体积排阻色谱在蛋白质药物聚集体领域的应用
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摘要
蛋白质聚集现象是生物制药行业面临的重大问题之一,对蛋白质药物有效性、安全性、质量可控性有很大影响。体积排阻色谱技术是蛋白质药物及其聚集体检测分析的标准技术,具有操作简单、分离条件温和、基本不破坏蛋白质药物结构等优点。但由于蛋白质与固定相存在非特异性相互作用,采用该法检测时存在洗脱延迟、色谱峰拖尾、基线漂移、蛋白质回收率低等问题。该文介绍了体积排阻色谱的分离原理及实际应用,并对该技术在蛋白质药物检测中存在的非特异性吸附问题及相关方法优化做了简要概述。同时列举了几种与体积排阻色谱互补的可用于蛋白质药物聚集体分析的技术。最后,对体积排阻色谱技术的发展前景进行了展望。
The phenomenon of protein aggregation during the production of a bio-therapeutic drug is an increasing challenge to many pharmaceutical research and development groups and companies.Aggregation may cause a number of deleterious effects on protein drugs,including the loss of efficacy,the induction of immunogenicity,alteration of pharmacokinetics and reduction of shelf life.Size exclusion chromatography(SEC) is a traditional technique widely employed for the qualitative and quantitative evaluation on pharmaceutical proteins and their aggregates,which possesses some advantages such as easy operation,mild mobile phase conditions and nondestructive detection of the conformational structure and local environment,etc.However,SEC method still remains a number of limitations,in which the most important one is the adsorption of protein to resin.The theory for SEC separation is outlined in this review,and some methods how to reduce the nonspecific adsorption problem are described.Some techniques mutually comlementary with SEC are listed, which could be used in the analysis on pharmaceutical protein aggregates.Finally,the future development and outlook for SEC technique are described.
The phenomenon of protein aggregation during the production of a bio-therapeutic drug is an increasing challenge to many pharmaceutical research and development groups and companies.Aggregation may cause a number of deleterious effects on protein drugs,including the loss of efficacy,the induction of immunogenicity,alteration of pharmacokinetics and reduction of shelf life.Size exclusion chromatography(SEC) is a traditional technique widely employed for the qualitative and quantitative evaluation on pharmaceutical proteins and their aggregates,which possesses some advantages such as easy operation,mild mobile phase conditions and nondestructive detection of the conformational structure and local environment,etc.However,SEC method still remains a number of limitations,in which the most important one is the adsorption of protein to resin.The theory for SEC separation is outlined in this review,and some methods how to reduce the nonspecific adsorption problem are described.Some techniques mutually comlementary with SEC are listed, which could be used in the analysis on pharmaceutical protein aggregates.Finally,the future development and outlook for SEC technique are described.
引文
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[2] Den Engelsman J,Garidel P,Smulders R,Koll H,Smith B,Bassarab S,Seidl A,Hainzl O,Jiskoot W.Pharm.Res.,2011,28(4):920-933.
[3] Berkowitz S A,Engen J R,Mazzeo J R,Jones G B.Nat.Rev.Drug Discov.,2012,11(7):527-540.
[4] Fekete S,Beck A,Veuthey J L,Guillarme D.J.Pharm.Biomed.Anal.,2014,101:161-173.
[5] Park S,Cho H,Kim Y,Ahn S,Chang T.J.Chromatogr.A,2007,1157(1/2):96-100.
[6] Engelhardt H,Ahr G.J.Chromatogr.A,1983,282(C):385-397.
[7] Mahler H C,Friess W,Grauschopf U,Kiese S.J.Pharm.Sci.,2009,98(9):2909-2934.
[8] Ripple D C,Hu Z.Pharm.Res.,2016,33(3):653-672.
[9] Philo J S.AAPS J.,2006,8(3):E564-E571.
[10] Vasudev R,Mathew S,Afonina N.J.Pharm.Sci.,2015,104(5):1622-1631.
[11] Popovici S T,Schoenmakers P J.J.Chromatogr.A,2005,1099(1/2):92-102.
[12] Ricker R D,Sandoval L A.J.Chromatogr.A,1996,743(1):43-50.
[13] Rebolj K,Pahovnik D,?agar E.Anal.Chem.,2012,84(17):7374-7383.
