Asprosin-neutralizing antibodies as a treatment for metabolic syndrome.
Asprosin-neutralizing antibodies as a treatment for metabolic syndrome.
复制标题
DOI：
10.7554/elife.63784
复制
发表时间：
2021-04-27
期刊：
影响因子：
7.7
通讯作者：
Chopra AR
中科院分区：
文献类型：
--
作者：
Mishra I;Duerrschmid C;Ku Z;He Y;Xie W;Silva ES;Hoffman J;Xin W;Zhang N;Xu Y;An Z;Chopra AR
最近，我们发现了一种新的生糖和中枢作用的促食欲素激素--天冬氨酸。代谢综合征(MS)患者Asprosin升高，其基因缺失会导致食欲下降、瘦弱和血糖负荷下降，从而保护MS。我们产生了三种识别独特Asprosin表位的独立单抗(MAbs)，并研究了它们在治疗MS的临床前有效性和耐受性。来自三个不同物种的抗Asprosin单抗降低了食欲和体重，并以剂量依赖和表位不可知的方式降低了血糖。单抗在体内的半衰期超过3天，平衡解离常数在皮摩尔至低纳摩尔范围内。我们证明，抗天冬氨酸单抗是针对MS的两个关键支柱-过度营养和高血糖-的双效药物治疗。这一证据为进一步开发研究中的新药应用和随后的治疗多发性硬化症的人体试验铺平了道路，多发性硬化症是我们这个时代的一种决定性的身体疾病。DK118290和DK125403(R01，国家糖尿病、消化和肾脏疾病研究所)、DK102529(K08，国家糖尿病、消化和肾脏疾病研究所)、Caroline Wiess Law奖学金(贝勒医学院、哈灵顿研究中心、哈灵顿发现研究所，克利夫兰大学医院)、Chao医生科学家奖(贝勒医学院)、RP150551和RP190561(德克萨斯州癌症预防研究所[CPRIT])。
Recently, we discovered a new glucogenic and centrally acting orexigenic hormone – asprosin. Asprosin is elevated in metabolic syndrome (MS) patients, and its genetic loss results in reduced appetite, leanness, and blood glucose burden, leading to protection from MS. We generated three independent monoclonal antibodies (mAbs) that recognize unique asprosin epitopes and investigated their preclinical efficacy and tolerability in the treatment of MS. Anti-asprosin mAbs from three distinct species lowered appetite and body weight, and reduced blood glucose in a dose-dependent and epitope-agnostic fashion in three independent MS mouse models, with an IC50 of ~1.5 mg/kg. The mAbs displayed a half-life of over 3days in vivo, with equilibrium dissociation-constants in picomolar to low nanomolar range. We demonstrate that anti-asprosin mAbs are dual-effect pharmacologic therapy that targets two key pillars of MS – over-nutrition and hyperglycemia. This evidence paves the way for further development towards an investigational new drug application and subsequent human trials for treatment of MS, a defining physical ailment of our time. DK118290 and DK125403 (R01; National Institute of Diabetes and Digestive and Kidney Diseases), DK102529 (K08; National Institute of Diabetes and Digestive and Kidney Diseases), Caroline Wiess Law Scholarship (Baylor College of Medicine, Harrington Investigatorship Harrington Discovery Institute at University Hospitals, Cleveland); Chao Physician Scientist Award (Baylor College of Medicine); RP150551 and RP190561 (Cancer Prevention and Research Institute of Texas [CPRIT]).