Immune responses to protein and peptide drugs can alter or reduce their efficacy and may be associated with adverse effects. While anti-drug antibodies (ADA) are a standard clinical measure of protein therapeutic immunogenicity, T cell epitopes in the primary sequences of these drugs are the key drivers or modulators of ADA response, depending on the type of T cell response that is stimulated (e.g., T helper or Regulatory T cells, respectively). In a previous publication on T cell-dependent immunogenicity of biotherapeutics, we addressed mitigation efforts such as identifying and reducing the presence of T cell epitopes or T cell response to protein therapeutics prior to further development of the protein therapeutic for clinical use. Over the past 5 years, greater insight into the role of regulatory T cell epitopes and the conservation of T cell epitopes with self (beyond germline) has improved the preclinical assessment of immunogenic potential. In addition, impurities contained in therapeutic drug formulations such as host cell proteins have also attracted attention and become the focus of novel risk assessment methods. Target effects have come into focus, given the emergence of protein and peptide drugs that target immune receptors in immuno-oncology applications. Lastly, new modalities are entering the clinic, leading to the need to revise certain aspects of the preclinical immunogenicity assessment pathway. In addition to drugs that have multiple antibody-derived domains or non-antibody scaffolds, therapeutic drugs may now be introduced via viral vectors, cell-based constructs, or nucleic acid based therapeutics that may, in addition to delivering drug, also prime the immune system, driving immune response to the delivery vehicle as well as the encoded therapeutic, adding to the complexity of assessing immunogenicity risk. While it is challenging to keep pace with emerging methods for the preclinical assessment of protein therapeutics and new biologic therapeutic modalities, this collective compendium provides a guide to current best practices and new concepts in the field.

对蛋白质和肽类药物的免疫反应会改变或降低其功效，并可能与不良反应有关。虽然抗药物抗体（ADA）是蛋白质治疗免疫原性的标准临床指标，但这些药物的主要序列中的T细胞表位是ADA反应的关键驱动器或调节剂，具体取决于刺激的T细胞反应的类型（例如T辅助细胞或调节性T细胞）。在先前有关生物疗法的T细胞依赖性免疫原性的出版物中，我们讨论了缓解措施，例如在进一步开发临床蛋白质治疗剂之前，确定和减少T细胞表位的存在或T细胞对蛋白质治疗剂的反应。在过去的5年中，对调节性T细胞表位的作用的更多了解以及自我（超越种系）对T细胞表位的保守性改善了免疫原性的临床前评估。另外，包含在治疗药物制剂中的杂质如宿主细胞蛋白也引起了人们的注意，并成为新型风险评估方法的焦点。鉴于在免疫肿瘤学应用中针对免疫受体的蛋白质和肽类药物的出现，靶向作用已成为焦点。最后，新的方法正在进入临床，导致需要修改临床前免疫原性评估途径的某些方面。除了具有多个抗体衍生域或非抗体支架的药物外，现在还可以通过病毒载体，基于细胞的构建体，或基于核酸的治疗剂，除了递送药物外，还可以引发免疫系统，驱动对递送载体的免疫反应以及编码的治疗剂，从而增加了评估免疫原性风险的复杂性。与蛋白质治疗的临床前评估和新的生物治疗方法同步发展的新方法具有挑战性，但该汇编汇编提供了该领域当前最佳实践和新概念的指南。