title: An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer.
abstract: Antibody-drug conjugate (ADC) is a novel class of therapeutics for cancer target therapy. This study assessed antitumor activity of ADC with an antimitotic agent, monomethyl auristatin E (MMAE) and a humanized monoclonal anti-HER2 antibody, hertuzumab, in gastric cancer. The efficacy of hertuzumab-MC-Val-Cit-PAB-MMAE (hertuzumab-vcMMAE) on human epidermal growth factor receptor 2 (HER2) positive human gastric cancer cells, NCI-N87, was evaluated in vitro and in vivo. The cytotoxicity of hertuzumab was significantly enhanced after conjugation with MMAE. Compared to trastuzumab, hertuzumab had a higher affinity to HER2 and had more potent antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. After conjugation with MMAE, the binding specificity for HER2 was not affected. Furthermore, the internalization of hertuzumab-vcMMAE in HER2 positive gastric cancer cells was verified. Although the conjugation of hertuzumab and MMAE decreased the ADCC effect, the overall cytotoxicity was dramatically increased in HER2 positive gastric cancer cells. In vitro data on this hertuzumab-vcMMAE has exerted much stronger antitumor activity compared to trastuzumab-DM1 in HER2 positive gastric cancer cells. A single administration of hertuzumab-vcMMAE at 5 or 10 mg/kg showed high potency and a sustained tumor inhibitory effect on NCI-N87 xenografts in mice. In conclusion, hertuzumab-vcMMAE conjugate is a highly effective anti-HER2 targeted therapy for HER2-positive gastric cancer.
authors: a School of Life Sciences and Technology, Tongji University , Shanghai , China.
authors: Hongwen
authors: H
authors: Li
authors: b RemeGen, Ltd. , Yantai , Shandong , China.
authors: Chao
authors: C
authors: Yu
authors: c School of Pharmacy, Binzhou Medical University , Yantai , Shandong , China.
authors: Jing
authors: J
authors: Jiang
authors: b RemeGen, Ltd. , Yantai , Shandong , China.
authors: Changjiang
authors: C
authors: Huang
authors: a School of Life Sciences and Technology, Tongji University , Shanghai , China.
authors: Xuejing
authors: X
authors: Yao
authors: b RemeGen, Ltd. , Yantai , Shandong , China.
authors: Qiaoyu
authors: Q
authors: Xu
authors: b RemeGen, Ltd. , Yantai , Shandong , China.
authors: Fang
authors: F
authors: Yu
authors: d Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China.
authors: Liguang
authors: L
authors: Lou
authors: a School of Life Sciences and Technology, Tongji University , Shanghai , China.|e Tongji University Suzhou Institute , Suzhou , Jiangsu , China.|f Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
authors: Jianmin
authors: J
authors: Fang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D009842:Oligopeptides; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse; C495575:monomethyl auristatin E
keywords: Antibody drug conjugate; HER2; gastric cancer; monomethyl auristatin E; target therapy