仿制低分子肝素的免疫原性研究
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摘要
低分子肝素(LMWH)是当前临床最常使用的抗凝剂,其应用中存在的重要不良反应为肝素诱导的血小板减少症。随着各种原研LMWH专利的到期,大量仿制LMWH涌现。为此,FDA发布指南要求各仿制LMWH厂家在进行注册申报时,需开展与此不良反应相关的免疫原性研究。本文介绍了LMWH免疫原性发生的背景及FDA指南中LMWH免疫原性研究的内容与方法,以冀为仿制LMWH的开发提供参考。
Low-molecular-weight heparin(LMWH) is the most commonly used anticoagulant in clinic, heparininduced thrombocytopenia(HIT) is the most severe side effect of LMWH. With the expiration of all patents for LMWH, a large number of generic LMWH have emerged. Therefore, FDA issued Immunogenicity-Related Considerations for Low Molecular Weight Heparin Guidance for Industry for the evaluation of related potential risk in drug registration. In this review, the background of LMWH immunogenicity and the contents and methods of immunogenicity study of LMWH required by FDA in this guidance have been summarized to provide reference for the development of generic LMWH.
Low-molecular-weight heparin(LMWH) is the most commonly used anticoagulant in clinic, heparininduced thrombocytopenia(HIT) is the most severe side effect of LMWH. With the expiration of all patents for LMWH, a large number of generic LMWH have emerged. Therefore, FDA issued Immunogenicity-Related Considerations for Low Molecular Weight Heparin Guidance for Industry for the evaluation of related potential risk in drug registration. In this review, the background of LMWH immunogenicity and the contents and methods of immunogenicity study of LMWH required by FDA in this guidance have been summarized to provide reference for the development of generic LMWH.
引文
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[3]Girolami B,Girolami A.Heparin-induced thrombocytopenia:a review[J].Semin Thromb Hemost,2006,32(8):803-809.
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[5]Hursting M J,Pai P J,Mccracken J E,et al.Platelet factor 4/heparin antibodies in blood bank donors[J].Am J Clin Path,2010,134(5):774-780.
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[7]Arepally G M,Ortel T L.Heparin-Induced Thrombocytopenia[J].Humana Press,2008,355(61):551-555.
[8]Lee S,Raw A,Yu L,et al.Scientific considerations in the review and approval of generic enoxaparin in the United States[J].Nat Biotechnol,2013,31(3):220-226.
[9]US Food and Drug Administration.Response to Citizen Petition,Docket No.FDA-2003-P-0273[Z].2010.
[10]Thanawiroon C,Rice K G,Toida T,et al.Liquid chromatography/mass spectrometry sequencing approach for highly sulfated heparin-derived oligosaccharides[J].J Bio Chem,2004,279(4):2608-2615.
[11]Mourier P A,Viskov C.Chromatographic analysis and sequencing approach of heparin oligosaccharides using cetyltrimethylammonium dynamically coated stationary phases[J].Anal Biochem,2004,332(2):299-313.
[12]Guerrini M,Bisio A,Torri G.Combined quantitative H-1 and C-13nuclear magnetic resonance spectroscopy for characterization of heparin preparations[J].Semin Thromb Hemost,2001,27(5):473-482.
[13]Chuang W L,Christ M D,Rabenstein D L.Determination of the primary structures of heparin-and heparan sulfate-derived oligosaccharides using band-selective homonucleardecoupled two dimensional H-1 NMR experiments[J].Anal Chem,2001,73(10):2310-2316.
[14]Keire D A,Buhse L F,Al-Hakim A.Characterization of currently marketed heparin products:Composition analysis by 2D-NMR[J].Anal Methods,2013,5(12):2984-2994.
[15]Linhardt R J.Hudson Award address in carbohydrate chemistry.Heparin:structure and activity[J].J Med Chem,2003,46(13):2551-2564.
[16]Capila I,Linhardt R J.Heparin-protein interactions[J].Angew Chem Int Ed Engl,2002,41(3):391-412.
[17]Linhardt R J,Gunay N S.Production and chemical processing of low molecular weight heparins[J].Semin Thromb Hemost,1999,25(3):5-16.
[18]Debrie R.Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events:US,5389618[P].1995-02-14.
[19]Sundaram M,Qi Y W,Shriver Z,et al.Rational design of lowmolecular weight heparins with improved in vivo activity[J].Proc Natl Acad Sci USA,2003,100(2):651-656.
[20]Toyoda H,Yamamoto H,Ogino N,et al.Rapid and sensitive analysis in heparin and heparin sulfate of reversed-phase ionpair chromatography on a 2μm porous silica gel column[J].JChromatogr A,1999,830(1):197-201.
