Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn

The analysis of the pharmacokinetics of wild-type and mutated Fc fragments derived from human IgG1 indicates that Ile253, His310 and His435 play a cen tral role in regulating serum half-life in mice. Reduced serum half-life of the recombinant, mutated fragments correlates with decreased binding to th e MHC class I-related neonatal Fc receptor, FcRn. In addition, the analysis of an Fc fragment in which His435 is mutated to Arg435 demonstrates that t he sequence difference at this position between human IgG1 (His435) and IgG 3 (Arg435) most likely accounts for the shorter serum half-life of IgG3 rel ative to IgG1. in contrast to His310 and His435, the data indicate that His 433 does not play a role in regulating the serum half-life of human IgG1. T hus, the interaction site of mouse FcRn on human and mouse IgG1 involves th e same conserved amino acids located at the CH2-CH3 domain interface of the IgG molecule. The sequence similarities between mouse and human FcRn sugge st that these studies have direct relevance to understanding the factors th at govern the pharmacokinetics of therapeutic IgG.