Please wait a minute...

中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志  2017, Vol. 37 Issue (5): 87-96    DOI: 10.13523/j.cb.20170511
综述     
治疗性抗体半衰期改造研究进展
陈静1, 康赐明1, 罗文新1,2
1. 厦门大学国家传染病诊断试剂与疫苗工程技术研究中心 生命科学学院 厦门 361102;
2. 厦门大学公共卫生学院 厦门 361102
Advance in Research on Antibody Half-Life Related Engineering
CHEN Jing1, KANG Ci-ming1, LUO Wen-xin1,2
1. National Institute of Diagnostics Vaccine Developmentin Infectious Disease, School of Life Sciences, Xiamen University, Xiamen 361102, China;
2. School of Public Health, Xiamen University, Xiamen 361102, China
 全文: PDF(898 KB)   HTML
摘要:

随着治疗性单克隆抗体在临床治疗方面发挥的作用日益突显,其全球药物市场所占份额和研发投入均在逐年增加。除了抗体新药的开发,抗体药物效力和安全性相关的基因工程改造也越来越受到重视。在这些基因工程改造中,抗体半衰期改造已成为近年来研究的热点之一。对几种抗体半衰期改造技术进行了介绍,并简要描述了半衰期改造后抗体的临床研究现状。

关键词: 抗体半衰期基因工程治疗性抗体    
Abstract:

Withthe growing development of therapeutic monoclonal antibodies in the clinical treatment, the market share and research cost of antibody drugs are increasing by years. In addition to the novel antibody drug development, the antibody engineering on efficacy and safety has been more strongly desired.Among theseengineering technologies, antibody half-life related engineeringhas been popularly used in improving antibody pharmacokinetic properties in recent years. Several kinds of antibody half-life modification methods are briefly described, as well as to their current status in clinical research.

Key words: Therapeutic antibody    Half-life of antibody    Genetic engineering
收稿日期: 2016-11-20 出版日期: 2017-05-25
ZTFLH:  Q78  
基金资助:

国家自然科学基金资助项目(81401668,2017J01066,31600748)

通讯作者: 罗文新     E-mail: wxluo@xmu.edu.cn
服务  
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章  

引用本文:

陈静, 康赐明, 罗文新. 治疗性抗体半衰期改造研究进展[J]. 中国生物工程杂志, 2017, 37(5): 87-96.

CHEN Jing, KANG Ci-ming, LUO Wen-xin. Advance in Research on Antibody Half-Life Related Engineering. China Biotechnology, 2017, 37(5): 87-96.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20170511        https://manu60.magtech.com.cn/biotech/CN/Y2017/V37/I5/87

