长效人凝血因子Ⅶ的研究进展
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摘要
人凝血因子Ⅶa(human factor Ⅶa,hFⅦa)是外源性凝血途径的起始酶,已被广泛用于血友病患者的出血及非血友病患者的创伤性大出血等治疗,具有令人满意的止血效果。但是,同其他蛋白质类药物一样,其存在体内循环半衰期短、易被酶水解等问题,极大限制了临床应用。由于长效蛋白质药物能延长药物在体内的滞留时间,增加患者用药的顺应性,降低用药相关的医护成本,因而开发长效的hFⅦa成为了研究热点。本文就长效hFⅦa药物的国内外研究进展做一综述。
Human factor Ⅶa( h FⅦa) is the initial enzyme which activates the exogenous coagulation pathway,and has been widely used for therapy of hemorrhage in patients with hemophilia and traumatic hemorrhage in patients without hemophilia,showing satisfactory hemostatic effect. However,it has some problems like other protein drugs,such as short circulating half-life,easiness to be hydrolyzed by enzymes and so on,which limit it's clinical applications greatly. And long-acting protein drugs can prolong residence time in vivo,increase medication compliance of patients,reduce drug-related health care costs,so development of long-acting h FⅦa has become a research hot spot. This article reviews the domestic and foreign research progress in long-acting h FⅦa.
Human factor Ⅶa( h FⅦa) is the initial enzyme which activates the exogenous coagulation pathway,and has been widely used for therapy of hemorrhage in patients with hemophilia and traumatic hemorrhage in patients without hemophilia,showing satisfactory hemostatic effect. However,it has some problems like other protein drugs,such as short circulating half-life,easiness to be hydrolyzed by enzymes and so on,which limit it's clinical applications greatly. And long-acting protein drugs can prolong residence time in vivo,increase medication compliance of patients,reduce drug-related health care costs,so development of long-acting h FⅦa has become a research hot spot. This article reviews the domestic and foreign research progress in long-acting h FⅦa.
引文
[1]LIEBMAN HA,CHEDIAK J,FINK KI,et al.Activated recombinant human coagulation factor VII(r FVIIa)therapy for abdomihal bleeding in patients with inhibitory antibodies to factor VIII[J].Am J Hematol,2000,63(3):109-113.
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[3]李俊英,梁宗安,董芸,等.重组人凝血因子VIIa对创伤性大出血的疗效观察[J].实用医院临床杂志,2016,13(6):45-47.
[4]付登科,陈大志.重组人凝血因子VIIa在肝脏移植中的应用进展[J].国际移植与血液净化杂志,2006,4(5):29-31.
[5]程念,胡中平,杨帆,等.多肽药物长效化研究进展[J].中国新药杂志,2016,25(22):2574-2580.
[6]张兵,邹文艺,范清林,等.长效重组药物研究进展[J].生物学杂志,2008,25(3):9-12.
[7]傅一鸣,王清明,安利国.蛋白质和多肽药物长效性研究进展[J].生命科学,2008,20(2):258-262.
[8]KRATZ F.Albumin as a drug carrier:design of prodrugs,drug conjugates and nanoparticles[J].J Control Release,2008,132(3):171-183.
[9]THOMAS W,STEFAN S,ULRICH K,et al.Modified coagulation factor vila with extended half-life:EP,WO2007090584A1[P].2007-08-16.
[10]ZOLLNER S,SCHUERMANN D,RAQUET E,et al.Pharmacological characteristics of a novel,recombinant fusion protein linking coagulation factor VIIa with albumin(r VIIa-FP)[J].Thromb Haemost,2014,12(2):220-228.
[11]HERZOG E,HARRIS S,MCEWEN A,et al.Recombinant fusion protein linking factor VIIa with albumin(r VIIa-FP)Tissue distribution in rats[J].Thromb Res,2014,134(2):495-502.
[12]WEIMER T,WORMSBACHER W,KRONTHALER U,et al.Prolonged in-vivo half-life of factor VIIa by fusion to albumin[J].Thromb Haemost,2008,99(4):659-667.
[13]T·魏默,S·舒尔特,U·克龙塞勒,等.具有延长的半衰期的经修饰的凝血因子VIIA:中国,CN101379189B[P].2009-03-04.
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[15]ANDERSEN JT,SANDLIE I.The Versatile MHC class I related Fc Rn protects Ig G and albumin from degradation:implications for development of new diagnostics and therapeutics[J].Drug Metab Pharmacokinet,2009,24(4):318-332.
[16]SALAS J,LIU T,LU Q,et al.Enhanced pharmacokinetics of factor VIIa as a monomeric Fc fusion[J].Thromb Res,2015,135(5):970-976.
