Background A significant advance in rheumatoid arthritis therapy has been the development of biologics targeting proinflammatory cytokines. Biologics are commonly used with methotrexate (MTX) because clinical trials of anti–tumor necrosis factor alpha (TNFα) antibodies, such as adalimumab (ADA), have shown that combination therapy is more effective than monotherapy based, in part, on the assumption that MTX reduces the immunogenicity of biologics. However, combining MTX with the anti–interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) does not demonstrate the same level of incremental benefit over monotherapy. Given the known biologic effects of TNFα, IL-6, and MTX, we hypothesized that because IL-6 has more diverse effects on the immune system than TNFα, MTX may have fewer supplementary effects than TNFα inhibitors when added to TCZ.
Objectives Using the BioMAP platform, we previously reported that TCZ, ADA, and MTX have distinct activity profiles. Here we used BioMAP systems to compare the profiles of combinations (ADA+MTX and TCZ+MTX) with the profiles of the individual agents (ADA or TCZ or MTX) to distinguish adjuvant effects.
Methods BioMAP systems model disease biology in early-passage human primary cells, cultured alone or with different stimulus combinations, and have been used extensively to characterize compounds based on phenotypic signatures.1,2 BioMAP systems were used to generate profiles of TCZ, ADA, and MTX alone and of TCZ+MTX and ADA+MTX combinations. Agents were profiled at concentrations that would include their clinical Cmax ranges for the respective approved dosing regimen. Changes in protein-based and clinically relevant endpoints (biomarkers) and other cellular events (eg, proliferation, cell cytotoxicity) were evaluated to determine whether activities detected with the combinations were significantly different from the individual agents profiled in parallel.
Results BioMAP profiling of ADA+MTX revealed more statistically significant different activities (p<0.01) than ADA and MTX profiled individually. MCP-1 (BF4T), IL-8, MCSF-1, fibroblast proliferation (HDF3CGF), VCAM-1 (lMphg), bFGF, and collagens-I and -IV were all significantly inhibited to a greater extent with ADA+MTX than with ADA or MTX alone. In contrast, the only synergistic activity of TCZ+MTX was an enhancement of antiproliferative effects on endothelial cells (3C) and B cells (BT) versus TCZ or MTX alone (p<0.01).
Conclusions These data show that TCZ has diverse effects on the immune response; the addition of MTX elicits few additional activities other than antiproliferative effects compared with TCZ alone. In contrast, ADA+MTX has statistically significantly more nonoverlapping effects on immune function, inflammation markers, and matrix-remodeling endpoints in primary human cell disease models than ADA or MTX alone. This finding supports our hypothesis that pharmacodynamic interactions between TCZ and MTX are less pronounced than those between MTX and ADA and may explain the clinical observation that TCZ is more effective than ADA as monotherapy.3
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Berg EL et al. J Biomol Screen. 2013; doi: 10.1177/1087057113505324.
Gabay C et al. Lancet. 2013;381:1541-1550.
Disclosure of Interest : A. O'Mahony Shareholder of: DiscoveRx, Employee of: DiscoveRx, E. Berg Employee of: DiscoveRx, M. John Employee of: Roche, K. Ganeshalingam Shareholder of: Roche, Employee of: Roche, E. Choy Grant/research support: Abbott, Boehringer Ingelheim, Chelsea Therapeutics, Chugai Pharma, GSK, Jazz Pharmaceuticals, MSD, Novartis, Pierre Fabre Medicament, Roche, UCB, Consultant for: Abbott, Allergan, AstraZeneca, Boehringer Ingelheim, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmaceutical, GSK, ISIS, Jazz Pharmaceuticals, MedImmune, Merrimack Pharmaceutical, MSD, Novartis, Pfizer, Pierre Fabre Medicament, Roche, Schering Plough, Synovate, UCB, Speakers bureau: Abbott, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Jazz Pharmaceuticals, MSD, Novartis, Pfizer, Pierre Fabre Medicament, Roche, Scheering Plough, Synovate, UCB