University of Virginia Tries CitH3-Targeting Against Sepsis-Induced ARDS

Researchers at the University of Virginia (UVA) have initiated a first-in-human clinical trial of hCitH3-mAb, an antibody designed to interrupt a key molecular mechanism driving sepsis-induced acute respiratory distress syndrome (ARDS). The investigational therapy targets CitH3, a molecule identified by UVA researchers as a central driver of immune system overreaction that can transform a protective immune response into a life-threatening inflammatory cascade. By neutralizing CitH3, the antibody aims to prevent the catastrophic organ damage that makes sepsis and ARDS leading causes of death in intensive care units.

The trial will proceed in two phases: a Phase 1a safety study in healthy volunteers, followed by a Phase 2a investigation in patients with sepsis-induced ARDS. Dr. Alpha Fowler from Virginia Commonwealth University will lead the initial safety assessment, with UVA Health’s Dr. Imre Noth co-leading subsequent clinical investigations.

The program is supported by the Virginia Catalyst Program, part of the university’s biotechnology translation efforts. The project represents a collaboration between academic researchers, the UVA spin-off company HTIC, Inc., and manufacturing partner SparX Biopharmaceutical Corp.

Research Context

Citrullinated histone H3 (CitH3) is a post-translationally modified histone protein, generated during neutrophil extracellular trap (NET) formation (NETosis). The rationale for hCitH3-mAb stems from emerging understanding of how extracellular histones, particualrly CitH3, act as a damage-associated molecular pattern (DAMP) that activates inflammatory pathways, induces cell death, and amplifies cytokine release. Elevated CitH3 levels are consistently observed in sepsis, ARDS, ischemia-reperfusion injury, autoimmune diseases (e.g., rheumatoid arthritis, lupus), diabetic wounds, and some cancers.

In terms of sepsis, preclinical studies have demonstrated that CitH3 is implicated in the development of acute lung injury and multi-organ dysfunction. The UVA approach represents a targeted intervention aimed at interrupting this destructive immune cycle at its molecular source.

The sepsis-induced ARDS therapeutic landscape remains largely uncharted. The first-in-class CitH3-targeted monoclonal antibody is Citryll’s CIT-013 (Citryll), designed to both enhance clearance of existing NETs and inhibit formation of new NETs, and in Phase II clinical trials for rheumatoid arthritis and hidradenitis suppurativa.