Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update.

Bryan D Fleming,Mitchell Ho

doi:10.3390/biom10060934

Bryan D Fleming, Mitchell Ho

Open Access

https://doi.org/10.3390/biom10060934

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Abstract

Hepatocellular carcinoma (HCC) accounts for most liver cancers and represents one of the deadliest cancers in the world. Despite the global demand for liver cancer treatments, there remain few options available. The U.S. Food and Drug Administration (FDA) recently approved Lumoxiti, a CD22-targeting immunotoxin, as a treatment for patients with hairy cell leukemia. This approval helps to demonstrate the potential role that immunotoxins can play in the cancer therapeutics pipeline. However, concerns have been raised about the use of immunotoxins, including their high immunogenicity and short half-life, in particular for treating solid tumors such as liver cancer. This review provides an overview of recent efforts to develop a glypican-3 (GPC3) targeting immunotoxin for treating HCC, including strategies to deimmunize immunotoxins by removing B- or T-cell epitopes on the bacterial toxin and to improve the serum half-life of immunotoxins by incorporating an albumin binding domain.

Highlights

Liver cancer remains one of the deadliest cancers in the world despite recent advances in anti-cancer therapeutics [1]
Diagnosis of liver cancer typically requires imaging with a computerized tomography (CT) or magnetic resonance imaging (MRI) scan, making it difficult to properly diagnose patients in rural settings [4]
Mutation of the phenylalanine (F) at position 41 to a hydrophilic glutamic acid (E) in this region was found to disrupt the binding of Wnt3a and reduce Wnt activation in a functional β-catenin signaling reporter assay [39]. We found that this same F41E mutation reduced HN3 binding for GPC3, supporting the fact that HN3 directly competes with Wnt for GPC3 binding [39]

Summary

Introduction

Liver cancer remains one of the deadliest cancers in the world despite recent advances in anti-cancer therapeutics [1]. The unique mechanism of action for inhibiting protein synthesis in cancer cells makes immunotoxins a viable class of antibody drugs that are distinct from almost any other common antibody drug format, including bispecific antibodies and antibody–drug conjugates These chimeric therapeutics combine an antibody’s antigen binding domain with the ribosomal inhibitory domain of the Pseudomonas exotoxin (PE) or other toxin domains, such as ricin and diphtheria toxin [57,58,59]. Ricin toxins are known for their ability to be rapidly cleared from blood circulation, so most therapeutics use a deglycosylated version of the A chain to help prevent toxin uptake by the liver [78] This helps to reduce some of the toxicities seen in the early clinical trials involving ricin [72,79]. We believe that decreasing the immunogenicity and increasing the serum half-life of immunotoxins will have the greatest impact on therapeutic efficacy

Optimizing Antibody Targeting of GPC3

Reducing the Immunogenicity of the Toxin Domain

Increasing the Serum Half-Life of Immunotoxins

Findings

Perspective and Future Direction