Pfeifer Serrahima, Jordi ; Schoenfeld, Katrin ; Kühnel, Ines ; Harwardt, Julia ; Macarrón Palacios, Arturo ; Prüfer, Maren ; Kolaric, Margareta ; Oberoi, Pranav ; Kolmar, Harald ; Wels, Winfried S. (2024)
Bispecific killer cell engagers employing species cross-reactive NKG2D binders redirect human and murine lymphocytes to ErbB2/HER2-positive malignancies.
In: Frontiers in Immunology, 15
doi: 10.3389/fimmu.2024.1457887
Artikel, Bibliographie
Dies ist die neueste Version dieses Eintrags.
Kurzbeschreibung (Abstract)
NKG2D is an activating receptor expressed by natural killer (NK) cells and other cytotoxic lymphocytes that plays a pivotal role in the elimination of neoplastic cells through recognition of different stress-induced cell surface ligands (NKG2DL). To employ this mechanism for cancer immunotherapy, we generated NKG2D-engaging bispecific antibodies that selectively redirect immune effector cells to cancer cells expressing the tumor-associated antigen ErbB2 (HER2). NKG2D-specific single chain fragment variable (scFv) antibodies cross-reactive toward the human and murine receptors were derived by consecutive immunization of chicken with the human and murine antigens, followed by stringent screening of a yeast surface display immune library. Four distinct species cross-reactive (sc) scFv domains were selected, and reformatted into a bispecific engager format by linking them via an IgG4 Fc domain to a second scFv fragment specific for ErbB2. The resulting molecules (termed scNKAB-ErbB2) were expressed as disulfide-linked homodimers, and demonstrated efficient binding to ErbB2-positive cancer cells as well as NKG2D-expressing primary human and murine lymphocytes, and NK-92 cells engineered with chimeric antigen receptors derived from human and murine NKG2D (termed hNKAR and mNKAR). Two of the scNKAB-ErbB2 molecules were found to compete with the natural NKG2D ligand MICA, while the other two engagers interacted with an epitope outside of the ligand binding site. Nevertheless, all four tested scNKAB-ErbB2 antibodies were similarly effective in redirecting the cytotoxic activity of primary human and murine lymphocytes as well as hNKAR-NK-92 and mNKAR-NK-92 cells to ErbB2-expressing targets, suggesting that further development of these species cross-reactive engager molecules for cancer immunotherapy is warranted.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Pfeifer Serrahima, Jordi ; Schoenfeld, Katrin ; Kühnel, Ines ; Harwardt, Julia ; Macarrón Palacios, Arturo ; Prüfer, Maren ; Kolaric, Margareta ; Oberoi, Pranav ; Kolmar, Harald ; Wels, Winfried S. |
| Art des Eintrags: | Bibliographie |
| Titel: | Bispecific killer cell engagers employing species cross-reactive NKG2D binders redirect human and murine lymphocytes to ErbB2/HER2-positive malignancies |
| Sprache: | Englisch |
| Publikationsjahr: | 29 August 2024 |
| Ort: | Lausanne |
| Verlag: | Frontiers Media S.A. |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Frontiers in Immunology |
| Jahrgang/Volume einer Zeitschrift: | 15 |
| Kollation: | 17 Seiten |
| DOI: | 10.3389/fimmu.2024.1457887 |
| Zugehörige Links: | |
| Kurzbeschreibung (Abstract): | NKG2D is an activating receptor expressed by natural killer (NK) cells and other cytotoxic lymphocytes that plays a pivotal role in the elimination of neoplastic cells through recognition of different stress-induced cell surface ligands (NKG2DL). To employ this mechanism for cancer immunotherapy, we generated NKG2D-engaging bispecific antibodies that selectively redirect immune effector cells to cancer cells expressing the tumor-associated antigen ErbB2 (HER2). NKG2D-specific single chain fragment variable (scFv) antibodies cross-reactive toward the human and murine receptors were derived by consecutive immunization of chicken with the human and murine antigens, followed by stringent screening of a yeast surface display immune library. Four distinct species cross-reactive (sc) scFv domains were selected, and reformatted into a bispecific engager format by linking them via an IgG4 Fc domain to a second scFv fragment specific for ErbB2. The resulting molecules (termed scNKAB-ErbB2) were expressed as disulfide-linked homodimers, and demonstrated efficient binding to ErbB2-positive cancer cells as well as NKG2D-expressing primary human and murine lymphocytes, and NK-92 cells engineered with chimeric antigen receptors derived from human and murine NKG2D (termed hNKAR and mNKAR). Two of the scNKAB-ErbB2 molecules were found to compete with the natural NKG2D ligand MICA, while the other two engagers interacted with an epitope outside of the ligand binding site. Nevertheless, all four tested scNKAB-ErbB2 antibodies were similarly effective in redirecting the cytotoxic activity of primary human and murine lymphocytes as well as hNKAR-NK-92 and mNKAR-NK-92 cells to ErbB2-expressing targets, suggesting that further development of these species cross-reactive engager molecules for cancer immunotherapy is warranted. |
| Freie Schlagworte: | bispecific killer cell engager, BiKE, NKG2D, ErbB2, HER2, natural killer cells, NK-92, chimeric antigen receptor |
| ID-Nummer: | Artikel-ID: 1457887 |
| Zusätzliche Informationen: | This article is part of the Research Topic: Community Series in Personalized Immunotherapy: Advancing Processes to Extend Patient Collectives, Volume II Sec. Cancer Immunity and Immunotherapy |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit |
| Fachbereich(e)/-gebiet(e): | Interdisziplinäre Forschungsprojekte Interdisziplinäre Forschungsprojekte > Centre for Synthetic Biology 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut |
| Hinterlegungsdatum: | 17 Sep 2024 06:04 |
| Letzte Änderung: | 17 Sep 2024 06:55 |
| PPN: | 521545773 |
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| Suche nach Titel in: | TUfind oder in Google |
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Bispecific killer cell engagers employing species cross-reactive NKG2D binders redirect human and murine lymphocytes to ErbB2/HER2-positive malignancies. (deposited 16 Sep 2024 11:16)
- Bispecific killer cell engagers employing species cross-reactive NKG2D binders redirect human and murine lymphocytes to ErbB2/HER2-positive malignancies. (deposited 17 Sep 2024 06:04) [Gegenwärtig angezeigt]
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