Construction and characterization of novel, recombinant immunotoxins targeting the Her2/neu oncogene product: in vitro and in vivo studies

Cancer Research
Yu Joshua CaoM G Rosenblum

Abstract

The goal of this study was to characterize a series of anti-Her2/neu immunotoxin constructs to identify how different antibodies and linker choices affect the specificity and cytotoxicity of these proteins. We constructed a series of immunotoxins containing either the human single-chain antibody (scFv) C6.5 or the murine scFv e23 fused to the highly toxic recombinant gelonin (rGel) molecule. Based on the flexible GGGGS linker (L), the fusion construct C6.5-L-rGel was compared with e23-L-rGel to evaluate the specific cytotoxic effects against Her2/neu-positive and Her2/neu-negative tumor cells. Both constructs retained the specificity of the original antibody as well as the biological activity of rGel toxin. The two constructs displayed similar cytotoxicity against different carcinoma cells. We additionally introduced the modified linkers TRHRQPRGWEQL (Fpe) and AGNRVRRSVG (Fdt), which contained furin cleavage sites, to determine the effect of these design changes on stability and cell killing efficiency. The introduction of furin cleavage linkers (Fpe or Fdt) into the molecules resulted in dissimilar sensitivity to protease cleavage compared with the constructs containing the L linker, but very similar intracellular rGel release...Continue Reading

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Citations

Dec 17, 2011·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Dong LiuZhaocong Chen
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Sep 24, 2015·Applied Microbiology and Biotechnology·Gang LiXin-Hui Xing
Jul 18, 2015·Chinese Journal of Cancer·Meiqi ZengOu Sha
Dec 22, 2017·Signal Transduction and Targeted Therapy·Hang ZhangJinliang Yang
Aug 23, 2020·Toxins·Maria E B BerstadAnette Weyergang
Jan 9, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·S John WerohaPaul Haluska
Aug 16, 2013·Molecular Cancer Therapeutics·Andrew J McCluskey, R John Collier
Dec 15, 2019·International Journal of Pharmaceutics·Li CaoZhangyong Hong
Apr 8, 2020·ACS Pharmacology & Translational Science·Akmal M AsrorovYongzhuo Huang
Jun 20, 2018·ACS Chemical Biology·Thomas PirzerHarald Kolmar
Sep 8, 2021·Cancer Cell International·Reza MahmoudiMohammad Rahmati

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