Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity
The glycoprotein CD2 is expressed on T and NK cells and contributes to cell-cell conjugation, agonistic signaling and actin cytoskeleton rearrangement. CD2 has previously been shown to have an important function in natural NK cell cytotoxicity but to be expendable in antibody-mediated cytotoxicity....
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.599526/full |
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| author | Christian Binder Christian Binder Felix Sellberg Felix Sellberg Filip Cvetkovski Stefan Berg Erik Berglund Erik Berglund David Berglund David Berglund |
| author_facet | Christian Binder Christian Binder Felix Sellberg Felix Sellberg Filip Cvetkovski Stefan Berg Erik Berglund Erik Berglund David Berglund David Berglund |
| author_sort | Christian Binder |
| collection | DOAJ |
| description | The glycoprotein CD2 is expressed on T and NK cells and contributes to cell-cell conjugation, agonistic signaling and actin cytoskeleton rearrangement. CD2 has previously been shown to have an important function in natural NK cell cytotoxicity but to be expendable in antibody-mediated cytotoxicity. Siplizumab is a monoclonal anti-CD2 IgG1 antibody that is currently undergoing clinical trials in the field of transplantation. This study investigated the effect of CD2 binding and Fc γ receptor binding by siplizumab (Fc-active) and Fc-silent anti-CD2 monoclonal antibodies in allogeneic mixed lymphocyte reaction and autologous lymphocyte culture. Further, induction of NK cell fratricide and inhibition of natural cytotoxicity as well as antibody-dependent cytotoxicity by these agents were assessed. Blockade of CD2 via monoclonal antibodies in the absence of Fc γ receptor binding inhibited NK cell activation in allogeneic mixed lymphocyte reaction. In contrast, siplizumab increased NK cell activation in both mixed lymphocyte reaction and autologous lymphocyte culture due to FcγRIIIA binding. However, experiments using purified NK cells did not show an inhibitory effect of CD2 blockade on natural cytotoxicity or antibody-dependent cytotoxicity. Lastly, it was shown that siplizumab induces NK cell fratricide. Concluding, siplizumab is a promising biopharmaceutical drug candidate for depletion of T and NK cells with minimal off-target effects. |
| first_indexed | 2024-12-17T08:58:36Z |
| format | Article |
| id | doaj.art-b681b0ce2a704f868ecdd8ecade323fd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T08:58:36Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b681b0ce2a704f868ecdd8ecade323fd2022-12-21T21:55:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.599526599526Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated CytotoxicityChristian Binder0Christian Binder1Felix Sellberg2Felix Sellberg3Filip Cvetkovski4Stefan Berg5Erik Berglund6Erik Berglund7David Berglund8David Berglund9Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, SwedenResearch and Development, ITB-Med AB, Stockholm, SwedenDepartment of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, SwedenResearch and Development, ITB-Med AB, Stockholm, SwedenResearch and Development, ITB-Med AB, Stockholm, SwedenResearch and Development, ITB-Med AB, Stockholm, SwedenResearch and Development, ITB-Med AB, Stockholm, SwedenDivision of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute and Karolinska University Hospital, Stockholm, SwedenDepartment of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, SwedenResearch and Development, ITB-Med AB, Stockholm, SwedenThe glycoprotein CD2 is expressed on T and NK cells and contributes to cell-cell conjugation, agonistic signaling and actin cytoskeleton rearrangement. CD2 has previously been shown to have an important function in natural NK cell cytotoxicity but to be expendable in antibody-mediated cytotoxicity. Siplizumab is a monoclonal anti-CD2 IgG1 antibody that is currently undergoing clinical trials in the field of transplantation. This study investigated the effect of CD2 binding and Fc γ receptor binding by siplizumab (Fc-active) and Fc-silent anti-CD2 monoclonal antibodies in allogeneic mixed lymphocyte reaction and autologous lymphocyte culture. Further, induction of NK cell fratricide and inhibition of natural cytotoxicity as well as antibody-dependent cytotoxicity by these agents were assessed. Blockade of CD2 via monoclonal antibodies in the absence of Fc γ receptor binding inhibited NK cell activation in allogeneic mixed lymphocyte reaction. In contrast, siplizumab increased NK cell activation in both mixed lymphocyte reaction and autologous lymphocyte culture due to FcγRIIIA binding. However, experiments using purified NK cells did not show an inhibitory effect of CD2 blockade on natural cytotoxicity or antibody-dependent cytotoxicity. Lastly, it was shown that siplizumab induces NK cell fratricide. Concluding, siplizumab is a promising biopharmaceutical drug candidate for depletion of T and NK cells with minimal off-target effects.https://www.frontiersin.org/articles/10.3389/fimmu.2021.599526/fullNK cellCD2siplizumabspontaneous cytotoxicityantibody-dependent cell-mediated cytotoxicityNK alloreactivity |
| spellingShingle | Christian Binder Christian Binder Felix Sellberg Felix Sellberg Filip Cvetkovski Stefan Berg Erik Berglund Erik Berglund David Berglund David Berglund Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity Frontiers in Immunology NK cell CD2 siplizumab spontaneous cytotoxicity antibody-dependent cell-mediated cytotoxicity NK alloreactivity |
| title | Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity |
| title_full | Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity |
| title_fullStr | Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity |
| title_full_unstemmed | Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity |
| title_short | Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity |
| title_sort | siplizumab induces nk cell fratricide through antibody dependent cell mediated cytotoxicity |
| topic | NK cell CD2 siplizumab spontaneous cytotoxicity antibody-dependent cell-mediated cytotoxicity NK alloreactivity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.599526/full |
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