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Effect of Hierarchical Cluster Formation on the Viscosity of Concentrated Monoclonal Antibody Formulations Studied by Neutron Scattering



P. Douglas Godfrin, Isidro E. Zarraga, Jonathan Zarzar, Lionel Porcar, Peter Falus, Norman J. Wagner, Yun Liu


Recently, reversible cluster formation has been identified as an underlying cause of anomalously large solution viscosities observed in some concentrated monoclonal antibody (mAb) formulations. As high solution viscosity prevents the use of subcutaneous injection as a delivery method for some mAbs, a fundamental understanding of the interactions responsible for high viscosities in concentrated mAb solutions is of significant relevance to mAb applications in human health care as well as of intellectual interest. Here, we present a detailed investigation of a well studied lgG1 based mAb to relate the short time dynamics and microstructure to significant viscosity changes over a range of pharmaceutically relevant physiochemical conditions. Using a combination of light scattering, small angle neutron scattering and neutron spin echo measurement techniques, it is found that upon adding Na2SO4, these antibodies dimerize in solution. Proteins form strongly bounded reversible dimers at dilute concentrations that, when concentrated, interact with each other to form loosely bounded, large, transient clusters. The combined effect of forming strongly bounded dimers and a large transient network is a significant increase in the solution viscosity. Strongly bounded, reversible dimers may exist in many lgG1 based mAb systems such that these results contribute to a more comprehensive understanding of the physical mechanisms producing high viscosities in concentrated protein solutions.
Journal of Physical Chemistry B


cluster, monoclonal antibody, protein, neutron spin echo, small angle neutron scattering


Godfrin, P. , Zarraga, I. , Zarzar, J. , Porcar, L. , Falus, P. , Wagner, N. and Liu, Y. (2016), Effect of Hierarchical Cluster Formation on the Viscosity of Concentrated Monoclonal Antibody Formulations Studied by Neutron Scattering, Journal of Physical Chemistry B, [online], (Accessed April 22, 2024)
Created January 20, 2016, Updated October 12, 2021