Development of a humanized anti-fibrin monoclonal antibody for the treatment of neuroinflammatory and retinal diseases

Vascular dysfunction and subsequent innate immune activation are key players of neurodegenerative, retinal, and inflammatory diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), diabetic retinopathy (DR), and age-related macular degeneration (AMD). At sites of vascular damage, conversion of the blood coagulation protein fibrinogen to fibrin exposes a cryptic inflammatory epitope, γ377–395, which can bind CD11b/CD18 and CD11c/CD18 complement receptors on microglia, macrophages, and dendritic cells. Genetic targeting of the fibrin γ377–395 epitope or its pharmacologic inhibition with the mouse monoclonal antibody 5B8 protects from inflammation and neurodegeneration in AD and MS mouse models. Here, we present the development of THN391, a first-in-class humanized antibody, to neutralize fibrin toxicity without adverse anticoagulant effects for the treatment of neurodegenerative, retinal, and inflammatory diseases. THN391 was affinity matured with 100-fold greater affinity than 5B8, engineered to lack Fc effector function, and have improved developability properties for clinical use. THN391 blocks the interaction of fibrin with CD11b/c and does not bind fibrinogen nor interfere with coagulation, consistent with the crystal structure of its binding interface to the γ377–395 epitope. THN391 and its Fc wild-type counterpart THN313 showed preclinical efficacy in experimental autoimmune encephalomyelitis (EAE) mouse models of MS and in a rodent model of retinal disease. Both THN391 and THN313 reduced demyelination, inflammatory foci, and clinical scores in EAE, demonstrating that anti-fibrin γ377-395 antibodies function as pure antagonists, blocking fibrin from activating CD11b/c complement receptors. THN391 was as effective as the standard of care vascular endothelial growth factor (VEGF) antagonists in reducing laser-induced neovascular lesions in a rat model of neovascular macular degeneration. Taken together, these results support the clinical development of THN391 for neurological diseases and ophthalmic indications.