Abstract
Onconase, a member of the pancreatic ribonuclease A superfamily, is currently in Phase III clinical trials for treatment of unresectable malignant mesothelioma. The anticancer effect of onconase may relate to its intracellular target, a non-coding RNA. Some non- coding RNAs are aberrantly expressed in cancer cells. This discovery is creating new interest in drugs that target RNA. Conjugating onconase to agents that recognize tumor associated molecules further increases its potency and specificity. Analysis of onconase activity when directed to two different internalizing and one noninternalizing receptor reveals that the ideal targeting agents would rapidly enter lysosomal compartments before onconase escaped to the cytosol. Antibody-onconase conjugates are effective in preclinical models, cause little non-specific toxicities in mice and have favorable formulation properties. Understanding the reason for their potency coupled with understanding novel RNA-based mechanisms of tumor cell death will lead to improved variations of targeted onconase.
Keywords: Ribonuclease, RNase A, Onconase, Antibody, Immunotoxin, Internalization
Current Pharmaceutical Biotechnology
Title: Antibody-Onconase Conjugates: Cytotoxicity and Intracellular Routing
Volume: 9 Issue: 3
Author(s): S. M. Rybak
Affiliation:
Keywords: Ribonuclease, RNase A, Onconase, Antibody, Immunotoxin, Internalization
Abstract: Onconase, a member of the pancreatic ribonuclease A superfamily, is currently in Phase III clinical trials for treatment of unresectable malignant mesothelioma. The anticancer effect of onconase may relate to its intracellular target, a non-coding RNA. Some non- coding RNAs are aberrantly expressed in cancer cells. This discovery is creating new interest in drugs that target RNA. Conjugating onconase to agents that recognize tumor associated molecules further increases its potency and specificity. Analysis of onconase activity when directed to two different internalizing and one noninternalizing receptor reveals that the ideal targeting agents would rapidly enter lysosomal compartments before onconase escaped to the cytosol. Antibody-onconase conjugates are effective in preclinical models, cause little non-specific toxicities in mice and have favorable formulation properties. Understanding the reason for their potency coupled with understanding novel RNA-based mechanisms of tumor cell death will lead to improved variations of targeted onconase.
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Cite this article as:
Rybak M. S., Antibody-Onconase Conjugates: Cytotoxicity and Intracellular Routing, Current Pharmaceutical Biotechnology 2008; 9 (3) . https://dx.doi.org/10.2174/138920108784567272
DOI https://dx.doi.org/10.2174/138920108784567272 |
Print ISSN 1389-2010 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4316 |
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