Efficacy of novel bispecific antibody targeting TNF-α/CXCL10 in the treatment of experimental arthritis

This study was aimed at generating and investigating the efficacy of a novel monoclonal bispecific antibody (BsAb) for the combined inhibition of tumor necrosis factor-alpha (TNF-alpha) and CXCL10 as a treatment option for rheumatoid arthritis (RA). A novel BsAb targeting TNF-alpha and CXCL10 was generated by conjugating a single-chain variable fragment (scFv) of the anti-CXCL10 monoclonal antibody to the Fc region of adalimumab (ADA). The effects of the BsAb on the inflammatory response in the in vitro and in vivo development of arthritis and joint destruction were evaluated in human TNF transgenic (hTNF-Tg) mice, and K/BxN serum transfer arthritis models. The BsAb inhibited CXCL10-mediated CD8(+) T cell migration. The binding affinity of the BsAb to TNF-alpha was comparable to that of ADA and suppressed TNF-alpha induced cell death and inhibited TNF-alpha induced ICAM-1 and VCAM-1 in RA fibroblast-like synoviocytes (FLSs). The BsAb decreased the expression of TNFSF11 and the production of IL-6 in RA-FLS cells stimulated with TNF-alpha and CXCL10. Treatment with the BsAb attenuated the development of arthritis in hTNF-Tg mice and suppressed LPS-induced bone erosion. In the K/BxN serum transfer model, BsAb effectively attenuated ankle swelling, synovial inflammation, cartilage damage, and bone destruction, reducing the activation of osteoclasts. The additional neutralization of TNF-alpha and CXCL10 from treatment with the novel BsAb was more effective than TNF-alpha inhibition alone in the in vitro and in vivo models of RA. Thus, the BsAb, targeting both TNF-alpha and CXCL10, may provide a new therapeutic opportunity for RA patients who fail to respond to the blockade of a single cytokine.

Automated summary

The study generated a novel BsAb targeting both TNF-alpha and CXCL10, showing efficacy in inhibiting inflammation and bone destruction in RA models, suggesting a new therapeutic opportunity for RA patients who do not respond to single cytokine blockade.