2020-03-01·Annals of translational medicine4区 · 医学
Tissue cross-reactivity studies of CPGJ701 in humans, cynomolgus monkeys and Sprague-Dawley rats and correlation analysis with in vivo toxicity.
4区 · 医学
作者: Zhe Qu ; Jianjun Lyu ; Yue Liu ; Xin Wang ; Zhi Lin ; Yanwei Yang ; Di Zhang ; Xingchao Geng ; Bo Li
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.