Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway.
Administration of therapeutic proteins by methods other than injection is limited, in part, by inefficient penetration of epithelial barriers. Therefore, unique approaches to breaching these barriers are needed. The neonatal constant region fragment (Fc) receptor (FcRn), which is responsible for IgG transport across the intestinal epithelium in newborn rodents, is expressed in epithelial cells in adult humans and non-human primates. Here we show that FcRn-mediated transport is functional in the lung of non-human primates and that this transport system can be used to deliver erythropoietin (Epo) when it is conjugated to the Fc domain of IgG1. FcRn-dependent absorption was more efficient when the EpoFc fusion protein was deposited predominantly in the upper and central airways of the lung, where epithelial expression of FcRn was most prominently detected. To optimize fusion protein absorption in the lung, we created a recombinant "monomeric-Epo" Fc fusion protein comprised of a single molecule of Epo conjugated to a dimeric Fc. This fusion protein exhibited enhanced pharmacokinetic and pharmacodynamic properties. The bioavailability of the EpoFc monomer when delivered through the lung was approximately equal to that reported for unconjugated Epo delivered s.c. in humans. These studies show that FcRn can be harnessed to noninvasively deliver bioactive proteins into the systemic circulation in therapeutic quantities.
Bitonti
Alan J
AJ
Syntonix Pharmaceuticals, Incorporated, Waltham, MA 02451, USA. abitonti@syntnx.com
Dumont
Jennifer A
JA
Low
Susan C
SC
Peters
Robert T
RT
Kropp
Keith E
KE
Palombella
Vito J
VJ
Stattel
James M
JM
Lu
Yichun
Y
Tan
Cristina A
CA
Song
Jeffrey J
JJ
Garcia
Ana Maria
AM
Simister
Neil E
NE
Spiekermann
Gerburg M
GM
Lencer
Wayne I
WI
Blumberg
Richard S
RS
D000042:Absorption; D000818:Animals; D019281:Dimerization; D016503:Drug Delivery Systems; D004921:Erythropoietin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008252:Macaca fascicularis / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics*; D012119:Respiration; D012995:Solubility
D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin