Background: Autoimmune disorders affect millions of individuals throughout the world and have complex pathogenic mechanisms. Interleukin-17 (IL-17) and B-cell activating factor (BAFF) emerge as critical players in the intricate landscape of autoimmune disorders, contributing significantly to the dysregulation of the immune system. IL-17, a cytokine produced by various immune cells, plays a central role in mediating inflammatory responses. In autoimmune disorders, overproduction of IL-17 can lead to excessive inflammation, tissue damage, and the initiation or exacerbation of the autoimmune process. On the other hand, BAFF, a protein crucial for B-cell survival and maturation, is implicated in the perpetuation of autoimmune responses by promoting the survival of autoreactive B cells. Together, IL-17 and BAFF create a complex interplay that fuels the chronic inflammation characteristic of autoimmune disorders. Rheumatoid arthritis (RA) presents as a prototypical autoimmune disease, characterized by chronic inflammation, joint pain, and potential disability.

Objectives: To investigate the individual and combinatorial benefit of IL-17A and BAFF blockade in a murine model of rheumatoid arthritis.

Methods: Male DBA/1 mice were intradermally immunized with chicken collagen type II on Day 0 and boosted on Day 22. LSN3043460 (anti-BAFF), LSN3067789 (anti-IL-17A), and/or an isotype-matched control antibody were subcutaneously injected on Days 22, 29, and 36 of the study. Clinical scores (signs of swelling and redness in the front and hind paws) were assessed 3 times a week starting on Day 22 until the end of the study (Day 42). Additionally, serum was collected at the end of the study to confirm target engagement and to assess antibody titers to chicken type II collagen.

Results: Cumulative disease scores were significantly reduced in mice treated with the combination of anti-BAFF and anti-IL-17A compared to the isotype control (p<0.001). Additionally, combination treatment resulted in greater reductions than treatment with either anti-BAFF or anti-IL-17 independently. Histological evaluation of the hind paw revealed significant reductions in inflammation in mice treated with anti-BAFF alone (histological score: 19.45±4.22), anti-IL-17A alone (17.0±5.33), and the combination of anti-BAFF and anti-IL-17A (5.58±3.71) when compared to mice treated with the isotype control (38.85±5.66) (p<0.05 for each comparison). Combined neutralization of BAFF and IL-17 was additionally associated with a significant reduction of anti-collagen antibodies compared to the isotype control (p<0.01).

Conclusion: This study demonstrated that the combined inhibition of IL-17A and BAFF provides the greatest reduction in signs and symptoms of arthritis in a collagen-induced arthritis model. These results suggest that neutralization of both BAFF and IL-17 may provide a significant clinical benefit to those with RA and other autoimmune diseases.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Parisa Faghihi ZuraBio, ZuraBio, Someit Sidhu ZuraBio, ZuraBio, Michael Howell ZuraBio, ZuraBio.