Antibodies have many advantages as therapeutic agents, however they are also large, fragile molecules that present unique challenges at the formulation stage. In particular, antibody solutions can be extremely viscous at the concentrations required for efficient delivery. While previous work has established that solution viscosity correlates with attractive antibody-antibody interactions, the mechanism by which these interactions increase the viscosity is unclear. We show that antibody viscosity cannot be explained by hard particle models and, instead, adopt a highly flexible model for the antibodies. Somewhat surprisingly, we find that the solution viscosity is consistent with reptation dynamics as would be expected in semi-dilute polymer solutions. The onset of the high viscosity regime is determined by the overlap concentration, which depends strongly on the association of antibodies into transient complexes. Fitting our model to viscosity data, we find that the free energy for intermolecular binding correlates strongly with the salt concentration and charge state of the variable region. The model predicts that the viscosity will show three distinct power law regimes as the concentration is increased. This is confirmed by experiments, however, the measured exponents reflect the reduced flexibility of antibodies relative to long polymers.Figure 1, Cartoon of the antibody entanglements that cause elevated viscosity.  Transient complexes (orange, red) have a higher potential to entangle with neighboring molecules.

Simple models of antibody solution viscosity

247th National Meeting (2014)

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