Genes for selectively modified tumor necrosis factor (SM-TNF) will be used to produce sufficient quantities of the proteins for testing. To accomplish this goal, the genes for TNF-alpha and TNF-beta will be altered as desired by use of site - directed mutagenesis. Desired traits are those predicted by computer modeling to produce proteins that retain their ability to trimerize and bind to cell surface receptors in a substantially normal fashion. In addition, these proteins will have either enhanced or diminished functional activity, as monitored in model target systems. The functional activities selected for testing the SM-TNF's will enable us to evaluate their potential to inhibit the effects of unmodified TNF (which is useful, e.g., in treating sepsis) as well as their potential to provide more active analogs of TNF.
