AD-214 anti CXCR4 i-body-Fc fusion for the treatment of idiopathic pulmonary fibrosis

Abstract Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease characterized by scarring and tissue remodelling. Current treatments have limited efficacy and significant side effects. To address these limitations, we developed AD-214, an anti-CXCR4-Fc-fusion protein comprised of an anti-CXCR4 i-body (AD-114) tethered at its C terminus to constant domains 2 and 3 of the Fc region of a mutated human IgG1 lacking effector function. AD-214 binds with high affinity and specificity to CXCR4, modulates intracellular signaling and inhibits key fibrotic pathways. Using fibrosis models, we demonstrate that AD-214 treatment significantly reduces collagen deposition and lung remodelling and has a unique mode of action. In Phase 1 clinical trials intravenous (IV) infusion of AD-214 led to high and sustained CXCR4 receptor occupancy (RO); however, whether RO and efficacy are causally linked remained to be determined. Herein, we demonstrate that CXCR4 RO by AD-214 inhibits primary human leukocyte migration, a model fibrotic process, and that migration inhibition is achievable at concentrations of AD-214 present in the serum of healthy human volunteers administered AD-214. Taken together, these data provide proof of concept for AD-214 as a novel treatment strategy for IPF, and suggest that clinically feasible dosing regimens may be efficacious.