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December 13, 2016

Sepsis Antibody Shrinks Tumors and Improves Drug Delivery

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    Schematic drawing of a blood vessel around tumors before and after treatment with ABTAA. Shown is 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. [Institute for Basic Science]

    The blood supply to cancerous tumors has been an important research topic for a number of years, with much of the focus centered around how to limit a tumor’s vital lifeline and starve it to death. Now researchers at the Korean Advanced Institute of Science and Technology’s (KAIST) Center for Vascular Research have just discovered that an antisepsis antibody helps normalize the chaotic and dysfunctional labyrinth of vasculature surrounding many tumors, improving the delivery of anticancer drugs while also reducing tumor volume. The antibody—called ABTAA, or angiopoietin-2 (Ang2)-binding and Tie2-activating antibody)—restored the structural and functional integrity of tumor blood vessels in three different tumor models: breast, lungs, and brain.    

    While the inner walls of healthy blood vessels are surrounded and supported by endothelial cells and other cells called pericytes, the endothelial junctions are broken apart in an established tumor and pericytes are also detached. Blood flow into and from the tumor is severely stunted 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. The Korean researchers found that ABTAA normalizes the tumor vessels—hence changing the whole tumor microenvironment.

    "We call it normalization of tumor vessels because it closely resembles the wall architecture of healthy, normal vessels," explained lead study investigator Jin-Sung Park, a graduate student at The Center for Vascular Research, within the Institute for Basic Science (IBS) at the KAIST. "Tumors can 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 create a favorable ground for tumor treatment."

    The findings from this study were published recently in Cancer Cell in an article entitled “Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment.”

    While trying to generate antibodies that target the protein Ang2, which is specifically expressed by endothelial cells in stressful conditions as in tumors, the investigators unexpectedly discovered that ABTAA has a peculiar way of working and a dual function. ABTAA indeed not only blocks Ang2, but it is also able to activate Tie2 at the same time. Tie2 is a receptor present on the cell membrane of endothelial cells. ABTAA causes Ang2 to cluster together and to strongly activate Tie2 receptors.

    "If we activate Tie2, we can efficiently normalize tumor vessels, enhance drug delivery and change the whole microenvironment," noted senior study investigator Gou Young Koh, M.D., Ph.D., director of the Center for Vascular Research.

  • Click Image To Enlarge +
    The antibody ABTAA alone and in combination with other anticancer drugs has a beneficial effect in reducing tumor volume. ABTAA was tested in mice with brain tumor (glioma) and 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. [Institute for Basic Science ]

    Ang2-blocking antibodies are currently being developed for anticancer therapy. However, even if these antibodies significantly inhibit tumor progression, they do not stop tumor hypoxia. Moreover, most anticancer drugs target tumors at their early stages, when tumors are still hard to diagnose. Instead, ABTAA 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 more mild, by reducing its progression and metastasis," remarked Dr. Koh.

    The 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 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 anticancer drugs into the tumor core region.

    Gliomas often come with a poor prognosis and clinical outcome. Yet, the investigators found that the glioma volume was reduced 39% by ABTAA and 17% by 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 lung cancer tumor model, the research team administered ABTAA together with the chemotherapeutic drug 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 areas within tumors.

    Finally, in a spontaneous breast cancer model, ABTAA delayed tumor growth and enhanced the antitumor effect of Cpt.

    Dr. Koh and his team were excited by their findings and are looking 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, that is the eye, and see if this antibody can be useful to treat eye diseases such as age-related macular degeneration and diabetic retinopathy," Dr. Koh concluded.

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