Vaccination against gonadotropin-releasing hormone (GnRH) using toxin receptor-binding domain-conjugated GnRH repeats
2000
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-GnRH 12 ) 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-GnRH 1 ) 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-GnRH 12 presents a potential
therapeutic application for the treatment of GnRH-sensitive ovarian
cancer.
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