Within a few years, all of the 70,000-I 00,000 protein coding sequences in the human genome will become available, providing an enormously- valuable resource for the discovery of new pharmacological targets. However, the realization of that value will require new methods for high- throughput identification and functional evaluation of new targets. The high-throughput potential of current methods for rapid antibody isolation is severely limited by the need for target purification. Cell-based selection methods, in which target and antibody are expressed in the same cell and target-antibody interaction produces a selectable phenotype, may be the only way to circumvent this bottleneck. The goal of the present proposal is to adapt a proprietary high-throughput cellular selection system, based on interaction-dependent beta-lactamase, for the rapid isolation of specific, high-affinity antibody Fab fragments to as much of the human proteome as possible for use in the functional evaluation of new pharmacological targets, and as leads for the development of new drugs and diagnostics. In a companion proposal we will use essentially the same methods to discover interaction networks among the domains of the human proteome. Such interactions will be expected to provide a rich source of potential new targets for pharmaceutical intervention in disease.
The primary goal of this work is to develop new technologies to accelerate the process for identifying and evaluating new pharmaceutical targets from genomics data.
