Tumor associated monoclonal antibodies (mAb's) are therapeutic agents as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents employed are radionuclides and their relative efficacy is evaluated in appropriate murine tumor model systems. The radionuclides chosen for study span the range of radionuclidic properties available thereby permitting the assay of the effects of emission energy, half-life, and type of emission. Current research is focused on performing extensive pre-clinical studies with alpha-particle emitting radionuclides 212Pb, 213Bi, and 211At. Ongoing clinical trials employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or tiuxetan) for sequestering 90Y with most now moving over to the third generation bifunctional chelating agent, CHX-A'' DTPA, for 111In, 90Y, 213Bi, and now potentially 177Lu. Current studies initiated and still ongoing this year also validate the use of the CHX-A'' DTPA for use in PET imaging with 86Y. The chelation chemistry for 213Bi is established and is routinely employed in pre-clinical and clinical studies. Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy with isotopes of interest continues. This is particularly active in regards to the combination of high stability with rapid formation rates for radio-lanthanides and alpha-particle emitting radionuclides such as 213Bi. Additionally, novel linking chemistry for extant bifunctional chelating agents have been developed that is also amenable to peptide usage and even in use within peptide synthesizer instrumentation. Thus, many of the established agents of the Chemistry Section are now being extended to peptides targeting receptors of interest. Studies with 211At that have been temporarily on hiatus after validation of the most stable 211At linker reagent, N-Me-SAPS, will be resumed late this year to open a parallel investigation to those ongoing with other alpha emitters to treat disseminated intra peritoneal disease. A highly extensive and focused pre-clinical investigation into the use of both 212Bi and 212Pb continues for the treatment of disseminated intraperitoneal disease such as that arising from either ovarian or pancreatic cancer continues to move forward towards a potential clinical trial at the NCI. In addition to evaluation of the efficacy of these radionuclides individually with specific mAbs, the use of combined radiolabeled mAbs, and their combinations with chemotherapeutics continues to be systematically investigated. This investigation rests on the hypothesis that single doses of a single, targeted radionuclide lacks a rational basis for cancer therapy and that combined modality therapies will achieve significant therapeutic enhancements. Current results indicate that substantial increases in median life expectancy in murine models are possible with single doses of 213Bi or 212Pb conjugated to clinically relevant antibodies such as CC49(Delta)CH2, Herceptin, and now Erbitux. Use of 212Pb in combination with Gemcitabine showed impressive enhanced therapeutic efficacy; fractionated dosing of both 212Pb and Gemcitabine provided evidence that optimization of both drug combination and scheduling will result in extended survival. Studies combining administration of 213Bi or 212Pb with taxol demonstrated significant extension of survival with a very strong dependence on administration scheduling. Studies are ongoing to obtain a greater understanding of this result thereby permitting more rational decisions in combining taxol with additional established drugs with these isotopes. Fractionation studies of 213Bi with taxol were executed this year under compromised conditions due to a forced scheduling conflict of isotope delivery and relocation of animal facilities; this study will be scheduled for re-investigation later this calendar year or early 2008. Preliminary investigations of the administration order impact of cisplatin combined with 212Pb labeled Herceptin are scheduled for Aug, 2007 along with a number of preliminary studies with 212Pb labeled Erbitux that lay the ground work for delivery of radiation targeted to multiple cell surface receptors to address tumor heterogenicity. Preliminary studies evaluating the use of 177Lu that were initiated along a parallel pathway to determine MTD, fractionation; initial combination therapy studies with gemcitabine and with taxol are being scheduled to be repeated later this calendar year
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