도마로부터 항체 제조
실시예 5.1. Serum free media에서 적응 배양
선택된 3가지 하이브리도마 세포(9G8, 4B10, 7D1)는 10% FBS가 있는 상태에서 배양되었다. FBS가 없는, 혹은 적은 상태의 배지에서 세포를 성장시키기 위해 배지 적응을 단계적으로 진행하였다. 무혈청 배지(SFM (Serum free media), Thermo fisher Cat No: 12045076)를 사용하였고, 단계적으로 FBS 농도를 낮춰주며 세포가 적응할 수 있도록 배양하였다. 1) DMEM 10% FBS 배지 75% + SFM 25%, 2) DMEM 10% FBS 배지 50% + SFM 50%, 3) DMEM 10% FBS 배지 25% + SFM 75%, 4) DMEM 10% FBS 배지 90% + SFM 10%, 4) SFM 100% 각 단계를 진행할 때 세포의 증식을 3회 진행하여 성장을 확인한 후 다음 단계로 넘어가 무혈청 배지로의 세포 적응을 완료하였다.
실시예 5.2. 하이브리도마로부터 9G8, 4B10, 7D1 항체 정제
무혈청 배지로 적응이 완료된 3종의 하이브리도마 세포주로부터 정제하는 방법을 설명한다. 9G8, 4B10, 7D1 하이브리도마 세포 2X106 개를 75T 플라스크 10 ml의 무혈청 배지에서 배양시켜 세포를 증식시킨다. 배양된 세포를 파이펫팅으로 잘 떼어낸 후 1,200 rpm, 3분, 상온에서 원심분리하여 세포를 모아준 후 세포수를 측정하여 1X105 세포/ml 들어가도록 삼각플라스크에 넣고 100 ml 무혈청 배지를 넣어주어 세포를 배양(1X107) 하였다. 37℃, 5% CO2, 100 rpm으로 인큐베이션 하여 8일 동안 배양하였다.
8일간 세포 배양 후, 3,000 rpm, 15분, 상온에서 원심분리하여 세포 및 파쇄물을 제거하고 상등액을 0.22 ㎛ 필터로 여과하였다. 평형화 용액(PBS pH 7.4)으로 Hitrap protein G HP 5 ml(GE healthcare)를 충분히 흘려준 후 여과된 배양액을 Hitrap protein G HP 5 ml(GE healthcare) 컬럼에 로딩하였다. 비특이적 결합은 PBS로 충분히 세척하여 제거한 후 결합된 항체 단백질은 항체 용출 용액(0.1M Glycine, pH 2.8)을 사용하여 회수하였다. 회수 후 즉시 1.5 M, Tris pH 9.0를 전체 볼륨의 1/10 만큼 넣어주어 pH를 중성화하였다. 마지막으로 10 kDa 투석막을 사용하여 PBS pH 7.4 용액으로 투석을 진행하였고, 정제 과정 동안의 Protein G chromatography 및 항체 확인은 12% SDS PAGE gel을 사용하였다. 그 결과를 도 5에 나타내었다(도 5).
실시예 6. PCSK9 Ag과 9G8, 4B10, 7D1 Mab의 결합 확인 : 웨스턴블랏
정제된 3종의 9G8, 4B10, 7D1 Mab(단클론항체)가 PCSK9 Ag과 결합하는지 확인하기 위해 웨스턴블랏으로 확인하였다. PCSK9 Ag(Human PCSK9 protein, Acro사 Cat No: PC9-H5223) 1 ug을 10% SDS PAGE에 로딩 후 0.45 μm PVDF membrane에 Transfer을 진행하였다. 5% skim milk가 포함된 PBST(pH 7.4)에 옮긴 후, 2시간 동안 실온에서 차단시켰다. 세척 용액(PBST)로 3회 세척 진행 하였다. 3종의 9G8, 4B10, 7D1 Mab를 정량하여 1 ug을 1 : 1,000으로 PBST에 희석 후 1시간 동안 실온에서 인큐베이션 하였다.
세척 용액으로 3회 세척 후 Goat anti Mouse IgG HRP(산타 크루즈 바이오테크놀러지)를 5% skim milk가 포함된 PBST(pH 7.4)에 1 : 2,500으로 희석하였다. 실온에서 1시간 인큐베이션 후, 세척 용액으로 3회 세척하고 ECL 플러스 키트를 사용하여 도 6에 도시된 바와 같이 정제된 정제된 3종의 9G8, 4B10, 7D1 Mab와 PCSK9 Ag의 결합된 밴드를 확인 하였다. 결합력의 세기는 4B10이 가장 높았으며, 다음으로 9G8이었고, 7D1이 낮았다(도 6).
실시예 7. PCSK9 Ag과 9G8, 4B10, 7D1 Mab 결합 확인 : ELISA
정제된 3종의 9G8, 4B10, 7D1 Mab가 PCSK9 Ag과 결합하는지 확인하기 위해 ELISA로 확인하였다. 96웰 플레이트(코닝 라이프 사이언시스)에 0.2 M sodium carbonate pH 9.5에 PCSK9 original(PCSK9 (human) recombinant protein, abnova사 Cat No: H00255738-P01)을 2 ug/ml로 희석하였다. 그 후, 절반씩 희석시킨 후, 100 ul/well로 넣었다. 4℃에서 밤새 인큐베이션하여 코팅하였다. 이어서, 플레이트를 세척 용액 PBS pH 7.4를 사용하여 3회 세척 후 플레이트를 5% skim milk가 포함된 PBS(pH 7.4) 200 ul, 1시간 실온에서 인큐베이션 하였다.
플레이트를 3회 세척 후 정제된 9G8, 4B10, 7D1 Mab를 정량하여 PBS pH 7.4에 1 ug/ml로 희석 후 각 well에 100 ul/well 넣어주었다. 1시간 실온에서 인큐베이션 후, 세척 용액 PBS pH 7.4를 사용하여 3회 세척을 진행하였다. 1:5,000 농도의 염소 항-마우스 IgG -HRP 100 ul/well를 플레이트에 첨가하고, 1시간 동안 실온에서 인큐베이션 하였다. 플레이트를 3회 세척 후 TMB 용액을 100 ul/well 첨가하여 20분 실온에서 반응시켰다. 1N 염산 100 ul/well을 첨가하고 10분 후에 실온에서 수행하였다. TECAN 플레이트 판독기를 사용하여 450 nm에서 즉시 판독하였다. 실시예 6의 웨스턴 블롯 결과와 동일하게 결합력의 세기는 4B10이 가장 높았으며 다음으로 9G8이였고, 7D1이 낮았다. 그 결과를 도 7에 나타내었다(도 7).
