Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers
Natural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) that redirect the cytotoxic potential of NK cells toward epidermal growth...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2315640 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832576581421236224 |
|---|---|
| author | Ammelie Svea Boje Lukas Pekar Katharina Koep Britta Lipinski Brian Rabinovich Andreas Evers Carina Lynn Gehlert Steffen Krohn Yanping Xiao Simon Krah Rinat Zaynagetdinov Lars Toleikis Sven Poetzsch Matthias Peipp Stefan Zielonka Katja Klausz |
| author_facet | Ammelie Svea Boje Lukas Pekar Katharina Koep Britta Lipinski Brian Rabinovich Andreas Evers Carina Lynn Gehlert Steffen Krohn Yanping Xiao Simon Krah Rinat Zaynagetdinov Lars Toleikis Sven Poetzsch Matthias Peipp Stefan Zielonka Katja Klausz |
| author_sort | Ammelie Svea Boje |
| collection | DOAJ |
| description | Natural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) that redirect the cytotoxic potential of NK cells toward epidermal growth factor receptor (EGFR)-expressing tumor cells. We investigated the impact of crucial parameters such as sdAb location, binding valencies, the targeted epitope on NKp30, and the overall antibody architecture on the redirection capacity. Our study exploited two NKp30-specific sdAbs, one of which binds a similar epitope on NKp30 as its natural ligand B7-H6, while the other sdAb addresses a non-competing epitope. For EGFR-positive tumor targeting, humanized antigen-binding domains of therapeutic antibody cetuximab were used. We demonstrate that NKCEs bivalently targeting EGFR and bivalently engaging NKp30 are superior to monovalent NKCEs in promoting NK cell-mediated tumor cell lysis and that the architecture of the NKCE can substantially influence killing capacities depending on the NKp30-targeting sdAb utilized. While having a pronounced impact on NK cell killing efficacy, the capabilities of triggering antibody-dependent cellular phagocytosis or complement-dependent cytotoxicity were not significantly affected comparing the bivalent IgG-like NKCEs with cetuximab. However, the fusion of sdAbs can have a slight impact on the NK cell release of immunomodulatory cytokines, as well as on the pharmacokinetic profile of the NKCE due to unfavorable spatial orientation within the molecule architecture. Ultimately, our findings reveal novel insights for the engineering of potent NKCEs triggering the NKp30 axis. |
| format | Article |
| id | doaj-art-dab9f66e27944e228e065c4ff4d03f51 |
| 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-dab9f66e27944e228e065c4ff4d03f512025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2315640Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagersAmmelie Svea Boje0Lukas Pekar1Katharina Koep2Britta Lipinski3Brian Rabinovich4Andreas Evers5Carina Lynn Gehlert6Steffen Krohn7Yanping Xiao8Simon Krah9Rinat Zaynagetdinov10Lars Toleikis11Sven Poetzsch12Matthias Peipp13Stefan Zielonka14Katja Klausz15Division of Antibody-Based Immunotherapy, Department of Internal Medicine II, University Medical Center Schleswig-Holstein and University of Kiel, Kiel, GermanyAntibody Discovery & Protein Engineering, Merck Healthcare KGaA, Darmstadt, GermanyDrug Metabolism and Pharmacokinetics, Merck Healthcare KGaA, Darmstadt, GermanyAntibody Discovery & Protein Engineering, Merck Healthcare KGaA, Darmstadt, GermanyDepartment of Oncology and Immuno-Oncology, EMD Serono Research & Development Institute Inc, 45A Middlesex Turnpike, Billerica, MA, USAAntibody Discovery & Protein Engineering, Merck Healthcare KGaA, Darmstadt, GermanyDivision of Antibody-Based Immunotherapy, Department of Internal Medicine II, University Medical Center Schleswig-Holstein and University of Kiel, Kiel, GermanyDivision of Antibody-Based Immunotherapy, Department of Internal Medicine II, University Medical Center Schleswig-Holstein and University of Kiel, Kiel, GermanyDepartment of Oncology and Immuno-Oncology, EMD Serono Research & Development Institute Inc, 45A Middlesex Turnpike, Billerica, MA, USAAntibody Discovery & Protein Engineering, Merck Healthcare KGaA, Darmstadt, GermanyDepartment of Oncology and Immuno-Oncology, EMD Serono Research & Development Institute Inc, 45A Middlesex Turnpike, Billerica, MA, USAEarly Protein Supply & Characterization, Merck Healthcare KGaA, Darmstadt, GermanyStrategic Innovation, Merck