KR20090046874A - 인슐린-유사 성장 인자-ｉ의 제조 방법 - Google Patents
인슐린-유사 성장 인자-ｉ의 제조 방법 Download PDFInfo
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- KR20090046874A KR20090046874A KR1020097003973A KR20097003973A KR20090046874A KR 20090046874 A KR20090046874 A KR 20090046874A KR 1020097003973 A KR1020097003973 A KR 1020097003973A KR 20097003973 A KR20097003973 A KR 20097003973A KR 20090046874 A KR20090046874 A KR 20090046874A
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- ala
- arg
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Abstract
본 발명은 프로펩티드의 C-말단에 연결되어 있는 N-말단을 가진 IGF-I을 포함하는 융합 단백질을 코딩하는 핵산을 함유하는 발현 벡터를 포함하는 원핵 숙주 세포를 배양함으로써 상기 프로펩티드가 그의 C-말단에서 아미노산 -Y-Pro을 갖게 하고, 이때 Y가 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro, or Pro-Arg-Pro로 구성된 군으로부터 선택되고, 상기 융합 단백질을 회수하여 IgA 프로티에이즈로 절단하고 IGF-I을 회수함을 특징으로 하는 IGF-I의 제조 방법을 제공한다. IGF-I은 알쯔하이머병과 같은 신경퇴행성 장애의 치료에 유용하다.
Description
본 발명은 인슐린-유사 성장 인자-I(IGF-I)의 제조 방법, 약학 조성물 및 사용 방법에 관한 것이다.
IGF-I은 인슐린과 구조적으로 관련되어 있는 순환 호르몬이다. 종래, IGF-I은 말초 조직에 대한 성장 호르몬 작용의 주 매개자인 것으로 인식되어 있다. IGF-I은 70개의 아미노산으로 구성되어 있고 소마토메딘(somatomedin) C로도 지칭되며 스위스프로트(SwissProt) 제P01343호에 의해 정의되어 있다. IGF-I의 용도, 활성 및 제조는 예를 들어, 문헌[le Bouc, Y., et al., FEBS Lett. 196 (1986) 108-112]; 문헌[de Pagter-Holthuizen, P., et al., FEBS Lett. 195 (1986) 179-184]; 문헌[Sandberg Nordqvist, A.C., et al., Brain Res. MoI. Brain Res. 12 (1992) 275-277]; 문헌[Steenbergh, P.H., et al., Biochem. Biophys. Res. Commun. 175 (1991) 507-514]; 문헌[Tanner, J.M., et al., Acta Endocrinol. (Copenh.) 84 (1977) 681-696]; 문헌[Uthne, K., et al., J. Clin. Endocrinol. Metab. 39 (1974) 548-554]; 유럽 특허 제0 123 228호; 유럽 특허 제0 128 733호; 미국 특허 제5,861,373호; 미국 특허 제5,714,460호; 유럽 특허 제0 597 033호; 국제특허출원 공개 제WO 02/32449호; 및 국제특허출원 공개 제WO 93/02695호에 기재되어 있다.
IGF-I 기능의 조절은 꽤 복잡하다. 순환계에서, IGF-1의 0.2%만이 유리 형태로 존재하는 반면, 대다수는 IGF에 대해 매우 높은 친화성을 나타내고 IGF-I 기능을 조절하는 IGF-결합 단백질(IGFBP)에 결합되어 있다. IGF-I은 이를 방출하는 기작, 예컨대, 프로티에이즈에 의한 IGFBP의 단백질분해에 의해 국소적으로 유리될 수 있다.
IGF-I은 발달중인 뇌 및 성숙 뇌에서 측분비 역할을 수행한다(Werther, G.A., et al., Mol. Endocrinol. 4 (1990) 773-778). 시험관내 연구는 IGF-I이 도파민성 신경[Knusel, B., et al., J. Neurosci. 10(1990) 558-570] 및 희소돌기아교세포(oligodendrocyte)[McMorris, F.A., and Dubois-Dalcq, M., J. Neurosci. Res. 21 (1988) 199-209; McMorris, F.A., et al., Proc. Natl. Acad. Sci. USA 83 (1986) 822-826; Mozell, R.L., and McMorris, F.A., J. Neurosci. Res. 30 (1991) 382-390]를 비롯한 CNS 내의 여러 유형의 신경에 대한 강력한 비-선택적 영양 물질(trophic agent)임을 보여준다[Knusel, B., et al., J. Neurosci. 10(1990) 558-570; Svrzic, D., and Schubert, D., Biochem. Biophys. Res. Commun. 172 (1990) 54-60]. 미국 특허 제5,093,317호에는 도파민성 신경 세포의 생존이 IGF-I의 투여에 의해 상승된다고 기재되어 있다. 또한, IGF-I은 말초 신경 재생을 자극하 고(Kanje, M., et al., Brain Res. 486 (1989) 396-398) 오르니틴 데카복실레이즈 활성을 상승시키는 것으로 공지되어 있다(미국 특허 제5,093,317호). 미국 특허 제5,861,373호 및 국제특허출원 공개 제WO 93/02695호에는 환자의 중추신경계에서 IGF-I 및/또는 이들의 유사체의 활성 농도를 증가시킴으로써 아교세포 및/또는 비-콜린성 신경 세포에 주로 영향을 미치는 중추신경계의 손상 또는 질환을 치료하는 방법이 개시되어 있다. 국제특허출원 공개 제 WO 02/32449호는 치료 유효량의 IGF-I 또는 이의 생물학적 활성 유사체를 포함하는 약학 조성물을 포유동물의 비강에 투여하여 포유동물의 중추신경계의 허혈 손상을 완화시키거나 예방하는 방법에 관한 것이다. IGF-I은 허혈과 관련된 허혈 손상의 완화 또는 예방에 효과적인 양으로 비강을 통해 흡수되어 포유동물의 중추신경계로 전달된다. 유럽 특허 제0874641호는 AIDS-관련 치매, 알쯔하이머병(AD), 파킨슨병, 픽병, 헌팅톤병, 간성 뇌병증, 피질-기저 신경절 증후군, 진행성 치매, 경직성 하반신마비를 수반한 가족성 치매, 진행성 핵상마비, 다발성 경화증, 쉴더(Schilder)의 뇌 경화증 또는 급성 괴사출혈뇌척수염으로 인한 중추신경계의 신경 손상을 치료하거나 예방하기 위한 약제의 제조에 있어서 IGF-I 또는 IGF-II의 용도를 청구하는데, 이때, 약제는 유효량의 상기 IGF를 혈액-뇌 장벽 또는 혈액-척수 장벽 외부에 비경구 투여하기 위한 형태로 존재한다.
