Antibody ABTAA alters tumor blood vessels

Antibodies, a type of protective proteins produced by the body to fight against foreign invaders, have emerged as an important class of immunotherapy, referred to as antibody therapy. Why is this class of therapy so attractive? The major reason might be that antibodies are capable of binding specifically to the target, such as certain cells or proteins. This is critical as our goal is to effectively fight the diseased part while causing as little impact as possible on the healthy part.

Now, a new study suggests that an antibody directed against components critical for regulation of blood vessels might offer a novel treatment option for brain, lung, breast and perhaps, other cancers. The antibody effectively suppresses tumor progression by normalizing tumor blood vessels, enhancing drug delivery, and favorably altering the tumor microenvironment.

The study, described in the journal Cancer Cell on December 12, 2016, was carried out by a group of researchers, headed by Gou Young Koh at Korea Advanced Institute of Science and Technology (KAIST). Its main discovery is that ABTAA (Ang2-Binding and Tie2-Activating Antibody) is more effective than ABA (Ang2-Blocking Antibody) in normalizing tumor blood vessels.^[1]

Cancers are not just masses of malignant cells but complex organs or tissues, to which many other cells are recruited and can be corrupted by the transformed cells. Interactions between malignant and non-transformed cells create the tumor microenvironment. The tumor microenvironment is hypoxic and components of it often have a tumor-promoting function or act as a barrier to drug delivery into tumors.^[2]

There are many differences between tumor tissue and normal tissue. One of those differences lies in blood vessels. Compared to blood vessels in normal tissues, blood vessels in a tumor are like a disorganized labyrinth. Tumor blood vessels are leaky and immature, which causes poor oxygen supply (hypoxia) that correlates with metastasis. The leakiness of tumor blood vessels not only contribute to cancer progression but also affects drug delivery. Thus, targeting molecules involved in the formation and regulation of tumor blood vessels is thought to be a promising therapeutic strategy for cancer.^[3][4]

One method to target tumor blood vessels is to suppress the formation of new vessels or induce the destruction of pre-existing vessels. As is known, blood vessels are responsible for transporting oxygen, nutrients, and other essential molecules to cells so that they can survive. To suppress vessel formation or to induce vessel destruction in a tumor is like to starve tumor cells, inhibiting their growth, proliferation, and progression. Components of the VEGF signaling pathway, which plays critical roles in vessel formation, have been proven to be important targets for anti-angiogenic drug development. But, this method often triggers serious hypoxia in tumors, which has been associated with metastasis and treatment resistance.

An alternative method to target tumor blood vessels is to normalize vessels, which could enhance drug delivery because of increased blood flow into tumors. But, previous efforts failed to produce persistent normalization. It's of significance to find novel molecular targets involved in regulation of blood vessel formation. Recent evidence suggests that another signaling pathway called the angiopoietin (Ang)-Tie pathway as an alternative regulator of tumor blood vessel formation and an opportunity for therapeutic intervention. The human Ang-Tie pathway consists of three ligands, Ang1, Ang2, and Ang4, and their receptors Tie1 and Tie2. Agents that target these components are currently under development, and encouraging anti-cancer activity was observed in early clinical studies.^[5]

The Ang-Tie pathway is not only crucial for blood vessel formation but also involved in inflammation. Sepsis, a widespread disorder with high mortality, is characterized by overwhelming inflammation and disintegration of blood vessels. Protection of vessel integrity by controlling inflammation has been recognized as a frontline approach to alleviating sepsis progression. There are reports that Tie2 agonists improve the devastating outcomes of sepsis. However, numerous hurdles remain in the development of efficacious Tie2 agonists. On the other hand, Ang2 mainly acts as a Tie2 antagonist in septic conditions and plays an augmenting role in vascular inflammation. Circulating Ang2 is elevated in patients with sepsis, and this increased Ang2 concentration is closely correlated with severity and poor prognosis. The evidence suggests Ang2 as a potential target to control for sepsis intervention.

In a previous study, Koh's team tried to develop antibodies that could target Ang2. To their surprise, they found that one of those antibodies, named the Ang2-Binding and Tie2-Activating Antibody (ABTAA), not only blocks Ang2 but also activates Tie2. The dual action of ABTAA protected blood vessels from septic damage and provided survival benefit in three mouse models of sepsis. Moreover, the effect of ABTAA in augmenting survival was greater than a conventional Ang2-blocking antibody (ABA).^[6]

These data demonstrated that simultaneous Ang2 inhibition and Tie2 activation by ABTAA are highly effective for preserving integrity of blood vessels, which represents a potential therapeutic avenue for sepsis.

