title: Development of improved soluble inhibitors of FasL and CD40L based on oligomerized receptors.
abstract: 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 research 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 affinity of Fas and CD40 (but not TNFR-1 and TRAIL-R2) to their ligands is increased by fusion to COMP, when compared to the respective Fc chimeras. In functional assays, Fas:COMP was at least 20-fold more active than Fas:Fc at inhibiting the action of sFasL, and CD40:COMP could block CD40L-mediated proliferation 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.
authors.affiliation: Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066, Epalinges, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Holler
authors.forename: T
authors.initials: T
authors.lastname: Kataoka
authors.forename: J L
authors.initials: JL
authors.lastname: Bodmer
authors.forename: P
authors.initials: P
authors.lastname: Romero
authors.forename: J
authors.initials: J
authors.lastname: Romero
authors.forename: D
authors.initials: D
authors.lastname: Deperthes
authors.forename: J
authors.initials: J
authors.lastname: Engel
authors.forename: J
authors.initials: J
authors.lastname: Tschopp
authors.forename: P
authors.initials: P
authors.lastname: Schneider
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053222:Fas Ligand Protein; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D064235:Matrilin Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006023:Glycoproteins; D008024:Ligands; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; D008562:Membrane Glycoproteins; D011961:Receptors, Fc; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C577553:TSP5 protein, human; D019014:fas Receptor; D023201:CD40 Ligand