Recombinant immunotoxins in targeted cancer cell therapy

Targeted cancer therapy in general and immunotherapy in particular combines rational drug design with the progress in understanding cancer biology. This approach takes advantage of our recent knowledge of the mechanisms by which normal cells are transformed into cancer cells, thus using the special properties of cancer cells to device novel therapeutic strategies. Recombinant immunotoxins are excellent examples of such processes, combining the knowledge of antigen expression by cancer cells with the enormous developments in recombinant DNA technology and antibody engineering. Recombinant immunotoxins are composed of a very potent protein toxin fused to a targeting moiety such as a recombinant antibody fragment or growth factor. These molecules bind to surface antigens specific for cancer cells and kill the target cells by catalytic inhibition of protein synthesis. Recombinant immunotoxins are developed for solid tumors and hematological malignancies and have been characterized intensively for their biological activity in vitro on cultured tumor cell lines as well as in vivo in animal models of human tumor xenografts. The excellent in vitro and in vivo activities of recombinant immunotoxins have lead to their preclinical development and to the initiation of clinical trail protocols. Recent trail results have demonstrated potent clinical efficacy in patients with malignant diseases that are refractory to traditional modalities of cancer treatment: surgery, radiation therapy, and chemotherapy. The results demonstrate that such strategies can be developed into a separate modality of cancer treatment with the basic rationale of specifically targeting cancer cells on the basis of their unique surface markers. Efforts are now being made to improve the current molecules and to develop new agents with better clinical efficacy. This can be achieved by development of novel targeting moieties with improved specificity that will reduce toxicity to normal tissues. In this review, the design, construction, characterization, and applications of recombinant immunotoxins are described. Results of recent clinical trails are presented, and future directions for development of recombinant immunotoxins as a new modality for cancer treatment are discussed.