MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth

Zhuobin Xu; Zegen Wang; Xuelian Jia; Luxuan Wang; Zhiguo Chen; Shijing Wang; Min Wang; Juan Zhang; Min Wu

doi:10.1016/j.canlet.2015.12.025

MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth

Cancer Lett. 2016 Mar 1;372(1):118-27. doi: 10.1016/j.canlet.2015.12.025. Epub 2015 Dec 29.

Authors

Zhuobin Xu¹, Zegen Wang¹, Xuelian Jia¹, Luxuan Wang¹, Zhiguo Chen¹, Shijing Wang¹, Min Wang², Juan Zhang³, Min Wu⁴

Affiliations

¹ State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
² State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: minwang@cpu.edu.cn.
³ State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: juancpu@126.com.
⁴ State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: mickeywu2001@163.com.

PMID: 26739060
DOI: 10.1016/j.canlet.2015.12.025

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.

Keywords: Angiogenesis; Antitumor; Breast cancer; DLL4 monoclonal antibody; Nonfunctional vessels; Notch.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Angiogenesis Inhibitors / pharmacology*
Animals
Antibodies, Monoclonal / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis / drug effects
Breast Neoplasms / blood supply
Breast Neoplasms / drug therapy*
Breast Neoplasms / immunology
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Calcium-Binding Proteins
Cell Proliferation / drug effects*
Docetaxel
Dose-Response Relationship, Drug
Epithelial-Mesenchymal Transition / drug effects
Female
HEK293 Cells
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / immunology
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Intercellular Signaling Peptides and Proteins / immunology*
Intercellular Signaling Peptides and Proteins / metabolism
MCF-7 Cells
Mice
Mice, Nude
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / immunology
Neoplastic Stem Cells / metabolism
Neovascularization, Pathologic*
Neovascularization, Physiologic / drug effects
Receptor, Notch1 / metabolism
Taxoids / pharmacology
Time Factors
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Signal Transducing
Angiogenesis Inhibitors
Antibodies, Monoclonal
Calcium-Binding Proteins
DLL4 protein, human
Intercellular Signaling Peptides and Proteins
NOTCH1 protein, human
Receptor, Notch1
Taxoids
Docetaxel