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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2019, Vol. 39 Issue (1): 82-89    DOI: 10.13523/j.cb.20190111
综述     
人血清白蛋白在蛋白多肽类药物长效化中的应用 *
徐欢,周美玲,葛琳,王志明()
华北制药集团新药研究开发有限责任公司 石家庄 050015
The Application of Human Serum Albumin in Protein and Peptide Drugs Half-life Extension
Huan XU,Mei-ling ZHOU,Lin GE,Zhi-ming WANG()
New Drug R&D Center,North China Pharmaceutical Corporation,Shijiazhuang 050015, China
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摘要：

重组蛋白/多肽类药物在人体血清内半衰期较短, 很大程度上限制了其临床应用。人血清白蛋白(HSA)具有半衰期长、生物相容性好、低免疫原性等优点,是理想的药物载体。各种基于HSA的蛋白质药物长效化技术得到了广泛的应用和发展,目前主要包括构建HSA融合蛋白,通过共价化学键与HSA偶联,通过非共价键与HSA可逆性结合。总结了近年来基于白蛋白药物长效化技术的发展,各项技术的优缺点及药物开发现状。
关键词： 白蛋白融合;  连接肽;  化学偶联;  脂肪酸修饰;  白蛋白结合肽    
Abstract:

Recombinant protein and peptide drugs have a short half-life in human serum, which largely limits their clinical application. Human serum albumin (HSA) has the advantages of long half-life, good biocompatibility and low immunogenicity, which is an ideal drug carrier. Various albumin-based strategies have been widely used and developed to create long-lasting protein therapeutics. At present, it mainly includes the construction of HSA fusion proteins, coupling with HSA through covalent chemical bonds, and reversible binding to HSA through non-covalent bonds. The development of albumin-based technologies to create long-lasting protein therapeutics in recent years, the advantages and disadvantages of various technologies and the status of their applications in drug development were summarized.
Key words: Albumin fusion    Linker    Chemical coupling    Modification with fatty acids    Albumin-binding peptide
收稿日期: 2018-08-17 出版日期: 2019-02-28
ZTFLH:  Q816  
基金资助: * 国家重大新药创制专项资助项目(2017ZX09303008)
通讯作者: 王志明     E-mail: wzm3994@163.com
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引用本文:

徐欢,周美玲,葛琳,王志明. 人血清白蛋白在蛋白多肽类药物长效化中的应用 *[J]. 中国生物工程杂志, 2019, 39(1): 82-89.

Huan XU,Mei-ling ZHOU,Lin GE,Zhi-ming WANG. The Application of Human Serum Albumin in Protein and Peptide Drugs Half-life Extension. China Biotechnology, 2019, 39(1): 82-89.

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https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20190111    或    https://manu60.magtech.com.cn/biotech/CN/Y2019/V39/I1/82

商品名 药物分子 半衰期的延长
(融合后/融合前)		 生物活性变化
(EC50比值)		 适应证 企业 FDA批准日期
Idelvion rIX-FP 5.35 1/2 B型血友病 CSL Behring 2016年
Tanzeum GLP-1/HSA 2 240 1/100 糖尿病 GSK 2014年
表1  已上市的白蛋白融合药物
代号 药物分子 半衰期的延长
(融合后/融合前)		 企业 适应证 阶段 参考文献
Albuferon IFN-α2b/HSA 18 Human Genome
Sciences/Novartis		 丙型肝炎 III 期完成后,
放弃上市		 [13-14]
N/A IFN-α2b/HSA — 中美福源生物技术 慢性乙型肝炎 I期 [15]
