A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction

Cell Rep Med. 2024 Nov 19;5(11):101795. doi: 10.1016/j.xcrm.2024.101795. Epub 2024 Oct 24.

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized* / pharmacology
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Heart / drug effects
  • Heart / physiopathology
  • Humans
  • Mice
  • Myocardial Infarction* / drug therapy
  • Myocardial Infarction* / metabolism
  • Myocardial Infarction* / pathology
  • Myocardium* / metabolism
  • Myocardium* / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Phosphoric Diester Hydrolases* / metabolism
  • Pyrophosphatases* / genetics
  • Pyrophosphatases* / metabolism

Substances

  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases
  • Antibodies, Monoclonal, Humanized
  • Phosphoric Diester Hydrolases