A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency |
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Authors: | Chodorge M Züger S Stirnimann C Briand C Jermutus L Grütter M G Minter R R |
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Affiliation: | MedImmune Ltd., Granta Park, Cambridge, UK. |
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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. |
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Keywords: | agonist antibody Fas affinity maturation phage display scFv |
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