Lipinski, Britta ; Arras, Paul ; Pekar, Lukas ; Klewinghaus, Daniel ; Boje, Ammelie Svea ; Krah, Simon ; Zimmermann, Jasmin ; Klausz, Katja ; Peipp, Matthias ; Siegmund, Vanessa ; Evers, Andreas ; Zielonka, Stefan (2023)
NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats.
In: Protein Science, 2023, 32 (3)
doi: 10.26083/tuprints-00023690
Artikel, Zweitveröffentlichung, Verlagsversion
Kurzbeschreibung (Abstract)
Herein, we describe the generation of potent NK cell engagers (NKCEs) based on single domain antibodies (sdAbs) specific for NKp46 harboring the humanized Fab version of Cetuximab for tumor targeting. After immunization of camelids, a plethora of different VHH domains were retrieved by yeast surface display. Upon reformatting into Fc effector‐silenced NKCEs targeting NKp46 and EGFR in a strictly monovalent fashion, the resulting bispecific antibodies elicited potent NK cell‐mediated killing of EGFR‐overexpressing tumor cells with potencies (EC₅₀killing) in the picomolar range. This was further augmented via co‐engagement of Fcγ receptor IIIa (FcγRIIIa). Importantly, NKp46‐specific sdAbs enabled the construction of various NKCE formats with different geometries and valencies which displayed favorable biophysical and biochemical properties without further optimization. By this means, killing capacities were further improved significantly. Hence, NKp46‐specific sdAbs are versatile building blocks for the construction of different NKCE formats.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2023 |
| Autor(en): | Lipinski, Britta ; Arras, Paul ; Pekar, Lukas ; Klewinghaus, Daniel ; Boje, Ammelie Svea ; Krah, Simon ; Zimmermann, Jasmin ; Klausz, Katja ; Peipp, Matthias ; Siegmund, Vanessa ; Evers, Andreas ; Zielonka, Stefan |
| Art des Eintrags: | Zweitveröffentlichung |
| Titel: | NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats |
| Sprache: | Englisch |
| Publikationsjahr: | 2023 |
| Ort: | Darmstadt |
| Publikationsdatum der Erstveröffentlichung: | 2023 |
| Verlag: | John Wiley & Sons |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Protein Science |
| Jahrgang/Volume einer Zeitschrift: | 32 |
| (Heft-)Nummer: | 3 |
| Kollation: | 16 Seiten |
| DOI: | 10.26083/tuprints-00023690 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/23690 |
| Zugehörige Links: | |
| Herkunft: | Zweitveröffentlichung DeepGreen |
| Kurzbeschreibung (Abstract): | Herein, we describe the generation of potent NK cell engagers (NKCEs) based on single domain antibodies (sdAbs) specific for NKp46 harboring the humanized Fab version of Cetuximab for tumor targeting. After immunization of camelids, a plethora of different VHH domains were retrieved by yeast surface display. Upon reformatting into Fc effector‐silenced NKCEs targeting NKp46 and EGFR in a strictly monovalent fashion, the resulting bispecific antibodies elicited potent NK cell‐mediated killing of EGFR‐overexpressing tumor cells with potencies (EC₅₀killing) in the picomolar range. This was further augmented via co‐engagement of Fcγ receptor IIIa (FcγRIIIa). Importantly, NKp46‐specific sdAbs enabled the construction of various NKCE formats with different geometries and valencies which displayed favorable biophysical and biochemical properties without further optimization. By this means, killing capacities were further improved significantly. Hence, NKp46‐specific sdAbs are versatile building blocks for the construction of different NKCE formats. |
| Freie Schlagworte: | ADCC, antibody engineering, bispecific antibody, multifunctional antibody, NK cell engager, NK cell redirection, NKp46, single domain antibody, valencies, VHH |
| Status: | Verlagsversion |
| URN: | urn:nbn:de:tuda-tuprints-236908 |
| 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): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie |
| Hinterlegungsdatum: | 12 Mai 2023 08:47 |
| Letzte Änderung: | 15 Mai 2023 05:11 |
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