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NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

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
Article, Secondary publication, Publisher's Version

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.

Item Type: Article
Erschienen: 2023
Creators: 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
Type of entry: Secondary publication
Title: NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats
Language: English
Date: 2023
Place of Publication: Darmstadt
Year of primary publication: 2023
Publisher: John Wiley & Sons
Journal or Publication Title: Protein Science
Volume of the journal: 32
Issue Number: 3
Collation: 16 Seiten
DOI: 10.26083/tuprints-00023690
URL / URN: https://tuprints.ulb.tu-darmstadt.de/23690
Corresponding Links:
Origin: Secondary publication DeepGreen
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.

Uncontrolled Keywords: ADCC, antibody engineering, bispecific antibody, multifunctional antibody, NK cell engager, NK cell redirection, NKp46, single domain antibody, valencies, VHH
Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-236908
Classification DDC: 500 Science and mathematics > 540 Chemistry
500 Science and mathematics > 570 Life sciences, biology
600 Technology, medicine, applied sciences > 610 Medicine and health
Divisions: 07 Department of Chemistry
07 Department of Chemistry > Clemens-Schöpf-Institut > Fachgebiet Biochemie
Date Deposited: 12 May 2023 08:47
Last Modified: 15 May 2023 05:11
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