Chen, Lu

Fleming, Bryan D

Hall, Matthew

Ho, Mitchell

Pastan, Ira

Urban, Daniel

English

VCU Scholars Compass

Virginia Commonwealth UniversityVCU Scholars CompassHepatobiliary Cancers: Pathobiology andTranslational Advances Dept. of Pathology2017Glypican-3 Targeting Immunotoxins for theTreatment of Liver CancerBryan D. FlemingNational Cancer Institute, bryan.fleming@nih.govDaniel UrbanNCATSLu ChenNCATSSee next page for additional authorsFollow this and additional works at: http://scholarscompass.vcu.edu/hepa_cancersPart of the Biochemistry Commons, and the Molecular Biology Commons© The Author(s)This Abstract Accepted for Presentation is brought to you for free and open access by the Dept. of Pathology at VCU Scholars Compass. It has beenaccepted for inclusion in Hepatobiliary Cancers: Pathobiology and Translational Advances by an authorized administrator of VCU Scholars Compass.For more information, please contact libcompass@vcu.edu.Downloaded fromhttp://scholarscompass.vcu.edu/hepa_cancers/27AuthorsBryan D. Fleming, Daniel Urban, Lu Chen, Matthew Hall, Ira Pastan, and Mitchell HoThis abstract accepted for presentation is available at VCU Scholars Compass: http://scholarscompass.vcu.edu/hepa_cancers/27 Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer Bryan Fleming1, Daniel Urban2, Lu Chen2, Matthew Hall2, Ira Pastan1, Mitchell Ho1 1National Cancer Institute, Laboratory of Molecular Biology, Bethesda, Maryland, 20770.               2National Center for Advancing Translational Sciences, Rockville, Maryland, 20850.   Our previous study has established that Glypican-3 (GPC3) is a promising target for immunotoxin therapy in hepatocellular carcinoma (HCC). GPC3 targeting immunotoxins can inhibit HCC cell proliferation by blocking Wnt binding and through the elimination of cellular protein synthesis. While immunotoxins have shown great success in the clinical for treating blood cancers, in particular hairy cell leukemia, the same clinical success has not been demonstrated in treating solid tumors. We believe that modification of the Pseudomonas toxin domain may help to overcome clinical limitations associated with the treatment of solid tumors. Clinical limitations include off-target toxicity associated with the development of vascular leak syndrome, a short serum half-life and the development of a neutralizing antibody responses. To understand the effect of deimmunization on the immunotoxins’ cytotoxic function, in the present study we constructed a panel of anti-GPC3 immunotoxins with point mutations to remove antigen residues predicted to be involved in B cell, T cell, or a combination of both responses. The deimmunizied immunotoxins exhibited similar levels of cytotoxic function in cell proliferation assays. All of the deimmunized versions showed a significant increase in overall survival as determined by Hep3B subcutaneous and HuH-7 intraperitoneal mouse models. The new deimmunized immunotoxins appear to be well tolerated in mice. To improve their serum half-life, we are further engineering the immunotoxins by incorporating albumin binding domains. The optimized immunotoxin will be clinically developed for the treatment of liver cancer.  

Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=1010&amp;context=hepa_cancers

Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

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