[14] Kiminami H,Krueger A B,Abe Y,Yoshino K,Carpenter J F.J.Pharm.Sci.,2017,106(4):1001-1007.
[15] Lancaster C,Rustandi R R,Pannizzo P,Ha S.Methods Mol.Biol.,2016,1476:279-287.
[16] Haberger M,Leiss M,Heidenreich A K,Pester O,Hafenmair G,Hook M,Bonnington L,Wegele H,Haindl M,Reusch D,Bulau P.mAbs,2016,8(2):331-339.
[17] Al-Ghobashy M A,Mostafa M M,Abed H S,Fathalla F A,Salem M Y.J.Chromatogr.B,2017,1060:1-9.
[18] Alley S C,Okeley N M,Senter P D.Curr.Opin.Chem.Biol.,2010,14(4):529-537.
[19] Lorusso P M,Weiss D,Guardino E,Girish S,Sliwkowski M X.Clin.Cancer Res.,2011,17(20):6437-6447.
[20] Li Y,Gu C,Gruenhagen J,Zhang K,Yehl P,Chetwyn N P,Medley C D.J.Chromatogr.A,2015,1393:81-88.
[21] Jones L S,Kaufmann A,Middaugh C R.J.Pharm.Sci.,2005,94(4):918-927.
[22] Thirumangalathu R,Krishnan S,Ricci M,Brems D,Randolph T W,Carpenter J F.J.Pharm.Sci.,2009,98(9):3167-3181.
[23] Gerhardt A,McGraw N R,Schwartz D K,Bee J S,Carpenter J F,Randolph T W.J.Pharm.Sci.,2014,103(6):1601-1612.
[24] Felsovalyi F,Janvier S,Jouffray S,Soukiassian H,Mangiagalli P.J.Pharm.Sci.,2012,101(12):4569-4583.
[25] Waxman L,Vilivalam V D.PDA J.Pharm.Sci.Technol.,2017,71(6):462.
[26] Sugimoto M A A,Toledo V D P C P,Cunha M R R C,Carregal V M,Jorge R,Leao P,Fialho S L,Silva-Cunha A.Arq.Bras.Oftalmol.,2017,80(2):108-113.
[27] Xiong J,Ji R D.Biophys Chem.,2017,220:42-48.
[28] Paul A J,Bickel F,R?hm M,Hospach L,Halder B,Rettich N,Handrick R,Herold E M,Kiefer H,Hesse F.Anal.Bioanal.Chem.,2017,409(17):4149-4156.
[29] Sadavarte R H,Ghosh R.J.Pharm.Sci.,2014,103(3):870-878.
[30] Carpenter J F,Randolph T W,Jiskoot W,Crommelin D J A,Middaugh C R,Winter G.J.Pharm.Sci.,2010,99(5):2200-2208.
[31] Arakawa T,Ejima D,Li T,Philo J S.J.Pharm.Sci.,2010,99(4):1674-1692.
[32] Goyon A,Beck A,Veuthey J L,Guillarme D,Fekete S.J.Pharm.Biomed.Anal.,2017,144:242-251.
[33] Kamberi M,Chung P,Devas R,Li L,Li Z,Sharon X M,Fields S,Riley C M.J.Chromatogr.B,2004,810(1):151-155.
[34] Yumioka R,Sato H,Tomizawa H,Yamasaki Y,Ejima D.J.Pharm.Sci.,2010,99(2):618-620.
[35] Z?lls S,Tantipolphan R,Wiggenhorn M,Winter G,Jiskoot W,Friess W,Hawe A.J.Pharm.Sci.,2012,101(3):914-935.
[36] Turner A,Yandrofski K,Telikepalli S,King J,Heckert A,Filliben J,Ripple D,Schiel J E.Anal.Bioanal.Chem.,2018,410(8):2095-2110.
[37] Dada O O,Rao R,Jones N,Jaya N,Salas-Solano O.J.Pharm.Biomed.Anal.,2017,145:91-97.
[38] Buecheler J W,Winzer M,Weber C,Gieseler H.J.Pharm.Pharmacol.,2018,70(5):625-635.
[39] Gervais D,Downer A,King D,Kanda P,Foote N,Smith S.J.Pharm.Biomed.Anal.,2017,139:215-220.
[40] Marassi V,Roda B,Zattoni A,Tanase M,Reschiglian P.J.Chromatogr.A,2014,1372C:196-203.
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