What are the other elements of the anticancer fusion protein?
The second component of our fusion protein is an activating element. Also in this case we were able to take advantage of naturally occurring mechanism. The role of activating element plays the amino acids sequence, which is recognized by enzymes from metalloprotease family. These molecules allow cells the metastasis (spread of cancer to other locations in the body) and neovascularization (the formation of blood vessels in the tumor). This sequence, which is also present in many of the basic matrix proteins, is able to activate only in the tumor, due to the presence of strong metalloprotease expression there (especially in the metastatic tumors characteristics for malignant neoplasms).
The third element of our fusion protein is an effector through which we can see the beauty of this molecule. So far, we have made 8 patent applications, from which 4 of them are already in the public phase in PCT procedure (Patent Cooperation Treatyis an international patent law providing a unified procedure for filing patent applications to protect inventions in each of its contracting states). We have developed a number of effectors, which are characterized by various physical and biological properties. We have molecules acting proapoptotic, stimulating the immune system as well as molecules, which are hindering angiogenesis, or supporting anti-proliferative effect. Our last application concerns the idea of bioconjugates. It is the idea of the fusion of our protein carrier with chemical molecule supporting its therapeutical effect with concomitant increase of the safety margin of the treatment.
Sounds impressive. And how such a fusion protein is better than monoclonal antibodies, which are now commonly applied in anticancer therapies?
The advantage of the molecule evaluated in our laboratories over antibodies and conjugates of antibodies with cytotoxic substances is based on its primary anticancer activity. If to mentioned above fusion protein we add an agent of antitumor activity, as a result we will obtain double activity against cancer – so called synergism. Commonly used antibodies are passive carrier. Their only function is to deliver cytostatics to the right place or to block fusion of ligands to receptors by interaction with them, resulting in strong inhibition of proliferation and tumor growth. Within 3-CLA project we have two elements of synergistical activity. An additional disadvantage of antibodies is also their size. Due to the large dimension of molecule, the penetration of particular cells of tumor, which is a spatial structure, is hindered. Our molecule is small and naturally adjusted to penetrate all tissues, including those modified by cancer.
To summarize. We have a fusion protein composed of three elements, which is introduced to the body. What happens next?
First of all, the molecule migrates with blood to tumors. There, using the EPR property (Enhanced vascular Permeability and Retention), which is also used by passive molecules like antibodies, it penetrates the tumor environment. Then, it recognized there receptors specifically present on the surface of cancer cells to which it is attached and thus initiates apoptosis. Simultaneously, being next to cancer cell our molecule is activated. It is based on presence of metalloproteases, which cut off the effector element aiming on the most conservative metabolic pathways, or those responsible for the division and growth or tumor cells. Classical cytostatic molecules are characterized by similar mode of action, but besides for large effectiveness (toxicity) are also characterized by lack of specificity towards cancer cells. Giving the patient such classic cytostatics, we can only hope that the majority of the dose will attack the tumor cells and not the healthy cells of organism, which may cause additional side effects.
Is the problem of cytotoxicity against healthy cells in the body not present in molecules developed by you?
For a preliminary estimation of the therapeutic range of our molecule, the incubation of healthy human hepatocytes, endothelial cells and kreatinocytes obtained from German company CRO was conducted in the presence of very high concentration of our proteins, not noticing any toxic effects. Our molecules are also applied to mice to determine the MTD (Maximum tolerated Dose), or other pharmacological parameters, that inform whether particular molecule has any potential toxicity against healthy organs or tissue. In the recent experiments, we gave animals by injection huge amounts of our protein, also not observing any toxic effect. These research is still ongoing, but so far obtained results give us hope for the development of effective and safe therapy at the same time.
End of part II
Interview taken by Tomasz Sznerch
Translated by Jacek Plewka
2018-02-24 19:30:41 +0100
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