KR20210005248A - 개선된 fviii 융합 단백질 및 이의 용도 - Google Patents
개선된 fviii 융합 단백질 및 이의 용도 Download PDFInfo
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Abstract
본 발명은 폴리알킬렌 글리콜과 접합되고 연장된 사이클 반감기를 갖는 응고 인자 VIII 융합 단백질, 이의 제조 방법 및 용도에 관한 것이고, 이때 응고 인자 VIII의 활성 모이어티는 펩티드 연결기에 의해 융합 파트너에 직접적으로 연결되거나 간접적으로 연결되고, 융합 단백질은 또한 폴리알킬렌 글리콜에 접합된다. 반감기는 폴리알킬렌 글리콜 없이 변형된 FVIII 융합 단백질과 비교하여 유의하게 증가된다.
Description
관련 출원에 대한 상호참고
본원은 발명의 명칭이 "개선된 FVIII 융합 단백질 및 이의 용도"이고 2018년 5월 18일자 출원된 중국 특허출원 제201810481941.X호(이의 전문은 본원에 참고로 혼입됨)를 우선권 주장한다.
기술분야
본 개시내용은 재조합 인간 응고 인자 VIII 융합 단백질, 특히 연장된 반감기를 갖는 융합 폴리펩티드, 및 이의 제조 방법 및 용도에 관한 것이다.
혈우병 A는 응고 인자 VIII(FVIII)의 불충분한 활성 또는 기능장애에 의해 유발되는 유전성 출혈 장애이고, 활성 FVIII의 보충이 효과적인 치료적 처치이다. FVIII 유전자는 지금까지 클로닝된 가장 긴 유전자 중 하나이고, FVIII 분자는 임상 실무에서 사용되는 가장 큰 분자량을 가진 단백질 약물이다. FVIII 단백질은 6개의 도메인을 포함한다: 3개의 A 도메인(A1, A2, A3), 비-필수 중심 도메인(B-도메인) 및 2개의 C 도메인(C1, C2). 재조합 FVIII의 시험관내 발현 수준은 유사한 특성을 가진 다른 유전자보다 현저히 낮다. 예를 들어, FVIII의 발현 수준은 FIX의 단지 1%이다. 또한, 혈액내 FVIII의 짧은 반감기가 단지 8 내지 12시간이므로, 중증 혈우병 A 환자는 예방적 처리를 받아야 하고, 매주 약 3회 정맥내 주사(i.v.) 되어야 한다.
바이오베라티브(Bioverativ, 미국)에서 개발한 단량체-이량체 하이브리드 재조합 FVIII-Fc 융합 단백질[엘록테이트(Eloctate)]는 2014년 6월에 미국 FDA의 시판 승인을 받았다. 임상 데이터는 인체 내의 반감기가 단지 1.5 내지 1.7배 연장됨을 나타내고(문헌[Dumont JA et al., Blood, 2012, 119: 3024-3030; Powell JS et al., Blood, 2012, 119: 3031-3037]), 3 내지 5일마다 주사되었다. 그러나, rFVIII Fc, 및 바이오베라티브에 의해 구축된 Fc의 이중 발현 벡터로 형질감염된 HEK-293 세포에서, rFVIIIFc 동종이량체가 예상되는 발현 산물에서 검출되지 않았고, 단지 단량체-이량체 하이브리드 rFVIIIFc 융합 단백질 및 Fc 이량체가 발현되었다. 이에 대해, 회사의 연구진은 숙주 세포가 동종이량체의 과도한 분자량으로 인해 약 400 kDa의 분자량을 갖는 rFVIIIFc 동종이량체 단백질을 분비하지 못했거나, 입체 장애로 인해 rFVIIIFc 단량체가 중합에 실패했다고 추측했다(문헌[Peters RT et al., J Thromb Haemost, 2013, 11(1): 132-41]). 동종이량체 형태의 FVIII 융합 단백질의 생산이 매우 어렵다는 것을 알 수 있다.
단백질 약물의 장기-작용 제형의 제조를 위해, 높은 용해도를 갖는 중합체[예컨대, 폴리에틸렌 글리콜(PEG)]가 단백질 약물의 표면을 화학적으로 변형시키기 위해 통상적으로 사용된다. 일반적으로, 변형률이 높을수록, 단백질 항원성 및 활성의 감소가 더 분명해진다. FVIII의 반감기를 연장하기 위해 폴리에틸렌 글리콜(PEG)을 사용하는 예가 보고되었고, 예를 들어, 노보노르디스크(Novonordisk, N8-GP), 바이엘(Bayer, BAY94-9027) 및 박스터(Baxter, Bax 855)는 모두 임상 연구에 진입한 개발된 페길화된(PEGylated) 장기-작용 FVIII 제품이다. 그러나, 약동학 연구 데이터는 페길화된 FVIII이 상당히 연장된 반감기를 얻지 못함을 나타냈다(문헌[Tiede A et al., J Thromb Haemost. 2013; 11: 670-678]); 문헌[Coyle T et al., Haemophilia. 2012; 18( Suppl 3): 22]; 문헌[Turecek PL et al., Hamostaseologie, 2012, 32 Suppl 1: S29-38]).
장기-작용 단백질 약물을 개발하기 위한 전략은 글리코실화, 페길화, 알부민, 트랜스페린, Fc, XTEN 등과의 융합 단백질 형성을 포함한다. 현재, 시판 중인 장기-작용 약물은 단백질의 반감기를 연장하기 위해 상기 전략 중 하나만 사용한다. 상기 전략 중 2개 이상의 조합, 특히 페길화 및 단백질과의 융합의 조합에 대한 문헌은 존재하지 않고, 2개 이상의 전략이 단일 전략이 채택된 경우보다 반감기를 길게 만들 수 있다고 보고하는 문헌은 존재하지 않는다.
혈우병 환자는 출혈을 멈추고 출혈을 예방하기 위해 응고 인자의 평생 수혈이 필요하다. 따라서, 연구자들은 투여 횟수를 줄이기 위해 반감기가 긴 응고 인자를 지속적으로 찾고 있다. 또한, 반감기를 연장하면서 양호한 생물학적 활성을 유지하는 방법은 연구자들이 직면한 어려운 문제이다.
수년간의 연구와 장기간의 실험 끝에, 본 발명자들은 응고 인자 VIII이 융합 파트너(예컨대, Fc 분절, 알부민, XTEN 또는 트랜스페린)와 융합되고, 생성된 융합 단백질이 중합체, 예컨대 폴리알킬렌 글리콜, 예를 들어 PEG, 예컨대 생체 내에서 는 mPEG와 추가로 접합될 때, 특히 접합된 파트가 분지 구조를 가질 때 및 접합된 파트의 분자량이 35 kDa 이상, 예컨대 40 kDa일 때, 단백질의 안정성을 효과적으로 개선할 수 있음을 발견하였다. 이를 바탕으로, 본 개시내용이 완성되었다.
본 개시내용은 다음과 같은 기술적 해법을 제공한다:
1. 활성 모이어티로서 응고 인자 VIII(FVIII)이 펩티드 연결기에 의해, 반감기를 연장하기 위한 융합 파트너에 직접적으로 연결되거나 간접적으로 연결되어 융합 단백질을 형성하고, 상기 융합 단백질이 또한 폴리알킬렌 글리콜에 접합되는, 폴리알킬렌 글리콜과 접합된 응고 인자 VIII 융합 단백질인 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
2. 활성 모이어티인 응고 인자 VIII이 인간, 예컨대 전장 또는 절두된 인간 응고 인자 VIII(예를 들어, 인간 B-도메인 결실된 응고 인자 VIII)로부터 유래하고; 상기 전장 또는 절두된 인간 응고 인자 VIII이 하나 이상의 아미노산 돌연변이를 함유할 수 있되, 여전히 FVIII 활성을 보유하고, 예를 들어, 상기 활성 모이어티인 응고 인자 VIII이 서열번호 1 또는 2에 제시된 아미노산 서열을 포함하거나, 서열번호 1 또는 2에 제시된 아미노산 서열과 적어도 90% 또는 95% 이상의 동일성을 갖는, 한 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
3. 융합 파트너가 면역글로불린 Fc 단편, 알부민, 트랜스페린 또는 XTEN이고, 상기 융합 파트너가, 예를 들어, 인간으로부터 유래하고, 바람직하게는 IgG Fc 단편, 예를 들어, 감소된 ADCC 효과 및/또는 CDC 효과 및/또는 FcRn 수용체에 대한 강화된 결합 친화도를 갖는 IgG Fc 단편, 더욱 바람직하게는 (i) 서열번호 3에 제시된 아미노산 서열, (ii) 서열번호 4에 제시된 아미노산 서열, 및 (iii) 서열번호 5에 제시된 아미노산 서열로부터 선택되는 아미노산 서열을 갖는 IgG Fc 단편인, 다른 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
4. 폴리알킬렌 글리콜이 폴리프로필렌 글리콜 또는 폴리에틸렌 글리콜이고;
상기 폴리알킬렌 글리콜이 말단-캐핑(end-capping)될 수 있고, 예를 들어, 알콕시 기, 예컨대 메톡시에 의해 말단-캐핑될 수 있고;
상기 폴리알킬렌 글리콜이 선형 또는 분지형, 바람직하게는 분지형, 예를 들어 분지형 폴리에틸렌 글리콜, 특히 분지형 메톡시-종결된 폴리에틸렌 글리콜이고;
상기 폴리알킬렌 글리콜의 분자량이 ≥1, ≥10, ≥20, ≥30, ≥40, ≥50, ≥60, ≥70, ≥80, ≥90, ≥100, ≥110, ≥120, ≥130, ≥140, ≥150 또는 ≥160 kDa, 예를 들어 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 또는 100 kDa, 또는 이들 중 임의의 2개의 값 사이의 범위일 수 있는,
일부 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
5. 융합 단백질 및 폴리알킬렌 글리콜의 접합 부분이 무작위 또는 특정 위치에 존재하고, 접합 위치가 유리 아미노 기, 설프하이드릴 기, 당 기 및/또는 카복실 기로 이루어진 군으로부터 선택되고, 바람직하게는 유리 아미노 기인, 일부 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
6. 변형제, 즉 본원의 폴리알킬렌 글리콜 또는 변형된 폴리알킬렌 글리콜이 접합에 사용되고, 상기 변형제가 활성화된 에스터의 형태일 수 있고, 예를 들어, 상기 변형제가 하기 화학식 1, 2 및 3의 변형제로부터 선택되는, 다른 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질:
[화학식 1]
[상기 식에서,
0≤m1≤6이고, m1은 바람직하게는 5이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다]
[화학식 2]
[상기 식에서,
0≤m2≤6이고, m2는 바람직하게는 2이고;
0≤m3≤6이고, m3은 바람직하게는 1이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다]
[화학식 3]
[상기 식에서,
0≤m4≤6이고, m4는 바람직하게는 2이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다].
