Sperm Antigens in Fertilization

Abstract

Based upon the preceding information, there are encouraging prospects for the development of a sperm-targeted immunocontraceptive in humans and other species. Much of the basic groundwork has been laid, although considerable work is still necessary. Use of mAbs has proved to be extremely valuable in the identification of potential candidate antigens and in the demonstration of general principles. Studies with both M42 and M29 mAbs, for instance, indicate that inhibition of a single sperm epitope during fertilization in vivo is sufficient to block sperm function and lead to infertility. Furthermore, use of the PH-20 protein in both male and female guinea pigs demonstrates the feasibility of generating complete, reversible fertility inhibition following active immunization with a single sperm-specific protein that participates in gamete interaction. Further encouragement can be derived from examining the effects of inhibiting more than one sperm antigen during the fertilization process. Passive immunization with both M42 and M29 mAbs in the same animal results in a multiplicative reduction of the fertility level. 84 In theory, one need generate only a 60 per cent probability of inhibited fertilization for each of three independent events if inhibitors for all three events are available simultaneously. 8 Therefore, an immunocontraceptive constructed to inhibit multiple independent events during the fertilization process could provide maximum protection for a diverse population without need for vast titers of antisperm antibodies. The development of such a reagent demands the identification and characterization of many more sperm antigens to serve as targets. Examination of the list of candidate antigens summarized in this article reveals that several components which appear to be involved in secondary binding to the ZP have been identified and studied, but their counterparts, involved in primary sperm binding to the ZP, are largely unknown. Research is required to identify antigens involved in all of the recognized events of gamete interaction because implementation of the strategy of a multicomponent immunocontraceptive will be possible only when many candidates are available. Recent findings mentioned here also suggest that immunocontraception can be considered for males as well as females. In female guinea pigs immunized with PH-20, the presumed site of anti-PH-20 activity is the oviduct. In immunized male guinea pigs, it has not yet been demonstrated at what stage of development the anti-PH-20 antibody has access to sperm. Irrespective of this, use of the guinea pig as a model for male contraception is noteworthy, owing to the high incidence of autoimmune orchitis in this species. No evidence for the induction of orchitis was observed in the PH-20-immunized males, who returned to fertile status several months after the final PH-20 immunization. Long-term studies on this topic will be necessary, but these initial experiments are promising. Detailed examination of the M42 antigen also suggests the possibility of male contraception because M42 antigen is an example of a sperm-specific protein that is modified during epididymal transit. Available evidence supports the idea that this structural modification of the protein is related to the acquisition of fertilizing function. It is possible that maintenance of M42 antigen in its immature state could render an individual infertile. If this is true, the corpus epididymis may be targeted selectively to prevent M42 antigen modification and thereby produce dysfunctional sperm. Although the use of mAbs in the identification of relevent sperm antigens has proved a successful strategy, it should be pursued carefully. Reports of the effects of antisperm antibodies on fertilization abound in the literature, but often information concerning the identity of the corresponding antigen(s) is not included. In those situations, it becomes difficult to recognize the significance and implications of the work, and to compare the findings with those of others. In some cases, considerable effort has been expended including, for instance, the production and use of anti-idiotypic antibodies directed against an mAb for which the corresponding antigen is unknown. Interpretation of such work becomes increasingly difficult because there are few meaningful ways to characterize these complex reagents. I have attempted to discuss here selected sperm antigens in the context of our current understanding of mammalian gamete interaction. One application of this area of research is the development of contraceptive vaccines. The use of mAbs has identified relevant antigens for testing this potential application in animal model systems. It should be possible to merge these cell biologic studies with molecular biologic techniques to assist this goal; genes for targeted sperm antigens could be cloned and then incorporated into an appropriate viral vector, such as vaccinia. With our rapidly increasing knowledge of sperm antigens involved in fertilization, the development and testing of contraceptive vaccines are exciting prospects for the not-too-distant future.