DOP027 Large-scale drug screen reveals benzimidazole anti-helminthics as potential anti-TNF co-therapy
M. Wildenberg*1, A. Levin2, A. Ceroni3, Z. Guo2, F. Bloemendaal2, D. Ebner3, G. van den Brink1
1Academic Medical Centre, Gastroenterology and Hepatology, Amsterdam, Netherlands, 2Academic Medical Centre, Tytgat Institute, Amsterdam, Netherlands, 3Oxford University, Target Discovery Institute, Oxford, United Kingdom
Wound-healing and immunosuppressive macrophages are important players in the regulation of mucosal immunity. We have previously shown that the clinical benefit of anti-TNF compounds in IBD patients correlates with their capacity to induce immunosuppressive macrophages in an in vitro model system. In line with the clinical data showing superior efficacy for thiopurine and anti-TNF combination therapy, addition of azathioprine enhanced the in vitro induction of regulatory macrophages, further validating the model system. Given the relatively high proportion of patients who do not tolerate thiopurine therapy, identification of alternative compounds that can be used as anti-TNF co-medication would be valuable. The aim of this study was to use our model system to screen a library of existing drugs for their potential in anti-TNF combination therapy.
A library of 1 600 FDA approved compounds were screened for their capacity to potentiate anti-TNF mediated induction of CD14+CD206+ regulatory macrophages in vitro. Positive compounds were further selected based on clinical applicability in IBD. Selected drugs were then functionally validated in vitro and in vivo in the T-cell transfer model of colitis.
The initial screen resulted in 154 compounds that potentiated anti-TNF effects in at least 1 concentration. Clustering of these compounds revealed significant enrichment in the anti-helminthic family of benzimidazoles. This family includes albendazole, a compound that has been in extensive clinical use with a good safety profile. We further validated these findings and confirmed that albendazole significantly increased the number of regulatory macrophages induced by anti-TNF therapy. Combination treated macrophages displayed similar expression of regulatory markers CD163 and CD206. Interestingly, anti-TNF macrophages induced in the presence of albendazole displayed enhanced immunosuppressive capacity compared with macrophages induced by anti-TNF monotherapy, suggesting enhanced functionality. In an in vivo colitis model, albendazole + anti-TNF combination treatment was significantly more effective therapeutically than either compound alone. In addition, combination treatment resulted in the increased presence of CD206+ regulatory macrophages in the colon, and this presence correlated significantly with clinical improvement.
The antihelminthic albendazole potentiates the induction of regulatory macrophages by anti-TNF. In vivo, combination therapy resulted in enhanced clinical benefit in a colitis model. Given the extensive clinical experience with this drug, anti-TNF plus albendazole combination therapy may be a new alternative for IBD patients who do not tolerate thiopurines.