Healthcare KGaA, Darmstadt, GermanyDivision of Antibody-Based Immunotherapy, Department of Internal Medicine II, University Medical Center Schleswig-Holstein and University of Kiel, Kiel, GermanyAntibody Discovery & Protein Engineering, Merck Healthcare KGaA, Darmstadt, GermanyDivision of Antibody-Based Immunotherapy, Department of Internal Medicine II, University Medical Center Schleswig-Holstein and University of Kiel, Kiel, GermanyNatural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) that redirect the cytotoxic potential of NK cells toward epidermal growth factor receptor (EGFR)-expressing tumor cells. We investigated the impact of crucial parameters such as sdAb location, binding valencies, the targeted epitope on NKp30, and the overall antibody architecture on the redirection capacity. Our study exploited two NKp30-specific sdAbs, one of which binds a similar epitope on NKp30 as its natural ligand B7-H6, while the other sdAb addresses a non-competing epitope. For EGFR-positive tumor targeting, humanized antigen-binding domains of therapeutic antibody cetuximab were used. We demonstrate that NKCEs bivalently targeting EGFR and bivalently engaging NKp30 are superior to monovalent NKCEs in promoting NK cell-mediated tumor cell lysis and that the architecture of the NKCE can substantially influence killing capacities depending on the NKp30-targeting sdAb utilized. While having a pronounced impact on NK cell killing efficacy, the capabilities of triggering antibody-dependent cellular phagocytosis or complement-dependent cytotoxicity were not significantly affected comparing the bivalent IgG-like NKCEs with cetuximab. However, the fusion of sdAbs can have a slight impact on the NK cell release of immunomodulatory cytokines, as well as on the pharmacokinetic profile of the NKCE due to unfavorable spatial orientation within the molecule architecture. Ultimately, our findings reveal novel insights for the engineering of potent NKCEs triggering the NKp30 axis.https://www.tandfonline.com/doi/10.1080/19420862.2024.2315640ADCCantibody engineeringbispecific antibodyEGFRNK cell engagerNKp30 |
| spellingShingle | Ammelie Svea Boje Lukas Pekar Katharina Koep Britta Lipinski Brian Rabinovich Andreas Evers Carina Lynn Gehlert Steffen Krohn Yanping Xiao Simon Krah Rinat Zaynagetdinov Lars Toleikis Sven Poetzsch Matthias Peipp Stefan Zielonka Katja Klausz Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers mAbs ADCC antibody engineering bispecific antibody EGFR NK cell engager NKp30 |
| title | Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers |
| title_full | Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers |
| title_fullStr | Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers |
| title_full_unstemmed | Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers |
| title_short | Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers |
| title_sort | impact of antibody architecture and paratope valency on effector functions of bispecific nkp30 x egfr natural killer cell engagers |
| topic | ADCC antibody engineering bispecific antibody EGFR NK cell engager NKp30 |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2315640 |
| work_keys_str_mv | AT ammeliesveaboje impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT lukaspekar impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT katharinakoep impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT brittalipinski impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT brianrabinovich impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT andreasevers impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT carinalynngehlert impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT steffenkrohn impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT yanpingxiao impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT simonkrah impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT rinatzaynagetdinov impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT larstoleikis impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT svenpoetzsch impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT matthiaspeipp impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT stefanzielonka impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers AT katjaklausz impactofantibodyarchitectureandparatopevalencyoneffectorfunctionsofbispecificnkp30xegfrnaturalkillercellengagers |