Funding opportunities

Recombinant Bispecific Antibody Targeting Cancer Stem Cells for the Therapy of Glioblastoma

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
Principle Investigator: 
Funds requested: 
$109 750
Funding Recommendations: 
Grant approved: 
Public Abstract: 
Glioblastoma multiforme is the most prevalent and aggressive type of brain tumor, and devastating to any patient unfortunate enough to receive its diagnosis. As the most populous state in the nation, more Californians are diagnosed with glioblastoma multiforme than any other state. Over the past 20 years, surgery, radiation therapy and chemotherapy have been utilized with frustrating results. Today, even with the most advanced treatments available, survival rates average only 14-15 months. 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-like properties. This “cancer stem cell” hypothesis states that if this small subset of cancer stem cells could be eliminated then the tumor would cease to grow. Cancer stem cells in glioblastoma have been identified using CD133, a well known marker for isolating normal neural stem cells. The fact that CD133 is present on normal stem cells means that only targeting this molecule would be potentially dangerous. To enhance targeting, we reasoned that a cancer-specific alteration found in glioblastoma could be used as a potential marker for cancer stem cells. EGFRvIII is a specific variant of the normal EGF receptor and is widely found in glioblastoma but is rarely present in normal tissues. We have now shown that tumor cells that express both CD133 and EGFRvIII have the most cancer stem cell properties—more so than cells that have CD133 or EGFRvIII alone. We then developed a “bispecific” antibody that simultaneously recognizes both of these markers and we have shown that this bispecific selectively kills the cancer cells in glioblastoma tumors that express both CD133 and EGFRvIII. However, the bispecific did not kill normal stem cells. These results are very promising and suggest that bispecific can be tested as a therapeutic for glioblastoma. To move this into patients, we will produce large quantities of the bispecific and perform rigorous tests to ensure that it is uniform and has the required properties. We will also determine that it is safe through a combination of cell based and animal studies. Extensive planning will be made for the correct format for the clinical trial to test this molecule. Once the properties of the bispecific are certified and plans for the clinical trial are finalized, we will submit the drug to the FDA for an Investigational New Drug application. Once approved by the FDA, we can then move forward with testing this compound in glioblastoma patients. We are particularly excited about the bispecific as it could serve as the paradigm for a new class of drugs that specifically target cancer stem cells.
Statement of Benefit to California: 
Glioblastoma is a devastating diagnosis. The most common and malignant form of brain cancer, the most aggressive treatments currently available yield an average survival of only 14-15 months. As the most populous state in the nation, more Californians are diagnosed with glioblastoma each year than any other state, with a consequent significant economic toll to the state as well as its emotional toll. As the leader in cutting edge biomedical research, California through CIRM has recognized the unmet need to provide a roadmap for the translation of stem cell research to clinical applications. Through CIRM there is an unparalleled opportunity to foster clearly-defined discovery that will not only benefit Californians with glioblastomas, but potentially those with many other cancers, and ultimately all Californians, through healthier citizens, increased employment opportunities, and reduced economic burdens. We have previously 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 healthy cells. When glioblastoma cells pre-treated with BsAb were injected into mice, tumor formation was significantly reduced, strongly suggesting that targeting of the EGFRvIII/CD133 cancer stem cell population can inhibit glioblastoma formation. The key objective of our project is to identify efficient and high yield methods for BsAb production, identify an effective dose and route of delivery for the treatment of brain tumors, and evaluate any potential effects on cells/tissues that express CD133. 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) With successful completion of the proposed project, a clinical trial will be the direct next step, 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. 5) Finally, funding this research will help raise awareness of California’s prominence as a national and international leader in stem cell research with the potential to benefit glioblastoma patients world-wide.
Review Summary: 
