title: Growth suppression of human hepatocellular carcinoma xenografts by a monoclonal antibody CH12 directed to epidermal growth factor receptor variant III.
abstract: Human hepatocellular carcinoma (HCC) is considered difficult to cure because it is resistant to radio- and chemotherapy and has a high recurrence rate after curative liver resection. Epidermal growth factor receptor variant III (EGFRvIII) has been reported to express in HCC tissues and cell lines. This article describes the efficacy of an anti-EGFRvIII monoclonal antibody (mAb CH12) in the treatment of HCC xenografts with EGFRvIII expression and the underlying mechanism of EGFRvIII as an oncogene in HCC. The results demonstrated that CH12 bound preferentially to EGFRvIII with a dissociation constant (K(d)) of 1.346 nm/liter. In addition, CH12 induces strong antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in Huh7-EGFRvIII (with exogenous expression of EGFRvIII) and SMMC-7721 (with endogenous expression of EGFRvIII) cells. Notably, CH12 significantly inhibited the growth of Huh7-EGFRvIII and SMMC-7721 xenografts in vivo with a growth inhibition ratio much higher than C225, a U. S. Food and Drug Administration-approved anti-EGFR antibody. Treatment of the two HCC xenografts with CH12 significantly suppressed tumor proliferation and angiogenesis. Mechanistically, in vivo treatment with CH12 reduced the phosphorylation of constitutively active EGFRvIII, Akt, and ERK. Down-regulation of the apoptotic protectors Bcl-x(L), Bcl-2, and the cell cycle regulator cyclin D1, as well as up-regulation of the cell-cycle inhibitor p27, were also observed after in vivo CH12 treatment. Collectively, these results indicate that the monoclonal antibody CH12 is a promising therapeutic agent for HCC with EGFRvIII expression.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Huamao
authors.initials: H
authors.lastname: Wang
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Tan
authors.forename: Suwen
authors.initials: S
authors.lastname: Hu
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.forename: Bizhi
authors.initials: B
authors.lastname: Shi
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Peiyong
authors.initials: P
authors.lastname: Li
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Zonghai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003603:Cytotoxins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; C494811:BCL2L1 protein, human; C436291:CDKN1B protein, human; D003603:Cytotoxins; D047908:Intracellular Signaling Peptides and Proteins; D051020:bcl-X Protein; C410723:epidermal growth factor receptor VIII; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases