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Biological Properties of a Novel Follicle-Stimulating Hormone/Human Chorionic Gonadotropin Chimeric Gonadotropin

Serono Research Institute, Inc. (L.M.G., T.S.B., D.J.F., J.L., K.L.A., T.M.I., E.K., A.T., S.M.), Rockland, Massachusetts 02370; Istituto di Ricerche Biomediche "Antoine Marxer" (E.A., E.G.T., C.C.), 10010 Colleretto Giacosa, Torino, Italy

Address all correspondence and requests for reprints to: Louise M. Garone, Serono Research Institute, One Technology Place, Rockland Massachusetts 02370. E-mail: louise.garone{at}serono.com.

A chimeric recombinant human gonadotropin, termed C3, demonstrates both follitropic and lutropic bioactivities. The -subunit construct for C3 is comprised of the recombinant wild-type human glycoprotein hormone -subunit. The ß-subunit DNA construct for C3 encodes residues 1–145 from human chorionic gonadotropin (hCG)-ß with the exceptions that FSHß amino acid 88 (D) is substituted for hCGß amino acid 94 (R) and FSHß amino acids 95–108 (TVRGLGPSYCSFGE) are substituted for hCGß 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.