유리 IGF-I의 뇌 및 혈청 농도의 감소는 산발성 형태의 AD 및 가족성 형태의 AD의 발병기전과 관련되어 있다. 뿐만 아니라, IGF-I은 Aβ에 의해 유도된 신경독성으로부터 신경을 보호한다(Niikura, T., et al., J. Neurosci. 21 (2001) 1902- 1910; Dore, S., et al., Proc. Natl. Acad. Sci. USA 94 (1997) 4772-4777; Dore, S., et al., Ann. NY Acad. Sci. 890 (1999) 356-364). 최근에, 말초 투여된 IGF-I은 래트 및 마우스에서 뇌 Aβ 수준을 감소시킬 수 있음이 밝혀져 있다(Carro, E., et al., Nat. Med. 8 (2002) 1390-1397). 또한, 상기 연구는 형질전환 AD 마우스 모델에서 장기간의 IGF-I 치료가 뇌 아밀로이드 플라크 적재를 상당히 감소시킴을 입증하였다. 이 데이터는 IGF-I이 뇌로부터 Aβ를 제거함으로써 뇌 Aβ 농도 및 플라크-관련 뇌 치매를 감소시킬 수 있다는 이론을 강하게 뒷받침한다.
IgA 프로티에이즈의 인식 부위는 Yaa-Pro.!.Xaa-Pro로서 기재되어 있다. Yaa는 Pro (또는 드물게는 Ala, Gly 또는 Thr과 조합된 Pro, 즉 Pro-Ala, Pro-Gly, 또는 Pro-Thr)를 나타낸다. Xaa는 Thr, Ser 또는 Ala을 나타낸다[문헌(Pohlner, J. et al., Bio/Technology 10 (1992) 799-804; Pohlner, J. et al., Nature 325 (1987) 458-462) 및 미국 특허 제5,427,927호]. 천연 절단 부위는 문헌[Wood, S.G. and Burton, J., Infect Immun. 59 (1991) 1818-1822]에서 확인되어 있다. 네이세리아 고노르호애(Neisseria gonorrhoeae)(타입 2)로부터 면역글로불린 A1 프로티에이즈에 대한 합성 펩티드 기질은 자가단백질분해 부위 Lys-Pro-Ala-Pro.!.Ser-Pro, Val-Ala-Pro-Pro.!.Ser-Pro, Pro-Arg-Pro-Pro.!.Ala-Pro, Pro-Arg-Pro-Pro.!.Ser-Pro 및 Pro-Arg-Pro-Pro.!.Thr-Pro, 및 IgA1 절단 부위 Pro-Pro-Thr-Pro.!.Ser-Pro 및 Ser-Thr-Pro-Pro.!.Thr-Pro이다.
국제특허출원 공개 제WO 2006/066891호는, 야생형 IGF-I 아미노산 서열의 아미노산 위치 27, 37, 65 및 68 중 3개 이하의 아미노산 위치에서 아미노산 변경을 가짐으로써 상기 아미노산 중 1 또는 2개의 아미노산이 라이신이고 아미노산 위치 27의 아미노산이 라이신을 제외한 극성 아미노산임을 특징으로 하는 IGF-I 및 1 또는 2개의 폴리(에틸렌 글리콜) 기로 구성된 접합체로서, 상기 IGF-I과 상기 1 또는 2개의 폴리(에틸렌 글리콜) 기가 상기 라이신의 1차 아미노기를 통해 접합되어 있고, 상기 폴리(에틸렌 글리콜) 기의 총 분자량이 20 내지 100 kDa인, 접합체를 개시한다. 이러한 접합체는 알쯔하이머병과 같은 신경퇴행성 장애의 치료에 유용하다.
국제특허출원 공개 제WO 2006/074390호에는 IGF-I 변이체, 및 IGF-I 변이체 및 특정한 융합 성분들을 포함하는 융합 단백질이 기재되어 있다. 국제특허출원 공개 제WO 2006/074390호에는 특정한 IGF-I 변이체가 기재되어 있다.
융합 단백질을 통한 IGF-I의 재조합 제조 방법은 예를 들어, 유럽 특허 제0155655호 및 미국 특허 제5,158,875호에 기재되어 있다. 그러나, 재조합 제조된 IGF-1의 미세불균질성이 종종 발견된다(Forsberg, G. et. al., Biochem. J. 271 (1990) 357-363).
본 발명은 원핵세포에 N-말단 부착 메티오닌을 갖지 않는 IGF-I을 고순도 및 고수율로 재조합 제조하는 방법을 제공한다. 본 발명은 a) N-말단이 프로펩티드의 C-말단에 연결되어 있는 IGF-I을 포함하는 융합 단백질을 코딩하는 핵산을 함유하는 발현 벡터를 포함하는 원핵 숙주 세포를 배양하여 상기 프로펩티드의 C-말단이 아미노산 -Y-Pro로 종결되게 하는 단계, b) 상기 융합 단백질을 회수하여 IgA 프로티에이즈로 절단하는 단계, c) IGF-I을 회수하는 단계를 포함하고, 이때 Y가 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택됨을 특징으로 하는 IGF-I의 제조 방법을 제공한다.
회수된 IGF-I은 N-말단에 부착된 메티오닌 잔기를 포함하지 않는다.
본 발명의 바람직한 실시양태는 서열번호 2 내지 5에 나타낸 펩티드로 구성된 군으로부터 선택된 프로펩티드이다.
본 발명의 추가 실시양태는 C-말단에서 아미노산 -Y-Pro을 가짐을 특징으로 하는 프로펩티드의 C-말단에 연결된 N-말단을 가진 IGF-I을 포함하는 융합 단백질로서, 이때 Y가 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro, 및 Pro-Arg-Pro로 구성된 군으로부터 선택된다. 상기 프로펩티드는 -Y-Pro 서열로 인해 IgA 프로티에이즈 처리에 의해 상기 IGF-I으로부터 분리될 수 있다.
바람직하게는, 본 발명에 따른 융합 단백질은 하기 화학식 1로 표시됨을 특징으로 한다:
상기 식에서,
Met는 메티오닌을 나타내고,
X1은 결합, 세린 또는 아스파라긴이고,
His는 히스티딘이고,
n은 0 내지 6의 수이고,
X2는 서열번호 6 내지 10의 펩티드로 구성된 군으로부터 선택된 링커 펩티드이고,
Pro는 프롤린이고,
Y는 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택된다.
