Kumar Sandeep, Zhou Shuxia, Singh Satish K
Pfizer Inc., AA4, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA.
Curr Pharm Des. 2014;20(8):1173-81. doi: 10.2174/13816128113199990063.
Metal ions that leach into biotherapeutic drug product solution during manufacturing and storage, result in contamination that can cause physico-chemical degradation of the active molecule. In this review, we describe various mechanisms by which metal ion leachates can interact with therapeutic proteins and antibodies. Site-specific modifications due to metal catalyzed oxidation (MCO) of the therapeutic proteins cause them to become destabilized and potentially increasingly aggregation prone. We have examined the molecular sequences and structures for three case studies, human relaxin (hRlx), human growth hormone (hGH) and an IgG2 mAb to rationalize the experimental findings related to their MCO. The analysis indicates that metal-binding sites lie in close spatial proximities to predicted aggregation prone regions in these molecules. From the perspective of pharmaceutical development of biotherapeutic drugs, this link between molecular origins of MCO and subsequent aggregation is undesirable. This article further suggests molecular design strategies involving disruption of APRs that may also help mitigate the impact of metal ion leachates on biotherapeutic drug products as well as improving their solubility.
在生物治疗药物产品的制造和储存过程中，金属离子会渗入溶液，导致污染，进而可能引起活性分子的物理化学降解。在本综述中，我们描述了金属离子渗出物与治疗性蛋白质和抗体相互作用的各种机制。治疗性蛋白质因金属催化氧化（MCO）而发生的位点特异性修饰会使其变得不稳定，并可能越来越容易聚集。我们研究了三个案例的分子序列和结构，即人松弛素（hRlx）、人生长激素（hGH）和一种IgG2单克隆抗体，以合理化与其MCO相关的实验结果。分析表明，金属结合位点在空间上紧邻这些分子中预测的易聚集区域。从生物治疗药物的药物开发角度来看，MCO的分子起源与随后的聚集之间的这种联系是不理想的。本文进一步提出了涉及破坏易聚集区域的分子设计策略，这也可能有助于减轻金属离子渗出物对生物治疗药物产品的影响，并提高其溶解度。
