Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity

B. J. Stish, S. Oh, H. Chen, A. Z. Dudek, R. A. Kratzke, D. A. Vallera

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Background: Potency, immunogenicity, and toxicity are three problems that limit the use of targeted toxins in solid tumour therapy. Methods: To address potency, we used genetic engineering to develop a novel bispecific ligand-directed toxin (BLT) called EGF4KDEL, a novel recombinant anti-mesothelioma agent created by linking human epidermal growth factor (EGF) and interleukin-4 (IL-4) to truncated pseudomonas exotoxin (PE38) on the same single-chain molecule. Immunogenicity was reduced by mutating seven immunodominant B-cell epitopes on the PE38 molecule to create a new agent, EGF4KDEL 7Mut. Results: In vitro, bispecific EGF4KDEL showed superior anti-mesothelioma activity compared with its monospecific counterparts. Toxicity in mice was diminished by having both ligands on the same molecule, allowing administration of a 10-fold greater dose of BLT than a mixture of monomeric IL4KDEL and EGFKDEL. EGF4KDEL 7Mut, retained all of its functional activity and induced about 87% fewer anti-toxin antibodies than mice given the parental, non-mutated form. In vivo, intraperitoneal (IP) injection of the BLT showed significant (P<0.01) and impressive effects against two aggressive, malignant IP mesothelioma models when treatment was begun 14-16 days post tumour innoculation. Conclusion: These data show that EGF4KDEL 7Mut is a promising new anti-mesothelioma agent that was developed to specifically address the obstacles facing clinical utility of targeted toxins.

Original languageEnglish (US)
Pages (from-to)1114-1123
Number of pages10
JournalBritish Journal of Cancer
Volume101
Issue number7
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
This work was supported in part by US Public Health Service Grants RO1-CA36725, RO1-CA082154, awarded by the NCI and NIAID, DHHS, and the Randy Shaver Foundation.

Keywords

  • EGF
  • IL-4
  • Immunotoxin
  • Mesothelioma
  • Molecular therapeutics
  • Nude mice

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