Funding opportunities

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

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05373
Funds requested: 
$19 999 347
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Glioblastoma is the most common and aggressive type of brain cancer in adults. Its treatment presents particular challenges—surgery to remove the tumor can cause collateral damage to healthy brain structures, the tumor often quickly re-grows after radiation and chemotherapy, and it tends to become resistant to treatment despite aggressive management. Standard therapies, which typically include a combination of surgery, radiation and chemotherapy often result in serious side effects and are ineffective long term. Unfortunately, most patients with glioblastoma survive an average of 14 months once diagnosed. Our research has the potential to dramatically extend the long-term survival rates of patients with this type of tumor using a highly targeted yet systemic and safe approach. It focuses on an exciting new theory that brain cancer cells begin and are maintained by a small fraction of all tumor cells with stem cell properties. The theory proposes that if this small subset of cancer stem cells could be inactivated, the tumor would stop growing. In our studies, we reasoned that cancer-specific gene alterations in glioblastoma could be a potential marker for cancer stem cells and zeroing in on these cells could result in targeted therapies. We discovered a tumor-specific marker of epidermal growth factor receptor (EGFR) called EGFRvIII and found that EGFRvIII often occurred in glioblastoma tumor cells with another marker found on normal stem cells called CD133. We then developed a “bispecific” antibody (BsAb) that recognizes both of these markers and we showed that BsAb selectively kills cancer stem cells in glioblastoma tumors that express both CD133 and EGFRvIII, but not normal stem cells. When glioblastoma cells treated with BsAb were injected into mice, tumor formation was severely inhibited and significantly more animals survived after treatment with it. To advance this discovery to the clinic, we have assembled a world-class and highly experienced multi-disciplinary team of experts who have carefully considered the pharmacology, toxicology and manufacturing issues that may occur during the development of BsAb for clinical use. As a result, we are ideally positioned to accomplish our immediate goal, which is to complete the necessary work to file an investigational new drug application with the Food and Drug Administration to study the safety of BsAb in a Phase 1 human clinical trial. Our ultimate goal is to generate a safer and far more effective treatment for patients with glioblastoma that significantly improves their quality of life and long-term survival. If successful, this will be the first antibody therapeutic that is specifically designed to attack cancer stem cells, and it could be applied to other types of cancers.
Statement of Benefit to California: 
According to the Central Brain Tumor Registry of the United States (CBTRUS), approximately 22,340 new cases of malignant brain tumors were diagnosed the United States in 2011 with associated healthcare costs in the billions of dollars. Glioblastoma is the most common and most aggressive form of malignant brain tumor, and more Californians are diagnosed with glioblastoma each year than any other state in the nation. There is a consequent significant economic toll not only to Californians suffering from glioblastoma but also to taxpayers who bear some of the financial burden due to uninsured healthcare costs and costs related to lost job productivity, not to mention the tremendous emotional toll this disease has on patients, their families and their communities. Therapies to improve both the quality and length of life are desperately needed for glioblastoma patients who live on average a dismal 14 months once diagnosed. In our research, we have shown that two markers of cancer stem cells, CD133 and EGFRvIII, are tightly associated in glioblastoma tumors. We have created a recombinant bispecific antibody (BsAb) to selectively target CD133 and EGFRvIII. This highly targeted approach kills glioblastoma tumor cells but not normal cells. Our primary objective for this study is to file the investigational new drug (IND) application necessary to advance the BsAb to a Phase 1 clinical trial for use in glioblastoma patients. Californians will experience tangible benefits from this research project in several significant ways: 1) Most important, this research has the promise to dramatically extend the long-term survival rates for Californians with glioblastoma and to improve their quality of life. This will result in healthier citizens, increased employment, and reduced economic burden to the state. In addition, this therapy is potentially applicable to multiple other human cancers with high rates of occurrence in California, such as colon, lung, breast, prostate, ovary and head and neck cancers. 2) Filing the IND application will result in employment and increased knowledge of California-based companies and consultants in such areas as contract manufacturing, analytical, clinical and preclinical research and development organizations necessary to generate clinical grade antibody, develop and interpret requisite assays, conduct preclinical development programs and prepare for clinical research efforts. 3) If the therapeutic BsAb generated is commercialized, profits derived from the production of the BsAb by CIRM policy will result in improved treatments to insured patients and lower-cost treatments to the uninsured, thus ultimately benefiting all Californians. 4) Funding this research will help raise awareness of California’s prominence as a national and international leader in translational stem cell research and could potentially benefit glioblastoma patients world-wide.
