Harrington Discovery Institute, University Hospitals, Cleveland, United States.
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, United States.
Elife. 2021 Apr 27;10:e63784. doi: 10.7554/eLife.63784.
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]).
最近，我们发现了一种新的生糖和中枢作用的食欲肽激素——天门冬氨酸。天门冬氨酸在代谢综合征（MS）患者中升高，其遗传缺失导致食欲下降、消瘦和血糖负担减轻，从而对 MS 有保护作用。
我们生成了三种识别天门冬氨酸独特表位的独立单克隆抗体（mAb），并研究了它们在治疗 MS 中的临床前疗效和耐受性。
三种不同物种的抗天门冬氨酸 mAb 以剂量依赖性和表位无关的方式降低了三种独立的 MS 小鼠模型的食欲和体重，并降低了血糖，IC50 约为 1.5mg/kg。mAb 在体内半衰期超过 3 天，平衡解离常数在皮摩尔至低纳摩尔范围内。
我们证明抗天门冬氨酸 mAb 是一种双重作用的药物治疗方法，针对 MS 的两个关键支柱——营养过剩和高血糖。这一证据为进一步开发治疗 MS 的新药申请和随后的人体试验铺平了道路，MS 是我们这个时代的一种典型的身体疾病。
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，Harrington 研究员，克利夫兰大学医院 Harrington 发现研究所）；Chao 医师科学家奖（贝勒医学院）；RP150551 和 RP190561（德克萨斯州癌症预防与研究协会 [CPRIT]）。
