Mathematical modeling as accounting: Predicting the fate of serum proteins and therapeutic monoclonal antibodies

This article reviews current efforts to mathematically model the half lives of serum proteins, especially antibodies. While it is recognized that the neonatal Fc receptor, FcRn, is necessary for longer serum persistence of certain proteins, particularly the high abundance IgGs and albumin, it is not clear that it is sufficient to completely determine the half lives of these proteins. More specifically, it is unclear why the high avidity (bivalent), high affinity FcRn-IgG interaction, with half saturation in the 10 to 100 nM range (at endosomal pH according to the currently proposed mechanism), would result in a salvage mechanism that saturates at serum concentrations in the 10 to 100 mg/ml range – a discrepancy of 4 to 5 orders of magnitude. Alternative explanations include the proposal that the very low affinity binding between FcRn and IgG at blood pH is also relevant to the salvage mechanism, and that factors in addition to FcRn binding modulate the maintenance and clearance of IgG from serum.