N/A IFN-α2a/HSA 16 中美福源生物技术 慢性乙型肝炎 I期 [16]
N/A IFN-α2a/HSA — 齐鲁制药 慢性乙型肝炎 I期 —
N/A FVIIa/HSA 3-4 CSL Behring 止血 I期 [17]
Balugrastim G-CSF/HSA 2 Teva 中性粒细胞减少症 III 期完成后,放弃上市 [18-19]
N/A G-CSF/HSA 6 中美福源生物技术 中性粒细胞减少症 II期 [20]
GW003 G-CSF/HSA — 江苏泰康生物 化疗后粒细胞减少症 I期 [21]
表2  在临床阶段的白蛋白融合药物
连接肽类型 优点 缺点
没有连接肽 避免产生额外的免疫原性 对蛋白质结构干扰大,影响活性
柔性 柔性、水溶性好,可允许蛋白质一定程度的活动 缺少刚性,可能降低蛋白质表达水平或生物活性
刚性 蛋白质之间的距离可固定,更有效分离两个蛋白质 柔性差,蛋白质不可活动
可断裂 克服了空间位阻问题,生物活性高 药物释放时间很难控制,改善药代学性质受影响
表3  各种连接肽的优缺点
图1  利用可断裂连接肽开发重组因子IX-白蛋白融合蛋白的先进理念
图2  Uox-HSA缀合物的示意图
名称 上市时间 半衰期 序列突变 脂肪酸侧链 连接子 修饰位点
地特胰岛素 2005年 5~7h B30位Thr C14 — B29位Lys
利拉鲁肽 2009年 13h Arg34 C16二羧酸 γ谷氨酸 Lys26
德谷胰岛素 2015年 25h B30位Thr C16 γ谷氨酸 B29位Lys
索玛鲁肽 2017年 40h Aib8, Arg34 C18二羧酸 谷氨酸-2*OEG Lys26
表4  已上市的脂肪链修饰蛋白质/多肽药
[1] Kontermann R E . Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol, 2011,22(6):868-876.
doi: 10.1016/j.copbio.2011.06.012 pmid: 21862310
[2] Kontermann R E . Half-life extended biotherapeutics. Expert Opin Biol Ther, 2016,16(7):903-915.
doi: 10.1517/14712598.2016.1165661
[3] Elliott S, Lorenzini T, Asher S , et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol, 2003,21(4):414-421.
doi: 10.1038/nbt799 pmid: 12612588
[4] Turecek P L, Bossard M J, Schoetens F , et al. Pegylation of biopharmaceuticals: a review of chemistry and nonclinical safety information of approved drugs. J Pharm Sci, 2016,105(2):460-475.
doi: 10.1016/j.xphs.2015.11.015 pmid: 26869412
[5] Rogers B, Dong D, Li Z . Recombinant human serum albumin fusion proteins and novel applications in drug delivery and therapy. Curr Pharm Des, 2015,21(14):1899-1907.
doi: 10.2174/1381612821666150302120047 pmid: 25732550
[6] Bai Y, Ann D K, Shen W C . Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent. Proc Natl Acad Sci USA, 2005,102(20):7292-7296.
doi: 10.1073/pnas.0500062102 pmid: 15870205
[7] Jafari R, Zolbanin N M, Rafatpanah H , et al. Fc-fusion proteins in therapy: an updated view. Curr Med Chem, 2017,24(12):1228-1237.
doi: 10.2174/0929867324666170113112759 pmid: 28088904
[8] Kratz F . Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release, 2008,132(3):171-183.
doi: 10.1016/j.jconrel.2008.05.010 pmid: 18582981
[9] Larsen M T, Kuhlmann M, Hvam M L , et al. Albumin-based drug delivery: harnessing nature to cure disease. Mol Cell Ther, 2016,4(3):1-12.
doi: 10.1186/s40591-016-0046-x pmid: 4728801
[10] Weber A E . Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J Med Chem, 2004,47(17):4128-4134.
doi: 10.1002/chin.200442239 pmid: 15293981
[11] Baggio L L, Huang Q, Brown T J , et al. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes, 2004,53(9):2492-2500.
doi: 10.2337/diabetes.53.9.2492
[12] Lyseng-williamson K A . Coagulation factor IX (recombinant), albumin fusion protein (Albutrepenonacog Alfa; Idelvion ?): a review of its use in haemophilia B . Drugs, 2017,77(1):97-106.
doi: 10.1007/s40265-016-0679-8 pmid: 27988873
[13] Osborn B L, Olsen H S, Nardelli B , et al. Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther, 2002,303(2):540-548.
doi: 10.1124/jpet.102.037002 pmid: 12388634
[14] Subramanian G M, Fiscella M, Lamouse-Smith A , et al. Albinterferon alpha-2b: a genetic fusion protein for the treatment of chronic hepatitis C. Nat Biotechnol, 2007,25(12):1411-1419.
doi: 10.1038/nbt1364 pmid: 18066038
[15] Fu Y, Yu Z L. Long acting human interferon analogs:United States:US 7572437. 2009-8-11[2018-9-18]. Long acting human interferon analogs:United States:US 7572437. 2009-8-11[2018-9-18]. .
[16] 富岩, 马金玲, 孙丽 , 等. 重组人血清白蛋白/干扰素α2a融合蛋白的药效学、药代动力学及安全性评价. 中国医药生物技术, 2012,7(6):401-411.
doi: 10.3969/cmba.j.issn.1673-713X.2012.06.001
Fu Y, Ma J L, Sun L , et al. Pharmacodynamics, pharmacokinetics and safety studies on recombinant human serum albumin/interferon-α2a fusion protein. Chin Med Biotechnol, 2012,7(6):401-411.
doi: 10.3969/cmba.j.issn.1673-713X.2012.06.001
[17] Golor G, Bensen-Kennedy D, Haffner S , et al. Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers. J Thromb Haemost, 2013,11(11):1977-1985.
doi: 10.1111/jth.12409 pmid: 24112951
[18] Pfeil A M, Allcott K, Pettengell R , et al. Efficacy, effectiveness and safety of long-acting granulocyte colony-stimulating factors for prophylaxis of chemotherapy-induced neutropenia in patients with cancer: a systematic review. Support Care Cancer, 2015,23(2):525-545.
doi: 10.1007/s00520-014-2457-z pmid: 25284721
[19] Volovat C, Gladkov O A, Bondarenko I M , et al. Efficacy and safety of balugrastim compared with pegfilgrastim in patients with breast cancer receiving chemotherapy. Clin Breast Cancer, 2014,14(2):101-108.
doi: 10.1016/j.clbc.2013.10.001 pmid: 24485296
[20] 富岩, 尹丽莉, 顾静良 , 等. 重组人血清白蛋白/粒细胞刺激因子融合蛋白的药效学、药理学和毒理学研究. 中国医药生物技术, 2012,7(4):241-256.
doi: 10.3969/cmba.j.issn.1673-713X.2012.04.001
Fu Y, Yin L L, Gu J L , et al. Studies on pharmacodynamics, pharmacology, and toxicology of recombinant human serum albumin/granulocyte colony-stimulating factor fusion protein. Chin Med Biotechnol, 2012,7(4):241-256.
doi: 10.3969/cmba.j.issn.1673-713X.2012.04.001
[21] 姜波, 孙明媛, 郑维维 , 等. 注射用重组人血清白蛋白-人粒细胞集落刺激因子(Ⅰ) 融合蛋白在健康受试者的耐受性研究. 中国临床药理学杂志, 2018,34(6):667-681.
doi: 10.13699/j.cnki.1001-6821.2018.06.017
Jiang B, Sun M Y, Zheng W W , et al. Tolerance of a novel recombinant human serum albumin /human granulocyte-colony stimulating factor(Ⅰ) fusion protein in healthy subjects. Chin J Clin Pharmacol, 2018,34(6):667-681.
doi: 10.13699/j.cnki.1001-6821.2018.06.017
[22] Zhao H L, Yao X Q, Xue C , et al. Increasing the homogeneity, stability and activity of human serum albumin and interferon-alpha2b fusion protein by linker engineering. Protein Expr Purif, 2008,61(1):73-77.
