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Enhanced disulphide bond stability contributes to the once-weekly profile of insulin icodec

Author

Listed:
  • František Hubálek

    (Novo Nordisk A/S)

  • Christian N. Cramer

    (Novo Nordisk A/S)

  • Hans Helleberg

    (Novo Nordisk A/S)

  • Eva Johansson

    (Novo Nordisk A/S)

  • Erica Nishimura

    (Novo Nordisk A/S)

  • Gerd Schluckebier

    (Novo Nordisk A/S)

  • Dorte Bjerre Steensgaard

    (Novo Nordisk A/S)

  • Jeppe Sturis

    (Novo Nordisk A/S)

  • Thomas B. Kjeldsen

    (Novo Nordisk A/S)

Abstract

Insulin icodec is a once-weekly insulin analogue that has a long half-life of approximately 7 days, making it suitable for once weekly dosing. The Insulin icodec molecule was developed based on the hypothesis that lowering insulin receptor affinity and introducing a strong albumin-binding moiety would result in a long insulin half-life, provided that non-receptor-mediated clearance is diminished. Here, we report an insulin clearance mechanism, resulting in the splitting of insulin molecules into its A-chain and B-chain by a thiol–disulphide exchange reaction. Even though the substitutions in insulin icodec significantly stabilise insulin against such degradation, some free B-chain is observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we identify thiol–disulphide exchange reactions to be an important insulin clearance mechanism and find that stabilising insulin icodec towards this reaction significantly contributes to its long pharmacokinetic/pharmacodynamic profile.

Suggested Citation

  • František Hubálek & Christian N. Cramer & Hans Helleberg & Eva Johansson & Erica Nishimura & Gerd Schluckebier & Dorte Bjerre Steensgaard & Jeppe Sturis & Thomas B. Kjeldsen, 2024. "Enhanced disulphide bond stability contributes to the once-weekly profile of insulin icodec," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50477-9
    DOI: 10.1038/s41467-024-50477-9
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    1. Frantisek Hubálek & Hanne H. F. Refsgaard & Sanne Gram-Nielsen & Peter Madsen & Erica Nishimura & Martin Münzel & Christian Lehn Brand & Carsten Enggaard Stidsen & Christian Hove Claussen & Erik Max W, 2020. "Molecular engineering of safe and efficacious oral basal insulin," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    2. Frantisek Hubálek & Hanne H. F. Refsgaard & Sanne Gram-Nielsen & Peter Madsen & Erica Nishimura & Martin Münzel & Christian Lehn Brand & Carsten Enggaard Stidsen & Christian Hove Claussen & Erik Max W, 2020. "Author Correction: Molecular engineering of safe and efficacious oral basal insulin," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
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