Grant: Operating Grant

As tumors grow, areas within the tumor are subjected to low oxygen tension, called hypoxia, due to poorly developed blood vessels. Tumor cells within these "hypoxic" regions adapt to the low oxygen tension by expressing proteins that allow the cells to survive. One such essential protein is a cell surface protein called Carbonic Anhydrase IX ( CAIX), which converts the excess carbon dioxide built up in the hypoxic regions into bicarbonate, which facilitates their survival. It is now well established that tumor cells within the hypoxic regions have aggressive properties of growth and ability to spread ( metastasize). These cells also have "stem cell" properties that make them resistant to chemo- and radiation therapies. We, and others, have previously demonstrated that inhibiting the function of CAIX results in tumor regression and inhibition of metastasis. Because CAIX is on the surface of tumor cells, it can be targeted with drugs, or with antibodies that can specifically bind to CAIX and block its function. Antibodies are some of the best "targeted therapeutics" in clinical use so far. An example in cancer is Herceptin, which is used for the treatment of breast cancer. We have identified several monoclonal antibodies that specifically bind to CAIX. Some are able to block its catalytic function, and others bind to CAIX and are internalized. We can utilize the latter as antibody-drug conjugates ( ADC) to deliver toxins into tumor cells in hypoxic regions. In this application we propose to extensively characterize these antibodies, develop them to specifically target and incapacitate CAIX, or use them to deliver toxins, test their eficacy in cultured cells for proof of principle, and then test them in various human tumor models in mice. This work will lead to the development of therapeutic anti-CAIX antibodies, with distinct modes of action, and will provide proof of principle data to translate the use of these antibodie in the clinic.