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Br J Cancer. 2009 Oct 6;101(7):1114-23. doi: 10.1038/sj.bjc.6605297.

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

Author information

1
Department of Therapeutic Radiology-Radiation Oncology, Section on Molecular Cancer Therapeutics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.

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.

PMID:
19755995
PMCID:
PMC2768099
DOI:
10.1038/sj.bjc.6605297
[Indexed for MEDLINE]
Free PMC Article
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