Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Therefore, fighting against such cancer is reasonable. Chemotherapy drugs are sometimes inefficient and often accompanied by undesirable side effects for patients. On the other hand, the emergence of chemoresistant HCC emphasizes the need for a new high-efficiency treatment strategy. Immunotoxins are armed and rigorous targeting agents that can purposefully kill cancer cells. Unlike traditional chemotherapeutics, immunotoxins because of targeted toxicity, insignificant cross-resistance, easy production, and other favorable properties can be ideal candidates against HCC. In this review, the characteristics of proper HCC-specific biomarkers for immunotoxin targeting were dissected. After that, the first to last immunotoxins developed for the treatment of liver cancer were discussed. So, by reviewing the strengths and weaknesses of these immunotoxins, we attempted to provide keynotes for designing an optimal immunotoxin against HCC.

Keywords: drug targeting; hepatocellular carcinoma; immunotoxin; liver cancer; targeted therapy.

Figure 1

The immunotoxin’s mechanism of action on hepatocellular cancer cells. After the ligand binding to receptors in clathrin-coated pits, receptor-mediated endocytosis begins, and then, the budding of the pits. In the early endosomal environment, the 37 kd toxin moiety of PE is separated. This process is related to the conformational change following exposure of the furin-cleavable motif (amino acids 274–280 from II domain, RHRQPRG). In the late endosome, the 37 kd toxin moiety uses Rab proteins to reach the trans-Golgi network (TGN). The toxin moiety of PE has an REDL motif (amino acids 609–612) in the C-terminus, which can bind to the KDEL receptor (KDEL R: green line in the picture) on the ER. Changing the C terminal RDEL to the KDEL motif is one modification on the PE in which the binding capacity to KDEL R has been improved. Thus, the toxin can be transported to the ER and then to the cytosol in a retrograde manner. In the cytosol, the 37 kd toxin moiety begins its enzymatic activity and causes ADP ribosylation in the elongation factor-2 (eEF-2) on the ribosomes. Accordingly, the eEF-2 is inactivated, and the protein synthesis of the target cells is inhibited, resulting in irreversible apoptosis induction.

Figure 2

HCC-specific immunotoxins since 2000 to 2015. In vitro, in vivo, and clinical trial results related to introduced immunotoxins are shown in pink, orange, and green background, respectively.

Figure 3

GPC3-targeted immunotoxins. Immunotoxins that target the GPC3 receptor were introduced from 2015 to now. Those studied by the same research group in the same year were compared together and presented in an identical background stain.