ArticleBritish journal of pharmacology2013
Protein engineering and preclinical development of a GM-CSF receptor antibody for the treatment of rheumatoid arthritis.
Article in British journal of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With Rheumatoid Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2018Trial
- A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2018Trial
- Targeting GM-CSF in Rheumatoid Arthritis: Advances in Cytokine-Directed Immunotherapy and Clinical Implications.Life (Basel, Switzerland) · 2025Review
- Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection.Journal of biomedical science · 2022Review
- Taking phototherapeutics from concept to clinical launch.Nature reviews. Chemistry · 2021Review
- Molecular Mechanism of HER2 Rapid Internalization and Redirected Trafficking Induced by Anti-HER2 Biparatopic Antibody.Antibodies (Basel, Switzerland) · 2020Article
- Model-Based Discovery and Development of Biopharmaceuticals: A Case Study of Mavrilimumab.CPT: pharmacometrics & systems pharmacology · 2018Article
- Review
- Article
- Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis.Annals of the rheumatic diseases · 2015Article
- Article
- Quantitative measurement of the target-mediated internalization kinetics of biopharmaceuticals.Pharmaceutical research · 2015Article
- Identification of rheumatoid arthritis and osteoarthritis patients by transcriptome-based rule set generation.Arthritis research & therapy · 2014Article
- Article
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Authors and funding
20 authors.
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Abstract
background and purposeFor antibody therapies against receptor targets, in vivo 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. 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 internalization assays were performed on the optimized antibody in vitro before refining the modelling 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
resultsAntibody 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(-1) and a study in cynomolgus monkeys confirmed in vivo efficacy at 1 mg kg(-1) dosing. CONCLUSIONS AND IMPLICATIONS: 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.
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