Evaluation of Protein Engineering and Process Optimization Approaches to Enhance Antibody Drug Manufacturability
Evaluation of Protein Engineering and Process Optimization Approaches to Enhance Antibody Drug Manufacturability
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DOI：
10.1002/bit.23220
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发表时间：
2011-11-01
影响因子：
3.8
通讯作者：
Chen, Jie
中科院分区：
文献类型：
--
作者：
Conley, Greg P.;Viswanathan, Malini;Chen, Jie
从噬菌体展示文库中鉴定出对感兴趣的抗原具有高度特异性的有效个位数皮摩尔全人单克隆抗体（hMAb）抑制剂。然而，当使用基于蛋白A的通用方法纯化时，hMAb表现出高度疏水性并且容易形成不溶性聚集体。使用蛋白质工程和工艺开发方法设计策略，以优化分子的氨基酸序列及其在工艺条件下的行为。通过CDR区中的一个单一氨基酸突变或通过切换到基于非ProA的纯化工艺来控制不溶性聚集问题。因此，我们的研究提出了未来单克隆抗体产品及其纯化工艺的合理可生产性设计，该设计是在设计质量概念下，通过工程化药物分子以适应现有平台工艺或优化工艺以适应制剂的特定性质。Biotechnol. Bioeng. 2011; 108：2634-2644. (C)2011 Wiley Periodicals，Inc.
A potent single digit picomolar fully human monoclonal antibody (hMAb) inhibitor with a high degree of specificity to the antigen of interest was identified from a phage display library. The hMAb, however, exhibited a high degree of hydrophobicity and easily formed insoluble aggregates when purified using a Protein A based generic process. Strategies were designed using both protein engineering and process development approaches to optimize the molecule's amino acid sequence and its behavior in process conditions. The insoluble aggregation issue was brought under control by one single amino acid mutation in CDR region or by switching to non-ProA based purification process. Our study therefore presents the rational manufacturability design for future monoclonal antibody product and its purification process under the quality by design concept by either engineering the drug molecule to adapt existing platform process or optimizing the process to fit the specific properties of the drug product. Biotechnol. Bioeng. 2011; 108: 2634-2644. (C) 2011 Wiley Periodicals, Inc.