Introduction and Objective: We are developing an ultra-stable insulin analog designed to address the intrinsic physical instability of current insulin formulations. Using advanced protein structural insights and protein engineering approaches originating from UT Southwestern, we focused on optimizing insulin analogs to reduce fibrillation and aggregation while improving resistance to thermal and mechanical stress across a broad range of storage and handling conditions. By targeting fundamental biophysical failure modes of insulin, this work aims to reduce dependence on cold-chain storage and improve the reliability and usability of insulin therapies in real-world settings. Importantly, elimination of fibril formation enables substantially greater flexibility in formulation design and pharmacokinetic optimization.Methods: We generated multiple ultra-stable insulin analog constructs and selected a lead candidate based on stability and activity profiles. Expression was evaluated in both Escherichia coli and yeast systems, followed by optimization of purification protocols. Biological activity and stability were assessed using in vitro functional assays and accelerated stress testing under elevated temperature and agitation conditions.Results: The lead insulin analog retains full biological activity comparable to native insulin while demonstrating complete resistance to fibril formation under conditions that induce fibrillation in existing insulin products. In addition, the lead molecule exhibits substantially improved stability under high-temperature stress relative to currently marketed insulins.Conclusion: Based on these results, the program is advancing into process development to support further formulation optimization and translational studies.
H. Tu: Board Member; Current; MEDNA SCIENTIFIC.
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