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Radically new anti-rejection drug shown to offer safe control of immune system in Stanford study

> 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 enzy
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Contact: Mitzi Baker
mitzibaker@stanford.edu
650-725-2106
Stanford University Medical Center
30-Oct-2003


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