Abstract
Surface plasmon resonance (SPR)-based optical biosensors offer real-time and label-free analysis of protein interactions, which has extensively contributed to the discovery and development of therapeutic monoclonal antibodies (mAbs). As the biopharmaceutical market for these biologics and their biosimilars is rapidly growing, the role of SPR biosensors in drug discovery and quality assessment is becoming increasingly prominent. One of the critical quality attributes of mAbs is the N-glycosylation of their Fc region. Other than providing stability to the antibody, the Fc N-glycosylation influences immunoglobulin G (IgG) interactions with the Fcγ receptors (FcγRs), modulating the immune response. Over the past two decades, several studies have relied on SPR-based assays to characterize the influence of N-glycosylation upon the IgG-FcγR interactions. While these studies have unveiled key information, many conclusions are still debated in the literature. These discrepancies can be, in part, attributed to the design of the reported SPR-based assays as well as the methodology applied to SPR data analysis. In fact, the SPR biosensor best practices have evolved over the years, and several biases have been pointed out in the development of experimental SPR protocols. In parallel, newly developed algorithms and data analysis methods now allow taking into consideration complex biomolecular kinetics. In this review, we detail the use of different SPR biosensing approaches for characterizing the IgG-FcγR interactions, highlighting their merit and inherent experimental complexity. Furthermore, we review the latest SPR-derived conclusions on the influence of the N-glycosylation upon the IgG-FcγR interactions and underline the differences and similarities across the literature. Finally, we explore new avenues taking advantage of novel computational analysis of SPR results as well as the latest strategies to control the glycoprofile of mAbs during production, which could lead to a better understanding and modelling of the IgG-FcγRs interactions.
Highlights
Surface plasmon resonance (SPR)-based biosensors have become a standard tool in the discovery and development pipelines of therapeutic monoclonal antibodies
Glycosylation is often presented as one of the most critical quality attributes of the immunoglobulin G (IgG) subfamily of monoclonal antibodies (mAbs) as it can modulate their interactions with the Fc gamma receptors (FcγRs), those being responsible for the IgG effector functions such as the antibody-dependent cell-mediated cytotoxicity (ADCC) [9]
A mix of injected IgG glycoforms in SPRbased experiments would lead to complex kinetics
Summary
Surface plasmon resonance (SPR)-based biosensors have become a standard tool in the discovery and development pipelines of therapeutic monoclonal antibodies (mAbs). Glycosylation is often presented as one of the most critical quality attributes of the IgG subfamily of mAbs as it can modulate their interactions with the Fc gamma receptors (FcγRs), those being responsible for the IgG effector functions such as the antibody-dependent cell-mediated cytotoxicity (ADCC) [9]. Other Fc receptors, DC-SIGN and CD23, are part of the C-type lectin family and bind to the Fc domain at the interface between the two constant domains CH2/CH3 with a stoichiometry of two receptors for one antibody The extent of their role in modulating IgG function is not yet fully understood but it is known that the DC-SIGN receptor triggers anti-inflammatory pathways [22]. This modulation of the Fc flexibility, in turn, impacts the binding affinity of the Fc domain to the FcγRs
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