AIDSWEEKLY Plus; Monday, August 9, 1999
Daniel J. DeNoon, Senior Editor

Researchers trying to develop new immunosuppressive therapies thus have encountered unexpected failure as well as the serendipitous discovery of marketable products.

These latter discoveries point to the need for a better understanding of the complex web of biochemical signals that mediate human immunity.

"The problem we are left with is better understanding the mechanisms of autoimmune disease," said Peter L. Amlot of the Royal Free Hospital, London.

Amlot spoke in a presentation to the XIV European League Against Rheumatism Congress, held June 6-11, 1999, in Glasgow, Scotland, UK..

"Today's breakthroughs are tomorrow's cul-de-sacs," Amlot said. "Our understanding of how the whole thing works is a very, very long way away."

Existing immunosuppressive drugs were developed to prevent rejection of transplants. But Amlot pointed out that it is one thing to prevent acute organ rejection, and quite another to stop an ongoing autoimmune response. There remains no good way to prevent chronic graft or transplant rejection, and autoimmunity clearly represents a greater challenge.

"For many of the diseases we are looking at, there are undefined antigenic determinants," he observed. "In fact, many so-called autoimmune diseases may not have anything to do with immunity at all and may in fact represent states of chronic inflammation."

Amlot first discussed inhibitors of DNA synthesis. He called the purine biosynthesis inhibitor mycophenylate mofetil "a boring drug, because it behaved impeccably as expected." The drug had much more specific activity than previous agents such as azothiaprim. There are case reports, he said, but no definitive proof that mycophenylate mofetil has alleviated symptoms of lupus nephritis and refractory myasthenia gravis.

"There is a complete question mark about what it really does in arthritis," he said.

More interesting to Amlot is the pyrimidine-synthesis inhibitor leflunomide, which is a selective inhibitor of dihydro-orotate dehydrogenase (DHOH) at low concentrations. Phase II clinical trials suggest that the drug may be clinically useful in the treatment of active rheumatoid arthritis.

What most interested Amlot is the ability of leflunomide to inhibit PTK (a tyrosine kinase) and to interfere with Bruton's tyrosine kinase, an anti-apoptotic pathway for B lymphocytes. He said that leflunomide also down-regulates inflammatory cytokines.

Unfortunately, these "interesting" effects occur only at higher concentrations of the drug. As therapeutic doses already are associated with significant toxicity - diarrhea in 17 percent of patients, nausea in 10 percent, alopecia in 8 percent, and rash in 10 percent - it is unlikely to be tolerated at higher doses. Amlot suggested that future leflunomide-derived drugs might have increased antiinflammatory effects and lower toxicity.

The search for drugs with similar modes of action to cyclosporine (disruption of signal transduction by inhibition of the NFAT regulator phosphatase calcineurin) at first led to the compound FK506, which duplicated cyclosporine's immunosuppressive activity as well as its nephrotoxicity. Efforts to improve this drug led to rapamycin, a compound similar to FK506 that exerts its antiproliferative effect at a completely different (later) stage of the cell cycle.

"So the search for a drug that was supposed to be a look-alike drug turned out to [find] something totally different," Amlot said.

The eminent transplant researcher briefly discussed monoclonal antibodies (MAbs), which target membrane receptors in order to exert their immunomodulating effects.

"Antibodies have had a real up and down, a euphoria and dejection about their use," he observed.

He briefly touched on the fusion protein now known as etanercept, developed by Immunex Corp., Seattle, Washington. Created by combining the recombinant human tumor necrosis factor (TNF) p75 receptor with the Fc portion of human IgG1, the chimeric antibody recently demonstrated Phase II efficacy in RA patients (Moreland, L.W. et al.; Ann Intern Med, 1999;130(6):478-86). Amlot noted that etanercept can be given over long periods of time and apparently does not give rise to significantly neutralizing antibodies.

Another chimeric monoclonal antibody, known as infliximab, has also demonstrated clinical efficacy in RA. Unfortunately, Amlot said, the Schering-Plough MAb is significantly immunogenic and most likely cannot be used for long-term treatment.

Amlot was most excited about the new immunosuppressive compound FTY720. It was derived from myriocen (ISP-1), an inhibitor of the inflammatory cytokine interleukin-2 that was too nephrotoxic for clinical use. Unexpectedly, FTY720 had neither of these effects. Instead, it proved to have the extraordinary ability to divert blood lymphocytes away from the circulation and into the spleen.

"The fact that it diverts lymphocytes away from the sites they would normally go to - and the fact that it is relatively nontoxic - makes it an extremely interesting drug to be used in immunologic procedures because if you [can modify] an ongoing immune response it may well work to stop diseases like rheumatoid arthritis," he said.

In response to a question from the floor, Amlot said that FY720 can interrupt chronic and ongoing immune responses.

990809
AW990802

Copyright © 1999 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA. Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 http://www.newsrx.net

Copyright ©1990, 2000. AEGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of ÆGIS, or the party credited as the provider of the content.