Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.S.M., R.J.H., J.W.D., C.Z., X.R., L.D., R.M.B., H.E.B.) and San Diego, California (C.D.D., J.M.B.)
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.S.M., R.J.H., J.W.D., C.Z., X.R., L.D., R.M.B., H.E.B.) and San Diego, California (C.D.D., J.M.B.).
J Pharmacol Exp Ther. 2022 Sep;382(3):346-355. doi: 10.1124/jpet.122.001105. Epub 2022 Jul 15.
The benefit of once-weekly basal insulin is less frequent dosing, which has the potential to reduce the barrier to injection therapy and impact patient activation, adherence and compliance, quality of life, and outcomes. Basal Insulin Fc (BIF, LY3209590, or insulin efsitora alfa) is a once-weekly basal insulin in clinical testing for type 1 and type 2 diabetes mellitus. BIF is comprised of a novel single-chain variant of insulin fused to a human IgG2 fragment crystallizable region of an antibody domain using a peptide linker. The in vitro binding affinity of BIF for the human insulin receptor (IR) was two orders of magnitude weaker relative to human insulin. BIF stimulated IR phosphorylation in cells with reduced potency, yet full agonism, and exhibited a significantly faster dephosphorylation kinetic profile than human insulin or AspB10 insulin. BIF stimulated de novo lipogenesis in 3T3-L1 adipocytes and cell proliferation in SAOS-2 and H4IIE cells with ≥70-fold reduction in in vitro potency compared with human insulin. BIF possessed markedly reduced binding to hIGF-1R, making definitive measurements unattainable. In vivo pharmacology studies using streptozotocin-treated diabetic rats demonstrated a significant decrease in blood glucose compared with vehicle-treated animals 24 hours post-injection, persisting through 336 hours following subcutaneous administration. In streptozotocin-treated rats, BIF reached time at maximum concentration at 48 hours and possessed a clearance rate of ∼0.85 ml/h per kg, with a terminal half-life of ∼120 hours following subcutaneous administration. These results demonstrate BIF has an in vitro pharmacological profile similar to native insulin, with significantly reduced potency and an extended time-action profile in vivo that supports once-weekly dosing in humans. SIGNIFICANCE STATEMENT: BIF is a novel basal insulin Fc-fusion protein designed for once-weekly dosing. In this study, we demonstrate that BIF has an in vitro pharmacological profile similar to human insulin, but with weaker potency across assays for IR binding and activity. BIF has a PD and PK profile in STZ-treated rats supportive of weekly dosing in humans.
贝凡胰岛素每周一次的优势在于减少了给药频率，这有可能降低注射治疗的障碍，从而影响患者的积极性、顺应性和依从性、生活质量和治疗结果。贝凡胰岛素 Fc（BIF，LY3209590 或胰岛素 efSitara 阿尔法）是一种每周一次的基础胰岛素，正在进行 1 型和 2 型糖尿病的临床试验。BIF 由胰岛素的新型单链变体与抗体结构域的人 IgG2 片段结晶区通过肽接头融合而成。BIF 与人胰岛素受体（IR）的体外结合亲和力比人胰岛素弱两个数量级。BIF 以降低效力但完全激动剂的方式刺激细胞中 IR 的磷酸化，并且表现出比人胰岛素或 AspB10 胰岛素更快的去磷酸化动力学特征。BIF 刺激 3T3-L1 脂肪细胞中的从头脂肪生成和 SAOS-2 和 H4IIE 细胞的增殖，与人类胰岛素相比，其体外效力降低了 70 倍以上。BIF 与人 IGF-1R 的结合明显减少，使得无法进行明确的测量。使用链脲佐菌素处理的糖尿病大鼠的体内药理学研究表明，与接受载体处理的动物相比，注射后 24 小时血液葡萄糖显着降低，在皮下给药后 336 小时内持续存在。在链脲佐菌素处理的大鼠中，BIF 在 48 小时达到最大浓度时间，清除率约为 0.85 ml/h/kg，皮下给药后半衰期约为 120 小时。这些结果表明，BIF 的体外药理学特征与天然胰岛素相似，但其效力显着降低，并且在体内的作用时间延长，支持在人类中每周一次给药。意义声明：BIF 是一种新型的基础胰岛素 Fc 融合蛋白，设计用于每周一次给药。在这项研究中，我们证明 BIF 的体外药理学特征与人胰岛素相似，但在用于 IR 结合和活性的测定中效力较弱。BIF 在 STZ 处理的大鼠中的 PD 和 PK 特征支持在人类中每周一次给药。
