Mammalian spermatozoa have been known to be antigenic for many years. More recently, it has been demonstrated that mammalian sperm contain an antigenic enzyme, which is known as the C.sub.4 isozyme of lactate dehydrogenase, (LDH-C.sub.4). LDH-C.sub.4 has been isolated in pure crystalline form from mouse testes. Goldberg (1972) J. Biol. Chem. 247:2044-2048. The enzyme has a molecular weight of 140,000 and is composed of four identical C subunits. The amino acid sequence and three-dimensional structure of LDH-C.sub.4 have been studied-described by a number of investigators: Musick, et al., (1976) J. Mol. Biol. 104: 659-668; Wheat, et al., (1977) Biochem & Biophys. Res. Comm. 74, No. 3:1066-1077; Li, et al., (1983) J. Biol. Chem. 258:7017-7028; and Pan, et al (1983) J. Biol. Chem. 258:7005-7016.
In 1974, Dr. Erwin Goldberg reviewed the effects of immunization with LDH-X (LDH-C.sub.4) on fertility, and advanced the possibility that "by using a defined macromolecular constituent of sperm it becomes possible to elucidate its primary structure in terms of amino acid sequence, to map specifically the antigenic determinant(s) responsible for inducing infertility, and then to construct synthetic peptides containing these determinants. Possessing the capability for synthesizing a molecule with such properties, makes the immunological approach to fertility control feasible". Karolinska Symposia on Research Methods in Reproductive Endrocrinology, 7th Symposium: Immunological Approaches to Fertility Control, Geneva, 1974 202-222.
Subsequent investigations by Dr. Goldberg and his research associates have identified several amino acid sequences of mouse LDH-C.sub.4 which in isolated form (e.g., as short chain peptides) bind to LDH-C.sub.4 antiserum. Wheat, et al., (1981), in Rich, et al., Peptides: Synthesis-Structure-Function, Proc. 7th Amer. Peptide Symp., pp. 557-560; and Gonzales-Prevatt, et al., (1982) Mol. Immunol. 19:1579-1585. Antigenic peptide compounds based on these sequences have been patented. See U.S. Pat. Nos. 4,290,944; 4,310,456; 4,353,822; 4,377,516; and 4,392,997.
These antigenic peptides are useful in preparing vaccines to reduce female fertility. Immunization of female mammals results in the development of circulating antibodies specific to LDH-C.sub.4. These immunoglobulins reach the female reproductive tract as a transudate of serum. Kille, et al., (1977), Biol. Reprod. 20:863-871. Antibody in cervical mucus, uterine fluids, and oviducal fluids combines with LDH-C.sub.4 on the sperm surface and impedes the progress of the male gamete, presumably by agglutination. Systemic immunization with LDH-C.sub.4 markedly interferes with sperm transport in the female reproductive tract. Kille, et al., (1980) J. Reprod. Immunol. 2:15-21.
The current status of research on LDH-C.sub.4 and antigenic peptides for use in female contraceptive vaccines are summarized in two recent publications by the Goldberg group: Goldberg, et al., (1983), In Immunology of Reproduction, Chapt. 22, p. 493-504; and Wheat, et al., (1983), In Isozymes: Current Topics in Biological and Medical Research, Vol. 7, p. 113-140.
The search for additional antigenic peptides containing antibody binding sequences of mouse LDH-C.sub.4 has continued. While it is known that this isozyme contains multiple antigenic domains, there is no recognized basis for locating such domains nor for predicting their effectiveness for antibody binding or for generating antibodies capable of interfering with sperm transport in female mammals. The effectiveness of immunocontraception by this route probably depends upon sufficiently high concentrations of antibodies in the reproductive tract. To date, laboratory trial and error experimentation has been the only available approach.
USPTO Backgrounds
USPTO Backgrounds