How Cell-Based Functional Assays Drive Precision Medicine and Targeted Therapies
Traditional drug discovery and development is an expensive and lengthy initiative. Most high throughput screening is conducted after confirming the target, followed by optimization of the compound structure, animal models, and clinical trials. However, drug failure rates are very high. These higher rates have increased the tendency to discover and identify newer targets for drug repurposing. The critical issue is identifying an appropriate target to provide a significant response to enhance drug discovery and development.
A lack of biological relevance during drug screening is a significant cause of drug failure. Traditional methods fail to distinguish compounds with subtle modifications. Cell-based assays or animal models are the only modalities to study drug properties in an in vivo environment. They offer a comprehensive picture of underlying disease biology and the mechanism of drug action. The current article discusses cell-based assays and cell-based functional assays and their role in precision medicine and targeted therapies.
Cell-based assays for targeted therapies and precision medicine
Cell-based assays are biologically more relevant surrogates in predicting complexities than non-cell-based biochemical assays. To differentiate them more precisely, let us quickly understand biochemical assays. So, what is biochemical analysis? Biochemical assessments use biochemical reactions to detect and quantify different levels of components in the body. These biochemical methods can identify organisms, study signaling events, differentiate microorganisms, etc.
Cell-based assays can enhance and accelerate drug development. They aid in lead candidate selection, drug efficacy, toxicity studies, safety assessments, deciphering therapeutic mechanisms of action, off-target effects, etc. Besides, they can identify patients responding to therapies and immunogenicity assessments and monitor pharmacodynamic biomarkers. Cell-based assays are critical for evaluating target saturation or engagement, monitoring resistance, and determining safety markers.
Cell-based assays can evaluate multiple functional and biochemical effects. These assays include cell viability assays, cell proliferation assays, cytotoxicity and apoptosis assays, signal transduction, reporter gene activity, receptor binding and occupancy, among others. The generated signal can be fluorescence, absorbance, colorimetric, luminescence, or radioactive based on the experimental availability and the target analyte.
The complexities of drug modalities have progressed from monoclonal antibodies to cell and gene therapies and antibody-drug conjugates with complex drug action. The drug effects in an organism are complex, involving interactions at several levels. Currently, cell-based functional assays are widely employed in high throughput screening. The primary advantage of this application is that cell-based assays are more physiologically relevant for screening drug compounds. For example, during the initial stage of the genomic era, researchers focused on enzyme-based biochemical screening for antibacterial drugs. As demand increases, drug developers will need more advanced and sophisticated approaches for cell-based assays. However, after extensive use of high throughput screening, researchers understood that this approach did not have higher success rates for developing drug products. Hence, the focus on antibiotic drug discoveries shifted back to whole cell-based screening.
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Selecting an ideal cell-based assay
Cell-based assays are unique. Researchers must consider several factors before selecting a relevant cell-based assay. This assay should not only be ideal for the current therapeutic development, but it should withstand difficulties and obstacles faced along the road depending on specific goals and stages of drug development.
A clear picture of the assay application and data collection should be established for driving the development of relevant cell-based assays. As a drug product progresses through different stages of drug development, the cell-based assay will evolve based on new information received in the program. Hence, a cell-based assay used in early discovery studies will be different from the one employed in the late stages of clinical trials.
Antibiotics are primarily discovered using cell-based screening assays. Screening whole cells reveals more data about the drug target and action mechanism compared to in vitro evaluations based on protein or enzyme targets. Biological context is critical in drug development. Hence, multiple preclinical models, such as in vivo and ex vivo models and in vitro models, are widely used in drug development. However, these approaches may not necessarily be sufficient. For example, out of more than 20,000 molecules screened for Alzheimer’s in the past 20 years, only one was approved by the US FDA. This number shows that a single modality cannot successfully reproduce all the characteristics of the human condition. Hence, drug developers should integrate multiple cell-based models to generate a multisystem model for different vital attributes.
Cell-based screening assays are usually 2D as these models are accepted standards for screening drug compounds in vitro. 2D cell cultures offer deeper insights into processes and drug effects at efficient workflows and low developmental costs. However, evidence suggests that 2D models cannot represent complex biological aspects such as extracellular matrix microenvironment and fail to predict drug response in vivo. Hence, drug developers are now considering 3D cell-based functional and screening assays to offer valuable insights into disease biology and drug effects.
