Colloidal interactions between monoclonal antibodies in aqueous solutions

Arzenšek, Dejan; Kuzman, Drago; Podgornik, Rudolf

doi:10.1016/j.jcis.2012.06.055

Cited by 63 publications

(97 citation statements)

References 48 publications

(92 reference statements)

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“…Changes to the values of k D with increasing ionic strength can be rationalized in terms of electrostatic interactions using the double layer force derived from Derjaguin-Landau-Verwey-Overbeek (DLVO) theory [6,59,71]. The double-layer force is given by a repulsive Yukawa potential that has a magnitude proportional to the protein net charge squared and follows an exponential decay with a range given by the Debye length (equal to the inverse of the Debye-Huckel parameter j).…”

Section: Protein-protein Interactions Characterized In Terms Of K Dmentioning

confidence: 99%

The effect of charge mutations on the stability and aggregation of a human single chain Fv fragment

Austerberry

Dajani

Panova

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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a b s t r a c tThe aggregation propensities for a series of single-chain variable fragment (scFv) mutant proteins containing supercharged sequences, salt bridges and lysine/arginine-enriched motifs were characterised as a function of pH and ionic strength to isolate the electrostatic contributions. Recent improvements in aggregation predictors rely on using knowledge of native-state protein-protein interactions. Consistent with previous findings, electrostatic contributions to native protein-protein interactions correlate with aggregate growth pathway and rates. However, strong reversible self-association observed for selected mutants under native conditions did not correlate with aggregate growth, indicating 'sticky' surfaces that are exposed in the native monomeric state are inaccessible when aggregates grow. We find that even though similar native-state protein-protein interactions occur for the arginine and lysine-enriched mutants, aggregation propensity is increased for the former and decreased for the latter, providing evidence that lysine suppresses interactions between partially folded states under these conditions. The supercharged mutants follow the behaviour observed for basic proteins under acidic conditions; where excess net charge decreases conformational stability and increases nucleation rates, but conversely reduces aggregate growth rates due to increased intermolecular electrostatic repulsion. The results highlight the limitations of using conformational stability and native-state protein-protein interactions as predictors for aggregation propensity and provide guidance on how to engineer stabilizing charged mutations.

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Section: Protein-protein Interactions Characterized In Terms Of K Dmentioning

confidence: 99%

The effect of charge mutations on the stability and aggregation of a human single chain Fv fragment

Austerberry

Dajani

Panova

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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“…Other applications of DLS are the interaction parameter (k d ) derived from the determination of the mutual diffusion coefficient, which can be a surrogate for the second virial coefficient (B 22 ) [12,13]. k d can be used to predict the colloidal stability of a protein which may impact the aggregation propensity of a protein within a formulation.…”

Section: Application Of Dls During Biopharmaceutical Developmentmentioning

confidence: 99%

Subvisible and Visible Particle Analysis in Biopharmaceutical Research and Development

Hawe¹,

Zölls²,

Freitag³

et al. 2015

Biophysical Characterization of Proteins in Developing Biopharmaceuticals

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“…To elucidate the mechanistic principle of the fouling process, it appears worthwhile to determine the nature of the species that cause these performance issues. In this context, it is important to distinguish two forms of aggregates, which are described as irreversible protein aggregation in contrast to reversible protein aggregation or self‐assembly . Irreversible protein aggregation denotes any irreversible formation of strongly linked aggregates that can be soluble or insoluble.…”

Section: Introductionmentioning

confidence: 99%

Investigation of fouling mechanisms of virus filters during the filtration of protein solutions using a high throughput filtration screening device

Bieberbach

Kosiol

Seay³

et al. 2019

Biotechnology Progress

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The downstream process development of novel antibodies (Abs) is often challenged by virus filter fouling making a better understanding of the underlying mechanisms highly desirable. The present study combines the protein characterization of different feedstreams with their virus filtration performance using a novel high throughput filtration screening system. Filtration experiments with Ab concentrations of up to 20 g/L using either low interacting or hydrophobically interacting pre‐filters indicate the existence of two different fouling mechanisms, an irreversible and a reversible one. At the molecular level, size exclusion chromatography revealed that the presence of large amount of high molecular weight species—considered as irreversible aggregates—correlates with irreversible fouling that caused reduced Ab throughput. Results using dynamic light scattering show that a concentration dependent increase of the mean hydrodynamic diameter to the range of dimers (17 nm at 20 g/L) together with a negative DLS interaction parameter kD (−18 mL/g) correlate with the propensity to form reversible aggregates and to cause reversible fouling, probably by a decelerated Ab transport velocity within the virus filter. The two fouling mechanisms are further supported by buffer flush experiments. Finally, concepts for reversible and irreversible fouling mechanisms are discussed together with strategies for respective fouling mitigation. © 2019 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2776, 2019.

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Colloidal interactions between monoclonal antibodies in aqueous solutions

Cited by 63 publications

References 48 publications

The effect of charge mutations on the stability and aggregation of a human single chain Fv fragment

The effect of charge mutations on the stability and aggregation of a human single chain Fv fragment

Subvisible and Visible Particle Analysis in Biopharmaceutical Research and Development

Investigation of fouling mechanisms of virus filters during the filtration of protein solutions using a high throughput filtration screening device

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