Ang2 and Tie2 are highly expressed in endothelial cells of tumor blood vessels. It is hypothesized that treatment with ABTAA could yield blockage of Ang2 and subsequent activation of Tie2 in tumor endothelial cells, which would ultimately lead to structural and functional changes in tumor blood vessels.

In the new study, Koh's team explored the effect of ABTAA on tumor vessels and tumor growth. They tested the antibody in three tumor models: brain, lung, and breast. The results were encouraging that the antibody induced normalization of tumor blood vessels, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened hypoxia, acidosis, tumor growth, and metastasis, and favorably altered the immune cell profile within tumors, creating a favorable tumor microenvironment. In comparison, ABA, the antibody that only blocks Ang1 but does not activates Tie2, only had very modest effects.

Using mice with Glioma (a brain tumor originating from glial cells), the researchers found that ABTAA reduced the tumor size by 39% while ABA only reduced it by 17%. In addition, ABTAA significantly reduced tumor vessel leakage and brain edema. If ABTAA was used in combination with the chemotherapy drug temozolomide, the tumor size was reduced further (76%). ABTAA treatment also led to favorably changes immune cell infiltration and reduced tumor hypoxia.

In a mouse model of Lewis Lung Carcinoma, the researchers observed that ABTAA-induced tumor vessel normalization, blood perfusion, and oxygenation hindered tumor progression and metastasis rather than promoted them. the researchers also compared the efficacy of the chemotherapy drug cisplatin used along with ABTAA and ABA. Consistently, the combination of ABTAA and cisplatin led to a greater suppression of tumor growth (52%) compared with the combination of ABA and Cpt (31%).

To see whether these results can be generalized, the searchers employed an additional mouse model of breast cancer and confirmed that ABTAA decreased tumor burden and enhanced the anti-cancer effect of cisplatin.

Taken together, these data demonstrated that simultaneous Tie2 activation and Ang2 inhibition by ABTAA not only inhibits vascular destabilization but also restores structural and functional vascular integrity, thus leading to normalization of tumor blood vessels. This provides a powerful therapeutic strategy to elicit a favorable tumor microenvironment to enhance drug delivery.

The new study suggests that the antibody ABTAA would be a useful tool to target tumor blood vessels and that ABTAA-induced Tie2 activation and Ang2 inhibition represent a promising anti-tumor approach that can maximize the therapeutic efficacy of conventional chemotherapy drugs. An advantage of ABTAA is that it favorably alters the whole tumor microenvironment, making it an alternative to current anti-angiogenic therapies. More investigation is required to evaluate its safety and efficacy in clinical settings.

"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," said Jin-Sung PARK from KAIST, first author of the new study.

In addition to tumors, ABTAA might also apply to other diseases that involve abnormal blood vessels. For instance, the eye is an organ rich in blood vessels, and abnormalities in the growth or development of blood vessels are seen in eye diseases such as age-related macular degeneration, diabetic retinopathy, and eye bleeding. The effect of ABTAA on these eye diseases is an issue that is worth studying, given the antibody's ability to normalize blood vessels and reduce leakage.

Therapeutic antibodies are the fastest growing class of new therapeutic molecules. As of 2016, more than 60 therapeutic monoclonal antibodies have been approved by the US FDA. These antibody therapies add to the treatment options for patients with cancer, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and viral infection. And there are a larger number of therapeutic monoclonal antibodies on different stages of development. Despite its high potential, antibody therapy faces many challenges such as drug resistance, side effects, and high price.

Reference:

[1] Jin-Sung Park et al, Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment, Cancer Cell (2016).

[2] Frances R. Balkwill et al, The tumor microenvironment at a glance, Journal of Cell Science (2012).

[3] Soo Jung Kim, Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery, Cancer Letters (2017).

[4] Donald M. McDonald et al, Significance of Blood Vessel Leakiness in Cancer, Cancer Research (2002).

[5] Hanhua Huang et al, Targeting the ANGPT–TIE2 pathway in malignancy, Nature Reviews Cancer (2010).

[6] Sangyeul Han et al, Amelioration of sepsis by TIE2 activation–induced vascular protection, Science Translational Medicine (2016).