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Intracellularly expressed antibodies, intrabodies, targeting cellular components offer a potent means for
treating a plethora of human diseases including cancer, AIDS, and Alzheimer's disease. Intracellular Ab (intrabodies) constitute neutralizing molecules with a great potential in gene therapy and represent an alternative to other methods of gene inactivation as antisense rna and RNA interference (RNAi).Although classically designed to divert proteins from their usual cellular compartment or to block protein-protein or protein-nucleic acid interactions, this concept is currently in expansion, with intrabodies capable of directly inhibiting the function of an enzyme, activating intracellular proteins, as caspase-3, or leading proteins to degradation in the ubiquitin-proteasome pathway using F-box-intrabody fusions Efforts to generate functional intrabodies include the isolation of naturally occurring intrabodies from large libraries and the creation of an artificial intrabody framework that relies on the pre-determined ability of certain to fold adequately and remain stable. Regarding their application in cancer therapy, intrabodies are suitable to downregulate proteins overexpressed in tumors, such as EGFR, erbB-2, cathepsin L and cyclin E or to target mutant oncogenic forms of Ras and p53 and fusion proteins as BCR-ABL.Antibody engineering represents an emerging technology that holds great promise for medical science Furthermore, genetic approaches provide antibody molecules with new functions in unexpected scenarios: expression of antibody domains in precise intracellular locations and grafting of new binding activities to engineered cells. Further improvement will require the design of in vivo selection systems to generate antibodies fully active in specific cellular compartments. Antibodies can be used as tools for functional gene identification and drug target validation (genomics- and proteomics-based high-throughput systems) and for better understanding of disease pathways. Antibodies are arguably the most powerful tools in biomedical research, and antibodies specific for extracellular or cell-surface targets are currently the fastest growing class of new therapeutic molecules.
Published: September 08, 2008