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Vaccination against Gonadotropin-releasing Hormone (GnRH) Using Toxin Receptor-binding Domain-conjugated GnRH Repeats¹

Graduate Institute of Life Science, National Defense Medical Center [C-T. H.]; Institute of Molecular Biology [C-T. H., C-Y. T., C-J. T., T-Y. C., J. W-P., J. H.], Academia Sinica; Taipei, 11529; Division of Drug Biology, National Laboratories of Foods and Drugs, Department of Health, Taipei, [C-P. C.], Taiwan

A method for the preparation of an immunogen containing multiple copies of a self-peptide in linear alignment was designed in order to overcome the difficulty of inducing an immune response to poorly immunogenic peptide antigens. DNA fragments encoding multiple repeats of the self-peptide were generated by a new technique, termed template-repeated polymerase chain reaction (TR-PCR), which could be subcloned into an expression vector for production of peptide repeats as an immunogen. This approach was tested by constructing fusion proteins containing the receptor-binding domain of Pseudomonas exotoxin A and multiple copies of the 10-residue sequence of the peptide hormone gonadotropin-releasing hormone (GnRH). Immunization of female rabbits with the immunogen that contained the exotoxin receptor-binding domain and 12 copies of GnRH (PEIa-GnRH₁₂) resulted in the generation of high-titer antibodies specific for GnRH. Although at equal molar basis of the GnRH moiety, the immunogen that contained single copy of GnRH (PEIa-GnRH₁) induced low-titer anti-GnRH antibodies. These observations suggest that the presence of multiple peptide repeats is a key factor in eliciting an immune response. In addition, anti-GnRH antibodies effectively neutralized GnRH activity in vivo, as demonstrated by the degeneration of the ovaries in the injected rabbits. Because anti-GnRH antibody could be functionally analogous to GnRH antagonist, which has been used to treat patients with ovarian cancer, vaccination of PEIa-GnRH₁₂ presents a potential therapeutic application for the treatment of GnRH-sensitive ovarian cancer.

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