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Radically New Anti-rejection Drug Shown To Offer Safe Control Of Immune System In Stanford Study

Date:
November 4, 2003
Source:
Stanford University Medical Center
Summary:
A new type of drug may help transplanted organs thrive without compromising the recipient, Stanford University School of Medicine researchers have shown. The drug specifically targets immune cells that lead to rejection, causing minimal side effects in animal studies.

STANFORD, Calif. - A new type of drug may help transplanted organs thrive without compromising the recipient, Stanford University School of Medicine researchers have shown. The drug specifically targets immune cells that lead to rejection, causing minimal side effects in animal studies. The drug also shows promise as a therapy for quieting the overactive immune system in patients with autoimmune diseases.

"We can say that it does as well if not better than the other immunosuppressive drugs we have now," said Dominic Borie, MD, PhD, senior research scientist and director of transplantation immunology in Stanford's Department of Cardiothoracic Surgery, and senior author of the study that appears in the Oct. 31 issue of Science. The Stanford team showed that the drug, discovered by Pfizer, Inc., and called CP-690,550, prevents organ transplant rejection in monkeys for longer periods of time with fewer of the troublesome side effects seen in traditional drugs.

Transplanted organs are recognized by the recipient's immune system as foreign objects, triggering an attack that can lead to organ failure. Immunosuppressive drugs curtail the rejection process but at a price. Current therapies affect a variety of cell types, leading to side effects that include a weakened ability to fight off infection; an increased rate of cancer, diabetes and high blood pressure and cholesterol; and damage to the nervous system and kidneys.

The ideal immunosuppressant would block the actions of the immune cells that cause organ rejection without interfering with other cells. CP-690,550 appears to be on that track. "Theoretically, the molecule that we are targeting with the drug is present only on immune cells, not throughout the body," said Borie. "We have shown that targeting a pathway that is specific to immune cells provides efficacy. And on the basis of the data we have now, we feel that very likely the side effects of the drug in humans will be limited."

Initial results testing the drug in mouse organ transplantation were promising at Pfizer, but organ transplantation in monkeys is much more challenging. Borie led the Stanford transplantation immunology team that tested the drug's effectiveness in cell cultures and in kidney transplants in monkeys, on the pathway leading to human clinical trials. They found that the drug works in low enough doses that the immune system of the organ recipient is not over-suppressed.

"The encouraging thing is that we haven't seen any of the major problems that we could have seen," said Borie. At the low effective doses, they saw no evidence of metabolic abnormalities, such as problems with glucose or lipid levels, and no increased rate of cancer or infections.

The success of this drug lies behind the process used to develop it, Borie said. "The difference between the previous immunosuppressive drugs and this one is that the previous ones were discovered randomly; for instance, they were antibiotics that turned out to also block the proliferation of immune cells," he said. "This drug started from the knowledge of mutations that explain a human disease."

On a quest for a highly selective immunosuppressive drug, researchers from Pfizer sought to learn from a human immune disorder: X-chromosome-linked severe combined immunodeficiency, or X-SCID, which is characterized by massively dysfunctional immune cells (both B and T cells). The researchers reasoned that they might be able to harness aspects of this disease's power to suppress the immune system but not completely incapacitate it.

X-SCID is caused by mutations in the gene for a protein critical to activating immune cells. The activation of these cells occurs through a signal from an enzyme called janus kinase 3, or JAK3. Knowing that a lack of JAK3 caused the same symptoms as seen in X-SCID patients, the Pfizer team screened thousands of compounds to look for inhibitors of that enzyme. They identified a promising molecule and then chemically modified it to produce CP-690,550, which turned out to be extremely potent in blocking JAK3 with little effect on closely related enzymes.

Pfizer has found that the drug is well-tolerated in healthy human volunteers, and has begun testing it as a treatment for psoriasis, an autoimmune condition in which skin cells grow more quickly than normal. "If we verify in humans that the side effects are minimal, then it may turn out that the drug could be used to treat a variety of autoimmune diseases in which the immune system needs to be controlled, and not just organ transplant recipients," Borie said.

###

Other Stanford researchers involved in this project are: Ming-Sing Si, MD, postdoctoral scholar in the Department of Medicine; Ricardo Paniagua, graduate student in the Department of Medicine; Michael Larson, DVM, veterinarian for the Department of Cardiothoracic Surgery; John Higgins, MD, assistant professor of pathology; Bari Holm, transplantation immunology lab manager; Bruce Reitz, MD, the Norman E. Shumway Professor in Cardiovascular Surgery; and Randall Morris, MD, research professor of cardiothoracic surgery. The Science publication also included 49 authors from Pfizer and two from the National Institutes of Health.

In addition to Pfizer, this work was funded by the Dr. Ralph and Marian C. Falk Medical Research Trust.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.


Story Source:

The above story is based on materials provided by Stanford University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Stanford University Medical Center. "Radically New Anti-rejection Drug Shown To Offer Safe Control Of Immune System In Stanford Study." ScienceDaily. ScienceDaily, 4 November 2003. <www.sciencedaily.com/releases/2003/11/031104063449.htm>.
Stanford University Medical Center. (2003, November 4). Radically New Anti-rejection Drug Shown To Offer Safe Control Of Immune System In Stanford Study. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2003/11/031104063449.htm
Stanford University Medical Center. "Radically New Anti-rejection Drug Shown To Offer Safe Control Of Immune System In Stanford Study." ScienceDaily. www.sciencedaily.com/releases/2003/11/031104063449.htm (accessed July 31, 2014).

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