EXECUTIVE SUMMARY Project Synopsis This proposal seeks to develop a bispecific monoclonal antibody therapeutic that simultaneously recognizes both CD133 and EGFRvIII, in order to selectively kill the stem-like cells within glioblastoma tumors. The rationale for this approach comes from the observation that glioblastoma tumor cells that express both CD133 and EGFRvIII have properties of cancer stem cells. The antibody has been generated and a preliminary characterization has been carried out. The primary objective of the proposed project is to perform the necessary preclinical studies to enable the filing of an Investigational New Drug application (IND) and to plan the initial phase I trial in glioblastoma patients. The scope of the work will include development of a manufacturing process, manufacture of the bispecific antibody according to Good Lab Practices (GLP) and the conduct of GLP safety studies. Significance and Impact -Glioblastoma (GBM) is a highly lethal disease with no effective therapies and thus represents a condition of high unmet medical need. ¬- If successful, this approach could have a significant clinical impact given the current lack of effective therapies. Any incremental improvement in GBM therapy will be a significant achievement. -Current treatments for GBM do not apparently target GBM cancer stem cells (CSCs) which may explain their relative inefficacy. Targeting cancer stem cells in GBM may represent the first steps to development of active therapies. Project Rationale and Feasibility: - The applicant has shown preclinical evidence consistent with the hypothesis of preferential targeting of GBM CSCs both in vitro and in mouse xenograft models. Preliminary data demonstrating activity in GBM xenografts suggests activity against CSCs. - Although the targeting strategy is interesting, a key concern is that published data indicate that tumor initiating activity is not confined to CD133 positive cells. This could significantly limit the effectiveness of the proposed therapy and diminished enthusiasm for this approach. This issue was not adequately referenced and discussed in the proposal. - It was not clear to reviewers that the proposed bispecific antibody approach would provide an advantage over improved targeting of EGFRvIII alone. EGFRvIII is specifically expressed on GBM cells, and a monospecific approach would reduce the potential for toxicity directed at normal stem cell populations. -The PI has assembled an excellent group of potential consultants and advisors to provide the appropriate technical and regulatory experience to move this project forward. Although reviewers liked the underlying idea behind this proposal, they had a number of recommendations that they felt would strengthen the application: - Reviewers expressed serious concerns about the preclinical plan outlined in the proposal. They pointed out that the animal species proposed for toxicity studies are not the appropriate species for evaluating a therapeutic antibody and they strongly recommended that the applicant get advice from consultants to propose an appropriate safety plan. - The applicant has established that the bispecific antibody can be produced in quantities sufficient for research purposes, but will need to set a timeline to attain levels of production needed for development activities. - An important issue to investigate is intellectual property. The antibodies used are covered by an extensive patent portfolio, and the technology to make the minibody may also be patented. - In addition, it will be important to provide more definitive data supporting the notion of preferential binding to GBM stem cells by showing binding of the bispecific antibody to normal stem cells versus tumor stem cells from primary tumors, where the target copy numbers might be very different than in transfected cells. - Given that the bispecific antibody is likely to be highly immunogenic, the proposal will need to contain a plan to address immunogenicity concerns. - There was no discussion about combinations of the bispecific antibody with other therapies. This is likely to be necessary since this agent will not target all tumor cells. Principal Investigator (PI) and Planning Leader - The PI is an established leader in the study of signaling pathways in GBM and in the development of antibody-based therapeutics. The PI has been involved in early development projects and is aware of current approaches to immunotherapy for GBM and brain tumors. The leadership of this PI is a key strength of this proposal. -The Planning Leader’s lack of relevant experience is a concern. The Planning Leader is relatively junior and does not have extensive experience with the translational process. The Planning Leader has little to no experience in assembling and leading a developmental team for the purpose of filing an IND application.
Programmatic review: 
  • A motion was made to move this application into Tier 1, Recommended for Funding, with a condition. To be eligible for the Disease Team Research Award competition, the applicant must provide at the time of Full Application a revised and appropriate development plan. The GWG recommended that the applicants work closely with their consultants to rationalize and redesign the development plan. The motion carried.

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