Engineered human IgG antibodies with longer serum half-lives in primates
Engineered human IgG antibodies with longer serum half-lives in primates
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DOI：
10.1074/jbc.c300470200
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发表时间：
2004-02-20
影响因子：
4.8
通讯作者：
Tsurushita, N
中科院分区：
文献类型：
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作者：
Hinton, PR;Johlfs, MG;Tsurushita, N
新生儿Fe受体（FcRn）在调节IgG抗体的血清半衰期中起重要作用。已经在IgG抗体对FcRn的pH依赖性结合亲和力与其在小鼠中的血清半衰期之间建立了相关性。在本研究中，使用分子建模来鉴定人IgG抗体中FcRn结合位点附近的Fe位置，其在突变时可能改变IgG与FcRn的结合亲和力。诱变后，在Fc位置250和428处鉴定了在pH 6.0下对人FcRn具有增加的结合亲和力的几种IgG突变体。这些突变体在pH 7.5下不与人FcRn结合。对两种FcRn结合亲和力增加的突变IgG（2）抗体的药代动力学研究表明，它们在恒河猴中的血清半衰期比野生型抗体长2倍。
The neonatal Fe receptor (FcRn) plays an important role in regulating the serum half-lives of IgG antibodies. A correlation has been established between the pH-dependent binding affinity of IgG antibodies to FcRn and their serum half-lives in mice. In this study, molecular modeling was used to identify Fe positions near the FcRn binding site in a human IgG antibody that, when mutated, might alter the binding affinity of IgG to FcRn. Following mutagenesis, several IgG, mutants with increased binding affinity to human FcRn at pH 6.0 were identified at Fc positions 250 and 428. These mutants do not bind to human FcRn at pH 7.5. A pharmacokinetics study of two mutant IgG(2) antibodies with increased FcRn binding affinity indicated that they had serum half-lives in rhesus monkeys similar to2-fold longer than the wild-type antibody.