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Topical interleukin (IL)-1 receptor (R)1 blockade is therapeutically active in reducing signs and symptoms of dry eye disease. Herein, we describe in vitro and in vivo nonclinical Investigational New Drug (IND)-enabling studies of EBI-005, a novel protein chimera of IL-1β and IL-1 receptor antagonist (IL-1Ra or anakinra) that potently binds IL-1R1 and blocks signaling. These studies provide an assessment of receptor affinity, drug bioavailability, immunogenic response, safety, and tolerability in mice and rabbits.In vitro and in silico along with Good Laboratory Practices (GLP) and non-GLP in vivo studies in mice and rabbits assessed the topical ocular and systemic immunogenicity and toxicology of EBI-005. Animals were treated with EBI-005 once daily subcutaneously or four times daily by topical ocular administration for up to 6 weeks (with 2-week recovery phase).EBI-005 has 500 times higher affinity than anakinra to IL-1R1. Predictive immunogenicity testing suggested that EBI-005 is not more immunogenic. Systemic bioavailability of EBI-005 is low (1.4% in mice and 0.2% in rabbits) after topical ocular administration. EBI-005 penetrated into the anterior ocular tissues within 15 min of topical ocular administration. However, it is low or undetectable after 4 hr and does not form a depot after repeated topical ocular administration. EBI-005 was safe and well tolerated, and exposure to drug was maintained despite an antidrug antibody response after systemic administration, based on IND-enabling toxicology and safety pharmacology studies.Ocular doses of EBI-005 at 50 mg/mL in mice and rabbits totaling 0.15 mg/eye in mice and 1.5 mg/eye in rabbits, administered 4 times daily, did not produce adverse effects, and demonstrated excellent bioavailability in target tissues with low systemic exposure. In addition, immunogenic response to the drug did not cause adverse effects or diminish the drug's activity in most cases. The results support drug administration of the highest anticipated human clinical study dose of a 20 mg/mL solution (40 μL 3 times daily in each eye).