Probing Protein-Protein Interactions in High-Concentration mAb-Formulations to Navigate Viscosity Challenges

Monoclonal antibodies are effective in targeting cancers, rare diseases, and metabolic diseases. For certain clinical programs, mAbs are formulated at high concentrations for convenient administration, shipping, and storage. In downstream processing and formulation, the solutions of certain mAb molecules at high concentration can become highly viscous whereas others maintain acceptable viscosity properties. Water Nuclear Magnetic Resonance spectroscopy (wNMR) was used to probe the underlying mAb protein-protein interactions (PPIs) that occur in such crowded (viscous) environments. Arginine (Arg) was found to effectively reduce viscosity via suppressing PPIs at high concentrations. More importantly, by combining NMR chemometric analysis of mAb structure and surface patch charge calculations, we will show that Arg doesn’t cause major structural changes while interacting extensively with polar sidechains (glutamine/asparagine) and possibly negatively charged groups (aspartic acid/glutamic acid) in mAbs. Co-solutes, such as Arg, can help control the stability, structure and molecular interactions and thereby alleviate high viscosity problems.