Summary: Researchers have developed a novel antibody strategy to prevent the association between a harmless protein and a disease mediator that could lead to sepsis, and ultimately death. The findings could help to prevent sepsis induced by COVID-19 infections.
Source: Feinstein Institute For Medical Research
Sepsis is a life-threatening illness caused by the human body’s immune response to infection, however if the body overreacts it can lead to death. Nearly 270,000 deaths occur in the United States annually related to sepsis.
The Feinstein Institutes for Medical Research scientists have discovered the development of novel antibody strategy to effectively prevent the association between a harmless protein and a disease mediator that could lead to sepsis death. The research, led by Haichao Wang, Ph.D., professor in the Institute of Molecular Medicine at Feinstein, published today in the journal Science Translational Medicine.
In 1999, Feinstein Institutes’ researchers discovered an important mediator of lethal sepsis termed as the “high mobility group box 1” (HMGB1) protein. Investigators then began to study another protein called “tetranectin” (TN) that turns HMGB1 into a killer of the body’s immune cells. This transformation induces cell death (pyroptosis) and immunosuppression, impairing the body’s ability to eradicate microbial infections and leads to death.
Now, Feinstein Institutes’ researchers uncovered and confirmed the TN protein’s role in capturing HMGB1 and exacerbating immune cell death. With that discovery, they developed a panel of TN-specific monoclonal antibodies that prevent this harmful TN/HMGB1 interaction, reversing sepsis-induced immunosuppression and fatality.
“We were able to identify and observe this unique interaction between two proteins that ultimately lead to the body’s innate immune cell depletion and lethal consequences,” said Dr. Wang. “By developing protective antibodies, we hope to commercialize and further assess their therapeutic potential in fighting sepsis.”
The research is particularly timely, as the development of these novel antibodies could be used to prevent sepsis induced by COVID-19, commonly known as the coronavirus, and other lethal pathogens.
“Sepsis is the leading cause of death in hospitals and Dr. Wang’s research is a huge step in stopping this escalating and urgent crisis,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes. “His work is a new path for developing possible cures for this complex condition.”
About this coronavirus research article
Source: Feinstein Institute For Medical Research Media Contacts: Matthew Libassi – Feinstein Institute For Medical Research Image Source: The image is credited to W. Chen et al., Science Translational Medicine.
Identification of tetranectin-targeting monoclonal antibodies to treat potentially lethal sepsis
For the clinical management of sepsis, antibody-based strategies have only been attempted to antagonize proinflammatory cytokines but not yet been tried to target harmless proteins that may interact with these pathogenic mediators. Here, we report an antibody strategy to intervene in the harmful interaction between tetranectin (TN) and a late-acting sepsis mediator, high-mobility group box 1 (HMGB1), in preclinical settings. We found that TN could bind HMGB1 to reciprocally enhance their endocytosis, thereby inducing macrophage pyroptosis and consequent release of lactate dehydrogenase and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain. The genetic depletion of TN expression or supplementation of exogenous TN protein at subphysiological doses distinctly affected the outcomes of potentially lethal sepsis, revealing a previously underappreciated beneficial role of TN in sepsis. Furthermore, the administration of domain-specific polyclonal and monoclonal antibodies effectively inhibited TN/HMGB1 interaction and endocytosis and attenuated the sepsis-induced TN depletion and tissue injury, thereby rescuing animals from lethal sepsis. Our findings point to a possibility of developing antibody strategies to prevent harmful interactions between harmless proteins and pathogenic mediators of human diseases.