1. Discovery and preclinical evaluation of KYS202004A, a novel bispecific fusion protein targeting TNF-α and IL-17A, in autoimmune disease models.
- Author
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Liu Z, Song L, Yang J, Liu H, Zhang Y, Pi X, Yan Y, Chen H, Yu D, Yin C, Liu T, Li X, Zhang C, Li D, Wang Z, and Xiao W
- Subjects
- Animals, Humans, Mice, Chemokine CXCL1 metabolism, Chemokine CXCL1 genetics, HT29 Cells, Autoimmune Diseases drug therapy, Autoimmune Diseases immunology, Mice, Transgenic, Disease Models, Animal, Antibodies, Bispecific therapeutic use, Antibodies, Bispecific pharmacology, Male, Drug Evaluation, Preclinical, Imiquimod, Anti-Inflammatory Agents therapeutic use, Anti-Inflammatory Agents pharmacology, Mice, Inbred DBA, Interleukin-17 metabolism, Tumor Necrosis Factor-alpha metabolism, Psoriasis drug therapy, Psoriasis immunology, Psoriasis chemically induced, Recombinant Fusion Proteins therapeutic use, Recombinant Fusion Proteins pharmacology, Arthritis, Experimental drug therapy, Arthritis, Experimental immunology, Macaca fascicularis
- Abstract
The treatment of autoimmune and inflammatory diseases often requires targeting multiple pathogenic pathways. KYS202004A is a novel bispecific fusion protein designed to antagonize TNF-α and IL-17A, pivotal in the pathophysiology of autoimmune and inflammatory diseases. Our initial efforts focused on screening for optimal structure by analyzing expression levels, purity, and binding capabilities. The binding affinity of KYS202004A to TNF-α and IL-17A was evaluated using SPR. In vitro, we assessed the inhibitory capacity of KYS202004A on cytokine-induced CXCL1 expression in HT29 cells. In vivo, its efficacy was tested using a Collagen-Induced Arthritis (CIA) model in transgenic human-IL-17A mice and an imiquimod-induced psoriasis model in cynomolgus monkeys. KYS202004A demonstrated significant inhibition of IL-17A and TNF-α signaling pathways, outperforming the efficacy of monotherapeutic agents ixekizumab and etanercept in reducing CXCL1 expression in vitro and ameliorating disease markers in vivo. In the CIA model, KYS202004A significantly reduced clinical symptoms, joint destruction, and serum IL-6 concentrations. The psoriasis model revealed that KYS202004A, particularly at a 2 mg/kg dose, was as effective as the combination of ixekizumab and etanercept. This discovery represents a significant advancement in treating autoimmune and inflammatory diseases, offering a dual-targeted therapeutic approach with enhanced efficacy over current monotherapies., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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