title: Effect of Hierarchical Cluster Formation on the Viscosity of Concentrated Monoclonal Antibody Formulations Studied by Neutron Scattering.
abstract: Recently, reversible cluster formation was identified as an underlying cause of anomalously large solution viscosities observed in some concentrated monoclonal antibody (mAb) formulations, which poses a major challenge to the use of subcutaneous injection for some mAbs. A fundamental understanding of the structural and dynamic origins of high viscosities in concentrated mAb solutions is thus of significant relevance to mAb applications in human health care, as well as being of scientific interest. Herein, we present a detailed investigation of an IgG1-based mAb to relate the short-time dynamics and microstructure to significant viscosity changes over a range of pharmaceutically relevant physiochemical conditions. The combination of light scattering, small-angle neutron scattering, and neutron spin echo measurement techniques conclusively demonstrates that, upon addition of Na2SO4, these antibodies form strongly bound reversible dimers at dilute concentrations that interact with each other to form large, loosely bound, transient clusters when concentrated. This hierarchical structure formation in solution causes a significant increase in the solution viscosity.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware , Newark, Delaware 19716, United States.
authors.forename: P Douglas
authors.initials: PD
authors.lastname: Godfrin
authors.affiliation: Late Stage Pharmaceutical Development, Genentech Inc. , South San Francisco, California 94080, United States.
authors.forename: Isidro E
authors.initials: IE
authors.lastname: Zarraga
authors.affiliation: Late Stage Pharmaceutical Development, Genentech Inc. , South San Francisco, California 94080, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zarzar
authors.affiliation: Institut Laue-Langevin , 71 Avenue des Martyrs, CS 20156, 38042 Grenoble Cedex 9, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Porcar
authors.affiliation: Institut Laue-Langevin , 71 Avenue des Martyrs, CS 20156, 38042 Grenoble Cedex 9, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Falus
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware , Newark, Delaware 19716, United States.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Wagner
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware , Newark, Delaware 19716, United States.|Center for Neutron Research, National Institute of Standards and Technology , Gaithersburg, Maryland 20899, United States.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D016000:Cluster Analysis; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D009502:Neutrons; D012542:Scattering, Radiation; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G