ZIA SC 006353 (ZIA) | |||
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Title | Metal Chelate Conjugated Monoclonal Antibodies for Tumor Diagnosis and Therapy | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Brechbiel, Martin | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $787,803 | Project Dates | 10/01/1982 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (100.0%) Digestive Diseases (30.0%) Taxol (15.0%) |
Breast (10.0%) Colon/Rectum (20.0%) Leukemia (30.0%) Ovarian Cancer (20.0%) Pancreas (10.0%) |
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Research Type | |||
Localized Therapies - Discovery and Development Systemic Therapies - Discovery and Development |
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Abstract | |||
Tumor associated monoclonal antibodies (mAbs) are therapeutic agents when used as selective carriers of cytotoxic agents to malignancies. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with human disease. The cytocidal agents employed are particle emitting radionuclides. The relative efficacy is evaluated in the appropriately validated murine tumor xenograft model system. The radionuclides chosen focus on appropriate alpha emitters and beta emitters. Current research continues to focus on Pb-212, a beta-emitting alpha particle source, in parallel with the alpha emitter, At-211. Ongoing pre-clinical trials employ chelating agents 1B4M-DTPA (aka MX-DTPA or tiuxetan) or CHX-A (double prime) DTPA. Both are well established in clinical applications; the former is a component of, Zevalin. The chemistry that makes Zevalin, the 1st FDA approved radiolabeled antibody therapeutic, possible was developed by the Chemistry Section. Nearly all ongoing studies now employ the 3rd generation bifunctional chelating agent, CHX-A (double prime) DTPA for sequestering In-111, Y-90, Bi-213, and Lu-177. Prior studies validated the use of CHX-A (double prime) DTPA in PET imaging with the cyclotron produced (refined and purified by the Chemistry Section) Y-86 through the number of PET imaging studies recently reported by the Chemistry Section regarding applications of Y-86 for PET imaging targeting HER2 and HER1(EGFR) for visualizing a variety of diseases such ovarian, colorectal, pancreatic, prostate cancer. Related studies on Y-86 for PET imaging targeting HER1(EGFR) for imaging mesothelioma have been published. Complementary to the development of Y-86 for immunoPET, the Chemistry Section continues to develop novel and superior bifunctional chelating agent useful for Zr-89 immunoPET. The current technology is cumbersome and not stable in vivo leading to bone deposition of released Zr-89. Lead compounds of significantly greater Zr-89 complex stability developed through this program of study have now been published and creation of bifunctional analogs has been achieved. Evaluation of these agents has started. Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy continues to refine conjugation chemistry options and radiolabeling improvements. These refinements stem from provision of agents for peptide chemistry as well as for site-specific conjugation strategies amenable for use with both radio-lanthanides and alpha-particle emitting radionuclides. Novel linkage chemistry agents for site-specific linkage strategies such as click chemistry and carbohydrate modification strategies have been created. Pre-clinical At-211 studies have been initiated with dose escalation survival studies targeting HER2 linking At-211 to trastuzumab employing the linker reagent, N-Me-SAPS. Replication of these studies with inclusion of toxicity assessments will provide an optimal dose for extension forward into long-term therapy studies. At-211 has been produced and supplied to collaborators at Johns Hopkins in an effort to establish an At-211 users/ investigators consortium to accelerate evaluation of the therapy potentials of this radionuclide and its clinical translation. The highly extensive and focused pre-clinical investigation into the use of Pb-212 continues for the treatment of disseminated intraperitoneal disease, e.g., from either ovarian or pancreatic cancer. Development of Pb-212 continued through to an open Phase I clinical trial with >14 patients treated, patient accrual continuing, and additional sites being opened. Murine toxicology experiments by the Section in support of the IND along with development of numerous additional documents, studies, and SOPs by the Section insured this Phase 1 trial, the first in the world using Pb-212, would proceed forward. Thus, the Section has routinely been at the forefront of truly novel translational bench to bedside research. E" |