Tumor associated monoclonal antibodies (mAbs) are therapeutic agents when used as selective vectors of cytotoxic agents towards malignant tissues. 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 validated murine tumor xenograft models. The radionuclides chosen focus on appropriate alpha emitters and beta emitters. Current research continues to focus on Pb-212, a beta-emitter and subsequent alpha particle source, in parallel with alpha emitters, At-211 and Th-227. Ongoing pre-clinical trials employ the chelating agent CHX-A (double prime) DTPA now a well-established standard for clinical applications. The chemistry that makes Zevalin, the 1st FDA approved radiolabeled mAb 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. Current technology is cumbersome and not stable in vivo leading to bone deposition of 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 continues. Pre-clinical At-211 studies have been completed with dose escalation survival studies targeting HER2 linking At-211 to trastuzumab employing the linker reagent, N-Me-SAPS. These studies provide an optimal dose for extension forward into long-term therapy studies as well as to provide a direct comparison of efficacy with Pb-212. At-211 has been produced and supplied to collaborators at Johns Hopkins in an effort to further establish the therapy potential of this radionuclide and its clinical translation. Similar studies are also ongoing with Th-227. Thus, with completion of those studies and the At-211 studies we will have in hand true comparative efficacy studies of Bi-213, Pb-212, At-211, and Th-227. The highly extensive and focused pre-clinical investigation into Pb-212 radioimmunotherapy continues for the treatment of disseminated intraperitoneal disease, e.g., ovarian cancer. Development of Pb-212 continued through to what is a now completed Phase I clinical trial at UAB. Murine toxicology experiments by the Section provided the data for the IND. 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. Evaluation of Pb-212 with specific mAbs and their combinations with chemotherapeutics continues systematically. A single dose of a single, targeted radionuclide lacks a rational basis for cancer therapy; the hypothesis is that combined modality therapies will achieve significant therapeutic enhancements. Substantial increases in median survival in model systems with single doses of Pb-212 conjugated to clinically relevant antibodies, e.g., trastuzumab or panitumumab have been achieved in combination with gemcitabine, paclitaxel, or carboplatin have been demonstrated and now this has been expanded to include topotecan. Actual mechanistic studies related to understanding in vivo cellular processes involved in tumor eradication have been non-existent. Three such studies have been reported by the Section to define the biological mechanisms at the cellular level of both damage response and repair as well as genetic regulation of the cell biology in response to high-LET radiation. Baseline studies revealed that not only are double strand breaks prevalent, but that the DNA repair mechanisms specific to the type of radiation being used are compromised, that apoptosis is enhanced, and that cell cycle impacted. Inclusion of gemcitabine demonstrated how that drug promoted therapy, while ongoing studies integrating taxol into the therapy regimen assess the impact of that drugs mechanism on this therapy. Parallel genetic profiling studies have been completed with the first two now published, and the 3rd pending. Studies pertaining to trifunctional imaging agents combining radionuclidic imaging (SPECT or PET) and NIR dye (Optical imaging) incorporating PEG continue. Critical discoveries regarding self-aggregation, covalent vs. non-covalent bonding, and appropriate characterization puts a significant body of literature in doubt. This advance provides real understanding of basic chemistry for creation of directly quantitative dual modality molecular imaging agents. Collaborative studies continue to be executed; reagents and/or expertise are supplied to facilitate all researchers to expeditiously perform experiments to fully define the clinical impact of targeted radiation therapy. To this end, the Section continues to enjoy strong and potent collaborations with the Metabolism Branch, NCI and with the Olivia Newton-John Research Institute. The collaborative relationship with AREVA Med and UAB to translate Pb-212 into its first clinical trial for treatment of disseminated ovarian cancer has now been completed and closed. However, the Section continues to pursue the use of both At-211 and Pb-212 in collaboration with researchers at Johns Hopkins.
Showing the most recent 10 out of 71 publications
