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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal / chemistry*
  • Electrolytes / chemistry
  • Humans
  • Models, Molecular
  • Protein Aggregates*
  • Protein Multimerization
  • Salts / chemistry
  • Scattering, Small Angle
  • Solutions
  • Viscosity
  • X-Ray Diffraction


  • Antibodies, Monoclonal
  • Electrolytes
  • Protein Aggregates
  • Salts
  • Solutions