Abstract
Myocardial infarction (MI) results in aberrant cardiac metabolism, but no therapeutics have been designed to target cardiac metabolism to enhance heart repair. We engineer a humanized monoclonal antibody against the ectonucleotidase ENPP1 (hENPP1mAb) that targets metabolic crosstalk in the infarcted heart. In mice expressing human ENPP1, systemic administration of hENPP1mAb metabolically reprograms myocytes and non-myocytes and leads to a significant rescue of post-MI heart dysfunction. Using metabolomics, single-nuclear transcriptomics, and cellular respiration studies, we show that the administration of the hENPP1mAb induces organ-wide metabolic and transcriptional reprogramming of the heart that enhances myocyte cellular respiration and decreases cell death and fibrosis in the infarcted heart. Biodistribution and safety studies showed specific organ-wide distribution with the antibody being well tolerated. In humanized animals, with drug clearance kinetics similar to humans, we demonstrate that a single "shot" of the hENPP1mAb after MI is sufficient to rescue cardiac dysfunction.