Abstract
Metuzumab is an affinity-optimized and nonfucosylated anti-CD147 human-mouse chimeric IgG1 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC). The purpose of this study was to characterize the pharmacokinetics, safety, and antitumor activities of metuzumab in mouse, rat, and monkey. The ADCC activity was assessed by a lactate dehydrogenase release assay. The pharmacokinetics of metuzumab were determined in Sprague-Dawley rats and in cynomolgus monkeys. Single- and repeat-dose toxicology studies of the i.v. administration of high-dose metuzumab were conducted in cynomolgus monkeys. Mice bearing human tumor xenografts were used to evaluate the antitumor efficacy of metuzumab. The ADCC potency of metuzumab was enhanced compared with the nonglycoengineered parental antibody. Metuzumab also effectively inhibited tumor growth in A549 and NCI-H520 xenograft models. In the monkey model, the total clearance of metuzumab decreased with increasing dose. The nonspecific clearance in monkeys was estimated to be 0.53 to 0.92 mL/h/kg. In single- and repeat-dose toxicology studies in cynomolgus monkeys, metuzumab did not induce any distinct or novel adverse findings and was well tolerated at all tested doses. These preclinical safety data facilitated the initiation of an ongoing clinical trial of metuzumab for the treatment of non-small cell lung cancer (NSCLC) in China.
Highlights
Lung cancer is the leading cause of cancer morbidity and mortality in men and women worldwide [1], and is prevalent in China
The glycan profile of the antibodies was determined by HPAECPAD (28, 29; Fig. 1A; see Supplementary Materials and Methods for more details); in cHAb18, fucosylated IgG secreted from the wild-type CHO cells, the core fucose was determined and G0F, G1F, G10F glycoforms were the most prominent forms; metuzumab exhibits homogeneous glycosylation with a single major N-glycan and generates a Man5 glycoform, but no fucose or xylose was detected
Our results revealed a trend of dosedependent trend of antitumor effect among the three metuzumab treatment groups (P 1⁄4 0.5699), and the antitumor effects observed in the metuzumab treatment groups were equal or a slight superior than those observed in the group treated with the chemical drug group alone
Summary
Lung cancer is the leading cause of cancer morbidity and mortality in men and women worldwide [1], and is prevalent in China. In China in 2012, there were an estimated 0.59 million new lung cancer cases (0.33 and 0.26 million men and women, respectively) and 0.68 million deaths (0.38 and 0.30 million men and women, respectively) representing 25.2% of all cancer deaths in China [2]. Lung cancer ranks as most common cancers in China in terms of incidence and mortality. The high rate of lethality of lung cancer is primarily attributed to an advanced stage of disease at the time of diagnosis. Non–small cell lung cancer (NSCLC) comprises approximately 75% to 80% of all lung cancer.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
