Project Summary Uveitis is a group of diseases characterized by sight-threatening intraocular inflammation and responsible for roughly 5-10% of blindness cases worldwide. Uveitis flare-ups can be caused by either an active infection or, in in the case of non-infectious uveitis (NIU), a dysregulated immune response including altered cytokine expression and processing. Thus, there is an urgent and unmet need for more effective treatments. The standard first line therapies for chronic NIU are corticosteroids delivered either topically, systemically, or locally through intravitreal injections or implants. However, long-term use of these treatments is associated with serious side effects. Alternative anti-inflammatory therapeutics are often used to minimize these side-effects and inhibition of the pro-inflammatory cytokine, TNFα has become a key approach. Systemic delivery of TNFα inhibitors is effective but costly and carries a risk of side-effects from long-term use. Valitor, Inc. is developing protein-polymer therapeutics to overcome the vision-threatening effects of chronic ocular inflammation with substantially fewer systemic side effects by enabling intravitreal delivery of a biologic anti-TNFα therapy. We have conjugated single-domain anti-TNFα antibodies (VHH) to linear chains of the natural biopolymer hyaluronic acid to generate multivalent anti-TNFα conjugates (Anti-TNFα MVP) that are substantially larger than any other drugs currently delivered by intravitreal injection. In our previous studies, we verified that the large sizes of our MVPs are sufficient to substantially reduce their clearance rate out of the vitreous, thereby providing a sustained treatment effect to inhibit intraocular TNFα. Thus, our strategy for sustained anti-TNFα therapy has the potential to improve the long-term efficacy, safety, and cost efficacy of anti-TNFα treatment. The overall objective of this Phase I SBIR project is to verify that our Anti-TNFα MVPs exhibit a rapid onset and durable anti-inflammatory treatment for chronic non-infections uveitis. In Specific Aim #1, we will evaluate the ability of an Anti-TNFα MVP to generate a rapid anti-inflammatory response compared to that of a corticosteroid. In Specific Aim #2, we will verify the anti-inflammatory durability of our Anti-TNFα MVP to that of a clinically available TNFα inhibitor. The results of this project will be used to continue the development of our Anti-TNFα MVP drug product and contribute to a productive pre-IND meeting to confirm the additional testing that required for our IND submission.