Screening of Unexplored FDA-approved Inactive Ingredients as Stabilizers for Monoclonal Antibody Products

Monoclonal antibodies (mAbs) are susceptible to physical and chemical degradation, which can compromise product quality, efficacy, safety, and shelf life. Although excipients play a critical role in stabilizing mAb formulations, only a limited number are routinely used in marketed products. Therefore, this study aimed to identify underexplored FDA-approved inactive ingredients with the potential to stabilize mAb formulations.

Fourteen FDA-approved inactive ingredients were screened using a size-exclusion chromatography (SEC)-based comparative forced-degradation approach. Trastuzumab was used as the model IgG1 antibody and subjected to thermal stress at 70°C and 65°C. Candidate excipients were evaluated through concentration optimization, SEC-HPLC, fluorescence spectroscopy, UV-vis spectroscopy, differential scanning calorimetry, surface plasmon resonance, haemolysis assays, and molecular docking.

Initial screening identified isomalt and myo-inositol as the most effective excipients, reducing high-molecular-weight species by up to 60%, whereas choline chloride produced a smaller but measurable reduction. Optimized concentrations of 400 mM isomalt, 150 mM myo-inositol, and 1.9 mM choline chloride reduced aggregation, preserved monomer content, and improved higher-order structural stability. These formulations retained HER2 and FcRn binding and exhibited haemolysis below 3% compared to PS80 containing mAb sample. Isomalt also improved the thermal stability of adalimumab and rituximab, while molecular docking suggested preferential association with aggregation-prone regions of the trastuzumab Fab domain.

Underexplored FDA-approved excipients, particularly isomalt and myo-inositol, improved mAb stability under thermal stress and represent promising candidates for further evaluation during therapeutic antibody formulation development.