바람직하게는, 프로펩티드는 하기 화학식 2로 표시된다:
상기 식에서,
Met는 메티오닌을 나타내고,
X1은 결합, 세린 또는 아스파라긴이고,
His는 히스티딘이고,
n은 0 내지 6의 수이고,
X2는 서열번호 6 내지 10의 펩티드로 구성된 군으로부터 선택된 링커 펩티드이고,
Pro는 프롤린이고,
Y는 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택된다.
프로펩티드의 C-말단은 IGF-I의 N-말단(글리신)에 연결되어 있다. 프로펩티드의 길이는 바람직하게는 30개 이하의 아미노산에 해당하는 길이이다. 바람직하게는, X1은 결합이다. 바람직하게는, n은 0 또는 6이다. 바람직하게는, X2는 서열번호 7의 펩티드이다. 바람직하게는, Y는 Pro-Arg-Pro이다.
또한, 본 발명은 바람직하게는 약학적으로 허용가능한 담체와 함께 본 발명에 따른 IGF-I을 함유하는 약학 조성물을 포함한다.
또한, 본 발명은 본 발명에 따른 IGF-I을 함유하는 약학 조성물의 제조 방법을 제공한다.
또한, 본 발명은 AD 치료용 약제의 제조를 위한 본 발명에 따른 IGF-I의 용도를 포함한다.
또한, 본 발명은 약학적 유효량의 아미노-반응성 IGF-I을 AD의 치료가 필요한 환자에게 바람직하게는 주당 1 또는 2회 투여함을 특징으로 하는 AD의 치료 방법을 포함한다.
놀랍게도, 본 발명자들은 IgA 프로티에이즈, 바람직하게는 네이세리아 고노르호애로부터 유래된 IgA 프로티에이즈가 아미노산 서열 Y-Pro.!.Gly-Pro를 절단할 수 있음을 발견하였다. Y는 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택된다. 바람직하게는, Pro-Pro.!.Gly-Pro 또는 Pro-Arg-Pro-Pro.!.Gly-Pro(서열번호 11)(.!.: 절단 위치)가 절단 부위로서 유용하다. 본 발명에 따른 방법에 있어서 IgA 프로티에이즈 절단 부위는 아미노산 컨센서스 서열 Y-Pro.!.Gly-Pro를 가짐으로써 Gly-Pro가 IGF-I의 첫 2개 아미노산이다. Y는 바람직하게는 아미노산 Pro, Pro-Ala, Arg-Pro 또는 Pro-Arg-Pro로 종결되는 아미노산 서열을 나타낸다. 이러한 Y 아미노산 서열, 특히 Pro-Arg-Pro는 예를 들어, Ala-Pro-Arg-Pro(서열번호 12) 또는 Pro-Ala-Pro-Arg-Pro(서열번호 13)에서와 같이 추가 Ala 또는 Pro-Ala 기에 의해 연장될 수 있다. 절단 아미노산 서열 Pro-Arg-Pro-Pro.!.Gly-Pro(서열번호 11), Pro-Ala-Pro.!.Gly-Pro(서열번호 14), Pro-Pro-.!.Gly-Pro(서열번호 15), Ala-Pro-Arg-Pro-Pro.!.Gly-Pro(서열번호 16) 또는 Pro-Ala-Pro-Arg-Pro-Pro.!.Gly-Pro(서열번호 17)가 특히 바람직하다.
본 발명에서 용어 "IgA 프로티에이즈"는 IgA를 특이적으로 절단할 수 있고 예를 들어, 문헌[Kornfeld, SJ. and Plaut, A.G., Rev. Infekt. Dis. 3 (1981) 521-534]에 예를 들어, 네이세리아 고노르호애(타입 2)로부터 유래된 IgA1 프로티에이즈로서 기재되어 있는 프로티에이즈를 포함한다. 재조합 IgA 프로티에이즈, 예컨대, 독일 특허 출원 제36 22 221호, 문헌[Koomey, J.M., et al. Proc. Natl. Acad. Sci. USA 79 (1982) 7881-7885], 문헌[Bricker, J., et al., Proc. Natl. Acad. Sci. USA 80 (1983) 2681-2685], 문헌[Pohlner, J., Nature 325 (1987) 458-462] 및 문헌[Halter, R., et al., EMBO J. 3 (1984) 1595-1601]에 기재된 재조합 IgA 프로티에이즈도 적합하다. 바람직하게는, 상기 IgA 프로티에이즈는 네이세리아 고노르호애로부터 유래된 IgA 프로티에이즈이다. 바람직하게는, 상기 네이세리아 고노르호애로부터 유래된 IgA1 프로티에이즈(타입 2)는 서열번호 21의 서열을 갖는다.
본 발명에 따른 IGF-I은 70개의 아미노산으로 구성되어 있고 소마토메딘 C로도 지칭되며 스위스프로트 제P01343호에 의해 정의되어 있다. IGF-I의 용도, 활성 및 제조는 예를 들어, 문헌[le Bouc, Y., et al., FEBS Lett. 196 (1986) 108-112]; 문헌[de Pagter-Holthuizen, P., et al., FEBS Lett. 195 (1986) 179-184]; 문헌[Sandberg Nordqvist, A.C., et al., Brain Res. Mol. Brain Res. 12 (1992) 275-277]; 문헌[Steenbergh, P.H., et al., Biochem. Biophys. Res. Commun. 175 (1991) 507-514]; 문헌[Tanner, J.M., et al., Acta Endocrinol. (Copenh.) 84 (1977) 681-696]; 문헌[Uthne, K., et al., J. Clin. Endocrinol. Metab. 39 (1974) 548-554]; 유럽 특허 제0 123 228호; 유럽 특허 제0 128 733호; 미국 특허 제5,861,373호; 미국 특허 제5,714,460호; 유럽 특허 제0 597 033호; 국제특허출원 공개 제WO 02/32449호; 및 국제특허출원 공개 제WO 93/02695호에 기재되어 있다.
본 발명에 따른 IGF-I은 IGF-I, C-말단이 제거된 IGF-I(3 내지 6개의 아미노산의 결실), R36A(위치 36의 아르기닌이 알라닌으로 치환됨) 및 R37A로 구성된 군으로부터 선택된 IGF-I을 포함한다. 바람직하게는, 상기 IGF-I의 C-말단은 IgG, 바람직하게는 IgG1 또는 IgG4로부터 유래된 인간 Fc에 연결되어 있다.
