Antibodies to human ZP3 induce reversible contraception in transgenic micewith 'humanized' zonae pellucidae

The initial spermatozoon-egg interaction of mammalian fertilization is medi ated by the zona pellucida, an extracellular matrix composed of three glyco proteins (ZP1, ZP2, ZP3). These proteins are sufficiently conserved between human and mouse to form chimeric zonae pellucidae, and genetically enginee red mice in which the endogenous mouse ZP3 has been replaced by human ZP3 h ave 'humanized' zonae, but normal fertility. Administration of monoclonal a ntibodies to mouse ZP3 does not affect fertility in these animals, but admi nistration of antibodies to human ZP3 results in long-term, reversible cont raception. The antibodies coat the zonae pellucidae surrounding growing ooc ytes within the ovary and their presence in the zona matrix inhibits, but d oes not eliminate, sperm binding. The contraceptive effect is attributed to steric hindrance that decreases sperm binding and prevents penetration thr ough the zona pellucida. The resumption of fertility is associated with the disappearance of antibodies from the zona matrix, No adverse effect on mat ing behaviour, ovarian histology or fetal development (if administered afte r fertilization) is detected in treated females. These results suggest that transgenic mice expressing human proteins will prove useful in assessing c ontraceptive efficacy of zona epitopes in the rational design of immunocont raception directed at the human zona pellucida.