7. 응고 인자 VIII 활성 모이어티가 펩티드 연결기에 의해 융합 파트너에 연결되고, 상기 펩티드 연결기가 가요성 펩티드 분절 및/또는 강직성 펩티드 분절, 예를 들어 1, 2, 3, 4 또는 5개 이상의 강직성 펩티드 분절을 포함하는, 일부 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
8. 가요성 펩티드 분절이 글리신, 세린, 알라닌 및 트레오닌으로부터 선택되는 2개 이상의 아미노산 잔기를 포함하고;
바람직하게는, 상기 가요성 펩티드 분절이 구조식 (GS)a(GGS)b(GGGS)c(GGGGS)d를 갖고, 이때 a, b, c 및 d는 0 이상의 정수이고, a+b+c+d≥1이고;
더욱 바람직하게는, 상기 가요성 펩티드 분절이
(i) GSGGGSGGGGSGGGGS(서열번호 6);
(ii) GSGGGGSGGGGSGGGGSGGGGSGGGGS(서열번호 7);
(iii) GGGGSGGGGSGGGGSGGGGS(서열번호 8);
(iv) GSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS(서열번호 9); 및
(v) GGGSGGGSGGGSGGGSGGGS(서열번호 10)
로 이루어진 군으로부터 선택되는 서열을 갖는,
다른 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
9. 강직성 펩티드 분절이 인간 융모성 생식선 자극호르몬(chorionic gonadotropin) β 아단위의 카복시-종결된 펩티드이거나, 강직성 펩티드 분절이 인간 융모성 생식선 자극호르몬 β 아단위의 카복시-종결된 펩티드와 적어도 70%, 80%, 90% 또는 95% 이상의 동일성을 갖고;
상기 강직성 펩티드 분절이 1 또는 2개 이상의 글리코실화 부위를 포함할 수 있고;
바람직하게는, 상기 강직성 펩티드 분절이
(i) PRFQDSSSSKAPPPSLPSPSRLPGPSDTPILPQ(서열번호 11);
(ii) SSSSKAPPPSLPSPSRLPGPSDTPILPQ(서열번호 12);
(iii) SSSSKAPPPS(서열번호 13); 및
(iv) SRLPGPSDTPILPQ(서열번호 14)
로부터 선택되는 아미노산 서열을 포함하고;
더욱 바람직하게는, 펩티드 연결기가 서열번호 15에 제시된 아미노산 서열을 포함하는,
일부 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
10. 효과량의 본 개시내용의 접합체 및 약학적으로 허용되는 담체를 포함하는 약학 조성물.
11. 본 개시내용의 접합체 또는 약학 조성물을 이를 필요로 하는 대상에게 투여함을 포함하는, 출혈성 질환을 예방하고/거나 치료하는 방법으로서, 상기 출혈성 질환이 바람직하게는 FVIII의 선천적 또는 후천적 결핍을 갖는 환자의 출혈성 질환, 및 혈우병 A를 갖는 환자에서의 자발적 또는 외과적 출혈로부터 선택되는, 방법.
12. 응고 인자 VIII 활성 모이어티가 펩티드 연결기에 의해, 반감기를 연장하기 위한 융합 파트너에 직접적으로 연결되거나 간접적으로 연결되고, 이어서 폴리알킬렌 글리콜에 또한 접합되는, 응고 인자 VIII의 반감기를 개선하는 방법.
13. 융합 파트너가 면역글로불린 Fc 단편, 알부민, XTEN 또는 트랜스페린이고, 상기 융합 파트너가, 예를 들어, 인간으로부터 유래하고, 바람직하게는 IgG Fc 단편, 예를 들어, 감소된 ADCC 효과 및/또는 CDC 효과 및/또는 FcRn 수용체에 대한 강화된 결합 친화도를 갖는 IgG Fc 단편, 더욱 바람직하게는 (i) 서열번호 3에 제시된 아미노산 서열, (ii) 서열번호 4에 제시된 아미노산 서열, 및 (iii) 서열번호 5에 제시된 아미노산 서열로부터 선택되는 아미노산 서열을 갖는 IgG Fc 단편인, 한 양태에 따른 방법.
14. 폴리알킬렌 글리콜이 폴리프로필렌 글리콜 또는 폴리에틸렌 글리콜이고; 상기 폴리알킬렌 글리콜이 말단-캐핑될 수 있고, 예를 들어, 알콕시 기, 예컨대 메톡시로 말단-캐핑될 수 있고; 상기 폴리알킬렌 글리콜이 선형 또는 분지형, 바람직하게는 분지형, 예를 들어 분지형 폴리에틸렌 글리콜, 특히 분지형 메톡시-종결된 폴리에틸렌 글리콜이고; 상기 폴리알킬렌 글리콜의 분자량이 ≥1, ≥10, ≥20, ≥30, ≥40, ≥50, ≥60, ≥70, ≥80, ≥90, ≥100, ≥110, ≥120, ≥130, ≥140, ≥150 또는 ≥160 kDa, 예를 들어 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 또는 100 kDa일 수 있거나, 이들 중 임의의 2개의 값 사이의 범위일 수 있는, 일부 양태에 따른 방법.
15. 융합 단백질 및 폴리알킬렌 글리콜의 접합이 무작위 또는 특정 위치에 존재하고, 접합 위치가 유리 아미노 기, 설프하이드릴 기, 당 기 및 카복실 기로 이루어진 군으로부터 선택되고, 바람직하게는 유리 아미노 기인, 일부 양태에 따른 방법.
16. 변형제, 즉 본원의 폴리알킬렌 글리콜 또는 변형된 폴리알킬렌 글리콜이 접합에 사용되고, 바람직하게는 상기 변형제가 활성화된 에스터의 형태일 수 있고, 더욱 바람직하게는 상기 변형제가 하기 화학식 1, 2 및 3의 변형제로부터 선택되고, 이때 임의의 활성화된 에스터 형태 변형제가 접합에 사용되고, 예를 들어, 상기 변형제가 하기 화학식 1, 2 및 3의 변형제로부터 선택되는, 일부 양태에 따른 방법:
[화학식 1]
[상기 식에서,
0≤m1≤6이고, m1은 바람직하게는 5이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이고;
화학식 1의 변형제의 분자량은 5 내지 60 kDa이다]
[화학식 2]
[상기 식에서,
0≤m2≤6이고, m2는 바람직하게는 2이고;
0≤m3≤6이고, m3은 바람직하게는 1이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이고;
화학식 2의 변형제의 분자량은 5 내지 100 kDa, 바람직하게는 40 kDa, 50 kDa, 60 kDa, 더욱 바람직하게는 40 kDa이다]
[화학식 3]
[상기 식에서,
0≤m4≤6이고, m4는 바람직하게는 2이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이고;
화학식 3의 변형제의 분자량은 5 내지 100 kDa이다].
17. 응고 인자 VIII이 펩티드 연결기에 의해 융합 파트너에 연결되고, 상기 펩티드 연결기가 가요성 펩티드 분절 및/또는 강직성 펩티드 분절, 예를 들어 1, 2, 3, 4 또는 5개 이상의 강직성 펩티드 분절을 포함하는, 일부 양태에 따른 방법.
18. 가요성 펩티드 분절이 글리신, 세린, 알라닌 및 트레오닌으로부터 선택되는 2개 이상의 아미노산 잔기를 포함하고, 바람직하게는 상기 가요성 펩티드 분절인 구조식 (GS)a(GGS)b(GGGS)c(GGGGS)d를 갖고, a, b, c 및 d가 0 이상의 정수이고, a+b+c+d≥1이고, 더욱 바람직하게는 상기 가요성 펩티드 분절이 하기 서열로 이루어진 군으로부터 선택되는 서열을 갖는, 한 양태에 따른 방법:
(i) GSGGGSGGGGSGGGGS(서열번호 6);
(ii) GSGGGGSGGGGSGGGGSGGGGSGGGGS(서열번호 7);
(iii) GGGGSGGGGSGGGGSGGGGS(서열번호 8);
(iv) GSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS(서열번호 9); 및
(v) GGGSGGGSGGGSGGGSGGGS(서열번호 10).
19. 강직성 펩티드 분절이 인간 융모성 생식선 자극호르몬 β 아단위의 카복시-종결된 펩티드이거나, 강직성 펩티드 분절이 인간 융모성 생식선 자극호르몬 β 아단위의 카복시-종결된 펩티드와 적어도 70%, 80%, 90% 또는 95% 이상의 동일성을 갖고; 상기 강직성 펩티드 분절이 1 또는 2개 이상의 글리코실화 부위를 포함할 수 있고; 바람직하게는 상기 강직성 펩티드 분절이 하기 아미노산 서열로부터 선택되는 아미노산 서열을 포함하고; 더욱 바람직하게는, 펩티드 연결기가 서열번호 15에 제시된 아미노산 서열을 포함하는, 일부 양태에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질:
(i) PRFQDSSSSKAPPPSLPSPSRLPGPSDTPILPQ(서열번호 11);
(ii) SSSSKAPPPSLPSPSRLPGPSDTPILPQ(서열번호 12);
(iii) SSSSKAPPPS(서열번호 13); 및
(iv) SRLPGPSDTPILPQ(서열번호 14).
본 개시내용의 양태 및 종래 기술의 기술적 해법을 보다 명확히 설명하기 위해, 이하 상기 양태 및 종래 기술에서 이용되어야 할 도면을 간략히 소개한다. 명백하게, 명세서의 하기 도면은 본 개시내용의 일부 양태만을 나타낸다. 당해 분야에서 통상의 지식을 가진 자라면, 이러한 도면에 기초하여 창의적인 작업 없이 다른 양태를 얻을 수 있다.
도 1a는 mPEG 변형이 없는 FVIII-Fc(FF-0)의 SEC-HPLC 검출의 결과를 도시한다.
도 1b는 5 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-5L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1c는 10 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-10L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1d는 20 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-20L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1e는 30 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-30L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1f는 40 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-40L)의 SEC-HPLC 검출의 결과를 도시한다.
도 2a는 mPEG 변형이 없는 FVIII-연결기 1-Fc(FL1F-0)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 99%, 응집체 < 1%).
도 2b는 20 kDa 분자량의 mPEG로 변형된 FVIII-L1-Fc(FL1F-20L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2c는 선형 30 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-30L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2d는 선형 40 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-40L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2e는 선형 50 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-50L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2f는 Y-형 40 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-40Y)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 3a는 G25와의 교환 전 및 후에 mPEG 변형이 없는 hFVIII-Fc(FF-0)의 저장 용액의 SDS-PAGE 검출의 결과를 도시한다(H는 환원 조건을 나타내고, F는 비-환원 조건을 나타냄).
