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

Joan E. Smallshaw, Victor Ghetie, Jose Rizo-Rey, John R. Fulmer, Linda L. Trahan, Maria Ana Ghetie, Ellen S Vitetta

Research output: Contribution to journalArticle

117 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)387-391
Number of pages5
JournalNature biotechnology
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2003

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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