Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies.
Highlights
The emergence of antibody-based therapeutics has been met with great success when used to treat cancer
By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated
This immunotoxin was found to be highly effective in the treatment of human Hepatocellular carcinoma (HCC) in mouse xenograft models
Summary
The emergence of antibody-based therapeutics has been met with great success when used to treat cancer. New forms of antibody-based therapeutics include antibody drug conjugates (ADC), chimeric antigen receptor T cells (CAR-T), and recombinant immunotoxins (RIT). Recombinant immunotoxins are fusion proteins that combine the antigen binding domain of an antibody with a bacterial toxin like Pseudomonas exotoxin A. A diphtheria toxin based immunotoxin is being evaluated in a Phase II clinical trial (NCT00611208), which includes patients with a variety of T cell lymphomas [46]. A paper published in 2014 described the identification of pachyerosin as a new ribosomal inactivating protein This toxin was used to create a novel immunotoxin targeting EpCAM and was demonstrated to be effective in the treatment of liver cancer [52]. The variety of immunotoxins will continue to grow as new ribosome inhibiting proteins are discovered
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