The Therapeutic Effect of an Anti-TNF-α/HSA/IL-6R Triple-Specific Fusion Protein Under Experimental Septic Conditions

Abstract

Sepsis caused by a dysregulated host response to infection is a life-threatening disease that can lead to organ dysfunction. Due to its unclear and complex mechanism, effective medicine for the treatment of sepsis is urgently required. The extensive release of cytokines and other mediators like TNF-α and interleukin-6 (IL-6) play critical roles in the development of sepsis. The present study aims to evaluate the potential protective effects of an anti-TNF-α/HSA/IL-6R triple-specific fusion protein (TAL-6) under septic experimental conditions. The anti-TNF-α/ HSA/IL-6R triple-specific fusion protein (TAL-6), which links three published single domain antibodies, was designed and constructed in our lab. High purity fusion proteins were obtained with high binding affinity for TNF-α (94.75 pM), human serum albumin (1.83 nM) and IL-6R (2.29 nM). TAL-6 protected mouse fibroblast fibrosarcoma cells (L929) from apoptosis induced by TNF-α, establishing that the expressed fusion proteins can selectively interact with TNF-α in vitro. In vivo, the survival rate of cecal ligation and puncture (CLP) was notably increased in the group with TAL-6 treatment and significantly higher compared with the single-targeted IL-6R and TNF-α fusion protein at the same dose. After treatment with TAL-6, the serum levels of TNF-α, IL-1β, and IL-6 were significantly decreased, and sepsis-induced pathological injuries in the kidney were remarkably attenuated. TAL-6 is therefore a potential candidate for the development of new drugs against sepsis in human.

Management of infected acute necrotizing pancreatitis

“…In infected pancreatic necrosis, proinflammatory factors, mainly TNF-α but also IL-6, IL-8 and monocyte chemotactic protein, activate the body’s defense response to inflammation, causing SIRS, which is called sepsis. If this initially beneficial reaction is not balanced by the compensatory anti-inflammatory response syndrome, then it will become uncontrolled and excessive, which leads to disseminated cell damage causing MODS and ultimately death[ 22 , 26 ]. Thus, the regulation of this balance by the use of antibodies or molecules against the most important inflammatory mediator of the cytokine cascade, TNF-α, would be crucial.…”

“…Thus, the regulation of this balance by the use of antibodies or molecules against the most important inflammatory mediator of the cytokine cascade, TNF-α, would be crucial. The levels of TNF-α were increased within 1-2 h of endotoxin injection in an experimental model[ 26 ].…”