Feinstein Institutes unveils peptide therapy for sepsis and rheumatoid arthritis

Scientists at Northwell Health's Feinstein Institutes for Medical Research have unveiled a novel drug discovery strategy that transforms a previously identified "detrimental" immune element into a potent therapeutic for both sepsis and rheumatoid arthritis (RA). The research, published today in Military Medical Research and led by Haichao Wang, PhD, professor in the Institute of Translational Research at the Feinstein Institutes, demonstrates that a peptide called P2-1, derived from an antibody epitope, effectively targets a critical inflammatory pathway common to both serious and potentially life-threatening conditions.

Sepsis and RA are two distinct, but related inflammatory conditions commonly driven by the body's dysregulated, overactive immune responses and excessive cytokine/chemokine production. Sepsis, a life-threatening condition where the body's dysregulated response to infection damages its own tissues, accounts for nearly 20 percent of global deaths. Similarly, RA is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Despite extensive research, effective therapies for sepsis remain elusive, and existing RA treatments have limited efficacy and significant side effects.

Challenging conventional wisdom, the researchers pursued a counterintuitive hypothesis: that a specific epitope – the part of an antigen that the host's immune system sees as foreign, thereby prompting an immune and inflammatory response – derived from an anti-tetranectin antibody previously linked to worsening sepsis outcomes, could be reengineered into a targeted therapeutic for both conditions.

The research team's new strategy is based on what they learned from anti-TNF drugs. These are powerful medicines that block the activities of certain inflammatory proteins – what often cause painful swelling and inflammation in the body. While anti-TNF drugs don't work for severe blood infections like sepsis, they are a primary treatment for RA and ultimately help by changing how the disease causes inflammation, whether it's all over the body or just in specific spots.

The team discovered that a specific epitope can be developed to create a treatment that precisely targets only the bad, overactive inflammatory pathways, while leaving the body's helpful immune signals alone. This new treatment is "activated by disease," meaning it only starts working where the problem is. This characteristic makes it much safer than other medicines that broadly weaken the body's entire immune system.

"Despite the significant challenges in translating sepsis research, our motivation is energized by its proven potential to drive therapeutic options for other inflammatory disorders like RA," said the lead researcher. "This work is the culmination of over two decades of collaborative research, aiming to translate fundamental scientific insights into impactful clinical applications for these diseases, and others."

The president and CEO of the Feinstein Institutes and co-author of the paper noted that for decades the lead researcher has been a leader in identifying molecular mediators of sepsis and systemic inflammation. "Historically, early insights into sepsis have fostered the development of new therapies for inflammation, something now that this new work may well accomplish."

Over the past decade, the research team was each awarded the Scientific Achievement Award by the Shock Society, a leading organization of basic science and medical professionals dedicated to advancing the understanding of trauma, shock and sepsis.