Investigating the Interaction between Excipients and Monoclonal Antibodies PGT121 and N49P9.6-FR-LS: A Comprehensive Analysis

N49P9.6-FR-LS and PGT121 are promising antibodies with significant therapeutic potential against HIV infection, but they are prone to precipitation at high concentrations. This study evaluates the influence of six excipients—L-arginine, L-alanine, sucrose, trehalose, methionine, and glutamate—on the biophysical stability of antibodies. We employed a comprehensive approach, combining computational mAb-excipient interaction analysis via the site-identification by ligand competitive saturation (SILCS) method with extensive experimental characterization. Our experimental matrix included viscosity measurements across temperature gradients, particle size distribution, zeta potential, pH value, and solution appearance, alongside a short-term stability study at 30°C and 65% relative humidity, with assessments at t0 (initial), t1 (14 days), and t2 (28 days). Results indicated that sucrose, arginine, alanine, and trehalose provided varying degrees of stabilization for both antibodies. Conversely, glutamate destabilized PGT121 but stabilized N49P9.6-FR-LS, while methionine had a negative effect on N49P9.6-FR-LS but a positive one on PGT121. SILCS-Biologics analysis suggested that stabilization by these excipients is linked to their ability to occupy regions involved in self-protein interactions. Debye–Hückel–Henry charge calculations further indicated that neutral excipients like sucrose and trehalose could alter mAb charges by affecting buffer binding, influencing aggregation propensity. These findings offer valuable insights for optimizing antibody formulations, ensuring enhanced stability and therapeutic efficacy for HIV treatment.