도 3b는 상이한 분자량을 갖는 mPEG와 가교결합된 hFVIII-Fc(FF-5L 내지 FF-40L)의 SDS-PAGE 검출(비-환원)의 결과를 도시한다.
도 3c는 상이한 분자량을 갖는 mPEG와 가교결합된 hFVIII-Fc(FF-5L 내지 FF-40L)의 SDS-PAGE 검출(환원)의 결과를 도시한다.
도 1a는 mPEG 변형이 없는 FVIII-Fc(FF-0)의 SEC-HPLC 검출의 결과를 도시한다.
도 1b는 5 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-5L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1c는 10 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-10L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1d는 20 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-20L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1e는 30 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-30L)의 SEC-HPLC 검출의 결과를 도시한다.
도 1f는 40 kDa 분자량의 mPEG로 변형된 FVIII-Fc(FF-40L)의 SEC-HPLC 검출의 결과를 도시한다.
도 2a는 mPEG 변형이 없는 FVIII-연결기 1-Fc(FL1F-0)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 99%, 응집체 < 1%).
도 2b는 20 kDa 분자량의 mPEG로 변형된 FVIII-L1-Fc(FL1F-20L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2c는 선형 30 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-30L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2d는 선형 40 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-40L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2e는 선형 50 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-50L)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 2f는 Y-형 40 kDa mPEG로 변형된 FVIII-L1-Fc(FL1F-40Y)의 SEC-HPLC 검출의 결과를 도시한다(순도 > 95%, 응집체 < 5%, 비-가교결합 < 1%).
도 3a는 G25와의 교환 전 및 후에 mPEG 변형이 없는 hFVIII-Fc(FF-0)의 저장 용액의 SDS-PAGE 검출의 결과를 도시한다(H는 환원 조건을 나타내고, F는 비-환원 조건을 나타냄).
도 3b는 상이한 분자량을 갖는 mPEG와 가교결합된 hFVIII-Fc(FF-5L 내지 FF-40L)의 SDS-PAGE 검출(비-환원)의 결과를 도시한다.
도 3c는 상이한 분자량을 갖는 mPEG와 가교결합된 hFVIII-Fc(FF-5L 내지 FF-40L)의 SDS-PAGE 검출(환원)의 결과를 도시한다.
본 개시내용의 목적, 기술적 해법 및 이점을 보다 명확하게 하기 위해, 이하 도면 및 양태를 참고하여 본 개시내용을 더욱 상세히 설명한다. 명백하게, 기술된 양태는 모든 양태가 아니라 본 개시내용의 양태의 일부일 뿐이다. 본 개시내용의 양태에 기초하여, 창조적인 작업 없이 당업자에 의해 수득된 다른 모든 양태는 본 개시내용의 보호 범위에 속한다.
용어 "응고 인자 VIII"(인자 VIII 또는 FVIII로도 지칭됨)은 주로 간 세포에 의해 생성되는 크고 복잡한 당단백질을 지칭한다. 용어 "응고 인자 VIII 활성 모이어티"는 FVIII 활성을 나타내는 본 개시내용의 융합 단백질의 모이어티를 지칭한다. 천연 인간 FVIII은 신호 펩티드를 비롯한 2,351개의 아미노산, 및 상동성에 의해 정의된 여러 상이한 도메인으로 구성된다: NH2-A1-A2-B-A3-C1-C2-COOH의 순서로 3개의 A 도메인, 1개의 B 도메인 및 2개의 C 도메인. 혈액에서, FVIII은 2가 금속 이온에 의해 연결된 2개의 쇄(B-A3의 경계에서 절단됨)로 구성되는 이종이량체로서 분비된다. A1-A2-B 쇄는 중쇄(HC)로 지칭되고, A3-C1-C2 쇄는 경쇄(LC)로 지칭된다.
내인성 인자 VIII 분자는 상이한 크기의 B 도메인을 갖는 분자의 풀로 체내에서 순환한다. B 도메인의 점진적인 효소 절단은 생체 내에서 발생할 수 있고, 상이한 크기의 B 도메인을 갖는 분자의 풀을 생성한다. 일반적으로, 위치 740에서의 절단의 발생(B 도메인의 마지막 부분이 이때 절제됨)은 트롬빈의 활성화와 관련되는 것으로 여겨진다.
본 개시내용의 "응고 인자 VIII"은 천연 야생형 서열(예컨대, 서열번호 1) 및 이의 변이체, 예를 들어 응고 인자 VIII의 활성을 유지하면서 하나 이상의 아미노산의 치환, 결실 또는 삽입에 의해 수득된 변이체 단백질을 지칭할 수 있다.
한 양태에서, 응고 인자 VIII은 B-도메인 결실된 분자이고, 이때 나머지 도메인은 서열번호 1의 아미노산 1 내지 745 및 1640 내지 2332에 실질적으로 대응한다. 또한, 본 개시내용의 B-도메인 결실된 분자는 서열번호 2에 제시된 서열과 약간의 차이를 가질 수 있고, 즉 나머지 도메인(즉, 3개의 A 도메인 및 2개의 C 도메인)은 서열번호 2에 제시된 아미노산 서열에 기초한 하나 이상의 아미노산의 치환, 부가 또는 결실을 가질 수 있고, 예를 들어 서열번호 2에 제시된 서열과 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개 이상의 아미노산 차이 또는 약 1%, 2%, 3%, 4% 또는 5% 차이를 가질 수 있다. 이러한 차이는 인자 VIII의 기본 활성을 유지하면서, 인자 VIII의 다양한 다른 성분(예컨대, LRP, 다중 수용체, 다른 응고 인자, 세포 표면)에 대한 결합 능력을 변화시킬 수 있거나, 글리코실 기를 도입하고/거나 제거할 수 있다.
용어 "융합 파트너"는 표적 폴리펩티드(반감기가 연장되는 것이 요구되는 폴리펩티드)와 융합된 폴리펩티드를 지칭한다. 융합 파트너는 다양한 상이한 기전, 예컨대 생체 내에서 표적 폴리펩티드의 반감기의 연장을 통해 융합 단백질의 특성을 변화시킬 수 있다.
한 양태에서, 융합 파트너는 신생아 Fc 수용체(FcRn)와 상호작용함으로써 FVIII의 생체내 제거를 지연시킨다. 한 양태에서, 융합 파트너는 면역 글로불린 Fc 영역(Fc 영역), 알부민, 트랜스페린, XTEN 또는 이의 일부이다. 바람직한 양태에서, IgG Fc는 비교적 긴 반감기에 기인하여 바람직하다.
Fc 도메인은 또한 이의 기능, 예컨대 보체 결합 및/또는 특정 Fc 수용체에 대한 결합을 변화시키도록 변형될 수 있다. IgG Fc 도메인의 위치 234, 235 및 237에서의 돌연변이는 통상적으로 FcyRI 수용체에 대한 결합을 감소시키고, 또한 FcyRIIa 및 FcyRIII 수용체에 대한 결합을 감소시킬 수 있다. 이러한 돌연변이는 FcRn 수용체에 대한 결합을 변화시키지 않고, 이는 엔도시토시스 및 재순환 경로를 통해 긴 순환 반감기를 촉진한다. 바람직하게는, 본 개시내용에서 융합 단백질의 변형된 IgG Fc 도메인은 이러한 돌연변이 중 하나 이상을 함유하고, 일부 돌연변이(L234A, L235E 및 G237A)는 특정 Fc 수용체에 대한 감소된 친화도를 야기하고, 다른 것(A330S 및 P331S)은 감소된 C1q-매개 보체 결합을 야기한다.
용어 "폴리알킬렌 글리콜"은 본 개시내용에서 응고 인자 VIII 및/또는 융합 파트너 상의 특정 위치에서 접합된 친수성 중합체이다. 폴리알킬렌 글리콜은 선형 또는 분지형일 수 있고, 하나 이상의 독립적으로 선택되는 중합체 모이어티를 함유할 수 있다. 바람직하게는, 폴리알킬렌 글리콜은 폴리에틸렌 글리콜(이의 메톡시-종결된 형태 m-PEG를 포함함), 폴리프로필렌 글리콜(mPPG를 포함함) 등이다.
본 개시내용의 폴리알킬렌 글리콜은 폴리에틸렌 글리콜(PEG)일 수 있고, 선형 또는 분지형일 수 있다. 분지형 중합체의 골격은 당해 분야에 주지되어 있다. 일반적으로, 분지형 중합체는 중심 분지형 코어 부분 및 상기 중심 분지형 코어에 연결된 하나 이상의 선형 중합체 쇄를 갖는다. 본 개시내용은 바람직하게는 PEG의 분지형 형태를 사용한다. 한 양태에서, 분지형 폴리에틸렌 글리콜은 구조식 R(-PEG-OH)m으로 표시될 수 있고, 이때 R은 코어 파트, 예컨대 글리세롤 또는 펜타에리트리톨을 나타내고, m은 아암/분지의 수를 나타낸다.
한 양태에서, 분지형 PEG(예컨대, mPEG)의 분지의 수는 2개이므로, "Y-형" PEG(예컨대, mPEG)로 지칭되고, 즉 분지형 PEG는 2개의 PEG를 함유하거나, 분지형 PEG는 선형 메톡시 PEG를 함유한다.
다른 적합한 중합체의 예는 비제한적으로 다른 폴리알킬렌 글리콜(예컨대, 폴리프로필렌 글리콜(PPG), 에틸렌 글리콜 및 프로필렌 글리콜의 공중합체), 폴리옥시에틸화된 폴리올, 올레핀계 알코올, 폴리비닐피롤리돈, 폴리하이드록시프로필메타크릴아미드, 폴리([α]-하이드록시산), 폴리비닐 알코올, 폴리포스파젠, 폴리옥사졸린, 폴리 N-아크릴로일모폴린 및 공중합체, 삼원 공중합체 및 이들의 혼합물을 포함한다.
본 개시내용의 한 양태에서, PEG 변형(즉, 접합), 더욱 바람직하게는 mPEG 변형이 사용되며, 이때 변형은 무작위 또는 특정 위치에 존재하고, 변형 위치는 유리 아미노 기, 설프하이드릴 기, 당 기 및/또는 카복실 기로 이루어진 군으로부터 선택되고, 바람직하게는 유리 아미노 기이다.
본 개시내용의 특정 양태에서, 유리 아미노 기에서 무작위 변형을 위해 사용되는 변형제, 본 명세서의 폴리알킬렌 글리콜 또는 변형된 폴리알킬렌 글리콜은 mPEG-SS(메톡시 폴리에틸렌 글리콜-석신이미딜 석신에이트), mPEG-SC(메톡시 폴리에틸렌 글리콜-석신이미딜 카보네이트), mPEG-SPA(메톡시 폴리에틸렌 글리콜-석신이미딜 프로피오네이트) 및 mPEG-SG(메톡시 폴리에틸렌 글리콜-석신이미딜 글루타레이트) 등으로부터 선택된다. N-말단 변형의 경우, mPEG-ALD(메톡시 폴리에틸렌 글리콜-아세트알데하이드), mPEG-pALD(메톡시 폴리에틸렌 글리콜-프로피온알데하이드) 및 mPEG-bALD(메톡시 폴리에틸렌 글리콜-부티르알데하이드) 등 중 하나가 선택된다. 변형제 mPEG-SS, mPEG-SC, mPEG-SPA, mPEG-SG, mPEG-ALD, mPEG-pALD, mPEG-bALD는 선형 또는 분지형이다.