C-말단이 제거된 IGF-I(3 내지 6개의 아미노산의 결실)은 C-말단에서 3 내지 6개의 아미노산이 결실되어 있는 서열번호 1의 IGF-I이다.
R36A는 아미노산 위치 36의 아르기닌이 알라닌으로 치환되어 있는 서열번호 1의 IGF-I을 표시한다.
R37A는 아미노산 위치 37의 아르기닌이 알라닌으로 치환되어 있는 서열번호 1의 IGF-I을 표시한다.
융합 단백질을 코딩하는 유전자는 바람직하게는 융합 단백질이 필요에 따라 생성될 수 있도록 적절한 (바람직하게는 유도성) 발현 신호의 조절 하에 있다. 적절한 원핵세포 또는 진핵세포(식물 및 동물)가 단백질 융합체의 제조를 위한 숙주 세포로서 사용될 수 있으나, 세포 무함유 시스템도 사용할 수 있다.
본 발명에 따른 방법의 바람직한 실시양태는, 숙주 세포가 본 발명에 따른 융합 단백질을 코딩하는 유전자의 하나 이상의 카피를 함유하는 재조합 DNA 또는 재조합 벡터로 형질전환되고, 이 형질전환된 세포는 적절한 배지 중에서 배양되고, 융합 단백질을 코딩하는 유전자는 형질전환된 세포에서 발현되도록 만들어지고, 융합 단백질은 IgA 프로티에이즈로 절단되고, IGF-I은 단리됨을 특징으로 한다.
본 발명에 따른 융합 단백질의 발현은 예를 들어, 라이신을 갖지 않는 베타-갈락토시데이즈 유전자의 단편과의 융합에 의해 DNA 수준에서 개선될 수 있다. 즉, Y는 라이신을 갖지 않은 베타-갈락토시데이즈 단백질의 일부를 포함한다. 융합 단백질의 발현을 증가시키는 다른 대안적 방법은 당업자에게 공지되어 있다. 발현 생성물의 정제 및 분리는 다른 폴리펩티드, 특히 고도로 하전된(예를 들어, 폴리(Lys, Arg)) 또는 높은 친화도로 특정한 물질에 결합할 수 있는(예를 들어, 스 트렙타비딘) 폴리펩티드 또는 단백질과의 융합에 의해 촉진될 수 있다(예를 들어, 유럽 특허 출원 제089 626호 및 제0 306 610호 참조). 특히 바람직한 링커 펩티드는 서열번호 6 내지 10의 펩티드, 바람직하게는 N-말단 앞에 SHHHHHH(서열번호 18), NHHHHHH(서열번호 19) 또는 HHHHHH(서열번호 20)이 있는 서열번호 6 내지 10의 펩티드이다.
본 발명은 본 발명에 따른 융합 단백질을 코딩하는 (재조합) 핵산도 제공하는데, 이때 IgA 프로티에이즈 절단 부위가 프로펩티드와 IGF-I 사이의 연접(junction) 영역에 도입되어 있다.
본 발명에 따른 재조합 DNA는 분자생물학 분야에서 숙련된 자에게 공지된 방식에 의해 수득될 수 있다. 이를 위해, IGF-I의 아미노산 서열을 코딩하는 DNA 서열을 함유하는 벡터를 통상적으로 이 유전자의 5' 말단의 영역에서 제한 엔도뉴클레이즈로 절단하여 원하는 서열을 보유하는 올리고뉴클레오타이드와 다시 연결시킨다.
또한, 본 발명은 본 발명에 따른 재조합 DNA의 하나 이상의 카피를 함유하는 재조합 벡터를 제공한다. 원핵 유기체에서의 단백질 발현을 위한 기초로서 적합한 벡터는 당업자에게 공지되어 있다. 이 벡터는 바람직하게는 본 발명에 따른 재조합 DNA의 고발현을 가능하게 하는 벡터이다. 벡터 상의 재조합 DNA는 바람직하게는 유도성 발현 신호(예를 들어, 람다, tac, lac 또는 trp 프로모터)의 조절 하에 있다.
본 발명에 따른 벡터는 숙주 유기체의 게놈 내로 도입될 수 있을 뿐만 아니 라(예를 들어, 박테리오파지 람다), 염색체 외부에 존재할 수 있다(예를 들어, 플라스미드). 본 발명에 따른 벡터는 바람직하게는 플라스미드이다. 각각의 경우 구체적인 숙주 유기체 내에서의 유전자 발현에 적합한 벡터는 분자생물학 분야의 숙련된 자에게 공지되어 있다. 벡터는 진핵 벡터일 수 있지만 원핵 벡터가 바람직하다. 본 발명에 따른 DNA를 원핵세포에서 발현시키기에 적합한 벡터의 예는 시판되는 pUC 및 pUR 벡터이다.
본 발명은 본 발명에 따른 재조합 DNA 및/또는 본 발명에 따른 재조합 벡터로 형질전환된 세포, 바람직하게는, 원핵세포, 특히 바람직하게는 이. 콜라이 세포를 제공한다.
융합 단백질이 원핵세포에서 발현되는 경우, 잘 용해되지 않는 불활성 응집체(굴절반사 소체, 봉입체)가 형성된다. 따라서, 융합 단백질은 그의 활성 형태로 전환되어야 한다. 당업자에게 공지된 절차를 이용하여(예를 들어, 유럽 특허 출원 제0 219 874호 및 제0 114 506호 및 국제특허출원 공개 제WO 84/03711호 참조) 변성화제의 첨가 후 재생 및 필요에 따라 추가 정제 단계를 통해 첫 번째 가용화를 실시한다.
IgA 프로티에이즈로 절단할 IGF-I 융합 단백질의 처리에 필요한 조건은 중요하지 않다. 그러나, 본 방법에서 IgA 프로티에이즈에 대한 IGF-I 융합 단백질의 중량비는 1:1 내지 100:1임이 바람직하다. 반응은 바람직하게는 pH 6.5 내지 8.5의 완충된 수용액 중에서 일어난다. 완충제 농도는 바람직하게는 필요에 따라 50 내지 500 mmol/ℓ이고, 0 내지 100 mmol/ℓ의 염화나트륨이 첨가된다. 절단은 바 람직하게는 실온에서 60분 이상 내지 5일 이하, 바람직하게는 24 내지 72시간 동안 실시한다.
가용화, 재생 및 IgA 프로티에이즈를 사용한 절단 후, 이 방식으로 수득한 절단 생성물은 바람직하게는 소수성 상호작용 크로마토그래피, 이온 교환 크로마토그래피 및/또는 크기에 따른 분획화에 의해 정제된다. 이 방식으로 수득한 IGF-I은 위치 -1에서 메티오닌을 갖지 않는다.
