Delivery of an Erythropoietin-Fc Fusion Protein by Inhalation in Humans through an Immunoglobulin Transport Pathway

Abstract

A novel drug delivery platform has been developed that utilizes a naturally occurring receptor known as the neonatal Fc receptor (FcRn). The receptor is specific for the Fc fragment of IgG and is expressed in epithelial cells where it functions to transport immunoglobulins across these cell barriers. It has been shown that FcRn is expressed in both the upper and central airways in non-human primates as well as in humans. Pulmonary delivery of an erythropoietin- Fc fusion molecule (EpoFc) was previously demonstrated in non-human primates using this FcRn pathway. We have now conducted a phase I clinical study to test whether the FcRn pathway functioned similarly in man using human erythropoietin (Epo) fused to the Fc portion of human IgG1. The design was a three leg, non-randomized study conducted in healthy male volunteers with rising doses (3, 10, and 30 microg/kg) of the fusion protein targeted to the central lung regions. Using a target range of 10-30% vital capacity and 15 breaths per minute, approximately 70% of the lung-deposited dose of aerosolized EpoFc was delivered safely and effectively to the central lung regions. We showed dose-dependent concentrations of the fusion protein in the serum and an increase in circulating reticulocytes was evident in the highest dose group, thus demonstrating that large therapeutic molecules can be delivered to humans via the lung, with retention of biological activity, using the FcRn-mediated transport pathway.

Tissue expression profile of human neonatal Fc receptor (FcRn) in Tg32 transgenic mice

“…20 Delivery of erythropoietin-Fc (EpoFc) fusion protein by inhalation in a human Phase 1 clinical study showed »70% of the Epo-Fc was delivered safely and effectively to the central lung region. 21 Furthermore, a mouse FcRn-incorporated PBPK model predicted that the skin could account for 33% of the total IgG elimination. 6 Our data support this prediction by taking into account that skin takes a large percentage of body weight.…”

Neonatal Fc receptor and IgG-based therapeutics

“…Transepithelial transport in the lung using monomeric erythropoietin-Fc fusion protein (a single erythropoietin protein fused with Fc dimer) is effective and safe in human trials with 70% deposition of aerosolized doses. 62,72 In a different configuration of Fc fusion with follicular stimulating hormone (FSH), which is composed of α and β subunits, both the single chain and the heterodimer FSH-Fc fusion proteins were successfully delivered to the circulation via oral and pulmonary administration in rats and cynomolgus monkeys. Immunization.…”

Novel Concept in Pulmonary Delivery

“…A few small-scale clinical trials have been conducted on inhalation of other systemicallyacting therapeutic proteins, including interferon alpha-2b (19.3 kDa), human growth hormone (22 kDa) (Walvoord et al, 2009), an erythropoietin-Fc fusion protein (112 kDa) (Dumont et al, 2005). Inhalation of growth hormone is a potential alternative to growth hormone injection, which could offer improved patient adherence especially in pediatric patients.…”

“…Although children preferred the inhalation route of therapy, ongoing development of growth hormone inhalation has been delayed due to its low bioavailability. An erythropoietin-Fc fusion protein was absorbed in www.intechopen.com the bloodstream following delivery to the central lung regions in humans, with a dosedependent concentrations in the serum, suggesting that large therapeutic molecules can be delivered to humans via the lungs using the FcRn-mediated transport pathway (Dumont et al, 2005).…”