실시예 8. PCSK9과 LDLR 결합을 억제하기 위한 항 PCSK9 항체의 효능 실험
LDLR과 PCSK9 결합을 차단하는 항 PCSK9 항체의 효능을 확인하기 위해 ELISA를 진행하였다. 96웰 플레이트(코닝 라이프 사이언시스)에 0.2 M sodium carbonate pH 9.5에 Goat anti LDLR ab(R&D, Cat No:AF2148)를 2 ug/ml로 희석한 후 50 ul/well 첨가하였다. 4℃에서 밤새 인큐베이션 진행하여 코팅하였다. 이어서, 플레이트를 세척 용액 PBS pH 7.4를 사용하여 3회 세척 후 플레이트를 2% skim milk가 포함된 PBS(pH7.4) 200 ul에, 1시간 실온에서 인큐베이션 하였다.
플레이트를 3회 세척 후 LDLR(R&D, Cat No: 2148LD/CF)를 PBS pH 7.4에 0.4 ug/ml로 희석 후 50 ul/well 첨가하였다. 2시간 실온에서 인큐베이션하고 PBS pH 7.4에 100 ng/ml로 희석한 Biotinylated PCSK9 original과 정제된 9G8, 4B10, 7D1 Mab와 대조 Mab, Mouse IgG를 PBS pH 7.4에 1 ug/ml로 희석하였다. 그 후, 절반씩 희석시킨 후, 50 ul/well 첨가하였다. 섞어준 후 2시간 실온에서 인큐베이션 하였다. 세척 용액 PBS pH 7.4를 사용하여 3회 세척 진행 후 혼합물(100 ul/well)을 넣어주고 1시간 실온에서 인큐베이션 하였다.
LDLR과 결합된 Biotinylated-PCSK9를 검출하기 위해 1% skim milk가 포함된 PBS(pH 7.4)에 500 ng/ml로 희석한 Streptavidin-HRP를 50 ul/well 넣어주고, 1시간 실온에서 인큐베이션 하였다. 플레이트를 3회 세척 후 TMB 용액을 100 ul/well 첨가하여 20분 실온에서 반응시켰다. 1N 염산 100 ul/well를 넣어준 후, 10분 후에 실온에서 수행하였다. TECAN 플레이트 판독기를 사용하여 450 nm에서 즉시 판독하였다.
도 8에서 나타낸 바와 같이 PCSK9과 항 PCSK9 항체의 결합력에 비례하지 않고 7D1 Mab가 LDLR와 PCSK9의 결합력을 가장 많이 억제하는 결과를 확인하였다. 항 PCSK9 항체가 기능적으로 효과가 좋다면 항체의 양이 증가할 수록 PCSK9와 결합하여 LDLR에 결합하는 Biotinylated-PCSK9의 양이 줄어들어 흡광도(Absorbance) 값이 줄어드는 결과를 나타낼 것이다. 대조군으로 비교한 대조 Mab(암젠 레파타)와 비슷한 결과값을 나타내었고, Mab를 넣지 않은 것에 비해 억제가 되었음을 확인하였다(도 8)
실시예 9. 항 PCSK9 항체의 HepG2 세포 LDL 흡수 영향
항 PCSK9 항체가 PCSK9 Ag과 결합하여 LDLR의 감소를 억제하여 HepG2 세포로 LDL 흡수를 증가시키는지 확인하기 위해 ELISA 진행하였다. 96웰 플레이트(코스타, 3603)에 HepG2 세포를 10% FBS, DMEM 배지를 사용하여 1 X 105/well을 넣어주고 37℃, 5% CO2에서 밤새 인큐베이션 하였다. 다음날 DMEM 배지로 교체한 후 37℃, 5% CO2에서 밤새 인큐베이팅 하였다.
DMEM 배지에 2 ug/ml로 희석한 PCSK9 Ag을 50 ul/well 만들고 항 PCSK9 항체(9G8, 4B10, 7D1 Mab)를 다양한 농도로 희석하여 50 ul/well을 첨가하였다. PCSK9 Ag과 항 PCSK9 항체의 복합체를 만들기 위해 1시간 동안 실온에서 인큐베이팅 하였다. 플레이트를 세척 용액 PBS pH7.4를 사용하여 3회 세척하였다. PCSK9 Ag/항 PCSK9 항체 혼합물을 세포에 첨가하고, 바로 DMEM에 6 ug/ml의 최종 농도로 희석한 LDL BODIPY(인비트로젠, Cat No:L3483)을 50 ul/well 첨가하였다. 37℃, 5% CO2에서 밤새 인큐베이션 하였다. 플레이트를 3회 세척 후, 세포 형광 신호를 485(Ex)/535(Em)에서 TECAN SafireTM을 사용하여 검출하였다.
도 9에서 나타낸 바와 같이 HepG2 세포에서 발현된 LDLR가 PCSK9에 영향을 받지 않고 LDL과 결합하여 흡수된 LDL의 형광값은 약 260정도이고 항 PCSK9 항체를 넣어주지 않은 PCSK9만 넣어준 형광값은 80정도이다. 항 PCSK9 항체 9G8, 4B10, 7D1, 대조군 Mab(암젠 레파타)으로 비교한 결과 7D1 Mab의 PCSK9과 LDLR 결합 억제 정도가 가장 높았으며 대조군 Mab와 비슷한 결과값을 나타내었다(도 9).
실시예 10. m7D1 항 PCSK9 항체의 에피토프 매핑
최종적으로 선택된 7D1 항 PCSK9 항체와 결합하는 PCSK9 Ag의 결합부위를 확인하기 위해 PEPperMAP® Epitope Substitution Scans로 에피토프 매핑을 확인하였다. 695개 아미노산으로 구성된 PCSK9 Ag을 15개씩 잘라 선형의 펩타이드를 만들어 펩타이드와 펩타이드가 14개의 아미노산이 겹치도록 한 개의 아미노산 간격을 두고 겹치도록 Duplicate로 코팅하였다. 코팅된 플레이트에 7D1 하이브리도마 세포 배양액을 1 : 100, 1 : 1000으로 희석한 후 4℃, 16시간, 140 rpm 인큐베이션 하였다.
Goat anti-mouse IgG (H+L) DyLight680을 0.2 μg/ml 희석 후 플레이트에 첨가하고, 대조군 항체(Control antibody) 확인을 위해 Mouse monoclonal anti-HA DyLight800을 0.5 μg/ml 희석 후 45분간, 실온에서 인큐베이션 하였다. LI-COR Odyssey Imaging System을 사용하여 red = 700 nm/green = 800 nm로 검출하였다. 코팅된 PCSK9 Ag의 선형의 펩타이드와 결합한 7D1 항 PCSK9 항체를 확인함으로서, PCSK9 Ag의 에피토프 아미노산 서열을 확인하였고, 실험 결과를 도 10에 나타내었다(도 10).
