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

Shen Li; Bo Tao; Jijun Wan; Enca Montecino-Rodriguez; Ping Wang; Feiyang Ma; Baiming Sun; Yiqian Gu; Sivakumar Ramadoss; Lianjiu Su; Qihao Sun; Johanna Ten Hoeve; Linsey Stiles; Jeffrey Collins; R Michael van Dam; Mikayla Tamboline; Richard Taschereau; Orian Shirihai; Douglas B Kitchen; Matteo Pellegrini; Thomas Graeber; Kenneth Dorshkind; Shili Xu; Arjun Deb

doi:10.1016/j.xcrm.2024.101795

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.

Authors

Shen Li¹, Bo Tao¹, Jijun Wan¹, Enca Montecino-Rodriguez², Ping Wang¹, Feiyang Ma³, Baiming Sun¹, Yiqian Gu⁴, Sivakumar Ramadoss¹, Lianjiu Su¹, Qihao Sun¹, Johanna Ten Hoeve⁵, Linsey Stiles⁶, Jeffrey Collins⁷, R Michael van Dam⁷, Mikayla Tamboline⁷, Richard Taschereau⁷, Orian Shirihai⁶, Douglas B Kitchen⁸, Matteo Pellegrini⁴, Thomas Graeber⁵, Kenneth Dorshkind², Shili Xu⁹, Arjun Deb¹⁰

Affiliations

¹ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
³ Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁴ Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA, USA; Crump Institute of Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA; Crump Institute of Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Discovery Services, Curia Global, Inc., Albany, NY 12212, USA.
⁹ California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA; Crump Institute of Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: adeb@mednet.ucla.edu.

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

Abstract

MeSH terms

Substances

Grants and funding