279488 Characterization of Monoclonal Antibody Conformations and Self-Associations At High Concentrations Using Neutron Scattering Techniques

Wednesday, October 31, 2012: 9:30 AM
Pennsylvania West (Westin )
Yun Liu1,2, Eric J. Yearley1, Isidro Zarraga3, Norman J. Wagner1, Thomas M. Scherer3, Steven J. Shire4 and Yatin R. Gokarn3, (1)Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, (2)Center for Neutron Science, NIST, Gaithersburg, MD, (3)Late Stage Pharmaceutical and Processing Development, Genentech Inc., South San Francisco, CA, (4)Pharmaceutical R&D, Genentech Inc., South San Francisco, CA

Monoclonal antibodies (MAb) have become a crucial therapeutic agent. However, some applications such as a subcutaneous injection need highly concentrated protein solutions that can have undesired large viscosity. Therefore, it is of great importance to examine the relation between MAb self-associated nanostructure and its viscosity under various concentration and excipient conditions with techniques which can probe both structure and dynamics that span the length scale of an individual protein to a larger aggregate.  We have investigated the protein-protein interactions and diffusive properties of highly concentrated MAbs using small angle neutron scattering (SANS) and neutron spin echo (NSE). Our results indicate that concentration, temperature, pH and surfactant do not have a strong effect on the individual MAb conformation for our MAb samples.  The short-range attraction of some MAb proteins is found to be highly anisotropic in contrast to many other protein solutions at low ionic strength. Using neutron spin echo, we have accurately measured the short-time self-diffusion coefficients of MAbs at very large concentrations. One of MAb proteins is found to form small clusters at a wide range of concentrations. We speculate that the cluster formation is thus the underlying cause of the dramatic increase in viscosity as a function of concentration in this specific MAb protein.

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