Controlling netosis to treat diabetic wounds. - title: controlling netosis to treat diabetic wounds

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Htic, Inc. $310,438 on September 15, 2025, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to establish proof-of-concept studies for a humanized monoclonal antibody (HCITH3-MAB) targeting diabetic wound treatment.

The work focuses on controlling netosis, a form of cell death in which neutrophils release neutrophil extracellular traps (NETs). Uncontrolled netosis impairs wound healing in diabetic patients and increases infection susceptibility. Citrullination of histone H3 (CITH3) initiates NET-induced immune cell death and tissue damage; elevated CITH3 is a risk factor for wound healing impairment and amputation in diabetic foot ulcers. Htic has developed HCITH3-MAB with superior binding capabilities to commercially available antibodies and has demonstrated improved survival in septic shock mouse models and enhanced wound healing in diabetic mice. The Phase 1 STTR proposal will formulate a topical delivery system for HCITH3-MAB enabling sustained release, then conduct proof-of-concept studies in animal models to validate efficacy prior to an IND application submission.

Performance occurs in Charlottesville, Virginia, with a completion date of November 14, 2026. The award is classified as a Project Grant, an assistance type supporting extramural research aimed at improving prevention, diagnosis, and treatment of diabetes and related diseases.

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.