실시예 11. m7D1 항 PCSK9 항체의 가변영역 서열 확인
7D1 Hybridoma cell line으로 부터 RNA 추출(RNA prep)을 진행한 다음, cDNA 합성 후에 경쇄(Light chain)와 중쇄(Heavy chain)의 Variable region gene을 PCR로 증폭하였다. PCR 증폭된 Light chain과 Heavy chain variable gene을 T-vector로 cloning 하였다. 서열 분석을 통해 경쇄와 중쇄 각각 1종류의 서열을 확인하였고 Kabat numbering 방법으로 CDR을 표시하였다.
서열이 확인된 7D1 클론의 항원 결합 여부를 확인하기 위하여 Fab construction cloning을 진행하였다. Fab은 서열 분석으로 확인된 7D1의 Variable region gene과 Reference constant region gene을 overlapping으로 연결한 다음 발현 벡터(Expression vector)에 클로닝하여 제작하였다. 7D1 Fab construct의 Periplasmic extract를 이용하여 ELISA를 진행하였다. 7D1 hybridoma 배양액과 Fab은 2차 항체가 다르므로 Signal의 차이가 있으며 Positive control은 7D1 hybridoma 배양액(2차 항체는 anti-mouse HRP)을 사용하였다. Negative control은 다른 항원에 결합하는 Fab(2차 항체는 anti-Fab HRP)을 사용하였다.
2종 항원(1.PCSK9 original, 2.BST PM1 Ag, 3. GST)을 이용하여 ELISA 실험을 진행한 결과, PCSK9 original과 BST PM1 Ag에 대해서는 7D1 Fab과 Positive control의 결합을 확인하였다. Background인 BSA 값 대비 PCSK9의 결합이 명확하여 Hybridoma sequencing 결과로 제작된 7D1 Fab은 PCSK9에 특이적인 항체로 판단하였다(도 11).
실시예 11. m7D1의 chimeric 항체 디자인
Humanization에 필요한 인간 항체를 서열을 확보하기 위해 항체 서열 데이터베이스인 IMGT(www.imgt.org)에서 서열 검색을 진행하였고, 검색 결과 m7D1 항체와 가장 유사한 인간항체 서열로 heavy chain은 IGHV1-2*02(75.69%) 와 IGKJ4*3 (79.17%)를 선정하였으며, light chain은 IGKV2-30*01(82.99%)과 IGHJ4*02 (80.56%)을 선정하였고(표 4), Homology는 nucleotide sequence를 기반으로 계산하였다.
실시예 12. m7D1 항 PCSK9 항체의 가변영역 서열 인간화 및 항체 생산
Mouse 유래에서 수득한 m7D1 항 PCSK9 항체의 가변영역 서열로부터 humanization된 가변영역 서열을 수득하였다. 선별된 인간 항체 서열에서 CDR 부위를 마우스 7D1 서열로 치환하여 ch7D1을 디자인 하였다. 디자인된 ch7D1 서열에서 frame work 부분에 해당하는 서열을 마우스 항체 서열로 back mutation 하는 방식으로 humanization을 진행하였으며, hz7D1 서열로 heavy chain 2 종(hz7D1.11 VH 와 hz7D1. 22 VH) 과 light chain 2 종(hz7D1.11 VL 및 hz7D1. 22 VL)을 디자인 하였다(표 5).
Heavy 및 Light chain의 humanized version 중에서 22 version이 보다 인간에 가까운 version이고 디자인된 ch7D1과 2종의 hz7D1 항체는 heavy chain이 IgG1 및 light chain이 kappa constant인 whole IgG 형태가 되도록 유전자 합성을 GenScript사를 통해 진행하였다. 각 항체의 heavy chain과 light chain은 각각 pcDNA3. 1(+) expression vector에 cloning 하였고, Humanization 된 2 종의 항체의 결합력을 확인하기 위해 IgG 형태의 affinity를 분석하기 위해서 IgG 생산을 진행하였다.
pcDNA3.1(+) vector에 클로닝된 각 항체의 중쇄 또는 경쇄에 대한 플라스미드는 염기서열 분석을 통하여 확인하였다. 확인된 plasmid를 HEK293F cell에 transient transfection 한 후 세포배양액에서 Protein A chromatography를 통해서 IgG를 정제하였다. 정제된 항체의 순도는 SDS PAGE 후 Coomassie Blue staining을 통하여 확인하였다(도 12). 그 결과 3 종의 항체 모두 높은 순도로 정제되었음을 확인하였다.
실시예 13. PCSK9 Ag과 인간화 7D1 항체의 결합 확인 ELISA
정제된 3종의 chimeric 7D1, hz7D1.11, hz7D1.22 Mab가 PCSK9 Ag과 결합하는지 확인하기 위해 ELISA로 확인 하였다. 96웰 플레이트(코닝 라이프 사이언시스)에 0.2 M sodium carbonate pH 9.5에 PCSK9 original(PCSK9 (human) recombinant protein-abnova사 Cat No: H00255738-P01)을 1 ug/ml로 희석한 후 30 ul/well로 넣어 후 4℃에서 밤새 인큐베이션 하여 코팅 하였다. 이어서, 플레이트를 세척 용액 PBS pH 7.4를 사용하여 3회 세척 후 플레이트를 5% skim milk가 포함된 PBS(pH 7.4) 200 ul에서, 1시간 실온에서 인큐베이션 하였다.
플레이트를 3회 세척 후 정제된 chimeric 7D1, hz7D1.11, hz7D1.22 Mab를 정량하여 10 ug/ml 시작으로 1/3씩 희석하여 30 ul/well 넣어준 후 1시간 실온에서 인큐베이션 후 세척 용액 PBS pH 7.4를 사용하여 3회 세척 진행 하였다. 1 : 3,000 농도의 anti-human IgG -HRP 30 ul/well를 플레이트에 첨가하고, 1시간 동안 실온에서 인큐베이션 하였다. 플레이트를 3회 세척 후 TMB 용액을 100 ul/well 첨가하여 5분 실온에서 반응 시키고, 1N 염산 100 ul/well 넣어주어 10분 후에 실온에서 수행하였다. 두 번의 독립적인 시험을 수행하였으며, 얻어진 결과는 Prism의 four parameter analysis를 통해서 분석하였고 EC50 값을 기준으로 2 종의 hz7D1 항체 모두 parental clone인 ch7D1 대비 PCSK9 original 항원에 대해 높은 결합력을 보였다(도 13).
실시예 14. PCSK9 Ag과 인간화 7D1 항체의 결합 확인
정제된 3종의 chimeric 7D1, hz7D1.11, hz7D1.22 Mab가 PCSK9 Ag과 결합하는지 확인하기 위해 Octet 방법으로 확인 하였다. Octet 시험은 IgG 항체를 sensor chip에 immobilization 한 후 다양한 농도의 항원을 analyte으로 사용하는 방식으로 진행하였다. Immobilization는 CM5 chip & AR2G buffer 사용하여 purified whole IgG 1 mg/mL loading 하였다. 또한, Analyte는 PCSK9 original antigen 200 nM을 시작으로 1/2씩 희석하여 5 point loading 하여 Affinity를 장비 내 1:1 interaction model을 통하여 분석 하였다. 그 결과, PCSK9 original을 사용하였을 경우 2 종의 hz7D1 항체는 모두 ch7D1과 동등한 수준의 결합력을 나타내었다(도 14a 내지 도 14d).
