Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function
The development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crys...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2297451 |
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| author | Jennifer L. Schwedler Maxwell A. Stefan Christine E. Thatcher Peter R. McIlroy Anupama Sinha Ashlee M. Phillips Christopher A. Sumner Colleen M. Courtney Christina Y. Kim Dina R. Weilhammer Brooke Harmon |
| author_facet | Jennifer L. Schwedler Maxwell A. Stefan Christine E. Thatcher Peter R. McIlroy Anupama Sinha Ashlee M. Phillips Christopher A. Sumner Colleen M. Courtney Christina Y. Kim Dina R. Weilhammer Brooke Harmon |
| author_sort | Jennifer L. Schwedler |
| collection | DOAJ |
| description | The development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crystallizable fragment (Fc) with complement proteins and Fc receptors on immune cells. Little is known about the role of Fc effector functions of neutralizing Abs in the context of encephalitic alphavirus infection. To determine the role of Fc effector function in therapeutic efficacy against Venezuelan equine encephalitis virus (VEEV), we compared the potently neutralizing anti-VEEV human IgG F5 (hF5) Ab with intact Fc function (hF5-WT) or containing the loss of function Fc mutations L234A and L235A (hF5-LALA) in the context of VEEV infection. We observed significantly reduced binding to complement and Fc receptors, as well as differential in vitro kinetics of Fc-mediated cytotoxicity for hF5-LALA compared to hF5-WT. The in vivo efficacy of hF5-LALA was comparable to hF5-WT at −24 and + 24 h post infection, with both Abs providing high levels of protection. However, when hF5-WT and hF5-LALA were administered + 48 h post infection, there was a significant decrease in the therapeutic efficacy of hF5-LALA. Together these results demonstrate that optimal therapeutic Ab treatment of VEEV, and possibly other encephalitic alphaviruses, requires neutralization paired with engagement of immune effectors via the Fc region. |
| format | Article |
| id | doaj-art-41cb4663916447a9b561b48ff9e50a25 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-41cb4663916447a9b561b48ff9e50a252025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2023.2297451Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector functionJennifer L. Schwedler0Maxwell A. Stefan1Christine E. Thatcher2Peter R. McIlroy3Anupama Sinha4Ashlee M. Phillips5Christopher A. Sumner6Colleen M. Courtney7Christina Y. Kim8Dina R. Weilhammer9Brooke Harmon10Biotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USABiosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA, USABiotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USAThe development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crystallizable fragment (Fc) with complement proteins and Fc receptors on immune cells. Little is known about the role of Fc effector functions of neutralizing Abs in the context of encephalitic alphavirus infection. To determine the role of Fc effector function in therapeutic efficacy against Venezuelan equine encephalitis virus (VEEV), we compared the potently neutralizing anti-VEEV human IgG F5 (hF5) Ab with intact Fc function (hF5-WT) or containing the loss of function Fc mutations L234A and L235A (hF5-LALA) in the context of VEEV infection. We observed significantly reduced binding to complement and Fc receptors, as well as differential in vitro kinetics of Fc-mediated cytotoxicity for hF5-LALA compared to hF5-WT. The in vivo efficacy of hF5-LALA was comparable to hF5-WT at −24 and + 24 h post infection, with both Abs providing high levels of protection. However, when hF5-WT and hF5-LALA were administered + 48 h post infection, there was a significant decrease in the therapeutic efficacy of hF5-LALA. Together these results demonstrate that optimal therapeutic Ab treatment of VEEV, and possibly other encephalitic alphaviruses, requires neutralization paired with engagement of immune effectors via the Fc region.https://www.tandfonline.com/doi/10.1080/19420862.2023.2297451Antibody dependent cell-mediated cytotoxicity (ADCC)antibody therapycomplementcomplement dependent cytotoxicity (CDC)Fc effector functionFc-engineering |
| spellingShingle | Jennifer L. Schwedler Maxwell A. Stefan Christine E. Thatcher Peter R. McIlroy Anupama Sinha Ashlee M. Phillips Christopher A. Sumner Colleen M. Courtney Christina Y. Kim Dina R. Weilhammer Brooke Harmon Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function mAbs Antibody dependent cell-mediated cytotoxicity (ADCC) antibody therapy complement complement dependent cytotoxicity (CDC) Fc effector function Fc-engineering |
| title | Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function |
| title_full | Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function |
| title_fullStr | Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function |
| title_full_unstemmed | Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function |
| title_short | Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function |
| title_sort | therapeutic efficacy of a potent anti venezuelan equine encephalitis virus antibody is contingent on fc effector function |
| topic | Antibody dependent cell-mediated cytotoxicity (ADCC) antibody therapy complement complement dependent cytotoxicity (CDC) Fc effector function Fc-engineering |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2297451 |
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