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Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

Bogen, Jan P. ; Carrara, Stefania C. ; Fiebig, David ; Grzeschik, Julius ; Hock, Björn ; Kolmar, Harald (2021)
Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture.
In: Frontiers in Immunology, 2021, 12
doi: 10.26083/tuprints-00019364
Article, Secondary publication, Publisher's Version

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Item Type: Article
Type of entry: Secondary publication
Title: Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture
Language: English
Date: 25 August 2021
Place of Publication: Darmstadt
Year of primary publication: 2021
Publisher: Frontiers
Journal or Publication Title: Frontiers in Immunology
Volume of the journal: 12
Collation: 16 Seiten
DOI: 10.26083/tuprints-00019364
Corresponding Links:
Origin: Secondary publication via sponsored Golden Open Access
Abstract:

Natural killer cell engagers gained enormous interest in recent years due to their potent anti-tumor activity and favorable safety profile. Simultaneously, chicken-derived antibodies entered clinical studies paving the way for avian-derived therapeutics. In this study, we describe the affinity maturation of a common light chain (cLC)-based, chickenderived antibody targeting EGFR, followed by utilization of the same light chain for the isolation of CD16a- and PD-L1-specific monoclonal antibodies. The resulting binders target their respective antigen with single-digit nanomolar affinity while blocking the ligand binding of all three respective receptors. Following library-based humanization, bispecific and trispecific variants in a standard 1 + 1 or a 2 + 1 common light chain format were generated, simultaneously targeting EGFR, CD16a, and PD-L1. The trispecific antibody mediated an elevated antibody-dependent cellular cytotoxicity (ADCC) in comparison to the EGFR×CD16a bispecific variant by effectively bridging EGFR/PD-L1 double-positive cancer cells with CD16a-positive effector cells. These findings represent, to our knowledge, the first detailed report on the generation of a trispecific 2 + 1 antibodies exhibiting a common light chain and illustrate synergistic effects of trispecific antigen binding. Overall, this generic procedure paves the way for the engineering of tri- and oligospecific therapeutic antibodies derived from avian immunizations.

Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-193648
Additional Information:

Keywords: bispecific antibody, trispecific antibody, NK cell engager, checkpoint inhibitor, common light chain

Classification DDC: 500 Science and mathematics > 540 Chemistry
Divisions: 07 Department of Chemistry > Clemens-Schöpf-Institut > Fachgebiet Biochemie
Date Deposited: 25 Aug 2021 12:33
Last Modified: 14 Nov 2023 19:04
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/19364
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