Review Summary: 
The overall goal of this project is to develop a bispecific antibody (bsAb) designed to target cancer stem cells (CSCs) in glioblastoma (GBM) tumors, by simultaneously binding to CD133 and EGFRvIII, co-expressed on the surface of GBM CSCs. The project plan lays out translational research and development activities leading to an Investigational New Drug (IND) filing, including construct optimization and humanization, evaluation of production systems, mechanism-of-action (MOA) studies, manufacturing activities and preclinical safety evaluation. Significance and Impact - GBM is a devastating disease with no effective treatment; this project could have high impact if successful. - If this bsAb is as specific as the applicants claim and without any serious off-target toxicity, the product could be a breakthrough for CD133+/EGFRvIII+ tumors. - It is difficult to determine, based on available preclinical data, if intravenous delivery of a bispecific antibody will be significantly more potent than previous strategies where monospecific antibodies were delivered directly to GBM/glioma in human clinical trials - It is unlikely that an antibody will effectively cross the blood brain barrier (BBB) based on previous studies in this area Rationale - A key question raised by the reviewers concerned whether the antibody will cross the BBB: -Getting antibodies across the BBB is a non-trivial issue; a serious concern is whether the concentration they will have to deliver to a patient to get enough across the BBB will have toxic effects peripherally. In addition, although the BBB may be open in glioma, GBM cells have migrated long distances and it is difficult to deliver antibody to all those areas to get the distribution needed. -It would be important to confirm if the bispecific antibody crosses the BBB before starting IND-enabling studies for an intravenous route. - It is not clear that this product will be sufficiently specific for tumor cells and will not target healthy cells expressing either target antigen, which raises a significant safety concern; it is unclear if there is any advantage to having a single molecule target two distinct epitopes; the applicant may not have thought through all the possible safety concerns. - The project rationale is based on the targeting of cells that co-express EGFRVIII and CD133, which may represent a subgroup of GBM cells in a patient, but this does not take into account tumor heterogeneity. - Reviewers were not convinced that the bispecific antibody targeted the CSC population. - The TPP for this application was relatively weak Therapeutic Development Readiness - The applicant has not yet selected the final development candidate. - Timelines do not appear to be feasible. - The project is at a stage that is still too early to be trying to formally develop this product for IND-enabling studies. Feasibility of the Project Plan - Overall, the product development plan is reasonably complete, but there are specific flaws in the plan indicative of a lack of experience on the part of the PI and team. - Defining the pharmacokinetics and specificity of a bispecific antibody will be complex. - The applicant is proposing to conduct a significant amount of mechanistic and cell biology work which may not be necessary from a regulatory perspective. More effort should be focused on defining the product affinity, specificity, selectivity, pharmacokinetics and safety in relevant animal models. - Knowing the effective route of delivery will have impact on formulation, concentration and dosing. Testing of the effectiveness of the bsAb (delivered in various routes) against implanted established GBMs in animal models would complement and significantly expand the in vivo information the applicants provide. Principal Investigator (PI) and Development Team - The PI has good understanding of GBM but limited product development experience - Although there is less concern with the team itself as a number of highly reputable experts have been brought into the team and a leadership plan is in place, reviewers were not convinced that this group understands what needs to be done or fully appreciates what is required to file a complete well-supported IND on this candidate antibody therapeutic. Collaborations, Resources and Environment - It's the wrong environment and capabilities (lack of drug development experience) to do a classic drug development project - IP will need to be licensed Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding.) - The budget appears high for just taking a product through to an IND filing. Conditions Applied by the Planning Award Grants Working Group - The Planning Award GWG set a condition that “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 GWG felt the condition was met.
Conflicts: 
  • Darin Weber
  • Joy Cavagnaro
  • Lauren Black

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