본 개시내용의 특정 양태에서, 유리 설프하이드릴 기에서 무작위 변형에 사용되는 변형제는 mPEG-mal(메톡시 폴리에틸렌 글리콜-말레이미드), mPEG-OPSS(메톡시 폴리에틸렌 글리콜-오르토피리딜 다이설파이드), mPEG-비닐설폰(메톡시 폴리에틸렌 글리콜-비닐설폰) 및 mPEG-티올(메톡시 폴리에틸렌 글리콜-티올) 등이다.
본 개시내용의 특정 양태에서, 당 기 및/또는 카복실 기에서 무작위 변형에 사용되는 변형제는 mPEG-ZH(메톡시 폴리에틸렌 글리콜-하이드라자이드)이다.
본 개시내용의 한 양태에서, 변형을 위한 변형제는 하기 화학식 1의 구조를 갖는다:
[화학식 1]
상기 식에서,
0≤m1≤6이고, m1은 바람직하게는 5이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다.
화학식 1의 변형제는 분자량이 5 내지 60 kDa(킬로달톤), 바람직하게는 40 kDa의 분자량을 갖는다. 바람직하게는, 본 개시내용의 한 양태에서, 화학식 1의 변형제는 유리 아미노 기에서 무작위 mPEG 변형을 위해 사용된다.
본 개시내용의 한 양태에서, 변형을 위한 변형제는 하기 화학식 2의 구조를 갖는다:
[화학식 2]
상기 식에서,
0≤m2≤6이고, m2는 바람직하게는 2이고;
0≤m3≤6이고, m3은 바람직하게는 1이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다.
화학식 2의 변형제는 5 내지 60 kDa, 바람직하게는 40 kDa의 분자량을 갖는다. 바람직하게는, 본 개시내용의 한 양태에서, 화학식 2의 변형제는 유리 아미노 기에서 무작위 mPEG 변형을 위해 사용된다.
본 개시내용의 한 양태에서, 변형을 위한 변형제는 하기 화학식 3의 구조를 갖는다:
[화학식 3]
상기 식에서,
0≤m4≤6이고, m4는 바람직하게는 2이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다.
화학식 3의 변형제는 5 내지 60 kDa, 바람직하게는 40 kDa의 분자량을 갖는다. 바람직하게는, 본 개시내용의 한 양태에서, 화학식 3의 변형제는 유리 설프하이드릴 기에서 무작위 mPEG 변형을 위해 사용된다.
중합체 골격의 크기는 다양할 수 있지만, 중합체(예컨대, PEG, mPEG, PPG 또는 mPPG)의 전형적인 크기 범위는 약 0.5 내지 약 160 kDa, 예를 들어 약 1 내지 약 100 kDa이다. 더욱 구체적으로, 본 개시내용에서 접합된 각각의 친수성 중합체의 크기는 주로 하기 범위 내에서 변한다: 약 1 내지 약 80 kDa, 약 2 내지 약 70 kDa; 약 5 내지 약 70 kDa; 약 10 내지 약 60 kDa, 약 20 내지 약 50 kDa; 약 30 내지 약 50 kDa 또는 약 30 내지 약 40 kDa. 이러한 크기는 당해 분야에서 인식되는 바와 같이 정확한 측정이 아닌 근사치를 나타냄이 이해되어야 한다.
특정 양태에서, 본 개시내용에 사용되는 PEG 또는 mPEG의 크기는 35 kDa 이상, 바람직하게는 40 kDa 이상, 45 kDa 이상, 50 kDa 이상, 55 kDa 이상, 60 kDa 이상, 65 kDa 이상 또는 70 kDa 이상이고, 예를 들어 분자량은 구체적으로 40 kDa, 50 kDa, 60 kDa, 70 kDa, 80 kDa, 90 kDa, 100 kDa, 110 kDa, 120 kDa, 130 kDa, 140 kDa, 150 kDa 또는 160 kDa이다.
용어 "개선된 순환 반감기"는 본 개시내용의 분자가 변경된 순환 반감기(혈장 반감기), 바람직하게는 야생형 인자 VIII에 비해 증가된 순환 반감기를 갖는 것을 의미한다. 순환 반감기는 바람직하게는 10% 이상, 바람직하게는 15% 이상, 바람직하게는 20% 이상, 바람직하게는 25% 이상, 바람직하게는 30% 이상, 바람직하게는 35% 이상, 바람직하게는 40% 이상, 바람직하게는 45% 이상, 바람직하게는 50% 이상, 바람직하게는 55% 이상, 바람직하게는 60% 이상, 바람직하게는 65% 이상, 바람직하게는 70% 이상, 바람직하게는 75% 이상, 바람직하게는 80% 이상, 바람직하게는 85% 이상, 바람직하게는 90% 이상, 바람직하게는 95% 이상, 바람직하게는 100% 이상, 더욱 바람직하게는 125% 이상, 더욱 바람직하게는 150% 이상, 더욱 바람직하게는 175% 이상, 더욱 바람직하게는 200% 이상, 가장 바람직하게는 250% 또는 300% 이상만큼 증가된다. 더욱 더 바람직하게는, 분자는 400%, 500%, 600% 또는 심지어 700% 이상만큼 증가된 순환 반감기를 갖는다.
용어 "약학적으로 허용되는 담체"는 비제한적으로 식염수, 완충액, 글루코스, 물, 글리세롤, 에탄올 및 이들의 조합을 포함한다. 일반적으로, 약학 제제는 투여 방식에 적합해야 한다. 본 개시내용의 약학 조성물은, 예를 들어, 생리 식염수, 또는 글루코스 및 기타 보조제를 함유하는 수용액을 사용하는 통상적인 방법에 의해 주사 형태로 제조될 수 있다. 약학 조성물은 무균 조건 하에 제조되어야 한다. 투여되는 활성 성분의 양은 치료 효과량이다. 본 발명의 약학 제제는 또한 서방성 제제로 제조될 수 있다.
실시예
실시예 1
mPEG-변형된 hFVIII 융합 단백질의 제조 및 정제
1.1. mPEG-변형된 hFVIII 융합 단백질의 제조
1.1.1. 일련의 hFVIII 융합 단백질 발현 플라스미드를 당업자에게 주지된 분자 클로닝 기술에 따라 구축하고, 발현 플라스미드를 각각 DHFR-결핍 CHO 세포(미국 특허공보 제4,818,679호 참고)로 형질감염시켜 각각의 hFVIII 융합 단백질을 발현시켰다(표 1). 융합 단백질의 특정 제조 단계에 대해서는 중국 특허공보 제ZL201610692838.0호(이의 전문이 본원에 참고로 혼입됨)를 참고한다.
[표 1]
융합 단백질의 조성 및 구조
1.1.2. 1.1.1.에서 각각의 융합 단백질의 발효액을 원심분리하고, 여과하고, 이어서 친화도 크로마토그래피/소수성 상호작용 크로마토그래피/이온-교환 크로마토그래피/크기 배제 크로마토그래피를 수행하여 5개의 hFVIII 융합 단백질 FF-0, FL1F-0, FL2F-0, F(전장)L1F'-0 및 F(전장)L2F"-0를 수득하고, SEC-HPLC 검출은 응집체가 5% 미만인 것으로 나타났다. 5개의 hFVIII 융합 단백질을 각각 0.95 mg/mL의 단백질 농도를 갖는 hFVIII 융합 단백질 저장 용액으로 제형화시켰다.
1.1.3. 1.1.2.에서 제조된 5개의 hFVIII 융합 단백질 저장 용액 각각 5 mL를 G25[지이 헬스케어(GE Healthcare)] 분자체 크로마토그래피에 적용하였다. 구체적인 공정은 다음과 같다.
완충액 제조: 20 mM 헤페스(Hepes), 0.1 M NaCl, 5.0 mM CaCl2, 0.02% 트윈(Tween) 8.0, pH 7.0.
크로마토그래피
(1) 평형: 크로마토그래피 컬럼을 pH 및 전도도가 완충액과 동일하게 될 때까지 컬럼 부피의 3배의 결합 완충액으로 평형화시켰고, 유량은 150 cm/시간으로 안정하였다.
(2) 샘플 로딩: 유량을 150 cm/시간으로 제어하였다.
(3) 평형: 크로마토그래피 컬럼을 pH 및 전도도가 완충액과 동일하게 될 때까지 컬럼 부피의 3배의 결합 완충액으로 평형화시켰고, 유량은 150 cm/시간으로 안정하였다.
(4) 평형: 크로마토그래피 컬럼을 완충액으로 평형화시키고, 1.8보다 큰 A280/A260을 갖는 피크를 수집하였다.
(5) 크로마토그래피 컬럼의 동일 반응계 세척: 컬럼을 컬럼 부피의 1.5배의 0.2 M NaOH로 60 cm/시간의 유량으로 역으로 세척하고, 완충액으로 중화시켰다.
(6) 크로마토그래피 컬럼의 보관: 실험 후, 컬럼을 컬럼 부피의 3배의 정제수로 100 cm/시간의 유량으로 세척하고, 이어서 컬럼 부피의 2배의 20% 에탄올로 보관하였다.
한외여과 농도: G25 교환 후 5개의 hFVIII 융합 단백질(FF-0, FL1F-0, FL2F-0, F(전장)L1F'-0 및 F(전장)L1F "-0) 저장 용액을 50 kDa 한외여과 필터 튜브로 한외여과에 의해 농축하고, 바람직하게는 1.5 mg/mL의 단백질 농도까지 3,800 rpm으로 4℃에서 원심분리에 의해 농축하였다.
1.1.4. 원하는 mPEG-SC(각각 분자량 5 kDa, 10 kDa, 20 kDa, 30 kDa 또는 40 kDa의 분자량을 갖고 화학식 1의 구조를 갖는 선형 L-형 mPEG-SC, 및 40 kDa의 분자량을 갖고 화학식 2의 구조를 갖는 분지형 Y-형 mPEG-SC)[베이징 젠켐 테크놀로지 캄파니 리미티드(Beijing jenkem Technology Co., Ltd.)]를 1:10 내지 1:100의 hFVIII 융합 단백질 대 mPEG-SC의 몰비에 따라 칭량하였다. 1.1.3.에서 한외여과 후 농축된 hFVIII 융합 단백질에 첨가하고, 4시간 동안 반응시켰다. 이어서, 기질 hFVIII 융합 단백질에 대해 10배 몰비의 히스티딘을 첨가하여 반응을 종료하고, 상이한 분자량을 갖는 mPEG-SC 변형된 hFVIII 융합 단백질을 수득하였다. 일부 변형된 생성물의 수 및 조성은 하기 표 2에 제시된다.
