The Use of Plant-Derived Ribosome Inactivating Proteins in Immunotoxin Development: Past, Present and Future Generations

Abstract

Ribosome inactivating proteins (RIPs) form a class of toxins that was identified over a century ago. They continue to fascinate scientists and the public due to their very high activity and long-term stability which might find useful applications in the therapeutic killing of unwanted cells but can also be used in acts of terror. We will focus our review on the canonical plant-derived RIPs which display ribosomal RNA N-glycosidase activity and irreversibly inhibit protein synthesis by cleaving the 28S ribosomal RNA of the large 60S subunit of eukaryotic ribosomes. We will place particular emphasis on therapeutic applications and the generation of immunotoxins by coupling antibodies to RIPs in an attempt to target specific cells. Several generations of immunotoxins have been developed and we will review their optimisation as well as their use and limitations in pre-clinical and clinical trials. Finally, we endeavour to provide a perspective on potential future developments for the therapeutic use of immunotoxins.

Keywords: immunotoxins; ribosome inactivating proteins; therapeutic applications.

Figure 1

Diagram depicting the different generations of immunotoxins. (a) First-generation immunotoxins. Purified toxins were chemically linked to a targeting antibody; (b) Second-generation immunotoxins. Purified type 1 ribosome inactivating proteins (RIPs) or type 2 RIPs with B-chain either blocked or removed were chemically linked to a targeting antibody; (c) Third-generation immunotoxins. Recombinant purified toxins were fused to antibody targeting fragments; (d) Future generation immunotoxins. Toxins are modified to remove immunogenic epitopes and exhibit dual targeting abilities to improve specificity. They can be co-administered with endosome disruptive agents, such as pore-forming agents, endosome disruptive peptides, or photosensitisers, to increase intracellular delivery and potency.