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

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          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 (EC 50killing) 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.

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          Functions of natural killer cells.

          Eric Vivier, Elena Tomasello, Myriam Baratin … (2008)
          Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.
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            Natural killer cells and other innate lymphoid cells in cancer

            Eric Vivier, Pierre-Yves Dumas, Margaux Vienne … (2018)
            Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.
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              Bispecific antibodies: a mechanistic review of the pipeline

              Aran F Labrijn, Maarten Janmaat, Janice M. Reichert … (2019)
              The term bispecific antibody (bsAb) is used to describe a large family of molecules designed to recognize two different epitopes or antigens. BsAbs come in many formats, ranging from relatively small proteins, merely consisting of two linked antigen-binding fragments, to large immunoglobulin G (IgG)-like molecules with additional domains attached. An attractive bsAb feature is their potential for novel functionalities - that is, activities that do not exist in mixtures of the parental or reference antibodies. In these so-called obligate bsAbs, the physical linkage of the two binding specificities creates a dependency that can be temporal, with binding events occurring sequentially, or spatial, with binding events occurring simultaneously, such as in linking an effector to a target cell. To date, more than 20 different commercialized technology platforms are available for bsAb creation and development, 2 bsAbs are marketed and over 85 are in clinical development. Here, we review the current bsAb landscape from a mechanistic perspective, including a comprehensive overview of the pipeline.
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                Author and article information

                Contributors
                Stefan Zielonka:
                ORCID: https://orcid.org/0000-0002-4649-2843
                stefan.zielonka@merckgroup.com
                Journal
                Journal ID (nlm-ta): Protein Sci
                Journal ID (iso-abbrev): Protein Sci
                Journal ID (doi): 10.1002/(ISSN)1469-896X
                Journal ID (publisher-id): PRO
                Title: Protein Science : A Publication of the Protein Society
                Publisher: John Wiley & Sons, Inc. (Hoboken, USA )
                ISSN (Print): 0961-8368
                ISSN (Electronic): 1469-896X
                Publication date (Electronic): 24 February 2023
                Publication date Collection: March 2023
                Publication date PMC-release: 24 February 2023
                Volume: 32
                Issue: 3 ( doiID: 10.1002/pro.v32.3 )
                Electronic Location Identifier: e4593
                Affiliations
                [ 1 ] Protein Engineering and Antibody Technologies Merck Healthcare KGaA Darmstadt Germany
                [ 2 ] Institute for Organic Chemistry and Biochemistry Technical University of Darmstadt Darmstadt Germany
                [ 3 ] Division of Antibody‐Based Immunotherapy, Department of Internal Medicine II University Hospital Schleswig‐Holstein and Christian‐Albrechts‐University Kiel Kiel Germany
                [ 4 ] Protein and Cell Sciences Merck Healthcare KGaA Darmstadt Germany
                [ 5 ] Computational Chemistry and Biology Merck Healthcare KGaA Darmstadt Germany
                Author notes
                [*] [* ] Correspondence

                Stefan Zielonka, Protein Engineering and Antibody Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, D‐64293 Darmstadt, Germany.

                Email: stefan.zielonka@ 123456merckgroup.com

                Author information
                https://orcid.org/0000-0002-4649-2843
                Article
                Publisher ID: PRO4593
                DOI: 10.1002/pro.4593
                PMC ID: 9951198
                PubMed ID: 36775946
                SO-VID: 3831715c-19c6-450a-b280-9c2cd50f0c5d
                Copyright © © 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date revision received : 07 February 2023
                Date received : 25 November 2022
                Date accepted : 09 February 2023
                Page count
                Figures: 4, Tables: 2, Pages: 16, Words: 10948
                Categories
                Subject: Full‐length Paper
                Subject: Full‐length Papers
                Custom metadata
                source-schema-version-number 2.0
                cover-date March 2023
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.5 mode:remove_FC converted:24.02.2023

                ScienceOpen disciplines: Biochemistry
                Keywords: adcc,antibody engineering,bispecific antibody,multifunctional antibody,nk cell engager,nk cell redirection,nkp46,single domain antibody,valencies,vhh
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: adcc, antibody engineering, bispecific antibody, multifunctional antibody, nk cell engager, nk cell redirection, nkp46, single domain antibody, valencies, vhh

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