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

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.

Keywords: albumin binding domain; glypican-3; hepatocellular carcinoma; recombinant immunotoxin; single-domain antibody.

Figure 1

(A) Illustration of glypican-3 and our various anti-glypican-3 antibodies. The approximate binding epitope of the key residue for the antibodies are indicated in the parentheses. (B) Schematic of the various Pseudomonas exotoxin domains discussed in this review. Exotoxins labeled as combined have both B cell and T cell deimmunizations. The mutations indicated in purple were common to both B cell and T cell deimmunizations.