title: A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency.
abstract: Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9 Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general.
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Chodorge
authors.forename: S
authors.initials: S
authors.lastname: Züger
authors.forename: C
authors.initials: C
authors.lastname: Stirnimann
authors.forename: C
authors.initials: C
authors.lastname: Briand
authors.forename: L
authors.initials: L
authors.lastname: Jermutus
authors.forename: M G
authors.initials: MG
authors.lastname: Grütter
authors.forename: R R
authors.initials: RR
authors.lastname: Minter
mesh_terms: D000906:Antibodies / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D018360:Crystallography, X-Ray; D053222:Fas Ligand Protein / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D016296:Mutagenesis; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000819:agonists* / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D053222:Fas Ligand Protein; D057127:Single-Chain Antibodies; D019014:fas Receptor