Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: In vitro co-cultures of human primary cells, including immune cells, fibroblasts, smooth muscle, keratinocytes, epithelial or endothelial cells were developed to capture the complexity of various disease states. Compound effects on protein biomarkers in these assay systems were used to generate phenotypic signatures to inform how drugs may behave in these settings. These activity profiles could also be used to help guide indication selection for either novel compounds or repurposing of approved drugs. With a library of clinically validated and experimental compounds in the BioMAP reference database, novel compounds can be mapped to the current therapeutic landscape as well as help guide indication expansion.
Methods: Three benchmark RA drugs, a DMARD (Methotrexate, MTX), an anti-TNFα antibody (Adalimumab, Humira, ADA), and a small molecule JAK kinase inhibitor (Tofacitinib, Xeljanz, TOF) were profiled across a panel of 12 human primary cell based systems to generate phenotypic profiles. Drug effects on a broad scope of disease relevant readouts related to immune cell activation, proliferation, vascular inflammation, epithelial cell activation, matrix remodeling, fibrosis, and tissue remodeling were used to generate sentinel effects consistent with the RA indication. Three development candidates, BIRB-796 (p38MAPK inhibitor), apremilast (PDE IV inhibitor), and idelalisib (PI3Kδ inhibitor) were similarly profiled to assess indication selection.
Results: ADA and TOF were broadly anti-inflammatory with decreased cytokines (TNFα, IL-17F) and inflammation markers (VCAM-1, Eotaxin-3). In contrast, MTX was more selectively active in a system modeling T cell dependent B cell activation (BT). Correlation of activities with impact on disease relevant processes such as vascular inflammation, immune cell activation and proliferation, modulation of matrix, and epithelial activation was used to confirm RA as a primary indication best suited to these drugs. Analysis of the developmental compounds BIRB-796, apremilast, and idelalisib, was performed to assess which compound best mapped to which indication. BIRB-796 and apremilast, but not idelalisib, suppressed TNFα production from LPS-stimulated monocytes, similar to ADA. Although analysis of BIRB-796 revealed impacts on RA relevant processes, there were additional pro-inflammatory activities in a wound-healing model using dermal fibroblasts. Skin adverse events (AEs) have been reported in clinical trials of BIRB-796 and other p38 MAPKi. The data support the repositioning of p38 inhibitors for indications such as lung disease including COPD. Conversely to the broad activities of BIRB-796, idelalisib’s anti-inflammatory activities were selective to the BT system, similar to MTX and TOF. These data suggest that idelalisib may be better suited for indications such as lupus or oncology (CLL) where B cell dysfunction is of greater importance with respect to the disease.
Conclusion: These in vitro human primary cell-based model systems provide a phenotypic screening platform that can used to evaluate indication-related efficacy, dosing, and safety.
To cite this abstract in AMA style:Ptacek J, Berg EL, O'Mahony A. Profiling Compounds in Human Primary Cell-Based Disease Models Guide Indication Selection [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/profiling-compounds-in-human-primary-cell-based-disease-models-guide-indication-selection/. Accessed September 26, 2022.
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