[21]Mourier P,Viskov C.Method for determining specific groups constituting heparins or low molecular weight heparins:US,7687274 B2[P].2010-03-30.
[22]Myette J R,Shriver Z,Kiziltepe T,et al.Molecular cloning of the heparin/heparin sulfate Delta 4,5 unsaturated glycuronidase from Flavobacterium heparinum,its recombinant expression in Escherichia coli,and biochemical determination of its unique substrate specificity[J].Biochem,2002,41(23):7424-7434.
[23]Stringer S E,Kandola B S,Pye D A,et al.Heparin sequencing[J].Glycobiology,2003,13(2):97-107.
[24]Ozug J,Wudyka S,Gunay N S,et al.Structural elucidation of the tetrasaccharide pool in enoxaparin sodium[J].Anal Bioanal Chem,2012,403(9):2733-2744.
[25]USP 41.Official monographs:enoxaparin sodium[S].2018:1510-1512.
[26]Newman P M,Swanson R L,Chong B H.Heparin-induced thrombocytopenia:IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid[J].Thromb Haemost,1998,79(2):292-297.
[27]Greinacher A,Alban S,Dummel V,et al.Characterization of the structural requirements for a carbohydrate-based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia[J].Thromb Haemost,1995,74(3):886-892.
[28]Maccarana M,Lindahl U.Mode of interaction between platelet factor 4 and heparin[J].Glycobiology,1993,3(3):271-277.
[29]Pattnaik P.Surface plasmon resonance:applications in understanding receptor-ligand interaction[J].Appl Biochem Biotechnol,2005,126(2):79-92.
[30]Kamberi M,Chung P,Devas R,et al.Analysis of non-covalent aggregation of synthetic hPTH(1-34)by size-exclusion chromatography and the importance of suppression of non-specific interactions for a precise quantitation[J].J Chromatogr B,2004,810(1):151-155.
[31]Lebowitz J,Lewis M S,Schuck P.Modern analytical ultracentrifugation in protein science:a tutorial review[J].Protein Sci,2002,11(9):2067-2079.
[32]Levin S.Field flow fractionation in biomedical analysis[J].Biomed Chromatogr,1991,5(3):133-138.
[33]Greinacher A,Gopinadhan M,Strobel U,et al.Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies[J].Arterioscler Thromb Vasc Biol,2006,26(10):2386-2393.
[34]Heinzelmann M,Miller M,Platz A,et al.Heparin and enoxaparin enhance endotoxin-induced tumor necrosis factor-alpha production in human monocytes[J].Ann Surg,1999,229(4):542-550.
[35]Hochart H,Jenkins P V,Preston R J,et al.Concentration-dependent roles for heparin in modifying lipopolysaccharideinduced activation of mononuclear cells in whole blood[J].Thromb Haemost,2008,99(3):570-575.
[2]Greinacher A,Juhl D,Strobel U,et al.Heparin-induced thrombocytopenia:a prospective study on the incidence,plateletactivating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG,IgM,and IgA classes[J].J Thromb Haemost,2007,5(8):1666-1673.
[3]Girolami B,Girolami A.Heparin-induced thrombocytopenia:a review[J].Semin Thromb Hemost,2006,32(8):803-809.
[4]Selleng S,Malowsky B,Itterman T,et al.Incidence and clinical relevance of anti-platelet factor 4/heparin antibodies before cardiac surgery[J].Am Heart J,2010,160(2):362-369.
[5]Hursting M J,Pai P J,Mccracken J E,et al.Platelet factor 4/heparin antibodies in blood bank donors[J].Am J Clin Path,2010,134(5):774-780.
[6]Martel N,Lee J,Wells P S.Risk for Heparin-induced thrombocytopenia with unfractionated and low-molecular weight heparin thromboprophylaxis:a meta-analysis[J].Blood,2005,106(8):2710-2715.
[7]Arepally G M,Ortel T L.Heparin-Induced Thrombocytopenia[J].Humana Press,2008,355(61):551-555.
[8]Lee S,Raw A,Yu L,et al.Scientific considerations in the review and approval of generic enoxaparin in the United States[J].Nat Biotechnol,2013,31(3):220-226.
[9]US Food and Drug Administration.Response to Citizen Petition,Docket No.FDA-2003-P-0273[Z].2010.
[10]Thanawiroon C,Rice K G,Toida T,et al.Liquid chromatography/mass spectrometry sequencing approach for highly sulfated heparin-derived oligosaccharides[J].J Bio Chem,2004,279(4):2608-2615.
