Improved Diffusion Interaction Parameter Measurement to Predict the Viscosity of Concentrated mAb Solutions

Area of Science:

• Biopharmaceutical Development
• Protein Biophysics
• Formulation Science

Background:

• Developability assessment of therapeutic monoclonal antibody (mAb) candidates requires robust predictive assays for early selection.
• High viscosity in concentrated mAbs poses challenges for manufacturability, stability, and administration, necessitating accurate prediction.
• The diffusion interaction parameter (k_D) in dilute solutions has been used to predict mAb viscosity, but with limitations.

Purpose of the Study:

• To develop and validate a high-throughput assay for predicting mAb viscosity at high concentrations.
• To improve the correlation between dilute solution measurements and high-concentration viscosity.
• To identify optimal conditions for measuring protein-protein interactions that are predictive of viscosity.

Main Methods:

• A high-throughput assay measuring protein-protein interactions (k_D) was employed.
• The assay was modified by adding salt to suppress electrostatic repulsions and probe short-range interactions.
• Salt types and concentrations were screened, and the optimized method was validated on test mAb sets.

Main Results:

• The standard k_D method showed weak correlation (R^2=0.24) with mAb viscosity at 140 mg/mL.
• The optimized k_D method, incorporating salt, significantly improved the correlation (R^2=0.80) for 37 mAbs.
• The enhanced method accurately predicts viscosity across a range of 6-230 cP.

Conclusions:

• The optimized k_D assay, by accounting for short-range interactions, provides a more accurate prediction of mAb viscosity.
• This improved assay is valuable for the developability assessment of therapeutic mAb candidates.
• The method enables more reliable selection of candidates with favorable viscosity profiles for late-stage development.