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

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-10-17 DOI:10.1016/j.xcrm.2024.101795

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

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引用次数: 0

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.

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针对外核苷酸酶的人源化单克隆抗体可挽救心肌梗死后的心脏代谢和心脏功能。

心肌梗塞（MI）会导致心脏新陈代谢失常，但目前还没有针对心脏新陈代谢的疗法来促进心脏修复。我们设计了一种针对外切核苷酸酶ENPP1的人源化单克隆抗体（hENPP1mAb），它能靶向梗死心脏的代谢串扰。在表达人ENPP1的小鼠体内，全身给药hENPP1mAb可对心肌细胞和非心肌细胞进行代谢重编程，从而显著缓解心肌梗死后的心脏功能障碍。通过代谢组学、单核转录组学和细胞呼吸研究，我们发现服用 hENPP1mAb 能诱导心脏器官的代谢和转录重编程，从而增强心肌细胞的细胞呼吸，减少梗死心脏的细胞死亡和纤维化。生物分布和安全性研究表明，该抗体具有特异性的全器官分布，且耐受性良好。在人源化动物中，药物清除动力学与人类相似，我们证明在心肌梗死后注射一针 hENPP1mAb 就足以挽救心脏功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.