A Colloid Approach to Self-Assembling Antibodies

Nicholas Skar-Gislinge, Michela Ronti, Tommy Garting, Christian Rischel, Peter Schurtenberger, Emanuela Zaccarelli, Anna Stradner

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Concentrated solutions of monoclonal antibodies have attracted considerable attention due to their importance in pharmaceutical formulations, yet their tendency to aggregate and the resulting high solution viscosity has posed considerable problems. It remains a very difficult task to understand and predict the phase behavior and stability of such solutions. Here we present a systematic study of the concentration dependence of the structural and dynamic properties of monoclonal antibodies using a combination of different scattering methods and microrheological experiments. To interpret these data, we use a colloid-inspired approach based on a simple patchy model, which explicitly takes into account the anisotropic shape and the charge distribution of the molecules. Combining theory, simulations and experiments, we are able to disentangle self-assembly and intermolecular interactions and to quantitatively describe the concentration dependence of structural and dynamic quantities such as the osmotic compressibility, the collective diffusion coefficient and the zero shear viscosity over the entire range of investigated concentrations. This simple patchy model not only allows us to consistently describe the thermodynamic and dynamic behavior of mAb solutions, but also provides a robust estimate of the attraction between their binding sites. It will thus be an ideal starting point for future work on antibody formulations, as it provides a quantitative assessment of the effects of additional excipients or chemical modifications on antibody interactions, and a prediction of their effect on solution viscosity.
Concentrated solutions of monoclonal antibodies have attracted considerable attention due to their importance in pharmaceutical formulations, yet their tendency to aggregate and the resulting high solution viscosity has posed considerable problems. It remains a very difficult task to understand and predict the phase behavior and stability of such solutions. Here we present a systematic study of the concentration dependence of the structural and dynamic properties of monoclonal antibodies using a combination of different scattering methods and microrheological experiments. To interpret these data, we use a colloid-inspired approach based on a simple patchy model, which explicitly takes into account the anisotropic shape and the charge distribution of the molecules. Combining theory, simulations and experiments, we are able to disentangle self-assembly and intermolecular interactions and to quantitatively describe the concentration dependence of structural and dynamic quantities such as the osmotic compressibility, the collective diffusion coefficient and the zero shear viscosity over the entire range of investigated concentrations. This simple patchy model not only allows us to consistently describe the thermodynamic and dynamic behavior of mAb solutions, but also provides a robust estimate of the attraction between their binding sites. It will thus be an ideal starting point for future work on antibody formulations, as it provides a quantitative assessment of the effects of additional excipients or chemical modifications on antibody interactions, and a prediction of their effect on solution viscosity.
LanguageEnglish
JournalMolecular Pharmaceutics
Volume16
Issue number6
Pages2394-2404
Number of pages11
ISSN1543-8384
DOIs
StatePublished - 2019

Keywords

  • Antibodies
  • Self-assembly
  • Patchy colloids

Cite this

Skar-Gislinge, N., Ronti, M., Garting, T., Rischel, C., Schurtenberger, P., Zaccarelli, E., & Stradner, A. (2019). A Colloid Approach to Self-Assembling Antibodies. Molecular Pharmaceutics, 16(6), 2394-2404. DOI: 10.1021/acs.molpharmaceut.9b00019
Skar-Gislinge, Nicholas ; Ronti, Michela ; Garting, Tommy ; Rischel, Christian ; Schurtenberger, Peter ; Zaccarelli, Emanuela ; Stradner, Anna. / A Colloid Approach to Self-Assembling Antibodies. In: Molecular Pharmaceutics. 2019 ; Vol. 16, No. 6. pp. 2394-2404
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Skar-Gislinge, N, Ronti, M, Garting, T, Rischel, C, Schurtenberger, P, Zaccarelli, E & Stradner, A 2019, 'A Colloid Approach to Self-Assembling Antibodies' Molecular Pharmaceutics, vol. 16, no. 6, pp. 2394-2404. DOI: 10.1021/acs.molpharmaceut.9b00019

A Colloid Approach to Self-Assembling Antibodies. / Skar-Gislinge, Nicholas; Ronti, Michela; Garting, Tommy; Rischel, Christian; Schurtenberger, Peter; Zaccarelli, Emanuela; Stradner, Anna.

In: Molecular Pharmaceutics, Vol. 16, No. 6, 2019, p. 2394-2404.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - A Colloid Approach to Self-Assembling Antibodies

AU - Skar-Gislinge,Nicholas

AU - Ronti,Michela

AU - Garting,Tommy

AU - Rischel,Christian

AU - Schurtenberger,Peter

AU - Zaccarelli,Emanuela

AU - Stradner,Anna

PY - 2019

Y1 - 2019

N2 - Concentrated solutions of monoclonal antibodies have attracted considerable attention due to their importance in pharmaceutical formulations, yet their tendency to aggregate and the resulting high solution viscosity has posed considerable problems. It remains a very difficult task to understand and predict the phase behavior and stability of such solutions. Here we present a systematic study of the concentration dependence of the structural and dynamic properties of monoclonal antibodies using a combination of different scattering methods and microrheological experiments. To interpret these data, we use a colloid-inspired approach based on a simple patchy model, which explicitly takes into account the anisotropic shape and the charge distribution of the molecules. Combining theory, simulations and experiments, we are able to disentangle self-assembly and intermolecular interactions and to quantitatively describe the concentration dependence of structural and dynamic quantities such as the osmotic compressibility, the collective diffusion coefficient and the zero shear viscosity over the entire range of investigated concentrations. This simple patchy model not only allows us to consistently describe the thermodynamic and dynamic behavior of mAb solutions, but also provides a robust estimate of the attraction between their binding sites. It will thus be an ideal starting point for future work on antibody formulations, as it provides a quantitative assessment of the effects of additional excipients or chemical modifications on antibody interactions, and a prediction of their effect on solution viscosity.

AB - Concentrated solutions of monoclonal antibodies have attracted considerable attention due to their importance in pharmaceutical formulations, yet their tendency to aggregate and the resulting high solution viscosity has posed considerable problems. It remains a very difficult task to understand and predict the phase behavior and stability of such solutions. Here we present a systematic study of the concentration dependence of the structural and dynamic properties of monoclonal antibodies using a combination of different scattering methods and microrheological experiments. To interpret these data, we use a colloid-inspired approach based on a simple patchy model, which explicitly takes into account the anisotropic shape and the charge distribution of the molecules. Combining theory, simulations and experiments, we are able to disentangle self-assembly and intermolecular interactions and to quantitatively describe the concentration dependence of structural and dynamic quantities such as the osmotic compressibility, the collective diffusion coefficient and the zero shear viscosity over the entire range of investigated concentrations. This simple patchy model not only allows us to consistently describe the thermodynamic and dynamic behavior of mAb solutions, but also provides a robust estimate of the attraction between their binding sites. It will thus be an ideal starting point for future work on antibody formulations, as it provides a quantitative assessment of the effects of additional excipients or chemical modifications on antibody interactions, and a prediction of their effect on solution viscosity.

KW - Antibodies

KW - Self-assembly

KW - Patchy colloids

KW - Antibodies

KW - Self-assembly

KW - Patchy colloids

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VL - 16

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JO - Molecular Pharmaceutics

T2 - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 6

ER -

Skar-Gislinge N, Ronti M, Garting T, Rischel C, Schurtenberger P, Zaccarelli E et al. A Colloid Approach to Self-Assembling Antibodies. Molecular Pharmaceutics. 2019;16(6):2394-2404. Available from, DOI: 10.1021/acs.molpharmaceut.9b00019