Asprosin neutralizing antibodies as a treatment for metabolic syndrome

  1. Ila Mishra
  2. Clemens Duerrschmid
  3. Zhiqiang Ku
  4. Yang He
  5. Wei Xie
  6. Elizabeth Sabath Silva
  7. Jennifer Hoffman
  8. Wei Xin
  9. Ningyan Zhang
  10. Yong Xu
  11. Zhiqiang An
  12. Atul R Chopra  Is a corresponding author
  1. Case Western Reserve University, United States
  2. University of Texas Health Science Center at Houston, United States
  3. Baylor College of Medicine, United States
  4. Case Western Reserve University,, United States
  5. Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, TX, United States
  6. Brown Foundation Institute of Molecular Medicine, United States

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 3 days 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 Scientists Award (Baylor College of Medicine); RP150551 and RP190561 (Cancer Prevention and Research Institute of Texas; CPRIT)

Data availability

All data analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Ila Mishra

    Harrington Discovery Institute, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  2. Clemens Duerrschmid

    Harrington Discovery Institute, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  3. Zhiqiang Ku

    Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    No competing interests declared.
  4. Yang He

    Department of Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Wei Xie

    Harrington Discovery Institute, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  6. Elizabeth Sabath Silva

    Harrington Discovery Institute, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  7. Jennifer Hoffman

    Harrington Discovery Institute, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  8. Wei Xin

    Department of Pathology, Case Western Reserve University,, Cleveland, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0987-0443
  9. Ningyan Zhang

    Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, TX, Houston, United States
    Competing interests
    No competing interests declared.
  10. Yong Xu

    Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  11. Zhiqiang An

    University of Texas Health Science Center at Houston, Brown Foundation Institute of Molecular Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9309-2335
  12. Atul R Chopra

    Harrington Discovery Institute, Case Western Reserve University, Cleveland, United States
    For correspondence
    atul.chopra@case.edu
    Competing interests
    Atul R Chopra, A.R.C. is a cofounder and director of Vizigen, Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1304-3777

Funding

Cancer Prevention and Research Institute of Texas (RP150551 and RP190561)

  • Atul R Chopra

Welch Foundation (AU-0042-20030616 and I-1834)

  • Zhiqiang An

National Institute of Diabetes and Digestive and Kidney Diseases (DK102529,DK118290)

  • Atul R Chopra

Harrington Discovery Institute

  • Atul R Chopra

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2018-0042) of the Case Western Reserve University. The protocol was approved by the Committee on the Ethics of Animal Experiments of Case Western Reserve University.

Reviewing Editor

  1. Carlos Isales, Medical College of Georgia at Augusta University, United States

Version history

  1. Received: October 7, 2020
  2. Accepted: April 22, 2021
  3. Accepted Manuscript published: April 27, 2021 (version 1)
  4. Version of Record published: May 6, 2021 (version 2)

Copyright

© 2021, Mishra et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ila Mishra
  2. Clemens Duerrschmid
  3. Zhiqiang Ku
  4. Yang He
  5. Wei Xie
  6. Elizabeth Sabath Silva
  7. Jennifer Hoffman
  8. Wei Xin
  9. Ningyan Zhang
  10. Yong Xu
  11. Zhiqiang An
  12. Atul R Chopra
(2021)
Asprosin neutralizing antibodies as a treatment for metabolic syndrome
eLife 10:e63784.
https://doi.org/10.7554/eLife.63784

Share this article

https://doi.org/10.7554/eLife.63784

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