[17]李强,刘长付,冯维,等.改良型人凝血因子FVII-Fc融合蛋白及其制备方法与用途:中国,CN104774269A[P].2015-07-15.
[18]SCHELLENBERGER V,WANG CW,GEETHING NC,et al.A recombinant polypeptide extends the in vivo half life of peptides and proteins in a tunable manner[J].Nat Biotech,2009,27(12):1186-1190.
[19]SCHELLENBERGER V,SILVERMAN J,WANG CW,et al.Binding fusion proteins,binding fusion protein-drug conjugates,xten-drug conjugates and methods of making and using same:US,WO2011123813A2[P].2011-10-06.
[20]TOMATO.百健艾迪与Amunix合作开发凝血因子VIII新产品[EB/OL].(2015-07-16).http://www.bioon.com/industry/enterprisenews/594859.shtml tomato.
[21]BIODRUGS.Table 6:examples of extended-half-life clinical and preclinical biobetter candidates generated via protein fusions[EB/OL].(2015-07-16).http://europepmc.org/articles/PMC4562006/table/Tab6.
[22]MARIA MA,ELENA NK,NANCY M,et al.Platelet-targeted r FVIIa-Xten improves thrombin generation and fibrin formation compared to recombinant FVIIa[J].Blood,2015,126(23):2269.
[23]GILI H,OREN H,AHUVA BI,et al.Mod-5014,a novel longacting FVIIa proposing an improved prophylactic and on demand treatment for hemophilic patients following SC and IV administration-comprehensive in-vitro and in-vivo evaluation in preparation for clinical studies[J].Blood,2013,122(21):3578.
[24]OPKO BIOLOGICS.Factor VIIA-CTP(MOD-5014)[EB/OL].(2016-03-08).http://www.opkobiologics.com/pipeline/product-candidates/factor-viia-ctp.
[25]VERONESE FM,PASUT G.PEGylation,successful approach to drug delivery[J].Drug Discov Today,2005,10(21):1451-1458.
[26]W·亨利.缀合的凝血因子VIIa:中国,CN102971013A[P].2013-03-13.
[27]N·K·克劳森,S·比约恩,C·贝伦斯,等.PEG化因子VII糖型:中国,CN101301475[P].2008-11-12.
[28]KLAUSEN NK,BJORN S,BEHRENS C,et al.Pegylated Factor VII Glycoforms:US,20090227504[P].2009-09-10.
[29]JOHANSEN PB,BJRN SE,AGERSH,et al.Prolonged effect of Glyco PEGylated r FVIIa(40k-PEG-r FVIIa)in rabbits correlates to activity in plasma[J].Thromb Haemost,2010,104(1):157-164.
[30]TURECEK P,SIEKMANN J,SCHEIFLINGER F,et al.Factor VIIa-polysialic acid conjugate having prolonged in vivo half-life:US,20080221032[P].2008-09-11.
[31]皮特·图雷切克,于尔根·西克曼,弗里德里·沙伊夫林格尔,等.具有延长的体内半衰期的因子VIIa-聚唾液酸结合物:中国,CN105838699A[P].2016-08-10.
[32]VERONESE FM,PASUT G.PEGylation,successful approach to drug delivery[J].Drug Discov Today,2005,10(21):1451-1458.
[2]GEROTZIAFAS GT,ZERVAS K,ARZOGLOU P,et al.On the mechanism of action of recombinant activated factor VII administered to patients with severe thrombocytopenia and life-threatening haemorrhage:focus on prothrombin activation[J].Br J Haematol,2002,117(3):705-708.
[3]李俊英,梁宗安,董芸,等.重组人凝血因子VIIa对创伤性大出血的疗效观察[J].实用医院临床杂志,2016,13(6):45-47.
[4]付登科,陈大志.重组人凝血因子VIIa在肝脏移植中的应用进展[J].国际移植与血液净化杂志,2006,4(5):29-31.
[5]程念,胡中平,杨帆,等.多肽药物长效化研究进展[J].中国新药杂志,2016,25(22):2574-2580.
[6]张兵,邹文艺,范清林,等.长效重组药物研究进展[J].生物学杂志,2008,25(3):9-12.
[7]傅一鸣,王清明,安利国.蛋白质和多肽药物长效性研究进展[J].生命科学,2008,20(2):258-262.
[8]KRATZ F.Albumin as a drug carrier:design of prodrugs,drug conjugates and nanoparticles[J].J Control Release,2008,132(3):171-183.
[9]THOMAS W,STEFAN S,ULRICH K,et al.Modified coagulation factor vila with extended half-life:EP,WO2007090584A1[P].2007-08-16.
