Peregrine Pharmaceuticals (PPHM) is a very good example of a company that focuses on new, non-validated targets. The company is developing a monoclonal antibody by the name of bavituximab, which targets phosphatidylserine molecules [PS] presented on the outer side of cancer blood vessel cells. PS is quite a unique target. While most TAAs are used by tumors in order to survive, grow and metastasize, PS is only a side-effect, a characteristic of cancerous tissues from which cancer does not benefit. In normal, healthy vascular cells, PS is tightly segregated to the internal side of the cell. This segregation appears to be impaired in many kinds of tumor blood vessels, where PS becomes present on the external side of the cells, likely in response to certain conditions in the tumor microenvironment. This phenomenon was observed in lung, breast, prostate and pancreatic cancer, among others. If peregrine’s claims are proven right, PS is a great example of a very specific TAA, since it only presented by cancer blood vessel cells. Since monoclonal antibodies that are injected into the blood stream can recognize only targets that are presented on the external side of cells, healthy cells that have PS exclusively on their inner side will be unaffected, while cancer blood vessels would be targeted by the antibody exclusively.
Targeting tumor blood vessels is a promising strategy for fighting solid tumors. Once a tumor reaches a certain size, it cannot rely on existing blood vessels for the supply of nutrients and oxygen, and therefore builds or manipulates its microenvironment to build additional blood vessels. One approach for targeting cancer vascular tissues is using treatments that inhibit the growth of such cells. A good example of such an agent (generally referred to as “antiangiogenic”) is Genentech’s (DNA) Avastin, a monoclonal antibody that targets a molecule that induces formation of new blood vessels. However, antiangiogenic drugs are designed to inhibit the formation of new vessels but have limited effect on the existing tumor vasculature. Vascular targeting agents such as bavituximab may be superior to antiangiogenic agents in many cases since they target existing tumor blood vessels.
Recognizing the importance of PS as a target is just the first step. The next one is trying to target PS with a monoclonal antibody and evaluate whether the antibody actually binds tumor blood vessels in a specific manner, without binding normal cells. Several experiments in mice were conducted using a mouse version of bavituximab, which was evaluated for its ability to bind tumor vessels. The experiments showed a clear localization of the antibody to tumor blood vessels, with virtually no binding to healthy blood vessel tissues.
Specific binding is still not a guarantee for actual clinical activity, as a clear anti-tumor effect should be demonstrated as a result of binding. There are several mechanisms by which antibodies can inhibit tumor growth. One such mechanism is the recruitment of the immune system against cells the antibody binds. When researchers examined tissues bound by bavituximab, there was a clear presence of white blood cells that infiltrated into the tissue. Strong tissue destruction in the core of tumors, with survival of a peripheral rim was observed, which was another validation of the antibody’s anti-tumor effect in mice. This pattern, where the inner core of the tumor is affected while the external parts of the tumor remain unaffected, seems to be typical of anti-vascular agents such as bavituximab. Blood vessels in the interior of the tumor are presumed to be more sensitive to such treatments due to their distance from the body’s normal blood system. In contrast, compounds that target the tumor cells directly tend to be more effective against the periphery, where cells multiply at a faster pace. Hence, combining vascular targeting with direct tumor targeting may result in an additive effect.
To date, numerous pre-clinical experiments that evaluated the synergistic effect of bavituximab and conventional therapies, in various different types of cancers, demonstrated a clear synergy with conventional therapies such as chemotherapy and radiotherapy. These experiments involved growth of human cancer cells inside mice, and the treatment with the antibody, traditional therapy or a combination of the two.
A recent publication evaluated the combination of radiation therapy and the mouse version of bavituximab for the treatment of lung cancer in mice. The combination of bavituximab with radiation seems promising since recent studies show that vascular cells may expose PS after irradiation, making them more sensitive to the antibody. Mice bearing lung cancer tumors that were considered resistant to radiation, were treated with radiation, the antibody or the combination of the two treatments. While radiation therapy alone had no effect on tumor growth, the combination regimen led to a relative reduction of 80% in tumor growth. Mice treated with the combination grew by only 1.8-fold over the course of the experiment, as oppose to 5-fold growth in mice treated with radiation. Furthermore, combination therapy reduced blood vessel density and enhanced white blood cells infiltration into the tumor mass beyond the reduction observedwith radiation therapy.
Another example might be an article published on 2005 evaluating the effect of combining the antibody with the chemotherapy agent gemcitabine for the treatment of mice bearing pancreatic cancer tumors. The antibody significantly enhanced the therapeutic efficacy of gemcitabine, leading to increased infiltration of white blood cells in the tumor and to decrease metastasis rate, especially in the liver.
The inevitable conclusion from numerous pre-clinical studies is that in mice, targeting PS can improve the efficacy of conventional therapy without additional side effects. The enhanced therapeutic effect seem to be due to the ability of these conventional therapies to increase exposure of PS on tumor blood vessels, amplifying the target, as well as the high sensitivity the tumor core has towards bavituximab.
