一种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功能。
A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction.
机构信息
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.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
出版信息
Cell Rep Med. 2024 Nov 19;5(11):101795. doi: 10.1016/j.xcrm.2024.101795. Epub 2024 Oct 24.
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.
心肌梗死（MI）导致心脏代谢异常，但目前尚无针对心脏代谢的治疗方法来增强心脏修复。我们设计了一种针对外核苷酸酶 ENPP1 的人源化单克隆抗体（hENPP1mAb），以靶向梗死心脏中的代谢串扰。在表达人 ENPP1 的小鼠中，全身性给予 hENPP1mAb 可使心肌细胞和非心肌细胞代谢重编程，并显著挽救 MI 后的心功能障碍。通过代谢组学、单核转录组学和细胞呼吸研究，我们表明 hENPP1mAb 的给药诱导心脏的全器官代谢和转录重编程，从而增强心肌细胞的细胞呼吸，并减少梗死心脏中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，且具有良好的耐受性。在具有与人相似的药物清除动力学的人源化动物中，我们证明 MI 后单次“注射”hENPP1mAb 即可挽救心功能障碍。
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