Asprosin-neutralizing antibodies as a treatment for metabolic syndrome

eLife

Yong Xu¹  Yang He¹  Wei Xin²  Ila Mishra³  Clemens Duerrschmid³  Jennifer Hoffman³  Wei Xie³  Elizabeth Sabath Silva³  Atul R Chopra⁴  Zhiqiang Ku⁵  Zhiqiang An⁵  Ningyan Zhang⁵ 

[1] Baylor College of Medicine, Houston, United States;Department of Pathology, Case Western Reserve University, Cleveland, United States;Harrington Discovery Institute, University Hospitals, Cleveland, United States;Harrington Discovery Institute, University Hospitals, Cleveland, United States;Department of Medicine, Case Western Reserve University, Cleveland, United States;Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States;Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, United States;

关键词: asprosin;    obesity;    pharmacokinetics;    pharmacodynamics;    metabolic syndrome;    therapeutic monoclonal antibodies;    Mouse;   

DOI  :  10.7554/eLife.63784

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Background: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.Methods:We generated three independent monoclonal antibodies (mAbs) that recognize unique asprosin epitopes and investigated their preclinical efficacy and tolerability in the treatment of MS.Results: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.Conclusions: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.Funding: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]).

【 授权许可】

CC BY