Controlling NETosis to Treat Diabetic Wounds.

Title: Controlling NETosis to Treat Diabetic Wounds. Project Summary This Phase 1 STTR proposal is focused on establishing proof-of-concept studies aimed at developing a novel humanized monoclonal antibody for the treatment of diabetic wounds. NETosis is a unique form of cell death characterized by neutrophils releasing net-like structures known as "neutrophil extracellular traps (NETs)" to combat bacterial pathogens. Initially lauded for its role in innate immunity, emerging evidence suggests the adverse effects of excessive NETosis in both infectious and non-infectious diseases. Diabetic individuals manifest a notable elevation in NETs-releasing products in their bloodstream, and uncontrolled NETosis has been linked to impaired wound healing in diabetes and increased infection susceptibility. Citrullination of histone H3 (CitH3) plays a pivotal role in initiating NETs-induced immune cell death and tissue damage. Elevated CitH3 has been identified as a risk factor for wound healing impairment and amputation in patients with diabetic foot ulcer. To translate our basic findings on CitH3 into practical applications for humans, we have recently developed a humanized anti-CitH3 monoclonal antibody (hCitH3-mAb). We have completed developability studies and established a protocol for scaled-up production and purification of hCitH3-mAb, demonstrating superior binding capabilities to CitH3 surpassing commercially available antibodies. In vivo studies have shown that hCitH3-mAb improves survival in septic shock mouse models and enhances wound healing in diabetic mice. Our proposal aims to formulate a topical delivery system for hCitH3-mAb, enabling sustained release for the treatment of diabetic ulcers. Following this, we will conduct proof-of-concept studies utilizing hCitH3-mAb to treat diabetic wounds in animal models. The successful completion of these studies brings us one step closer to submitting an IND application to the FDA, potentially revolutionizing the treatment of diabetic ulcers.