Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity
Preferential interactions of excipients with the antibody surface govern their effect on the stability of antibodies in solution. We probed the preferential interactions of proline, arginine.HCl (Arg.HCl), and NaCl with three therapeutically relevant IgG1 antibodies via experiment and simulation. Wi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2020.1816312 |
| _version_ | 1817987926236069888 |
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| author | Theresa K. Cloutier Chaitanya Sudrik Neil Mody Sathish A. Hasige Bernhardt L. Trout |
| author_facet | Theresa K. Cloutier Chaitanya Sudrik Neil Mody Sathish A. Hasige Bernhardt L. Trout |
| author_sort | Theresa K. Cloutier |
| collection | DOAJ |
| description | Preferential interactions of excipients with the antibody surface govern their effect on the stability of antibodies in solution. We probed the preferential interactions of proline, arginine.HCl (Arg.HCl), and NaCl with three therapeutically relevant IgG1 antibodies via experiment and simulation. With simulations, we examined how excipients interacted with different types of surface patches in the variable region (Fv). For example, proline interacted most strongly with aromatic surfaces, Arg.HCl was included near negative residues, and NaCl was excluded from negative residues and certain hydrophobic regions. The differences in interaction of different excipients with the same surface patch on an antibody may be responsible for variations in the antibody's aggregation, viscosity, and self-association behaviors in each excipient. Proline reduced self-association for all three antibodies and reduced aggregation for the antibody with an association-limited aggregation mechanism. The effects of Arg.HCl and NaCl on aggregation and viscosity were highly dependent on the surface charge distribution and the extent of exclusion from highly hydrophobic patches. At pH 5.5, both tended to increase the aggregation of an antibody with a strongly positive charge on the Fv, while only NaCl reduced the aggregation of the antibody with a large negative charge patch on the Fv. Arg.HCl reduced the viscosities of antibodies with either a hydrophobicity-driven mechanism or a charge-driven mechanism. Analysis of this data presents a framework for understanding how amino acid and ionic excipients interact with different protein surfaces, and how these interactions translate to the observed stability behavior. |
| first_indexed | 2024-04-14T00:27:32Z |
| format | Article |
| id | doaj.art-845e3276a66b4344926f68a17ae37043 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-14T00:27:32Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-845e3276a66b4344926f68a17ae370432022-12-22T02:22:40ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2020.1816312Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosityTheresa K. Cloutier0Chaitanya Sudrik1Neil Mody2Sathish A. Hasige3Bernhardt L. Trout4Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Maryland, USADepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Maryland, USADosage Form Design and Development, AstraZeneca, Gaithersburg, Maryland, USADosage Form Design and Development, AstraZeneca, Gaithersburg, Maryland, USADepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Maryland, USAPreferential interactions of excipients with the antibody surface govern their effect on the stability of antibodies in solution. We probed the preferential interactions of proline, arginine.HCl (Arg.HCl), and NaCl with three therapeutically relevant IgG1 antibodies via experiment and simulation. With simulations, we examined how excipients interacted with different types of surface patches in the variable region (Fv). For example, proline interacted most strongly with aromatic surfaces, Arg.HCl was included near negative residues, and NaCl was excluded from negative residues and certain hydrophobic regions. The differences in interaction of different excipients with the same surface patch on an antibody may be responsible for variations in the antibody's aggregation, viscosity, and self-association behaviors in each excipient. Proline reduced self-association for all three antibodies and reduced aggregation for the antibody with an association-limited aggregation mechanism. The effects of Arg.HCl and NaCl on aggregation and viscosity were highly dependent on the surface charge distribution and the extent of exclusion from highly hydrophobic patches. At pH 5.5, both tended to increase the aggregation of an antibody with a strongly positive charge on the Fv, while only NaCl reduced the aggregation of the antibody with a large negative charge patch on the Fv. Arg.HCl reduced the viscosities of antibodies with either a hydrophobicity-driven mechanism or a charge-driven mechanism. Analysis of this data presents a framework for understanding how amino acid and ionic excipients interact with different protein surfaces, and how these interactions translate to the observed stability behavior.https://www.tandfonline.com/doi/10.1080/19420862.2020.1816312Preferential interaction coefficientsprolinearginine.HClNaclmAbsaggregation |
| spellingShingle | Theresa K. Cloutier Chaitanya Sudrik Neil Mody Sathish A. Hasige Bernhardt L. Trout Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity mAbs Preferential interaction coefficients proline arginine.HCl Nacl mAbs aggregation |
| title | Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity |
| title_full | Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity |
| title_fullStr | Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity |
| title_full_unstemmed | Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity |
| title_short | Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity |
| title_sort | molecular computations of preferential interactions of proline arginine hcl and nacl with igg1 antibodies and their impact on aggregation and viscosity |
| topic | Preferential interaction coefficients proline arginine.HCl Nacl mAbs aggregation |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2020.1816312 |
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