A First Insight into the Developability of an Immunoglobulin G3: A Combined Computational and Experimental Approach

Georgina B. Armstrong*, Alan Lewis, Vidhi Shah, Paul Taylor, Craig J. Jamieson, Glenn A. Burley, William Lewis and Zahra Rattray*, 
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Abstract

Immunoglobulin G 3 (IgG3) monoclonal antibodies (mAbs) are high-value scaffolds for developing novel therapies. Despite their wide-ranging therapeutic potential, IgG3 physicochemical properties and developability characteristics remain largely under-characterized. Protein–protein interactions elevate solution viscosity in high-concentration formulations, impacting physicochemical stability, manufacturability, and the injectability of mAbs. Therefore, in this manuscript, the key molecular descriptors and biophysical properties of a model anti-IL-8 IgG1 and its IgG3 ortholog are characterized. A computational and experimental framework was applied to measure molecular descriptors impacting their downstream developability. Findings from this approach underpin a detailed understanding of the molecular characteristics of IgG3 mAbs as potential therapeutic entities. This work is the first report examining the manufacturability of IgG3 for high-concentration mAb formulations. While poorer conformational and colloidal stability and elevated solution viscosity were observed for IgG3, future efforts controlling surface potential through sequence-engineering of solvent-accessible patches can be used to improve biophysical parameters that dictate mAb developability.

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首次洞察免疫球蛋白 G3 的可开发性:计算与实验相结合的方法
免疫球蛋白 G 3(IgG3)单克隆抗体(mAbs)是开发新型疗法的高价值支架。尽管 IgG3 具有广泛的治疗潜力,但其理化性质和可开发性特征在很大程度上仍未得到充分描述。蛋白质与蛋白质之间的相互作用会提高高浓度制剂的溶液粘度,从而影响 mAbs 的理化稳定性、可制造性和可注射性。因此,本手稿对模型抗 IL-8 IgG1 及其 IgG3 同源物的关键分子描述符和生物物理特性进行了表征。应用计算和实验框架测量了影响其下游可开发性的分子描述因子。这一方法的研究结果有助于详细了解作为潜在治疗实体的 IgG3 mAbs 的分子特性。这项工作是首次对 IgG3 用于高浓度 mAb 制剂的可制造性进行研究的报告。虽然观察到 IgG3 的构象和胶体稳定性较差,溶液粘度升高,但今后通过序列工程设计可溶解的补丁来控制表面电位的工作可用于改善决定 mAb 可制造性的生物物理参数。
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来源期刊
ACS Pharmacology and Translational Science
ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)
CiteScore
10.00
自引率
3.30%
发文量
133
期刊介绍: ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.
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