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Hum. Reprod. Advance Access published online on April 7, 2005
Human Reproduction, doi:10.1093/humrep/deh896
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received January 27, 2005
Revised March 3, 2005
Accepted March 8, 2005

Article

Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis

S.C. Low 1*, S.L. Nunes 2, A.J. Bitonti 1, and J.A. Dumont 3

1 Syntonix Pharmaceuticals, Inc., 9 Fourth Avenue,Waltham, MA 02451, USA
2 Current address: Protein Structure Group/Discovery Technologies, Novartis Institutes for Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA
3 Syntonix Pharmaceuticals, Inc., 9 Fourth Avenue,Waltham, MA 02451, USA,

* To whom correspondence should be addressed.
S.C. Low, E-mail: slow{at}syntnx.com


  Abstract

BACKGROUND: The {alpha} and {beta} subunits of FSH were fused to the Fc domain of IgG1 either in a single chain or a heterodimer format. These molecules were absorbed through the epithelium in lung and intestine by neonatal Fc receptor (FcRn)-mediated transcytosis. METHODS AND RESULTS: Single chain and heterodimer FSH-Fc were made recombinantly in Chinese hamster ovary cells. Treatment of rats with a single s.c. dose of single chain or heterodimer FSH-Fc resulted in greater stimulation of ovarian weight (20.8±3.9 and 26.9±6.1 mg respectively) compared to those receiving vehicle (12.1±1.0 mg) or an equimolar dose of recombinant human FSH (14.3±1.7 mg). Both FSH-Fc fusion proteins were absorbed after oral dosing of newborn rats with long terminal half-lives of ~60 h, and pulmonary delivery in four cynomolgus monkeys produced maximum serum concentrations between 69 and 131 ng/ml with long terminal half-lives between 55 and 210 h. Serum inhibin levels increased after pulmonary dosing with single chain FSH-Fc (1.3- and 1.4-fold) and heterodimer FSH-Fc (5.9- and 7.1-fold) and remained elevated for >12 days after treatment with heterodimer FSH-Fc. CONCLUSIONS: We have shown that FSH-Fc fusion proteins have increased stability in blood and improved bioactivity in vivo, and that heterodimer FSH-Fc is more active in rats and monkeys than single chain FSH-Fc. These data suggest that Fc fusion proteins offer the potential for oral and pulmonary delivery of FSH.

Keywords: FcRn; FSH; lung; pulmonary delivery.
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