Stable High-Concentration Monoclonal Antibody Formulations Enabled by an Amphiphilic Copolymer Excipient.
Stable High-Concentration Monoclonal Antibody Formulations Enabled by an Amphiphilic Copolymer Excipient.
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由两亲性共聚物赋形剂实现的稳定的高浓度单克隆抗体制剂。
DOI：
10.1002/adtp.202200102
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发表时间：
2023
影响因子：
4.6
通讯作者：
Appel,EricA
中科院分区：
文献类型：
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作者：
Klich,JohnH;Kasse,CatherineM;Mann,JosephL;Huang,Yaoqi;d'Aquino,AndreaI;Grosskopf,AbigailK;Baillet,Julie;Fuller,GeraldG;Appel,EricA
单克隆抗体（mab）是现代药物治疗的重要组成部分。不幸的是，这些生物制药受到配方中聚集的趋势的限制，导致稳定性差，并且通常需要低浓度的药物配方。现有的用于稳定配方的赋形剂往往受到其毒性和形成胶束等颗粒的倾向的限制。本研究证明了一种简单的“滴入式”两亲共聚物赋形剂在不改变其药代动力学或注射性的情况下增强临床相关单克隆抗体高浓度制剂稳定性的能力。通过界面流变学和表面张力测量，证明了共聚物赋形剂在配方界面上的竞争性吸附。此外，通过测定应激老化后的单体组成和保留的生物活性，表明该赋形剂对高浓度抗体制剂具有显著的稳定性益处。最后，研究表明，赋形剂作为一种非活性成分，对临床相关抗体在小鼠体内的药代动力学特征没有显著影响。这种两亲性共聚物辅料有望作为一种添加剂，用于制造稳定的高浓度抗体配方，从而改善治疗选择，如从低浓度静脉注射（IV）到高浓度皮下注射（SC）的给药途径切换，同时减少对冷链的依赖。
Monoclonal antibodies (mAbs) are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Existing excipients designed to stabilize formulations are often limited by their toxicity and tendency to form particles such as micelles. Here, the ability of a simple “drop‐in,” amphiphilic copolymer excipient to enhance the stability of high concentration formulations of clinically relevant mAbs without altering their pharmacokinetics or injectability is demonstrated. Through interfacial rheology and surface tension measurements, it is demonstrated that the copolymer excipient competitively adsorbs to formulation interfaces. Further, through determination of monomeric composition and retained bioactivity after stressed aging, it is shown that this excipient confers a significant stability benefit to high concentration antibody formulations. Finally, it is demonstrated that the excipient behaves as an inactive ingredient, having no significant impact on the pharmacokinetic profile of a clinically relevant antibody in mice. This amphiphilic copolymer excipient demonstrates promise as an additive to create stable, high concentration antibody formulations, thereby enabling improved treatment options such as a route‐of‐administration switch from low concentration intravenous (IV) to high concentration subcutaneous (SC) delivery while reducing dependence on the cold chain.