AsianScientist (Dec. 22, 2016) – Researchers from the Institute for Basic Science (IBS) in South Korea have shown that a dual-target antibody can improve the delivery of anti-cancer drugs by normalizing the blood vessels within the tumor. Their study has been published in Cancer Cell.
Blood vessels inside and around an established tumor can be described as a chaotic and dysfunctional labyrinth. While the inner walls of healthy blood vessels are surrounded and supported by endothelial cells and other cells called pericytes; in the established tumor, the endothelial junctions are broken apart and pericytes are also detached. This microenvironment causes limited drug delivery to the tumor and leads to inadequate oxygen supply (hypoxia) and even metastasis.
In previous research to generate antibodies targeting the Ang2 protein to treat sepsis, a team led by Professor Koh Gou Young discovered ABTAA (Ang2-Binding and Tie2-Activating Antibody), a dual-targeting antibody that not only blocks Ang2 but also actives another protein called Tie2 at the same time. Tie2 is a receptor present on the cell membrane of endothelial cells, while Ang2 is specifically expressed by endothelial cells in stressful conditions like sepsis or a tumor.
The team tested ABTAA in mice with three different types of tumors that show high levels of Ang2: glioma, lung carcinoma and breast cancer. They also compared the effect of ABTAA with ABA, another antibody that blocks Ang2 but lacks Tie2 activating properties. In all three cases, ABTAA was superior to ABA in inducing tumor vessel normalization, which led to a better delivery of the anti-cancer drugs into the tumor core region.
“If we activate Tie2, we can efficiently normalize tumor vessels, enhance drug delivery and change the whole microenvironment,” explained Koh, who is the director of the Center for Vascular Research at IBS.
“We call it normalization of tumor vessels, because it resembles closely the wall architecture of healthy, normal vessels,” explained Professor Park Jin-Sung, first author of the study. “In this way, we create a favorable ground for tumor treatment.”
Several pharmaceutical companies are developing Ang2-blocking antibodies to treat cancer. However, even if these antibodies significantly inhibit tumor progression, they do not stop tumor hypoxia. Moreover, most anti-cancer drugs target the tumor at its early stage, when tumors are still hard to diagnose. In contrast, ABTAA works with tumors that are already established.
“When the tumor is established, hypoxia is the main driver of tumor progression. So, if we eliminate hypoxia, we make the tumor more mild by reducing its progression and metastasis,” Koh added.
In the future, the team would like to further understand the underlying relationship between faulty blood vessels and other diseases.
“We would like to apply this antibody to an organ that is rich in blood vessels, such as the eye, and see if this antibody can be useful to treat eye diseases such as age-related macular degeneration and diabetic retinopathy,” Koh concluded.
The article can be found at: Park et al. (2016) Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment.
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Source: Institute for Basic Science.
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