Demonstrating similarity to the reference product is essential to ensure comparable safety and efficacy for a biosimilar. For some formats, such as IgG2, IgG4 and engineered IgG1 variants, this may include confirming the absence of Fc-mediated binding and function. Regulators such as the CDSCO, FDA and EMA require robust evidence that all pertinent biological activities, whether present or absent, are matched to the originator, as differences may impact clinical outcomes.
However, assumptions about complete Fc silencing can be misleading, for example, LALA mutations often considered ‘silent’ may retain receptor interactions and residual activity. Advanced binding and functional assays are therefore critical to characterise Fc properties with high sensitivity and physiological relevance. This approach supports biosimilar developers in meeting regulatory expectations and achieving a totality of evidence framework for comparability.