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Fab–Fc and Fab–Fab interactions of variable strength and valency contribute to the high concentration viscosity of IgG1 antibodies.

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Title: Fab–Fc and Fab–Fab interactions of variable strength and valency contribute to the high concentration viscosity of IgG1 antibodies.
Authors: Heisler, Joel1, Hofmann, Jennifer L.2, Tan, Zhenyu1, Zarzar, Jonathan3, Izadi, Saeed3, Carter, Paul J.1 pjc@gene.com
Source: Proceedings of the National Academy of Sciences of the United States of America. 3/31/2026, Vol. 123 Issue 13, p1-11. 11p.
Subjects: Immunoglobulin G, Viscosity, Viscometry, Protein-protein interactions, Immunotechnology, Mutagenesis
Abstract: The variable domains in Fab regions are well-established contributors to high concentration viscosity of IgG, primarily through charge and hydrophobic interactions. In contrast, the roles of the Fc and the number of self-interacting sites (valency) are less well understood. Here, we investigate the relative contributions of Fab–Fab and Fab–Fc interactions to high concentration viscosity for a diverse panel of 20IgG1 antibodies, by rheometry, coarse-grained simulations, and molecular surface property analysis. Strikingly, fragmentation ofIgG1 into F(ab′)2 plus Fc reduced viscosity (−11 to −93%) for all antibodies tested, demonstrating prevalent contributions of Fc to viscosity. Coarse-grained simulations with one site per Fab and two sites per Fc qualitatively tracked trends in experimental rheometry data for 20 parental antibodies and their fragments. In these simulations Fab–Fab and Fab–Fc interaction strengths were independently varied to capture possible interaction differences arising from parental sequences or any mutations. These coarse-grained simulations suggest that Fab–Fc attractions generate branchedIgG1 networks and disproportionately larger clusters relative to Fab–Fab interactions of comparable strength. This study suggests that a four-site self-interaction model, previously proposed for a single antibody (omalizumab), is broadly applicable to diverseIgG1. Beyond well-established variable domain engineering, this self-interaction model predicts that Fc engineering may reduce IgG1 viscosity, a much sought after goal to enable subcutaneous delivery. Clinically validated Fc mutations are demonstrated here to substantially reduce the viscosity for multipleIgG1 (−33 to −91% reduction, n = 6), supporting this emerging antibody design concept. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
An: 192945252
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
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  Label: Title
  Group: Ti
  Data: Fab–Fc and Fab–Fab interactions of variable strength and valency contribute to the high concentration viscosity of IgG<subscript>1</subscript> antibodies.
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  Data: <searchLink fieldCode="AR" term="%22Heisler%2C+Joel%22">Heisler, Joel</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Hofmann%2C+Jennifer+L%2E%22">Hofmann, Jennifer L.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Tan%2C+Zhenyu%22">Tan, Zhenyu</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Zarzar%2C+Jonathan%22">Zarzar, Jonathan</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Izadi%2C+Saeed%22">Izadi, Saeed</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Carter%2C+Paul+J%2E%22">Carter, Paul J.</searchLink><relatesTo>1</relatesTo><i> pjc@gene.com</i>
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  Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 3/31/2026, Vol. 123 Issue 13, p1-11. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Immunoglobulin+G%22">Immunoglobulin G</searchLink><br /><searchLink fieldCode="DE" term="%22Viscosity%22">Viscosity</searchLink><br /><searchLink fieldCode="DE" term="%22Viscometry%22">Viscometry</searchLink><br /><searchLink fieldCode="DE" term="%22Protein-protein+interactions%22">Protein-protein interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Immunotechnology%22">Immunotechnology</searchLink><br /><searchLink fieldCode="DE" term="%22Mutagenesis%22">Mutagenesis</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The variable domains in Fab regions are well-established contributors to high concentration viscosity of IgG, primarily through charge and hydrophobic interactions. In contrast, the roles of the Fc and the number of self-interacting sites (valency) are less well understood. Here, we investigate the relative contributions of Fab–Fab and Fab–Fc interactions to high concentration viscosity for a diverse panel of 20IgG1 antibodies, by rheometry, coarse-grained simulations, and molecular surface property analysis. Strikingly, fragmentation ofIgG1 into F(ab′)2 plus Fc reduced viscosity (−11 to −93%) for all antibodies tested, demonstrating prevalent contributions of Fc to viscosity. Coarse-grained simulations with one site per Fab and two sites per Fc qualitatively tracked trends in experimental rheometry data for 20 parental antibodies and their fragments. In these simulations Fab–Fab and Fab–Fc interaction strengths were independently varied to capture possible interaction differences arising from parental sequences or any mutations. These coarse-grained simulations suggest that Fab–Fc attractions generate branchedIgG1 networks and disproportionately larger clusters relative to Fab–Fab interactions of comparable strength. This study suggests that a four-site self-interaction model, previously proposed for a single antibody (omalizumab), is broadly applicable to diverseIgG1. Beyond well-established variable domain engineering, this self-interaction model predicts that Fc engineering may reduce IgG1 viscosity, a much sought after goal to enable subcutaneous delivery. Clinically validated Fc mutations are demonstrated here to substantially reduce the viscosity for multipleIgG1 (−33 to −91% reduction, n = 6), supporting this emerging antibody design concept. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1073/pnas.2526550123
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      – Code: eng
        Text: English
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        PageCount: 11
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    Subjects:
      – SubjectFull: Immunoglobulin G
        Type: general
      – SubjectFull: Viscosity
        Type: general
      – SubjectFull: Viscometry
        Type: general
      – SubjectFull: Protein-protein interactions
        Type: general
      – SubjectFull: Immunotechnology
        Type: general
      – SubjectFull: Mutagenesis
        Type: general
    Titles:
      – TitleFull: Fab–Fc and Fab–Fab interactions of variable strength and valency contribute to the high concentration viscosity of IgG1 antibodies.
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            NameFull: Heisler, Joel
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              M: 03
              Text: 3/31/2026
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              Y: 2026
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