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 for study focus on appropriate alpha emitters and beta emitters. Current research focuses on the beta-emitting alpha particle source, Pb-212, and parallel studies with the alpha emitter, At-211. Ongoing collaborative clinical trials employ the chelating agent 1B4M-DTPA (aka MX-DTPA or tiuxetan) for sequestering Y-90, a high energy pure beta emitting radionuclide well established in clinical applications and in the commercial product, 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.Current studies initiated and ongoing continue to validate use of CHX-A (double prime) DTPA in PET imaging with the cyclotron produced (refined and purified by the Chemistry Section) Y-86. There have been a number of PET imaging studies recently reported by the Chemistry Section regarding the application 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 has been submitted for publication. Complementary to the development of Y-86 for immunoPET, the Chemistry Section proceeds with study on the development of a novel and superior bifunctional chelating agent for use with Zr-89 for immunoPET as the current technology is cumbersome and not stable in vivo leading to bone deposition of the freed Zr-89.Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy with isotopes of interest continues primarily to refine conjugation chemistry functional group options and radiolabeling improvements. These refinements stem from the 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. The Section has created a number of novel linkage chemistry agents for site-specific linkage strategies such as click chemistry and carbohydrate modification strategies.At-211 studies have been fully activated this past year while upgrading the production facilities for this radionuclide. The Chemistry section previously reported on validation of the most stable At-211 linker reagent, N-Me-SAPS;an entire re-synthesis of the agent facilitates the ongoing therapy studies parallel to the prior Pb-212 studies. Progress on this project has resulted in dose escalation studies with At-211 labeled trastuzumab that extend forward into long-term therapy studies. Production activities have been ungraded by the addition of new personnel to the Section over the past year to the point where At-211 has been produced and supplied to collaborators at Johns Hopkins in an effort to establish an At-211 users/ investigators consortium will accelerate progress on the evaluation of the therapy potentials of tis radionuclide.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. Investigation of Bi-213 reached a point of cost-effectiveness combined with failed national availability effectively forced termination of study of this radionuclide. Despite significant efficacy, the full range of use and value of Bi-213 will probably never be defined.Development of Pb-212 continues to move forward with FDA approval of an IND for a Phase I clinical trial that was relocated to UAB due to unresponsive leadership within the NCI. Murine toxicology experiments were completed by the Section in support of the IND along with numerous additional documents, studies, and SOPs developed by the Section. The Phase 1 trial, the first ever using Pb-212 is actively recruiting and treating patients. Thus, for a second time, this Section has been at the forefront of truly novel translational clinical research.Evaluation of Pb-212 with specific mAbs, use of combined radiolabeled mAbs, and their combinations with chemotherapeutics continues systematically. The hypothesis that single doses of a single, targeted radionuclide lacks a rational basis for cancer therapy;combined modality therapies will achieve significant therapeutic enhancements. Substantial increases in median life expectancy in model systems with single doses of Pb-212 conjugated to clinically relevant antibodies, e.g., trastuzumab or panitumumab have been achieved;cetuximab has been eliminated from study. Pb-212 labeled trastuzumab in combination with gemcitabine provided impressive enhanced therapeutic efficacy;multi-dosing of Pb-212 and gemcitabine provided significant evidence that optimization of drug combination and scheduling extends survival. Studies combining administration of Pb-212 with paclitaxel resulted in significant extension of survival with a dependence on administration scheduling. Similarly, combination with carboplatin also extended survival and is ongoing. Delivery of radiation to multiple molecular tumor targets overcoming antigen heterogeneity was reported;combining, CC49(Delta)CH2 and trastuzumab radiolabeled with Pb-212 demonstrated the requirement for empirical determination of administration order to optimize therapeutic efficacy vs. reliance on in vitro studies that fail to predict in vivo tumor environments.Results have confirmed superior therapeutic response from Pb-212 therapies. Bi-213. Studies 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 are ongoing by the Section. Initial baseline studies of targeted Pb-212 revealed that not only are double strand break prevalent, but that the DNA repair mechanisms are compromised, that apoptosis is enhanced, and that cell cycle impacted. Inclusion of gemcitabine replicating prior therapy studies 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.Studies continue to expand use trifunctional imaging agents combining radionuclidic imaging (SPECT or PET) and NIR dye (Optical imaging) to incorporate a PEG moiety. Critical discoveries regarding self-aggregation and signal quenching properties of dye-antibody conjugates put a significant body of literature in doubt. This advance provides actual understanding of fundamental chemistry for creation of directly quantitative optical-radiological 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 very strong and potent collaborations with the Metabolism Branch, NCI and with the Ludwig Institute, and has fully extended this activity to a collaborative relationship with AREVAMed and UAB to translate Pb-212 into its first clinical trial for treatment of disseminated ovarian cancer while extending At-211 collaborations to researchers at Johns Hopkins.
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