doi: 10.1016/j.pep.2008.04.013 pmid: 18541441
[23] Zhu R Y, Xin X, Dai H Y , et al. Expression and purification of recombinant human serum albumin fusion protein with VEGF165b in Pichia pastoris. Protein Expr Purif, 2012,85(1):32-37.
doi: 10.1016/j.pep.2012.06.009 pmid: 22750397
[24] Matthews J E, Stewart M W, De Boever E H , et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab, 2008,93(12):4810-4817.
doi: 10.1210/jc.2008-1518 pmid: 18812476
[25] Zhao H L, Xue C, Wang Y , et al. Circumventing the heterogeneity and instability of human serum albumin-interferon-alpha2b fusion protein by altering its orientation. J Biotechnol, 2007,131(3):245-252.
doi: 10.1016/j.jbiotec.2007.04.016 pmid: 17698234
[26] Chen X, Zaro J L, Shen W C . Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev, 2013,65(10):1357-1369.
doi: 10.1016/j.addr.2012.09.039 pmid: 23026637
[27] Argos P . An investigation of oligopeptides linking domains in protein tertiary structures and possible candidates for general gene fusion. J Mol Biol, 1990,211(4):943-958.
doi: 10.1016/0022-2836(90)90085-Z pmid: 2313701
[28] Huston J S, Levinson D, Mudgett-Hunter M , et al. Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci USA, 1988,85(16):5879-5883.
doi: 10.1073/pnas.85.16.5879 pmid: 3045807
[29] Bird R E, Hardman K D, Jacobson J W , et al. Single-chain antigen-binding proteins. Science, 1988,242(4877):423-426.
doi: 10.1126/science.3140379 pmid: 3140379
[30] Aurora R, Creamer T P, Srinivasan R , et al. Local interactions in protein folding: lessons from the alpha-helix. J Biol Chem, 1997,272(3):1413-1416.
doi: 10.1074/jbc.272.3.1413 pmid: 9019474
[31] George R A, Heringa J . An analysis of protein domain linkers: their classification and role in protein folding. Protein Eng, 2002,15(11):871-879.
doi: 10.1093/protein/15.11.871 pmid: 12538906
[32] Thorpe P E, Wallace P M, Knowles P P , et al. New coupling agents for the synthesis of immunotoxins containing a hindered disulfide bond with improved stability in vivo. Cancer Res, 1987,47(22):5924-5931.
pmid: 3499221
[33] Zhao H L, Xue C, Du J L , et al. Balancing the pharmacokinetics and pharmacodynamics of interferon-alpha2b and human serum albumin fusion protein by proteolytic or reductive cleavage increases its in vivo therapeutic efficacy. Mol Pharm, 2012,9(3):664-670.
doi: 10.1021/mp200347q pmid: 22224503
[34] Stefan S . Half-life extension through albumin fusion technologies. Thrombosis Research, 2010,124(Supplement S2):S6-S8.
doi: 10.1016/S0049-3848(09)70157-4 pmid: 20109653
[35] Nolte M W, Nichols T C, Mueller-Cohrs J , et al. Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and haemophilia B dogs. J Thromb Haemost, 2012,10:1591-1599.
doi: 10.1111/j.1538-7836.2012.04826.x pmid: 3928127
[36] Mannucci P M . Half-life extension technologies for haemostatic agents. Thromb Haemost. 2015,113(1):165-176.
doi: 10.1160/TH14-04-0332 pmid: 25274414
[37] Baggio L L, Huang Q, Cao X , et al. An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. Gastroenterology, 2008,134(4):1137-1147.
doi: 10.1053/j.gastro.2008.01.017 pmid: 18313669
[38] Kim J G, Baggio L L, Bridon D P , et al. Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes, 2003,52(3):751-759.
doi: 10.2337/diabetes.52.3.751 pmid: 12606517
[39] Giannoukakis N . CJC-1131 ConjuChem. Curr Opin Investig Drugs, 2003,4(10):1245-1249.
