An important parcel must be delivered to the correct place. It is so important that it can be a question of life or death. However, uneven streets and missing railings risk derailing it, and leaving it undelivered. This is not the trailer of a drama, but what happens to anti-cancer drugs traveling towards a tumor area, but unable to reach it because of dysfunctional blood vessels. The Center for Vascular Research, within the Institute for Basic Science (IBS) discovered the antisepsis antibody ABTAA (Ang2-Binding and Tie2-Activating Antibody) reduces tumor volume and improves the delivery of anti-cancer drugs. Published in Cancer Cell, the study demonstrates that ABTAA restores the structural and functional integrity of tumor blood vessels in three different tumor models: Breast, lungs and brain.

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 an established tumor, the endothelial junctions are broken apart and pericytes also detach. Blood flowing in and out from the tumor is severely restricted and tumor vessels lacking an intact vessel wall become leaky. This microenvironment causes limited drug delivery to the tumor and leads to inadequate oxygen supply (hypoxia) and even metastasis. IBS scientists found the antibody ABTAA normalizes the tumor vessels and hence, changes the whole tumor microenvironment. "We call it normalization of tumor vessels, because it resembles closely the wall architecture of healthy, normal vessels," explains PARK Jin-Sung, first author of the study. "Tumors adapt to hypoxia and get more aggressive, so we tried to prevent this transition by normalizing tumor vessels. ABTAA changes the whole tumor environment, oxygenation status and level of lactate, so that the immune cells and drugs can reach the core regions of the tumor more easily. In this way, we created a favorable ground for tumor treatment."

In an attempt to generate antibodies targeting the protein Ang2, which is specifically expressed by endothelial cells in stressful conditions like in a tumor, the team unexpectedly discovered that ABTAA has a dual function and a peculiar way of working. ABTAA not only blocks Ang2, but simultaneously activates Tie2. Tie2 is a receptor present on the cell membrane of endothelial cells. ABTAA causes Ang2 to cluster together and strongly activates Tie2 receptors. "If we activate Tie2, we can efficiently normalize tumor vessels, enhance drug delivery and change the whole microenvironment," explains KOH Gou Young, Director of the Center for Vascular Research.

Several pharmaceutical companies are developing Ang2-blocking antibodies to cure cancer. However, even if these antibodies significantly inhibit tumor progression, they do not stop tumor hypoxia. Moreover, most of the anti-cancer drugs target the tumor at its early stage, when tumors are still hard to diagnose. ABTAA, instead, works with tumors that are already rooted: "When the tumor is established, hypoxia is the main driver of tumor progression. So, if we eliminate hypoxia, we make the tumor milder, by reducing its progression and metastasis," comments Koh.

▲ Schematic drawing of a blood vessel around tumors before and after treatment with ABTAA. The picture above shows a typical tumor vasculature characterized by damaged walls, red blood cells leakage and detached pericytes. Activating Tie2 on endothelial cells with the antibody ABTAA restores the normal vessel architecture: endothelial and pericytes on the vessel walls are stabilized. The delivery of blood is improved, and the anticancer drugs are more likely to reach the tumor core.

IBS researchers tested ABTAA in mice with three different types of tumors that show high levels of Ang2: Glioma (a type a brain tumor), lung carcinoma and breast cancer. They also compared the effect of ABTAA with ABA, another antibody that blocks Ang2 but misses the activating properties of Tie2. 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.

Glioma is one of the so-called intractable diseases, because of its poor prognosis and treatment. IBS scientists found that the glioma volume reduced by 39% when treated with ABTAA and 17% with ABA. ABTAA profoundly reduced vascular leakage and edema formation in glioma through promoting vascular tightening. Moreover, when ABTAA was administered together with the chemotherapeutic drug temozolomide (TMZ), the tumor volume reduces further (76% by ABTAA+TMZ, 51% by ABA+TMZ, and 36% by TMZ).

In the Lewis Lung Carcinoma (LLC) tumor model, the research team administered ABTAA together with a chemotherapeutic drug called cisplatin (Cpt) and observed a greater suppression of tumor growth (52%) compared with the controls and increased overall survival. Moreover, ABTAA+Cpt led to a marked increase in necrotic area within tumors. Finally, in a spontaneous breast cancer model, ABTAA delayed tumor growth and enhanced the anti-tumor effect of Cpt.

▲ The antibody ABTAA and in combination with other anti-cancer drugs have a beneficial effect in reducing tumor volume. ABTAA was tested in mice with brain (glioma), lung or breast cancer. The image shows the improvements: Reduction in glioma tumor size, reduction in metastatic colonies in lung tumor and decrease in necrotic regions in breast tumor.

In the future, the team would like to further understand the underlying relationship between faulty blood vessels and diseases. "We would like to apply this antibody to an organ that is rich in blood vessels, like the eye; and see if this antibody can be useful to treat eye diseases such as age-related macular degeneration and diabetic retinopathy," concludes Koh.

▲ Gou Young Koh (left) and Jin-Sung Park, the corresponding and first authors of the paper.

Letizia Diamante