抗体药物偶联物抗药抗体中和活性分析研究进展

Advance on neutralizing activity analysis of anti-drug antibody for antibody-drug conjugates

抗体药物偶联物(ADCs)是由单克隆抗体、连接子和小分子细胞毒素构成的多结构域分子。ADCs通过单克隆抗体特异性地结合肿瘤细胞表面高表达的靶抗原,经抗原介导的内化作用进入细胞并释放细胞毒素,可提高疗效并降低细胞毒素对正常组织、细胞的毒性。与常规单克隆抗体一样,ADCs作为蛋白药物,具有免疫原性。此外,由于偶联引入了新的抗原表位,ADCs药物有可能诱导机体产生更为复杂的免疫反应,从而可能影响药物的有效性和安全性。对ADCs诱导的抗药抗体(ADA)进一步表征,尤其是中和活性试验,有助于分析和预测因ADA的产生而可能导致的对有效性和安全性的影响。由于ADCs药物结构和作用机理的特殊性,针对不同结构域而产生的ADA均可能具有中和活性,通过多种机制阻断ADCs药物内化,或阻碍细胞毒素分子释放,从而降低细胞杀伤效应或导致脱靶毒性。因此,ADCs药物的中和抗体检测方法的设计和开发不同于常规抗体类药物,且具有较大的挑战。本文简述了ADCs药物免疫原性分析中中和活性检测方法及目前存在的挑战,以期对该领域的相关研究提供借鉴和参考。

Antibody-drug conjugates(ADCs) are multi-domain molecules composed of monoclonal antibody,linker and small molecule cytotoxin. ADCs specifically bind to the target antigens highly expressed on the surface of tumor cells by monoclonal antibodies,enter the tumor cells via antigen-mediated internalization,and then release cytotoxins,which can improve the therapeutic effect and reduce the toxicity of cytotoxin to normal tissues and cells. As biotherapeutics,ADCs are immunogenic just like conventional monoclonal antibodies. Besides,due to the new antigenic epitopes introduced via conjugation,ADCs may induce increasingly complex immune responses,which may have potential impacts on its efficacy and safety. In immunogenicity analysis of ADCs,further characterization of the anti-drug antibodies(ADA),particularly neutralizing activities,would be helpful in analyzing and predicting the possible effects of ADA on drug efficacy and safety. Due to the complexity of the molecular structure and action mechanisms of ADCs,ADAs that are specificly induced by different domains of an ADC molecule may have neutralizing activities. The neutralizing ADAs may block the internalization of ADCs by various mechanisms,or block the release of cytotoxic molecules,thereby reducing the cytotoxic effects or resulting in off-target toxicity. Therefore,the format design and development of the assay on neutralizing antibody for ADCs have unique features compared with conventional monoclonal antibodies,and will face greater challenges. This review describes the analytical methods for neutralizing activity analysis in the immunogenicity test of ADCs and the existing challenges in order to provide reference for related researches in this field.