Development of improved soluble inhibitors of FasL and CD40L based on oligomerized receptors

TNF receptor family members fused to the constant domain of immunoglobulin G have been widely used as immunoadhesins in basic in vitro and in vivo res earch and in some clinical applications. In this study, we assemble soluble , high avidity chimeric receptors on a pentameric scaffold derived from the coiled-coil domain of cartilage oligomeric matrix protein (COMP). The affi nity of Fas and CD40 (but not TNFR-1 and TRAIL-R2) to their ligands is incr eased by fusion to COMP, when compared to the respective Fc chimeras. In fu nctional assays, Fas:COMP was at least 20-fold more active than Fas:Fc at i nhibiting the action of sFasL, and CD40:COMP could block CD40L-mediated pro liferation of B cells, whereas CD40:Fc could not. In conclusion, members of the TNF receptor family can display high specificity and excellent avidity for their ligands if they are adequately multimerized. (C) 2000 Elsevier S cience B.V. All rights reserved.