<110> Biostream Technologies Co., Ltd.
<120> ANTI PCSK9 ANTIBODY AND USE THEREOF
<130> SPD20-075BST
<160> 58
<170> KoPatentIn 3.0
<210> 1
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 1
Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 2
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 2
Leu Val Ser Lys Leu Asp Ser
1 5
<210> 3
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 3
Trp Gln Gly Thr His Phe Pro Gln Thr
1 5
<210> 4
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR1
<400> 4
Asp Tyr Tyr Met His
1 5
<210> 5
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 5
Tyr Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe Gln
1 5 10 15
Gly
<210> 6
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR3
<400> 6
Ser Pro Phe Thr Tyr
1 5
<210> 7
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> VL FR1
<400> 7
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys
20
<210> 8
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> VL FR2
<400> 8
Trp Leu Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr
1 5 10 15
<210> 9
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> VL FR3
<400> 9
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 10
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> VL FR4
<400> 10
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 11
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> VH FR1
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys
20 25 30
<210> 12
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> VH FR2
<400> 12
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 13
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> VH FR3
<400> 13
Arg Ala Thr Met Thr Ala Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Arg Ser
20 25 30
<210> 14
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> VH FR4
<400> 14
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 15
<211> 444
<212> PRT
<213> Artificial Sequence
<220>
<223> ch7D1 heavy chain amino acid
<400> 15
Glu Val Lys Leu Val Glu Ser Gly Ala Glu Leu Val Arg Ser Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Arg Ser Ser Pro Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 16
<211> 1332
<212> DNA
<213> Artificial Sequence
<220>
<223> ch7D1 heavy chain DNA
<400> 16
gaggtgaagc tggtggagag cggagcagag ctggtgcggt ccggagcctc tgtgaagctg 60
agctgcacag cctccggctt caacatcaag gattactata tgcactgggt gaagcagcgg 120
cccgagcagg gcctggagtg gatcggctac atcgaccccg agaacggcga taccgagtat 180
gcccctaagt ttcagggcaa ggccaccatg acagccgaca ccagctccaa tacagcctac 240
ctccagctgt ctagcctgac cagcgaggat acagccgtgt actattgcag gtcctctccc 300
ttcacctatt ggggacaggg caccctggtg acagtgagcg ccgcctccac aaaaggcccc 360
tccgtgtttc cactggcccc cagctccaag agcacctccg gaggcacagc cgccctgggc 420
tgtctggtga aggactactt cccagagccc gtgaccgtgt cttggaacag cggcgccctg 480
accagcggag tgcacacatt tcccgccgtg ctccagagca gcggcctgta ctccctgtcc 540
tctgtggtga ccgtgccaag ctcctctctg ggcacccaga catatatctg caacgtgaat 600
cacaagccta gcaatacaaa ggtggacaag aaggtggagc caaagtcctg tgataagacc 660
cacacatgcc ccccttgtcc tgcaccagag ctgctgggcg gcccaagcgt gttcctgttt 720
ccacccaagc ccaaggacac cctgatgatc tctcgcaccc cagaggtgac atgcgtggtg 780
gtggacgtga gccacgagga ccccgaggtg aagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ccaagaccaa gcctcgggag gagcagtaca attctaccta tagagtggtg 900
agcgtgctga cagtgctgca ccaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg ccctgcccgc ccctatcgag aaaaccatca gcaaggccaa gggccagcct 1020
agggagccac aggtgtacac actgcctcca tcccgcgagg agatgaccaa gaaccaggtg 1080
tctctgacat gtctggtgaa gggcttctat cccagcgaca tcgccgtgga gtgggagtcc 1140
aatggccagc ctgagaacaa ttacaagacc acaccccctg tgctggactc cgatggctct 1200
ttctttctgt attccaagct gaccgtggat aagtctcggt ggcagcaggg caacgtgttt 1260
tcttgtagcg tgatgcacga ggccctgcac aatcactaca cacagaagtc cctgtctctg 1320
agccccggca ag 1332
<210> 17
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> ch7D1 light chain amino acid
<400> 17
Asp Val Leu Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 18
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> ch7D1 light chain DNA
<400> 18
gatgtgctga tgacccagac acctctgacc ctgtccgtga caatcggcca gccagccagc 60
atctcctgca agagcagcca gtccctgctg gactctgatg gcaagacata cctgaactgg 120
ctgctccagc ggcccggcca gagccccaag agactgatct atctggtgag caagctggac 180
tccggcgtgc ccgataggtt caccggctct ggcagcggca ccgacttcac cctgaagatc 240
agccgggtgg aggcagagga tctgggcgtg tactattgct ggcagggcac ccacttcccc 300
cagacatttg gcggaggcac caagctggag ctgaagagga cagtggcagc accttccgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgccagcgt ggtgtgcctg 420
ctgaacaatt tctacccaag ggaggccaag gtgcagtgga aggtggataa cgccctccag 480
tccggcaatt ctcaggagag cgtgacagag caggactcca aggattctac ctatagcctg 540
tctagcaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcctgcgag 600
gtgacacacc agggcctgtc ctctcccgtg accaagtcct ttaatcgggg cgagtgt 657
<210> 19
<211> 444
<212> PRT
<213> Artificial Sequence
<220>
<223> hz7D1.11 heavy chain amino acid
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ala Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Arg Ser Ser Pro Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 20
<211> 1332
<212> DNA
<213> Artificial Sequence
<220>
<223> hz7D1.11 heavy chain DNA
<400> 20
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggcgcctc tgtgaaggtg 60
agctgcaagg cctccggctt caacatcaag gactactata tgcactgggt gaggcaggcc 120
cctggccagg gcctggagtg gatcggctac atcgaccccg agaatggcga taccgagtat 180
gcccctaagt ttcagggccg cgccaccatg acagccgata cctccatctc tacagcctac 240
atggagctgt ctcggctgag aagcgacgat accgccgtgt actactgccg gagcagccca 300
ttcacatatt ggggccaggg caccctggtg acagtgtcta gcgcctccac caaaggcccc 360
agcgtgttcc cactggcccc ctcctctaag agcacctccg gaggcacagc cgccctgggc 420
tgtctggtga aggattactt cccagagccc gtgacagtgt cctggaactc tggcgccctg 480
acctccggag tgcacacatt tcccgccgtg ctccagagca gcggcctgta cagcctgtct 540
agcgtggtga ccgtgccttc ctctagcctg ggcacccaga catatatctg caacgtgaat 600
cacaagcctt ccaatacaaa ggtggacaag aaggtggagc caaagtcttg tgataagacc 660
cacacatgcc ccccttgtcc tgcaccagag ctgctgggcg gcccaagcgt gttcctgttt 720
ccacccaagc ccaaggacac cctgatgatc tcccggaccc cagaggtgac atgcgtggtg 780
