Background Mavrilimumab, an antibody to the GMCSFR alpha chain has demonstrated significant improvements in disease activity in a Phase IIa study in subjects with moderate to severe rheumatoid arthritis (Burmester et al., 2013). As mavrilimumab does not cross-react with rodent GM-CSFR, we used the BioMAP® platform to explore its mechanism of action across a panel of human primary cell based systems.
Objectives To compare the phenotypic impact of the anti-GM-CSFRa biologic, mavrilimumab, with the anti-TNF therapy, infliximab, in human primary cell based BioMAP® systems.
Methods BioMAP® systems employing primary human cell types to model tissue and disease biology have been used to validate compounds and targets, identify mechanisms of action, potential toxicities and determine phenotypic signatures (Berg et al. 2006). Human GMCSF and GMCSFR mRNA expression levels were determined across all co-culture systems in the BioMAP Diversity Plus panel. Mavrilimumab was tested across the BioMAP platform at concentrations from 100ng/ml to 100mg/ml equivalent to the doses in the Phase I study (Burmester et al., 2011). Mavrilimumab-mediated effects on protein-based biomarker readouts, changes in proliferation and cell cytotoxicity endpoints were used to generate an activity plot (i.e. BioMAP profile). Profiles from this screen were then compared with anti-TNF inhibitor (infliximab) from the BioMAP database to determine compound-specific activities relevant for clinical efficacy. Mavrilimumab was further evaluated by generating dose response curves in select BioMAP systems modeling T and B cell activation responses.
Results GMCSF mRNA was highly expressed in many of the stimulated BioMAP systems. GMCSFRa levels were broadly similar across the panel while being elevated in the BT system and expression of the common b chain was largely restricted to systems containing peripheral blood mononuclear cells. BioMAP profiling revealed that Mavrilimumab was most active in the BT system modeling T cell dependent B cell activation resulting in inhibition of IL-17A, IL-17F, IL-6, IL-2 and TNF production. In contrast, infliximab only significantly reduced TNF levels in this system. Potency of both agents was evaluated on IL-17A, IL17F and IL-6 production in the BT system. Mavrilimumab was 30 and 100 fold more potent than infliximab in reducing IL-17A and IL-17F production with IC50 of 2.79ng/ml and 10.8ng/ml compared with IC50s for infliximab of 69.4 and 135ng/ml respectively. Of note IL-6 inhibition in BT was broadly equivalent between both antibodies.
Conclusions In an in vitro human primary cell model of T cell dependent B cell activation, mavrilimumab inhibited production of soluble cytokines including IL-17A and IL-17F that are induced by endogenous release of GMCSF in the system. As TH17 biology has been implicated in the pathogenesis of RA (Gaffen, 2009) these data suggest that mavrilimumab could impact IL-17 production from pathogenic T cells in the rheumatic joint.
Burmester GR et al. (2013) Ann Rheum Dis 72(9):1445-1452.
Burmester GR et al. (2011) Ann Rheum Dis 70(9):1542-9.
Berg, EL et al. (2006) J. Pharmacol Toxicol Methods 53:67-74.
Melton AC et al. (2013) PLoS One 8(3):e58966.
Gaffen SL (2009) Curr Rheumatol Rep. Oct;11(5):365-70.
Disclosure of Interest M. Sleeman Shareholder of: Astrazeneca., Employee of: MedImmune Ltd (A wholly owned subsidiary of Astrazeneca), A. O'Mahony Employee of: Bioseek Inc., M. Polokoff Employee of: Bioseek Inc., I. Scott Shareholder of: Astrazeneca., Employee of: MedImmune Ltd (A wholly owned subsidiary of Astrazeneca)
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