Asprosin-neutralizing antibodies as a treatment for metabolic syndrome.

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]).