Novel NKG2D-directed bispecific antibodies enhance antibody-mediated killing of malignant B cells by NK cells and T cells
Copyright © 2023 Lutz, Klausz, Albici, Ebinger, Sellmer, Teipel, Frenzel, Langner, Winterberg, Krohn, Hust, Schirrmann, Dübel, Scherließ, Humpe, Gramatzki, Kellner and Peipp..
The activating receptor natural killer group 2, member D (NKG2D) represents an attractive target for immunotherapy as it exerts a crucial role in cancer immunosurveillance by regulating the activity of cytotoxic lymphocytes. In this study, a panel of novel NKG2D-specific single-chain fragments variable (scFv) were isolated from naïve human antibody gene libraries and fused to the fragment antigen binding (Fab) of rituximab to obtain [CD20×NKG2D] bibodies with the aim to recruit cytotoxic lymphocytes to lymphoma cells. All bispecific antibodies bound both antigens simultaneously. Two bibody constructs, [CD20×NKG2D#3] and [CD20×NKG2D#32], efficiently activated natural killer (NK) cells in co-cultures with CD20+ lymphoma cells. Both bibodies triggered NK cell-mediated lysis of lymphoma cells and especially enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by CD38 or CD19 specific monoclonal antibodies suggesting a synergistic effect between NKG2D and FcγRIIIA signaling pathways in NK cell activation. The [CD20×NKG2D] bibodies were not effective in redirecting CD8+ T cells as single agents, but enhanced cytotoxicity when combined with a bispecific [CD19×CD3] T cell engager, indicating that NKG2D signaling also supports CD3-mediated T cell activation. In conclusion, engagement of NKG2D with bispecific antibodies is attractive to directly activate cytotoxic lymphocytes or to support their activation by monoclonal antibodies or bispecific T cell engagers. As a perspective, co-targeting of two tumor antigens may allow fine-tuning of antibody cancer therapies. Our proposed combinatorial approach is potentially applicable for many existing immunotherapies but further testing in different preclinical models is necessary to explore the full potential.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Frontiers in immunology - 14(2023) vom: 15., Seite 1227572 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lutz, Sebastian [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 20.03.2024 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.3389/fimmu.2023.1227572 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Novel NKG2D-directed bispecific antibodies enhance antibody-mediated killing of malignant B cells by NK cells and T cells |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Lutz, Klausz, Albici, Ebinger, Sellmer, Teipel, Frenzel, Langner, Winterberg, Krohn, Hust, Schirrmann, Dübel, Scherließ, Humpe, Gramatzki, Kellner and Peipp. | ||
| 520 | |a The activating receptor natural killer group 2, member D (NKG2D) represents an attractive target for immunotherapy as it exerts a crucial role in cancer immunosurveillance by regulating the activity of cytotoxic lymphocytes. In this study, a panel of novel NKG2D-specific single-chain fragments variable (scFv) were isolated from naïve human antibody gene libraries and fused to the fragment antigen binding (Fab) of rituximab to obtain [CD20×NKG2D] bibodies with the aim to recruit cytotoxic lymphocytes to lymphoma cells. All bispecific antibodies bound both antigens simultaneously. Two bibody constructs, [CD20×NKG2D#3] and [CD20×NKG2D#32], efficiently activated natural killer (NK) cells in co-cultures with CD20+ lymphoma cells. Both bibodies triggered NK cell-mediated lysis of lymphoma cells and especially enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by CD38 or CD19 specific monoclonal antibodies suggesting a synergistic effect between NKG2D and FcγRIIIA signaling pathways in NK cell activation. The [CD20×NKG2D] bibodies were not effective in redirecting CD8+ T cells as single agents, but enhanced cytotoxicity when combined with a bispecific [CD19×CD3] T cell engager, indicating that NKG2D signaling also supports CD3-mediated T cell activation. In conclusion, engagement of NKG2D with bispecific antibodies is attractive to directly activate cytotoxic lymphocytes or to support their activation by monoclonal antibodies or bispecific T cell engagers. As a perspective, co-targeting of two tumor antigens may allow fine-tuning of antibody cancer therapies. Our proposed combinatorial approach is potentially applicable for many existing immunotherapies but further testing in different preclinical models is necessary to explore the full potential | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CD20 | |
| 650 | 4 | |a FcγRIIIA | |
| 650 | 4 | |a NKG2D | |
| 650 | 4 | |a antibody therapy | |
| 650 | 4 | |a bispecific antibody | |
| 650 | 4 | |a lymphoma | |
| 650 | 4 | |a phage display | |
| 650 | 7 | |a Antibodies, Bispecific |2 NLM | |
| 650 | 7 | |a NK Cell Lectin-Like Receptor Subfamily K |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Antigens, CD19 |2 NLM | |
| 700 | 1 | |a Klausz, Katja |e verfasserin |4 aut | |
| 700 | 1 | |a Albici, Anca-Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Ebinger, Lea |e verfasserin |4 aut | |
| 700 | 1 | |a Sellmer, Lea |e verfasserin |4 aut | |
| 700 | 1 | |a Teipel, Hannah |e verfasserin |4 aut | |
| 700 | 1 | |a Frenzel, André |e verfasserin |4 aut | |
| 700 | 1 | |a Langner, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Winterberg, Dorothee |e verfasserin |4 aut | |
| 700 | 1 | |a Krohn, Steffen |e verfasserin |4 aut | |
| 700 | 1 | |a Hust, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Schirrmann, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Dübel, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Scherließ, Regina |e verfasserin |4 aut | |
| 700 | 1 | |a Humpe, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Gramatzki, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Kellner, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Peipp, Matthias |e verfasserin |4 aut | |
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