Intrabodies: Development and Application in Functional Genomics and Therapy

The human genome project has led to the identification of a large number of genes and respective proteins, thus providing the pharmaceutical industry with thousands of new potential drug targets, most of which function in intracellular compartments (Lander et al., 2001; Venter et al., 2001). This fact opens new perspectives for therapy of human diseases; however, it also demands reliable approaches for understanding the role and the function of these new genes and proteins (functional genomics) and for identifying those that can be validated as drug targets (target validation). Different experimental tools are currently used for investigating the function of these new intracellular proteins, including their potential role in disease, and for evaluating them as potential drug targets. The classical way to investigate the function of genes, and thereby determine the physiological and pathological relevance of gene products, is to interfere with their expression (Ihle, 2000). Approaches such as gene knockout, antisense oligonucleotide or RNA interference (RNAi) are currently used to study gene and protein function and to validate candidate drug targets by analysing the effects of their deletion. One limitation of all these techniques is that they eliminate all functions of a target gene product at once, thus making it difficult to dissect potentially distinct roles of different domains and to mimic the effects of a small molecule that presumably will act at a specific domain of the protein (Kamb and Caponigro, 2001).