While Xoma Corp.'s E5 and Centocor Inc.'s (NASDAQ:CNTO)Centoxin monoclonal antibody treatments for gram-negativesepsis await final U.S. marketing approval and resolution ofprolonged patent litigation, other potential treatments for thedeadly infection are being developed. Following are three newreports:
Xoma scientists were to present new data on a potentialtreatment for sepsis, bactericidal/permeability increasingprotein (BPI), at a meeting Sunday of the American Society ofHematology in Denver.
BPI appears to be a powerful antibiotic that white blood cellsproduce and release to counter infections, including thebodywide invasion of E. coli that can result in septic shock anddeath.
The protein attacks and kills gram-negative bacteria, andneutralizes the toxic portion of endotoxin released by thebacteria.
Xoma (NASDAQ:XOMA) is collaborating with scientists at NewYork University who first discovered the protein. NYU in 1990entered into a licensing agreement with Xoma that gaveexclusive rights to BPI and fragments of BPI to the Berkeley-based biotech company. Patent applications are pending in theUnited States and elsewhere on the Xoma-NYU molecules.
Genentech Inc. (NYSE:GNE) and privately held IncytePharmaceuticals Inc. of Palo Alto, Calif., announced inSeptember that they are co-developing the protein, which hasprotected animals against lethal doses of endotoxin. Thecompanies are developing the whole molecule, while Xoma isfocusing on a fragment.
Genentech spokesman Jack Murphy told BioWorld, "I know thepatent situation isn't entirely clear.
"It's the same with most biotech patents," Murphy said. "Youcan negotiate and do cross-licensing, you can collaborate, oryou can go to court."
In their presentation Sunday, NYU scientists were to show thata fragment of BPI inhibits release of tumor necrosis factor, IL-6and IL-8, and that the fragment protects mice from the lethaleffect of endotoxin.
Various biotech companies are developing products to countersepsis based on TNF or the interleukins. BPI, its developersclaim, may fight sepsis better because it stops the wholecascade of cytokines, such as TNF and interleukins. Thecytokines, made by white blood cells, have been implicated inthe sharp fall of blood pressure and organ failure that canfollow bodywide infection with gram-negative E. coli bacteria.
Interleukin-1 Receptor Antagonist
Healthy humans produce the antagonist to interleukin-1 as aresponse to injections of the bacterial toxin that causes septicshock, researchers from Tufts University and Brigham andWomen's Hospital in Boston report.
Results from the experiment with nine volunteers, which"received ethical approval," showed that "treatment withexogenous IL-1ra during sepsis is likely to be of benefit," theresearchers wrote Saturday in The Lancet.
Synergen Inc. (NASDAQ:SYGN) of Boulder, Colo., is enteringPhase III trials of its Antril version of the IL-1 receptorantagonist as a treatment for sepsis.
The body appears to make a molecule similar to IL-1, whichsimply occupies the receptors for IL-1 without causing anyeffects on its own.
Although the body can respond to sepsis with its own IL-1antagonist, the Boston researchers said that giving more of theIL-1ra should be therapeutically effective. Only 5 percent ofthe IL-1 receptors need to be activated to produce a biologicresponse, they pointed out.
Synergen is in registration for a stock offering, and companyofficials declined to comment on the findings.
Tumor Necrosis Factor Antagonist
Genentech scientists have created an antagonist to TNF that canprevent death in a mouse model of septic shock.
Reporting in the current issue of the Proceedings of theNational Academy of Sciences, the South San Francisco, Calif.,researchers showed that TNFR, the outer portion of the humancell receptor for TNF, linked to part of the IgG antibody,produces a protein that "acts as a potent antagonist of TNF.
"These results suggest that TNFR-IgG may be useful against thepotentially lethal consequences of sepsis in humans," thescientists concluded.
This same strategy of linking a receptor to the hinge and Fcregion of IgG has helped Genentech create a candidate AIDStherapeutic, in the form of an HIV receptor that persists longerin the body than does the naked receptor, CD4, by itself.
-- Roberta Friedman, Ph.D. Special to BioWorld
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