Tumor associated monoclonal antibodies (mAb's) are potential 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 assaying the effects of emission energy, half-life, and type of emission. Current research is focused on performing extensive pre-clinical studies with a-particle emitting radionuclides 212,203Pb, 212,213Bi,and 211At. Ongoing clinical trials currently employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or Tiuxetan) for sequestering 90Y and or the CHX-A'' DTPA for 90Y and / or 213Bi. Both are suitable for scintigraphy with either 111In or PET imaging with 86Y. Pre-clinical results in the ongoing development of novel bifunctional chelating agents and linkers for targeted radiotherapy with the a-particle emitting radionuclides 212,213Bi, 225Ac, and 211At are either completed, discontinued, or on-going. In the case of 212,213Bi chelation chemistry is established and is employed now is pre-clinical studies (vide infra). Studies addressing the possibility of using 225Ac have been terminated. Independent studies indicated significant unacceptable toxicity originating from the decay product daughters. While potentially useful in a limited setting, the challenges associated with coordination chemistry eliminate this radionuclide from clinical contention. Unfortunately, termination of this effort also eliminates any further opportunity to acquire any fundamental understanding of the coordination chemistry of 225Ac. Studies with 211At have yielded a novel protein modification reagent wherein the linking moiety has been removed from being the traditional aryl carboxylate active ester and placed several atoms away from the aryl astatine bond. Pre-clinical studies with this novel reagent termed SAPS conjugated to humanized monoclonal antibody anti-Tac indicate this agent to be stable in vivo and equivalent to indirectly radio-iodinated protein. Studies to assess use of the CHX-A'' DTPA for sequestering 177Lu revealed comparable in vivo stablity to DOTA conjugates thereby prompting use of this reagent with yet another radionuclide of medical import. Studies to assess the production and purification of 86Y as a PET agent for more precise dosimetry of 90Y radioimmunotherapy have been completed and indicated advantages for more accurate assessment of dose limiting bone marrow toxicity. Studies with 213Bi have expanded to include investigation of pre-targeting protocols. Preliminary results of streptavidin conjugated monoclonal antibody humanized anti-Tac in a murine T-cell leukemia model have been completed with significant therapeutic levels of efficacy being obtained with single doses of 213Bi while no therapy could be achieved using the b-emitter 90Y. With a recent revival in availability of both 212Bi and 212Pb-212, a highly extensive and focused pre-clinical investigation into the use of these isotopes and the b-emitting lanthanide radionuclides was initiated for the treatment of disseminated intraperitoneal disease such as that arising from either ovarian and pancreatic cancer. In addition to the use of these radionuclides, their combination, the use of combined monoclonal antibodies to address tumor heterogeneity, and their combination with chemotherapeutics is being 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 only via combined modality will significant therapeutic success be achieved. Preliminary results have indicated that substantial increases in median life expectancy in murine models are possible with single doses of these isotopes conjugated to clinically relevant antibodies such as CC49DCH2 or Herceptin However, greater effective therapy was found in treatment with targeted 212Pb in conjunction with gemcitabine. Extension of this result to fractionated dosing of both radiation and gemcitabine while investigating the combination of other chemotherapeutics with this isotope and the lanthanides continues.
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