Early Developability And Analytical Toolbox For The Production Of Multi-Chain Biotherapeutics

Source: Lonza

By Dr. Rebecca Michael, Principal Group Leader, Early Development Services, and Karl Rogerson, Senior Principal Scientist, Global Process and Analytical Development Sciences, Lonza Biologics


Complex proteins are extremely diverse and can often encompass more than one chain. They typically have complex and less predictable assemblies and include bispecific molecules that contain three or four chains, resulting in multiple binding sites for the target cell. Due to a wide range of therapeutic benefits, there are a growing number of bispecific molecules entering the clinical trial landscape, with 161 new trials for these products initiated in 2020.1 This is the highest number ever seen in the history of bispecific antibodies.

Due to their unique characteristics and assemblies, there are several challenges related to the expression and manufacturing of multichain modalities. For example, multichain molecules can have a heavier molecular weight and are highly engineered. This creates risks for aggregation and post-translational modifications, which can have implications on immunogenicity and immunotoxicity. Combining multiple chains in single vectors can also lead to unwanted byproducts that increase the risk of aggregation and lower titers; therefore, considerations must be made to ensure proper pairing, and robust analytical tools should be utilized to detect other potential issues, such as mis-assemblies.

To de-risk the production of bispecific molecules, Lonza has developed a toolbox approach using in silico tools, vector design/screening, and analytical method development, allowing for screening of titer and product assembly at an early stage in your product’s life cycle.


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