Diamonds in the Rough: Identifying and Developing Biologics for Disease Research

For both synthetic and biological agents, bringing an agent from the bench to the bedside is a long and arduous process, usually taking well beyond 10 years of work and costing billions of dollars.1,2 The process is fraught with trial and error, with only a minute fraction of the initially proposed candidates eventually proving suitable for clinical use.2 While the process required to deliver new agents to the researcher’s toolbox is not as long or as costly, many of the steps, especially the early ones, are the same. 

Needle in a Haystack: Identifying New Biological Agents

The identification of a potential agent candidate first requires the identification and validation of a potential target. This process entails extensive laboratory experimentation using cellular, genetic, and in vivo techniques–first to search for possible targets, and second, to evaluate whether target modulation is efficacious and feasible for research purposes.1 Target identification has been greatly expedited by the increasing utility and accessibility of bioinformatics and big data, with genetic and phenotypic screening popularly employed. Similarly, validation strength and legitimacy has been enhanced by the promotion of multi-validation approaches that have been made feasible by increased accessibility to both the existing body of literature on any given topic and a variety of different potential validation techniques.1

After a potential target has been identified and validated, the next step is to locate and/or design an agent to modulate the target. Given the complexity of biological systems, proposed targets are almost never endogenously inert, and these natural mechanisms immediately provide researchers with potential candidate agents. Often, however, researchers will have to devise non-endogenous mechanisms of target modulation. For example, the premise of antibody therapy is based on the ability to derive antibodies capable of selectively targeting molecules that the body normally does not. Likewise, CAR-T cell therapy is predicated on the artificial redirection of T cell-targeting to antigens that would not be naturally considered. 

From One to Many: Producing Biologic Agents

The drug discovery and development process does not end with the establishment and validation of a suitable agent-target relationship. In order to bring a validated agent into research laboratories, large-scale production and distribution is necessary. This poses both scientific and logistical challenges for researchers working with biologics. Scientifically, biological agents are naturally more responsive to subtle shifts in environmental conditions, whether in culture, during storage, or in vivo. This, combined with their inherent heterogeneity caused by their natural production methods (e.g., protein transcription), means that biological products are more prone to potentially deleterious variability. A change in protein folding conformation, for example, can lead to a dramatic decrease in efficacy, a spike in immunogenicity, unpredicted off-target effects, or all three. Logistically, this means that biologics–both end products and production workflows–are subjected to additional regulatory requirements designed to ensure the safety, consistency, and efficacy of all biological agents entering the laboratory.

Reaping the Rewards: the Potential of Biologics

With the agent-target relationship characterized and production workflows established, a biological agent can now be subjected to extensive experimental testing and screening. The depth and breadth of this runs the gamut from in vitro assays designed to characterize the kinetics of the agent-target relationship, to animal models designed to examine agent tolerance, persistence, and clearance, to clinical trials looking at safety and efficacy in humans.2 Higher-model studies are especially important for biological agents because of their elevated immunogenicity, their inherent potential for heterogeneity, and in general, their greater interactivity within biological systems.3

Ultimately, identifying, developing, and producing biologics is challenging, and the journey is fraught with risk and failure. Yet each failed study contributes to the overall body of knowledge, and this incremental learning will fuel future improvements in our understanding of biological systems and the steps necessary to produce better biological medicines.2 The short-term may seem intimidating, but the long-term potential is worth the risk.

References
  1. J.P. Hughes et al., “Principles of early drug discovery,” Br J Pharmacol, 162(6):1239-1249, 2011.
  2. R.C. Mohs and N.H. Greig, “Drug discovery and development: Role of basic biological research,” Alzheimers Dement (N Y), 3(4):651-657, 2017. 
  3. T. Morrow and L.H. Felcone, “Defining the difference: What makes biologics unique,” Biotechnol Healthc, 1(4):24-29, 2004.
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