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A Novel Retro-Inverso Gonadotropin-Releasing Hormone (GnRH) Immunogen Elicits Antibodies That Neutralize the Activity of Native GnRH

Division of Medical Biochemistry, University of Cape Town Faculty of Health Sciences (B.F., A.K., R.M.), 7925 Observatory, South Africa; Immunochemistry Laboratory (UPR9021), Institut de Biologie Moleculaire et Cellulaire du Centre National de la Recherche Scientifique (P.E., M.R., J.H.), 67084 Strasbourg, France; School of Biotechnology, Centre National de la Recherche Scientifique, Strasbourg University (M.V.R.), Illkirch 67400, France; Human Reproductive Sciences Unit, University of Edinburgh (R.M.), Edinburgh, United Kingdom EH16 4SB; and Forenap Therapeutic Discovery, Institute of Pharmacology School of Medicine (P.E.), 67000 Strasbourg, France

Address all correspondence and requests for reprints to: Dr. R. Millar, Division of Medical Biochemistry, University of Cape Town Faculty of Health Sciences, 7925 Observatory, South Africa.

GnRH vaccines have been successfully used for the inhibition of gonadotropin secretion and gonadal function. As an alternative to native GnRH, retro-inverso (RI) GnRH might be an improved immunogen. The RI peptides are composed of D-amino acids assembled in the reverse order (C to N terminus) in relation to the parent L peptide. These peptides are immunogenic and can produce high titers of antibodies that bind the parent peptide with high affinity and specificity. We show that RI-GnRH peptides conjugated to ovalbumin as well as unconjugated RI-GnRH elicit high titers of anti-GnRH antibodies in rabbits and mice. Antibodies were affinity purified and shown by ELISA to be selective for mammalian GnRH compared with GnRH II and [Gln⁸]GnRH. The binding kinetics of antibody-peptide interactions was determined using biosensor technology (BIACORE). The purified anti-GnRH antibodies inhibited GnRH-stimulated signal transduction in COS-1 cells expressing the human GnRH receptor. Immunization of mice with unconjugated and conjugated RI-GnRH peptide, in the absence of complete Freund’s adjuvant, produced antisera that cross-reacted with mammalian GnRH. As RI peptides are resistant to cleavage by proteolytic enzymes, they are potentially orally active. The ability of RI-GnRH peptides to produce antibodies to GnRH without conjugation and without Freund’s complete adjuvant constitutes a novel vaccine with improved properties of potential application in animal management and sex hormone-dependent cancers.

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