약학 제제
IGF-I은 예를 들어, 소수성 상호작용 크로마토그래피, 이온 교환 크로마토그래피 또는 크기 배제 크로마토그래피에 의해 분리되는 혼합물 또는 다양한 종으로서 투여될 수 있다. 본 발명의 혼합물은 약학 조성물의 제조 방법으로서 당업자에게 공지된 방법에 따라 제제화될 수 있다. 이러한 조성물의 제조에 있어서, 본 발명에 따른 IGF-I은 바람직하게는 약학 조성물의 원하는 성분들을 함유하는 수용액에 대한 투석 또는 정용여과에 의해 약학적으로 허용가능한 담체와의 혼합물로 조합된다. 이러한 약학적으로 허용가능한 담체는 예를 들어, 문헌[Remington's Pharmaceutical Sciences, 18th edition, 1990, Mack Publishing Company, edited by Oslo et al.(예를 들어, 제1435면 내지 제1712면)]에 기재되어 있다. 전형적인 조성물은 적절한 양의 담체와 함께 유효량, 예를 들어, 약 0.1 내지 100 mg/㎖의 본 발명에 따른 물질을 함유한다. 조성물은 비경구적으로 투여될 수 있다. 본 발명에 따른 IGF-I은 바람직하게는 복강내, 피하, 정맥내 또는 비강내 경로를 통해 투여된다.
본 발명에 따른 약학적 제제는 당업계에 공지된 방법에 따라 제조될 수 있다. 통상적으로, IGF-I 용액은 약학 조성물에 사용될 완충제에 대해 투석되거나 정용여과되고, 원하는 최종 단백질 농도는 농축 또는 희석에 의해 조절된다.
하기 실시예 및 서열은 본 발명의 이해를 돕기 위해 제공된 것이고, 본 발명의 진정한 범위는 첨부된 청구범위에 기재되어 있다. 본 발명의 기술적 사상을 벗어나지 않으면서 기재된 방법에서 변경을 가할 수 있음을 이해할 것이다. 아미노산의 명칭은 1 문자 코드(예를 들어, R) 또는 3 문자 코드(예를 들어, Arg)를 사용하여 약칭한다. R36A는 아미노산 위치 36에 있는 아르기닌이 알라닌으로 치환되어 있는 IGF-I 돌연변이체를 의미한다.
서열목록
서열번호 1: 인간 IGF-I의 아미노산 서열(스위스프로트 P01343으로부터 아미노산 49 내지 118)
서열번호 2: 바람직한 프로펩티드의 아미노산 서열
서열번호 3: 바람직한 프로펩티드의 아미노산 서열
서열번호 4: 바람직한 프로펩티드의 아미노산 서열
서열번호 5: 바람직한 프로펩티드의 아미노산 서열
서열번호 6 내지 10: 링커
서열번호 11 내지 17: 절단 서열
서열번호 18 내지 20: 기타
서열번호 21: 네이세리아 고노르호애(타입 2)로부터 유래된 IgA1 프로티에이즈의 아미노산 서열
유용한 발현 벡터 및 이. 콜라이 균주는 유럽 특허 제0 972 838호에 기재되어 있다. 선별 아가 플레이트 상에서 생장된, 융합 단백질을 발현하는 이. 콜라이 클론으로부터 1개의 접종 루프를 선별 배지(100 ㎖)로 옮기고 광학 밀도(578 nm)가 2 내지 4에 도달할 때까지 37℃에서 13시간 동안 배양하였다. 이 배양물을 다음 6시간 동안 얼음 위에 저장한 후 37℃에서 실시되는 주 배양의 자동화 접종을 수행하였다. IGF-1 돌연변이체의 발현은 광학 밀도(578 nm)가 50일 때 1.0 mM IPTG를 첨가하여 개시하였다. 전체 발효를 최대 16시간까지 지속하였다. 단백질의 양은 SDS-PAGE 겔 상에서 생성물의 단백질 밴드의 부피 강도를 IGF 기준물의 밴드와 비교하여 밀도측정 방식으로 측정하였다. 배양 브로쓰는 원심분리하여 수거하였다.
정제된 봉입체(IB) 물질을 수득하기 위해, 표준 발효로부터 수거한 생체물질(biomass)을 다음 절차에 따라 처리하였다: 0.3 g/100 g 생체 건조 중량의 라이소자임 및 5 U/1 g 생체 건조 중량의 벤조네이즈(Benzonase)를 20분 동안 항온처리하고 균질화시켰다. 30 U/1 g 생체 건조 중량의 벤조네이즈를 첨가하고 60분 동안 37℃에서 항온처리하였다. 0.5 ℓ의 Brij-완충제/ℓ를 첨가하고 실온에서 30분 동안 항온처리하였다. 원심분리 후, 펠렛을 100 g 생체 습윤 중량(정제된 IB 습윤 중량) 당 300 ㎖의 Tris-EDTA-완충제 중에 재현탁시키고, 실온에서 30분 동안 항온 처리하고 원심분리하였다. 1 g IB/ℓ를 실온에서 6.8 M 구아니딘-HCl, 0.1 M TrisHCl 및 0.1 M DTT(pH 8.5) 중에서 밤새 가용화시켰다. 혼탁 용액을 6.8 M 구아니딘-HCl 및 0.1 M TrisHCl(pH 8.0)에 대해 4℃에서 투석하였다. 투석 후, 불용성 성분들을 원심분리하여 제거하였다. 실온에서 프로-IGF-I 용액을 0.8 M 아르기닌, 0.1 M TrisHCl, 0.1 M 구아닌-HCl, 1 mM GSH 및 1 mM GSSH(pH 8.5)로 50배 희석하여 폴딩(folding) 수행하였다. 2시간 후, 용액을 2 M 염화나트륨으로 보충하고, 여과하고, 2 M NaCl, 0.8 M 아르기닌, 0.1 M TrisHCl 및 0.1 M 구아니딘-HCl(pH 8.5)로 실온에서 평형화시킨 HIC 컬럼(부틸 세파로스 4 패스트 플로우; GE, Amersham Biosciences)에 10 ㎖/분의 유속으로 가하였다. 기준선에 도달할 때가지 평형 완충제로 컬럼을 세척한 후, 평형 완충제로 출발하여 0.1 M TrisHCl 및 5% 에틸렌 글리콜(pH 8.5)을 함유하는 완충제로 종결하는 10배 컬럼 부피의 선형 구배로 용출하였다. 용출된 분획을 역상 고성능 크로마토그래피(rpHPLC)로 분석하였다. 정확하게 형성된 SS-가교를 가진 단백질을 함유하는 분획을 모았다. 반응 혼합물을 네이세리아 고노르호애(타입 2)로부터 유래된 IgA1 프로티에이즈(중량/중량 비 = 1:50)로 보충하고 실온에서 밤새 항온처리하였다(도 2 참조). 반응 혼합물을 pH 4.5의 50 mM 아세트산으로 1:2로 희석한 후, 50 mM 아세트산으로 평형화시킨 양이온 IEC 컬럼(마크로캡(MacroCap) SP 지지체, GE, Amersham Biosciences, 스웨덴 웁살라 소재)에 가하거나 SEC 수퍼덱스(Superdex™) 200(General Electric)에 가하였다. 기준선에 도달할 때까지 컬럼을 세척한 후, 50 mM 아세트산으로 출발하여 1 M 염화나트륨으로 보충된 50 mM 아세트산으로 종결하는 20 컬럼 부피의 선형 구배로 용출하였다. 용출된 분획을 SDS-PAGE로 분석하였다. IGF-I 분자 크기를 가진 단일 밴드를 함유하는 분획을 IGF-I으로서 풀링하였다. IGF-I의 확인은 정적 광 산란 검출을 수반한 분석 크기 배제 크로마토그래피(SEC), 트립신 분해물의 MS 분석, Asp-N 분해물의 MS 분석 및 분석 양이온 IEC 또는 SEC로 검증하였다.
