IN SILICO INVESTIGATIONS OF N-GLYCOSYLATION ROLE IN MODULATING IGG1 CONFORMATIONAL BEHAVIOR AND FC EFFECTOR FUNCTIONS

Nowadays, monoclonal antibodies (mAbs) occupy a relevant position in the pharmaceutical market, since they are often the preferred choice in the treatment of several diseases. Both for mAbs and other biopharmaceutical products, a decisive step in their development is represented by the critical quality attribute (CQA) assessment. Recently, with the advent of novel computational resources and high-performance computers, many in silico approaches have been implemented by companies to speed up the identification of potential CQAs and to drive the product characterization. Within this context, among the most common attributes, N-glycosylation can be highly critical in terms of biological activity and immunogenicity of mAbs, because of its role in regulating Fc effector functions. On this basis, the aim of this PhD thesis, that arises from a collaboration between the Laboratory of Computational Biochemistry and Biophysics at the Università degli Studi di Milano and Merck S.p.A., is to further characterize the structural role of N-glycosylation on IgG1, with particular attention to the role of core fucose. The final goal of the project, entirely performed using computational biochemistry approaches and considering adalimumab as a model IgG1, is to better understand at an atomistic level the role of glycans in modulating the structural and functional behavior of mAbs and to give a scientific contribution to the pharmaceutical development of these biotherapeutics.