Contraceptive Research and Development Looking to the Future (1996) / Chapter Skim
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Appendix C: Immunocontraceptive Approaches
Appendix C: Immunocontraceptive Approaches
Pages 401-429
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From page 401... ...
As of the summer of 1995, no immunocontraceptive had been marketed in any country, either for human or veterinary application. This review discusses some general concepts regarding contraceptive immunization, reviews several promising immunogen candidates, identifies hurdles on the path to developing an immunocontraceptive, and cites new approaches that may offer opportunities for significant scientific advances.
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From page 402... ...
fundamental discovery and characterization of appropriate immunogens derived from reproductive hormones and/or from the sperm, egg, egg investments, conceptus, or accessory reproductive organs; (2) development of methods for producing the immunogens to high standards of purity through (a)
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From page 403... ...
; (3) gamete interaction (capacitation, the acrosome reaction, penetration of the egg investments, fusion with the oolemma)
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From page 404... ...
The target antigen must therefore be secreted by the target cells and/or appear displayed on the surface membrane or glycocalyx of the target cells. In the case of sperm, which undergo remodeling of the sperm surface after the acrosome reaction, this criterion includes the inner-acrosomal membrane, which is the limiting membrane on the anterior portion of the sperm head after the completion of the acrosome reaction.
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From page 405... ...
. Yet, despite the capability of both men and women to develop antisperm antibodies, development of amounts of such antibody sufficient to reduce fertility in the female reproductive tract appears much more feasible, simply by virtue of numbers.
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From page 406... ...
This category subsumes proteins associated with the sperm plasma membrane and the acrosomal membranes. Proteins associated with the inner-acrosomal membrane are of interest, since this membrane becomes the limiting membrane of the anterior sperm head following the acrosome reaction, an event occurring prior to fertilization.
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From page 407... ...
Current GnRH formulations have coupled this decapeptide to various carriers, including tetanus toxoid, and have found that, in rats inoculated with GnRH-TT immunogen on five occasions over a 15-week period, there was atrophy of the testes and accessory sex organs (prostate and seminal vesicles) , decreased testosterone as antibodies to GnRH increase, suppressed spermatogenesis, and a decline in libido (Ladd et al.
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From page 408... ...
Future work on this contraceptive immunogen is likely to move toward a formula based on recombinant proteins or synthetic peptides
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From page 409... ...
by which an hCG formulation might exert antifertility effects are unknown, but there are several possibilities. First, because the hCG hormone is the stimulus for continued maintenance of the corpus luteum and progesterone production which, in turn, sustains the endometrium in a receptive state for receiving the embryo, it may play a direct role in implantation.
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From page 410... ...
The results from human trial of this hCG formulation (Talwar et al.
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From page 411... ...
receiving a control injection of diphtheria toxin alone, 14 of 20 ovulatory menstrual cycles resulted in pregnancy, for a 70 percent fertility rate. In baboons inoculated with the hCG peptide coupled to diphtheria toxin, 2 of 44 menstrual cycles resulted in pregnancy, a 4.6 percent fertility rate.
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From page 412... ...
. In mice, a synthetic peptide corresponding to amino acids 328→342 of ZP3 has been shown to induce autoimmune oophoritis (Rhim et al.
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Such differentiation antigens often fulfill the important criterion of tissue specificity discussed above. Several promising sperm antigens are discussed below in connection with possible mechanisms of action induced by a sperm-based immunocontraceptive.
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From page 414... ...
Multideterminant Sperm Immunocontraceptives An ideal sperm immunocontraceptive might contain sperm-specific immunogens that would induce antibodies to all the sperm-surface domains that are accessible to antibody, that is, the sperm head, midpiece, and tail plasmalemma, as well as the inner-acrosomal membrane that forms a major part of the anterior surface of the sperm head following the acrosome reaction. This concept guides the work in this field overall and suggests that there is an opportunity for various groups, each working on individual immunogens, to eventually combine their efforts to create the "ultimate immunocontraceptive." As sperm progress through the female reproductive tract, immune effectors in female secretions may exert contraceptive effects that act in various regions (see Figure C-1)
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From page 415... ...