SEQUENCE LISTING
<110> F. Hoffmann-La Roche AG
<120> Method for the production of insulin-like growth factor-I
<130> 23908 WO
<150> EP06018171
<151> 2006-08-31
<160> 21
<170> PatentIn version 3.2
<210> 1
<211> 70
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> amino acid sequence of human IGF-I (amino acids 49-118 from
SwissProt P01343).
<400> 1
Gly Pro Glu Thr Leu Cys Gly Ala Glu Leu Val Asp Ala Leu Gln Phe
1 5 10 15
Val Cys Gly Asp Arg Gly Phe Tyr Phe Asn Lys Pro Thr Gly Tyr Gly
20 25 30
Ser Ser Ser Arg Arg Ala Pro Gln Thr Gly Ile Val Asp Glu Cys Cys
35 40 45
Phe Arg Ser Cys Asp Leu Arg Arg Leu Glu Met Tyr Cys Ala Pro Leu
50 55 60
Lys Pro Ala Lys Ser Ala
65 70
<210> 2
<211> 19
<212> PRT
<213> Artificial
<220>
<223> amino acid sequence of a preferred propeptide
<400> 2
Met His His His His His His Arg Ala Arg Arg Phe Arg Arg His Pro
1 5 10 15
Arg Pro Pro
<210> 3
<211> 18
<212> PRT
<213> Artificial
<220>
<223> amino acid sequence of a preferred propeptide
<400> 3
Met Ser His His His His His His Asn His Asn Arg Glu His Pro Arg
1 5 10 15
Pro Pro
<210> 4
<211> 17
<212> PRT
<213> Artificial
<220>
<223> amino acid sequence of a preferred propeptide
<400> 4
Met Asn His His His His His His Ile Glu Gly Arg His Pro Arg Pro
1 5 10 15
Pro
<210> 5
<211> 20
<212> PRT
<213> Artificial
<220>
<223> amino acid sequence of a preferred propeptide
<400> 5
Met Asn His His His His His His Thr Glu Phe Glu Asn Ile Glu His
1 5 10 15
Pro Arg Pro Pro
20
<210> 6
<211> 8
<212> PRT
<213> Artificial
<220>
<223> linker
<400> 6
Lys Ala Lys Arg Phe Lys Lys His
1 5
<210> 7
<211> 8
<212> PRT
<213> Artificial
<220>
<223> linker
<400> 7
Arg Ala Arg Arg Phe Arg Arg His
1 5
<210> 8
<211> 8
<212> PRT
<213> Artificial
<220>
<223> linker
<400> 8
Asn Thr Glu His Asn Arg Glu His
1 5
<210> 9
<211> 5
<212> PRT
<213> Artificial
<220>
<223> linker
<400> 9
Ile Glu Gly Arg His
1 5
<210> 10
<211> 8
<212> PRT
<213> Artificial
<220>
<223> linker
<400> 10
Thr Glu Phe Glu Asn Ile Glu His
1 5
<210> 11
<211> 6
<212> PRT
<213> Artificial
<220>
<223> cleavage sequence
<400> 11
Pro Arg Pro Pro Gly Pro
1 5
<210> 12
<211> 4
<212> PRT
<213> Artificial
<220>
<223> cleavage sequence
<400> 12
Ala Pro Arg Pro
1
<210> 13
<211> 5
<212> PRT
<213> Artificial
<220>
<223> cleavage sequence
<400> 13
Pro Ala Pro Arg Pro
1 5
<210> 14
<211> 5
<212> PRT
<213> Artificial
<220>
<223> cleavage sequence
<400> 14
Pro Ala Pro Gly Pro
1 5
<210> 15
<211> 4
<212> PRT
<213> Artificial
<220>
<223> cleavage sequence
<400> 15
Pro Pro Gly Pro
1
<210> 16
<211> 7
<212> PRT
<213> Artificial
<220>
<223> cleavage sequence
<400> 16
Ala Pro Arg Pro Pro Gly Pro
1 5
<210> 17
<211> 8
<212> PRT
<213> Artificial
<220>
<223> cleavage sequence
<400> 17
Pro Ala Pro Arg Pro Pro Gly Pro
1 5
<210> 18
<211> 7
<212> PRT
<213> Artificial
<220>
<223> other
<400> 18
Ser His His His His His His
1 5
<210> 19
<211> 7
<212> PRT
<213> Artificial
<220>
<223> other
<400> 19
Asn His His His His His His
1 5
<210> 20
<211> 6
<212> PRT
<213> Artificial
<220>
<223> other
<400> 20
His His His His His His
1 5
<210> 21
<211> 960
<212> PRT
<213> Neisseria gonorrhoeae
<220>
<221> MISC_FEATURE
<223> amino acid sequence of an IgA1 protease from Neisseria gonorrhoea
(type 2)
<400> 21
Met Ala Leu Val Arg Asp Asp Val Asp Tyr Gln Ile Phe Arg Asp Phe
1 5 10 15
Ala Glu Asn Lys Gly Lys Phe Phe Val Gly Ala Thr Asp Leu Ser Val
20 25 30
Lys Asn Lys Arg Gly Gln Asn Ile Gly Asn Ala Leu Ser Asn Val Pro
35 40 45
Met Ile Asp Phe Ser Val Ala Asp Val Asn Lys Arg Ile Ala Thr Val
50 55 60
Val Asp Pro Gln Tyr Ala Val Ser Val Lys His Ala Lys Ala Glu Val
65 70 75 80
His Thr Phe Tyr Tyr Gly Gln Tyr Asn Gly His Asn Asp Val Ala Asp
