Abstract

In this study we have examined the potential of recombinant mouse zona pellucida glycoprotein 2 (ZP2) as a target for immunocontraception. Immunogenicity studies and fertility trials were performed in outbred Swiss–Webster mice using four ZP2 constructs: Val 35–Gly 200 (ZP2 V35–G200), Val 35–Leu 331 (ZP2 V35–L331), Pro 325–Ala 637 (ZP2 P325–A637), and Val 35–Ala 637 (ZP2 V35–A637). A significant antibody response occurred to three of the four immunogens, however antibodies capable of recognizing native ZP occurred only after immunization with ZP2 V35–A637 and ZP2 P325–A637. Only immunization with ZP2 V35–A637 correlated with a reduction in fertility. Examination of the physiological basis for infertility revealed that: (1) passive transfer of ZP2 antiserum induced infertility in non-immune mice; (2) ovaries of infertile mice appeared histologically normal; (3) infertile mice produced normal numbers of eggs and (4) ZP of ovulated eggs from infertile mice demonstrated a significant reduction in the number of sperm bound compared to eggs from adjuvant controls. Infertility can be caused entirely by ZP2 antibodies without the incidence of significant ovarian pathology. This study also demonstrated that immunization with the bioactive (sperm binding) region of ZP2, recombinant ZP2 V35–G200, did not result in a significant immune response that recognized native ZP or inhibited fertility. Consequently we designed a ZP2–sperm antigen construct, replacing the C-terminal region of ZP2 with Sp17. This construct proved to be immunogenic and reduce fertility while directing the immune response to the Val 35–Gly 200 region of ZP2.

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