[1] Scott A M, Wolchok J D, Old L J. Antibody therapy of cancer. Nature reviews Cancer, 2012, 12(4):278-287.
[2] Marasco W A, Sui J. The growth and potential of human antiviral monoclonal antibody therapeutics. Nature Biotechnology, 2007, 25(12):1421-1434.
[3] Chan A C, Carter P J. Therapeutic antibodies for autoimmunity and inflammation. Nature Reviews Immunology, 2010, 10(5):301-316.
[4] Igawa T, Tsunoda H, Kuramochi T, et al. Engineering the variable region of therapeutic IgG antibodies. mAbs, 2011, 3(3):243-252.
[5] Grevys A, Bern M, Foss S, et al. Fc Engineering of Human IgG1 for altered binding to the neonatal Fc receptor affects Fc effector functions. Journal of Immunology, 2015, 194(11):5497-508.
[6] Tabrizi M A, Tseng C M, Roskos L K. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discovery Today, 2006, 11(1-2):81-88.
[7] Morell A, Terry W D, Waldmann T A. Metabolic properties of IgG subclasses in man. The Journal of Clinical Investigation, 1970, 49(4):673-680.
[8] Roopenian D C, Akilesh S. FcRn:the neonatal Fc receptor comes of age. Nature reviews Immunology, 2007, 7(9):715-725.
[9] Popov S, Hubbard J G, Kim J, et al. The stoichiometry and affinity of the interaction of murine Fc fragments with the MHC class I-related receptor, FcRn. Molecular Immunology, 1996, 33(6):521-530.
[10] Ober R J, Martinez C, Lai X, et al. Exocytosis of IgG as mediated by the receptor, FcRn:an analysis at the single-molecule level. Proceedings of the National Academy of Sciences of the United States of America, 2004, 101(30):11076-11081.
[11] Li B, Tesar D, Boswell C A, et al. Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge. mAbs, 2014, 6(5):1255-1264.
[12] Datta-Mannan A, Lu J, Witcher D R, et al. The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies. mAbs, 2015, 7(6):1084-1093.
[13] Sharma V K, Patapoff T W, Kabakoff B, et al. In silico selection of therapeutic antibodies for development:viscosity, clearance, and chemical stability. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(52):18601-18606.
[14] Hotzel I, Theil F P, Bernstein L J, et al. A strategy for risk mitigation of antibodies with fast clearance. mAbs, 2012, 4(6):753-760.
[15] Wang W, Lu P, Fang Y, et al. Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. Drug Metabolism and Disposition:the Biological Fate of Chemicals, 2011, 39(9):1469-1477.
[16] Suzuki T, Ishii-Watabe A, Tada M, et al. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1:a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. Journal of Immunology, 2010, 184(4):1968-1976.
[17] Stracke J, Emrich T, Rueger P, et al. A novel approach to investigate the effect of methionine oxidation on pharmacokinetic properties of therapeutic antibodies. mAbs, 2014, 6(5):1229-1242.
[18] Wang W, Vlasak J, Li Y, et al. Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies. Molecular Immunology, 2011, 48(6-7):860-866.
[19] Goetze A M, Liu Y D, Zhang Z, et al. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology, 2011, 21(7):949-959.
[20] Bumbaca D, Boswell C A, Fielder P J, et al. Physiochemical and biochemical factors influencing the pharmacokinetics of antibody therapeutics. The AAPS Journal, 2012, 14(3):554-558.
[21] Burmeister W P, Huber A H, Bjorkman P J. Crystal structure of the complex of rat neonatal Fc receptor with Fc. Nature, 1994, 372(6504):379-383.
[22] Junghans R P, Anderson C L. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proceedings of the National Academy of Sciences of the United States of America, 1996, 93(11):5512-5516.
[23] Dall'Acqua W F, Woods R M, Ward E S, et al. Increasing the affinity of a human IgG1 for the neonatal Fc receptor:biological consequences. Journal of Immunology, 2002, 169(9):5171-5180.
[24] Ghetie V, Popov S, Borvak J, et al. Increasing the serum persistence of an IgG fragment by random mutagenesis. Nature Biotechnology, 1997, 15(7):637-640.
[25] Ober R J, Radu C G, Ghetie V, et al. Differences in promiscuity for antibody-FcRn interactions across species:implications for therapeutic antibodies. International Immunology, 2001, 13(12):1551-1559.
[26] Haraya K, Tachibana T, Nanami M, et al. Application of human FcRn transgenic mice as a pharmacokinetic screening tool of monoclonal antibody. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 2014, 44(12):1127-1134.
[27] Proetzel G, Roopenian D C. Humanized FcRn mouse models for evaluating pharmacokinetics of human IgG antibodies. Methods (San Diego, Calif), 2014, 65(1):148-153.
[28] Shields R L, Namenuk A K, Hong K, et al. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RⅡ, Fc gamma RⅢ, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. The Journal of Biological Chemistry, 2001, 276(9):6591-604.
[29] Yeung Y A, Leabman M K, Marvin J S, et al. Engineering human IgG1 affinity to human neonatal Fc receptor:impact of affinity improvement on pharmacokinetics in primates. Journal of Immunology, 2009, 182(12):7663-7671.
[30] Hinton P R, Johlfs M G, Xiong J M, et al. Engineered human IgG antibodies with longer serum half-lives in primates. The Journal of Biological Chemistry, 2004, 279(8):6213-6216.
[31] Hinton P R, Xiong J M, Johlfs M G, et al. An engineered human IgG1 antibody with longer serum half-life. The Journal of Immunology, 2006, 176(1):346-356.
[32] Zalevsky J, Chamberlain A K, Horton H M, et al. Enhanced antibody half-life improves in vivo activity. Nature Biotechnology, 2010, 28(2):157-159.
[33] Monnet C, Jorieux S, Souyris N, et al. Combined glyco-and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody. mAbs, 2014, 6(2):422-436.
[34] Monnet C, Jorieux S, Urbain R, et al. Selection of IgG variants with increased FcRn binding using random and directed mutagenesis:impact on effector functions. Frontiers in Immunology, 2015, 6(39.