85 90 95
Lys Glu Asn Glu Tyr Arg Val Val Glu Gln Asn Asn Tyr Glu Pro His
100 105 110
Lys Ala Trp Gly Ala Ser Asn Leu Gly Arg Leu Glu Asp Tyr Asn Met
115 120 125
Ala Arg Phe Asn Lys Phe Val Thr Glu Val Ala Pro Ile Ala Pro Thr
130 135 140
Asp Ala Gly Gly Gly Leu Asp Thr Tyr Lys Asp Lys Asn Arg Phe Ser
145 150 155 160
Ser Phe Val Arg Ile Gly Ala Gly Arg Gln Leu Val Tyr Glu Lys Gly
165 170 175
Val Tyr His Gln Glu Gly Asn Glu Lys Gly Tyr Asp Leu Arg Asp Leu
180 185 190
Ser Gln Ala Tyr Arg Tyr Ala Ile Ala Gly Thr Pro Tyr Lys Asp Ile
195 200 205
Asn Ile Asp Gln Thr Met Asn Thr Glu Gly Leu Ile Gly Phe Gly Asn
210 215 220
His Asn Lys Gln Tyr Ser Ala Glu Glu Leu Lys Gln Ala Leu Ser Gln
225 230 235 240
Asp Ala Leu Thr Asn Tyr Gly Val Leu Gly Asp Ser Gly Ser Pro Leu
245 250 255
Phe Ala Phe Asp Lys Gln Lys Asn Gln Trp Val Phe Leu Gly Thr Tyr
260 265 270
Asp Tyr Trp Ala Gly Tyr Gly Lys Lys Ser Trp Gln Glu Trp Asn Ile
275 280 285
Tyr Lys Lys Glu Phe Ala Asp Lys Ile Lys Gln His Asp Asn Ala Gly
290 295 300
Thr Val Lys Gly Asn Gly Glu His His Trp Lys Thr Thr Gly Thr Asn
305 310 315 320
Ser His Ile Gly Ser Thr Ala Val Arg Leu Ala Asn Asn Glu Gly Asp
325 330 335
Ala Asn Asn Gly Gln Asn Val Thr Phe Glu Asp Asn Gly Thr Leu Val
340 345 350
Leu Asn Gln Asn Ile Asn Gln Gly Ala Gly Gly Leu Phe Phe Lys Gly
355 360 365
Asp Tyr Thr Val Lys Gly Ala Asn Asn Asp Ile Thr Trp Leu Gly Ala
370 375 380
Gly Ile Asp Val Ala Asp Gly Lys Lys Val Val Trp Gln Val Lys Asn
385 390 395 400
Pro Asn Gly Asp Arg Leu Ala Lys Ile Gly Lys Gly Thr Leu Glu Ile
405 410 415
Asn Gly Thr Gly Val Asn Gln Gly Gln Leu Lys Val Gly Asp Gly Thr
420 425 430
Val Ile Leu Asn Gln Lys Ala Asp Ala Asp Lys Lys Val Gln Ala Phe
435 440 445
Ser Gln Val Gly Ile Val Ser Gly Arg Gly Thr Leu Val Leu Asn Ser
450 455 460
Ser Asn Gln Ile Asn Pro Asp Asn Leu Tyr Phe Gly Phe Arg Gly Gly
465 470 475 480
Arg Leu Asp Ala Asn Gly Asn Asp Leu Thr Phe Glu His Ile Arg Asn
485 490 495
Val Asp Glu Gly Ala Arg Ile Val Asn His Asn Thr Asp His Ala Ser
500 505 510
Thr Ile Thr Leu Thr Gly Lys Ser Leu Ile Thr Asn Pro Asn Ser Leu
515 520 525
Ser Val His Ser Ile Gln Asn Asp Tyr Asp Glu Asp Asp Tyr Ser Tyr
530 535 540
Tyr Tyr Arg Pro Arg Arg Pro Ile Pro Gln Gly Lys Asp Leu Tyr Tyr
545 550 555 560
Lys Asn Tyr Arg Tyr Tyr Ala Leu Lys Ser Gly Gly Arg Leu Asn Ala
565 570 575
Pro Met Pro Glu Asn Gly Val Ala Glu Asn Asn Asp Trp Ile Phe Met
580 585 590
Gly Tyr Thr Gln Glu Glu Ala Arg Lys Asn Ala Met Asn His Lys Asn
595 600 605
Asn Arg Arg Ile Gly Asp Phe Gly Gly Phe Phe Asp Glu Glu Asn Gly
610 615 620
Lys Gly His Asn Gly Ala Leu Asn Leu Asn Phe Asn Gly Lys Ser Ala
625 630 635 640
Gln Asn Arg Phe Leu Leu Thr Gly Gly Ala Asn Leu Asn Gly Lys Ile
645 650 655
Ser Val Thr Gln Gly Asn Val Leu Leu Ser Gly Arg Pro Thr Pro His
660 665 670
Ala Arg Asp Phe Val Asn Lys Ser Ser Ala Arg Lys Asp Ala His Phe
675 680 685
Ser Lys Asn Asn Glu Val Val Phe Glu Asp Asp Trp Ile Asn Arg Thr
690 695 700
Phe Lys Ala Ala Glu Ile Ala Val Asn Gln Ser Ala Ser Phe Ser Ser
705 710 715 720
Gly Arg Asn Val Ser Asp Ile Thr Ala Asn Ile Thr Ala Thr Asp Asn
725 730 735
Ala Lys Val Asn Leu Gly Tyr Lys Asn Gly Asp Glu Val Cys Val Arg
740 745 750
Ser Asp Tyr Thr Gly Tyr Val Thr Cys Asn Thr Gly Asn Leu Ser Asp
755 760 765
Lys Ala Leu Asn Ser Phe Asp Ala Thr Arg Ile Asn Gly Asn Val Asn
770 775 780
Leu Asn Gln Asn Ala Ala Leu Val Leu Gly Lys Ala Ala Leu Trp Gly
785 790 795 800
Lys Ile Gln Gly Gln Gly Asn Ser Arg Val Ser Leu Asn Gln His Ser
805 810 815
Lys Trp His Leu Thr Gly Asp Ser Gln Val His Asn Leu Ser Leu Ala
820 825 830
Asp Ser His Ile His Leu Asn Asn Ala Ser Asp Ala Gln Ser Ala Asn
835 840 845
