Siegel Michel, Steiner Guido, Franssen Linnea C, Carratu Francesca, Herron James, Hartman Katharina, Looney Cary M, Ducret Axel, Bray-French Katharine, Rohr Olivier, Hickling Timothy P, Smith Noel, Marban-Doran Céline
Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4070 Basel, Switzerland.
Lonza Biologics, Chesterford Research Park, Saffron Walden CB10 1XL, UK.
Pharmaceutics. 2022 Dec 1;14(12):2672. doi: 10.3390/pharmaceutics14122672.
Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development.
免疫原性被定义为引发免疫反应的能力，它既可能是我们所期望的（如疫苗），也可能是不期望出现的。后者是指对蛋白质或肽类治疗药物产生的免疫反应，其特征是产生抗药物抗体，这可能会影响这些药物的疗效和/或安全性。因此，在生物治疗药物研发早期评估免疫原性风险对于确定其疗效和安全性至关重要。在此，我们描述并验证了一种适用于评估药物特异性T细胞反应的基于荧光斑点法的体外检测方法。在该检测中对一组24种具有广泛临床抗药物抗体反应率的生物治疗药物进行了测试。我们证明，使用合适的临界值和供体队列规模，该检测方法能够识别出大多数具有高临床免疫原性率的化合物（敏感性和特异性分别为71%和78%），同时我们还对检测变异性的主要来源进行了特征描述。总体而言，这些数据表明本文发表的树突状细胞和CD4+ T细胞再刺激检测方法可能是评估药物特异性T细胞反应风险的有价值工具，并有助于在早期研发阶段选择临床候选药物。
