Plasma pharmacokinetics of high-affinity transferrin receptor antibody-erythropoietin fusion protein is a function of effector attenuation in mice

Erythropoietin (EPO) is a potential therapeutic for Alzheimer’s disease (AD), however limited blood-brain barrier (BBB) penetration reduces its applicability as a CNS therapeutic. Antibodies against the BBB transferrin receptor (TfRMAbs) act as molecular Trojan horses for brain drug delivery, and a fusion protein of erythropoietin (EPO) and TfRMAb, designated TfRMAb-EPO, is protective in a mouse model of AD. TfRMAbs have Fc effector function side-effects, and removal of the Fc N-linked glycosylation site by substituting Asn with Gly reduces Fc effector function. However, the effect of such Fc mutations on the pharmacokinetics of plasma clearance of TfRMAb-based fusion proteins, such as TfRMAb-EPO, is unknown. To examine this, the plasma pharmacokinetics of TfRMAb-EPO (wild-type), which expresses the mouse IgG1 constant heavy chain region and includes the Asn residue at position 292, was compared to the mutant TfRMAb-N292G-EPO, in which the Asn residue at position 292 is mutated to Gly. Plasma pharmacokine...