Utrecht Institute of Pharmaceutical Sciences; Department of Pharmaceutics; Utrecht University; Utretcht, the Netherlands.
MAbs. 2013 Sep-Oct;5(5):810-6. doi: 10.4161/mabs.25234. Epub 2013 Jun 6.
The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.
生物制药在临床实践中的免疫原性仍然是药物开发中未解决的挑战。非人类灵长类动物（NHP）通常是非抗体类单克隆药物（mAbs）开发的唯一相关动物模型，但由于物种差异，NHP 对治疗性 mAbs 的免疫反应并不被认为可预测人类的反应。在这项研究中，我们查阅了在欧盟注册的所有 mAbs 的药物注册文件，以确定 mAbs 在 NHP 和人类中的相对免疫原性。只有 59%的情况下，NHP 和患者中形成抗药物抗体的发生率是可比的。此外，在 59%的情况下，NHP 和人类中的抗药物抗体反应类型不同。人源化并不一定能降低人类的免疫原性。免疫原性在清除或中和抗体形成时会干扰非临床药物开发中的安全性评估。虽然对解释研究结果很重要，但免疫原性降低了安全性评估中 NHP 数据的质量。这些发现证实了比较 NHP 和人类中 mAbs 的相对免疫原性的能力较低。此外，免疫原性限制了有信息价值的 NHP 研究的价值。