[11]Mourier P A,Viskov C.Chromatographic analysis and sequencing approach of heparin oligosaccharides using cetyltrimethylammonium dynamically coated stationary phases[J].Anal Biochem,2004,332(2):299-313.
[12]Guerrini M,Bisio A,Torri G.Combined quantitative H-1 and C-13nuclear magnetic resonance spectroscopy for characterization of heparin preparations[J].Semin Thromb Hemost,2001,27(5):473-482.
[13]Chuang W L,Christ M D,Rabenstein D L.Determination of the primary structures of heparin-and heparan sulfate-derived oligosaccharides using band-selective homonucleardecoupled two dimensional H-1 NMR experiments[J].Anal Chem,2001,73(10):2310-2316.
[14]Keire D A,Buhse L F,Al-Hakim A.Characterization of currently marketed heparin products:Composition analysis by 2D-NMR[J].Anal Methods,2013,5(12):2984-2994.
[15]Linhardt R J.Hudson Award address in carbohydrate chemistry.Heparin:structure and activity[J].J Med Chem,2003,46(13):2551-2564.
[16]Capila I,Linhardt R J.Heparin-protein interactions[J].Angew Chem Int Ed Engl,2002,41(3):391-412.
[17]Linhardt R J,Gunay N S.Production and chemical processing of low molecular weight heparins[J].Semin Thromb Hemost,1999,25(3):5-16.
[18]Debrie R.Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events:US,5389618[P].1995-02-14.
[19]Sundaram M,Qi Y W,Shriver Z,et al.Rational design of lowmolecular weight heparins with improved in vivo activity[J].Proc Natl Acad Sci USA,2003,100(2):651-656.
[20]Toyoda H,Yamamoto H,Ogino N,et al.Rapid and sensitive analysis in heparin and heparin sulfate of reversed-phase ionpair chromatography on a 2μm porous silica gel column[J].JChromatogr A,1999,830(1):197-201.
[21]Mourier P,Viskov C.Method for determining specific groups constituting heparins or low molecular weight heparins:US,7687274 B2[P].2010-03-30.
[22]Myette J R,Shriver Z,Kiziltepe T,et al.Molecular cloning of the heparin/heparin sulfate Delta 4,5 unsaturated glycuronidase from Flavobacterium heparinum,its recombinant expression in Escherichia coli,and biochemical determination of its unique substrate specificity[J].Biochem,2002,41(23):7424-7434.
[23]Stringer S E,Kandola B S,Pye D A,et al.Heparin sequencing[J].Glycobiology,2003,13(2):97-107.
[24]Ozug J,Wudyka S,Gunay N S,et al.Structural elucidation of the tetrasaccharide pool in enoxaparin sodium[J].Anal Bioanal Chem,2012,403(9):2733-2744.
[25]USP 41.Official monographs:enoxaparin sodium[S].2018:1510-1512.
[26]Newman P M,Swanson R L,Chong B H.Heparin-induced thrombocytopenia:IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid[J].Thromb Haemost,1998,79(2):292-297.
[27]Greinacher A,Alban S,Dummel V,et al.Characterization of the structural requirements for a carbohydrate-based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia[J].Thromb Haemost,1995,74(3):886-892.
[28]Maccarana M,Lindahl U.Mode of interaction between platelet factor 4 and heparin[J].Glycobiology,1993,3(3):271-277.
[29]Pattnaik P.Surface plasmon resonance:applications in understanding receptor-ligand interaction[J].Appl Biochem Biotechnol,2005,126(2):79-92.
[30]Kamberi M,Chung P,Devas R,et al.Analysis of non-covalent aggregation of synthetic hPTH(1-34)by size-exclusion chromatography and the importance of suppression of non-specific interactions for a precise quantitation[J].J Chromatogr B,2004,810(1):151-155.
[31]Lebowitz J,Lewis M S,Schuck P.Modern analytical ultracentrifugation in protein science:a tutorial review[J].Protein Sci,2002,11(9):2067-2079.
[32]Levin S.Field flow fractionation in biomedical analysis[J].Biomed Chromatogr,1991,5(3):133-138.
[33]Greinacher A,Gopinadhan M,Strobel U,et al.Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies[J].Arterioscler Thromb Vasc Biol,2006,26(10):2386-2393.
[34]Heinzelmann M,Miller M,Platz A,et al.Heparin and enoxaparin enhance endotoxin-induced tumor necrosis factor-alpha production in human monocytes[J].Ann Surg,1999,229(4):542-550.
[35]Hochart H,Jenkins P V,Preston R J,et al.Concentration-dependent roles for heparin in modifying lipopolysaccharideinduced activation of mononuclear cells in whole blood[J].Thromb Haemost,2008,99(3):570-575.