Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity.
Br J Cancer
; 101(7): 1114-23, 2009 Oct 06.
Article
em En
| MEDLINE
| ID: mdl-19755995
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Toxinas Bacterianas
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Imunotoxinas
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Interleucina-4
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ADP Ribose Transferases
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Fatores de Virulência
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Fator de Crescimento Epidérmico
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Exotoxinas
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Mesotelioma
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article