An engineered human IgG1 antibody with longer serum half-life
An engineered human IgG1 antibody with longer serum half-life
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DOI：
10.4049/jimmunol.176.1.346
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Tsurushita, N
中科院分区：
文献类型：
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作者：
Hinton, PR;Xiong, JM;Tsurushita, N
IgG Ab 的血清半衰期受新生儿 Fc 受体 (FcRn) 调节。通过与内涵体中的 FcRn 结合，IgG Ab 可以避免溶酶体降解并循环至循环系统。多项研究已经证明 IgG Ab 与 FcRn 的结合亲和力与其在小鼠体内的血清半衰期之间存在相关性，包括具有更长血清半衰期的工程化 Ab 片段。我们最近的研究将这种相关性扩展到灵长类动物中的人类 IgG2 Ab 变异。在当前的研究中，产生了几种在 pH 6.0 下与人 FcRn 结合亲和力增加的人 IgG1 突变体，并保留了 pH 依赖性释放。对恒河猴进行的一项 IgG1 变体的药代动力学研究表明，其血清半衰期比野生型抗体长 2.5 倍。 Ag 结合不受 Fc 突变的影响，而一些效应子功能似乎变化很小。这些特性表明，具有更长血清半衰期的工程化抗体可能被证明是对人类有效的治疗方法。
The serum half-life of IgG Abs is regulated by the neonatal Fc receptor (FcRn). By binding to FcRn in endosomes, IgG Abs are salvaged from lysosomal degradation and recycled to the circulation. Several studies have demonstrated a correlation between the binding affinity of IgG Abs to FcRn and their serum half-lives in mice, including engineered Ab fragments with longer serum half-lives. Our recent study extended this correlation to human IgG2 Ab variants in primates. In the current study, several human IgG1 mutants with increased binding affinity to human FcRn at pH 6.0 were generated that retained pH-dependent release. A pharmacokinetics study in rhesus monkeys of one of the IgG1 variants indicated that its serum half-life was similar to 2.5-fold longer than the wild-type Ab. Ag binding was unaffected by the Fc mutations, while several effector functions appeared to be minimally altered. These properties suggest that engineered Abs with longer serum half-lives may prove to be effective therapeutics in humans.