Scientists at the University of Virginia School of Medicine and the University of Michigan have developed a monoclonal antibody that could become the first treatment to directly target the immune system dysregulation responsible for sepsis. The humanized antibody showed "transformative potential for combatting life-threatening inflammatory diseases" in initial mouse studies, according to research published in Nature Communications.
Sepsis strikes up to 50 million people worldwide every year, killing approximately 11 million. It represents a leading cause of death in U.S. hospitals, with mortality risk increasing every hour the condition goes untreated. Even with aggressive treatment, up to 40% of patients who reach the most severe stage of sepsis still die.
Targeting Cytokine Storms Without Immune Suppression
The new antibody targets citrullinated histone H3 and aims to prevent the "cytokine storms" that drive sepsis pathology by shutting down the body's hyperactive immune response before organ damage occurs. Unlike existing sepsis treatments, early testing suggests the antibody can achieve this without unwanted side effects such as unintended immune system suppression.
"Our humanized antibody has shown both safety and effectiveness in blocking the cytokine storm and restoring healthy immune function," said Yongqing Li, MD, PhD, of the University of Michigan Medical School. "Beyond treating acute infections, it has the potential to address a spectrum of diseases caused by faulty immune regulation, including autoimmune disorders, cancer, and diabetes."
In the initial studies, the antibody successfully stopped inflammatory cytokines and restored the function of immune cells called macrophages, while protecting against sepsis-induced lung injury. The research team identified changes in macrophages that create harmful "feedback loops" driving the body's uncontrolled inflammatory response, which their antibody interrupts.
Broader Therapeutic Applications
The antibody's versatility extends beyond sepsis treatment. Potential applications include acute respiratory distress syndrome (ARDS), which gained prominence during the COVID-19 pandemic, and ischemia-reperfusion injury—tissue damage that occurs when blood flow is cut off and restored, representing a major challenge in organ transplantation.
"This is the kind of breakthrough that can change the standard of care," said Jianjie Ma, PhD, of UVA's Department of Surgery and UVA Cancer Center. "By combining complementary expertise in basic science, innovation and translational medicine, and by working closely with our industry partners, we've developed a first-in-class antibody with the potential to save countless lives from sepsis and other severe inflammatory diseases."
Integrated Diagnostic Platform
Alongside the therapeutic antibody, the researchers developed a diagnostic platform called PEdELISA that can quantify six cytokines from a single drop of plasma within two hours. This tool may prove valuable for detecting and monitoring sepsis progression.
"Integrating PEdELISA with this first-in-class antibody therapy enables a comprehensive approach to sepsis management, allowing not only earlier and more accurate diagnosis but also continuous, near real-time monitoring of the patient's immune status throughout treatment," said industry partner Guidong Zhu. "This integration could facilitate timely therapeutic adjustments, prevent disease progression and ultimately increase the likelihood of achieving complete resolution."
Clinical Translation
The researchers have received $800,000 from Virginia Catalyst to launch a clinical trial of the antibody at UVA Health and Virginia Commonwealth University. The antibody has been extensively engineered for clinical application and presents significant translational potential when coupled with the PEdELISA diagnostic platform.
"UVA is proud to be part of this groundbreaking discovery," said Melina R. Kibbe, MD, dean of UVA's School of Medicine. "Our leadership is eager to work hand-in-hand with clinicians and industry partners to move this bench discovery into the clinic, where it could make the difference between life and death."
