Scientists mimicked a powerful immune-system disease in creating a pill that may block the rejection of transplanted organs without as many of the side effects that patients now face, researchers reported Thursday.
The experimental drug helped monkeys that had been given kidney transplants _ a crucial hurdle, the researchers said. Although much more research is needed, human safety studies are beginning.
If it works, the drug, created by Pfizer Inc., could mark a more sophisticated way to prevent transplant rejection. Unlike today's anti-rejection drugs, it was specially engineered to inhibit a molecule called JAK3 that is key to marshaling the immune cells that attack and destroy newly implanted organs.
Ironically, the new compound was inspired by the deadly "bubble boy disease," in which children are born without a functioning immune system. A complete lack of JAK3 is at the root of the genetic disease, also called SCID or severe combined immunodeficiency. With the new compound, Pfizer scientists hope to harness JAK3's immune suppression powers enough to help transplant recipients without overwhelming the body's defenses.
"It's a brand new concept," said Dr. Dominic Borie, transplant immunology chief at Stanford University School of Medicine, who tested Pfizer's drug in 12 monkeys given varying doses for three months.
While it completely protected only a third, "indeed it works, and does as well as other immunosuppressive drugs," with fewer side effects, he said,
Borie, along with scientists from Pfizer and the National Institutes of Health, reported the results in the journal Science.
The big question is how well the drug will work in people who are already sick instead of monkeys who start off healthy, cautioned Dr. John Fung, transplant chief at the University of Pittsburgh Medical Center, who was not involved with the research.
Still, he's intrigued.
"It looks like a very promising approach," Fung said. "It ushers in a new era of drugs that are targeted at specific pathways" of organ rejection.
The body's reaction to a new organ is thousands of times more aggressive than its fight against routine infections, so transplant recipients take powerful immune-suppressing drugs, sometimes for the rest of their lives.
Despite the obvious benefits, today's anti-rejection drugs can cause debilitating, even deadly, side effects. Some raise blood pressure and cholesterol levels, increasing the risk of heart disease. Some cause anemia. And some gradually destroy the kidneys, eventually forcing many transplant recipients onto dialysis.
Those side effects arise because the older drugs' molecular targets are found in cells throughout the body. Because the new compound's target, JAK3, is an enzyme found only in immune cells, it shouldn't cause kidney, heart and other problems, explained Pfizer lead researcher Paul Changelian.
The hunt for the drug _ so far known by the unwieldy code name CP-690,550 _ began almost a decade ago, when the NIH discovered JAK3 and found it's crucial in activating infection-fighting white blood cells. Working with NIH, Pfizer then designed a pill to curb white blood cells' attack on donated organs by inhibiting JAK3's action.
It worked in mice given heart transplants. Stanford then tested 12 monkeys. Four had no signs of kidney problems after three months, and others had varying degrees of rejection earlier, suggesting the drug is comparable to other medications, Borie said. The monkeys' only side effect was anemia from the highest dose.
No problems arose in first-stage safety tests, in which healthy people volunteer to take a dose, Changelian said. Pfizer now is testing various doses in people with the autoimmune disease psoriasis before attempting studies in more fragile kidney transplant recipients.