Initial characterization of an immunotoxin constructed from domains II and III of cholera exotoxin
| Autor: | Tara Tendler, Jingli Zhang, David J. FitzGerald, Raffit Hassan, Antonella Antignani, Roberta Traini, Matheusz Makowski, Maureen Kiley, Robert Sarnovsky |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cholera Toxin
Cancer Research Recombinant Fusion Proteins Blotting Western Molecular Sequence Data Immunology Exotoxins Cross Reactions Biology medicine.disease_cause Article Neutralization Epitope Immunotoxin Neoplasms Pseudomonas Receptors Transferrin medicine Animals Humans Immunology and Allergy Pseudomonas exotoxin Amino Acid Sequence Base Sequence Toxin Immunotoxins Antibodies Neutralizing Fusion protein Virology Oncology biology.protein Antibody Exotoxin Single-Chain Antibodies |
| Zdroj: | Cancer Immunol Immunother |
| ISSN: | 1432-0851 0340-7004 |
| DOI: | 10.1007/s00262-009-0794-4 |
| Popis: | Immunotoxins are antibody-toxin fusion proteins under development as cancer therapeutics. In early clinical trials, immunotoxins constructed with domains II and III of Pseudomonas exotoxin (termed PE38), have produced a high rate of complete remissions in Hairy Cell Leukemia and objective responses in other malignancies. Cholera exotoxin (also known as cholix toxin) has a very similar three-dimensional structure to Pseudomonas exotoxin (PE) and when domains II and III of each are compared at the primary sequence level, they are 36% identical and 50% similar. Here we report on the construction and activity of an immunotoxin made with domains II and III of cholera exotoxin (here termed CET40). In cell viability assays, the CET40 immunotoxin was equipotent to tenfold less active compared to a PE-based immunotoxin made with the same single-chain Fv. A major limitation of toxin-based immunotoxins is the development of neutralizing antibodies to the toxin portion of the immunotoxin. Because of structure and sequence similarities, we evaluated a CET40 immunotoxin for the presence of PE-related epitopes. In western blots, three-of-three anti-PE antibody preparations failed to react with the CET40 immunotoxin. More importantly, in neutralization studies neither these antibodies nor those from patients with neutralizing titers to PE38, neutralized the CET40-immunotoxin. We propose that the use of modular components such as antibody Fvs and toxin domains will allow a greater flexibility in how these agents are designed and deployed including the sequential administration of a second immunotoxin after patients have developed neutralizing antibodies to the first. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink