Engineering Proteases to Inactivate TNF

DESCRIPTION (provided by applicant): AdZymes are the next generation of protein therapeutics designed to catalytically inactivate the biological activity of specific regulatory proteins. AdZymes are co-translational fusions of Address domains and enZyme domains coupled by a polypeptide linker to yield a cooperative function. We propose to design an AdZyme with a proteolytic enzyme domain that will be directed by TNF-specific binding proteins. An anti-TNF AdZyme will have greater potency, better selectivity and potentially greater efficacy in blocking TNF's inflammatory role in rheumatoid arthritis. The overall goal of this Phase I proposal is to develop TNF-specific lead series AdZymes that will be suitable for testing in animal models of rheumatoid arthritis in Phase II studies. We suggest that AdZymes selected for in vivo testing must: 1) possess high affinity and demonstrate proteolytic inactivation of TNF, which would predict bioactivity at physiological concentrations; 2) be resistant to autoproteolysis, thus maintain activity under physiological concentrations overextended periods of time, and; 3) maintain a high level of bioactivity in biological fluids. The Specific Aims of this revised Phase I SBIR proposal are designed to address these issues and establish the feasibility of advancing a lead series AdZymes into animal models of TNF-mediated inflammation. Our initial product candidate will both validate the AdZyme concept and have significant commercial potential as a marketable drug. We believe that AdZymes will offer substantial benefits, and we intend to stress these benefits to potential development partners and to the clinical community in future commercialization and marketing programs. AdZymes directed to inactivate TNF will have an enzymatic mechanism of action, which will provide a unique therapeutic option for treatment of rheumatoid arthritis. Further, we suggest that by virtue of enhanced potency, AdZymes will attack refractory disease states. In addition, AdZymes potency will translate into lower doses, thus fewer and less severe side effects. Another benefit will be reduced manufacturing costs and increased research and development opportunities. These benefits make it possible to advance protein-based therapies that will compete more effectively in the marketplace.