Targeting Glioblastoma Cancer Stem Cells Using a Novel Bispecific Antibody
Glioblastoma multiforme is the most prevalent and aggressive type of brain tumor. Our proposed research focuses on a new theory that brain tumor cells are initiated and maintained by a small fraction of cells with stem cell properties and if this small subset of cancer stem cells could be inactivated, the tumor would cease to grow. We reasoned that cancer-specific genetic alterations in a glioblastoma tumor could be a potential marker for cancer stem cells and zeroing in on these cells could result in targeted therapeutics. CD133 is a marker for normal neural and hematopoietic stem cells and EGFRvlll is a receptor that is genetically altered in glioblastoma tumors. We found that CD133 and the EGFRvIII are both tightly associated in glioblastoma tumors and tumor cells that express both CD133 and EGFRvIII grow more quickly. We have already developed a “bispecific” antibody that recognizes both of these markers and we have shown that this antibody selectively kills the cancer cells in glioblastoma tumors that express both CD133 and EGFRvIII, but not normal stem cells. When we injected glioblastoma cells pre-treated with BsAb into mice or used this to treat established brain tumors, tumor formation was severely inhibited. Our goal is to ready this antibody for the investigational new drug phase and to ultimately generate a human therapeutic effective against glioblastoma.
As the most populous state in the U.S., more Californians are diagnosed with glioblastoma each year than any other state, with a consequent significant economic toll to the state. We have shown that two markers of cancer stem cells, CD133 and EGFRvIII, are tightly associated in glioblastoma tumors. We created a recombinant bispecific antibody (BsAb) selectively targeting CD133 and EGFRvIII. This antibody selectively kills glioblastoma tumor cells but not normal cells. Our goal is to ready the BsAb for investigational new drug-related development.
Californians will benefit from this research project in several significant ways. 1. Most importantly, this research has the promise to dramatically extend the long-term survival rates for Californians with glioblastomas, with potential applications to multiple other human cancers. 2. The research will take place in California with direct benefit to the California economy through the hiring of employees and purchase of supplies and reagents. 3. An investigational new drug application will be the direct next step, requiring employing a local contract research organization to generate clinical grade antibody, requiring additional employees along with associated expenditures. 4. If the therapeutic BsAb generated is commercialized, profits derived from the production of the BsAbs by CIRM policy will result in improved treatments to insured patients and lower cost treatments to the uninsured, thus ultimately benefiting all Californians.