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Immunocontraceptives an Update BioDrugs 1997 Dec; 8 (6); 457-468 BIOPHARMACEUTICALS 1173-8804197/0012-0457/$06.00/0 © Adis International limited , All rights reserved . Immunocontraceptives An Update Vernon C. Stevens,l P David Griffin 2 and Warren R. Jones 3 1 Division of Reproductive Biology, Department of Obstetrics and Gynecology, Ohio State University, Columbus, Ohio, USA 2 UNDP /UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland 3 Department of Obstetrics and Gynaecology, Flinders Medical Centre, Bedford Park, South Australia, Australia Contents Summary . .... .. .... .. 457 1. The Immunocontraceptive Development Process .. 458 2. Current Status of Immunocontraceptive Development 458 2.1 Gonadotropin-Releasing Hormone Immunocontraceptives 458 2.2 Follicle-Stimulating Hormone Immunocontraceptives . 460 2.3 Sperm Immunocontraceptives .. ........ .. ... 461 2.4 Ovum Immunocontraceptives .. ......... .. 462 2.5 Human Chorionic Gonadotropin Immunocontraceptives 463 3. Perspectives of the Pharmaceutical Industry . 466 4. Conclusions . 466 Summary The advent of immunocontraceptives represents the first truly novel approach to the development of family planning methods in over 30 years. Such products would have many advantages over existing contraceptives in that they would not elicit metabolic disturbances, would provide long-acting (i.e. 6 to 12 months) protection from pregnancy, be easy to administer, be economical to manufacture and distribute, and could, depending on their composition, be used by either men or women. Several lines of research and development currently in progress are aimed at the development of safe and effective immunocontraceptives based on reproductive hormones, components of the gametes (sperm and ova) and products of the early pre-implantation conceptus. The only prototype immunocontra­ ceptives to have reached the stage of clinical trials in women are those based on the hormone human chorionic gonadotropin, and in men that based on follicle­ stimulating hormone. However, extensive research is also underway on im­ munocontraceptives based on sperm and ovum components for use by women, and on immunocontraceptives based on sperm components and gonadotropin­ releasing hormone for use by men. Before such preparations can be made available for wide-scale use, further research is needed on ways to overcome genetically determined variations in individual immune responses so that protective responses of a predetermined 458 Stevens et al. duration can be elicited in all recipients. It is anticipated that these technical problems can be solved and the clinical testing of lead products will be completed in the next decade. Almost all of the financial support for the research and development of im­ munocontraceptives has been provided by academic institutions and public sector agencies. In general, the pharmaceutical industry has not been willing to engage in new contraceptive development, largely because of concerns about product liability claims, anticipated low profitability and/or the risk of negative pUblicity. Therefore, the further development, manufacture and distribution of im­ munocontraceptives will probably require the collaboration of public sector agen­ cies, governments and industry in order to overcome the current paucity of effort being put into the development and provision of new, safe, effective and accept­ able methods of family planning. The purpose of this review is to provide information on the current status of research and development of potential im­ munocontraceptives and to attempt to stimulate pharmaceutical companies to reassess their positions with regard to the development, manufacture and distri­ bution of these products. The basic principle of an immunocontraceptive new contraceptives in the last 30 years, the devel­ is to use the body's own immune defence mecha­ opment and testing of immunocontraceptives nisms to provide protection against an unplanned seems justified. The aim of this review is to provide pregnancy. In principle, anyone of a number of up-to-date information on the ongoing research in molecules involved in different stages of the repro­ this field and to encourage the pharmaceutical in­ ductive process can be used for immunocontracep­ dustry to more actively participate in the process tive development. In practice, however, logistical of making these new leads into suitable products and safety considerations restrict the selection of for general use. candidate molecules to certain reproductive hor­ mones, the gametes and the pre-implantation blas­ 1. The Immunocontraceptive tocYSt.