gtggacgtga gccacgagga ccccgaggtg aagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ccaagaccaa gcctagggag gagcagtaca acagcaccta tcgcgtggtg 900
tccgtgctga cagtgctgca ccaggactgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg ccctgcccgc ccctatcgag aaaaccatca gcaaggcaaa gggacagcct 1020
cgggagccac aggtgtacac actgcctccc agccgggagg agatgaccaa gaaccaggtg 1080
agcctgacat gtctggtgaa gggcttctat ccctccgaca tcgccgtgga gtgggagtct 1140
aatggccagc ctgagaacaa ttacaagacc acaccccctg tgctggacag cgatggctcc 1200
ttctttctgt attctaagct gaccgtggat aagagcagat ggcagcaggg caacgtgttt 1260
tcttgtagcg tgatgcacga ggccctgcac aatcactaca cacagaagtc cctgtctctg 1320
agccccggca ag 1332
<210> 21
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> hz7D1.11 light chain amino acid
<400> 21
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 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 Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 22
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> hz7D1.11 light chain DNA
<400> 22
gacgtggtca tgacccagtc tccactgagc ctgcccgtga cactgggaca gccagccagc 60
atctcctgca agagcagcca gtccctgctg gactctgatg gcaagaccta cctgaactgg 120
ctccagcaga ggcctggcca gtctccacgg agactgatct atctggtgag caagctggac 180
tccggcgtgc ccgataggtt ctctggcagc ggctccggca ccgactttac actgaagatc 240
agccgcgtgg aggcagagga tgtgggcgtg tactattgct ggcagggcac ccacttcccc 300
cagacatttg gcggcggcac caaggtggag atcaagcgga cagtggccgc cccttccgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgccagcgt ggtgtgcctg 420
ctgaacaatt tctaccctag agaggccaag gtgcagtgga aggtggataa cgccctccag 480
tccggcaatt ctcaggagag cgtgacagag caggactcca aggattctac ctatagcctg 540
tctagcaccc tgacactgag caaggccgac tacgagaagc acaaggtgta tgcctgcgag 600
gtgacacacc agggcctgtc ctctccagtg accaagtcct ttaatagagg cgagtgt 657
<210> 23
<211> 444
<212> PRT
<213> Artificial Sequence
<220>
<223> hz7D1.22 heavy chain amino acid
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Arg Ser Ser Pro Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 24
<211> 1332
<212> DNA
<213> Artificial Sequence
<220>
<223> hz7D1.22 heavy chain DNA
<400> 24
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggcgcctc tgtgaaggtg 60
agctgcaagg cctccggcta cacattcaag gactactata tgcactgggt gaggcaggcc 120
cctggccagg gcctggagtg gatgggctac atcgaccccg agaacggcga taccgagtat 180
gcccctaagt ttcagggccg cgtgaccatg acagccgata cctccatctc tacagcctac 240
atggagctgt ctcggctgag aagcgacgat accgccgtgt actactgccg gagcagccca 300
ttcacatatt ggggccaggg caccctggtg acagtgtcta gcgcctccac caaaggcccc 360
agcgtgttcc cactggcccc ctcctctaag agcacctccg gaggcacagc cgccctgggc 420
tgtctggtga aggattattt cccagagccc gtgaccgtgt cctggaactc tggcgccctg 480
acctccggag tgcacacatt tcccgccgtg ctccagagca gcggcctgta cagcctgtct 540
agcgtggtga ccgtgccttc ctctagcctg ggcacccaga catatatctg caacgtgaat 600
cacaagcctt ccaatacaaa ggtggacaag aaggtggagc caaagtcttg tgataagacc 660
cacacatgcc ccccttgtcc tgcaccagag ctgctgggcg gcccaagcgt gttcctgttt 720
ccacccaagc ccaaggacac cctgatgatc tcccggaccc cagaggtgac atgcgtggtg 780
gtggacgtga gccacgagga ccccgaggtg aagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ccaagaccaa gcctagggag gagcagtaca atagcaccta tcgcgtggtg 900
tccgtgctga cagtgctgca ccaggactgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg ccctgcccgc ccctatcgag aaaaccatca gcaaggcaaa gggacagcct 1020
cgggagccac aggtgtacac actgcctccc agccgggagg agatgaccaa gaaccaggtg 1080
agcctgacat gtctggtgaa gggcttctat ccctccgaca tcgccgtgga gtgggagtct 1140
aatggccagc ctgagaacaa ttacaagacc acaccccctg tgctggacag cgatggctcc 1200
ttctttctgt attctaagct gaccgtggat aagagcagat ggcagcaggg caacgtgttt 1260
tcttgtagcg tgatgcacga ggccctgcac aatcactaca cacagaagtc cctgtctctg 1320
agccccggca ag 1332
<210> 25
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> hz7D1.22 light chain amino acid
<400> 25
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 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 Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 26
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> hz7D1.22 light chain DNA
<400> 26
gacgtggtca tgacccagtc tccactgagc ctgcccgtga cactgggaca gccagccagc 60
atctcctgca agagcagcca gtccctgctg gactctgatg gcaagaccta cctgaactgg 120
ttccagcaga ggcctggcca gtctccacgg agactgatct atctggtgag caagctggac 180
tccggcgtgc ccgataggtt ctctggcagc ggctccggca ccgactttac actgaagatc 240
agccgcgtgg aggcagagga tgtgggcgtg tactattgct ggcagggcac ccacttcccc 300
cagacatttg gcggcggcac caaggtggag atcaagcgga cagtggccgc cccttccgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgccagcgt ggtgtgcctg 420
ctgaacaatt tctaccctag agaggccaag gtgcagtgga aggtggataa cgccctccag 480
tccggcaatt ctcaggagag cgtgacagag caggactcca aggattctac ctatagcctg 540
tctagcaccc tgacactgag caaggccgac tacgagaagc acaaggtgta tgcctgcgag 600
gtgacacacc agggcctgtc ctctccagtg accaagtcct ttaatagagg cgagtgt 657
<210> 27
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope
<400> 27
Pro Glu Glu Asp Gly Thr Arg Phe His Arg
1 5 10
<210> 28
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 1
<400> 28
Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val Val Leu
1 5 10 15
<210> 29
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 2
<400> 29
Phe Ala Gln
1
<210> 30
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 3
<400> 30
Cys Gln Gly Lys
1
<210> 31
<211> 2
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 4
<400> 31
Asn Phe
111
<210> 32
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 5
<400> 32
Leu Gly Thr Leu Gly Thr
1 5
<210> 33
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 6
<400> 33
Val Ser Gln Ser Gly
1 5
<210> 34
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 7
<400> 34
Glu Asp Gln Arg Val Leu Thr Pro Asn Leu
1 5 10
<210> 35
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 8
<400> 35
Cys Arg Thr Val Trp Ser Ala
1 5
<210> 36
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 9
<400> 36
Cys Ala Pro Asp
1
<210> 37
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 10
<400> 37
His Lys Pro Pro Val Leu Arg Pro Arg
1 5
<210> 38
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 Ag epitope 11
<400> 38
Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val Thr
1 5 10
<210> 39
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> IGHV1-2*02/IGHJ4*03
