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ENPP1 blockade with a humanized monoclonal antibody enhances renal repair after acute kidney injury
Lianjiu Su1, Qihao Sun1, Ziheng Zhou1
1Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Abstract:
The kidney possesses a poor ability to robustly regenerate and repair after acute injury. We show 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 mice enhanced renal repair. A humanized monoclonal antibody, targeting human ENPP1 (hENPP1mAb), when administered in humanized mice, led to tubular cell proliferation, enhanced renal glomerular filtration rate, decreased fibrosis, and rescued renal function after kidney injury. hENPP1mAb augmented nucleotide metabolism and cellular energetics, enabling proliferation and rescuing cell cycle arrest. Single-cell transcriptomics demonstrated expanded signatures of effective repair with hENPP1mAb. In a good laboratory practice (GLP)-compliant dose escalation study, hENPP1mAb was found to be non-toxic and highly tolerated in non-human primates. Our findings identify ENPP1 as a central regulator of acute kidney injury and demonstrate the therapeutic benefit of targeting ENPP1 ectonucleotidase activity with a humanized monoclonal antibody.
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