Asprosin-neutralizing antibodies as a treatment for metabolic syndrome

Elife. 2021 Apr 27:10:e63784. doi: 10.7554/eLife.63784.

Abstract

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]).

Keywords: asprosin; medicine; metabolic syndrome; mouse; obesity; pharmacodynamics; pharmacokinetics; therapeutic monoclonal antibodies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Appetite
  • Blood Glucose / analysis
  • Body Weight
  • Dose-Response Relationship, Immunologic
  • Enzyme-Linked Immunosorbent Assay
  • Fibrillin-1 / immunology*
  • Humans
  • Male
  • Metabolic Syndrome / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / immunology*
  • Peptide Hormones / immunology*

Substances

  • Antibodies, Monoclonal
  • Blood Glucose
  • Fibrillin-1
  • Peptide Fragments
  • Peptide Hormones
  • asprosin protein, mouse