title: The influence of charge distribution on self-association and viscosity behavior of monoclonal antibody solutions.
abstract: The present work investigates the influence of electrostatic surface potential distribution of monoclonal antibodies (MAbs) on intermolecular interactions and viscosity. Electrostatic models suggest MAb-1 has a less uniform surface charge distribution than MAb-2. The patches of positive and negative potential on MAb-1 are predicted to favor intermolecular attraction, even in the presence of a small net positive charge. Consistent with this expectation, MAb-1 exhibits a negative second virial coefficient (B₂₂), an increase in static structure factor, S((q→0)), and a decrease in hydrodynamic interaction parameter, H((q→0)), with increase in MAb-1 concentration. Conversely, MAb-2 did not show such heterogeneous charge distribution as MAb-1 and hence favors intermolecular repulsion (positive B₂₂), lower static structure factor, S((q→0)), and repulsion induced increase in momentum transfer, H((q→0)), to result in lower viscosity of MAb-2. Charge swap mutants of MAb-1, M-5 and M-7, showed a decrease in charge asymmetry and concomitantly a loss in self-associating behavior and lower viscosity than MAb-1. However, replacement of charge residues in the sequence of MAb-2, M-10, did not invoke charge distribution to the same extent as MAb-1 and hence exhibited a similar viscosity and self-association profile as MAb-2.
authors.affiliation: Late Stage Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Yadav
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Laue
authors.forename: Devendra S
authors.initials: DS
authors.lastname: Kalonia
authors.forename: Shubhadra N
authors.initials: SN
authors.lastname: Singh
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Shire
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry*; D055672:Static Electricity; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal; D012996:Solutions