Cluster Percolation Causes Shear Thinning Behavior in Concentrated Solutions of Monoclonal Antibodies

Alfredo Lanzaro; Aisling Roche; Nicole Sibanda; Daniel Corbett; Peter Davis; Maryam Shah; Jai A. Pathak; Shahid Uddin; Christopher F. van der Walle; Xue-Feng Yuan; Alain Pluen; Robin Curtis

doi:10.1021/acs.molpharmaceut.1c00198

Cluster Percolation Causes Shear Thinning Behavior in Concentrated Solutions of Monoclonal Antibodies

Alfredo Lanzaro, Aisling Roche, Nicole Sibanda, Daniel Corbett, Peter Davis, Maryam Shah, Jai A. Pathak, Shahid Uddin, Christopher F. van der Walle, Xue-Feng Yuan, Alain Pluen, Robin Curtis

Research output: Contribution to journal › Article › peer-review

Abstract

High-concentration (>100 g/L) solutions of monoclonal antibodies (mAbs) are typically characterized by anomalously large solution viscosity and shear thinning behavior for strain rates ≥10 ³s ^-1. Here, the link between protein-protein interactions (PPIs) and the rheology of concentrated solutions of COE-03 and COE-19 mAbs is studied by means of static and dynamic light scattering and microfluidic rheometry. By comparing the experimental data with predictions based on the Baxter sticky hard-sphere model, we surprisingly find a connection between the observed shear thinning and the predicted percolation threshold. The longest shear relaxation time of mAbs was much larger than that of model sticky hard spheres within the same region of the phase diagram, which is attributed to the anisotropy of the mAb PPIs. Our results suggest that not only the strength but also the patchiness of short-range attractive PPIs should be explicitly accounted for by theoretical approaches aimed at predicting the shear rate-dependent viscosity of dense mAb solutions.

Original language	English
Pages (from-to)	2669-2682
Number of pages	14
Journal	Molecular Pharmaceutics
Volume	18
Issue number	7
Early online date	14 Jun 2021
DOIs	https://doi.org/10.1021/acs.molpharmaceut.1c00198
Publication status	Published - 5 Jul 2021

Keywords

bioprocessing
monoclonal antibodies
protein−protein interactions
rheology
shear thinning

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10.1021/acs.molpharmaceut.1c00198

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@article{8940097526d449feacb0a734087cb68b,

title = "Cluster Percolation Causes Shear Thinning Behavior in Concentrated Solutions of Monoclonal Antibodies",

abstract = "High-concentration (>100 g/L) solutions of monoclonal antibodies (mAbs) are typically characterized by anomalously large solution viscosity and shear thinning behavior for strain rates ≥10 3s -1. Here, the link between protein-protein interactions (PPIs) and the rheology of concentrated solutions of COE-03 and COE-19 mAbs is studied by means of static and dynamic light scattering and microfluidic rheometry. By comparing the experimental data with predictions based on the Baxter sticky hard-sphere model, we surprisingly find a connection between the observed shear thinning and the predicted percolation threshold. The longest shear relaxation time of mAbs was much larger than that of model sticky hard spheres within the same region of the phase diagram, which is attributed to the anisotropy of the mAb PPIs. Our results suggest that not only the strength but also the patchiness of short-range attractive PPIs should be explicitly accounted for by theoretical approaches aimed at predicting the shear rate-dependent viscosity of dense mAb solutions. ",

keywords = "bioprocessing, monoclonal antibodies, protein−protein interactions, rheology, shear thinning",

author = "Alfredo Lanzaro and Aisling Roche and Nicole Sibanda and Daniel Corbett and Peter Davis and Maryam Shah and Pathak, {Jai A.} and Shahid Uddin and {van der Walle}, {Christopher F.} and Xue-Feng Yuan and Alain Pluen and Robin Curtis",

