ABSTRACT
Irreversible, non-native protein aggregation-whether
deleterious or advantageous-is a ubiquitous concern dur-
ing development of biopharmaceuticals, biotechnology,
and food products. Non-native aggregation, as its name
suggests, occurs via incompletely unfolded, non-native
protein chains. In most cases, the final aggregates formed
are found to be effectively irreversible unless disrupted by
the addition of high concentrations of chemical additives
such as denaturants. Therefore, unlike reversible, native
aggregation processes such as crystallization and precipi-
tation, preventing non-native aggregation necessarily
requires understanding and control of the kinetics of the
process. Although purely thermodynamic considerations
are not sufficient to robustly control non-native aggrega-
tion, the aggregation process does include a number of
early-stage, reversible steps such as folding, unfolding,
and association. Therefore it is possible in many cases to
favorably influence the observed kinetics by manipulating
the thermodynamics of these steps; such a strategy forms
the basis of most commonly employed stabilization
approaches. Although such strategies neglect additional,
dynamic components of the aggregation process, they may
provide useful ways to qualitatively control aggregation
rates. Quantitative control is presently muchmore difficult,
and requires consideration of dynamic components that are
reviewed only briefly here.
