Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO, United States.
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States.
Front Immunol. 2021 Sep 27;12:728694. doi: 10.3389/fimmu.2021.728694. eCollection 2021.
Monoclonal antibodies (mAbs) are an important class of therapeutics used to treat cancer, inflammation, and infectious diseases. Identifying highly developable mAb sequences could greatly reduce the time and cost required for therapeutic mAb development. Here, we present position-specific scoring matrices (PSSMs) for antibody framework mutations developed using baseline human antibody repertoire sequences. Our analysis shows that human antibody repertoire-based PSSMs are consistent across individuals and demonstrate high correlations between related germlines. We show that mutations in existing therapeutic antibodies can be accurately predicted solely from baseline human antibody sequence data. We find that mAbs developed using humanized mice had more human-like FR mutations than mAbs originally developed by hybridoma technology. A quantitative assessment of entire framework regions of therapeutic antibodies revealed that there may be potential for improving the properties of existing therapeutic antibodies by incorporating additional mutations of high frequency in baseline human antibody repertoires. In addition, high frequency mutations in baseline human antibody repertoires were predicted to reduce immunogenicity in therapeutic mAbs due to the removal of T cell epitopes. Several therapeutic mAbs were identified to have common, universally high-scoring framework mutations, and molecular dynamics simulations revealed the mechanistic basis for the evolutionary selection of these mutations. Our results suggest that baseline human antibody repertoires may be useful as predictive tools to guide mAb development in the future.
单克隆抗体 (mAbs) 是一类重要的治疗药物，用于治疗癌症、炎症和传染病。鉴定高度可开发的 mAb 序列可以大大减少治疗性 mAb 开发所需的时间和成本。在这里，我们使用基线人类抗体库序列为抗体框架突变开发了位置特异性评分矩阵 (PSSM)。我们的分析表明，基于人类抗体库的 PSSM 在个体之间是一致的，并显示出相关种系之间的高度相关性。我们表明，仅从基线人类抗体序列数据就可以准确预测现有治疗性抗体中的突变。我们发现使用人源化小鼠开发的 mAbs 比最初使用杂交瘤技术开发的 mAbs 具有更多的类人 FR 突变。对治疗性抗体整个框架区域的定量评估表明，通过纳入基线人类抗体库中高频的额外突变，可能有潜力改善现有治疗性抗体的特性。此外，由于去除了 T 细胞表位，基线人类抗体库中的高频突变被预测会降低治疗性 mAb 的免疫原性。一些治疗性 mAb 被鉴定出具有共同的、普遍得分较高的框架突变，分子动力学模拟揭示了这些突变的进化选择的机制基础。我们的结果表明，基线人类抗体库可能是未来指导 mAb 开发的有用预测工具。
