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

Autor:	Biesemann N; Sanofi R&D, Immunology and Inflammation Therapeutic Area, Type 1/17 Immunology Cluster, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Margerie D; Sanofi R&D, Digital and Data Science, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Asbrand C; Sanofi R&D, Immunology and Inflammation Therapeutic Area, Type 1/17 Immunology Cluster, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Rehberg M; Sanofi R&D, Digital and Data Science, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Savova V; Precision Medicine and Computational Biology, Sanofi R&D, 350 Water St., Cambridge, MA 02141, USA., Agueusop I; Sanofi R&D, Biostatistics and Programming, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Klemmer D; Sanofi R&D, Biostatistics and Programming, Non-Clinical Efficacy and Safety, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Ding-Pfennigdorff D; Sanofi R&D, Immunology and Inflammation Therapeutic Area, Type 1/17 Immunology Cluster, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Schwahn U; Sanofi R&D, Translational Medicine and Early Development, Biomarkers and Clinical Bioanalysis, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Dudek M; Sanofi R&D, Translational Medicine and Early Development, Biomarkers and Clinical Bioanalysis, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Heyninck K; Sanofi R&D, NANOBODY Research Platform, Technologiepark 21, 9052 Zwijnaarde, Belgium., De Tavernier E; Sanofi R&D, NANOBODY Research Platform, Technologiepark 21, 9052 Zwijnaarde, Belgium., Cornelis S; Sanofi R&D, NANOBODY Research Platform, Technologiepark 21, 9052 Zwijnaarde, Belgium., Kohlmann M; Sanofi R&D, Early Clinical Development Therapeutic Area Immunology and Inflammation, Industriepark Hoechst, 65926 Frankfurt am Main, Germany., Nestle FO; Sanofi R&D, 350 Water St., Cambridge, MA 02141, USA., Herrmann M; Sanofi R&D, Immunology and Inflammation Therapeutic Area, Type 1/17 Immunology Cluster, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2023 Feb; Vol. 15 (681), pp. eabq4419. Date of Electronic Publication: 2023 Feb 01.
DOI:	10.1126/scitranslmed.abq4419
Abstrakt:	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 H 17) 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.
Databáze:	MEDLINE
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