[35] Borrok M J, Wu Y, Beyaz N, et al. pH-dependent binding engineering reveals an FcRn affinity threshold that governs IgG recycling. The Journal of Biological Chemistry, 2015, 290(7):4282-4290.
[36] Datta-Mannan A, Wroblewski V J. Application of FcRn binding assays to guide mAb development. Drug Metabolism and Disposition:the Biological Fate of Chemicals, 2014, 42(11):1867-1872.
[37] Ward E S, Devanaboyina S C, Ober R J. Targeting FcRn for the modulation of antibody dynamics. Molecular Immunology, 2015, 67(2 Pt A):131-141.
[38] Dall'Acqua W F, Kiener P A, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). The Journal of Biological Chemistry, 2006, 281(33):23514-23524.
[39] Datta-Mannan A, Witcher D R, Tang Y, et al. Humanized IgG1 variants with differential binding properties to the neonatal Fc receptor:relationship to pharmacokinetics in mice and primates. Drug Metabolism and Disposition:the Biological Fate of Chemicals, 2007, 35(1):86-94.
[40] Datta-Mannan A, Witcher D R, Tang Y, et al. Monoclonal antibody clearance. Impact of modulating the interaction of IgG with the neonatal Fc receptor. The Journal of Biological Chemistry, 2007, 282(3):1709-1717.
[41] Yeung Y A, Wu X, Reyes A E, 2nd, et al. A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life. Cancer Research, 2010, 70(8):3269-3277.
[42] Zheng Y, Scheerens H, Davis J C, Jr., et al. Translational pharmacokinetics and pharmacodynamics of an FcRn-variant anti-CD4 monoclonal antibody from preclinical model to phase I study. Clinical Pharmacology and Therapeutics, 2011, 89(2):283-290.
[43] Datta-Mannan A, Chow C K, Dickinson C, et al. FcRn affinity-pharmacokinetic relationship of five human IgG4 antibodies engineered for improved in vitro FcRn binding properties in cynomolgus monkeys. Drug Metabolism and Disposition:the Biological Fate of Chemicals, 2012, 40(8):1545-1555.
[44] Robbie G J, Criste R, Dall'acqua W F, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrobial Agents and Chemotherapy, 2013, 57(12):6147-6153.
[45] Burvenich I J, Farrugia W, Lee F T, et al. Cross-species analysis of Fc engineered anti-Lewis-Y human IgG1 variants in human neonatal receptor transgenic mice reveal importance of S254 and Y436 in binding human neonatal Fc receptor. mAbs, 2016, 8(4):775-786.
[46] Igawa T, Tsunoda H, Tachibana T, et al. Reduced elimination of IgG antibodies by engineering the variable region. Protein Engineering, Design & Selection:PEDS, 2010, 23(5):385-392.
[47] Datta-Mannan A, Thangaraju A, Leung D, et al. Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics. mAbs, 2015, 7(3):483-493.
[48] Schoch A, Kettenberger H, Mundigl O, et al. Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(19):5997-6002.
[49] Kelly R L, Yu Y, Sun T, et al. Target-independent variable region mediated effects on antibody clearance can be FcRn independent. mAbs, 2016, 8(7):1269-1275.
[50] Bumbaca Yadav D, Sharma V K, Boswell C A, et al. Evaluating the use of antibody variable region (Fv) charge as a risk assessment tool for predicting typical cynomolgus monkey pharmacokinetics. The Journal of Biological Chemistry, 2015, 290(50):29732-29741.
[51] Boswell C A, Tesar D B, Mukhyala K, et al. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjugate Chemistry, 2010, 21(12):2153-2163.
[52] Sampei Z, Igawa T, Soeda T, et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VⅢ cofactor activity. PLoS One, 2013, 8(2):e57479.
[53] Kitazawa T, Igawa T, Sampei Z, et al. A bispecific antibody to factors IXa and X restores factor VⅢ hemostatic activity in a hemophilia A model. Nature Medicine, 2012, 18(10):1570-1574.
[54] Igawa T, Ishii S, Tachibana T, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nature Biotechnology, 2010, 28(11):1203-1207.
[55] Igawa T, Haraya K, Hattori K. Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation. Immunological Reviews, 2016, 270(1):132-151.
[56] Igawa T, Mimoto F, Hattori K. pH-dependent antigen-binding antibodies as a novel therapeutic modality. Biochimica et Biophysica Acta, 2014, 1844(11):1943-1950.
[57] Chaparro-Riggers J, Liang H, DeVay R M, et al. Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. The Journal of Biological Chemistry, 2012, 287(14):11090-11097.
[58] Henne K R, Ason B, Howard M, et al. Anti-PCSK9 antibody pharmacokinetics and low-density lipoprotein-cholesterol pharmacodynamics in nonhuman primates are antigen affinity-dependent and exhibit limited sensitivity to neonatal Fc receptor-binding enhancement. The Journal of Pharmacology and Experimental the Rapeutics, 2015, 353(1):119-131.
[59] Murtaugh M L, Fanning S W, Sharma T M, et al. A combinatorial histidine scanning library approach to engineer highly pH-dependent protein switches. Protein Science:a Publication of the Protein Society, 2011, 20(9):1619-1631.
[60] Schroter C, Gunther R, Rhiel L, et al. A generic approach to engineer antibody pH-switches using combinatorial histidine scanning libraries and yeast display. mAbs, 2015, 7(1):138-151.
[61] Bonvin P, Venet S, Fontaine G, et al. De novo isolation of antibodies with pH-dependent binding properties. mAbs, 2015, 7(2):294-302.
[62] Hironiwa N, Ishii S, Kadono S, et al. Calcium-dependent antigen binding as a novel modality for antibody recycling by endosomal antigen dissociation. mAbs, 2016, 8(1):65-73.
[63] Chen W, Bardhi A, Feng Y, et al. Improving the CH1-CK heterodimerization and pharmacokinetics of 4Dm2m, a novel potent CD4-antibody fusion protein against HIV-1. mAbs, 2016, 8(4):761-774.
[64] Lyon R P, Bovee T D, Doronina S O, et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nature Biotechnology, 2015, 33(7):733-735.
[65] Igawa T, Maeda A, Haraya K, et al. Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PLoS One, 2013, 8(5):e63236.

