Qu Zhe, Lyu Jianjun, Liu Yue, Wang Xin, Lin Zhi, Yang Yanwei, Zhang Di, Geng Xingchao, Li Bo
Beijing Key Laboratory for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing 100176, China.
Sunshine Guojian Pharmaceuticals (Shanghai) Co., Ltd., Shanghai 201203, China.
Ann Transl Med. 2020 Mar;8(6):325. doi: 10.21037/atm.2020.02.106.
CPGJ701 is a recombinant humanized anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody-derivative of the cytotoxic agent maytansine (DM1) conjugate for the treatment of HER2-positive metastatic breast cancer. Tissue cross-reactivity (TCR) studies of CPGJ701 in a complete panel of normal human, cynomolgus monkey and Sprague-Dawley were performed to provide evidence for selecting animal species for use in preclinical toxicity studies and predicting primary target organs and clinical adverse drug reactions (ADRs).
TCR studies were carried out to evaluate the distribution of reactivity and the TCR of CPGJ701 in paraffin sections of 32 tissues and/or organs (such as the heart, lung, liver, and kidney) from at least three unrelated normal human, cynomolgus monkey and Sprague-Dawley rat donors. The TCR of CPGJ701was detected by one-step immunohistochemical method using 50 µg/mL biotin-labeled CPGJ701 as the primary antibody. Moreover, a negative biotin-labeled human IgG control group, a blank phosphate-buffered saline (PBS) control group, and a positive human breast cancer tissue control group were also used to exclude false positive and false negative results. The specific positive binding and distribution of reactivity of CPGJ701 were detected in the human breast cancer tissue and 32 tissues from normal humans, cynomolgus monkeys and Sprague-Dawley rats under a microscope.
The TCR of CPGJ701 in humans and cynomolgus monkeys was highly consistent but showed some differences compared to the TCR of CPGJ701 in Sprague-Dawley rats. The binding of CPGJ701 to target tissues, such as the liver, adrenal gland, thyroid, fallopian tube, spinal cord and skin, was observed in humans and cynomolgus monkeys but not in Sprague-Dawley rats. Specific binding to the placenta was only found in Sprague-Dawley rats. The cell types to which CPGJ701 specifically bound, including epithelial cells, cardiomyocytes and nerve cells, were identical in humans, cynomolgus monkeys and rats.
The TCR of CPGJ701 was in accord with the targeting characteristics of the humanized anti-HER2 monoclonal antibody. The consistency of CPGJ701 binding to human and cynomolgus monkey tissues indicated that the cynomolgus monkey is a relevant animal species for evaluating the preclinical safety of CPGJ701. The targeting (binding site) of CPGJ701 in Sprague-Dawley rats indicated that it is also a useful animal species for evaluating antibody-dependent toxicity and non-antibody-dependent toxicity. In conclusion, these TCR studies of CPGJ701 could provide information for selecting relevant animal species for nonclinical studies and predicting clinical ADRs.
CPGJ701是一种重组人源化抗人表皮生长因子受体2（HER2）单克隆抗体，它是细胞毒性药物美登素（DM1）的共轭物，用于治疗HER2阳性转移性乳腺癌。对CPGJ701在一整套正常人、食蟹猴和Sprague-Dawley大鼠组织中进行组织交叉反应性（TCR）研究，为选择用于临床前毒性研究的动物物种以及预测主要靶器官和临床药物不良反应（ADR）提供依据。
进行TCR研究，以评估CPGJ701在来自至少三只无关的正常人、食蟹猴和Sprague-Dawley大鼠供体的32种组织和/或器官（如心脏、肺、肝脏和肾脏）石蜡切片中的反应性分布和TCR。使用50μg/mL生物素标记的CPGJ701作为一抗，通过一步免疫组织化学方法检测CPGJ701的TCR。此外，还使用生物素标记的人IgG阴性对照组、空白磷酸盐缓冲盐水（PBS）对照组和人乳腺癌组织阳性对照组来排除假阳性和假阴性结果。在显微镜下检测CPGJ701在人乳腺癌组织以及正常人、食蟹猴和Sprague-Dawley大鼠的32种组织中的特异性阳性结合和反应性分布。
CPGJ701在人和食蟹猴中的TCR高度一致，但与Sprague-Dawley大鼠中CPGJ701的TCR相比存在一些差异。在人和食蟹猴中观察到CPGJ701与肝脏、肾上腺、甲状腺、输卵管、脊髓和皮肤等靶组织的结合，但在Sprague-Dawley大鼠中未观察到。仅在Sprague-Dawley大鼠中发现与胎盘的特异性结合。CPGJ701特异性结合的细胞类型，包括上皮细胞、心肌细胞和神经细胞，在人、食蟹猴和大鼠中是相同的。
CPGJ701的TCR符合人源化抗HER2单克隆抗体的靶向特征。CPGJ701与人及食蟹猴组织结合的一致性表明，食蟹猴是评估CPGJ701临床前安全性的相关动物物种。CPGJ701在Sprague-Dawley大鼠中的靶向（结合位点）表明，它也是评估抗体依赖性毒性和非抗体依赖性毒性的有用动物物种。总之，这些CPGJ701的TCR研究可为选择用于非临床研究的相关动物物种以及预测临床ADR提供信息。