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 40
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> IGKV2-30*01/IGKJ4*2
<400> 40
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp 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 Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 41
<211> 343
<212> DNA
<213> Artificial Sequence
<220>
<223> Heavy chain variable region DNA of m7D1 antibody
<400> 41
gaggtgaagc tggtggagtc tggggcagag cttgtgaggt caggggcctc agtcaagttg 60
tcctgcacag cttctggctt caacattaaa gactactata tgcactgggt gaagcagagg 120
cctgaacagg gcctggagtg gattggatat attgatcctg agaatggtga tactgaatat 180
gccccgaagt tccagggcaa ggccactatg actgcagaca catcctccaa cacagcctac 240
ctgcagctca gcagcctgac atctgaggac actgccgtct attactgtcg tagtagcccg 300
tttacttact ggggccaagg gactctggtc actgtctctg cag 343
<210> 42
<211> 337
<212> DNA
<213> Artificial Sequence
<220>
<223> Light chain variable region DNA of m7D1 antibody
<400> 42
gatgttttga tgacccagac tccactcact ttgtcggtta ccattggaca accagcctcc 60
atctcttgca agtcaagtca gagcctctta gatagtgatg gaaagacata tttgaattgg 120
ttgttacaga ggccaggcca gtctccaaag cgcctaatct atctggtgtc taaactggac 180
tctggagtcc ctgacaggtt cactggcagt ggatcaggga cagatttcac actgaaaatc 240
agcagagtgg aggctgagga tttgggagtt tattattgct ggcaaggtac acattttcct 300
cagacgttcg gtggagggac caagctggag ctgaaag 337
<210> 43
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region of m7D1 antibody
<400> 43
Glu Val Lys Leu Val Glu Ser Gly Ala Glu Leu Val Arg Ser Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Arg Ser Ser Pro Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ala
<210> 44
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region of m7D1 antibody
<400> 44
Asp Val Leu Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 45
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region of 7D1 antibody
<400> 45
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ala Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Arg Ser Ser Pro Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 46
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region of 7D1 antibody
<400> 46
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 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 Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 47
<211> 344
<212> DNA
<213> Artificial Sequence
<220>
<223> Heavy chain variable region DNA of 7D1 antibody
<400> 47
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggcgcctc tgtgaaggtg 60
agctgcaagg cctccggctt caacatcaag gactactata tgcactgggt gaggcaggcc 120
cctggccagg gcctggagtg gatcggctac atcgaccccg agaatggcga taccgagtat 180
gcccctaagt ttcagggccg cgccaccatg acagccgata cctccatctc tacagcctac 240
atggagctgt ctcggctgag aagcgacgat accgccgtgt actactgccg gagcagccca 300
ttcacatatt ggggccaggg caccctggtg acagtgtcta gcgc 344
<210> 48
<211> 337
<212> DNA
<213> Artificial Sequence
<220>
<223> Light chain variable region DNA of 7D1 antibody
<400> 48
gacgtggtca tgacccagtc tccactgagc ctgcccgtga cactgggaca gccagccagc 60
atctcctgca agagcagcca gtccctgctg gactctgatg gcaagaccta cctgaactgg 120
ctccagcaga ggcctggcca gtctccacgg agactgatct atctggtgag caagctggac 180
tccggcgtgc ccgataggtt ctctggcagc ggctccggca ccgactttac actgaagatc 240
agccgcgtgg aggcagagga tgtgggcgtg tactattgct ggcagggcac ccacttcccc 300
cagacatttg gcggcggcac caaggtggag atcaagc 337
<210> 49
<211> 693
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9[homo sapiens]
<400> 49
Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gln Glu
20 25 30
Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu
35 40 45
Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe
50 55 60
His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val
65 70 75 80
Val Leu Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr Ala Arg
85 90 95
Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys Ile Leu
100 105 110
His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly
115 120 125
Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile Glu
130 135 140
Glu Asp Ser Ser Val Phe Ala Gln Ser Ile Pro Trp Asn Leu Glu Arg
145 150 155 160
Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro Asp Gly
165 170 175
Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln Ser Asp
180 185 190
His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val
195 200 205
Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys Cys Asp
210 215 220
Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly
225 230 235 240
Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gln
245 250 255
Gly Lys Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg
260 265 270
Lys Ser Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu Leu Pro
275 280 285
Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln Arg Leu
290 295 300
Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp
305 310 315 320
Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val
325 330 335
Gly Ala Thr Asn Ala Gln Asp Gln Pro Val Thr Leu Gly Thr Leu Gly
340 345 350
Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp Ile
355 360 365
Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gln Ser Gly
370 375 380
Thr Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu
385 390 395 400
Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile
405 410 415
His Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Glu Asp
420 425 430
Gln Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr
435 440 445
His Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser Ala His
450 455 460
Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg Cys Ala Pro Asp
465 470 475 480
Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg
485 490 495
Gly Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg Ala His
500 505 510
Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu
515 520 525
Leu Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala
530 535 540
Ser Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val Leu Thr
545 550 555 560
Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro
565 570 575
Pro Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly His Arg
580 585 590
Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys
595 600 605
Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr Val
610 615 620
Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly
625 630 635 640
Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val
645 650 655
Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val
660 665 670
Thr Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln Ala Ser
675 680 685
Gln Glu Leu Gln Ala
690
<210> 50
<211> 616
<212> PRT
<213> Artificial Sequence
<220>
<223> PCSK9 fragment
<400> 50
Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gln Glu
20 25 30
Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu
35 40 45
Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe
50 55 60
His Arg Cys Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr Ala
65 70 75 80
Arg Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys Ile
85 90 95
Leu His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser
100 105 110
Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile
115 120 125
Glu Glu Asp Ser Ser Val Ser Ile Pro Trp Asn Leu Glu Arg Ile Thr
130 135 140
Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro Asp Gly Gly Ser
145 150 155 160
Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln Ser Asp His Arg
165 170 175
Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val Pro Glu
180 185 190
Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys Cys Asp Ser His
195 200 205
Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly Val Ala
210 215 220
Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Gly Thr Val Ser
225 230 235 240
Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg Lys Ser Gln Leu Val Gln
245 250 255
Pro Val Gly Pro Leu Val Val Leu Leu Pro Leu Ala Gly Gly Tyr Ser
260 265 270
Arg Val Leu Asn Ala Ala Cys Gln Arg Leu Ala Arg Ala Gly Val Val
275 280 285
Leu Val Thr Ala Ala Gly Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala
290 295 300
Ser Ala Pro Glu Val Ile Thr Val Gly Ala Thr Asn Ala Gln Asp Gln
305 310 315 320
Pro Val Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu
325 330 335
Asp Ile Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Thr Ser Gln
340 345 350
Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu Ser Ala Glu
355 360 365
Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile His Phe Ser
370 375 380
Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Val Ala Ala Leu Pro
385 390 395 400
Pro Ser Thr His Gly Ala Gly Trp Gln Leu Phe His Ser Gly Pro Thr
405 410 415
Arg Met Ala Thr Ala Val Ala Arg Glu Glu Leu Leu Ser Cys Ser Ser
420 425 430
Phe Ser Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala Gln Gly
435 440 445
Gly Lys Leu Val Cys Arg Ala His Asn Ala Phe Gly Gly Glu Gly Val
450 455 460
Tyr Ala Ile Ala Arg Cys Cys Leu Leu Pro Gln Ala Asn Cys Ser Val
465 470 475 480
His Thr Ala Pro Pro Ala Glu Ala Ser Met Gly Thr Arg Val His Cys
485 490 495
His Gln Gln Gly His Val Leu Thr Gly Cys Ser Ser His Trp Glu Val
500 505 510
Glu Asp Leu Gly Thr Gly Gln Pro Asn Gln Cys Val Gly His Arg Glu
515 520 525
Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys Lys
530 535 540
Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr Val Ala
545 550 555 560
Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly Thr
565 570 575
Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val Arg
580 585 590
Ser Arg Asp Val Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala
595 600 605
Gln Ala Ser Gln Glu Leu Gln Ala
610 615
<210> 51
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR1 of m7D1
<400> 51
Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 52
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR2 of m7D1
<400> 52
Leu Val Ser Lys Leu Asp Ser
1 5
<210> 53
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR3 of m7D1
<400> 53
Trp Gln Gly Thr His Phe Pro Gln Thr
1 5
<210> 54
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR1 of m7D1
<400> 54
Asp Tyr Tyr Met His
1 5
<210> 55
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR2 of m7D1
<400> 55
Tyr Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe Gln
1 5 10 15
Gly
<210> 56
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR3 of m7D1
<400> 56
Ser Pro Phe Thr Tyr
1 5
<210> 57
<211> 809
<212> PRT
<213> Artificial Sequence
<220>
<223> GST-PCSK9 amino acid sequence
<400> 57
Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg
210 215 220
Gly Ser Gln Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala
225 230 235 240
Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr
245 250 255
Thr Ala Thr Phe His Arg Cys Lys Glu Glu Thr His Leu Ser Gln Ser
260 265 270
Glu Arg Thr Ala Arg Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr
275 280 285
Leu Thr Lys Ile Leu His Val Phe His Gly Leu Leu Pro Gly Phe Leu
290 295 300
Val Lys Met Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His
305 310 315 320
Val Asp Tyr Ile Glu Glu Asp Ser Ser Val Ser Ile Pro Trp Asn Leu
325 330 335
Glu Arg Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro
340 345 350
Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln
355 360 365
Ser Asp His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu
370 375 380
Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys
385 390 395 400
Cys Asp Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp
405 410 415
Ala Gly Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn
420 425 430
Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg Lys Ser
435 440 445
Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu Leu Pro Leu Ala
450 455 460
Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln Arg Leu Ala Arg
465 470 475 480
Ala Gly Val Val Leu Val Thr Ala Ala Gly Arg Asp Asp Ala Cys Leu
485 490 495
Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val Gly Ala Thr Asn
500 505 510
Ala Gln Asp Gln Pro Val Thr Asn Phe Gly Arg Cys Val Asp Leu Phe
515 520 525
Ala Pro Gly Ile Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Thr
530 535 540
Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu Ser
545 550 555 560
Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile His
565 570 575
Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Val Ala Ala
580 585 590
Leu Pro Pro Ser Thr His Gly Ala Gly Trp Gln Leu Phe His Ser Gly
595 600 605
