An innovative immunotherapeutic strategy for rheumatoid arthritis: selectively suppressing angiogenesis and osteoclast differentiation by fully human antibody targeting thymocyte antigen-1

Abstract

Abstract Background: Thymocyte antigen-1 (THY-1) is a potential therapeutic target for rheumatoid arthritis (RA) treatment, and THY-1 positive fibroblast-like synoviocytes (FLS) are enriched in the synovium of RA patients and participate in angiogenesis to accelerate rheumatoid arthritis development. In this study, we screened a full human antibody targeting THY-1 and exploring its anti-RA activity and mechanism. Methods: We screened antibody targeting THY-1 (i.e. THY-1 Ab), an antagonistic antibody from human ScFv phage antibody library, by using THY-1 as a target. After proving its binding ability with surface plasmon resonance (SPR), we explored its effect on RA based on FLS transcriptomic analysis and bioinformatics analysis tips treated with THY-1 Ab. Both in vivo and in vitro experiments have proved its effectiveness in the treatment of rheumatoid arthritis. What’s up, we clarified the mechanism of action of the scFv antibody. Results:THY-1 Ab could not only bind to human THY-1 extracellular domains, but also combine to Murine THY-1. In addition, THY-1 Ab restrained the proliferation and secretion of the proinflammatory factors. THY-1 Ab restrained angiogenesis by inhibiting VEGF expression in RA FLS, and the THY-1 Ab and RA FLS combination can effectively inhibit the differentiation of osteoclasts, which down-regulated the expression of JUNB via hsa_circ_0094342—miRNA-155-5P—SPI1 axis, thus regulating AP-1 to suppress angiogenesis and osteoclast differentiation. In Collagen induced arthritis (CIA), disease progression was effectively alleviated by THY-1 Ab. Conclusions: These findings support that THY-1 Ab is a potential drug for the rheumatoid arthritis treatment.