Fundamental Considerations For Bispecific Antibody-Based Cell Line Development

By Seahee Kim, Samsung Biologics

Bispecific antibodies (BsAbs) are a rapidly growing class of molecules offering new therapeutic perspectives due to their distinct ability to simultaneously bind two separate and unique antigens (or different epitopes of the same antigen). BsAbs also hold the potential to reduce treatment resistance, since they can target multiple pathways.

However, due to the complexity of controlling advanced biotherapeutics, the industry still faces several challenges, including difficulty in maintaining the affinity of parental mAbs and poor manufacturability. Additionally, since knob-in-hole (KiH) BsAbs are composed of two distinct heavy and light chains (or two distinct heavy chains and common light chains), multiple final forms can arise during their assembly. The mispairing of heavy and light chains can lead to unwanted impurities that are difficult to remove due to their similarity to the desirable form. Therefore, consistent production of structurally complex molecules that exhibit high yield and purity, with commercialization in mind, requires keen expertise and experience.

Keeping commercialization in mind from the start of development generally means maintaining awareness on two important elements: titer and protein quality. Regarding quality, testing as early as the pool screening step allows for accurate first-time measurements. Supplemented by the appropriate considerations and relevant expertise, early testing helps biologics developers to plan, mitigate, and resolve open elements.

Low titers, meanwhile, can significantly impact cost of goods sold (COGS) by driving up the amount of raw materials necessary to produce the desired product, as well as marring batch-to-batch consistency. Often, Samsung Biologics is able to glean between 3 g/L and 5 g/L with purity over 95%, minimizing risk as we move through cell line development, process development, and manufacture.