Protein engineering and preclinical development of a GM‐CSF receptor antibody for the treatment of rheumatoid arthritis. (18th December 2012)

• Record Type: Journal Article
• Authors: Minter, RR; Cohen, ES; Wang, B; Liang, M; Vainshtein, I; Rees, G; Eghobamien, L; Harrison, P; Sims, DA; Matthews, C; Wilkinson, T; Monk, P; Drinkwater, C; Fabri, L; Nash, A; McCourt, M; Jermutus, L; Roskos, L; Anderson, IK; Sleeman, MA
• Is Part Of: British journal of pharmacology. Volume 168:Number 1(2013:Jan.)
• Page Start: 200
• Page End: 211
• Publication Date: 2012-12-18
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/j.1476-5381.2012.02173.x
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph2173-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>For antibody therapies against receptor targets, <italic>in vivo</italic> outcomes can be difficult to predict because of target‐mediated clearance or antigen 'sink' effects. The purpose of this work was to engineer an antibody to the GM‐CSF receptor α (GM‐CSFRα) with pharmacological properties optimized for chronic, s.c. treatment of rheumatoid arthritis (RA) patients.</p> </sec> <sec id="bph2173-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We used an <italic>in silico</italic> model of receptor occupancy to guide the target affinity and a combinatorial phage display approach for affinity maturation. Mechanism of action and internalization assays were performed on the optimized antibody <italic>in vitro</italic> before refining the modelling predictions of the eventual dosing in man. Finally, <italic>in vivo</italic> pharmacology studies in cynomolgus monkeys were carried out to inform the predictions and support future clinical development.</p> </sec> <sec id="bph2173-sec-0003" sec-type="section"> <title>Key Results</title> <p>Antibody potency was improved 8600‐fold, and the target affinity was reached. The refined model predicted pharmacodynamic effects at doses as low as 1 mg kg<sup>−1</sup> and a study in cynomolgus monkeys confirmed <italic>in vivo</italic> efficacy at 1 mg kg<sup>−1</sup> dosing.</p> </sec> <sec id="bph2173-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>This rational approach to antibody drug discovery enabled the isolation of a potent molecule compatible with chronic, s.c. self‐administration by RA patients. We believe this general approach enables the development of optimal biopharmaceuticals.</p> </sec> </abstract>