Development of recombinant therapeutic proteins in animal cells: Challenges and solutions

EDUARDO MUFARREGE; LUCÍA PEÑA; MARIANELA MASIN

Frontiers in Drug Design and Discovery

Bentham Science

Año: 2021; p. 28 - 74

Recombinant therapeutic proteins also referred to as biotherapeutics or biologics are widely used for the treatment of numerous diseases such as cancer, diabetes and other non-communicable diseases. In addition, they also brought a solution to several chronic and emerging viral diseases.Most of biologics are produced in animal host cells as they provide relevant protein features such as folding and post-translational modifications similar to those produced by humans.However, these products usually face great challenges mainly related to high manufacturing costs that may limit their use. To circumvent these issues, numerous strategies were proposed. While some approaches were focused to improve protein yield by introducing regulatory elements into the gene sequence other were specifically aimed to optimize cell protein expression performance through cell engineering. Here, we will review the state of the art in the field of protein expression focusing on the most promising strategies to improve protein yield in animal cells.Product safety constitutes another concern that may restrict the use of biotherapeutics. Indeed, the development of unwanted immune responses against these drugs was extensively reported. These immunogenicity events are triggered as a consequence of breakdown in immune tolerance to the product. When a given biologic is administered to a patient, it encounters a variety of innate and adaptive immune cells that ultimately may orchestrate pro-inflammatory responses. Consequently, different scenarios may take place ranging from the development of anti-drug neutralizing antibodies to tissue damage. Hence, product immunogenicity is a main concern and should be closely monitored during product manufacturing and also in the clinic. To this respect, numerous in vitro and in vivo strategies are currently available and other more are still in development. These experimental platforms include the use of specific human immune cells, transgenic animals and even lymphatic micro-organoids. In this chapter we will comprehensively describe these experimental strategies and their use on pre-clinical studies and clinical trials.