Biological properties of a novel follicle-stimulating hormone/human chorionic gonadotropin chimeric gonadotropin.
A chimeric recombinant human gonadotropin, termed C3, demonstrates both follitropic and lutropic bioactivities. The alpha-subunit construct for C3 is comprised of the recombinant wild-type human glycoprotein hormone alpha-subunit. The beta-subunit DNA construct for C3 encodes residues 1-145 from human chorionic gonadotropin (hCG)-beta with the exceptions that FSH beta amino acid 88 (D) is substituted for hCG beta amino acid 94 (R) and FSH beta amino acids 95-108 (TVRGLGPSYCSFGE) are substituted for hCG beta amino acids 101-114 (GGPKDHPLTCDDPR). C3 is a potent FSH and LH agonist able to bind and to signal through FSH and LH receptors in vitro. In in vivo bioassays optimized to quantify each type of activity, C3 was found to have lutropin and follitropin potencies at levels similar to those of recombinant human LH and recombinant human FSH, respectively. In immature rats, C3 was sufficient to support the maturation of normal ovarian follicles. Moreover, a significant portion of follicles matured by C3 ruptured in response to an ovulatory hCG stimulus and gave rise to morphologically normal oocytes. Furthermore, a low dose of C3 promoted weight gain in the rodent uterus, suggesting it also supported preparation for implantation without histological evidence of excessive luteinization of the ovary. In summary, the biological properties of C3 indicate that its chimeric nature has resulted in a fully functional, dual-acting human gonadotropin.
Garone
Louise M
LM
Serono Research Institute, Inc., One Technology Place, Rockland Massachusetts 02370, USA. louise.garone@serono.com
Ammannati
Elena
E
Brush
Theresa S
TS
Fischer
David J
DJ
Tos
Enrico Gillio
EG
Luo
Jiangping
J
Altobello
Kimberley L
KL
Ciampolillo
Cinzia
C
Ihley
Thomas M
TM
Kurosawa
Emmi
E
Tiebout
Angela
A
McKenna
Sean
S
D000595:Amino Acid Sequence; D000818:Animals; D006063:Chorionic Gonadotropin / Q000235:genetics* / Q000494:pharmacology; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000737:chemistry / Q000235:genetics; D003338:Corpus Luteum / Q000187:drug effects / Q000502:physiology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000235:genetics* / Q000494:pharmacology; D037201:Follicle Stimulating Hormone, beta Subunit / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011962:Receptors, FSH / Q000378:metabolism; D011974:Receptors, LH / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016415:Sequence Alignment; D014599:Uterus / Q000033:anatomy & histology
D006063:Chorionic Gonadotropin; D018997:Chorionic Gonadotropin, beta Subunit, Human; D037201:Follicle Stimulating Hormone, beta Subunit; D011962:Receptors, FSH; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; D005640:Follicle Stimulating Hormone