Pro Thr Arg Met Ala Thr Ala Ile Ala Arg Glu Glu Leu Leu Ser Cys
610 615 620
Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala
625 630 635 640
Gln Gly Gly Lys Leu Val Cys Arg Ala His Asn Ala Phe Gly Gly Glu
645 650 655
Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu Leu Pro Gln Ala Asn Cys
660 665 670
Ser Val His Thr Ala Pro Pro Ala Glu Ala Ser Met Gly Thr Arg Val
675 680 685
His Cys His Gln Gln Gly His Val Leu Thr Gly Cys Ser Ser His Trp
690 695 700
Glu Val Glu Asp Leu Gly Thr Gly Gln Pro Asn Gln Cys Val Gly His
705 710 715 720
Arg Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu
725 730 735
Cys Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr
740 745 750
Val Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro
755 760 765
Gly Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val
770 775 780
Val Arg Ser Arg Asp Val Ala Val Ala Ile Cys Cys Arg Ser Arg His
785 790 795 800
Leu Ala Gln Ala Ser Gln Glu Leu Gln
805
<210> 58
<211> 2427
<212> DNA
<213> Artificial Sequence
<220>
<223> GST-PCSK9 DNA sequence
<400> 58
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaatcggat 660
ctggttccgc gtggatccca agaagatgaa gatggtgatt atgaggaact ggtgctggcg 720
ctgcgtagcg aagaggacgg tctggcggag gcgccggaac acggtaccac cgcgaccttc 780
caccgttgca aagaggaaac ccacctgagc cagagcgaac gtaccgcgcg tcgtctgcaa 840
gcgcaagcgg cgcgtcgtgg ctacctgacc aaaatcctgc acgtgttcca cggtctgctg 900
ccgggctttc tggttaagat gagcggtgac ctgctggagc tggcgctgaa actgccgcac 960
gtggactata ttgaggaaga tagcagcgtt agcatcccgt ggaacctgga gcgtattacc 1020
ccgccgcgtt accgtgcgga cgaatatcag ccgccggatg gtggtagcct ggttgaggtg 1080
tacctgctgg acaccagcat ccaaagcgat caccgtgaga ttgaaggtcg tgtgatggtt 1140
accgacttcg aaaacgtgcc ggaggaagat ggcacccgtt ttcaccgtca ggcgagcaaa 1200
tgcgacagcc acggcaccca tctggcgggt gtggttagcg gccgtgatgc gggtgttgcg 1260
aaaggcgcga gcatgcgtag cctgcgtgtg ctgaacggca ccgtgagcgg caccctgatc 1320
ggtctggagt tcattcgtaa gagccagctg gtgcaaccgg ttggtccgct ggttgtgctg 1380
ctgccgctgg cgggtggcta cagccgtgtg ctgaacgcgg cgtgccagcg tctggcgcgt 1440
gcgggcgtgg ttctggttac cgcggcgggt cgtgatgatg cgtgcctgta tagcccggcg 1500
agcgcgccgg aagtgatcac cgttggtgcg accaacgcgc aggaccaacc ggtgaccaac 1560
tttggtcgtt gcgtggacct gttcgcgccg ggtatcattg gcgcgagcag cgactgcagc 1620
acctgcttta ccagccaagc tgcggcgcat gttgcgggta ttgcggcgat gatgctgagc 1680
gcggagccgg aactgaccct ggcggaactg cgtcaacgtc tgatccactt cagcgcgaaa 1740
gatgtgatta acgaggcgtg gtttccggtt gcggcgctgc cgccgagcac ccacggtgcg 1800
ggttggcagc tgtttcatag cggtccgacc cgtatggcga ccgcgattgc gcgtgaggaa 1860
ctgctgagct gcagcagctt tagccgtagc ggcaagcgtc gtggtgagcg tatggaagcg 1920
cagggtggca aactggtgtg ccgtgcgcac aacgcgtttg gtggcgaagg cgtttacgcg 1980
attgcgcgtt gctgcctgct gccgcaagcg aactgcagcg tgcacaccgc tccgccggcg 2040
gaggcgagca tgggcacccg tgtgcactgc caccagcaag gccacgttct gaccggttgc 2100
agcagccact gggaagtgga agatctgggc accggccagc cgaaccaatg cgttggtcac 2160
cgtgaagcga gcattcatgc gagctgctgc catgcgccgg gcctggagtg caaggttaaa 2220
gaacacggta ttccggcgcc gcaggagcaa gtgaccgttg cgtgcgagga aggctggacc 2280
ctgaccggtt gcagcgcgct gccgggcacc agccacgtgc tgggtgcgta tgcggttgac 2340
aacacctgcg tggttcgtag ccgtgatgtg gcggtggcga tctgctgccg tagccgtcat 2400
ctggcgcaag cgagccaaga actgcaa 2427
Claims (16)
- 인간 PCSK9의 209번째 내지 218번째 아미노산에 특이적으로 결합하는 항체를 유효성분으로 포함하는 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물.
- 제1항에 있어서,
상기 PCSK9은 서열번호 49의 아미노산 서열을 가지는 것인, 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물. - 제1항에 있어서,
인간 PCSK9의 209번째 내지 218번째 아미노산 서열은 서열번호 27인 것인, 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물. - 제1항 내지 제3항 중 어느 한 항에 있어서,
상기 콜레스테롤 관련 질환은 고콜레스테롤혈증, 고지혈증, 죽상경화성 심혈관질환(ACVD), 급성관상동맥증후군(ACS), 고혈압, 당뇨병, 뇌졸중, 알츠하이머 및 이상지질혈증으로 이루어진 군에서 선택되는 어느 하나인 것인, 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물. - 서열번호 1의 LCDR1, 서열번호 2의 LCDR2, 및 서열번호 3의 LCDR3을 포함하는 경쇄가변영역; 및
서열번호 4의 HCDR1, 서열번호 5의 HCDR2, 및 서열번호 6의 HCDR3을 포함하는 중쇄가변영역을 포함하는 PCSK9에 특이적인 항체. - 제5항에 있어서,
상기 항체는 PCSK9의 서열번호 27 및/또는 서열번호 50의 아미노산 서열을 갖는 항원에 특이적으로 결합하는 것인, PCSK9에 특이적인 항체. - 제5항에 있어서,
상기 중쇄영역은 서열번호 19 또는 서열번호 23의 아미노산 서열을 가지는 것인, PCSK9에 특이적인 항체. - 제5항에 있어서,
상기 경쇄영역은 서열번호 21 또는 서열번호 25의 아미노산 서열을 가지는 것인, PCSK9에 특이적인 항체. - 제5항에 있어서,
상기 항체가 인간화 항체인, PCSK9에 특이적인 항체. - 제5항의 항체를 유효성분으로 포함하는 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물.
- 제10항에 있어서,
상기 약학 조성물이 약제학적으로 허용가능한 담체를 더 포함하는 것인, 콜레스테롤 관련 질환 치료 또는 예방용 약학 조성물. - 제10항에 있어서,
상기 콜레스테롤 관련 질환은 고콜레스테롤혈증, 고지혈증, 죽상경화성 심혈관질환(ACVD), 급성관상동맥증후군(ACS), 고혈압, 당뇨병, 뇌졸중, 알츠하이머 및 이상지질혈증으로 이루어진 군에서 선택되는 어느 하나인 것인, 약학 조성물. - 제5항 내지 제9항 중 어느 한 항의 PCSK9에 특이적인 항체를 암호화하는 폴리뉴클레오티드.
- 제13항의 폴리뉴클레오티드를 포함하는 벡터.
- 제14항의 벡터가 도입된 형질전환 세포.
- 제15항의 형질전환 세포를 배양하는 단계;
상기 배양액으로부터 제5항의 항체를 수득하는 단계를 포함하는
PCSK9에 특이적인 항체를 제조하는 방법.
Priority Applications (3)
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KR1020200077370A KR20210158693A (ko) | 2020-06-24 | 2020-06-24 | 항 pcsk9 항체 및 이의 용도 |
PCT/KR2021/007876 WO2021261906A1 (ko) | 2020-06-24 | 2021-06-23 | 항 pcsk9 항체 및 이의 용도 |
US18/003,121 US20230242673A1 (en) | 2020-06-24 | 2021-06-23 | Anti-pcsk9 antibody and use thereof |
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KR1020200077370A KR20210158693A (ko) | 2020-06-24 | 2020-06-24 | 항 pcsk9 항체 및 이의 용도 |
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US8598320B2 (en) * | 2007-10-26 | 2013-12-03 | Merck Sharp & Dohme Corp. | Anti-PCSK9 and methods for treating lipid and cholesterol disorders |
TWI516501B (zh) * | 2008-09-12 | 2016-01-11 | 禮納特神經系統科學公司 | Pcsk9拮抗劑類 |
RS54639B1 (en) * | 2011-09-13 | 2016-08-31 | Affiris Ag | PCSK9 VACCINE |
WO2013148284A1 (en) * | 2012-03-29 | 2013-10-03 | Genentech, Inc. | Antibodies that bind to a pcsk9 cleavage site and methods of use |
US9255154B2 (en) * | 2012-05-08 | 2016-02-09 | Alderbio Holdings, Llc | Anti-PCSK9 antibodies and use thereof |
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- 2021-06-23 WO PCT/KR2021/007876 patent/WO2021261906A1/ko active Application Filing
Non-Patent Citations (1)
Title |
---|
Maxwell, K.N, et.al. Novel putative SREP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res. 44, 2109-2119, 2003]. |
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WO2021261906A1 (ko) | 2021-12-30 |
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