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

• Published in: Nature communications Vol. 15; no. 1; pp. 6124 - 11
• Main Authors: Hubálek, František, Cramer, Christian N., Helleberg, Hans, Johansson, Eva, Nishimura, Erica, Schluckebier, Gerd, Steensgaard, Dorte Bjerre, Sturis, Jeppe, Kjeldsen, Thomas B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 140/58; 631/154/309/2144; 631/535/1266; 631/92/152; 692/699/2743/137/773; 82/16; Animals; Clearances; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Disulfides; Disulfides - chemistry; Exchanging; Half-Life; Humanities and Social Sciences; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Insulin; Insulin - administration & dosage; Insulin - chemistry; Insulin - metabolism; Insulin - pharmacokinetics; Male; multidisciplinary; Pharmacodynamics; Pharmacokinetics; Receptor, Insulin - metabolism; Receptors; Science; Science (multidisciplinary); Splitting; Stability; Sulfhydryl Compounds - chemistry; Swine; Swine, Miniature
• DOI: 10.1038/s41467-024-50477-9
• ISSN: 2041-1723

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. In this work, the authors described how the enhanced disulphide bond stability of insulin icodec enables its once-weekly profile. Disulphide bonds in insulin are subject to thiol-disulphide exchange in plasma leading to splitting insulin into its inactive chains, making the insulin disulfide stability crucial for its long duration of action.