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A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models

Author

Listed:
  • Fabian Wirth

    (Neurimmune AG)

  • Fabrice D. Heitz

    (Neurimmune AG)

  • Christine Seeger

    (Neurimmune AG)

  • Ioana Combaluzier

    (Neurimmune AG)

  • Karin Breu

    (Neurimmune AG)

  • Heather C. Denroche

    (University of British Columbia)

  • Julien Thevenet

    (Univ-Lille, Inserm, CHU Lille)

  • Melania Osto

    (Vetsuisse Faculty of the University of Zürich)

  • Paolo Arosio

    (ETH Zürich)

  • Julie Kerr-Conte

    (Univ-Lille, Inserm, CHU Lille)

  • C. Bruce Verchere

    (University of British Columbia)

  • François Pattou

    (Univ-Lille, Inserm, CHU Lille)

  • Thomas A. Lutz

    (Vetsuisse Faculty of the University of Zürich)

  • Marc Y. Donath

    (University Hospital Basel)

  • Christoph Hock

    (Neurimmune AG
    University of Zürich)

  • Roger M. Nitsch

    (Neurimmune AG
    University of Zürich)

  • Jan Grimm

    (Neurimmune AG)

Abstract

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.

Suggested Citation

  • Fabian Wirth & Fabrice D. Heitz & Christine Seeger & Ioana Combaluzier & Karin Breu & Heather C. Denroche & Julien Thevenet & Melania Osto & Paolo Arosio & Julie Kerr-Conte & C. Bruce Verchere & Franç, 2023. "A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41986-0
    DOI: 10.1038/s41467-023-41986-0
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    References listed on IDEAS

    as
    1. Aubin Michalon & Andreas Hagenbuch & Christian Huy & Evita Varela & Benoit Combaluzier & Thibaud Damy & Ole B. Suhr & Maria J. Saraiva & Christoph Hock & Roger M. Nitsch & Grimm, 2021. "A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Paolo Arosio & Thomas C. T. Michaels & Sara Linse & Cecilia Månsson & Cecilia Emanuelsson & Jenny Presto & Jan Johansson & Michele Vendruscolo & Christopher M. Dobson & Tuomas P. J. Knowles, 2016. "Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
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    4. Yong Xu & Roberto Maya-Martinez & Nicolas Guthertz & George R. Heath & Iain W. Manfield & Alexander L. Breeze & Frank Sobott & Richard Foster & Sheena E. Radford, 2022. "Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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