ABSTRACT
The specific delivery of proteins or peptides to the cytosol of target eukaryotic cells is now the subject of intense investigation. While the concept of targeted delivery of toxic materials to disease-causing cells dates back to the tum of the century (Erlich, 1956), it has been only in recent years that the confluence of cell biology, DNA, and protein technologies has allowed this goal to be realized. The application of recombinant DNA methodologies, DNA sequence analysis, X-ray crystal structure determination, protein engineering, and the understanding of the cell biology of receptor-mediated endocytosis and membrane trafficking has led to the design and genetic assembly of fusion toxins with extraordinary cytotoxic potency and selectivity. Indeed, the first of the cell surface receptor specific "designer" fusion proteins that is based upon the diphtheria toxin platform has been studied in phase 1111 human clinical trials for the past several years. It is now clear that the administration of the interleukin-2 receptor (IL-2R)-targeted fusion toxin DAB48JL-2 to patients is safe and may result in the induction of durable clinical remission
in diseases ranging from hematologic malignancies to autoimmune disease (LeMaistre et al., 1992). Since this area has been well reviewed in recent years (Murphy and Strom, 1990; Murphy and Williams, 1991; Strom et al., 1993a,b), we focus this review on the emerging understanding of the molecular events involved in the diphtheria toxin mediated delivery of proteins and peptides into target cells.
