Optimal PEGylation can Improve the Exposure of Interferon in the Lungs Following Pulmonary Administration

The utility of inhaled protein therapeutics to treat lung-resident diseases is limited by protein degradation in the lungs and rapid clearance. This study therefore aimed to evaluate the impact of PEGylation on the lung and systemic exposure of interferon (IFN) alpha 2 after intratracheal administration to rats. An inverse correlation was observed between PEG chain length and systemic exposure, where bioavailability was 5.5% for the 31 kDa PEGylated construct and <0.4% for the 60 kDa PEGylated construct when compared with 15% for native IFN (19 kDa). Retention of PEGylated IFN alpha within the lungs increased 2.5-fold to threefold when compared with native IFN. When comparing the lung and systemic exposure of PEGylated and native IFN in terms of protein biological activity, the 31 kDa PEGylated construct increased exposure by 50% and 100%, respectively, when compared with native IFN, but the 60 kDa PEG construct offered no benefit. Preliminary work also indicated that the conjugation of IFN gamma with 10 kDa PEG significantly increases the retention of the protein within the lung. Optimal PEGylation may therefore be used as a means to improve the exposure of lung-resident diseases to therapeutic cytokines and potentially reduce systemic exposure and side effects as well as dosing frequency. (C) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association