Genetic engineering of an immunotoxin to eliminate pulmonary vascular leak in mice.
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.
Smallshaw
Joan E
JE
Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8576, USA.
Ghetie
Victor
V
Rizo
Jose
J
Fulmer
John R
JR
Trahan
Linda L
LL
Ghetie
Maria-Ana
MA
Vitetta
Ellen S
ES
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
D000922:Immunotoxins; D011994:Recombinant Proteins; D012276:Ricin