The effect of a monoclonal antibody coupled to ricin a chain-derived peptides on endothelial cells in vitro: Insights into toxin-mediated vascular damage

Roxana Baluna, Elaine Coleman, Chandria Jones, Victor Ghetie, Ellen S. Vitetta

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Immunotoxins (ITs) containing plant or bacterial toxins have a dose- limiting toxicity of vascular leak syndrome (VLS) in humans. The active A chain of ricin texan (RTA), ether toxins, ribosome-inactivating proteins, and the VLS-inducing cytokine IL-2 contain the conserved sequence motif (x)D(y) where x = L, I, G, or V and y = V, L, or S. RTA-derived LDV-containing peptides attached to a monoclonal antibody, RFB4, induce endothelial cell (EC) damage in vitro and vascular leak in two animal models in vivo. We have now investigated the mechanism(s) by which this occurs and have found that (1) the exposed D75 in the LDV sequence in RTA and the C-terminal flanking threonine play critical roles in the ability of RFB4-conjugated RTA peptide to bind to and damage ECs and (2) the LDV sequence in RTA induces early manifestations of apoptosis in HUVECs by activating caspase-3. These data suggest that RTA-mediated inhibition of protein synthesis (due to its active site) and apoptosis (due to LDV) may be mediated by different portions of the RTA molecule. These results suggest that ITs prepared with RTA mutants containing alterations in LDVT may kill tumor cells in vivo in the absence of EC-mediated VLS. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)417-424
Number of pages8
JournalExperimental Cell Research
Volume258
Issue number2
DOIs
Publication statusPublished - Aug 1 2000

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Keywords

  • Endothelial cells
  • Immunotoxins disintegrins
  • Vascular leak syndrome

ASJC Scopus subject areas

  • Cell Biology

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