title: Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy.
abstract: Antibody-drug conjugates (ADCs) have exhibited potent clinical benefits in cancer therapy. However, development of ADCs against epidermal growth factor receptor (EGFR) has limitations because of wide expression of EGFR in both normal and tumor tissues. Previously, we developed an anti-EGFR protease-activated antibody (pro-antibody), termed as PanP, which remains inert against EGFR until activated by tumor-specific protease. Herein, we for the first time report a new class of pro-antibody-drug conjugate (PDC) against EGFR, denoted as PanP-DM1. It has been designed to selectively target the EGFR-overexpressing tumor cells and exert greater anti-tumor activity compared with PanP. Our data showed that PanP-DM1 also could be selectively activated by tumor-specific protease 'uPA'. Furthermore, activated PanP-DM1 was potently cytotoxic against EGFR-overexpressing tumor cell lines in vitro. Crucially, our data indicated that PanP-DM1 was significantly more effective in eradicating EGFR-overexpressing tumors in vivo. Additionally, toxicity was preliminarily evaluated in mice as measured by body weight loss. In summary, our study suggests that PanP-DM1, a novel pro-antibody-drug conjugate, has cancer-selectivity, efficacy and safety profile that supports its potential use for EGFR-overexpressing tumors.
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|b School of Basic Medical Sciences, Xinxiang Medical University , Xinxiang , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.
authors.forename: Qingcheng
authors.initials: Q
authors.lastname: Guo
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.|f School of Bioscience and Bioengineering, South China University of Technology , Guangzhou , China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.|d Zhangjiang Biotechnology Co. Ltd , Shanghai , China.
authors.forename: Huaizu
authors.initials: H
authors.lastname: Guo
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.|d Zhangjiang Biotechnology Co. Ltd , Shanghai , China.
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.affiliation: c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.|e School of Pharmacy, Liaocheng University , Liaocheng , China.|f School of Bioscience and Bioengineering, South China University of Technology , Guangzhou , China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|c State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China.|e School of Pharmacy, Liaocheng University , Liaocheng , China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D011498:Protein Precursors / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology
chemical_list: D000912:Antibodies, Neoplasm; D011498:Protein Precursors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Cancer-selective activation; EGFR; Pro-antibody-drug conjugate; Therapeutic efficacy; Toxicity evaluation