A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction
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.
Authors
- Feiyang Ma (ORCID: https://orcid.org/0000-0002-6260-0787)
- Douglas B. Kitchen (ORCID: https://orcid.org/0000-0001-8988-759X)
- Richard Taschereau (ORCID: https://orcid.org/0000-0002-1035-0421)
- Matteo Pellegrini (ORCID: https://orcid.org/0000-0001-9355-9564)
- Encarnacion Montecino‐Rodriguez (ORCID: https://orcid.org/0000-0002-2826-7503)
- Jun Wan (ORCID: https://orcid.org/0000-0001-7308-0150)
- Thomas G. Graeber (ORCID: https://orcid.org/0000-0001-8574-9181)
- Orian S. Shirihai (ORCID: https://orcid.org/0000-0001-8466-3431)
- Shili Xu (ORCID: https://orcid.org/0000-0002-4933-8673)
- Baiming Sun
- Johanna ten Hoeve (ORCID: https://orcid.org/0000-0003-0226-749X)
- R. Michael van Dam (ORCID: https://orcid.org/0000-0003-2316-0173)
- L. Joseph Su (ORCID: https://orcid.org/0000-0001-6822-6602)
- Mikayla Tamboline (ORCID: https://orcid.org/0000-0002-3675-2904)
- Jeffrey Collins
- Arjun Deb
- Qihao Sun (ORCID: https://orcid.org/0000-0002-6505-7142)
- Kenneth Dorshkind (ORCID: https://orcid.org/0000-0002-9005-631X)
- Linsey Stiles (ORCID: https://orcid.org/0000-0002-1514-458X)
- Ping Wang (ORCID: https://orcid.org/0000-0002-1557-0394)
- Shen Li (ORCID: https://orcid.org/0000-0001-8114-1136)
- Yiqian Gu (ORCID: https://orcid.org/0009-0000-9131-6278)
- Bo Tao (ORCID: https://orcid.org/0000-0002-9215-3877)
- Sivakumar Ramadoss
Institutions
- Northwestern University (US)
- University of California, Los Angeles (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101795
- Citations
- 8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- U.S. Department of Defense
- Foundation for the National Institutes of Health
- California Institute of Regenerative Medicine
- National Institutes of Health