A Better Transplant Drug in the Works

Compound can prevent rejection with fewer side effects in animal studies

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HealthDay Reporter

THURSDAY, Oct. 31, 2003 (HealthDayNews) -- Using a clue from children with severely defective immune systems, researchers say they have developed a compound that promises to prevent the rejection of organ transplants with few of the dangerous side effects of existing drugs.

The compound, called CP-690,550, is designed to suppress the activity of immune cells that attack foreign tissue, but not the cells that protect the body against infection, explains Paul S. Changelian, a principal research investigator at Pfizer Inc. and leader of the pharmaceutical company's team that's been working to develop the drug.

"We've been at it for eight years, and it will be five years or so before it might enter clinical practice," Changelian says. "But we're excited by it, and we will stay the course."

The study thus far, told in a report in the Oct. 31 issue of Science, began when scientists at the National Institutes of Health discovered the molecular cause of a genetic condition called severe combined immunodeficiency (SCID), which cripples the immune system so badly that its young victims must live in a completely sterile environment to avoid even a minor infection that could be fatal.

Those children have mutations in a gene for an enzyme called janus kinase 3 (JAK3), which activates immune cells when foreign tissue invades the body. The Pfizer researchers prepared a pure version of JAK3 and began a long search for a compound that would inactivate it without affecting other protective immune system cells.

"We began in 1995, screening a library of about half a million compounds," Changelian says. "After six months, we had one which had some activity against JAK3 that was reasonably specific but not enough to be useful. Then the chemists took over."

Change after change was made to the compound, with the altered molecules tested for activity in cell cultures. "It took about four years of screening to get something promising enough to go to animal tests," Changelian says.

The first studies were done in mice. The results were strong enough to warrant trials with monkeys, simian relatives of humans. The Pfizer people then took their compound to Stanford University, which has one of the few facilities capable of such testing, Changelian says.

"We started our experiments in 2002, with macaques," says Dr. Dominic Borie, director of transplantation immunology in Stanford's department of cardiothoracic surgery. "The results have been good, in the sense that untreated monkeys rejected kidney transplants while treated monkeys did not. We have several animals going up to 90 days, the limit of the study, showing normal kidney function."

Some side effects, such as kidney damage, were seen with the high doses of the drug in the first tests, but "we have found how to manage them by reducing the dosage," Borie says. "At lower doses, all the side effects disappear."

The Pfizer researchers have begun their first human trials, giving the compound to healthy volunteers to see how well it is tolerated and how much of an oral dose gets into the bloodstream, Changelian says.

The next step will be with people who have psoriasis, an autoimmune condition that affects the skin, Changelian says. "Their lesions are very accessible, and they can be treated for a short period of time," he explains.

Changelian can't estimate when trials with transplant patients might begin. Animal studies are continuing at Stanford, as Borie and his colleagues run a variety of tests to determine the most effective way to manage the treatment.

When they find the right mix, human transplant studies probably will start by adding the new medication to existing rejection-preventing therapies, Changelian says.

"It will be a pretty long-term thing, to convince transplant surgeons to trade our drug for their current drugs," he says. "Until we do a large number of such studies, no self-respecting transplant surgeon would make the change."

More information

You can learn about transplant rejection and what is now done to prevent it from the National Library of Medicine. The United Network for Organ Sharing has more on organ donations.

SOURCES: Paul S. Changelian, Ph.D, principal research investigator, Pfizer Inc., Groton, Conn.; Dominic Borie, M.D., Ph.D, director, transplant immunology, department of cardiothoracic surgery, Stanford University, Palo Alto, Calif.; Oct. 31, 2003, Science

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