Designing a new bispecific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 using in silico studies for the treatment of rheumatoid arthritis.

Abstract

Rheumatoid arthritis disease is a chronic auto-immune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. The tumor necrosis factor-α (TNF-α) is a pivotal cytokine that plays an important role in rheumatoid arthritis. The treatments focusing on a single cytokine inhibition are clinically able to produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bispecific tandem single-chain variable fragment was designed in order to suppress both human tumor necrosis factor-α and interleukin-23 (IL23) as a potential therapeutic drug candidate for this disease. To do so, at first, eight bispecific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders by the homology modeling, and then 50ns molecular dynamics simulation was performed for each one and then structural properties were exploited. The MD simulation results indicate the fact that the domains' order strongly affects tandem single-chain variable fragment properties, and in overall, the fragment VLAIL23+Linker+VHAIL23+linker+VLATNF+Linker +VHATNF +His6 (VL and VH are light and heavy chain variable fragments and AIL23 and ATNF are anti-interleukin 23 and anti-tumor necrosis factor-α, respectively, and His6 is the six histidine) not only separated antibody domains accurately but also had better stability and solvation free energy. Therefore, this structure can be considered as an effective potential drug for rheumatoid arthritis. It is expected that the findings of this research could shed a light on the treatment approaches of the rheumatoid arthritis disease.