ON104, a novel antibody targeting oxidized Macrophage Migration Inhibitory Factor (oxMIF) shows efficacy in preclinical models of chronic inflammation

Abstract

Abstract Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine, ubiquitously present in various tissues and the circulation of healthy subjects. MIF is a primary counter-actor of glucocorticoids that emerged as a pivotal regulator of chronic inflammation. During inflammation, MIF converts into oxidized (ox)MIF which was described as the pathogenic and druggable isoform of MIF. ON104, a fully human antibody, was engineered to specifically neutralize oxMIF without triggering immune cell effector functions. ON104 was tested in three experimental models of chronic inflammatory diseases (CIDs): Glomerulonephritis (GN) in WKY rats, Collagen-Induced Arthritis (CIA) in DBA/1j mice; and adoptive T-cell transfer colitis in SCID mice. At disease onset, ON104 was administered at different dose levels twice a week for 1, 3, and 8 weeks in GN, CIA, and colitis, respectively. Clinical evaluations, blood and tissue sampling were done for all individual animals. In the GN model, ON104 significantly reduced proteinuria, hematuria, and CD68 +macrophage infiltration within the inflamed kidneys. During CIA, ON104 ameliorated the severity of arthritis as indicated by reduced paw thickness, and decreased disease score. Furthermore, treatment with ON104 substantially attenuated clinical signs of colitis by preventing body weight loss and restoring stool consistency compared to the vehicle-treated controls. Our findings substantiate the role of oxMIF in the pathogenesis of various CIDs. Thus, ON104 has the potential to become a well-tolerated therapeutic antibody for treating patients with CIDs.