title: Efficacy of anti-RON antibody Zt/g4-drug maytansinoid conjugation (Anti-RON ADC) as a novel therapeutics for targeted colorectal cancer therapy.
abstract: OBJECTIVE
  The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4-maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy.
  
  
  METHODS
  Zt/g4 (IgG1a/κ) was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. CRC cell lines expressing different levels of RON were tested in vitro to determine Zt/g4-DM1-induced RON endocytosis, cell-cycle arrest, and cytotoxicity. Efficacy of Zt/g4-DM1 in vivo was evaluated in mouse xenograft CRC tumor model.
  
  
  RESULTS
  Zt/g4-DM1 rapidly induced RON endocytosis, arrested cell cycle at G2-M phase, reduced cell viability, and caused massive cell death within 72 hours. In mouse xenograft CRC models, Zt/g4-DM1 at a single dose of 20 mg/kg body weight effectively delayed CRC cell-mediated tumor growth up to 20 days. In a multiple dose-ranging study with a five injection regimen, Zt/g4-DM1 inhibited more than 90% tumor growth at doses of 7, 10, and 15 mg/kg body weight. The minimal dose achieving 50% of tumor inhibition was approximately 5.0 mg/kg. The prepared Zt/g4-DM1 is stable at 37°C for up to 30 days. At 60 mg/kg, Zt/g4-DM1 had a moderate toxicity in vivo with an average of 12% reduction in mouse body weight.
  
  
  CONCLUSIONS
  Zt/g4-DM1 is highly effective in targeted inhibition of CRC cell-derived tumor growth in mouse xenograft models. This work provides the basis for development of humanized Zt/g4-DM1 for RON-targeted CRC therapy in the future.
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China. Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.
authors.forename: Liang
authors.initials: L
authors.lastname: Feng
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China.
authors.forename: Hang-Ping
authors.initials: HP
authors.lastname: Yao
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, First Hospital of Zhejiang University School of Medicine, Zhejiang, China.
authors.forename: Yong-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.affiliation: Department of Molecular Cell Biology and Toxicology, Nanjing Medical University School of Public Health, Jiangsu, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China. Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas. minghai.wang@ttuhsc.edu.
authors.forename: Ming-Hai
authors.initials: MH
authors.lastname: Wang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D008453:Maytansine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D008453:Maytansine; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases