Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

conserved 28S rRNA loop, the so called "sarcin/ricin loop" [251] [252] [253] . This modification renders the ribosome unable to interact with elongation factors 2 (eEF2), resulting in inhibition of translation and ultimately apoptotic cell death [201, [254] [255] [256] [257] [258] [259] [260] [261] [262] [263] [264] . In addition to their classical ribosome-inactivating glycosidase activity, other activities and enzymatic properties were associated with RIPs: antiviral activity [265] , depurination of (non-ribosomal) RNA and adenine DNA glycosylase activity [266] [267] [268] [269] [270] , deoxyribonuclease activity [271] [272] [273] [274] [275] [276] [277] [278] , ribonuclease activity [279, 280] , removal of adenine from poly(ADP-ribosyl)ated poly(ADP-ribose) polymerase (an enzyme involved in DNA repair) [281, 282] , depurination of the capped RNA template [283, 284] , superoxide dismutase (SOD) activity [285] [286] [287] and phospholipase activities [288] . The involvement of these non-classical RIP activities in cytotoxicity is debatable, though accumulating evidence suggests that ribosome inactivation is not the sole means by which RIPs execute their toxic effects [264, [289] [290] [291] [292] [293] [294] [295] CD25 and CD30 are lymphoid activation markers which are highly expressed on the surface of Hodgkin's lymphoma cells and only present on a minority of normal human cells [135, [296] [297] [298] . In order to target these cells, two immunotoxins, RFT5-dgA (IMTOX25) and ki-4.dgA, were constructed. The toxic moiety in these immunotoxins was a chemically deglycosylated form of ricin A chain (dgA) (deglycosylation was demonstrated to minimize nonspecific carbohydrate-receptors mediated uptake of RTA based immunotoxins by reticuloendothelial cells in the liver [299] [300] [301] [302] [303] [304] [305] ) linked to the targeting moieties RFT5 (anti-CD25) and ki-4 (anti-CD30) monoclonal antibodies, respectively. Phase I/II trials with i.v. administrated RFT5-dgA on 18 patients with refractory Hodgkin's disease (HD), resulted in two partial remissions (PR), one minor response (MR) and five stable diseases (SD) [75] . In a Phase I study of Ki-4-dgA on 15 patients, one PR, one MR and two SD were observed. Dose-limiting toxicities were related to vascular leak syndrome, consisting of edema, tachycardia, dyspnea, weakness and myalgia [75] . A Phase II study evaluating the side effects and efficiency of RFT5-dgA (IMTOX25) treatment in patients with relapsed or refractory cutaneous T-cell non-Hodgkin lymphoma (CTCL) was completed recently, and the immunotoxin is currently evaluated as a treatment for metastatic melanoma (http://clinicaltrials.gov/).