note = "Funding Information: The authors would like to acknowledge the financial support of the Biotechnology and Biological Sciences Research Council (BB/K011146) and of AstraZeneca, and to thank Prasad Sarangapani, Peter Schurtenberger, Jan Dhont, Anna Stradner, Felix Roosen-Runge and the anonymous reviewers for helpful discussions and comments. A. L. was also funded by the European Research Council (ERC-339678-COMPASS). Publisher Copyright: {\textcopyright} 2021 American Chemical Society",

year = "2021",

month = jul,

day = "5",

doi = "10.1021/acs.molpharmaceut.1c00198",

language = "English",

volume = "18",

pages = "2669--2682",

journal = "Molecular Pharmaceutics",

issn = "1543-8384",

publisher = "American Chemical Society",

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TY - JOUR

T1 - Cluster Percolation Causes Shear Thinning Behavior in Concentrated Solutions of Monoclonal Antibodies

AU - Lanzaro, Alfredo

AU - Roche, Aisling

AU - Sibanda, Nicole

AU - Corbett, Daniel

AU - Davis, Peter

AU - Shah, Maryam

AU - Pathak, Jai A.

AU - Uddin, Shahid

AU - van der Walle, Christopher F.

AU - Yuan, Xue-Feng

AU - Pluen, Alain

AU - Curtis, Robin

N1 - Funding Information: The authors would like to acknowledge the financial support of the Biotechnology and Biological Sciences Research Council (BB/K011146) and of AstraZeneca, and to thank Prasad Sarangapani, Peter Schurtenberger, Jan Dhont, Anna Stradner, Felix Roosen-Runge and the anonymous reviewers for helpful discussions and comments. A. L. was also funded by the European Research Council (ERC-339678-COMPASS). Publisher Copyright: © 2021 American Chemical Society

PY - 2021/7/5

Y1 - 2021/7/5

N2 - High-concentration (>100 g/L) solutions of monoclonal antibodies (mAbs) are typically characterized by anomalously large solution viscosity and shear thinning behavior for strain rates ≥10 3s -1. Here, the link between protein-protein interactions (PPIs) and the rheology of concentrated solutions of COE-03 and COE-19 mAbs is studied by means of static and dynamic light scattering and microfluidic rheometry. By comparing the experimental data with predictions based on the Baxter sticky hard-sphere model, we surprisingly find a connection between the observed shear thinning and the predicted percolation threshold. The longest shear relaxation time of mAbs was much larger than that of model sticky hard spheres within the same region of the phase diagram, which is attributed to the anisotropy of the mAb PPIs. Our results suggest that not only the strength but also the patchiness of short-range attractive PPIs should be explicitly accounted for by theoretical approaches aimed at predicting the shear rate-dependent viscosity of dense mAb solutions.

AB - High-concentration (>100 g/L) solutions of monoclonal antibodies (mAbs) are typically characterized by anomalously large solution viscosity and shear thinning behavior for strain rates ≥10 3s -1. Here, the link between protein-protein interactions (PPIs) and the rheology of concentrated solutions of COE-03 and COE-19 mAbs is studied by means of static and dynamic light scattering and microfluidic rheometry. By comparing the experimental data with predictions based on the Baxter sticky hard-sphere model, we surprisingly find a connection between the observed shear thinning and the predicted percolation threshold. The longest shear relaxation time of mAbs was much larger than that of model sticky hard spheres within the same region of the phase diagram, which is attributed to the anisotropy of the mAb PPIs. Our results suggest that not only the strength but also the patchiness of short-range attractive PPIs should be explicitly accounted for by theoretical approaches aimed at predicting the shear rate-dependent viscosity of dense mAb solutions.

KW - bioprocessing

KW - monoclonal antibodies

KW - protein−protein interactions

KW - rheology

KW - shear thinning

U2 - 10.1021/acs.molpharmaceut.1c00198

DO - 10.1021/acs.molpharmaceut.1c00198

M3 - Article

SN - 1543-8384

VL - 18

SP - 2669

EP - 2682

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 7

ER -

Cluster Percolation Causes Shear Thinning Behavior in Concentrated Solutions of Monoclonal Antibodies

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