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 continues to focus on the beta-emitting alpha particle source, Pb-212, in parallel with the alpha emitter, At-211. Ongoing pre-clinical trials employ the chelating agents 1B4M-DTPA (aka MX-DTPA or tiuxetan) or CHX-A (double prime) DTPA both now being well established in clinical applications and in the former, 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. Ongoing studies 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 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 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. The first 2 stages in this effort has been completed providing lead compounds of significantly greater Zr089 complex stability. Thus, pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy 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 novel linkage chemistry agents for site-specific linkage strategies such as click chemistry and carbohydrate modification strategies. 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 progress on evaluation of the therapy potentials of this 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. Development of Pb-212 has continued through to an open Phase I clinical trial that treated an 8th patient in May of 2013 and continues to accrue patients. Unfortunately, the trial 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 in insure that this Phase 1 trial, the first ever in the world using Pb-212, would proceed forward. Thus, once again this Section has successfully been at the forefront of truly novel translational bench to bedside 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. While 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 in combination with gemcitabine, paclitaxel, or carboplatin have been demonstrated, actual mechanistic studies related to fully understanding the in vivo cellular processes involved in tumor eradication are non-existent. The first 3 such studies to be reported 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 have been reported 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. Genetic profiling studies are now ongoing of targeted Pb-212 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC006353-31
Application #
8763676
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
31
Fiscal Year
2013
Total Cost
$1,147,554
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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Guérard, François; Lee, Yong-Sok; Brechbiel, Martin W (2014) Rational design, synthesis, and evaluation of tetrahydroxamic acid chelators for stable complexation of zirconium(IV). Chemistry 20:5584-91
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