Finally, antibodies to spermsurface domains, if present in oviductal fluids or embedded in the zona pellucida (which is permeable to immunoglobulins) might coat key sperm receptors at any of the key stages of sperm-egg interaction: penetration of the cumulus mass, zona binding, capacitation, induction of the acrosome reaction, shedding of the acrosomal ghost, penetration of the zona pellucida, binding to the oolemma, or internalization of the spermatozoon by the egg (see Figure C-2 and Figure C-3)
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1987) ; in addition to being one of the best characterized human sperm proteins, it is the sperm antigen that has undergone the most extensive animal and primate testing (Lee et al.
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A second formulation based on mouse LDH-C4, consisting of a synthetic peptide (amino acids 5–16, coupled to diphtheria toxoid) , has also been shown to reduce fertility in female baboons.
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From page 418... ...
Further, hSp17 is recognized by sera from vasectomized men who have antisperm antibody titers, indicating that hSpa18 is a human sperm autoantigen (Lea et al.
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From page 419... ...
PH-20 PH-20 is an integral membrane protein of 64 kDa, present on both the plasma membrane and inner-acrosomal membrane of guinea pig sperm. The protein is anchored in the plasma membrane by phosphatidylinositol and undergoes proteolytic processing during the acrosome reaction (Phelps et al.
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From page 420... ...
The Inner-acrosomal Membrane as a Target for Immunocontraception While considerable attention has been given to sperm plasmalemma antigens as targets for immunocontraception, less consideration has been given to components associated with the acrosomal membranes. Human sperm must undergo the acrosome reaction in order to penetrate the zona pellucida (Singer et al.
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From page 421... ...
Antibody levels must be sufficient to block one or several stages in the cascade of events involving primary and secondary binding to the zona, induction of the acrosome reaction, shedding of the acrosomal ghost, penetration of the zona pellucida, and binding to the oolemma. Sperm plasma membrane antigens should undoubtedly receive the major focus of attention in research efforts; it is still too soon to tell whether intra-acrosomal antigens will have a place as one component of a multideterminant immunocontraceptive.
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From page 422... ...
Anti-SP-10 antibody titers could be further elevated by secondary and tertiary oral administrations of the recombinant Salmonella. These quite recent results are the first indication that a gene encoding a human sperm antigen can be delivered in an oral immunogen vector and induce a secretory immune response against sperm-specific antibodies in the reproductive tract.
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From page 423... ...
and nonequilibrating gel electrophoresis (NEPHGE) have been employed to separate human sperm proteins, which were then stained with silver to obtain protein spots over a range of pH four to ten.
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From page 424... ...
With advances in protein chemistry came the possibility of using synthetic peptides based on important epitopes or immunodominant regions and, more recently, with recombinant DNA technology, there is now the capability for selectively attenuating organisms, engineering and expressing recombinant protein subunits, and developing immunogens consisting of recombinant proteins. Another quantum leap in the field builds on the work by Wolff et al.
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From page 425... ...
Monoclonal antibodies to human trophoblast and sperm antigens: Report of two WHO-sponsored workshops, 30 June 1986, Toronto, Canada. Journal of Reproductive Immunology 10:231–257, 1987.
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From page 426... ...
Biochemical and morphological characterization of the intra-acrosomal antigen SP-10 from human sperm. Biology of Reproduction 42:181–193, 1990a.
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Acrosome reaction in human spermatozoa. Fertility and Sterility 45:701–707, 1986.
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From page 428... ...
Oral immunization with attenuated Salmonella expressing human sperm antigen induces antibodies in serum and the reproductive tract. Biology of Reproduction 53:462–471, 1995.
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Ultrastructural studies of the early events of the human sperm acrosome reaction as initiated by human follicular fluid. Gamete Research 20:11–24, 1988.
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