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 approximately 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.
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 approximately 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.
Authors: Masahiro Sakagami; Yadollah Omidi; Lee Campbell; Lana E Kandalaft; Christopher J Morris; Jaleh Barar; Mark Gumbleton Journal: Pharm Res Date: 2006-01-01 Impact factor: 4.200
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Authors: Eric M Pridgen; Frank Alexis; Timothy T Kuo; Etgar Levy-Nissenbaum; Rohit Karnik; Richard S Blumberg; Robert Langer; Omid C Farokhzad Journal: Sci Transl Med Date: 2013-11-27 Impact factor: 17.956
Authors: Timothy T Kuo; Kristi Baker; Masaru Yoshida; Shuo-Wang Qiao; Victoria G Aveson; Wayne I Lencer; Richard S Blumberg Journal: J Clin Immunol Date: 2010-10-01 Impact factor: 8.317