Impact of Neonatal Fc Receptor on Transferrin Receptor Antibody Fusion Protein Pharmacokinetics

<b>Background</b>: Transferrin receptor-targeting monoclonal antibodies (TfRMAbs) enhance brain drug delivery by facilitating TfR-mediated transcytosis across the blood-brain barrier (BBB). Data suggest that chronic TfRMAb dosing reduces their plasma exposure in a dose- and fusion partner-dependent manner; however, the underlying mechanisms remain unclear. The neonatal Fc receptor (FcRn) extends IgG half-life via recycling, but its saturation after repeated doses may alter the pharmacokinetics (PK) of IgG fusion proteins. This study evaluated the role of the FcRn on the PK and biodistribution of TfRMAb fusion proteins. <b>Methods</b>: We examined TfRMAb alone and TfRMAb fused to erythropoietin (TfRMAb-EPO) or TNFα receptor (TfRMAb-TNFR) in wild-type (WT) and FcRn knockout (KO) mice following acute (single dose) or chronic (3× weekly for 4 weeks) subcutaneous administration at 3 mg/kg. Plasma levels, tissue biodistribution, and FcRn binding were measured using immunoassays. <b>Results</b>: Our results show that fusion partners influenced FcRn-mediated recycling and PK of TfRMAb fusion proteins. After acute dosing, TfRMAb-TNFR exhibited the greatest reduction in plasma exposure in FcRn KO versus WT mice, compared with TfRMAb and TfRMAb-EPO. Chronic dosing reduced the plasma persistence of all fusion proteins in WT mice. In FcRn KO mice, plasma exposure of TfRMAb and TfRMAb-EPO decreased with chronic dosing, whereas TfRMAb-TNFR showed no further reduction. Differences in FcRn binding affinity likely explain these patterns. Tissue distribution largely mirrored plasma concentrations. <b>Conclusions</b>: FcRn regulates plasma concentrations of TfRMAb fusion proteins in a fusion partner-dependent manner. While FcRn-mediated protection regulates plasma exposure with acute dosing, additional mechanisms beyond FcRn saturation appear to regulate plasma exposure during chronic dosing.