Conformational implications of an inversed pH-dependent antibody aggregation

  • Perico N
  • Purtell J
  • Dillon T
 et al. 
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Abstract

Antibody formulation development relies on accelerated stability data at elevated temperatures to optimize formulation parameters. However, the pH- and temperature-dependence of aggregation is complicated for antibody formulations. In this study, a human monoclonal IgG2 antibody exhibited typical pH-dependent dimer formation under normal storage conditions (4 and/or 29°C). However, an inversed pH-dependence was discovered for high molecular weight aggregate formation at elevated temperatures (37°C). The different stability profiles exhibited at the various storage conditions resulted in nonlinearity of the Arrhenius kinetics. Thermal unfolding at or below 37°C was not evident by differential scanning calorimetry. Enriched populations of the structural isoforms of the IgG2 subclass were tested for their unique temperature and pH-dependence of aggregation. The Arrhenius kinetics of aggregation for each of the individual IgG2 isoforms was also nonlinear. However, the temperature-dependence of clipping suggested that clip-mediated aggregation was responsible for the increased higher order aggregates at low pH and elevated temperatures. Unique clip species resulting from the conformational differences between the IgG2 isoforms lead to increased aggregation. These results have implications on the mechanisms of antibody aggregation and on the validity of accelerated data to predict shelf-life accurately. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association.

Author-supplied keywords

  • Aggregation
  • Antibody
  • Clipping
  • Conformation
  • Disulfide
  • Heterogeneity
  • IgG2
  • Immunoglobulin
  • Isoform
  • Redox
  • Refold
  • Self-association

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Authors

  • Natalie Perico

  • Judith Purtell

  • Thomas M. Dillon

  • Margaret S. Ricci

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