Featured Publication in Focus: Additive Efficacy of a Bispecific Anti–TNF/IL-6 Nanobody Compound in Translational Models of Rheumatoid Arthritis

Authors:

Nadine Biesemann, Daniel Margerie, Chrisitan Asbrand, Markus Rehberg, Virginia Savova, Inoncent Agueusop, Daniel Klemmer, Danping Ding-Pfennigdorff, Uwe Schwahn, Markus Dudek, Karen Heyninck, Evelyn De Tavernier, Sigrid Cornelis, Markus Kohlmann, Frank O. Nestle, Matthias Herrmann

Science Translational Medicine. 2023 February 1.

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Product referenced:

Collagen Type II, Chicken, Lyophilized

Catalogue # 804002-lyo

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ABSTRACT

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 (T_H17) 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.

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DOI: 10.1126/scitranslmed.abq4419