[표 2]
1.2. mPEG-변형된 hFVIII 융합 단백질의 정제
1.2.1. 실시예 1의 1.1.4.에서 제조된 각각의 mPEG-변형된 hFVIII 융합 단백질을 각각 S200(지이 헬스케어) 분자체 크로마토그래피에 적용하였다. 구체적인 공정은 다음과 같다.
완충액 제조: 20 mM 히스티딘, 0.1 M NaCl, 5.0 mM CaCl2, 0.02% 트윈 8.0, pH 7.0.
크로마토그래피
(1) 평형: 크로마토그래피 컬럼을 pH 및 전도도가 완충액과 동일하게 될 때까지 3 컬럼 부피의 결합 완충액으로 평형화시키고, 유량을 150 cm/시간으로 제어하였다.
(2) 샘플 로딩: 샘플 유량을 150 cm/시간으로 제어하였다.
(3) 평형: 크로마토그래피 컬럼을 pH 및 전도도가 완충액과 동일하게 될 때까지 컬럼 부피의 3배의 완충액으로 평형화시키고, 유량을 150 cm/시간으로 제어하였다.
(4) 평형: 크로마토그래피 컬럼을 완충액으로 평형화시키고, 1.8보다 큰 A280/A260을 갖는 피크를 수집하였다.
(5) 크로마토그래피 컬럼의 동일 반응계 세척: 컬럼을 컬럼 부피의 1.5배의 0.2 M NaOH로 60 cm/시간의 유량으로 역으로 세척하고, 완충액으로 중화시켰다.
(6) 크로마토그래피 컬럼의 보관: 실험 후, 컬럼을 컬럼 부피의 3배의 정제수로 100 cm/시간의 유량으로 세척하고, 이어서 컬럼 부피의 2배의 20% 에탄올로 보관하였다.
1.2.2. 1.2.1.에서 수득된 크로마토그래피 생성물을 소스(Source) 15Q(지이 헬스케어) 음이온 크로마토그래피에 적용하였다.
완충액 제조
결합 완충액: 20 mM 히스티딘, 0.1 M NaCl, 5.0 mM CaCl2, 0.02% 트윈 8.0, pH 7.0; 용리 완충액: 20 mM 히스티딘, 2.0 M NaCl, 5.0 mM CaCl2, 0.02% 트윈 8.0, pH 7.0; CIP: 0.5 M NaOH.
크로마토그래피
(1) 평형: 크로마토그래피 컬럼을 pH 및 전도도가 완충액과 동일하게 될 때까지 3 컬럼 부피의 결합 완충액으로 평형화시키고, 유량을 150 cm/시간으로 제어하였다.
(2) 샘플 로딩: 유량은 균일하게 150 cm/시간였다.
(3) 평형: 크로마토그래피 컬럼을 pH 및 전도도가 완충액과 동일하게 될 때까지 컬럼 부피의 3배의 완충액으로 평형화시키고, 유량을 150 cm/시간으로 제어하였다.
(4) 용리: 샘플을 컬럼 부피의 20배의 완충액 B로 100 cm/시간의 균일한 유량으로 0 → 100% 선형 구배로 용리하였다. 1.8보다 큰 A280/A260을 갖는 용리 피크를 별도의 튜브에 수집하고, SEC-HPLC 검출을 수행하였다.
(5) 크로마토그래피 컬럼의 동일 반응계 세척: 컬럼을 컬럼 부피의 1.5배의 0.5 M NaOH로 60 cm/시간의 유량으로 역으로 세척하고, 결합 완충액으로 중화시켰다.
(6) 크로마토그래피 컬럼의 보관: 실험 후, 컬럼을 컬럼 부피의 3배의 정제수로 100 cm/시간의 유량으로 세척하고, 이어서 컬럼 부피의 2배의 20% 에탄올로 보관하였다.
1.2.3. SEC-HPLC 검출
1.2.2.에서 수득된 크로마토그래피 생성물을 SEC-HPLC 검출에 적용하였다.
컬럼: G3000/G4000; 유량: 0.5 mL/분; 검출 파장: 280 nm; 컬럼 온도: 25℃; 주입 부피: 100 μL(주입량: 20 μg); 이동상: 0.30 M 나트륨 클로라이드, 0.02 M 이미다졸, 0.01 M 칼슘 클로라이드, 25 ppm 트윈 80, 10% 에탄올, pH 7.0; 실행 시간: 35 내지 50분.
FF-0 내지 FF-40L의 검출 결과는 도 1a 내지 1f에 도시된다. FL1F-0 내지 FL1F-50L 및 FL1F-40Y의 검출 결과는 도 2a 내지 2f에 도시된다. 이러한 결과는 FL1F-0 내지 FL1F-60L의 경우 순도가 95% 초과이고, 중합체가 5% 미만이고, 비-가교결합이 1% 미만임을 나타낸다.
1.2.4. SDS-PAGE 겔 전기영동 검출
1.2.2.에서 수득된 생성물을 SDS-PAGE 검출에 적용하였다.
(1) 겔 제조. 1x 트리스-글리신 전기영동 완충액: SDS 0.4 g, 트리스 베이스 1.21 g, 글리신 7.5 g, 및 400 mL로 구성하기 위한 이중-증류수.
5% 적층 겔: 이중-증류수 4.1 mL, 1 M 트리스-HCl(pH 6.8) 0.75 mL, 30% (w/v) 폴리아크릴아미드 1 mL, 10% (w/v) 암모늄 퍼설페이트 60 μL, 10% (w/v) SDS 60 μL, TEMED 6 μL.
6% 분리 겔: 이중-증류수 4.9 mL, 1.5 M 트리스-HCl(pH 8.8) 3.8 mL, 30% (w/v) 폴리아크릴아미드 6 mL, 10%(w/v) 암모늄 퍼설페이트 150 μL, 10% (w/v) SDS 150 μL, TEMED 6 μL.
(2) 5x 단백질 로딩 완충액: 글리세롤 5 mL, 1 M 트리스-HCl(pH 6.8) 2.5 mL, 브로모페놀 블루 0.05 g, SDS 1 g, 10 mL로 구성하기 위한 이중-증류수, 4℃에서 보관하고, β-머캅토에탄올 0.5 mL를 사용하기 전에 첨가하였다.
(3) 샘플 제조: 시험할 샘플을 동일한 부피의 로딩 완충액과 혼합하였다. 환원 SDS-PAGE의 경우, 0.1 mg/mL 2-머캅토에탄올을 샘플과 동일한 부피로 첨가하고, 비-환원 SDS-PAGE의 경우 2-머캅토에탄올을 첨가하지 않았다. 샘플을 로딩 완충액과 혼합한 후, 끓는 물에서 10분 동안 가열하였다.
(4) 전기영동: 10 μL의 시험할 샘플 및 단백질 마커를 각각 겔의 웰에 로딩하고, 60 V 전압에서 전기영동하였다. 브로모페놀 블루 염료를 분리 겔에 도입한 후, 브로모페놀 블루 염료가 분리 겔의 바닥에 도달할 때까지 전압은 120 V로 증가하였고, 이어서 전원을 껐다.
(5) 염색: SDS-PAGE 겔을 조심스럽게 제거하고, 쿠마시 브릴리언트 블루(Coomassie Brilliant Blue) 염색 용액을 함유하는 플라스틱 상자에 위치시키고, 이어서 상기 상자를 마이크로파 오븐에 위치시켜 1분 동안 가열하였다.
(6) 탈색: 염색된 SDS-PAGE 겔을 탈색 용액에 위치시키고, 진탕 하에 탈색하 고, 탈색 용액을 2시간마다 교체하고, 육안으로 보이는 투명한 밴드가 나타난 후 중단하였다.
(7) 기록: 완성된 SDS-PAGE 겔을 촬영하거나 건조하고 보관하였다. 도 3a 내지 3c는 FF-5L 내지 FF-40L의 SDS-PAGE 검출의 결과를 도시한다.
실시예 2
색원체 기질 검정에 의한 mPEG-변형된 hFVIII 융합 단백질의 시험관내 활성의 간접 측정
색원체 기질 검정은 실시예 1에서 제조된 mPEG-변형된 hFVIII 융합 단백질의 활성을 측정하기 위해 사용되었다. 크로모제닉스코티스트(ChromogenixCoatest) FVIII 키트(크로모제닉, 참고번호 K824086)를 사용하였다. 검출 원리는 트롬빈에 의해 활성화된 후 인지질 및 칼슘 이온의 존재 하에 FVIIIa가 FIXa와 결합하여 효소 복합체를 형성하고, 이는 인자 X를 활성화시켜 활성 형태 Xa로 전환하고, 이어서 활성 Xa가 다시 특정 색원체 기질(S-2765)을 절단하고, 발색단 pNA를 방출할 수 있다. 405 nm에서 pNA의 양을 측정함으로써, FXa의 양에 정비례하는 FXa의 활성을 측정할 수 있다. 시스템에서 인자 IXa 및 인자 X의 함량이 과도하므로, FXa의 활성은 FVIIIa의 함량과 단지 직접적인 관련이 있다. 색원체 기질 검정에 의한 FVIII 생물학적 활성의 간접 측정 결과는 표 3에 제시된다.
[표 3]
색원체 기질 검정에 의한 FVIII의 생물학적 활성의 간접 측정
실시예 3
인간 인자 VIII의 역가 측정
본 개시내용에서 사용되는 응고 인자 VIII 역가의 측정을 위한 검정은 또한 1-단계 응고 검정으로 지칭된다. 구체적인 단계는 중국 약전(2010년 버전)의 제2 파트를 참고한다. FVIII 생물학적 활성에 대한 1-단계 응고 분석은 응고 시간을 연장하기 위해 FVIII-결핍 혈장을 교정하는 능력에 기초한다. 지멘스(Siemens) 사(독일)의 키트 응고 인자 VIII 결핍 플라즈마(카탈로그 번호 OTXW17)를 사용하였다. 검정은 다음과 같이 수행되었다: 먼저, 공지된 역가를 가진 표준 물질 WHO 국제 표준 제8 국제 표준 표준 인자 VIII 농축물(카탈로그 번호 07/350)을 4 IU/mL로 희석하고, 이어서 구배 희석하여 상이한 역가(IU/mL)에 도달하고; 이들의 표준 샘플을 활성화된 부분 트롬보플라스틴 시간(APTT)을 측정하기 위해 FVIII 결핍 혈장과 혼합하고; 상응하는 응고 시간(초)의 로그에 대한 FVIII 활성 표준 용액의 역가(IU/mL)의 로그의 선형 회귀를 사용하여 표준 곡선을 설정하고; 이어서, 시험할 샘플을 희석하고, FVIII 결핍 혈장과 혼합하고, APTT 측정을 수행하였다. 표준 곡선에 정합함으로써, FVIII 샘플의 효능을 측정할 수 있고, FVIII 샘플의 IU/mg 단위의 특정 활성을 계산할 수 있다. 결과는 표 4에 제시된다.
