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United States Patent 19 11 Patent Number: 5,646,003 Barnea Et Al US005646003A United States Patent 19 11 Patent Number: 5,646,003 Barnea et al. 45 Date of Patent: Jul. 8, 1997 54 PREIMPLANTATION FACTOR Collier M, O'Neill C, Ammit AJ, Saunders DM, Biochemi cal and pharmacological characterization of human embryo 76) Inventors: Eytan R. Barnea, 1697 Lark La., -derived activating factor. Hum Reprod. 1988:3:993-998. Cherry Hill, N.J. 08003; Carolyn B. O'Neill C, Gidley-Baird AA, Amnit AJ. Saunders DM. Use Coulam, 11015 Bryar Lynn Ct., Fairfax of a bioassay for embryo-derived platelet activating factor Sta. Va., 22039 as a means of assessing quality and pregnancy potential of human embryos. Fertill Steril. 1987:47:967-975. 21 Appl. No.: 216,618 O'Neill C. Gidley-Baird AL, Pike AL, Porter RN, Sinosich MJ, Saunders DM. Maternal blood platelet physiology and (22 Filed: Mar 23, 1994 luteal phase endocrinology as a means of monitoring preand (51 int. Cl. ................... G01N 33/53 postimplantation embryo viability following in vitro fertili zation. J. Vitro Fertil Embryo Transfer. 1985:2:59-65. 52 U.S. Cl. ........................ 435/7.24; 435/723; 435/806; O'Neill C, Collier M. Saunders DM. Embryo-derived plate 436/501; 436/510 let activating factor: its diagnosis and therapeutic future. 58 Field of Search ................................ 435/723, 7.24, Ann NY Acad Sci. 1988:541:398-403. 435/806; 436/501, 510 Smart YC, Roberts TK, Clancy RL, Cripps AW. Early 56 References Cited pregnancy factor: its role in mammalian reproduction-re search review. Ferti Steril. 1981:35:397-403. PUBLICATIONS Chen C. Jones WR, Bastin F. Forde C. Monitoring embryos after in vitro fertilization using early pregnancy factor. Ann Clarke, et al., "Identification of Molecules and Mechanisms NY Acad Sci. 1984:442:420-424. Involved in the Early Pregnancy Factor System.” Reprod. Tinneberg H-R, Staves RP, Semm K. Improvement of the Fertil. Dev., vol. 4, pp. 423–423, 1992 (abstract only), Feb. rosette inhibition assay for the detection of early pregnancy 18, 1996. factor (EPF) in humans using the monoclonal antibody Bose, et al., “Purified Human Early Pregnency Factor from anti-human-Lyt-3. Am J Reprod Immunol. Preimplantation Embryos Possesses Immunosuppressive 1984;5:151-155. Properties.” Am. J. Obstet. Gynecol., vol. 160, No. 4, pp. Morton H, Rolfe B, Clunie GJA, Anderson MJ, Morrison J. 954-996, 1989 (abstract only) Feb. 18, 1996. An early pregnancy factor detected in human serum by the Bose, et al., "Production and Characterization of Mono rosette inhibition test. Lancet. 1977:1:394–399. clonal-Antibodies to Embryo-AssociatedImmunosupressor Quin ZH, Zheng ZQ. Detection of early pregnancy factor in Factor (EASF) Produced by Human Preimplantation human serum. Am J Reprod Immunol Microbiol. Embryo.” Immunology Letters, vol. 38, No. 1, pp. 47-54, 1987:13:15-19. Sep. 1993. Feb. 18, 1996. Hanahan DJ. Platelet activating factor: Abiologically active Bose, "Properties of Human Preimplantation and Postim phosphoglyceride. Annu Reve Biochem. 1986:SS:483-509. plantation Embryo-Associated Immunosuppressor Fac O'Neill C. Partial characterization of the embryo-derived tor(s).” Immunology Letters, vol. 30. No. 3, pp. 325–333, platelet activating factor in mice. J Reprod Fertil. 1991. Feb. 18, 1996. 1985:75:375-380. Clarke, et al., “Identification of Molecules Involved in the Battye KM, O'Neill C, Evans G. Production of platelet Early Pregnancy Factor Phenomenon.” J. Reprod Fertil., activating factor by the preimplantation sheep embryo. J vol. 93, No. 2, pp. 525-539, 1991, Feb. 18, 1996. Reprod Fertil 1991:93:507-514. Rolfe-BE. Detection of fetal wastage. Fertill Steril. Smart YC, Roberts TK, Fraser IS, Cripps AW, Clancy RL. 1982:37:655-701. Validation of the rosette inhibition test for the detection of Smart YC, Fraser IS, Roberts TK, Clancy RL, CrippsAW. early pregnancy in women. Fertill Steril. 1982c:37:779-785. Fertilization and early pregnancy loss in healthy women Smart YC, Roberts TK. Rosetta inhibition test: assay for attempting conception. Clin Reprod Fertil. 1982:1:177-182. detection of early pregnancy factor. In: Ellendorf F. Koch E Morton H. Hegh V. Clunie GJA. Studies of the rosette inhibition test in pregnant mice: evidence of immunosup (eds.) Early Pregnancy Factors. Perinatology Press, Ithaca, pression? Proc R Soc Lond Biol. 1976;193:413-417. NY pp. 105-116; 1985. Chard T. Grudzinskas J.G. Early pregnancy factor. Biol Res (List continued on next page.) in Preg. 1987:8:53-56. U.S. Congress, Office of Technology Assessment. Infertility, Primary Examiner-Toni R. Scheiner Medical and Social Choices. DTABA358. Washington, DC: Attorney, Agent, or Firm-Brumbaugh, Graves, Donohue & US Government Printing Office; May 1988. Raymond Mosher WD, Pratt WF. Fecundity, infertility and reproduc 57 ABSTRACT tive health in the United States, 1992. Vital and Health Statistics. Series 23, no. 14. National Center for Health A factor that indicates fertilization of an ovum before Statistics, Public Health Service. Washington, DC: US Gov implantation, Preimplantation Factor (PIF), has been found. ernment Printing Office, 27; 1987. PIF also provides an early indication of pregnancy, Templeton AA, Penny GC. The incidence of characteristics malignancy, and autoimmune diseases. Assays for PIF are and prognosis of patents whose infertility is unexplained. described. Detection of PIF in mammalian blood and other Fertill Steril. 1982:37:175. fluids is utilized in various diagnostic tests. Coulam CB. Evaluation of Immunologic infertility. Am J Reprod Immunol. 1992:27:130-135. 14 Claims, 2 Drawing Sheets 5,646,003 Page 2 PUBLICATIONS O'Neill C. Thrombocytopenia is an initial maternal response to fertilization in the mouse. J Reprod Fertil. Whyte A, Heap RB. Early pregnancy factor. Nature. 1983; 1985:73:559-564. 304:121-122. Nahas F., Barnea E. Human embrionic origin early preg Thomson AW, Milton JI, Campbell DM, Horne CHW. nancy factor before and after implantation. J ReprodImmu Rosette inhibition levels during early human gestation. J nol. 1990:22:105-108. Reprod Immunol 1980:2:263-266. Sanyal MK. Brami CJ, Bischof P., Simmons E., Barner ER, Dwyer JM, Naftolin F. Immunoregulatory activity in super Cooper DW. Aitken R.J. Failure to detect altered rosette natants from cultures of normal human trophoblast cells of inhibition titres in human pregnancy serum. J Reprod Fert. the first trimester. Am J Obstet Gynecol. 1989; 1981;61:241-244. 161:44.6453. U.S. Patent Jul. 8, 1997 Sheet 1 of 2 5,646,003 00|| 08 U.S. Patent Jul. 8, 1997 Sheet 2 of 2 5,646,003 5,646,003 1. 2 PREMPLANTATION FACTOR promptly after fertilization of an ovum has occurred, before the fertilized ovum becomes implanted, and continues dur BACKGROUND OF THE INVENTION ing pregnancy. We have developed a novel bioassay, the lymphocyte/platelet binding assay, for PIF in blood or other Infertility is a major health care concern affecting millions bodily fluids such as urine, saliva, tears and/or media used of couples worldwide, including approximately five million to culture in vitro fertilized ova. Development of other in the United States (5). Diagnosis and treatment of infer assays such as ELISA and other immunoassays and tility are costly. About one million couples have no discern chemolucent assays for PIF are made possible by use of the able cause for their infertility (7). Reproductive life table bioassay as standard. Known immunoassay techniques are analysis indicates that the majority of reproductive failures 10 employed to determine the presence or absence of PIF in occur immediately after fertilization during the preimplian blood by contacting with monoclonal antibodies to PIF and tation period (8). determining the amount of PEF, if any, that becomes bound It is important to be able to identify infertile individuals to a fixed quantity of antibody. Isolation and identification of experiencing recurrent post fertilization failures. Identifica proteins constituting PIF, made possible by use of PIF assay tion of such individuals would allow more focused investi 15 permits their application to development of diagnostic and gations for specific treatment of recurrent post fertilization therapeutic tools. failure. Exclusion of these individuals from treatment pro Early pregnancy factor (EPF) binds to lymphocytes and grams designed to enhance fertilization rather than implan decreases their rosette formation in the sheep red blood cell tation would decrease the cost of infertility therapy by inhibition assay (RIT) (3). By contrast, in our assay PIF eliminating inefficient treatments. 20 enhances lymphocyte binding to platelets demonstrating the After fertilization the developing human pre-embryo ability of PIF to cause enhanced platelet-lymphocyte inter takes approximately six days to traverse the oviduct, enter actions. Whatever the mechanisms of action, PIF can be the uterine cavity and implant in the maternal endometrium. measured in our bioassay by virtue of its enhancement of Implantation of the embryo, rather than fertilization, is the interaction between platelets and lymphocytes. This phe rate limiting process in human reproduction differentiating nomenon is pregnancy specific, and is not the result of fertile from nonfertile cycles. Yet in the human female the actions of pregnancy hormones such as progesterone or events occurring between ovulation and implantation in vivo human chorionic gonadotropin (hCG). are clinically silent. Amarker for fertilization before implan Until now, the major limitation in applying the measure tation was sought. ment of an early pregnancy factor as a clinical tool has been Two factors have been reported as markers offertilization 30 the difficulty and lack of reproducibility of results obtained in women-embryo derived platelet activating factor when using other assays. Our new lymphocyte/platelet bind (EPAF) (9-12) and early pregnancy factor (EPF) (1.2, ing assay which detects PIF is easy (4 reagents), reproduc 13-17). PAF (platelet activating factor) is a potent phospho ible (intra-and interassay variabilities of less than 3%) and lipid mediator which is produced by many cell types and has cost efficient (time for each assay is less than 5 minutes).
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