Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: IL-6 plays a central pathogenic role in rheumatoid arthritis (RA). IL-6 signals through a complex of transmembrane IL-6R or soluble IL-6R (sIL-6R) with gp130 to mediate classic or trans-signaling, respectively. Sirukumab (CNTO 136) is a human IgG1 k monoclonal antibody (mAb) specific for human IL-6 cytokine and is currently in clinical trials for the treatment of adults with moderately to severely active RA and other diseases. A human primary cell-based phenotypic screening systems (BioMAP®) was used to investigate the effects of sirukumab and to identify discriminating biological activities compared to tocilizumab, an anti-IL-6R mAb. Comparisons were also made with a reference database that includes profiles of drugs used to treat RA.
Methods: BioMAP® systems model disease biology in primary human cells. Sirukumab was profiled across a panel of 12 BioMAP® systems, relevant to inflammatory diseases, at different concentrations in the presence or absence of sIL-6R (50ng/ml). Sirukumab profiles were directly compared to those of tocilizumab and indirectly to compounds already profiled in the BioMAP® reference database including adalimumab, tofacinitib, methotrexate and prednisolone in the presence or absence of sIL-6R. Serum samples from the RA phase 3 sirukumab studies (SIRROUND-M, D, T, & H) were also analyzed at baseline and week 4 post-treatment using the SomaLogic SOMAscanTM.
Results: Sirukumab significantly inhibited expression of biomarkers linked to inflammation (P-selectin), immunomodulation (CD69, M-CSF) and tissue remodeling (MMP-9, aSMA, Collagen IV) in the BioMAP® systems. Addition of sIL-6R induced further biomarkers that sirukumab completely blocked. A direct comparison of sirukumab to tocilizumab showed that whilst there was a similar impact on multiple mediators, there were significant differences across all systems assessed. Sirukumab significantly decreased 5 (CD40, Collagen III & IV, TF, PAI-I) and increased 8 (IL-8, ICAM-1, IL-1a, IP-10, IL-2, EGFR, MIG, IL-10) biomarkers under sIL-6R trans-signaling; these mediators were not affected by tocilizumab. Conversely, tocilizumab significantly decreased 9 (P-selectin, uPAP, IL-18, MMP3, EGFR, IP-10, MCP-1, MIP-1a E-selectin) and increased 1 (VCAM-1) biomarkers which were not affected by sirukumab. Of note, the serum analysis of RA patients treated with sirukumab confirmed some of the changes seen in the BioMAP® systems, including reduction of PAI-I, increase in IP-10, and lack of decrease in MMP3, MCP-1, MIP-1a, and E-selectin levels. Indirect comparisons of sirukumab to adalimumab, tofacinitib, methotrexate and prednisolone using the BioMAP® algorithm showed that overall the drugs were not similar, reflecting different mechanisms of action.
Conclusion: Sirukumab has a unique BioMAP® phenotypic signature that is further separated from tocilizumab (as well as other reference profiles) with addition of sIL-6R. This signature was confirmed in sera from RA patients treated with sirukumab supporting the hypothesis that the impact of sirukumab on IL-6R signaling is distinct from tocilizumab. The clinical significance of these data requires further experimental exploration.
To cite this abstract in AMA style:Chavele KM, Gardner D, Loza MJ, Dasgupta B, Sims M, Shealy D, Reid J, Rao R. In Vitro Cellular Profiling of Sirukumab, an Anti–IL-6 Cytokine Monoclonal Antibody, Reveals a Distinct Phenotypic Signature Compared to Tocilizumab, an Anti–IL-6 Receptor Monoclonal Antibody [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/in-vitro-cellular-profiling-of-sirukumab-an-anti-il-6-cytokine-monoclonal-antibody-reveals-a-distinct-phenotypic-signature-compared-to-tocilizumab-an-anti-il-6-receptor-monoclonal-a/. Accessed November 25, 2020.
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