Asprosin-neutralizing antibodies as a treatment for metabolic syndrome

Authors: MISHRA, ILA - University Hospitals; DUERRSCHMID, CLEMENS - University Hospitals; KU, ZHIQIANG - University Of Texas Health Science Center; HE, YANG - Children'S Nutrition Research Center (CNRC); XIE, WEI - University Hospitals; SILVA, ELIZABETH - University Hospitals; HOFFMAN, JENNIFER - University Hospitals; XIN, WEI - Case Western Reserve University (CWRU); ZHANG, NINGYAN - University Of Texas Health Science Center; XU, YONG - Children'S Nutrition Research Center (CNRC); AN, ZHIQIANG - University Of Texas Health Science Center; CHOPRA, ATUL - University Hospitals

Submitted to: eLife
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2021
Publication Date: 4/27/2021
Citation: Mishra, I., Duerrschmid, C., Ku, Z., He, Y., Xie, W., Silva, E., Hoffman, J., Xin, W., Zhang, N., Xu, Y., An, Z., Chopra, A. 2021. Asprosin-neutralizing antibodies as a treatment for metabolic syndrome. eLife. 10. Article e63784. https://doi.org/10.7554/eLife.63784.
DOI: https://doi.org/10.7554/eLife.63784

Interpretive Summary: Metabolic syndrome (MS) is an umbrella term comprising obesity and its co-morbidities. MS affects nearly 1 in 4 people in the world. Asprosin is a recently discovered hormone that is higher in patients with MS. Here, we created three independent monoclonal antibodies that recognize asprosin. When introduced into mice with MS, these antibodies lowered appetite and body weight and reduced blood glucose. These results are promising for treating MS through targeting asprosin.

Technical Abstract: 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.