IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab
IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab
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DOI：
10.1097/fpc.0b013e32832a06bf
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发表时间：
2009-05-01
影响因子：
2.6
通讯作者：
Watier, Herve
中科院分区：
文献类型：
--
作者：
Magdelaine-Beuzelin, Charlotte;Vermeire, Severine;Watier, Herve
目的抗肿瘤坏死因子-α嵌合抗体英夫利昔单抗（Infliximab）在治疗患者中可诱导产生抗英夫利昔单抗抗体（ATI）。预期在鼠可变结构域中具有免疫原性;然而，其人重γ 1链的恒定结构域也可能涉及，因为其表达G1 m1和G1 m17同种异型。这种等位基因形式可能是免疫原性的患者是纯合子的G1 m3同种异型通常表达在Caucasoid population.Methods作为G1 m同种异型分歧可能解释ATI的存在或可能影响其浓度，开发并验证了一种基因分型方法，（即相互排斥）G1 m3和G1 m17同种异型（根据国际ImmMunoGeneTics信息系统唯一编号的CH 1的氨基酸120）（CH 1 359 g/a核苷酸多态性）。245名献血员和118名以前描述的患者患有克罗恩病，英夫利昔单抗治疗，并已开发ATI在其中73人，进行了基因分型。结果IGHG 1 CH 1 359 g/a多态性不偏离哈迪-温伯格平衡在对照人群中，和等位基因频率在对照组和患者相似。患者G1 m同种异型与ATI的存在或其浓度之间没有发现关联。结论IGHG 1基因多态性在ATI的发生中可能不起主要作用。需要进一步分析以确定是否也是携带相同G1 m同种异型的人源化或全人抗体的情况。药理遗传学和基因组学19：383-387（C）2009年沃尔特斯·克鲁沃健康垂直栏Lippincott威廉姆斯&威尔金斯。
Objective The chimeric anti-tumor necrosis factor-alpha antibody infliximab is known to induce antibodies-to-infliximab (ATI) in some treated patients. Immunogenicity in murine variable domains is expected; however, constant domains of its human heavy gamma 1 chain may also be implicated as it expresses G1m1 and G1m17 allotypes. This allelic form may be immunogenic in patients that are homozygous for the G1m3 allotype commonly expressed in Caucasoid populations.Methods As G1m allotypic divergence may explain the presence of ATI or may influence their concentration, a genotyping method was developed and validated to determine antithetical (i.e. mutually exclusive) G1m3 and G1m17 allotypes (amino acid 120 of CH1 according to the international ImMunoGeneTics information system unique numbering) at the IGHG1 gene level (CH1 359g/a nucleotide polymorphism). Two hundred forty-five blood donors and 118 previously described patients suffering from Crohn's disease, treated with infliximab, and having developed ATI in 73 of them, were genotyped.Results The IGHG1 CH1 359g/a polymorphism does not depart from the Hardy-Weinberg equilibrium in the control population, and allele frequencies were similar in controls and patients. No association was found between the patient G1m allotypes and the presence of ATI or their concentration. It remains possible that anti-Gm1 antibodies are not well detected by the enzyme-linked immunosorbent assays used for ATI detection and/or that the G1m allotypes are minor antigens on IgG1.Conclusion The IGHG1 polymorphism does not seem to play a major role in the induction of ATI. Further analyses will be required to determine whether it is also the case for humanized or fully human antibodies bearing the same G1m allotypes. Pharmacogenetics and Genomics 19:383-387 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.