Designing a new bi-specific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 via in silico studies for the treatment of Rheumatoid arthritis

Abstract

Background: Rheumatoid arthritis disease is a chronic autoimmune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. 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 able to clinically produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bi-specific 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 bi-specific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders and then 50 ns molecular dynamics simulation was performed for each one and thereafter structural properties were exploited. Results: MD simulation results indicate that the domains' order strongly affects tandem single-chain variable fragment properties and in overall, the fragment VLIL23+Linker+VHIL23+linker+VLTNF+Linker+VHTNF +His6 (VL is variable light and VH is variable heavy fragments and His6 is six histidine) not only separated antibody domains but also had better stability and solvation energy. Conclusions: Hence, this structure can be considered as a potential drug for rheumatoid arthritis. It is hoped that this research could shed a light for the treatment of Rheumatoid arthritis disease.