抗体药物偶联物的免疫原性检测：ado曲妥珠单抗（ado-trastuzumab emtansine）的案例研究
Immunogenicity assays for antibody-drug conjugates: case study with ado-trastuzumab emtansine.
作者信息
Carrasco-Triguero Montserrat, Yi Joo-Hee, Dere Randall, Qiu Zhihua Julia, Lei Corinna, Li Yanhong, Mahood Connie, Wang Bei, Leipold Douglas, Poon Kirsten Achilles, Kaur Surinder
机构信息
Department of Bioanalytical Sciences, Genentech, South San Francisco, CA 94080, USA.
出版信息
Bioanalysis. 2013 May;5(9):1007-23. doi: 10.4155/bio.13.64.
BACKGROUND
Antibody-drug conjugates (ADCs) such as Kadcyla™ (ado-trastuzumab emtansine [T-DM1]) present covalently bound cytotoxic drugs, which may influence their immunogenicity potential compared with antibody therapies. Therefore, ADCs require assay strategies that allow measurement of responses to all the molecular components.
RESULTS
The immunogenicity strategy for T-DM1 used a risk-based, tiered approach that included screening and titration to detect antitherapeutic antibodies; confirmation of positive responses; and characterization to assess whether the immune response is primarily to the antibody or to the linker-drug and/or new epitopes in trastuzumab resulting from conjugation.
CONCLUSION
The tiered immunogenicity assay strategy for T-DM1 allowed detection of antitherapeutic antibodies to all components of the ADC in multiple nonclinical and clinical studies. Characterization strategies implemented in clinical studies provided additional insights into the specificity of the immune response.
背景
诸如赫赛莱（ado曲妥珠单抗偶联物[T-DM1]）等抗体药物偶联物（ADC）呈现共价结合的细胞毒性药物，与抗体疗法相比，这可能会影响其免疫原性潜力。因此，ADC需要能够测量对所有分子成分反应的检测策略。
结果
T-DM1的免疫原性检测策略采用基于风险的分层方法，包括筛选和滴定以检测抗治疗性抗体；确认阳性反应；以及进行特性分析以评估免疫反应主要是针对抗体，还是针对连接子-药物和/或曲妥珠单抗中因偶联产生的新表位。
结论
T-DM1的分层免疫原性检测策略能够在多项非临床和临床研究中检测到针对ADC所有成分的抗治疗性抗体。临床研究中实施的特性分析策略为免疫反应的特异性提供了更多见解。
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