Abstract Text: Rheumatoid Arthritis is one of the most common autoimmune diseases affecting primarily the joints. Despite successful therapies including antibodies against TNF and IL-6R, only 20-30% of patients experience remission. We studied whether inhibiting both, TNF and IL-6, would result in improved efficacy. Using backtranslation from single cell RNASeq data from RA patients, we hypothesized that TNF and IL-6 act synergistically on fibroblast-like synoviocytes (FLS) and T cells. We could prove this hypothesis in a coculture of FLS from RA patients with T cells, both on disease-driving pathways and biomarkers. This translated into superiority of a combination of anti-TNF and anti-IL-6 antibodies in collagen-induced arthritis (CIA) mouse models including sustained long-term remission, improved histology scores and effects on bone remodeling pathways. These promising data initiated the development of a novel anti-TNF/IL-6 bispecific NANOBODY® compound, with similar potencies against both, TNF and IL-6. We observed also additive efficacy of this NANOBODY® compound in a FLS/T cell coculture affecting arthritis and Th17 pathways. The NANOBODY® transcript signature inversely overlapped with described RA patient endotypes, indicating a potential efficacy in a broader patient population. Finally, we developed a quantitative systems pharmacology model for Rheumatoid Arthritis. The QSP model highlighted an increased efficacy versus the current monospecific therapies blocking either TNF or IL-6R, even with a lower dose. In summary, we showed superiority of our bispecific anti-TNF/IL-6 NANOBODY® compound over monospecific treatments in in vitro, in vivo and system pharmacology disease models and expect improved efficacy in current clinical studies.
