<br/>Monoclonal antibodies must be both chemically and physically stable to be developed into safe and effective drugs. While there has been considerable progress in separately understanding the molecular determinants of antibody chemical and physical stability, it remains less well understood how defects in one property (e.g., chemical stability) impact the other one (e.g., physical stability). Here we have investigated the impact of a common chemical modification (deamidation) on the physical stability of monoclonal antibodies as a function of pH (pH 3.8-7.4). Interestingly, we find that deamidation has the largest negative impact on antibody physical stability at low pH values (e.g., pH 3.8) that are common during antibody purification. Deamidation causes increased antibody self-association and aggregation at low pH without significant reductions in conformational (folding) stability. The molecular origins of this deamidation-dependent behavior appear to be due (at least in part) to increased antibody hydrophobicity at low pH, which we identify via a modified form of self-interaction nanoparticle spectroscopy. We expect that our findings will motivate broader studies of the role of deamidation in determining antibody physical (colloidal) stability, which is important for improving the development of robust and potent therapeutic antibodies.

Deamidation compromises antibody colloidal stability and solubility in a pH-dependent manner

2019 Spring National Meeting

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