Asprosin-neutralizing antibodies as a treatment for metabolic syndrome.

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]).

• Authors: Ila Mishra, Clemens Duerrschmid, Zhiqiang Ku, Yang He, Wei Xie, Elizabeth Sabath Silva, Jennifer Hoffman, Wei Xin, Ningyan Zhang, Yong Xu, Zhiqiang An, Atul R Chopra
• Journal: eLife (Elife) Vol. 10 (04 27 2021) ISSN: 2050-084X [Electronic] England
• PMID: 33904407 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021, Mishra et al.

Chemical References

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

Topics

• Animals
• Antibodies, Monoclonal (immunology, 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)