Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

Three targeting strategies in toxin based therapy. Ligand targeted toxins: a ligand (antibody, antibody derivative, cytokine, etc.), which specifically binds to a disease related cell-surface antigen/receptor is linked to a toxic moiety, preferentially as a replacement to the natural cell binding domain of that toxin. Upon administration to patients, the construct selectively binds, is internalized and intoxicates diseased cells, sparing healthy cells that do not display the target on their surface. Protease activated toxins: the toxin is engineered to be cleaved and activated by a disease-related intracellular or extracellular protease. Toxin cleavage may enhance cell-binding and/or translocation, stabilization or catalytic activity of the toxic moiety specifically in protease expressing cells, leading to their eradication. Toxin based suicide gene therapy: a DNA construct, encoding for a toxic polypeptide whose expression is regulated by a specific transcription regulation element (TRE), is delivered to a heterogeneous cell population. However, intoxication occurs only in diseased cells that express an active disease-associated transcription factor (DATF) that specifically binds to the TRE and activates the transcription machinery (RP: RNA polymerase).