Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease
Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease
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DOI：
10.1093/intimm/dxl110
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发表时间：
2006-12-01
影响因子：
4.4
通讯作者：
Roopenian, Derry C.
中科院分区：
文献类型：
--
作者：
Petkova, Stefka B.;Akilesh, Shreeram;Roopenian, Derry C.
MHC I类样Fc受体FcRn在延长循环中IgG抗体和基于IgG-Fc的治疗药物的半衰期（t（1/2））方面发挥着重要作用。本研究的目的是分析与FcRn体外结合增强的人IgG 1（hIgG 1）抗体对表达人FcRn（hFcRn）的小鼠体内t（1/2）的影响。针对人表皮生长因子受体2（p185（HER 2））的人源化单克隆赫赛汀抗体（Hu 4D 5-IgG 1）突变体在体外与hFcRn的pH依赖性结合发生改变。与野生型抗体相比，两种工程化IgG 1突变体（N434 A和T307 A/E380 A/N434 A）在表达hFcRn转基因（Tg）的小鼠中显示出显著延长的体内t（1/2），但在表达内源性小鼠FcRn的小鼠中则没有。hFcRn介导的保护效率依赖于hFcRn Tg拷贝数。此外，当以足以使hFcRn部分饱和的浓度注射到FcRn人源化小鼠中时，具有延长的血清t（1/2）的工程化IgG 1突变体在降低示踪剂hIgG 1抗体的t（1/2）方面最有效。最后，施用与hFcRn具有高结合的突变体改善了由人病原体血浆被动转移诱导的关节炎。这些结果表明，针对对hFcRn的高结合亲和力而修饰的Fc区增加了治疗性抗体的血清持久性，相同的方法可以用作抗自身免疫疗法以促进内源性致病性IgG的清除，并且FcRn人源化小鼠是hIgG治疗开发的有希望的替代物。
The MHC class I-like Fc receptor FcRn plays an essential role in extending the half-life (t(1/2)) of IgG antibodies and IgG-Fc-based therapeutics in the circulation. The goal of this study was to analyze the effect of human IgG1 (hIgG1) antibodies with enhanced in vitro binding to FcRn on their in vivo t(1/2) in mice expressing human FcRn (hFcRn). Mutants of the humanized monoclonal Herceptin antibody (Hu4D5-IgG1), directed against human epidermal growth factor receptor 2 (p185 (HER2)), show altered pH-dependent binding to hFcRn in vitro. Two engineered IgG1 mutants (N434A and T307A/E380A/N434A) showed a considerably extended t(1/2) in vivo compared with wild-type antibody in mice expressing an hFcRn transgene (Tg) but not in mice expressing the endogenous mouse FcRn. The efficiency of hFcRn-mediated protection was dependent on hFcRn Tg copy number. Moreover, when injected into FcRn-humanized mice at a concentration sufficient to partially saturate hFcRn, the engineered IgG1 mutants with an extended serum t(1/2) were most effective in reducing the t(1/2) of a tracer hIgG1 antibody. Finally, administration of mutant with high binding to hFcRn ameliorated arthritis induced by passive transfer with human pathogenic plasma. These results indicate that Fc regions modified for high binding affinity to hFcRn increases serum persistence of therapeutic antibodies, that the same approach can be exploited as an anti-autoimmune therapy to promote the clearance of endogenous pathogenic IgG and that FcRn-humanized mice are a promising surrogate for hIgG therapeutic development.