ABSTRACT: Background and purpose: For antibody therapies against receptor targets, in vivo outcomes can be challenging to predict due to target-mediated clearance or antigen "sink" effects. The purpose of this work was to engineer an antibody to Granulocyte-Macrophage Colony-Stimulating Factor Receptor-α??GM-CSFRα) such that its pharmacological properties were optimised for chronic, subcutaneous treatment of rheumatoid arthritis (RA) patients. Experimental approach: We used an in silico model of receptor occupancy to guide the target affinity and a combinatorial phage display approach for affinity maturation. Mechanism of action and internalisation assays were performed on the optimised antibody in vitro before refining the modeling predictions of the eventual dosing in man. Finally in vivo pharmacology studies in cynomolgus monkeys were carried out to inform the predictions and support future clinical development. Key results: Antibody potency was improved 8,600-fold and the target affinity reached. The refined model predicted pharmacodynamic effects at doses as low as 1 mg/kg and a surrogate potency read-out in cynomolgus monkeys confirmed in vivo efficacy at 1 mg/kg dosing. Conclusions and Implications: This rational approach to antibody drug discovery enabled the isolation of a potent molecule compatible with chronic, sub-cutaneous self-administration by RA patients. We believe this general approach enables the development of optimal biopharmaceuticals. © 2012 The MedImmune. British Journal of Pharmacology © 2012 The British Pharmacological Society.
British Journal of Pharmacology 08/2012; · 4.41 Impact Factor