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In the presented work, we reviewed the protein glycation effect on recombinant monoclonal antibodies (MAbs), and demonstrated an in vitro glycation model on rhuMAb A was a successful tool to evaluate site-specific glycation. We also implemented this model to study MAb glycation in three aspects: the formation of glycation, the change of glycation adducts under thermal stress, and the control of glycation adducts stability by formulation compositions. A protein characterization study demonstrated that the in vitro forced glycation model generated seven glycated amino acid sites on rhuMAb A. The lysine residue K49 was the preferably site, while others sites were at various low levels of glycation. Molecular dynamics (MD) analysis suggested that the high abundance of lysine 49 glycation observed on rhMAb A may be assisted by a strong electrondonating environment created by three aspartates, with D30, D31, and D105 near K49. In the thermal stress stability study, the glycation adduct hydrolysis reaction was more pronounced than the AGE formation. It was found that glycation adducts hydrolysis continued for four weeks, but AGEs formation plateaued after one week. The overall combination of both reactions caused a loss of glycation with a first order reaction rate. The structure analysis of final degradation products agreed with kinetic observation that reverse of glycation adducts was the main degradation pathway of glycated rhuMAb A at 40°C in pH 6.5 phosphate formulation buffer. Reverse of glycation adducts on K49 could be catalyst by its adjacent aspartic acids. Influencing parameters of glycation adduct degradation were also evaluated. Three formulation composition factors: pH, buffer, and oxidation control were compared. The study demonstrated the pH value was the key parameter that controls degradation pathways. pH also determined the rate constant of hydrolysis of glycated rhuMAb A. Buffer species and oxidation levels did not affect on the glycation adduct stability under the studied conditions. In addition, the effect of rhuMAb A’s initial glycation level was also evaluated. The study demonstrated that higher protein glycation levels slow down the overall hydrolysis rate of glycation adduct, presumably by providing a complex electron transferring system on protein.

Study of Glycation and Advanced Glycation on a Humanized Monoclonal Antibody