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Electrostatics and viscosity are strongly linked in concentrated antibody solutions

Camerin, Fabrizio LU orcid ; Polimeni, Marco LU ; Stradner, Anna LU ; Zaccarelli, Emanuela and Schurtenberger, Peter LU orcid (2025) In Proceedings of the National Academy of Sciences of the United States of America 122(40).
Abstract

Monoclonal antibodies are among the most promising therapeutic agents in modern medicine, yet their formulation into high-concentration solutions for subcutaneous self-administration poses a major challenge. A key obstacle is the marked increase in viscosity often observed under these conditions. To gain deeper insights into this phenomenon, coarse-grained models derived from soft matter physics have been widely employed. However, these models have yet to be fully leveraged for analyzing the rheological collective properties of such systems. In this study, using molecular dynamics simulations, we directly compute the antibody solution viscosity by starting from commonly used models in which electrostatic interactions are treated through... (More)

Monoclonal antibodies are among the most promising therapeutic agents in modern medicine, yet their formulation into high-concentration solutions for subcutaneous self-administration poses a major challenge. A key obstacle is the marked increase in viscosity often observed under these conditions. To gain deeper insights into this phenomenon, coarse-grained models derived from soft matter physics have been widely employed. However, these models have yet to be fully leveraged for analyzing the rheological collective properties of such systems. In this study, using molecular dynamics simulations, we directly compute the antibody solution viscosity by starting from commonly used models in which electrostatic interactions are treated through effective screened Coulomb potentials. We demonstrate that this approach fails to reproduce experimental evidence and we show, by analyzing stress correlations in the system, that it is necessary to treat the heterogeneously charged domains with explicit Coulomb interactions, also including counterions and salt ions. By thoroughly analyzing the microscopic structure of the system, we further reveal the presence of transient strongly correlated antibodies which would not be present if charges were treated implicitly, thus pointing to a prominent role of electrostatics in determining the increase in viscosity at high concentrations. By taking advantage of our realistic treatment, new approaches can be devised to ensure that antibody solutions exhibit the desired characteristics for their intended broad use and effective deployment.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
antibodies, charge heterogeneity, coarse-grained modeling, explicit ions, viscosity
in
Proceedings of the National Academy of Sciences of the United States of America
volume
122
issue
40
article number
e2425974122
publisher
National Academy of Sciences
external identifiers
  • scopus:105017804141
  • pmid:41037634
ISSN
0027-8424
DOI
10.1073/pnas.2425974122
language
English
LU publication?
yes
id
396298ab-d568-4f54-9ea6-9521f4d2c041
date added to LUP
2025-11-25 12:34:34
date last changed
2025-11-26 03:42:58
@article{396298ab-d568-4f54-9ea6-9521f4d2c041,
  abstract     = {{<p>Monoclonal antibodies are among the most promising therapeutic agents in modern medicine, yet their formulation into high-concentration solutions for subcutaneous self-administration poses a major challenge. A key obstacle is the marked increase in viscosity often observed under these conditions. To gain deeper insights into this phenomenon, coarse-grained models derived from soft matter physics have been widely employed. However, these models have yet to be fully leveraged for analyzing the rheological collective properties of such systems. In this study, using molecular dynamics simulations, we directly compute the antibody solution viscosity by starting from commonly used models in which electrostatic interactions are treated through effective screened Coulomb potentials. We demonstrate that this approach fails to reproduce experimental evidence and we show, by analyzing stress correlations in the system, that it is necessary to treat the heterogeneously charged domains with explicit Coulomb interactions, also including counterions and salt ions. By thoroughly analyzing the microscopic structure of the system, we further reveal the presence of transient strongly correlated antibodies which would not be present if charges were treated implicitly, thus pointing to a prominent role of electrostatics in determining the increase in viscosity at high concentrations. By taking advantage of our realistic treatment, new approaches can be devised to ensure that antibody solutions exhibit the desired characteristics for their intended broad use and effective deployment.</p>}},
  author       = {{Camerin, Fabrizio and Polimeni, Marco and Stradner, Anna and Zaccarelli, Emanuela and Schurtenberger, Peter}},
  issn         = {{0027-8424}},
  keywords     = {{antibodies; charge heterogeneity; coarse-grained modeling; explicit ions; viscosity}},
  language     = {{eng}},
  number       = {{40}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Electrostatics and viscosity are strongly linked in concentrated antibody solutions}},
  url          = {{http://dx.doi.org/10.1073/pnas.2425974122}},
  doi          = {{10.1073/pnas.2425974122}},
  volume       = {{122}},
  year         = {{2025}},
}