Optimizing glypican-3 targeting immunotoxins for the treatment of liver cancer

Authors

• BD Fleming
• D Urban
• M Hall
• T Longerich
• T Greten
• I Pastan
• M Ho

Abstract

Glypican-3 (GPC3) is an emerging target in hepatocellular carcinomas (HCC). While GPC3 targeting immunotoxins have had promising pre-clinical results, their immunogenic nature and short serum half-life in patients may need to be addressed. To optimize GPC3 targeting immunotoxin therapy for human use, we compare deimmunized HN3 based immunotoxins to identify a suitable candidate for clinical transition. We constructed deimmunized immunotoxins using the mPE24, T20, T19, and M11 toxins. These domains that have undergone mutation strategies to target B cell, T cell or a combination of both B/T responses. To further optimize the immunotoxin, we added albumin binding domains that were isolated from a llama heavy chain antibody and Streptococcal protein G. WST cell proliferation assay and ADP-ribosylation were used to access the immunotoxin’s ability to inhibit cancer cell proliferation. Hep3B xenografts were used test the immunotoxin’s safety and in vivo performance. The in vitro assays revealed that mPE24, T20 and T19 immunotoxins had a similar activity level to the wild type HN3-LR. HN3-T20 was well tolerated in the mice and caused the greatest increase in overall survival with mice surviving 33 days longer than the control group. Addition of the albumin binding domains to HN3-T20 did not change the in vitro activity but cause a 10-fold increase in the in vivo performance. Tumor regression with the HN3-ABD-T20 immunotoxin was observed at doses as low as 1 mg/kg. These data suggest that the deimmunized HN3 based immunotoxins with an albumin binding domain represent a high potency therapeutic that should be further explored for the ability to treat HCC.

Scientific Focus Area: Molecular Biology and Biochemistry

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