Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1996-12-19
1999-08-10
Caputa, Anthony C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4241841, 530350, 530397, 514843, A61K 3900
Patent
active
059355786
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention provides sperm surface proteins and DNA sequences encoding the proteins which are useful in the prevention of fertilization. More particularly, the cloning and characterization of the mouse and human PH30 beta chain genes, as well as their use as contraceptive vaccines, are described.
BACKGROUND OF THE INVENTION
Four methods of family planning are currently available in the U.S., sterilization, abstinence, abortion and contraception. Of these four birth control methods, contraception is the most widely utilized. Despite the substantial U.S. and global demand for contraception, the presently available methodologies fall short of market needs. Oral contraceptives and barrier methods dominate today's contraceptive market but have significant shortcomings. Oral contraceptives, though efficacious, are documented to be associated with significant side effects including increased risks of cardiovascular disease and breast cancer and are not recommended for women over the age of 35. Barrier methods, while safe, have failure rates approaching 20%. There is a clear need for increased availability of and improvements in contraceptives that offer superior safety, efficacy, convenience, acceptability and are affordable to women and men worldwide. Identification of novel approaches for controlling fertility is therefore necessary.
Immunization of male and female animals with extracts of whole sperm is 1; 145-158 (1979); Menge, A., et al., Biol. of Reproduction, 20, 931-937 (1979)!. Moreover, men and women who spontaneously produce antisperm Fert. and Sterile, 42, 171-183 (1984)!. Although the critical sperm antigens are unknown, these observations have led to the proposal that sperm proteins might be useful in the development of a contraceptives vaccine.
In mammalian species, sperm proteins are believed to have a role in sperm adhesion to the zona pellucida of the egg. The PH30 protein is known to be involved in sperm egg binding and antibodies that bind to PH30 inhibit this interaction. PH30 is an integral membrane protein present on posterior head of sperm which mediates sperm-oocyte fusion. The PH30 protein consists of two immunologically distinct alpha and beta subunits. Both subunits are made as larger precursors and then finally processed in al., J. Cell Biology, 104, 141-149 (1987); Blobel, C. P., et al., J. Cell Biology, 111, 69-78 (1990)!. Monoclonal antibodies that recognize PH30 inhibit sperm-oocyte fusion in vitro, indicating its importance in (1987)!.
Guinea pig PH30 alpha and beta chains have been cloned by Blobel et al. Mature PH30 alpha chain consists of 289 amino acids and encodes a transmembrane domain as well as an integral fusion peptide (82-102) that is similar to a potential fusion peptide of E2 glycoprotein of rubella virus. Guinea Pig PH30 beta chain has an open reading frame of 353 amino Nature, 356, 248-251 (1992)!. The predicted amino acid sequence of the PH30 beta chain protein contains significant homology to a class of proteins called disintigrins found in snake venom. These proteins are known to bind to a family of proteins called integrins and prevent their normal functioning in cell adhesion (a well studied example is platelet aggregation). The N-terminal ninety amino acids integrin binding disintigrin domain of PH30 beta has been postulated to mediate the binding of PH30 to its putative integrin receptor on oocytes. The cloning and sequence determination of the mouse and human PH30 beta chain genes would permit novel approaches to the control of sperm egg binding and fusions. These approaches include, but are not limited to, eliciting an immune response directed at all or part of the PH30 beta chain protein and using the PH30 beta chain protein as part of a screen to identify small molecules that alter sperm egg interactions.
Mammalian fertilization is, in most cases, species specific. Thus, the identification and isolation of sperm surface proteins essential for fertilization in species other than guinea pig would be useful for providing
REFERENCES:
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Bowie et al. Science 247:1306-1310, Mar. 1990.
Kumar et al. PNAS 87:1337-1341, Feb. 1990.
Blobel et al. nature 356:248-252, Mar. 1992.
Lazar et al. Mol. Cell Biol. 8(3):1247-52, Mar. 1988.
Burgess et al. J. Cell Biol. 111:2129-38, Nov. 1990.
J.A. Parsons et al. (Ed.) "Peptide Hormones", published by University Park Press, see Chapter 1 by Rudinger et al., see pp. 1-6, Jun. 1976.
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Alves Kenneth
Gupta Sunil K.
Hollis Gregory Franklin
Bakalyar Heather A.
Caputa Anthony C.
Merck & Co. , Inc.
Walton Kenneth R.
Winokur Melvin
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