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

Background: 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 PK and biodistribution of TfRMAb fusion proteins. Methods: 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. Results: 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 to 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. Conclusion: 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.