It is recommended to replace follicle-stimulating hormone (FSH) in stimulating spermatogenesis in man who are infertile due to secondary hypogonadism whose sperm counts have not responded to human chorionic gonadotropin (hCG) alone. However, FSH have a short serum half-life which requires frequent administration to maintain the therapeutic efficacy. To improve the pharmacokinetic properties, we had developed one of unique albumin-related technology, coined as “anti-serum albumin Fab-associated” (SAFA) technology. We tested the feasibility of applying SAFA technology in creating a long-acting FSH as a therapeutic candidate for secondary hypogonadism patients.
SAFA-FSH was produced in a Chinese hamster ovary (CHO) expression system. To confirm the biological function, production of cyclic AMP and phosphorylation of ERK1/2 and CREB were measured in TM4-FSHR cells. The effect on spermatogenesis in a hypogonadal rat model treated with gonadotropin releasing hormone (GnRH) agonist was investigated.
In cell line experiments, SAFA-FSH treatment increased production of cyclic AMP and increased phosphorylation of ERK1/2 and CREB in a dose dependent manner. In animal experiments, sperm production wasn't restored after hCG alone treatment. However, Sperm production was restored after additional conventional FSH treatment at intervals of 3 times per week or once every 5 days. Further, sperm production was restored even after additional SAFA-FSH treatment at intervals once every 5 days or once every 10 days.
In conclusion, long-acting FSH with bioactivity was successfully created by using SAFA technology. The data support further development of SAFA-FSH in the clinical setting, potentially representing an important advance in treatment of secondary hypogonadism patients.