Additive efficacy of a bispecific anti-TNF/IL-6 nanobody compound in translational models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases affecting primarily the joints. Despite successful therapies including antibodies against tumor necrosis factor (TNF) and interleukin-6 (IL-6) receptor, only 20 to 30% of patients experience remission. We studied whether inhibiting both TNF and IL-6 would result in improved efficacy. Using backtranslation from single-cell RNA sequencing (scRNA-seq) data from individuals with RA, we hypothesized that TNF and IL-6 act synergistically on fibroblast-like synoviocytes (FLS) and T cells. Coculture of FLS from individuals with RA and T cells supported this hypothesis, revealing effects on both disease-driving pathways and biomarkers. Combining anti-TNF and anti-IL-6 antibodies in collagen-induced arthritis (CIA) mouse models resulted in sustained long-term remission, improved histology, and effects on bone remodeling pathways. These promising data initiated the development of an anti-TNF/IL-6 bispecific nanobody compound 1, with similar potencies against TNF and IL-6. We observed additive efficacy of compound 1 in a FLS/T cell coculture affecting arthritis and T helper 17 (TH17) pathways. This nanobody compound transcript signature inversely overlapped with described RA endotypes, indicating a potential efficacy in a broader patient population. In summary, we showed superiority of a bispecific anti-TNF/IL-6 nanobody compound or combination treatment over monospecific treatments in both in vitro and in vivo models. We anticipate improved efficacy in upcoming clinical studies.

Survival of the simplest in microbial evolution.

The evolution of microbial and viral organisms often generates clonal interference, a mode of competition between genetic clades within a population. Here we show how interference impacts systems biology by constraining genetic and phenotypic complexity. Our analysis uses biophysically grounded evolutionary models for molecular phenotypes, such as fold stability and enzymatic activity of genes. We find a generic mode of phenotypic interference that couples the function of individual genes and the population's global evolutionary dynamics. Biological implications of phenotypic interference include rapid collateral system degradation in adaptation experiments and long-term selection against genome complexity: each additional gene carries a cost proportional to the total number of genes. Recombination above a threshold rate can eliminate this cost, which establishes a universal, biophysically grounded scenario for the evolution of sex. In a broader context, our analysis suggests that the systems biology of microbes is strongly intertwined with their mode of evolution.