Background Biologics represent a rapidly growing class of approved and investigational drugs routinely used to treat multiple diseases, including inflammatory and rheumatic diseases1. Unfortunately, the success of such therapeutics is undermined by their immunogenicity and the development of anti-drug antibodies (ADA) associated with treatment failure and hypersensitivity reactions2. Methotrexate (MTX) has been shown to reduce the generation of an ADA response3. The ability of other conventional synthetic Disease Modifying Anti-Rheumatic Drugs (csDMARDs) to mitigate unwanted immunogenicity, and prolong efficacy in patients who cannot tolerate methotrexate, is less clear.
Objectives We previously reported that MTX markedly inhibited the production and release of soluble immunoglobulin (sIgG) by human primary B cells co-cultured with PBMC (BT system) in the in vitro BioMAP® phenotypic screening panel4,5. MTX also had anti-proliferative effects on human primary tissue and immune cell types6. We evaluated other csDMARDs to determine if they were broadly active or, were more similar to MTX in selectively blocking sIgG production and therefore would be more likely to reduce ADA associated with biologics.
Methods A series of csDMARDS (sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide and azathioprine) were profiled at 4 concentrations across the BioMAP Diversity PLUS™ panel to generate phenotypic activity profiles. In addition to assessing sIgG production, effects on a broad scope of disease-relevant readouts related to primary cell activation and proliferation, inflammation, wound healing, tissue/matrix remodeling, and fibrosis were also evaluated.
Results Similar to MTX, cyclosporine, leflunomide and azathioprine strongly inhibited sIgG production at all tested concentrations. In contrast, treatment with sulfasalazine or hydroxychloroquine did not decrease sIgG indicating these compounds may not mitigate the immunogenicicty of biologics. In contrast to MTX, several csDMARDS were broadly active in many BioMAP systems. Bioinformatics analysis was used to identify distinct mechanistic signatures for these agents in the BioMAP Panel.
Conclusions These results support application of the BioMAP in vitro assay systems, widely utilized for preclinical drug discovery, to determine the suitability of csDMARDS as anti-immunogenic co-treatments to extend the clinical efficacy of biologics. Clinical studies are needed to confirm these results, however, in inflammatory bowel diseases and to a less extent in rheumatoid arthritis, azathioprine has been shown to reduce immunogenicity of biologics7.
Rosman, Z, et al., (2013) BMC Medicine. April;11:882.
Mok CC., (2013) Clin Rheumatol. Oct;32(10):1429–35.
Jani M, (2014) Rheumatology. Feb;53(2):213–22.
Berg EL, et al., (2015) Int J Mol Sci. Jan 5;16(1):1008–295.
Tan, T, et al., (2013) Arthritis & Rheumatism. 65 Supplement 10:18666.
O'Mahony et al., (2014) Annals of the Rheumatic Diseases. June. 73(Suppl 2):365–365.
Krieckaert CLM et al. (2010) Arthritis Res Ther. May; 12(5): 217.
Acknowledgements We acknowledge the contributions of BioMAP operations, bio-analytics and support staff to this data. Thanks to the BioMAP Research Biology team for their analysis and interpretation of BioMAP profiling data.
Disclosure of Interest None declared