Metal Chelate Conjugated Monoclonal Antibodies for Tumor Diagnosis and Therapy

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Tumor associated monoclonal antibodies (mAb's) 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 span the range of radionuclidic properties available permitting an assay of the effects of emission energy, half-life, and type of emission. Current research focuses on performing extensive pre-clinical studies with the alpha-particle emitting radionuclide Pb-212, with decreased interest in Bi-213, and full activation of parallel studies with the alpha emitter, At-211. Ongoing collaborative clinical trials employ the second generation bifunctional 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. Note that the chemistry that makes Zevalin, the 1st FDA approved radiolabeled antibody therapeutic, possible was developed by the Chemistry Section. Nearly all of those studies ongoing and planned by the Section now employ the 3rd generation bifunctional chelating agent, CHX-A'' DTPA for sequestering In-111, Y-90, Bi-213, and Lu-177. Current studies initiated and ongoing continue to validate use of CHX-A'' 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 applications, the Chemistry Section also has an active area of study on development of novel and superior bifunctional chelating agents for use with Zr-89 for immunoPET applications as the current technology is both cumbersome, limiting clinical/radiopharmacy translation, and not stable in vivo leading to bone deposition of the freed Zr-89 in vivo. 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. Novel linking chemistry for extant bifunctional chelating agents has been developed for peptide usage and in use with peptide synthesizer instrumentation. The established agents of the Section are being extended to peptides and other small delivery vectors targeting receptors of interest. This novel chemistry and discoveries therein are frequently found to be appropriate to the Section's other project. 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 pending operation status of the cyclotron. The Section continues to upgrade the production facilities for this radionuclide. The Chemistry section previously reported on validation of the most stable At-211 linker reagent, N-Me-SAPS, and a recent entire re-synthesis of the agent will facilitate studies parallel to the prior Pb-212 studies. The recent addition of new personnel to the Section will accelerate progress on this project later this year incorporating additional production and radiolabeling technology refinements. 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. Bi-213 reached a point whereby evaluation of cost-effectiveness combined with failed national availability effectively forced termination of study of this radionuclide. Despite its significant efficacy, the full range of use and value of Bi-213 for therapy 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. Evaluation of the efficacy of Pb-212 with specific mAbs, use of combined radiolabeled mAbs, and their combinations with chemotherapeutics continues with systematically. The hypothesis is 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 murine models result with single doses of Pb-212 conjugated to clinically relevant antibodies, e.g., trastuzumab and panitumumab. Radiolabeling difficulties eliminated cetuximab from further 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 indicated superior therapeutic response to Pb-212 vs. Bi-213. Studies 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. Studies with the Camphausen lab to evaluate tumor growth environment impact on genotype are being initiated. Studies with the Citrin lab are being initiated to assess impact of targeted radiation combined with external beam radiation. Studies to expand use trifunctional imaging agents combining radionuclidic imaging (SPECT or PET) and NIR dye (Optical imaging) incorporated a PEG moiety. Critical discoveries were made regarding self-aggregation and signal quenching properties of dye-antibody conjugates putting a significant body of literature in doubt. This advance provides actual understanding of fundamental chemistry for creation of directly quantitative Optical-radionuclidic 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 required to fully define the clinical impact of targeted radiation therapy. To this end, the Section continues to enjoy very strong and potent collaborative relationships with the Metabolism Branch, NCI and with the Ludwig Institute, and has fully extended this activity to a collaborative relationship with UAB to translate Pb-212 into its first clinical trial for treatment of disseminated ovarian cancer.