The road leading to a treatment for septic or toxic shock has proven tobe a boulevard of broken dreams for many biotechnology companies.But a syndrome that strikes 200,000 Americans a year, and kills 70,000of them, keeps researchers trying - and failing.Recent headlines in BioWorld Today tally their disappointingmilestones:- "Synergen Antril Trials for Sepsis End in Failure " (July 19, 1994,p.1);- "Possible Toxic Results From Immunex's TNFr Trial" (March 9,1994, p. 1);- "Septic Shock Drug Falters" (Oct. 21, 1993);- "Xoma To Restrict Patients in (Sepsis) Trial" (June 16, 1993, p. 1);A prime target in the ongoing anti-sepsis war is tumor necrosis factor(TNF). This is a traitorous immune-system cytokine that can turnagainst a patient's body, in sepsis, as well as against his cancer.Although Immunex Corp.'s TNF receptor "was shown not to bebeneficial in the sepsis indication," as the company's executive vicepresident, Steven Gillis, told BioWorld Today yesterday, he added,"Basically, there's another way to skin the TNF cat."Seattle-based Immunex reveals its "other way" in this week's Nature,out today in a research paper titled "Protection against a lethal dose ofendotoxin by an inhibitor of tumor necrosis factor processing."Gillis explained that "this is essentially a different way of approachingTNF inhibition." He recalled that several years ago Immunexdiscovered ICE - the interleukin-1 converting enzyme, which cleavesthe full-length IL-1 molecule into an active form."We suspected that TNF is first produced as an insoluble cell-surfaceprotein," he added, "and we spent a lot of time trying to determine, aswas the case with IL-1, whether a specific protease exists involved inclipping full-length TNF into soluble TNF."Extensive drug-screening, as the Nature paper describes, hit upon ametalloprotease as the enzyme that does indeed cleave full-length TNF.Its inhibitor, which keeps the cytokine in one piece, turns out to be alow-MW molecule, "compound 2," related to hydroxamic acid, whichthey synthesized.The researchers at Immunex saw this TNF-specific protease inhibitor,Gillis, said, "as a whole new way of preventing release of TNF fromthe cell surface, and its accumulation in the periphery, which may wellbe responsible for the toxicity attributed to TNF."To test whether such inhibition might have a therapeutic effect, theyenlisted a standard animal model used in studying therapeutic agentsfor acute infection and septic shock. This model is a mouse shot full ofendotoxin, the lethal protein synthesized by infectious bacteria. Itinduces the over-expression of immune-defense cytokines, notablyTNF and interleukin, and of white blood cells, mainly neutrophils,which can actually kill the patient.The mouse studies relied on two basic Immunex findings, Gillis said:(1) That animals challenged with endotoxin respond by producing highlevels of TNF; (2) that inhibiting this TNF over-expression "wouldsave a large percentage of the animals."In one defining experiment, 10 out of 10 mice injected intravenouslywith lethal doses of lipopolysaccharide, (the active ingredient ofendotoxin), followed by treatment with the "compound 2" proteaseinhibitor, survived. Nine out of 10 saline-treated control animals weredead in 24 hours."Is this predictive of what might occur in man?" Gillis askedrhetorically, and answered, "I don't think so."Further preclinical evaluation of the inhibitor is necessary, he said."We're trying to formulate this agent in a user-friendly formulation,and aim to further evaluate its utility, before making a decision abouttaking it into the clinic."The results just reported in Nature, he said, "are highly speculative andtheoretical at this point in time."The underlying speculation, he explained, is that the body needs thecell-associated TNF, and that it's only large accumulations of thedetached soluble molecule that account for the cytokine's deleteriouseffects.Thus, he concluded, "having an inhibitor of the protease, you wouldinhibit only that accumulation of soluble molecule, and leave theimmune system intact to deliver signals of TNF through the cell-surface molecules that would still be there."Immunex protein chemist Roy Black, the Nature paper's principalauthor, told BioWorld Today, "This strategy for controlling TNF levelsin the human body should be applicable not only to sepsis but to thebroad range of pathological conditions that we believe excessive TNFcauses, including arthritis, asthma and organ transplantation." n

-- David N. Leff Science Editor

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