ALC - BioAgil

The Human Genome Project (HGP) was largely successful in its goal to identify the genetic blueprint of life. The scientific community has begun to translate this genetic information to identify new potential therapeutic targets. Further progress may be possible by continuing to screen patients and identifying subsets from a larger disease population that have increased frequency or severity of the disease. These patients may be carrying a mutation (or mutations) that exacerbate the disease. These screens are useful predictors towards what genes correspond to what disease and also help to identify potential biomarkers that could be targeted for therapeutic use. 

Strategies to overcome bioanalytical challenges in Cell & Gene Therapies development

With advancements in molecular and cellular engineering techniques, the number of cell and gene therapy (C&GTs) drug development programs has increased significantly in the last 5 years. Following the first gene therapy gaining FDA approval in 2017, the biopharma industry quickly expanded within the C&GT space, leading to a further 21 C&GTs being approved by 2022. As drug developers begin to realize the potential of these new modalities, it is no surprise that the number of C&GT approvals is predicted to rise, with over 1,000 C&GT clinical trials currently ongoing.¹ The FDA has predicted it will be approving between 10 and 20 C&GT products per year by 2025.¹

As we look towards the development of the next generation of drugs and therapies, it starts to beg the question of whether we are creating the next “cure” or the next “treatment.” A cure would require actively restoring the patient to full health with no disease left whereas a treatment shows an improvement in health but the underlying disease still remains. Both cures and treatments are obviously important but the goal of actively curing a disease remains the ultimate outcome we strive to achieve. However to develop a cure is highly difficult thereby making treatments just as important to develop. A treatment could be a “bandage” on a problem while a cure is developed or implemented. 

ADCC

Antibody dependent cellular cytotoxicity (ADCC) is a mechanism in host immune defense where antibodies bind to an antigen on the surface of a cell, targeting that cell for killing by an immune effector cell, such as a Natural Killer Cell (NK cell). The effector cell “recognizes” the antibody bound cell by binding to the antibody via the Fc gamma receptor (FcγR) and uses a variety of methods to kill the target cell. With the advent of monoclonal antibody therapies and other biotherapeutics containing Fc regions derived from antibodies, it is possible that these biotherapeutics will induce ADCC. In the case of a monoclonal antibody targeting a tumor cell, ADCC would be a desired outcome, leading to tumor death. However, for biotherapeutics whose MOA does not involve depletion of target cells, ADCC is not a desirable outcome. To best predict the body’s response to a potential biotherapeutic, in vitro ADCC assays need to be performed prior to use in the clinic. While multiple immune cells including neutrophils, macrophages, and NK cells express FcRs, NK cells are the principal effector cells in ADCC. The binding of FcγR to the Fc domain of  the biotherapeutic on the target cell induces receptor crosslinking, leading to the release of perforins and granzymes from the NK cells. Their release results in lysis of the target cell. Therefore, the ability of a biotherapeutic to induce ADCC activity can be measured by target cell lysis. Commonly used methods to measure target cell lysis include both flow cytometry which measures fluorescently labeled target cells or spectrophotometry which measures radioactive labels (51Cr) or endogenous enzymes released by the target cell (LDH).  

Cell-based assays are an important tool in drug development. One of the biggest challenges when developing a drug is mimicking the appropriate physiological setting to predict the mechanism of action and safety profile when a drug is administered in vivo. However, appropriately designed cell-based assays can provide a solution for this by recreating the key components of the physiological setting in vitro.  Such assays can be utilized to provide information ranging from off-target effects and potential toxicity to effective dose ranges. Prior to moving a drug into an in vivo model, it is crucial to understand what happens at the cellular level in response to the compound or molecule. Cellular assays enable characterization of the activity and safety of a potential drug early in development. Generating this data early in the process allows for key decisions to be made which increase the chance of success in later stages of drug development by guiding the design of in vivo proof of concept studies and even informing aspects of later preclinical stage studies as well.