title: A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity.
abstract: Human epidermal growth factor receptor-2 (HER2) is a validated therapeutic target for breast cancer and trastuzumab (Herceptin), a humanized anti-HER2 antibody, has significant anti-cancer effects in the clinic. However, breast cancer patients often experience disease progression after prolonged Herceptin treatment. To develop a more effective therapy, we generated humanized monoclonal antibody hertuzumab and hertuzumab-drug conjugates as novel breast cancer therapies. The hertuzumab was conjugated with small molecule cytotoxic agents monomethylauristatin E (MMAE) or monomethylauristatin F (MMAF) with various linkers to generate antibody-drug conjugates (ADCs), which were evaluated for their in vitro and in vivo anti-cancer activities. Among these ADCs, hertuzumab-vc-MMAE can be effectively internalized and potently kill HER2 over-expressing tumor cells. In xenograft tumor models, hertuzumab-vc-MMAE showed a more potent anti-tumor activity than T-DM1, a FDA-approved ADC drug. More importantly, this novel ADC drug also showed superior anti-tumor activity than T-DM1 in trastuzumab- and lapatinib-resistant xenograft tumor models, suggesting its potential as an improved therapy for HER2-positive breast cancers. The novel ADC, hertuzumab-vc-MMAE, is an effective and selective agent for the treatment of HER2-positive breast tumors.
authors.affiliation: School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Yao
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Changjiang
authors.initials: C
authors.lastname: Huang
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Kuan
authors.initials: K
authors.lastname: Xie
authors.forename: Qiaoyu
authors.initials: Q
authors.lastname: Xu
authors.forename: Hongwen
authors.initials: H
authors.lastname: Li
authors.forename: Zhuanglin
authors.initials: Z
authors.lastname: Li
authors.forename: Liguang
authors.initials: L
authors.lastname: Lou
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000494:pharmacology*; D000915:Antibody Affinity / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C495575:monomethyl auristatin E