Challenges with afucosylation content in antibody-based drugs: Guidance provided by mathematical modeling

What is it about?

The therapeutic activity of antibody drugs often depends on molecular forms present in the therapeutic antibody mixture whose molar concentrations are unknown. This is highly undesirable since knowledge of the molar concentration of a drug is fundamental to drug characterization. This work describes a method to account for the activity of the three IgG forms that result from Ig heavy chain Fc afucosylation. Once differences in the molar concentrations of the different IgG forms are taken into account, differences in the specific activities of the different IgG forms are able to be deduced. The latter being fundamental to demonstrating "identity."

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Why is it important?

Current methods for characterizing IgG glycosylation-based heterogeneity rely on empirically correlating sample average metrics to biological activity. For example, the fraction of Fc glycans that are afucosylated is often correlated to sample activity. However a given "activity" measurement may result from two very different samples. Therefore empirical methods alone are incapable of properly characterizing biologics. The shortcomings of current methods becomes critical when "biosimilarity" is to be demonstrated between drugs produced by different manufacturers. In essence, manufacturers must argue for "biosimilarity" without basic molecular composition and specific activity information!