title: Genetic engineering of an immunotoxin to eliminate pulmonary vascular leak in mice.
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.
authors.affiliation: Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8576, USA.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Smallshaw
authors.forename: Victor
authors.initials: V
authors.lastname: Ghetie
authors.forename: Jose
authors.initials: J
authors.lastname: Rizo
authors.forename: John R
authors.initials: JR
authors.lastname: Fulmer
authors.forename: Linda L
authors.initials: LL
authors.lastname: Trahan
authors.forename: Maria-Ana
authors.initials: MA
authors.lastname: Ghetie
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Vitetta
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019559:Capillary Leak Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D004727:Endothelium / Q000187:drug effects*; D005818:Genetic Engineering / Q000379:methods*; D000922:Immunotoxins / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D007928:Lethal Dose 50; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008223:Lymphoma / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D016297:Mutagenesis, Site-Directed; D015202:Protein Engineering / Q000379:methods; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012276:Ricin / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism / Q000633:toxicity
chemical_list: D000922:Immunotoxins; D011994:Recombinant Proteins; D012276:Ricin