[표 4]
1-단계 응고 검정에 의한 생물학적 활성의 직접 측정
표 3 및 표 4는 색원체 기질 검정에 의해 측정된 FL1F-40Y, FL2F-40Y, F(전장)L1F'-40Y 및 F(전장)L2F"-40Y의 생물학적 활성을 나타낸다. 1-단계 응고 검정은 mPEG 변형이 없는 엘록테이트/FL1F-0/FL2F-0보다 낮다. 이는 변형된 단백질의 공간 구조에 대한 mPEG 변형의 효과에 기인하고, 종래 기술의 다른 mPEG-변형된 단백질(예컨대, PEG-INTRON, 페그필그라스팀)은 유사한 결과를 나타낸다. 예기치 않게, 40 kD 이상의 mPEG로 변형된 FVIII Fc 융합 단백질은 여전히 상대적으로 높은 활성을 유지할 수 있다. 또한, 후속 실험은 이러한 단백질의 반감기가 크게 연장됨을 추가로 확인하였다.
실시예 4
혈우병 A 마우스의 꼬리 정맥 절개 출혈 모델을 사용하는 약력학 시험
본 실시예에서, 혈우병 A 마우스(HA 마우스)에서 mPEG-변형된 hFVIII 융합 단백질 각각의 반감기를 꼬리 정맥 절개(TVT) 실험에 의해 비교하였다.
4.1. 문헌에 보고된 방법에 따라서, 10 내지 12주령의 수컷 HA 마우스[상하이 서던 모델 바이오로지컬 리서치 센터(Shanghai Southern Model Biological Research Center)에서 구입함]를 무작위로 군 당 12마리 마우스의 군으로 나누었다. 마우스에 각각 15 IU/kg의 투약량으로 꼬리 정맥을 통해 약물, 즉 본 개시내용의 mPEG-변형된 융합 단백질 또는 양성 대조군 엘록테이트를 투여하였다. 약물 투여 48시간 후, 꼬리를 측정하여 2.7 mm 내경의 캐뉼라로 표시하고, 좌측 정맥을 11개의 직선형 수술용 칼날로 절개하였다. 절개 후, 꼬리를 미리 데운 13 mL의 식염수를 함유하는 튜브에 즉시 넣고, 출혈 시간을 기록하였다. 출혈이 멈춘 후(절개로 인한 혈류가 뚜렷하지 않음), 식염수 튜브에서 마우스의 꼬리를 제거하고, 이어서 마우스를 37℃의 가열 패드에 위치시켜 상처를 건드리지 않도록 주의하면서 체온을 유지하였다. 마우스가 깨어난 후, 바닥에 흰 종이가 있는 우리에 넣고, 각각의 동물을 단일 우리에 넣었다. 출혈 정도를 측정하기 위해 각각의 관찰 후 백지 또는 우리를 교체하였다. 꼬리 절개 후 48시간 이내의 마우스의 생존율 및 12시간 이내의 재출혈 횟수를 계수하였다(총 12시간 계수하고, 1시간 이내의 다중 출혈을 1회 출혈로 계수함). 결과는 표 5에 제시된다.
재출혈률은 실험 기간 동안 재출혈이 발생한 마우스의 비율을 지칭한다. 중증 출혈률은 12시간 내에 중증 출혈(+++) 또는 다중 중등도 출혈(++)이 있는 마우스의 비율을 지칭한다. 이들 중 중등도 출혈(++)은 30% 이상의 도포 면적을 갖는 백지 상의 많은 혈액 얼룩이 존재하지만, 큰 면적(면적 > 3 cm2)의 혈액 풀이 존재하지 않는 경우를 지칭하고, 중증 출혈(+++)은 30% 이상의 도포 면적을 갖는 백지 상의 많은 혈액 얼룩이 존재하고, 혈액 얼룩의 색이 진하고, 큰 면적의 혈액 풀이 존재하는 경우를 지칭하고; 일부 경우에, 도포 면적이 적더라도, 마우스가 많은 혈액을 잃고 운동 범위가 감소되고 백지가 심각하게 피로 젖은 경우, 중증 출혈을 갖는 것으로 계수할 수 있다.
[표 5]
약물 투여 48시간 후 TVT 실험에서 48시간 생존율 및 12시간 재출혈률
결과는 mPEG 변형이 없는 엘록테이트/FL1F-0/FL2F-0 군과 비교하여 FL1F-40Y 군, FL2F-40Y 군, F(전장)L1F'-40Y 군 및 F(전장)L2F"-40Y 군이 각각 다른 군보다 유의하게 높은 83.3%, 75.0%, 83.3% 및 83.3%의 생존율을 가짐을 나타낸다. 또한,이러한 군은 다른 군에 비교하여 유의하게 낮은 12시간 재출혈률 및 낮은 중증 출혈률을 갖는다. 따라서, FL1F-40Y, FL2F-40Y, F(전장)L1F'-40Y 및 F(전장)L2F"-40Y는 혈우병 A 마우스의 꼬리 정맥 절개 모델에서 더 긴 보호 시간을 제공한다.
4.2. 4.1.에 기술된 동일한 방법을 사용하여 약물 투여 84시간 후에 10 내지 12주령 수컷 HA 마우스(군 당 12마리 마우스)에 대해 TVT 실험을 수행하였다. 결과는 표 6에 제시된다.
[표 6]
약물 투여 48시간 후 TVT 실험에서 48시간 생존율 및 12시간 재출혈률
결과는 엘록테이트 및 PEG 변형이 없는 다른 군과 비교하여 FL1F-40Y 군, FL2F-40Y 군, F(전장)L1F'-40Y 군 및 F(전장)L2F"-40Y 군이 각각 다른 군보다 유의하게 높은 66.7%, 75.0%, 75.0% 및 75.0%의 생존율을 갖고, 재출혈률이 유의하게 감소됨을 나타낸다. 따라서, FL1F-40Y, FL2F-40Y, F(전장)L1F'-40Y 및 F(전장)L2F"-40Y는 약물 투여 84시간 후 혈우병 A 마우스의 꼬리 정맥 절개 모델에서 출혈을 예방하는 데 특정 효과를 여전히 나타낸다.
4.3. 4.1.에 기술된 동일한 방법을 사용하여 약물 투여 90시간 후에 10 내지 12주령 HA 마우스 20마리(10마리 수컷, 10마리 암컷)/군에 대해 TVT 실험을 수행하였다. 결과는 표 7에 제시된다.
[표 7]
약물 투여 90시간 후 TVT 실험에서 48시간 생존율 및 12시간 재출혈률
결과는 FL1F-50L이 PEG 변형이 없는 엘록테이트 군과 비교하여 유사한 생존율 및 재출혈률을 가짐을 나타낸다. 실험 동물은 단일 성별이 아니므로, 실험 결과는 다른 단일 성별 실험과 비교되지 않는다.
4.4. 4.1.에 기술된 동일한 방법을 사용하여 약물 투여 96시간 후에 10 내지 12주령 수컷 HA 마우스, 12마리 마우스/군에 대한 TVT 실험을 수행하였다. 결과는 표 8에 제시된다.
[표 8]
약물 투여 96시간 후 TVT 실험에서 48시간 생존율 및 12시간 재출혈률
결과는 PEG 변형이 없는 엘록테이트 군과 비교하여 FL1F-40Y/FL2F-40Y는 약간 개선된 생존율을 갖고, 12시간 재출혈률을 유의하게 감소시켰다. FL1F-40Y/FL2F-40Y는 다른 군과 비교하여 유의하게 개선된 생존율 및 다른 군과 비교하여 유의하게 감소된 12시간 재출혈률을 가졌다. 따라서, FL1F-40Y/FL2F-40Y 군은 혈우병 A 마우스의 꼬리 정맥 절개 모델에서 다른 군보다 긴 예방 시간을 가진다.
상기 내용은 본 개시내용의 바람직한 양태일 뿐이고, 본 개시내용을 제한하려는 의도는 아니다. 본 개시내용의 사상 및 원리 내에서 이루어진 모든 변형, 동등한 대체 또는 개선은 본 개시내용의 보호 범위에 포함되어야 한다.
SEQUENCE LISTING
<110> ZHENGZHOU GENSCIENCES INC.
