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Biophys J. 2014 Apr 15;106(8):1763-70. doi: 10.1016/j.bpj.2014.02.036.

Observation of small cluster formation in concentrated monoclonal antibody solutions and its implications to solution viscosity.

Author information

1
Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland; Department of Chemical and Biomolecular Engineering, Center for Neutron Science, University of Delaware, Newark, Delaware.
2
Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland; Institute for Research and Applied Physics, University of Maryland, College Park, Maryland.
3
Institut Laue-Langevin, Grenoble, France.
4
Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland; Center for Exploration of Energy and Matter, Indiana University, Bloomington, Indiana.
5
Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland.
6
Theranos Inc., Palo Alto, California.
7
Late Stage Pharmaceutical Development, Genentech Inc., South San Francisco, California.
8
Late Stage Pharmaceutical Development, Genentech Inc., South San Francisco, California. Electronic address: zarraga.isidro@gene.com.
9
Department of Chemical and Biomolecular Engineering, Center for Neutron Science, University of Delaware, Newark, Delaware.
10
Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland; Department of Chemical and Biomolecular Engineering, Center for Neutron Science, University of Delaware, Newark, Delaware. Electronic address: yunliu@udel.edu.

Abstract

Monoclonal antibodies (mAbs) are a major class of biopharmaceuticals. It is hypothesized that some concentrated mAb solutions exhibit formation of a solution phase consisting of reversibly self-associated aggregates (or reversible clusters), which is speculated to be responsible for their distinct solution properties. Here, we report direct observation of reversible clusters in concentrated solutions of mAbs using neutron spin echo. Specifically, a stable mAb solution is studied across a transition from dispersed monomers in dilute solution to clustered states at more concentrated conditions, where clusters of a preferred size are observed. Once mAb clusters have formed, their size, in contrast to that observed in typical globular protein solutions, is observed to remain nearly constant over a wide range of concentrations. Our results not only conclusively establish a clear relationship between the undesirable high viscosity of some mAb solutions and the formation of reversible clusters with extended open structures, but also directly observe self-assembled mAb protein clusters of preferred small finite size similar to that in micelle formation that dominate the properties of concentrated mAb solutions.

PMID:
24739175
PMCID:
PMC4008822
DOI:
10.1016/j.bpj.2014.02.036
[Indexed for MEDLINE]
Free PMC Article
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