Metal Chelate Conjugated Monoclonal Antibodies

Clinical Sciences

Investigators

Linked publications & trials

Abstract

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 alpha-particle emitting radionuclides 212Pb, 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. The chelation chemistry for 213Bi is established and is employed now is pre-clinical and clinical studies (vide infra). Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy with isotopes of interest continues particularly in regards to the combination of high stability with rapid formation rates for radio-lanthanides and a-particle emitting radionuclides such as 213Bi. Studies with 211At have continued with additional pre-clinical studies with the novel reagent termed SAPS conjugated to the monoclonal antibody 7G7 in several ATL murine tumor models. Studies have been executed to assess the inclusion of a dative bond pi donor system with appropriate donor heteroatoms ortho to the 211At labeling site. 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. In addition to evaluation of the efficacy of these radionuclides individually with each mAb, the use of combined radiolabeld 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 HuCC49deltaCH2 or Herceptin. Use of 212Pb in combination with Gemcitabine has shown impressive enhanced therapeutic efficacy. Extension of this result to address fractionated dosing of both 212Pb and Gemcitabine continued to provide evidence that optimization of both drug combination and scheduling will result in extended survival. Studies combining administration of 213Bi or 212Pb with taxol have not only have demonstrated a significant extension of survival, but also a very strong dependence on administration scheduling. Studies pertaining to this latter aspect are planned for next year to obtain a greater understanding of this result thereby permitting more rational decisions in combining established drugs with these isotopes. Lastly, the combination of two non-cross-reactive mAbs, HuCC49deltaCH2 and Herceptin, both radiolabeled with 213Bi demonstrated a significant extension of survival with a very strong dependence on administration scheduling. While results clearly indicated use of 90Y to be inappropriate in such a model, 177Lu remains a distinct possible option, despite being a source of mixed results at this time.