[40] Lim S I, Hahn Y S, Kwon I . Site-specific albumination of a therapeutic protein with multi-subunit to prolong activity in vivo. J Control Release, 2015,207:93-100.
doi: 10.1016/j.jconrel.2015.04.004 pmid: 25862515
[41] Varshney A, Sen P, Ahmad E , et al. Ligand binding strategies of human serum albumin: how can the cargo be utilized? Chirality, 2010,22(1):77-87.
doi: 10.1002/chir.20709 pmid: 19319989
[42] Myers S R, Yakubu-Madus F E, Johnson W T , et al. Acylation of human insulin with palmitic acid extends the time action of human insulin in diabetic dogs. Diabetes, 1997,46(4):637-642.
doi: 10.2337/diabetes.46.4.637 pmid: 9075804
[43] Johannsson G, Feldt-Rasmussen U, Hakonsson I H , et al. Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial. Eur J Endocrinol, 2018,178(5):491-499.
doi: 10.1530/EJE-17-1073 pmid: 29500310
[44] Battelino T, Rasmussen M H, De Schepper J , et al. Somapacitan, a once-weekly reversible -binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial. Clin Endocrinol(Oxf), 2017,87(4):350-358.
doi: 10.1111/cen.13409 pmid: 28656605
[45] Home P, Kurtzhals P . Insulin detemir: from concept to clinical experience. Expert Opin Pharmacother, 2006,7(3):325-343.
doi: 10.1517/14656566.7.3.325 pmid: 16448327
[46] Tambascia M A, Eliaschewitz F G . Degludec: the new ultra-long insulin analogue. Diabetol Metab Syndr, 2015,7:57.
doi: 10.1186/s13098-015-0037-0
[47] Sjoholm A . Liraglutide therapy for type 2 diabetes: overcoming unmet needs. Pharmaceuticals (Basel), 2010,3(3):764-781.
doi: 10.3390/ph3030764 pmid: 4033979
[48] Lau J, Bloch P, Schaffer L , et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue Semaglutide. J Med Chem, 2015,58(18):7370-7380.
doi: 10.1021/acs.jmedchem.5b00726 pmid: 26308095
[49] Roberts M J, Bentley M D, Harris J M . Chemistry for peptide and protein pegylation. Adv Drug Deliv Rev, 2002,54(4):459-476.
doi: 10.1016/j.addr.2012.09.025 pmid: 12052709
[50] Madsen P, Hostrup S, Munzel M , et al. An A22K, DESB27, B29R, DES B30, at epsilon position of lysine 22 acylated human insulin analogue: European, EP3110840A2.2017-1-4[2018-9-18].
[51] Hopp J, Horning N, Zettlitz K A , et al. The effects of affinity and valency of an albumin- binding domain (ABD) on the half-life of a single-chain diabody-ABD fusion protein. Protein Eng Des Sel, 2010,23(11):827-834.
doi: 10.1093/protein/gzq058 pmid: 20817756
[52] Mark S D, Min Z, Gloria M Y , et al. Albumin binding as a general strategy for improving the pharmacokinetics of proteins. J Bio Chem, 2002,277(38):35035-35043.
doi: 10.1074/jbc.M205854200 pmid: 12119302
[53] Merlot A M, Kalinowski D S, Kovacevic Z , et al. Making a case for albumin-a highly promising drug-delivery system. Future Med Chem, 2015,7(5):553-556.
doi: 10.4155/fmc.15.15 pmid: 25921396
[54] Nguyen A, Reyes A E, Zhang M , et al. The pharmacokinetics of an albumin-binding Fab (AB.Fab) can be modulated as a function of affinity for albumin. Protein Eng Des Sel, 2006,19(7):291-297.
doi: 10.1093/protein/gzl011 pmid: 16621915
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