Generation and characterization of QLS22001, a humanized monoclonal antibody that neutralizes IL-17A and IL-17F with an extended half-life.

Abstract

Therapeutic intervention to block IL-17A signaling has proven to be an effective treatment for numerous autoimmune diseases, including psoriasis, psoriatic arthritis, and axial spondylarthritis. Among the IL-17 family members, IL-17F, which shares 55% sequence homology with IL-17A, has been reported to functionally overlap with IL-17A in many inflammatory diseases. In this study, we describe the generation and characterization of QLS22001, a humanized monoclonal IgG1 antibody with an extended half-life and high affinity for both IL-17A and IL-17F. QLS22001 effectively blocks IL-17A and IL-17F mediated signaling pathways both in vitro and in vivo. Briefly, the YTE (M225Y/S254T/T256E) modification was introduced into the Fc fragment of QLS22001 WT Fc to prolong its half-life, and the resulting construct was named QLS22001. Functionally, it significantly inhibits IL-17A- and IL-17F-stimulated signaling in cell-based IL-6 release and reporter assays. The dual neutralization of the endogenous IL-17A and IL-17F produced by Th17 cells, as opposed to the selective blockade of IL-17A alone, results in a greater suppression of inflammatory cytokine secretion, according to in vitro blockade assays. Furthermore, in an in vivo mouse pharmacodynamic study, QLS22001 blocked human IL-17A-induced mouse keratinocyte chemoattractant (KC) release. In cynomolgus monkey pharmacokinetics evaluation, QLS22001 showed linear pharmacokinetic characteristics with a mean half-life of 31.2days, while its parent antibody, QLS22001 WT Fc, had a mean half-life of 17.2days. In addition, QLS22001 does not induce cytokine release in a human whole-blood assay. Collectively, these data provide a comprehensive preclinical characterization of QLS22001 and support its clinical development.