Protein-based therapeutics have emerged as an important class of pharmaceuticals that have substantially increased the number of treatable diseases. Of particular interest are the multi-functioning antibodies, each composed of two Fab regions capable of binding antigen and one Fc region that modulates antibody clearance and activation of antigen destruction through effector function pathways such as ADCC and CDC. IgG Fc regions have two attached oligosaccharides (glycans). The composition of the glycan is known to activate specific effector function pathways. For example, truncating the most prevalent G2F glycoform by degalatactosylation to G0F decreases CDC activation without impacting ADCC activation. Glycoengineering thus presents an attractive strategy to provide maximum efficacy for specific indications by modulating effector function pathways. However, glycans impact stability of the Fc region and their truncation or deglycosylation is also known to reduce Fc thermostability and promote aggregation. Therefore, understanding how glycan stabilize human Fc region is important to the pharmaceutical development of glycoengineered antibody based modalities. We have performed long MD simulations on human IgG1 region to understand the impact of de-glycosylation and glycan truncation on the stability of human IgG1 Fc in atomic details. The simulations also helped us understand how different glycan moieties interact with the human IgG1 Fc.

Impact of glycan truncation on stability of a human IgG1 Fc: Inferences for glycoengieering and effector function modulation

245th National Meeting (2013)

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