By David N. Leff

A newly described "fertilization antigen" works both sides of the street: In early human trials, it is correcting a form of male infertility. In preclinical in vivo studies, the molecule has the makings of a contraceptive vaccine.

"The fertilization antigen [FA-1]," said its discoverer, reproductive immunologist Rajesh Naz, "is localized to the sperm, where it is present on the post-acrosomal region -- the lower part of the head -- with a little bit on the tail and middle piece."

He added, "FA-1 functions as a receptor, by which the sperm attaches to the zona pellucida that envelopes the oocyte, or egg." (See BioWorld Today, Nov. 28, 1994, p. 1.)

Naz, director of research at the Medical College of Ohio, in Toledo, is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated April 29, 1997. Its title: "Fertilization antigen-1: cDNA cloning, testis-specific expression, and immunocontraceptive effects."

To illustrate these effects, Naz described a recent experiment since submitting his paper to PNAS: "We immunized seven female mice with recombinant FA-1. Five of the seven produced very high-titer antibodies to the male antigen, and there was complete block of fertility in the five. When we mated them with the male, there was no conception."

Naz continued: "Just today we ordered 40 more mice to immunize with the murine antigen, and to see how long its effect persists and what titers are required for complete inhibition of fertility."

He is also "cloning and sequencing the human antigen at this time, with encouraging results."

To test his antigen's reverse effect -- as therapy for male infertility -- Naz is supplying the native human molecule to a long-time research collaborator, Alan Menge, who is director of reproductive technologies at the University of Michigan, in Ann Arbor.

Menge is using FA-1 to treat a relatively uncommon form of autoimmune male infertility, in which the fertilization receptor in the patients' sperm is blocked by anti-antigen antibodies. "About 5 percent or 6 percent of the men who are referred to our laboratory for semen analysis show up positive with anti-sperm antibodies."

"The sperm cells," he continued, "if they do have anti-sperm antibodies attached to them, are generally quite incapable of participating in the fertility process. They can't swim through the cervix, they get tied up in the mucus, or sometimes if they're high enough they will actually block fertilization."

He pointed out that "as for the idea of in vitro fertilization, sperm that are bound with these antibodies are incapable of participating in that process.

"What Naz's antigen does in many of these men," Menge went on, "is to absorb the antibody that competes with the antibodies on their sperm cells, and removes them, or a proportion of them, so that many more sperm are free.

"I process the sperm," he explained, "to free them up of seminal fluid. Then we treat them with the antigen to remove their auto-antibodies, then process some more to remove free antigen."

He continued: "We use these sperm cells, after they've been treated, for artificial insemination, and then attempt to determine pregnancy. It's very preliminary because we haven't done a really thorough investigation in determining dose responses and everything, so it's sort of a standard treatment for every man who turns up positive."

Three Pregnancies In 20 Women

As for clinical results, Menge observed, "We have something over 20 women in the study right now, and have had three pregnancies so far. That's some degree of success in men who haven't gotten their wives pregnant before.

"It's just a first step into a larger, wider clinical trial at several centers," Menge concluded.

Naz observed: "We've been working with this antigen for a long time." Science published his first paper on the subject in 1984.

He cites "three criteria for the utility of an antigen for contraceptive development," which his FA-1 fulfills. "First, it has to be sperm-specific, expressed only in testis, with complexing antibodies that bind to spermatozoa. Second, this antigen should be relevant to the fertilization process. We demonstrate in this PNAS paper that it completely blocked interaction between sperm and the egg's zona pellucida.

"Third, it should be involved in human infertility, as Menge is demonstrating. At the present time, there is no modality, no treatment, for men with this form of immunoinfertility."

Naz is principal inventor of a patent application on FA-1, which his university has recently filed. *