A carbohydrate teamed with a protein is moving toward in vivo trialsaimed at preventing the human complement system from committinginflammatory overkill.
Cell biologist Una Ryan, vice-president of research at T CellSciences Inc., will report today in San Francisco to IBEX, theInternational Biotechnology Exposition, on "Carbohydrate-targetedcomplement inhibition to activated endothelium."
The body's complement system is a cascade of blood enzymes thatend up killing off cells damaged by injury or infection. Toofrequently, this process goes too far, and contributes to destroyingendothelial cells. This causes such inflammatory disorders as adultrespiratory distress syndrome (ARDS), cardiac reperfusion injury,autoimmune diseases and hyperacute organ graft rejection.
Complement activation also mobilizes neutrophils, white blood cells,which adhere to the endothelium lining the inner walls of bloodvessels, making them leaky. Breaching this barrier allows thoseneutrophils, and other mediators of inflammation, to penetrate andsavage adjoining tissues.
T Cell Sciences, of Cambridge, Mass., initially developed a solublecomplement receptor inhibitor, sCR1, a protein which went intoPhase I clinical studies this past September, in patients at risk ofARDS. Now, as Ryan is reporting, the company has added on to ananalog of that protein a carbohydrate derivative that cuts offneutrophils at the endothelial pass.
Preclinical animal models of inflammation are now evaluating thedual compound.
Ryan's in vitro data will show the IBEX session on glycobiology thatT Cell's double-acting lead compound curbs both sources ofendothelial inflammation _ complement and neutrophils _ in adose-related manner. Demonstrating that the two-pronged defenseinhibits complement on a par with sCR1, the current single-threatproduct, 90 percent of rabbit red blood cells resisted lysis equally atoptimum concentrations of both products.
Similarly, neutrophil adhesion to endothelial cells in culture droppedfrom 100 percent in no-drug controls to less than 20 percent atoptimum concentrations of the protein-plus-carbohydratecombination.
T Cell Sciences spokeswoman Susan Primrose told BioWorld Todaythat the sCR1, which checks complement only, will soon begin aseparate Phase I study against cardiac reperfusion injury. This occurswhen blood flow to the heart is restored after a myocardial infarct,but brings complement enzymes into the ischemic cardiac tissue,ravaging the heart with tissue-threatening inflammation.
The ongoing trial of sCR1 for ARDS, Primrose said, should becompleted by the end of 1995. ARDS strikes over 100,000 patients ayear in the U.S.; its lung injury is a leading cause of death inintensive-care units.
"Until now," Ryan will point out, "no therapeutic exists to limitactivation of the complement cascade or its effects." For othercascade systems, drug treatments are available, notablyanticoagulants and tissue plasminogen activators for the clottingcascades.
"The combined complement-cell adhesion approach," Ryan says,"has great potential to yield highly potent therapeutic compounds forinflammatory disorders. In addition to inhibiting two well-recognized initiating events in the inflammatory process, thecarbohydrate structure targets the compound to the area ofinflammation." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.