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Hum. Reprod. Advance Access originally published online on April 7, 2005
Human Reproduction 2005 20(7):1805-1813; 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{at}oupjournals.org

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

S.C. Low1,3, S.L. Nunes2, A.J. Bitonti and J.A. Dumont

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 To whom correspondence should be addressed: Email: slow{at}syntnx.com

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.

Key words: FcRn/FSH/lung/pulmonary delivery


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