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Downloaded from Bioscientifica.Com at 09/26/2021 02:22:48PM Via Free Access 20 M Journal of Reproduction and Fertility (2000) 120, 19–32 Effectiveness of zona pellucida protein ZPB as an immunocontraceptive antigen M. L. Martinez and J. D. Harris* Zonagen, Inc., 2408 Timberloch Place, B4, The Woodlands, TX 77380, USA Immunization of female mammals with native zona pellucida (ZP) proteins is known to cause infertility. Since each human ZP protein is now available as a purified recombinant protein, is it possible to compare the immunocontraceptive potential of each ZP protein. A breeding study was conducted in cynomolgus monkeys (Macaca fasicularis) after immunization with recombinant human ZP (rhZP) proteins (ZPA, ZPB, ZPC) separately and in combinations. This study demonstrated that immunization with recombinant human ZPB (rhZPB) protein caused cynomolgus monkeys to become infertile for 9–35 months. A second study was conducted in baboons (Papio cynocephalus), which yielded a similar result. The baboons immunized with rhZPB became infertile for 9 to > 20 months. During the time of maximum antibody titre, some animals experienced disruption of the menstrual cycle, but eventually all of the animals resumed normal menstrual cycles. Control animals and animals immunized with other rhZP proteins all became pregnant before any of the rhZPB-treated animals. This is the first study in which a recombinant ZP protein has consistently induced infertility in a primate without permanent disruption of the normal menstrual cycle. Introduction Table 1. Examples of zona pellucida nomenclature The use of the zona pellucida (ZP) proteins as immuno- Other mammalsa Mice Rabbits Pigsb Humans contraceptive antigens has a long and diverse history. The use of crude extracts of oocytes from pig ovaries has been ZPA ZP2 rec75 ZP1, ZP2, ZP4 ZP2 ongoing for the past two decades (Mahi-Brown et al., 1982; ZPB ZP1 rec55 ZP3α ZPB Kirkpatrick et al., 1996). ZPC ZP3 ZPC ZP3β ZP3 Purified recombinant proteins are available for use as vaccine antigens (Harris et al., 1999). There are three classes aIncludes clones of the following species: cattle, cat, dog, cynomolgus monkey (Harris et al., 1994). of ZP proteins (Harris et al., 1994): ZPA (also called ZP1, ZP2 b α These refer to proteins separated by gel electrophoresis (Sacco, et al. 1989 and or ZP4), ZPB (also called ZP1 or ZP3 ) and ZPC (also called Hedrick and Wardrip, 1987); the other columns refer to clones. The individual ZP3 or ZP3β). The variety of nomenclature is presented clones were assigned ZPA, ZPB and ZPC (Harris et al., 1994). (Table 1). This multiplicity exists because the first Additional references: mice: ZP2, Bleil et al., 1988; ZP1, Epifano et al., 1995a; identification of zona pellucida proteins was made using ZP3, Ringuette et al., 1988; rabbits: rec75, Lee et al., 1993; rec55, Schwoebel et al., 1991; ZPC, Harris et al., 1994; humans: ZP2, Liang and Dean, 1993; ZPB, Harris PAGE: the largest proteins were assigned ZP1, next largest, et al., 1994; ZP3, Chamberlin and Dean, 1990. ZP2, and so on. However, due to post-translational modification, the species to species correlation is not exact. Thus, pig ZP1 and ZP2 are derived from the same gene and are related to mouse ZP2, but not to mouse ZP1. been discouraging, the zona pellucida offers a variety of Furthermore, a human homologue to mouse ZP1 has been antigens that could prove to be more effective targets. identified (Hughes and Barratt, 1999), which implies that the VandeVoort et al. (1995) vaccinated cynomolgus monkeys with mouse ZP1 is not homologous to the other mammalian ZPB bacterially expressed proteins derived from two partial genes. In this paper the ZPA, ZPB and ZPC nomenclature complementary DNA rabbit ZPA clones or a full-length rabbit will be used. ZPB clone. Since no breeding data were published with this Paterson et al. (1996) used recombinant human ZPC (rhZPC) study, it was not possible to predict whether ZPAor ZPB would protein to immunize marmoset monkeys, but infertility was be effective immunocontraceptive agents. only achieved in animals in which the ovarian cycle was Kerr, et al. (1999) reported that alloimmunization of rabbits completely disrupted. Although the results using rhZPC have with recombinant rabbit ZPB induced infertility in most of the treated animals. However, the rabbit ZPA and ZPC *Correspondence. proteins were not tested and thus could not be compared Received 9 November 1999. with ZPB. © 2000 Journals of Reproduction and Fertility Ltd 0022–4251/2000 Downloaded from Bioscientifica.com at 09/26/2021 02:22:48PM via free access 20 M. L. Martinez and J. D. Harris Because a breeding study compares fertility versus study, but as she became pregnant, the illness did not appear infertility directly, the best way to measure the effect of an to impair her reproductive capabilities. immunocontraceptive vaccine on fertility is to conduct breeding trials in a well-controlled environment. No breeding study has ever compared the immunocontraceptive Vaccine preparation potential of all three proteins. A breeding study was performed