Factors that Determine Sensitivity and Resistances of Tumor Cells Towards Antibody-Targeted Protein Toxins

Recombinant immunotoxins are composed of antibody-derived targeting entities fused to truncated toxins. Pseudomonas toxins inactivate eEF2 by ADP-ribosylation and are potent antitumoral agents in clinical development. The sensitivity of tumor cells towards such fusion proteins, and hence their therapeutic efficacy, is influenced by multiple factors: (i) access to tumor cells, (ii) target antigen binding and internalization, (iii) entry into the cytosol, (iv) enzymatic modification of the intracellular target eEF2, and (v) induction of apoptosis. Parameters that affect these steps and hence modulate sensitivity include: (i) protein stability and immunogenicity, (ii) presence, density and internalization of target antigen, (iii) cellular factors involved in processing, routing or translocation of the toxin, (iv) factors involved in diphthamide synthesis on eEF2, and (v) factors that influence cellular susceptibility towards apoptosis. This chapter describes sensitivity or resistance factors for Pseudomonas exotoxin -derived immunotoxins that were identified experimentally and/or observed in clinical studies.