Targeting a ectonucleotidase in the heart with a monoclonal antibody to prevent post-infarct heart failure

用单克隆抗体靶向心脏中的核酸外切酶以预防梗死后心力衰竭

基本信息

批准号：
10711469
负责人：
Arjun Deb
金额：
$ 74.98万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-14 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711469
关键词：
Acute Acute myocardial infarction Adenine Adenosine Adrenergic beta-Antagonists Affect Aldosterone Aldosterone Antagonists Anabolism Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensins Animals Apoptosis Apoptotic Attenuated Biodistribution Biological Biological Response Modifier Therapy Biotechnology CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiovascular system Catalytic Domain Cell Cycle Cell Death Cell Death Induction Cell Proliferation Cells Chronic Cicatrix Clinical Collaborations Computational Biology DNA Damage Data Development Diagnosis Dilatation - action Dose Drug Kinetics Endothelial Cells Engineering Enzymes Fibroblasts Fibrosis Functional disorder Future Generations Genetic Genetic Transcription Genetically Engineered Mouse Goals Half-Life Heart Heart Injuries Heart failure Human Impairment Infarction Inflammation Inflammatory Integral Membrane Protein Investments Journals Macrophage Medical Metabolic Metabolism Modeling Molecular Monoclonal Antibodies Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Necrosis Nuclear Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphorylases Physiological Physiology Prevention Proteins Publishing Purine Nucleosides Purines Pyrimidine Role Signal Transduction Survival Rate Technology Testing Therapeutic Therapeutic Uses Time Tissue-Specific Gene Expression Tissues Toxic effect Transgenes United States Ventricular Ventricular Remodeling Western World antagonist antibody engineering base cardiac repair cardiovascular pharmacology clinical candidate clinical investigation ecto-nucleotidase efficacy study extracellular gain of function healing heart function hemodynamics humanized monoclonal antibodies humanized mouse insight ischemic injury loss of function metabolomics mouse model multidisciplinary novel pharmacologic phosphoric diester hydrolase plasma cell membrane glycoprotein PC-1 porcine model preclinical study preservation prevent pyrophosphatase repaired response response to injury safety study treatment strategy wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT The mammalian heart possesses a poor ability to regenerate after myocardial infarction and heals via a fibrotic repair response. Scar tissue increases the hemodynamic burden on the remaining cardiac muscle and over time, the ventricle fails leading to the development of heart failure. Myocardial infarction contributes to almost 40-70% of all cases of heart failure and 700,000 patients are annually diagnosed with heart failure in the United States alone. The main thrust of cardiovascular pharmacology for the treatment /prevention of heart failure after heart attacks has centered on chronic antagonism of the sympatho-adrenal-angiotensin- aldosterone axis (Beta blockers, ACE inhibitors, Angiotensin receptor blockers and aldosterone antagonists) but despite available pharmacological therapies, the 5 year survival rate of heart failure is less than 50%. There thus exists an immense unmet need to identify novel pharmacological strategies for the treatment and prevention of heart failure. We have recently demonstrated the role of a specific ectonucleotidase, ENPP1 (ectonucleotide pyrophosphatase/ phosphodiesterase 1) in cardiac repair following myocardial infarction. ENPP1 is induced by orders of magnitude after myocardial infarction and show that hydrolytic products generated by ectonucleotidase activity contribute to inflammation and impair the cardiac injury response. Using genetic loss of function approaches, we showed that inhibition of ENPP1 in the infarcted heart leads to decreased non- myocyte cell death, decreased inflammation and significantly superior post infarct cardiac function. Considering these observations, in collaboration with an antibody engineering biotech company, we in this proposal have engineered a humanized monoclonal antibody targeting ENPP1 as a therapeutic biologic to treat post infarct decline in cardiac function. We provide proof of concept efficacy studies demonstrating the ability of the administered clinical candidate to modulate inflammation in the infarcted heart and lead to significantly better preservation of post infarct function and decreased post infarct ventricular remodeling. Further development of the monoclonal antibody combined with definitive preclinical studies in humanized mice models as well as large animal infarct models forms the substance of the proposal. Using a variety of “omics” approaches and genetically engineered mice, we will also interrogate in depth the downstream pathways that are affected by the ENPP1mAb to exert salutary effects on cardiac repair and post infarct heart function. If our studies are successful, the proposal will directly lead to the identification of a clinical monoclonal antibody candidate to attenuate post infarct cardiac remodeling and dysfunction.

项目摘要/摘要哺乳动物的心脏在心肌梗塞后具有较差的再生能力，并通过纤维化治愈维修响应。疤痕组织会增加剩余的心肌的血流动力学燃烧时间，通风失败导致心力衰竭的发展。心肌梗塞几乎有助于在所有心力衰竭病例中，有40-70％的患者每年被诊断出患有70万名患者仅美国。心血管药理学治疗 /预防心脏的主要推力心脏病发作后的失败集中于交感 - 肾上腺肾上腺血管紧张素的慢性拮抗作用 - 醛固酮轴（β受体阻滞剂，ACE抑制剂，血管紧张素受体阻滞剂和醛固酮拮抗剂）但是所需的可用药物疗法，心力衰竭的5年生存率小于50％。因此，存在巨大的未满足的需求，以确定治疗的新型药物策略和预防心力衰竭。我们最近证明了特定的Eton核苷酸ENPP1（Ecton核苷酸）的作用心肌梗塞后心脏修复中的焦磷酸酶/磷酸二酯酶1）。 ENPP1由心肌梗死后的数量级，并表明由依顿核苷酸酶活性有助于炎症并损害心脏损伤反应。使用遗传损失在功能方法中，我们表明，在梗塞心脏中抑制ENPP1导致非 - 心肌细胞死亡，感染降低和梗塞后心脏功能明显更高。考虑到这些观察结果，与抗体工程生物技术公司合作，我们在此中提案已经设计了一种人源化的单克隆抗体，将ENPP1作为一种治疗生物学治疗心脏功能梗塞后下降。我们提供了概念有效性的证明研究证明管理的临床候选者调节梗塞心脏感染的能力并导致明显更好地保留了梗塞后功能，并改善了梗塞后心室重塑。单克隆抗体的进一步发展与人性化的确定临床前研究结合小鼠模型以及大型动物梗塞模型构成了该提案的实质。使用各种 “ OMICS”方法和一般设计的小鼠，我们还将深入审问下游受ENPP1MAB影响的途径对心脏修复和梗塞心脏发挥有益的影响功能。如果我们的研究成功，该提案将直接导致临床单克隆的识别抗体候选者可减弱梗塞后心脏重塑和功能障碍的抗体。