DLL4, short for delta-like protein 4, is a Notch ligand that participates in the Notch signaling pathway, activating NOTCH1 and NOTCH4. It is involved in angiogenesis and negatively regulates endothelial cell proliferation and migration, as well as angiogenesis, making DLL4 an attractive therapeutic target.
Expression distribution of DLL4
DLL4 is expressed in adipocytes, endothelial cells, intestinal goblet cells, lymphatic endothelial cells, and primarily in the tip cells of new blood vessels. Studies have found that DLL4 expression is abnormally elevated in tumor tissues such as breast cancer, bladder cancer, colorectal cancer, liver cancer, ovarian cancer, and pancreatic cancer.
(Data source: uniprot)
The structure of DLL4:
DLL4 is a type I single-pass transmembrane protein composed of 658 amino acids, with an N-terminal extracellular domain, a C-terminal cytoplasmic domain, and a transmembrane domain. The extracellular domain contains eight epidermal growth factor (EGF)-like repeats that bind to and activate Notch receptors, four glycosylation sites, and a highly conserved DSL region. The intracellular domain is cleaved upon DLL4 binding to Notch, regulating gene transcription.
(Data source: Luca VC, et al. Science. 2015)
The role of DLL4 signaling regulation in vascular regulation
Upon binding to the Notch receptor, DLL4 triggers a series of proteolytic cleavage events, including the involvement of ADAM10 and γ-secretase. These cleavage events lead to the release of the Notch receptor intracellular domain (NICD) from the cell membrane and its translocation to the nucleus, where it interacts with cofactors to regulate the expression of target genes involved in EndoMT, angiogenesis, and CSC biology.
(Data source: Akil A, et al. Front Cell Dev Biol. 2021)
DLL4 can negatively regulate angiogenesis in vascular endothelial cells by activating the Notch1 signaling pathway, thereby inhibiting abnormal angiogenesis. DLL4 also plays a crucial role in arteriogenesis, potentially regulating the differentiation and survival of arterial endothelial cells through cross-talk with factors such as VEGF. In the tumor microenvironment, inhibition of the DLL4/Notch1 signaling pathway can lead to abnormal tumor angiogenesis, thereby suppressing tumor growth. Targeting the DLL4/Notch1 signaling pathway may be an effective anti-angiogenic therapeutic strategy.
(Data source: Akil A, et al. Front Cell Dev Biol. 2021)
DLL4-targeted drugs
There are currently seven antibodies targeting DLL4 under research, of which three bispecific antibodies have entered the clinical research stage.
(Data source: New Drug Intelligence Database)
Navicixizumab is a bispecific antibody developed by Oncomed that targets DLL4 and VEGF. It is used to treat platinum-resistant fallopian tube cancer, platinum-resistant ovarian cancer, primary peritoneal cancer, advanced malignant solid tumors and other diseases. It is in the clinical III research stage.
TR-009 (CTX-009), a bispecific antibody developed by ABL Bio that targets DLL4 and VEGF-A, induces tumor cell death by inhibiting the formation of new blood vessels in cancer. It is currently in Phase II/III clinical trials for the treatment of cholangiocarcinoma, ampulla of Vater carcinoma, and gallbladder cancer. COMPANION-002 is a Phase II/III trial of CTX-009 in combination with paclitaxel in patients with advanced biliary tract cancer. CTX-009 received Fast Track designation from the U.S. Food and Drug Administration (FDA) in April 2024, which supports rapid drug development. Another Phase II clinical trial in patients with colorectal cancer is also ongoing.
Dilpacimab, developed by AbbVie, is an IgG1 bispecific antibody targeting DLL4 and VEGF-A for the treatment of advanced malignant solid tumors and is currently in Phase I clinical trials.
(Data source: You WK, et al. Mol Cancer Ther. 2023)
