Preclinical pharmacokinetics, tolerability, and pharmacodynamics of metuzumab, a novel CD147 human-mouse chimeric and glycoengineered antibody.
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.
Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xian, PR China.
Zheng
Z
Zhang
Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xian, PR China.
Yang
Y
Zhang
Pacific Meinuoke Biopharmaceutical Company, Changzhou, PR China.
Qian
Q
Sun
Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xian, PR China.
Fei
F
Feng
Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xian, PR China.
Muren
M
Huhe
Pacific Meinuoke Biopharmaceutical Company, Changzhou, PR China. znchen@fmmu.edu.cn milicec@pmbp.cn.
Li
L
Mi
Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xian, PR China. znchen@fmmu.edu.cn milicec@pmbp.cn.
Zhinan
Z
Chen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051926:Basigin / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007694:Killer Cells, Natural; D008175:Lung Neoplasms / Q000188:drug therapy*; D008252:Macaca fascicularis; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; C000601492:metuzumab; D051926:Basigin