The first goal of this proposal is to extend our existing studies concerning the molecular mechanisms by which murine IgGs persist in the circulation and are transcytosed across the neonatal intestine to maternal-fetal transfer across the yolk sac. To date, we have used site- directed mutagenesis to locate the region of the murine IgG1 molecule that is involved in the first two of these processes. Our available data suggest that the serum persistence of IgGs and IgG transcytosis (across neonatal intestine and yolk sac) are regulated by similar mechanisms, involving closely related receptors. Thus, our second goal is to use current protein engineering techniques to isolate Fc mutants that have higher affinity for binding to the receptor involved in IgG transcytosis, FcRn. This receptor is expressed at high levels in both neonatal intestine and murine yolk sac, consistent with its role in maternal-fetal and neonatal transfer. The increased affinity mutants would be expected to compete more effectively with the high levels of endogenous IgGs for binding to FcRn on murine yolk sac, resulting in higher efficiency of maternal-fetal transfer. Furthermore, the overlap between the catabolic site of murine IgG and the FcRn binding site suggest that the mutants may also persist for longer in the circulation. This study has direct relevance to the improvement of antibodies for maternal-fetal transfer in humans, as first, a receptor that is a homolog of rodent FcRn has recently been isolated from human placenta, and is therefore most likely the receptor involved in IgG transcytosis. Second, the amino acid residues of the murine IgG1 molecule that regulate serum persistence and IgG transytosis are highly conserved in human IgGs, suggesting that the molecular mechanisms involved in these processes are shared between mouse and man.
Showing the most recent 10 out of 41 publications