Clinical Immunology, Amgen, Inc., Thousand Oaks, CA 91320, United States.
Curr Opin Microbiol. 2012 Jun;15(3):337-47. doi: 10.1016/j.mib.2012.05.015. Epub 2012 Jul 4.
Recent ICH S6 guidance on preclinical safety evaluation of biotechnology derived biopharmaceuticals indicates that testing for anti-drug antibodies is not always required to establish the safety of a protein therapeutic. Most human protein therapeutics will induce a rapid and robust anti-drug antibody response in preclinical studies and the presence of high levels of circulating drug complicates the detection of anti-drug antibodies. The presence of anti-drug antibodies in preclinical studies does not predict if a protein therapeutic will be immunogenic in the clinic. When testing for anti-drug antibodies is warranted, there are a variety of analytical procedures that can be utilized, although each of these methods has advantages as well as limitations. Immunoassays can be used to identify if antibodies are present that bind to the therapeutic, and when necessary, biological assays can be used to identify if those antibodies neutralize the effect of the therapeutic. Under certain circumstances including intravenous dosing of a mAb therapeutic, anti-drug antibodies can form large immune complexes that can result in a safety issue. The value of immunogenicity data in preclinical studies is to aid in interpretation of other study data when necessary.
最近的 ICH S6 指导原则指出，在生物技术衍生的生物制药的临床前安全性评估中，并非总是需要检测抗药物抗体来确定蛋白治疗药物的安全性。大多数人类蛋白治疗药物在临床前研究中会引起快速而强烈的抗药物抗体反应，而循环药物水平高会使抗药物抗体的检测变得复杂。临床前研究中存在抗药物抗体并不能预测蛋白治疗药物是否会在临床上具有免疫原性。当需要检测抗药物抗体时，可以使用各种分析程序，但这些方法各有优缺点。免疫测定可用于确定是否存在与治疗药物结合的抗体，必要时，生物学测定可用于确定这些抗体是否中和治疗药物的作用。在某些情况下，包括静脉内给予单抗治疗药物时，抗药物抗体可能会形成大的免疫复合物，从而导致安全性问题。临床前研究中免疫原性数据的价值在于在必要时帮助解释其他研究数据。
