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Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis.
- Source :
-
Human reproduction (Oxford, England) [Hum Reprod] 2005 Jul; Vol. 20 (7), pp. 1805-13. Date of Electronic Publication: 2005 Apr 07. - Publication Year :
- 2005
-
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.<br />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.<br />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.
- Subjects :
- Administration, Oral
Aerosols
Animals
Animals, Newborn
Base Sequence
Biological Transport, Active
CHO Cells
Cricetinae
DNA, Complementary genetics
Female
Follicle Stimulating Hormone pharmacokinetics
Humans
Immunoglobulin Fc Fragments metabolism
Macaca fascicularis
Male
Organ Size drug effects
Ovary anatomy & histology
Ovary drug effects
Rats
Receptors, Fc metabolism
Recombinant Fusion Proteins administration & dosage
Recombinant Fusion Proteins pharmacokinetics
Testis anatomy & histology
Testis drug effects
Follicle Stimulating Hormone administration & dosage
Immunoglobulin Fc Fragments administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 0268-1161
- Volume :
- 20
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Human reproduction (Oxford, England)
- Publication Type :
- Academic Journal
- Accession number :
- 15817590
- Full Text :
- https://doi.org/10.1093/humrep/deh896