Using a recombinant single chain antibody for targeting liver myofibroblasts with anti-fibrogenic therapeutics

Abstract 

Chronic liver disease results in a liver scarring response termed fibrosis. Excessive scarring leads to cirrhosis which is associated with high morbidity and mortality. The only treatment for liver cirrhosis is liver transplantation, therefore much attention has been directed toward therapies that will slow or reverse fibrosis. Although anti-fibrogenic therapeutics have been shown to be effective in experimental animal models, licensed therapies have yet to emerge. A potential problem for any anti-fibrogenic therapy in the liver is the existence of the body’s major drug metabolising cell (the hepatocyte) adjacent to the primary fibrosis-causing cell, the myofibroblast. A human recombinant single chain antibody that binds to the surface of myofibroblasts was therefore developed. This antibody bound specifically to myofibroblasts in fibrotic mouse livers. When conjugated with a compound that stimulates myofibroblast apoptosis, the antibody directed the specific apoptosis of myofibroblasts with greater specificity and efficacy than the free compound. The antibody also reduced the side-effect of liver macrophage apoptosis and – in contrast to the free compound – reversed fibrosis in the sustained injury model used. These data suggest that specifically stimulating the apoptosis of liver myofibroblasts using a targeting antibody has potential in the treatment of liver fibrosis.

Keywords: C1-3, Gliotoxin, Hepatic stellate cell, Fibrosis, Kupffer cell, Matrix metalloproteinase 13