of cynomolgus monkeys The recombinant glycoproteins, which were used as vaccinated with the three rhZP proteins, alone and in various antigens, were expressed in Chinese hamster ovary (CHO) combinations. These results showed that rhZPB can be used cells. These glycoproteins were prepared and characterized alone as an immunocontraceptive antigen in cynomolgus as described by Harris et al. (1999), and PAGE analysis of the monkeys. A breeding study was also conducted using purified proteins is shown (Fig. 1). Vaccine consisted of baboons that had been vaccinated with individual rhZP 500 µg heat solubilized pig zona pellucida (HSPZ) or 250 µg proteins and did not include any antigen combinations to purified protein (250 µg of each protein was used when a test whether the result could be repeated in a second primate combination was given) formulated to a maximum volume species. The vaccination regimen was reduced since it had of 1 ml with adjuvant. A variety of adjuvants was used in the become obvious that extremely high antibody titres against cynomolgus monkey study because the aim was to compare the ZPB were not necessary to achieve infertility. complete Freund’s adjuvant with two adjuvants developed at Zonagen, ImmuMax and ImmuMaxSR. The CFA was modified as described by Paterson et al. (1992) and was used as the adjuvant for 16 cynomolgus monkeys: the four Materials and Methods controls, the four monkeys immunized with HSPZ, four of the monkeys that received rhZPB and four of the monkeys Animals that received rhZPC. For the modified complete Freund’s All animals were maintained in accordance with the adjuvant vaccine, each 1 ml final vaccine contained 80 µl National Institutes of Health guidelines for the care and use Bacillus Calmette Guerin vaccine, 125 µl aluminium of laboratory animals. All the cynomolgus monkey (Macaca hydroxide gel, 500 µl non-ulcerative Freund’s adjuvant and a fasicularis) females were nulliparous and 3–4 years of age total of 355 µl of antigen plus PBS. Boosters for these animals when the study was commenced. All the females were were formulated in incomplete Freund’s adjuvant. domestic, born in the Philippines and were routinely tested ImmuMax SR adjuvant (Zonagen, The Woodlands, TX), a negative for tuberculosis, filovirus, herpes B virus, simian chitosan-based oil emulsion formulation, was used with two retrovirus, simian immunodeficiency virus and herpes of the cynomolgus monkeys that were immunized with simplex I virus. Each animal received a complete physical rhZPB vaccine and with two of the monkeys that were examination by a veterinarian and was determined to be in immunized with rhZPC vaccine. ImmuMax adjuvant good health before she was accepted for study. Monkeys (Zonagen, The Woodlands, TX), a chitosan–zinc chelating were housed in outdoor cribs in south Texas. Males were introduced into stable female groups, consisting of four to seven females each belonging to a different vaccination ZPA ZPB ZPC ZPA ZPB ZPC group, to normalize any possible male effect on fertility. They kDa remained in continuous co-habitation throughout the study. 250 The numbers of pregnancies were comparable between cribs, indicating that there was no significant male effect on fertility rates. Males cannot be rotated between cribs, as this would disrupt the necessarily stable social groups that are 98 established under these breeding conditions. 64 For the baboons (Papio cynocephalus), the four vaccination groups of females were assigned so that the groups were 50 comparable for weight and age. Baboons were housed in groups at a facility in San Antonio, Texas. When assigned to 36 the two different breeding groups, the baboons ranged in age 30 from 7.7 to 15.3 years. The 20 animals in the study were placed 16 into two breeding groups with males with good breeding 6 records so that the four different vaccination groups were 4 represented comparably in both groups. All of the females had Coomassie stain Silver stain previously given birth and the number of offspring ranged Fig. 1. An SDS-PAGE gel of recombinant human zona pellucida from one to nine (correlated with the age of the animal). All (ZP) proteins rhZPA, rhZPB and rhZPC stained with either animals received a complete physical examination by a Coomassie G-250 (BioRad, Hercules, CA) or silver stain (Novex, San veterinarian and were determined to be in good health before Diego, CA). In the Coomassie stained gel each lane has 2 µg, whereas they were accepted for study. One of the ZPB-vaccinated in the silver stained gel each lane has 0.5 µg. The markers are animals, number 4587, contracted histoplasmosis and Seablue molecular mass markers (Novex, San Diego, CA). required hospitalization, treatment and surgery during the Reproduced from Harris et al., 1999. Downloaded from Bioscientifica.com at 09/26/2021 02:22:48PM via free access Effectiveness of ZPB as an immunocontraceptive antigen 21 formulation designed for use with histidine-6 tagged females was observed each day to monitor for sexual recombinant proteins, was used with the remainder of the receptivity and pregnancy.
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