Nature Biotechnology
21, 387 - 391 (2003)
Published online: 10 March 2003; | doi:10.1038/nbt800
Genetic engineering of an immunotoxin to eliminate pulmonary vascular
leak in miceJoan E. Smallshaw1, Victor Ghetie1, 2, Jose Rizo3, John R. Fulmer1, Linda L. Trahan1, Maria-Ana Ghetie1, 2
& Ellen S. Vitetta1, 21
Cancer Immunobiology Center, University of Texas
Southwestern Medical Center at Dallas, Dallas, TX
75390-8576. 2
Department of Microbiology, University of Texas
Southwestern Medical Center at Dallas, Dallas, TX
75390-8576. 3
Department of Biochemistry, University of Texas
Southwestern Medical Center at Dallas, Dallas, TX
75390-8576.
Correspondence should be addressed to Ellen S. Vitetta ellen.vitetta@utsouthwestern.eduVascular 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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