From an industrial R&D perspective, the design and development of protein therapeutics today appears somewhat akin to the rational design of small-molecule discovery back in the 1970s when lead compounds were generated from known physiological substrates or ligands. Facing a need to find novel and diverse small-molecule leads, attention in the 1980s centered on high-throughput screening (HTS) technologies and compound libraries. Those libraries, albeit large, were hardly diverse, with most therapeutic agents coming from a few target protein classes. Complementation of libraries with natural products, the development of combinatorial chemistry, and application of focused-library sets followed. This evolution, together with automated methods for content-rich assay systems and fast make-test cycles, enhanced discovery of novel, potent, and diverse lead series.
Contrast this with the present analagous processes for protein therapeutics: the discovery and development of novel biologics is hardly diverse, efficient or rapid. State-of-the art protein discovery and development use multiple expression hosts (e.g., mouse, E.coli, Chinese hamster ovary (CHO), and NS0) and several reformatting steps between hosts are often necessary during testing, scale-up, and production. The process of developing cell-based protein expression systems that are efficient, consistent, and scalable often is difficult and sometimes impossible using currently available technology.
To date, more than 150 protein drugs have been approved for clinical use, nearly all of which are produced in cell-based expression systems, such as E. coli, CHO cells, and Saccharomyces cerevisiae (S. cerevisea). These cell-based systems have several limitations, and many biologics can't be developed in these systems. For example, these systems only allow the overexpression of proteins that don't affect the physiology of the host cells. For many expression systems, identifying cell lines that stably synthesize high protein titers of the desired product is a time-consuming and labor-intensive process. Ideally, the same production host for rapid variant discovery, production for animal testing, and manufacturing of a clinical candidate would be used.Ideally, one would want to emulate the huge leap made in iterative drug design seen in small-molecule discovery, namely, rapid make-test cycles and generation of multiple parallel libraries of drug candidates with diverse structural elements to optimize activity while maintaining feasibility for manufacture. An ideal system would do the following:
As ambitious as such a system would seem, several exciting technologies are emerging that improve expression systems and enhance diversity to enable modification of intrinsic properties of proteins, such as enzyme catalytic efficiency or binding. Others combine different properties in single therapeutics by conjugation chemistries. Further emerging technologies can lead to more rapid and parallel expression of many protein drug candidates. Getting all of these desirable technologies into a single amenable platform that has the flexibility to be scaled and support cGMP manufacturing is in sight.