Abstract
The neonatal Fc 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 Fc 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 IgG2 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 IgG2 antibodies with increased FcRn binding affinity indicated that they had serum half-lives in rhesus monkeys approximately 2-fold longer than the wild-type antibody.
Highlights
The neonatal Fc receptor (FcRn) plays an important role in regulating the serum half-lives of IgG antibodies
Several IgG2 mutants with increased binding affinity to human FcRn at pH 6.0 were identified at Fc positions 250 and 428
A pharmacokinetics study of two mutant IgG2 antibodies with increased FcRn binding affinity indicated that they had serum half-lives in rhesus monkeys ϳ2-fold longer than the wild-type antibody
Summary
A pharmacokinetics study of two mutant IgG2 antibodies with increased FcRn binding affinity indicated that they had serum half-lives in rhesus monkeys ϳ2-fold longer than the wild-type antibody. FcRn mediates both transcytosis of maternal IgG to the fetus or neonate and IgG homeostasis in adults [8] Evidence for the latter role initially came from studies indicating an unusually short serum halflife for IgG antibodies in 2m-deficient mice (9 –11). Several studies have identified human IgG1 mutants with enhanced FcRn binding [6, 13], no improvement in the serum half-lives of these mutants was observed in mice [13] or reported in primates. A pharmacokinetics study in rhesus monkeys showed that two mutant IgG2 antibodies with increased FcRn binding affinity had considerably longer serum half-lives than the wild-type antibody
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