Discriminating phenotypic signatures identified for tocilizumab, adalimumab, and tofacitinib monotherapy and their combinations with methotrexate.

ABSTRACT: BACKGROUND:Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity. METHODS:TCZ, ADA, and TOF, alone and in combination with MTX, were profiled in BioMAP systems at concentrations close to clinical exposure levels: TCZ, 200 ?g/ml; TOF1, 1.1 ?M; TOF2, 0.12 µM; MTX, 10 ?M. Changes in biomarkers were evaluated by statistical methods to determine whether combinations differed from the individual agents. RESULTS:Although the BioMAP activity profile for TCZ?+?MTX was not significantly different from that for TCZ alone, profiles for ADA?+?MTX and TOF1?+?MTX or TOF2?+?MTX had a greater number of statistically significant different activities (P?

SUBMITTER: O'Mahony A 

PROVIDER: S-EPMC5992722 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature