Intracellular antibody-caspase-mediated cell killing: an approach for application in cancer therapy.
Antibodies have been expressed inside cells in an attempt to ablate the function of oncogene products. To make intracellular antibodies more generally applicable and effective in cancer therapy, we have devised a method in which programmed cell death or apoptosis can be triggered by specific antibody-antigen interaction. When intracellular antibodies are linked to caspase 3, the "executioner" in the apoptosis pathway, and bind to the target antigen, the caspase 3 moieties are self-activated and thereby induce cell killing. We have used this strategy in a model system with two pairs of intracellular antibodies and antigens. In vivo coexpression of an antibody-caspase 3 fusion with its antigenic target induced apoptosis that was specific for antibody, antigen, and active caspase 3. Moreover, the antibody-caspase 3 fusion protein was not toxic to cells in the absence of antigen. Therefore, intracellular antibody-mediated apoptosis should be useful as a specific therapeutic approach for the treatment of cancers, a situation where target cell killing is required.
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Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge CB2 2QH, United Kingdom.
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D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology; D001483:Base Sequence; D016466:CHO Cells; D053148:Caspase 3; D020169:Caspases / Q000627:therapeutic use*; D006224:Cricetinae; D017931:DNA Primers; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D001616:beta-Galactosidase / Q000276:immunology
D000906:Antibodies; D017931:DNA Primers; D001616:beta-Galactosidase; D053148:Caspase 3; D020169:Caspases