Department of BioAnalytical Sciences, Genentech Inc, South San Francisco, CA, United States.
Front Immunol. 2023 Sep 1;14:1237754. doi: 10.3389/fimmu.2023.1237754. eCollection 2023.
Therapeutic antibodies can elicit unwanted immune responses in a subset of patients, which leads to the production of anti-drug antibodies (ADA). Some of these ADAs have been reported to effect the pharmacokinetics, efficacy and/or safety of the therapeutic antibodies. The sequence diversity of antibodies are generated by VDJ recombination and mutagenesis. While the antibody generation process can create a large candidate pool for identifying high-affinity antibodies, it also could produce sequences that are foreign to the human immune system. However, it is not clear how VDJ recombination and mutagenesis impact the clinical ADA rate of therapeutic antibodies. In this study, we identified a positive correlation between the clinical ADA rate and the number of introduced mutations in the antibody sequences. We also found that the use of rare V alleles in human-origin antibody therapeutics is associated with higher risk of immunogenicity. The results suggest that antibody engineering projects should start with frameworks that contain commonly used V alleles and prioritize antibody candidates with low number of mutations to reduce the risk of immunogenicity.
治疗性抗体在一部分患者中会引起不必要的免疫反应，导致产生抗药物抗体（ADA）。一些这些 ADA 已被报道会影响治疗性抗体的药代动力学、疗效和/或安全性。抗体的序列多样性是通过 VDJ 重组和突变产生的。虽然抗体产生过程可以为识别高亲和力抗体创造一个大量的候选池，但它也可能产生对人体免疫系统来说是陌生的序列。然而，目前尚不清楚 VDJ 重组和突变如何影响治疗性抗体的临床 ADA 发生率。在这项研究中，我们发现抗体序列中引入的突变数量与临床 ADA 发生率之间存在正相关关系。我们还发现，在人源抗体治疗药物中使用罕见的 V 等位基因与更高的免疫原性风险相关。研究结果表明，抗体工程项目应从包含常用 V 等位基因的框架开始，并优先选择突变数量较少的抗体候选物，以降低免疫原性风险。
