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Nat Biotechnol. 2003 Apr;21(4):387-91. Epub 2003 Mar 10.

Genetic engineering of an immunotoxin to eliminate pulmonary vascular leak in mice.

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1
Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8576, USA.

Abstract

Vascular leak syndrome is a major and often dose-limiting side effect of immunotoxins and cytokines. We postulated that this syndrome is initiated by damage to vascular endothelial cells. Our earlier studies identified a three-amino acid motif that is shared by toxins, ribosome-inactivating proteins, and interleukin-2, all of which cause this problem. We have now generated a panel of recombinant ricin A chains with mutations in this sequence or in amino acids flanking it in the three-dimensional structure. These have been evaluated alone and as immunotoxins for activity, ability to induce pulmonary vascular leak in mice, pharmacokinetics, and activity in tumor-xenografted mice. One mutant was comparable to the ricin A chain used before in all respects except that it did not cause vascular leak at the same dose and, when used as an immunotoxin, was more effective in xenografted SCID mice.

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PMID:
12627168
DOI:
10.1038/nbt800
[Indexed for MEDLINE]

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