[ll Development Process Immunological contraception has several po­ A plan for the development of a useful immuno­ tential collective advantages over currently avail­ contraceptive must take into consideration several able methods of family planning: critical factors needed for success. Figures 1 to 3 • choice of several sites of action in the reproduc­ show the major steps required in a research and tive process, including possible use by either development programme to produce such a prod­ men or women uct. • freedom from menstrual, systemic, metabolic, or endocrine sequelae, or undesirable local 2. Current Status of physical effects Immunocontraceptive Development • no interference with sexual response or activity • confidentiality of use 2.1 Gonadotropin-Releasing • ease of administration Hormone Immunocontraceptives • sustained and defined duration of action (e.g. 6 Gonadotropin-releasing hormone (GnRH; gon- or 12 months) adorelin) has been investigated as a possible com­ • high intrinsic efficacy and low user failure ponent of an immunocontraceptive because this • economical manufacture and distribution hypothalamic peptide hormone regulates the secre­ In view of these advantages and the paucity of tion of the pituitary gonadotropins, follicle-stimu- © Adis International Umited. All rights reserved. BioDrugs 1997 Dec; 8 (6) Immunocontraceptives 459 function in women that would result from im­ munisation with a GnRH immunocontraceptive would deny them the estrogen and progesterone needed to regulate menstrual cycles and to support essential physiological functions such as bone me­ tabolism, libido and psychological well-being. Organ specIficity Men immunised with a GnRH immunocontracep­ tive would be denied testosterone and would expe­ • rience loss of libido and changes in secondary sex characteristics, such as hair growth and breast de­ Punflcatoon --------.. SynthesIs velopment. These states of nonsurgical castration would result in an unacceptable menopausal-like • condition for women and a feminising effect in men. Investigators have proposed that a GnRH immunocontraceptive be used in men together with Conjugation Co-synthesis Crossreactove non·human androgen replacement therapy to compensate for the loss of natural testosterone. It has been demonstrated • that libido can be restored in testosterone-depleted animals with much lower doses of exogenously­ Adjuvant substance administered androgen than those required to re­ Dehvery system --~ store spermatogenesis and fertility.[3] The concept of GnRH inhibition, together with Testable product androgen replacement, has been demonstrated in laboratory animals. Ladd et al.[3] and Awoniyi et Fig. 1. Schematic representation of the steps involved in im· al.[4] have used these combined treatments success­ munocontraceptive development up to the stage of attaining a fully in male rats and have shown that fertility can testable product. be suppressed while maintaining normal mating behaviour. There is little doubt that GnRH im­ lating hormone (FSH) and luteinising hormone munisations will cause infertility in men, and the (LH), which, in turn, control the development and likely efficacy of this method is not questioned. function of the gonads in both males and females. However, the overall safety and acceptability of Although GnRH has other physiological functions, this approach as a contraceptive for men has not its inhibition by antibodies has been shown to re­ yet been fully established. To date, GnRH im­ sult in gonadal atrophy and sterility.[2] These ef­ munocontraceptives have been successfully devel­ fects, which can be induced by both active and oped for application only in domestic pets and farm passive immunisation against GnRH, offer an at­ animals.[5.6] Although no adverse effects have been tractive approach to controlling estrus and fertility reported by those developing these immuno­ in domestic pets, livestock and certain wildlife spe­ contraceptives for animals, I report has been pub­ cies where the total arrest of gonadal function and lished suggesting that hypothalamic lesions can re­ gonadal steroid secretion (estrogen and progester­ sult from immunising pigs against GnRH.17] one in females and testosterone in males) is either Another major problem facing the use of a GnRH desirable, temporary or of no concern. immunocontraceptive by healthy men is determin­ However, the immunological inhibition of ing the appropriate dose of androgen that will GnRH in humans for contraceptive purposes poses maintain male sex characteristics but not restore significant problems. The inhibition of gonadal spermatogenesis. Whether these problems will © Adis International Limited . All rig hts reserved. BioDrugs 1997 Dec; 8 (6) 460 Stevens et al. Testable product GMP productlon ---~ In vitro testing In vivo testing Antigen SpecifICity Biological aelion 01
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