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

František Hubálek (), Christian N. Cramer, Hans Helleberg, Eva Johansson, Erica Nishimura, Gerd Schluckebier, Dorte Bjerre Steensgaard, Jeppe Sturis and Thomas B. Kjeldsen
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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

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50477-9

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