<120> IMPROVED FVIII FUSION PROTEIN AND USE THEREOF
<130> OP2019-XX-0320
<140> PCT/CN2019/087156
<141> 2019-05-16
<150> CN 201810481941.X
<151> 2018-05-18
<160> 15
<170> PatentIn version 3.2
<210> 1
<211> 2332
<212> PRT
<213> Homo sapiens
<400> 1
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1 5 10 15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20 25 30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35 40 45
Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro
50 55 60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65 70 75 80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85 90 95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100 105 110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115 120 125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130 135 140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145 150 155 160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165 170 175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180 185 190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195 200 205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210 215 220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225 230 235 240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245 250 255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260 265 270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275 280 285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290 295 300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305 310 315 320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325 330 335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340 345 350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355 360 365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370 375 380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385 390 395 400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405 410 415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420 425 430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435 440 445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450 455 460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465 470 475 480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485 490 495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500 505 510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515 520 525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530 535 540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545 550 555 560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565 570 575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580 585 590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe
595 600 605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610 615 620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625 630 635 640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645 650 655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660 665 670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675 680 685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690 695 700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705 710 715 720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725 730 735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg
740 745 750
Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys
755 760 765
Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn
770 775 780
Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro
785 790 795 800
His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe
805 810 815
Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser
820 825 830
Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val
835 840 845
Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly
850 855 860
Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser
865 870 875 880
Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala
885 890 895
Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met Pro Val His
900 905 910
Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys Ser Ser Pro
915 920 925
Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu Asn Asn Asp
930 935 940
Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu Ser Ser Trp
945 950 955 960
Gly Lys Asn Val Ser Ser Thr Glu Ser Gly Arg Leu Phe Lys Gly Lys
965 970 975
Arg Ala His Gly Pro Ala Leu Leu Thr Lys Asp Asn Ala Leu Phe Lys
980 985 990
Val Ser Ile Ser Leu Leu Lys Thr Asn Lys Thr Ser Asn Asn Ser Ala
995 1000 1005
Thr Asn Arg Lys Thr His Ile Asp Gly Pro Ser Leu Leu Ile Glu
1010 1015 1020
Asn Ser Pro Ser Val Trp Gln Asn Ile Leu Glu Ser Asp Thr Glu
1025 1030 1035
Phe Lys Lys Val Thr Pro Leu Ile His Asp Arg Met Leu Met Asp
1040 1045 1050
Lys Asn Ala Thr Ala Leu Arg Leu Asn His Met Ser Asn Lys Thr
1055 1060 1065
Thr Ser Ser Lys Asn Met Glu Met Val Gln Gln Lys Lys Glu Gly
1070 1075 1080
Pro Ile Pro Pro Asp Ala Gln Asn Pro Asp Met Ser Phe Phe Lys
1085 1090 1095
Met Leu Phe Leu Pro Glu Ser Ala Arg Trp Ile Gln Arg Thr His
1100 1105 1110
Gly Lys Asn Ser Leu Asn Ser Gly Gln Gly Pro Ser Pro Lys Gln
1115 1120 1125
Leu Val Ser Leu Gly Pro Glu Lys Ser Val Glu Gly Gln Asn Phe
1130 1135 1140
Leu Ser Glu Lys Asn Lys Val Val Val Gly Lys Gly Glu Phe Thr
1145 1150 1155
Lys Asp Val Gly Leu Lys Glu Met Val Phe Pro Ser Ser Arg Asn
1160 1165 1170
Leu Phe Leu Thr Asn Leu Asp Asn Leu His Glu Asn Asn Thr His
1175 1180 1185
Asn Gln Glu Lys Lys Ile Gln Glu Glu Ile Glu Lys Lys Glu Thr
1190 1195 1200
Leu Ile Gln Glu Asn Val Val Leu Pro Gln Ile His Thr Val Thr
1205 1210 1215
Gly Thr Lys Asn Phe Met Lys Asn Leu Phe Leu Leu Ser Thr Arg
1220 1225 1230
Gln Asn Val Glu Gly Ser Tyr Asp Gly Ala Tyr Ala Pro Val Leu
1235 1240 1245
Gln Asp Phe Arg Ser Leu Asn Asp Ser Thr Asn Arg Thr Lys Lys
1250 1255 1260
His Thr Ala His Phe Ser Lys Lys Gly Glu Glu Glu Asn Leu Glu
1265 1270 1275
Gly Leu Gly Asn Gln Thr Lys Gln Ile Val Glu Lys Tyr Ala Cys
1280 1285 1290
Thr Thr Arg Ile Ser Pro Asn Thr Ser Gln Gln Asn Phe Val Thr
1295 1300 1305
Gln Arg Ser Lys Arg Ala Leu Lys Gln Phe Arg Leu Pro Leu Glu
1310 1315 1320
Glu Thr Glu Leu Glu Lys Arg Ile Ile Val Asp Asp Thr Ser Thr
1325 1330 1335
Gln Trp Ser Lys Asn Met Lys His Leu Thr Pro Ser Thr Leu Thr
1340 1345 1350
Gln Ile Asp Tyr Asn Glu Lys Glu Lys Gly Ala Ile Thr Gln Ser
1355 1360 1365
Pro Leu Ser Asp Cys Leu Thr Arg Ser His Ser Ile Pro Gln Ala
1370 1375 1380
Asn Arg Ser Pro Leu Pro Ile Ala Lys Val Ser Ser Phe Pro Ser
1385 1390 1395
Ile Arg Pro Ile Tyr Leu Thr Arg Val Leu Phe Gln Asp Asn Ser
1400 1405 1410
Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys Asp Ser Gly Val
1415 1420 1425
Gln Glu Ser Ser His Phe Leu Gln Gly Ala Lys Lys Asn Asn Leu
1430 1435 1440
Ser Leu Ala Ile Leu Thr Leu Glu Met Thr Gly Asp Gln Arg Glu
1445 1450 1455
Val Gly Ser Leu Gly Thr Ser Ala Thr Asn Ser Val Thr Tyr Lys
1460 1465 1470
Lys Val Glu Asn Thr Val Leu Pro Lys Pro Asp Leu Pro Lys Thr
1475 1480 1485
Ser Gly Lys Val Glu Leu Leu Pro Lys Val His Ile Tyr Gln Lys
1490 1495 1500
Asp Leu Phe Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu
1505 1510 1515
Asp Leu Val Glu Gly Ser Leu Leu Gln Gly Thr Glu Gly Ala Ile
1520 1525 1530
Lys Trp Asn Glu Ala Asn Arg Pro Gly Lys Val Pro Phe Leu Arg
1535 1540 1545
Val Ala Thr Glu Ser Ser Ala Lys Thr Pro Ser Lys Leu Leu Asp
1550 1555 1560
Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro Lys Glu
1565 1570 1575
Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe Lys
1580 1585 1590
Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His
1595 1600 1605
Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu
1610 1615 1620
Val Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln
1625 1630 1635
Asn Pro Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr
1640 1645 1650
Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile
1655 1660 1665
Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp
1670 1675 1680
Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr
1685 1690 1695
Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser
1700 1705 1710
Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro
1715 1720 1725
Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe
1730 1735 1740
Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu
1745 1750 1755
Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val
1760 1765 1770
Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser
1775 1780 1785
Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg
1790 1795 1800
Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys
1805 1810 1815
Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys
1820 1825 1830
Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His
1835 1840 1845
Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu
1850 1855 1860
Asn Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu
1865 1870 1875
Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu
1880 1885 1890
Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu
1895 1900 1905
Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly
1910 1915 1920
Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln
1925 1930 1935
Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile
1940 1945 1950
His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys
1955 1960 1965
Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe
1970 1975 1980
Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val
1985 1990 1995
Glu Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu
2000 2005 2010
Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala
2015 2020 2025
Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr
2030 2035 2040
Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser
2045 2050 2055
Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val
2060 2065 2070
Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly
2075 2080 2085
Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile
2090 2095 2100
Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn
2105 2110 2115
Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser
2120 2125 2130
Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr
2135 2140 2145
Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg
2150 2155 2160
Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu
2165 2170 2175
Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser
2180 2185 2190
Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala
2195 2200 2205
Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val
2210 2215 2220
Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met
2225 2230 2235
Lys Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr
2240 2245 2250
Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly
2255 2260 2265
His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe
2270 2275 2280
Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp
2285 2290 2295
Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp
2300 2305 2310
Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala
2315 2320 2325
Gln Asp Leu Tyr
2330
<210> 2
<211> 1438
<212> PRT
<213> Homo sapiens
<400> 2
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1 5 10 15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20 25 30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35 40 45
Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro
50 55 60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65 70 75 80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85 90 95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100 105 110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115 120 125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130 135 140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145 150 155 160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165 170 175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180 185 190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195 200 205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210 215 220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225 230 235 240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245 250 255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260 265 270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275 280 285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290 295 300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305 310 315 320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325 330 335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340 345 350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355 360 365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370 375 380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385 390 395 400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405 410 415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420 425 430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435 440 445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450 455 460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465 470 475 480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485 490 495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500 505 510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515 520 525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530 535 540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545 550 555 560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565 570 575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580 585 590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe
595 600 605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610 615 620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625 630 635 640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645 650 655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660 665 670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675 680 685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690 695 700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705 710 715 720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725 730 735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Pro Pro Val Leu Lys Arg His
740 745 750
Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu Glu Ile
755 760 765
Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp
770 775 780
Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys
785 790 795 800
Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly
805 810 815
Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser
820 825 830
Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser
835 840 845
Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu
850 855 860
Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr
865 870 875 880
Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile
885 890 895
Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe
900 905 910
Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His
915 920 925
Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe
930 935 940
Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro
945 950 955 960
Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln
965 970 975
Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr
980 985 990
Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro
995 1000 1005
Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg
1010 1015 1020
Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu
1025 1030 1035
Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met
1040 1045 1050
Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly His Val
1055 1060 1065
Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn
1070 1075 1080
Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys
1085 1090 1095
Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His
1100 1105 1110
Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln
1115 1120 1125
Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile
1130 1135 1140
Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg
1145 1150 1155
Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro
1160 1165 1170
Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile His
1175 1180 1185
Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr
1190 1195 1200
Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp
1205 1210 1215
Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe
1220 1225 1230
Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro
1235 1240 1245
Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser
1250 1255 1260
Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn
1265 1270 1275
Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp
1280 1285 1290
Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr
1295 1300 1305
Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser Asn
1310 1315 1320
Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val
1325 1330 1335
Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly
1340 1345 1350
Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile
1355 1360 1365
Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn
1370 1375 1380
Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro
1385 1390 1395
Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg
1400 1405 1410
Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg Met Glu
1415 1420 1425
Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
1430 1435
<210> 3
<211> 227
<212> PRT
<213> Homo sapiens
<400> 3
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 4
<211> 223
<212> PRT
<213> Homo sapiens
<400> 4
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
1 5 10 15
Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr
20 25 30
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
35 40 45
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
50 55 60
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
65 70 75 80
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
85 90 95
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Ser Ile Glu Lys Thr Ile
100 105 110
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
115 120 125
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
130 135 140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
145 150 155 160
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
165 170 175
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
180 185 190
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu
195 200 205
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215 220
<210> 5
<211> 229
<212> PRT
<213> Homo sapiens
<400> 5
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 6
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide segment
<400> 6
Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 7
<211> 27
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide segment
<400> 7
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 8
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide segment
<400> 8
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 9
<211> 37
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide segment
<400> 9
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
Gly Gly Gly Gly Ser
35
<210> 10
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide segment
<400> 10
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Ser
20
<210> 11
<211> 33
<212> PRT
<213> Artificial Sequence
<220>
<223> Rigid peptide segment
<400> 11
Pro Arg Phe Gln Asp Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu
1 5 10 15
Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro
20 25 30
Gln
<210> 12
<211> 28
<212> PRT
<213> Artificial Sequence
<220>
<223> Rigid peptide segment
<400> 12
Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg
1 5 10 15
Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln
20 25
<210> 13
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Rigid peptide segment
<400> 13
Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser
1 5 10
<210> 14
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Rigid peptide segment
<400> 14
Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln
1 5 10
<210> 15
<211> 55
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser Ser Ser Lys
20 25 30
Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser
35 40 45
Asp Thr Pro Ile Leu Pro Gln
50 55
Claims (11)
- 응고 인자 VIII 활성 모이어티(FVIII)가 펩티드 연결기에 의해, 반감기를 연장하기 위한 융합 파트너에 직접적으로 또는 간접적으로 연결되어 융합 단백질을 형성하고, 상기 융합 단백질이 또한 폴리알킬렌 글리콜에 접합되는, 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질.
- 제1항에 있어서,
응고 인자 VIII 활성 모이어티가 인간, 예컨대 전장 또는 절두된 인간 응고 인자 VIII, 예컨대 인간 B-도메인 결실된 응고 인자 VIII로부터 유래하고; 상기 전장 또는 절두된 인간 응고 인자 VIII이 하나 이상의 아미노산 돌연변이를 함유할 수 있되, 여전히 FVIII 활성을 보유하고, 예를 들어, 상기 응고 인자 VIII 활성 모이어티가 서열번호 1 또는 2에 제시된 아미노산 서열을 포함하거나, 서열번호 1 또는 2에 제시된 아미노산 서열과 적어도 90% 또는 95% 이상의 동일성을 갖는, 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질. - 제1항 또는 제2항에 있어서,
융합 파트너가 면역글로불린 Fc 단편, 알부민, 트랜스페린 또는 XTEN이고, 상기 융합 파트너가, 예를 들어, 인간으로부터 유래하고, 바람직하게는 IgG Fc 단편, 예를 들어, 감소된 ADCC 효과 및/또는 CDC 효과 및/또는 FcRn 수용체에 대한 강화된 결합 친화도를 갖는 IgG Fc 단편, 더욱 바람직하게는 (i) 서열번호 3에 제시된 아미노산 서열, (ii) 서열번호 4에 제시된 아미노산 서열, 및 (iii) 서열번호 5에 제시된 아미노산 서열로부터 선택되는 아미노산 서열을 갖는 IgG Fc 단편인, 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질. - 제1항 내지 제3항 중 어느 한 항에 있어서,
폴리알킬렌 글리콜이 폴리프로필렌 글리콜 또는 폴리에틸렌 글리콜이고;
상기 폴리알킬렌 글리콜이 말단-캐핑(end-capping)될 수 있고, 예를 들어, 알콕시 기, 예컨대 메톡시에 의해 말단-캐핑될 수 있고;
상기 폴리알킬렌 글리콜이 선형 또는 분지형, 바람직하게는 분지형, 예를 들어 분지형 폴리에틸렌 글리콜, 특히 분지형 메톡시-종결된 폴리에틸렌 글리콜이고;
상기 폴리알킬렌 글리콜의 분자량이 ≥1, ≥10, ≥20, ≥30, ≥40, ≥50, ≥60, ≥70, ≥80, ≥90, ≥100, ≥110, ≥120, ≥130, ≥140, ≥150 또는 ≥160 kDa, 예를 들어 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 또는 100 kDa, 또는 이들 중 임의의 2개의 값 사이의 범위일 수 있는,
폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질. - 제1항 내지 제4항 중 어느 한 항에 있어서,
융합 단백질 및 폴리알킬렌 글리콜의 접합이 무작위 또는 특정 위치에 존재하고, 접합 위치가 유리 아미노 기, 설프하이드릴 기, 당 기 및 카복실 기로 이루어진 군으로부터 선택되고, 바람직하게는 유리 아미노 기인, 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질. - 제5항에 있어서,
변형제가 접합에 사용되고, 상기 변형제가 활성화된 에스터의 형태일 수 있고, 예를 들어, 상기 변형제가 하기 화학식 1, 2 및 3의 변형제로부터 선택되는, 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질:
[화학식 1]
[상기 식에서,
0≤m1≤6이고, m1은 바람직하게는 5이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다]
[화학식 2]
[상기 식에서,
0≤m2≤6이고, m2는 바람직하게는 2이고;
0≤m3≤6이고, m3은 바람직하게는 1이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다]
[화학식 3]
[상기 식에서,
0≤m4≤6이고, m4는 바람직하게는 2이고;
mPEG는 모노메톡시-종결된 폴리에틸렌 글리콜 기이다]. - 제1항 내지 제6항 중 어느 한 항에 있어서,
응고 인자 VIII 활성 모이어티가 펩티드 연결기에 의해 융합 파트너에 연결되고, 상기 펩티드 연결기가 가요성 펩티드 분절 및/또는 강직성 펩티드 분절, 예를 들어 1, 2, 3, 4 또는 5개 이상의 강직성 펩티드 분절을 포함하는, 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질. - 제7항에 있어서,
가요성 펩티드 분절이 글리신, 세린, 알라닌 및 트레오닌으로부터 선택되는 2개 이상의 아미노산 잔기를 포함하고;
바람직하게는, 상기 가요성 펩티드 분절이 구조식 (GS)a(GGS)b(GGGS)c(GGGGS)d를 갖고, 이때 a, b, c 및 d는 0 이상의 정수이고, a+b+c+d≥1이고;
더욱 바람직하게는, 상기 가요성 펩티드 분절이
(i) GSGGGSGGGGSGGGGS(서열번호 6);
(ii) GSGGGGSGGGGSGGGGSGGGGSGGGGS(서열번호 7);
(iii) GGGGSGGGGSGGGGSGGGGS(서열번호 8);
(iv) GSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS(서열번호 9); 및
(v) GGGSGGGSGGGSGGGSGGGS(서열번호 10)
로 이루어진 군으로부터 선택되는 서열을 갖는,
폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질. - 제7항 또는 제8항에 있어서,
강직성 펩티드 분절이 인간 융모성 생식선 자극호르몬(chorionic gonadotropin) β 아단위의 카복시-종결된 펩티드이거나, 강직성 펩티드 분절이 인간 융모성 생식선 자극호르몬 β 아단위의 카복시-종결된 펩티드와 적어도 70%, 80%, 90% 또는 95% 이상의 동일성을 갖고;
상기 강직성 펩티드 분절이 1 또는 2개 이상의 글리코실화 부위를 포함할 수 있고;
바람직하게는, 상기 강직성 펩티드 분절이
(i) PRFQDSSSSKAPPPSLPSPSRLPGPSDTPILPQ(서열번호 11);
(ii) SSSSKAPPPSLPSPSRLPGPSDTPILPQ(서열번호 12);
(iii) SSSSKAPPPS(서열번호 13); 및
(iv) SRLPGPSDTPILPQ(서열번호 14)
로부터 선택되는 아미노산 서열을 포함하고;
더욱 바람직하게는, 펩티드 연결기가 서열번호 15에 제시된 아미노산 서열을 포함하는,
폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질. - 효과량의 제1항 내지 제9항 중 어느 한 항에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질, 및 약학적으로 허용되는 담체를 포함하는 약학 조성물.
- 제1항 내지 제9항 중 어느 한 항에 따른 폴리알킬렌 글리콜-접합된 응고 인자 VIII 융합 단백질 또는 제10항에 따른 약학 조성물을 이를 필요로 하는 대상에게 투여함을 포함하는, 출혈성 질환을 예방하고/거나 치료하는 방법으로서, 상기 출혈성 질환이 바람직하게는 FVIII의 선천적 또는 후천적 결핍을 갖는 환자의 출혈성 질환, 및 혈우병 A를 갖는 환자에서의 자발적 또는 외과적 출혈로부터 선택되는, 방법.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011101284A1 (en) * | 2010-02-16 | 2011-08-25 | Novo Nordisk A/S | Factor viii fusion protein |
WO2013106787A1 (en) * | 2012-01-12 | 2013-07-18 | Biogen Idec Ma Inc. | Chimeric factor viii polypeptides and uses thereof |
CN106279437A (zh) * | 2016-08-19 | 2017-01-04 | 安源医药科技(上海)有限公司 | 高糖基化人凝血因子viii融合蛋白及其制备方法与用途 |
WO2017117631A1 (en) * | 2016-01-07 | 2017-07-13 | Csl Limited | Mutated truncated von willebrand factor |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4818679A (en) | 1985-02-19 | 1989-04-04 | The Trustees Of Columbia University In The City Of New York | Method for recovering mutant cells |
EP1003894A2 (en) * | 1997-07-18 | 2000-05-31 | Chiron Corporation | Lentiviral vectors |
US7645860B2 (en) * | 2006-03-31 | 2010-01-12 | Baxter Healthcare S.A. | Factor VIII polymer conjugates |
CN102770449B (zh) * | 2010-02-16 | 2016-02-24 | 诺沃—诺迪斯克有限公司 | 具有降低的vwf结合的因子viii分子 |
CA2850579A1 (en) * | 2011-10-18 | 2013-04-25 | Carsten Horn | Method for improving the stability of purified factor viii after reconstitution |
CN103172745A (zh) * | 2011-12-21 | 2013-06-26 | 北京韩美药品有限公司 | 包含免疫球蛋白Fc片段的长效人内皮抑素 |
EP2870250B2 (en) * | 2012-07-06 | 2022-06-29 | Bioverativ Therapeutics Inc. | Cell line expressing single chain factor viii polypeptides and uses thereof |
US20160000884A1 (en) * | 2012-08-13 | 2016-01-07 | Novo Nordisk A/S | Liquid Factor VIII Formulations |
EP2796145B1 (en) * | 2013-04-22 | 2017-11-01 | CSL Ltd. | A covalent complex of von willebrand factor and faktor viii linked by a disulphide bridge |
CN109790529A (zh) * | 2016-06-24 | 2019-05-21 | 财团法人牧岩生命科学研究所 | 包含FVIII和vWF因子的嵌合蛋白及其用途 |
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2019
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- 2019-05-16 US US17/055,403 patent/US20210361775A1/en active Pending
- 2019-05-16 EP EP19804136.0A patent/EP3816181A4/en active Pending
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- 2019-05-16 JP JP2020564649A patent/JP2021530437A/ja active Pending
- 2019-05-16 CN CN201980033170.0A patent/CN113039200B/zh active Active
- 2019-05-16 KR KR1020207034852A patent/KR102575788B1/ko active IP Right Grant
- 2019-05-16 WO PCT/CN2019/087156 patent/WO2019219049A1/zh unknown
- 2019-05-16 CN CN202310860049.3A patent/CN117467019A/zh active Pending
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2023
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011101284A1 (en) * | 2010-02-16 | 2011-08-25 | Novo Nordisk A/S | Factor viii fusion protein |
WO2013106787A1 (en) * | 2012-01-12 | 2013-07-18 | Biogen Idec Ma Inc. | Chimeric factor viii polypeptides and uses thereof |
WO2017117631A1 (en) * | 2016-01-07 | 2017-07-13 | Csl Limited | Mutated truncated von willebrand factor |
CN106279437A (zh) * | 2016-08-19 | 2017-01-04 | 安源医药科技(上海)有限公司 | 高糖基化人凝血因子viii融合蛋白及其制备方法与用途 |
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EP3816181A4 (en) | 2022-04-20 |
CN117467019A (zh) | 2024-01-30 |
KR102575788B1 (ko) | 2023-09-08 |
BR112020023168A2 (pt) | 2021-02-09 |
MA53020A (fr) | 2021-05-05 |
JP2021530437A (ja) | 2021-11-11 |
EP3816181A1 (en) | 2021-05-05 |
CN113039200B (zh) | 2023-07-25 |
WO2019219049A1 (zh) | 2019-11-21 |
CN113039200A (zh) | 2021-06-25 |
US20210361775A1 (en) | 2021-11-25 |
JP2023093634A (ja) | 2023-07-04 |
JP7492780B2 (ja) | 2024-05-30 |
MX2020012103A (es) | 2021-01-29 |
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