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 [scRNA-seq]

The human kidney possesses a poor ability to robustly regenerate after acute injury and chronic kidney disease affects millions of individuals worldwide. There are no drugs that enhance tissue repair after acute kidney injury. Here, we demonstrate, in a cohort of individuals with kidney disease, that the ectonucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase-1) is robustly expressed in diseased human kidneys and strongly correlates with clinical indices of renal dysfunction. Genetic targeting of ENPP1 in mouse models of kidney disease enhanced renal repair, decreased fibrosis and was associated with significant rescue of post injury kidney function. A humanized monoclonal antibody, targeting the catalytic domain of human ENPP1 when administered to humanized mouse models led to proliferation of tubular cells, enhanced renal glomerular filtration rate, decreased fibrosis and rescued kidney function in multiple pre-clinical models of kidney injury. 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.