Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn.

ABSTRACT: Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affi

SUBMITTER: Yang D 

PROVIDER: S-EPMC5627591 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature