The inadequacy of the reductionist approach in discovering new therapeutic agents against complex diseases.

For more than 20 years, drug discovery has relied on two assumptions, i.e. (i) a therapeutic response can be triggered by modulating the activity of a single gene product, and (ii) a compound uncovered by its activity on a recombinant protein in vitro can perform its activity in vivo. Drug discovery operates accordingly by using the concepts of targets and pipelines. The target, such as a gene product, is the intended point of therapeutic intervention, and compounds that modulate its activity in vitro follow a series of downstream developments. This reductionist approach has developed due to advances in combinatorial chemistry, robotics, molecular biology, and genomics. The expectation of this approach is that the frequency of drug discovery will dramatically increase, while its associated cost would decrease. However, the frequency of new drug discovery has decreased, while the associated costs have surged. We performed a retrospective study that examined how successful development programs have led to marketed drugs for all indications except anti-infective and anti-neoplastic agents. We concluded that the target and pipeline paradigms are limited and are actually causing the drug development industry to collectively fail to meet the critical medical needs. Impact statement The initial scope of this investigation was to build the set of human genes that are presumed to be the therapeutic intervention points of US FDA-approved drugs, in all therapeutics areas but oncology. The prerequisite for this study was the establishment of the non-redundant set of all active pharmaceutical ingredients for these disease areas. Pertaining to complex diseases, the main observation was that there is not a single instance in the history of drug discovery, where a compound, initially selected by means of a biochemical assay, achieved a significant therapeutic response. The whole field of Drug R&D faces an unacceptable lack of new treatments to address unmet medical needs. The conclusion is that complex biological assays have to be designed for the primary selection of candidate therapeutics.

Monoclonal antibody proteomics: discovery and prevalidation of chronic obstructive pulmonary disease biomarkers in a single step.

We define mAb proteomics as the global generation of disease specific antibodies that permit mass screening of biomarkers. An integrated, high-throughput, disease-specific mAb-based biomarker discovery platform has been developed. The approach readily provided new biomarker leads with the focus on large-scale discovery and production of mAb-based, disease-specific clinical assay candidates. The outcome of the biomarker discovery process was a highly specific and sensitive assay, applicable for testing of clinical validation paradigms, like response to treatment or correlation with other clinical parameters. In contrast to MS-based or systems biology-based strategies, our process produced prevalidated clinical assays as the outcome of the discovery process. By re-engineering the biomarker discovery paradigm, the encouraging results presented in this paper clearly demonstrate the efficiency of the mAb proteomics approach, and set the grounds for the next steps of studies, namely, the hunt for candidate biomarkers that respond to drug treatment.