[10]ZOLLNER S,SCHUERMANN D,RAQUET E,et al.Pharmacological characteristics of a novel,recombinant fusion protein linking coagulation factor VIIa with albumin(r VIIa-FP)[J].Thromb Haemost,2014,12(2):220-228.
[11]HERZOG E,HARRIS S,MCEWEN A,et al.Recombinant fusion protein linking factor VIIa with albumin(r VIIa-FP)Tissue distribution in rats[J].Thromb Res,2014,134(2):495-502.
[12]WEIMER T,WORMSBACHER W,KRONTHALER U,et al.Prolonged in-vivo half-life of factor VIIa by fusion to albumin[J].Thromb Haemost,2008,99(4):659-667.
[13]T·魏默,S·舒尔特,U·克龙塞勒,等.具有延长的半衰期的经修饰的凝血因子VIIA:中国,CN101379189B[P].2009-03-04.
[14]医谷网.长效蛋白药物市场全景扫描[EB/OL].(2016-05-18).http://mt.sohu.com/20160518/n450117540.shtml.
[15]ANDERSEN JT,SANDLIE I.The Versatile MHC class I related Fc Rn protects Ig G and albumin from degradation:implications for development of new diagnostics and therapeutics[J].Drug Metab Pharmacokinet,2009,24(4):318-332.
[16]SALAS J,LIU T,LU Q,et al.Enhanced pharmacokinetics of factor VIIa as a monomeric Fc fusion[J].Thromb Res,2015,135(5):970-976.
[17]李强,刘长付,冯维,等.改良型人凝血因子FVII-Fc融合蛋白及其制备方法与用途:中国,CN104774269A[P].2015-07-15.
[18]SCHELLENBERGER V,WANG CW,GEETHING NC,et al.A recombinant polypeptide extends the in vivo half life of peptides and proteins in a tunable manner[J].Nat Biotech,2009,27(12):1186-1190.
[19]SCHELLENBERGER V,SILVERMAN J,WANG CW,et al.Binding fusion proteins,binding fusion protein-drug conjugates,xten-drug conjugates and methods of making and using same:US,WO2011123813A2[P].2011-10-06.
[20]TOMATO.百健艾迪与Amunix合作开发凝血因子VIII新产品[EB/OL].(2015-07-16).http://www.bioon.com/industry/enterprisenews/594859.shtml tomato.
[21]BIODRUGS.Table 6:examples of extended-half-life clinical and preclinical biobetter candidates generated via protein fusions[EB/OL].(2015-07-16).http://europepmc.org/articles/PMC4562006/table/Tab6.
[22]MARIA MA,ELENA NK,NANCY M,et al.Platelet-targeted r FVIIa-Xten improves thrombin generation and fibrin formation compared to recombinant FVIIa[J].Blood,2015,126(23):2269.
[23]GILI H,OREN H,AHUVA BI,et al.Mod-5014,a novel longacting FVIIa proposing an improved prophylactic and on demand treatment for hemophilic patients following SC and IV administration-comprehensive in-vitro and in-vivo evaluation in preparation for clinical studies[J].Blood,2013,122(21):3578.
[24]OPKO BIOLOGICS.Factor VIIA-CTP(MOD-5014)[EB/OL].(2016-03-08).http://www.opkobiologics.com/pipeline/product-candidates/factor-viia-ctp.
[25]VERONESE FM,PASUT G.PEGylation,successful approach to drug delivery[J].Drug Discov Today,2005,10(21):1451-1458.
[26]W·亨利.缀合的凝血因子VIIa:中国,CN102971013A[P].2013-03-13.
[27]N·K·克劳森,S·比约恩,C·贝伦斯,等.PEG化因子VII糖型:中国,CN101301475[P].2008-11-12.
[28]KLAUSEN NK,BJORN S,BEHRENS C,et al.Pegylated Factor VII Glycoforms:US,20090227504[P].2009-09-10.
[29]JOHANSEN PB,BJRN SE,AGERSH,et al.Prolonged effect of Glyco PEGylated r FVIIa(40k-PEG-r FVIIa)in rabbits correlates to activity in plasma[J].Thromb Haemost,2010,104(1):157-164.
[30]TURECEK P,SIEKMANN J,SCHEIFLINGER F,et al.Factor VIIa-polysialic acid conjugate having prolonged in vivo half-life:US,20080221032[P].2008-09-11.
[31]皮特·图雷切克,于尔根·西克曼,弗里德里·沙伊夫林格尔,等.具有延长的体内半衰期的因子VIIa-聚唾液酸结合物:中国,CN105838699A[P].2016-08-10.
[32]VERONESE FM,PASUT G.PEGylation,successful approach to drug delivery[J].Drug Discov Today,2005,10(21):1451-1458.