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评估和整合体外相关性以获得抗体可开发性工作流程中的药代动力学结果。

Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows.

机构信息

Department of Computational Biology, Adimab LLC, Mountain View, CA, USA.

Department of Antibody Discovery, Adimab LLC, Lebanon, NH, USA.

出版信息

MAbs. 2024 Jan-Dec;16(1):2384104. doi: 10.1080/19420862.2024.2384104. Epub 2024 Jul 31.

Abstract

In vitro assessments for the prediction of pharmacokinetic (PK) behavior of biotherapeutics can help identify corresponding liabilities significantly earlier in the discovery timeline. This can minimize the need for extensive early in vivo PK characterization, thereby reducing animal usage and optimizing resources. In this study, we recommend bolstering classical developability workflows with in vitro measures correlated with PK. In agreement with current literature, in vitro measures assessing nonspecific interactions, self-interaction, and FcRn interaction are demonstrated to have the highest correlations to clearance in hFcRn Tg32 mice. Crucially, the dataset used in this study has broad sequence diversity and a range of physicochemical properties, adding robustness to our recommendations. Finally, we demonstrate a computational approach that combines multiple in vitro measurements with a multivariate regression model to improve the correlation to PK compared to any individual assessment. Our work demonstrates that a judicious choice of high throughput in vitro measurements and computational predictions enables the prioritization of candidate molecules with desired PK properties.

摘要

体外评估可用于预测生物治疗药物的药代动力学(PK)行为,有助于在发现阶段更早地识别相应的缺陷。这可以最大程度地减少对早期体内 PK 特征的广泛需求,从而减少动物的使用并优化资源。在这项研究中,我们建议在具有与 PK 相关的体外测量的经典可开发性工作流程中进行强化。与当前文献一致,评估非特异性相互作用、自相互作用和 FcRn 相互作用的体外测量被证明与 hFcRnTg32 小鼠中的清除率具有最高的相关性。至关重要的是,本研究中使用的数据集具有广泛的序列多样性和一系列物理化学特性,为我们的建议增加了稳健性。最后,我们展示了一种计算方法,该方法将多种体外测量与多元回归模型相结合,与任何单个评估相比,提高了与 PK 的相关性。我们的工作表明,明智地选择高通量的体外测量和计算预测,可以优先选择具有所需 PK 特性的候选分子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce09/11296533/fc867ed5c797/KMAB_A_2384104_F0001_B.jpg

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