Small molecule interleukin (IL) 17A/A antagonists and antibodies blocking both IL17A/A and IL17A/F demonstrate equivalent degrees of efficacy in preclinical models of skin and joint inflammation

T-helper 17 (Th17) cells produce homodimeric IL17A/A and IL17F/F cytokines as well as the heterodimeric IL17A/F isoform, all having well known roles in defense against extracellular pathogens including fungal infection. Antibodies targeting IL17A (such as secukinumab and ixekizumab) have been approved to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis and are under further investigation as therapies in inflammatory disorders such as hidradenitis suppurativa and giant cell arteritis. Because many patients dislike injections with needles, orally bioavailable small molecule IL17 antagonists are desirable as next-generation drugs as long as they can replicate the degree of efficacy observed with anti-IL17A biologics. We recently described novel small molecules binding as 2 copies to the IL17A/A homodimer with only weak effects on the IL17A/F heterodimer. Because approved antibodies binding IL17A neutralize both IL17A/A and IL17A/F, we assessed whether targeting IL17A/A would be sufficient to bring efficacy comparable to IL17A biologics. In comparison to IL17A/F and IL17F/F, we found that the IL17A/A homodimer is the strongest initiator of signaling and that comparable IL17A/A to IL17A/F ratios are expressed in Th17 cells and in human psoriatic skin tissue. Furthermore, our IL17A/A-specific small molecules block the effects of Th17 cell supernatants on keratinocytes to similar maximal responses as anti-IL17A. Our IL17A/A-selective antagonists deliver comparable efficacy to anti-IL17A biologics in several rodent inflammatory models of psoriasiform dermatitis and arthritis. These results support neutralizing IL17A/A with oral small molecule antagonists is an attractive approach to provide differentiated, next-generation therapies for inflammatory disorders. Significance Statement: This study found that orally active small molecule antagonists of the proinflammatory cytokine IL17A that preferentially bind the IL17A/A form produced equivalent efficacy to monoclonal antibodies that can neutralize both IL17A/A and IL17A/F. This indicates that the IL17A/A homodimer is the dominant isoform driving inflammation in diseases such as psoriasis and that oral inhibitors targeting IL17A/A may be useful next-generation IL17 therapeutics. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.