A humanized monoclonal antibody targeting human ENPP1, an ectonucleotidase expressed in the diseased human kidney, enhances tubular proliferation and kidney repair and is safe in non-human primates

In animals that express human ENPP1 and exhibit clearance kinetics of immunoglobulins similar to those in humans, a single dose of the monoclonal was sufficient to rescue kidney function after an acute insult. Metabolic profiling demonstrated that antibody mediated ENPP1 inhibition led to beneficial effects on nucleotide metabolism and cellular energetics enabling proliferation and rescuing cell cycle arrest. Single cell transcriptomics and pulse chase labeling demonstrated that hENPP1mAb promotes tubular repair by expanding regenerative tubular cell subsets and reducing populations associated with failed repair.

In a multi dose GLP (good laboratory practice) compliant study, the humanized monoclonal antibody was found to be non-toxic and highly tolerated when administered to non-human primates at high doses. Taken together, our findings identify ENPP1 as a central regulator of epithelial injury and metabolic control after acute kidney injury and provide proof of concept of an engineered humanized monoclonal antibody targeting human ENPP1, as a potential therapeutic agent for enhancing human kidney repair.