[1] 彭向雷,王烨,王丽男,苏彦斌,付远辉,郑妍鹏,何金生. 单引物PCR法引入定点突变 *[J]. 中国生物工程杂志, 2020, 40(8): 19-23.
[2] 刘迪,张洪春. 慢性阻塞性肺疾病基因工程动物模型研究进展 *[J]. 中国生物工程杂志, 2020, 40(4): 59-68.
[3] 陈春琳,秦松,宋宛霖,刘志丹,刘正一. 褐藻寡糖生物法制备研究进展 *[J]. 中国生物工程杂志, 2020, 40(10): 85-95.
[4] 马淑霞,张玲,闫晋飞,游松. 裂壶藻脂肪酸合酶途径合成多不饱和脂肪酸的研究 *[J]. 中国生物工程杂志, 2018, 38(9): 27-34.
[5] 贺雪婷,张敏华,洪解放,马媛媛. 大肠杆菌丁醇耐受机制及耐受菌选育研究进展 *[J]. 中国生物工程杂志, 2018, 38(9): 81-87.
[6] 陶宇,李高建,舒建洪,吴月红,杨芳,何玉龙. 猪支原体肺炎基因工程疫苗的研究进展 *[J]. 中国生物工程杂志, 2018, 38(2): 95-101.
[7] 石红璆,查代明,张炳火,李汉全. 全细胞脂肪酶研究进展 *[J]. 中国生物工程杂志, 2018, 38(11): 51-58.
[8] 吴锁伟,万向元. 利用生物技术创建主要作物雄性不育杂交育种和制种的技术体系[J]. 中国生物工程杂志, 2018, 38(1): 78-87.
[9] 郜娇娇, 杨树林. 基因工程技术优化透明质酸生产的研究进展[J]. 中国生物工程杂志, 2017, 37(8): 72-77.
[10] 尹舒贤, 赵月华, 刘超, 吕占军, 王秀芳. 人源Alu RNA工程菌的构建和表达[J]. 中国生物工程杂志, 2017, 37(7): 88-96.
[11] 王得华, 马义, 韩磊, 肖兴, 李艳伟, 党诗莹, 范志勇, 文涛, 洪岸. 新型基因重组PACAP衍生物MPL-2的制备及其抗2型糖尿病作用研究[J]. 中国生物工程杂志, 2017, 37(5): 59-65.
[12] 甘春杨, 刘亚, 罗英英, 张文露, 黄爱龙, 蔡雪飞, 胡接力. 一种适用于片段替换/插入突变扫描的克隆方法[J]. 中国生物工程杂志, 2016, 36(8): 55-63.
[13] 梅雪昂, 陈艳, 王瑞钊, 肖文海, 王颖, 李霞, 元英进. 产玉米黄质的人工酵母细胞的构建[J]. 中国生物工程杂志, 2016, 36(8): 64-72.
[14] 吕若芸, 陈忱, 魏敬双. 治疗性抗体药物开发中IgG亚型选择[J]. 中国生物工程杂志, 2016, 36(7): 104-111.
[15] 刘婷婷, 梁梓强, 梁士可, 郭技星, 王方海. 利用生物工程技术生产蜘蛛丝的研究进展[J]. 中国生物工程杂志, 2016, 36(5): 132-137.