Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins

Abstract

Plant Ribosome-inactivating proteins (RIPs) including the type I RIP Saporin have been used for the construction of Immunotoxins (ITxs) obtained via chemical conjugation of the toxic domain to whole antibodies or by generating genetic fusions to antibody fragments/targeting domains able to direct the chimeric toxin against a desired sub-population of cancer cells. The high enzymatic activity, stability and resistance to conjugation procedures and especially the possibility to express recombinant fusions in yeast, make Saporin a well-suited tool for anti-cancer therapy approaches. Previous clinical work on RIPs-based Immunotoxins (including Saporin) has shown that several critical issues must be taken into deeper consideration to fully exploit their therapeutic potential. This review focuses on possible combinatorial strategies (chemical and genetic) to augment Saporin-targeted toxin efficacy. Combinatorial approaches may facilitate RIP escape into the cytosolic compartment (where target ribosomes are), while genetic manipulations may minimize potential adverse effects such as vascular-leak syndrome or may identify T/B cell epitopes in order to decrease the immunogenicity following similar strategies as those used in the case of bacterial toxins such as Pseudomonas Exotoxin A or as for Type I RIP Bouganin. This review will further focus on strategies to improve recombinant production of Saporin-based chimeric toxins.

Exploiting the internalization feature of an antibody against the glycosphingolipid SSEA‐4 to deliver immunotoxins in breast cancer cells

“…Saporin is a ribosome‐inactivating protein found in the seeds of the plant Saponaria officinalis . It functions as an rRNA N ‐glycosylase that inhibits protein synthesis by cleaving a specific adenine base from ribosomal RNA (28S), irreversibly damaging the ribosomes . We found that administering MC‐813‐70 and saporin as an immunotoxin complex gave rise to a significant reduction in the viability of SSEA‐4‐expressing MDA‐MB‐231 cells.…”

Saponin Facilitates Anti-Robo1 Immunotoxin Cytotoxic Effects on Maxillary Sinus Squamous Cell Carcinoma

“…Saporin is approximately 30kd molecular weight. It does not have a natural cell binding domain, so it is active only when it is endocytosed with a receptor-specific molecule or similar mechanism and transferred into the cytosol [11]. e type I RIP is a very powerful toxin in cancer therapy, and the major problem with its use is the need to combine it with some means to transfer it from the endosome to the cytosol.…”

Chlorotoxin Conjugated with Saporin Reduces Viability of ML-1 Thyroid Cancer Cells In Vitro

“…This study addressed the effectiveness of Saporin, Chlorotoxin and CTX-SAP conjugate in decreasing cell viability of ML-1 cells. Saporin, a toxin from the plant seed Saponaria officinalis , inhibits proliferation or cell viability of cancer cells (23). Previous studies have proven that Saporin is an effective ribosome-inactivating protein (RIP) that inhibits protein synthesis and growth of both normal and tumor cells (24).…”