Relation of protein-protein interactions to rheological properties and stability of highly concentrated of monoclonal antibodies




Dear, Barton Joseph

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Solutions of monoclonal antibodies (mAbs) at high concentration are strongly desirable for subcutaneous delivery for the treatment of many autoimmune diseases and cancer. However, at the high concentrations necessary for practical application, mAbs tend to have strongly attractive protein-protein interactions (PPI) that cause the solutions to be highly viscous and prone to aggregation. Herein, the PPI of various mAbs and other proteins at concentrations up to 250 mg/ml are tuned by the addition of the small molecule co-solutes that can screen both electrostatic and hydrophobic PPI to produce low viscosities. The effects of the co-solutes on PPI were directly measured using small angle x-ray scattering, dynamic light scattering, and shear-dependent rheology as well as indirectly through the viscosity and storage stability. MAb solutions with attractive net PPI will be shown to be generally more viscous and aggregation prone than solutions with less attractive net PPI; however, these correlations remain challenging to understand across mAbs. Alternatively, the formation of reversible oligomers, or clusters in solution, as determined by fitting SAXS structure factors with molecular dynamic simulations, or the polydispersity of DLS data, will be demonstrated to be a key factor in determining high concentration viscosity. The storage stability will be shown to be influenced by both PPI and conformational stability; therefore, co-solutes that improve both will cause yield the highest stabilities.


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