Fc-enhanced anti-CCR6 antibody elicits Robust Therapeutic Effects Across Multiple Autoimmune Diseases

Md Jahangir Alam¹Yu-Anne Yap¹Caroline Ang¹Liang Xie¹Hillary L. Shane²Charles R. Mackay¹Remy Robert^1*

• ¹Biomedicine Discovery Institute, Faculty of Medicine, Nursing & Health Sciences, Monash University, Clayton, Australia
• ²Dragonfly Therapeutics Inc, Waltham, United States

Activation of the chemokine receptor CCR6 orchestrates the trafficking of IL-17-producing pathogenic immune cells to the sites of inflammation, thus contributing to the development of numerous inflammatory and autoimmune diseases. As such, CCR6 has emerged as a promising therapeutic target for treating Th17-mediated inflammatory disorders. In this study, we employed a targeted strategy, which we term 'immunological surgery', using an Fc-engineered anti-human CCR6 monoclonal antibody (αhCCR6 DLE-mut mAb) designed to engage effector mechanisms against CCR6⁺ immune cells, and evaluated the therapeutic efficacy of this approach in preclinical mouse models of representative autoimmune conditions, including scleroderma, psoriasis and rheumatoid arthritis. Selective targeting of CCR6+ cells with αhCCR6 DLE-mut mAb exhibited remarkable efficacy in reducing established inflammation across all disease models. In a bleomycin-induced scleroderma model, ahCCR6 mAb treatment markedly reduced dermal thickening and attenuated scleroderma-associated lung inflammation and fibrosis. In the imiquimod-induced psoriasis model, administration of ahCCR6 mAb led to significant reductions in skin thickening, epidermal hyperplasia, and dermal immune cell infiltration. Similarly, in the collagen-induced arthritis (CIA) model, ahCCR6 mAb treatment significantly alleviated all signs of joint inflammation. Thus, our findings demonstrated that CCR6-targeted therapy could be a promising and effective approach for the treatment of Th17-mediated inflammatory disorders. Moreover, we believe this approach may overcome the challenge of chemokine receptor redundancy by leveraging receptor-specific signatures to eliminate pathogenic leukocyte subsets with high precision.