TransMabs: cell-penetrating antibodies, the next generation

Abstract

Intracellular proteins are becoming attractive targets in diagnosis and for therapy such as in signal pathways, on enzymes, transcription factors and structural proteins. Antibodies have been used therapeutically for extracellular pathogens and for targeting cell-surface antigens. Antibodies normally do not pass easily through intact cellular or subcellular membranes in living cells. Methods to shuttle antibodies into living cells are either labour-intensive and/or compromise the structural and functional integrity of the cell or require the integration of genes for heavy and light chain production through gene therapy approaches. A new technology platform, 'SuperAntibody Technology', enables antibodies to be shuttled into living cells without harming them. Such cell-penetrating antibodies open new diagnostic and therapeutic windows. The term 'TransMabs' has been coined for these antibodies. Proof of principle has been achieved with a 17-amino acid peptide with membrane translocating properties, conjugated with anti-caspase-3 antibody. Such a TransMab inhibits significantly in vitro apoptosis-related events, such as caspase-3 activity, DNA fragmentation and spectrin cleavage. Anti-caspase-3 TransMab, therefore, could be utilised to inhibit apoptosis in a variety of diseases, such as Alzheimer's, Huntington's and Parkinson's. Unlike peptide inhibitors available at present, this TransMab is not expected to have invivo toxic side effects and can only target activated forms of the enzyme. This paper discusses the advantages and limitations of cell-penetrating antibodies (TransMabs) compared with existing small molecule drug development approaches.