Lys Tyr His Thr Ile Lys Ile Asn His Leu Ser Gly Asn Gly His Phe
850 855 860
His Tyr Leu Thr Asp Leu Ala Lys Asn Leu Gly Asp Lys Val Leu Val
865 870 875 880
Lys Glu Ser Ala Ser Gly His Tyr Gln Leu His Val Gln Asn Lys Thr
885 890 895
Gly Glu Pro Asn Gln Glu Gly Leu Asp Leu Phe Asp Ala Ser Ser Val
900 905 910
Gln Asp Arg Ser Arg Leu Phe Val Ser Leu Ala Asn His Tyr Val Asp
915 920 925
Leu Gly Ala Leu Arg Tyr Thr Ile Lys Thr Glu Asn Gly Ile Thr Arg
930 935 940
Leu Tyr Asn Pro Tyr Ala Gly Asn Arg Arg Pro Val Lys Pro Ala Pro
945 950 955 960
Claims (7)
- a) N-말단이 프로펩티드의 C-말단에 연결되어 있는 IGF-I을 포함하는 융합 단백질을 코딩하는 핵산을 함유하는 발현 벡터를 포함하는 원핵 숙주 세포를 배양하여 상기 프로펩티드의 C-말단이 아미노산 -Y-Pro로 종결되게 하는 단계, b) 상기 융합 단백질을 회수하여 IgA 프로티에이즈로 절단하는 단계, c) IGF-I을 회수하는 단계를 포함하고, 이때 Y가 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택됨을 특징으로 하는, IGF-I의 제조 방법.
- 제1항에 있어서,IGF-I이 IGF-I(서열번호 1), C-말단이 제거된 IGF-I(3 내지 6개 아미노산), R36A 및 R37A로 구성된 군으로부터 선택됨을 특징으로 하는 방법.
- 제1항 또는 제2항에 있어서,IGF-I의 C-말단이 IgG로부터 유래된 인간 Fc에 연결되어 있음을 특징으로 하는 방법.
- 제1항 내지 제3항 중 어느 한 항에 있어서,프로펩티드가 하기 화학식 2로 표시됨을 특징으로 하는 방법:화학식 2Met-X1-Hisn-X2-Y-Pro-상기 식에서,Met는 메티오닌을 나타내고,X1은 결합, 세린 또는 아스파라긴이고,His는 히스티딘이고,n은 0 내지 6의 수이고,X2는 서열번호 6 내지 10의 펩티드로 구성된 군으로부터 선택된 링커 펩티드이고,Pro는 프롤린이고,Y는 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택된다.
- 프로펩티드의 C-말단에 연결된 IGF-I을 포함하는 융합 단백질로서, 상기 프로펩티드의 C-말단이 아미노산 -Y-Pro로 종결되고, 이때 Y가 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택됨을 특징으로 하는 융합 단백질.
- 제5항에 있어서,프로펩티드의 길이가 30개 이하의 아미노산에 해당하는 길이임을 특징으로 하는 융 합 단백질.
- 제5항 또는 제6항에 있어서,하기 화학식 1로 표시됨을 특징으로 하는 융합 단백질:화학식 1Met-X1-Hisn-X2-Y-Pro-[IGF-I]상기 식에서,Met는 메티오닌을 나타내고,X1은 결합, 세린 또는 아스파라긴이고,His는 히스티딘이고,n은 0 내지 6의 수이고,X2는 서열번호 6 내지 10의 펩티드로 구성된 군으로부터 선택된 링커 펩티드이고,Pro는 프롤린이고,Y는 Pro, Pro-Ala, Pro-Gly, Pro-Thr, Ala-Pro, Gly-Pro, Thr-Pro, Arg-Pro 및 Pro-Arg-Pro로 구성된 군으로부터 선택된다.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06018171 | 2006-08-31 | ||
| EP06018171.6 | 2006-08-31 | ||
| PCT/EP2007/007539 WO2008025527A1 (en) | 2006-08-31 | 2007-08-29 | Method for the production of insulin-like growth factor-i |
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| KR20090046874A true KR20090046874A (ko) | 2009-05-11 |
| KR101106795B1 KR101106795B1 (ko) | 2012-01-18 |
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| US (1) | US8552158B2 (ko) |
| EP (1) | EP2059530B1 (ko) |
| JP (1) | JP4958975B2 (ko) |
| KR (1) | KR101106795B1 (ko) |
| CN (1) | CN101484469B (ko) |
| AU (1) | AU2007291501B2 (ko) |
| BR (1) | BRPI0715754A2 (ko) |
| CA (1) | CA2658736C (ko) |
| ES (1) | ES2393373T3 (ko) |
| IL (1) | IL195664A (ko) |
| MX (1) | MX2009001691A (ko) |
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|---|---|---|---|---|
| US8552158B2 (en) | 2006-08-31 | 2013-10-08 | Hoffmann-La Roche Inc. | Method for the production of insulin-like growth factor-1 |
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| AU2007291501A1 (en) | 2008-03-06 |
| ES2393373T3 (es) | 2012-12-20 |
| US8552158B2 (en) | 2013-10-08 |
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| IL195664A (en) | 2012-07-31 |
| WO2008025527A8 (en) | 2009-07-02 |
| CA2658736A1 (en) | 2008-03-06 |
| CN101484469B (zh) | 2012-12-12 |
| AU2007291501B2 (en) | 2012-07-12 |
| EP2059530A1 (en) | 2009-05-20 |
| US20100121036A1 (en) | 2010-05-13 |
| CA2658736C (en) | 2014-08-12 |
| WO2008025527A1 (en) | 2008-03-06 |
| BRPI0715754A2 (pt) | 2013-07-09 |
| IL195664A0 (en) | 2011-08-01 |
| JP2010501606A (ja) | 2010-01-21 |
| CN101484469A (zh) | 2009-07-15 |
| KR101106795B1 (ko) | 2012-01-18 |
| MX2009001691A (es) | 2009-02-25 |
| JP4958975B2 (ja) | 2012-06-20 |
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