title: MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth.
abstract: Increasing evidence suggests that DLL4 (Delta-like 4)-Notch signaling plays a critical role in cell fate determination and differentiation in tissues. Blocking DLL4-Notch signaling results in inhibition of tumor growth, which is associated with increased nonfunctional vessels and poor perfusion in the tumor. We successfully generated a human DLL4 monoclonal antibody MMGZ01 that binds specifically to DLL4 to disrupt the interaction between DLL4 and Notch1. MMGZ01 showed high affinity to DLL4 to inhibit the DLL4-mediated human umbilical vein endothelial cell (HUVEC) phenotype. Furthermore, MMGZ01 stimulated HUVEC vessel sprouting and tubule formation in vitro. In addition, MMGZ01 had a pronounced effect in promoting immature vessels and reduced breast cancer cell growth in vivo. Finally, MMGZ01 treatment inhibited the proliferation of breast cancer cells, induced tumor cell apoptosis, suppressed mammosphere formation, decreased CD44(+)/CD24(-) cell population, and reduced epithelial mesenchymal transition (EMT). These findings suggest that antagonism of the DLL4-Notch signaling pathway might provide a potential therapeutic approach for breast cancer treatment.
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhuobin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zegen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Luxuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Shijing
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: minwang@cpu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: juancpu@126.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: mickeywu2001@163.com.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation / Q000187:drug effects*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051881:Receptor, Notch1 / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D043823:Taxoids; D000077143:Docetaxel
keywords: Angiogenesis; Antitumor; Breast cancer; DLL4 monoclonal antibody; Nonfunctional vessels; Notch