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PEDS Advance Access published online on October 21, 2005
Protein Engineering Design and Selection, doi:10.1093/protein/gzi073
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received July 6, 2005
Revised September 9, 2005
Accepted September 13, 2005

Article

Cytotoxicity of human RNase-based immunotoxins requires cytosolic access and resistance to ribonuclease inhibition

Heidi A. Erickson 1, Michelle D. Jund 1, and Christopher A. Pennell 1*

1 Department of Laboratory Medicine and Pathology, Cancer Center and Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA

* To whom correspondence should be addressed.
Christopher A. Pennell, E-mail: penne001{at}umn.edu


  Abstract

Immunotoxins are targeted therapeutics designed to kill cancer cells. The targeting moiety of an immunotoxin selectively binds to a tumor cell and targets it for death via an attached toxin. Because the toxins are typically of plant or bacterial origin, their clinical use is limited by immunogenicity and nonspecific toxicity. To circumvent these problems, we have begun to engineer immunotoxins containing human pancreatic ribonuclease. Here we describe the generation of ribonuclease mutants designed to evade a ubiquitous cytosolic inhibitor that would otherwise block cytotoxicity. Two mutants retained catalytic activity and were relatively resistant to the inhibitor. To deliver them to human T leukemic cells, these ribonuclease variants were fused to a single chain Fv fragment specific for CD7. The ribonuclease-sFv fusion proteins bound CD7+ T cells and were internalized yet were not cytotoxic. Transfection of the proteins directly into the cytosol reduced cell viability, suggesting that the failure of the immunotoxins to kill cells when added externally resulted from the inability of the ribonuclease moiety to access the cytosol efficiently. Our results indicate appropriate intracellular routing, as well as resistance to inhibition, is critical to the cytotoxicity of human ribonuclease-based immunotoxins.

Keywords: cancer therapy; human RNase; immunotoxin; Onconase; ribonuclease inhibitor.
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