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

Hum Reprod. 2005 Jul;20(7):1805-13. doi: 10.1093/humrep/deh896. Epub 2005 Apr 7.

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 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.

MeSH terms

  • Administration, Oral
  • Aerosols
  • Animals
  • Animals, Newborn
  • Base Sequence
  • Biological Transport, Active
  • CHO Cells
  • Cricetinae
  • DNA, Complementary / genetics
  • Female
  • Follicle Stimulating Hormone / administration & dosage*
  • Follicle Stimulating Hormone / pharmacokinetics
  • Humans
  • Immunoglobulin Fc Fragments / administration & dosage*
  • 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

Substances

  • Aerosols
  • DNA, Complementary
  • Immunoglobulin Fc Fragments
  • Receptors, Fc
  • Recombinant Fusion Proteins
  • Follicle Stimulating Hormone