Schering-Plough and Bristol-Myers Squibb scientists havecreated a recombinant clot-busting chimera that links the clot-dissolving action of urokinase to a monoclonal antibody thattargets the protein meshwork of clots.

Limitations posed by existing recombinant clot-busters, such ast-PA, have prompted the use of recombinant technology togenerate "hundreds of plasminogen activator mutants, whichhave produced, at best, only modest improvements inthrombolytic efficacy," the researchers noted.

The scientists' alternative strategy is to target more specificallythe fibrin of clots and avoid fibrin's precursor that circulates inthe blood, thereby avoiding dangerous bleeding.

Reporting this week in the Proceedings of the NationalAcademy of Sciences, the company researchers and theircolleagues at Emory, Harvard, Princeton and Heidelberguniversities presented a combination protein that in two assaysof clot dissolving power was sixfold and twentyfold morepotent than single-chain urokinase alone. Binding of thecombination protein to fibrin was comparable to that of themonoclonal antibody by itself.

"Molecules of this type may serve as prototypes for highlyspecific, antibody-targeted enzymes suitable for human use,"the research team concluded. -- Roberta Friedman, Ph.D.

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