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传统体外毒性试验在评估单克隆抗体不良反应中的适用性：利妥昔单抗和曲妥珠单抗的案例研究

Applicability of Traditional In Vitro Toxicity Tests for Assessing Adverse Effects of Monoclonal Antibodies: A Case Study of Rituximab and Trastuzumab.

作者信息

Kizhedath Arathi, Wilkinson Simon, Glassey Jarka

机构信息

School of Engineering, Newcastle University, Newcastle Upon Tyne NE17RU, UK.

Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.

出版信息

Antibodies (Basel). 2018 Aug 17;7(3):30. doi: 10.3390/antib7030030.

DOI:10.3390/antib7030030
PMID:31544882
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6640679/
Abstract

Monoclonal antibody (mAb) therapeutics have a promising outlook within the pharmaceutical industry having made positive strides in both research and development as well as commercialisation, however this development has been hampered by manufacturing failures and attrition. This study explores the applicability of traditional in vitro toxicity tests for detecting any off-target adverse effect elicited by mAbs on specific organ systems using hepatocarcinoma cell line (HepG2) and human dermal fibroblasts neonatal (HDFn), respectively. The mechanism of antibody dependent cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) via complement activation, and complement dependent cellular cytotoxicity (CDCC) were assessed. Major results: no apparent ADCC, CDCC, or CDC mediated decrease in cell viability was measured for HepG2 cells. For HDFn cells, though ADCC or CDCC mediated decreases in cell viability wasn't detected, a CDC mediated decrease in cell viability was observed. Several considerations have been elucidated for development of in vitro assays better suited to detect off target toxicity of mAbs.

摘要

单克隆抗体（mAb）疗法在制药行业前景广阔，在研发和商业化方面均取得了积极进展，然而，这一发展受到生产失败和损耗的阻碍。本研究探讨了传统体外毒性试验在检测单克隆抗体对特定器官系统引发的任何脱靶不良反应方面的适用性，分别使用肝癌细胞系（HepG2）和新生儿人皮肤成纤维细胞（HDFn）。评估了抗体依赖性细胞毒性（ADCC）、通过补体激活的补体依赖性细胞毒性（CDC）和补体依赖性细胞毒性（CDCC）的机制。主要结果：未检测到HepG2细胞因ADCC、CDCC或CDC介导的细胞活力明显下降。对于HDFn细胞，虽然未检测到ADCC或CDCC介导的细胞活力下降，但观察到CDC介导的细胞活力下降。已阐明了一些考虑因素，以开发更适合检测单克隆抗体脱靶毒性的体外试验。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/9215da951ca3/antibodies-07-00030-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/afa860f713d5/antibodies-07-00030-g0A1a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/1e35ec06af7c/antibodies-07-00030-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/abdc8bfb2ab2/antibodies-07-00030-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/74d73153ba03/antibodies-07-00030-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/fa452aca2c46/antibodies-07-00030-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/9215da951ca3/antibodies-07-00030-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/afa860f713d5/antibodies-07-00030-g0A1a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/1e35ec06af7c/antibodies-07-00030-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/abdc8bfb2ab2/antibodies-07-00030-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/74d73153ba03/antibodies-07-00030-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/fa452aca2c46/antibodies-07-00030-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cab/6640679/9215da951ca3/antibodies-07-00030-g005.jpg

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本文引用的文献

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使用体外试验评估基于抗体的生物治疗药物的免疫原性风险。
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