Clinical Immunology Department, Amgen Inc., Thousand Oaks, California, USA.
J Immunotoxicol. 2006 Sep 1;3(3):165-72. doi: 10.1080/15476910600908852.
Immunogenicity is an important factor that manufacturers must consider as they develop new protein therapeutics. It is important to understand the immunogenicity of new proteins both at the preclinical phase and in the clinical phase of development. This paper provides an overview of the issues that manufacturers should consider including some of the potential reasons that some proteins induce an immune response, a discussion regarding current methodology used to understand immunogenicity, and some examples of marketed protein therapeutics with immunogenicity issues. Given the increasing scrutiny from regulatory agencies around the way immunogenicity is assessed by manufacturers, the strategy of detecting and characterizing antibodies that are formed against protein therapeutics is becoming an important topic. Screening assays are typically performed first on all serum samples collected in the course of a trial to detect the presence of antibodies that can bind to the protein therapeutic. There are several platforms in use: radioimmune precipitation assays (RIP), enzyme linked immunosorbent assays (ELISA), electrochemiluminescent assays (ECL), and biosensor-based assays. Each has its advantages and disadvantages, and needs to be evaluated to identify the optimal platform for a specific therapeutic protein. Once antibodies are identified, a confirmatory assay is performed to verify and characterize the antibodies. A biological assay should be used next to test if these antibodies are capable of neutralizing the biological effect of the drug. Any sample that is positive for neutralizing antibodies, indicates that the antibody is probably having an impact on the patient's ability to derive full benefit from the therapeutic protein, and may be critical for patient safety.
免疫原性是制造商在开发新的蛋白质治疗药物时必须考虑的一个重要因素。了解新蛋白质在临床前和临床开发阶段的免疫原性非常重要。本文概述了制造商应该考虑的问题，包括一些导致某些蛋白质引起免疫反应的潜在原因，讨论了当前用于了解免疫原性的方法，以及一些具有免疫原性问题的上市蛋白质治疗药物的示例。鉴于监管机构对制造商评估免疫原性的方式越来越严格，检测和表征针对蛋白质治疗药物形成的抗体的策略正成为一个重要话题。筛选检测通常首先在试验过程中收集的所有血清样本上进行，以检测是否存在可以结合蛋白质治疗药物的抗体。有几种平台在使用：放射性免疫沉淀检测（RIP）、酶联免疫吸附检测（ELISA）、电化学发光检测（ECL）和基于生物传感器的检测。每种方法都有其优点和缺点，需要进行评估以确定特定治疗性蛋白质的最佳平台。一旦确定了抗体，就会进行确证检测以验证和表征抗体。接下来应该使用生物学检测来测试这些抗体是否能够中和药物的生物学效应。任何对中和抗体呈阳性的样本都表明抗体可能对患者从治疗性蛋白质中获得全部益处的能力产生影响，并且可能对患者安全至关重要。
