we engineered a long-acting bioavailable enzyme biologic with dual DNASE1 and DNASE1L3 activity and tested the biologic in murine genetic and non-genetic models of lupus and acute autoinflammatory disease
A defining feature of lupus is the loss of tolerance to self-DNA, and extracellular chromatin extruded by neutrophils, called NETs, have been proposed as a putative antigenic driver of lupus autoimmunity. Although defective DNA and/or chromatin clearance in the pathogenesis of Lupus has been discussed for decades, there remains no consensus regarding its role in the development and disease progression of lupus. To investigate the role of NET clearance in the pathogenesis of lupus we engineered a long-acting bioavailable enzyme biologic with dual DNASE1 and DNASE1L3 activity and tested the biologic in murine genetic and non-genetic models of lupus and acute autoinflammatory disease. We found that the enzyme biologic prevented the development of autoimmunity and death in a genetic model of lupus, and rescued animals from death in the non-genetic acute autoinflammatory models. Our results support the hypothesis that NETs are antigenic drivers of lupus autoimmunity and suggests that morbidity and mortality in immune and autoinflammatory disorders may be ameliorated by their efficient clearance from the blood