EXPRESSION OF AN EFFICIENT SMALL MOLECULAR-WEIGHT TUMOR-NECROSIS-FACTOR LYMPHOTOXIN ANTAGONIST

TNF-alpha and lymphotoxin are proinflammatory cytokines that are non-h omologous in sequence, have similar homotrimeric structure and they ex ert their biological activity by aggregating two types of shared cell surface receptors, The natural inhibitors of TNF and lymphotoxin are t he shed extracellular domains of the p55 and p75 TNF receptors, Howeve r recombinant inhibitors composed of the extracellular domains of p75 or p55 receptors dimerized on IgG backbone have been shown to be much more effective. We have produced a dimeric form of the human p75 TNF r eceptor extracellular domain based on the structure of the native solu ble shed receptor, The dimer was engineered by genetically linking the monomeric forms,vith a polyglycine-serine linker, Biochemical charact erization showed that this dimeric TNF receptor elutes from a TNF affi nity column at a lower pH than the monomeric form. Biological assay re vealed this novel antagonist to be as efficient as a dimer based on an immunoglobulin backbone. However this new dimer is smaller, stable, a nd could have greater penetration into tissues. (C) 1996 Academic Pres s Limited