Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity
| Autor: | Robert A. Kratzke, Arkadiusz Z. Dudek, Hua Chen, Daniel A. Vallera, Bradley J. Stish, Seung Uk Oh |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Mesothelioma Cancer Research Pharmacology medicine.disease_cause law.invention Mice 0302 clinical medicine Immunotoxin law Peritoneal Neoplasms ADP Ribose Transferases Mice Inbred BALB C 0303 health sciences Immunotoxins Immunogenicity Biological activity Ligand (biochemistry) nude mice Recombinant Proteins immunotoxin 3. Good health Oncology 030220 oncology & carcinogenesis Recombinant DNA Female molecular therapeutics Virulence Factors Bacterial Toxins Exotoxins Biology complex mixtures 03 medical and health sciences Immune system Cell Line Tumor medicine Animals Humans neoplasms Interleukin 4 EGF 030304 developmental biology Epidermal Growth Factor Toxin IL-4 Xenograft Model Antitumor Assays respiratory tract diseases Immunology Interleukin-4 Translational Therapeutics |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6605297 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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