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Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity

Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic c...

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Autores principales: Zaitseva, Olena, Hoffmann, Annett, Löst, Margaretha, Anany, Mohamed A., Zhang, Tengyu, Kucka, Kirstin, Wiegering, Armin, Otto, Christoph, Wajant, Harald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402896/
https://www.ncbi.nlm.nih.gov/pubmed/37545514
http://dx.doi.org/10.3389/fimmu.2023.1194610
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author Zaitseva, Olena
Hoffmann, Annett
Löst, Margaretha
Anany, Mohamed A.
Zhang, Tengyu
Kucka, Kirstin
Wiegering, Armin
Otto, Christoph
Wajant, Harald
author_facet Zaitseva, Olena
Hoffmann, Annett
Löst, Margaretha
Anany, Mohamed A.
Zhang, Tengyu
Kucka, Kirstin
Wiegering, Armin
Otto, Christoph
Wajant, Harald
author_sort Zaitseva, Olena
collection PubMed
description Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.
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spelling pubmed-104028962023-08-05 Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity Zaitseva, Olena Hoffmann, Annett Löst, Margaretha Anany, Mohamed A. Zhang, Tengyu Kucka, Kirstin Wiegering, Armin Otto, Christoph Wajant, Harald Front Immunol Immunology Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK. Frontiers Media S.A. 2023-07-11 /pmc/articles/PMC10402896/ /pubmed/37545514 http://dx.doi.org/10.3389/fimmu.2023.1194610 Text en Copyright © 2023 Zaitseva, Hoffmann, Löst, Anany, Zhang, Kucka, Wiegering, Otto and Wajant https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zaitseva, Olena
Hoffmann, Annett
Löst, Margaretha
Anany, Mohamed A.
Zhang, Tengyu
Kucka, Kirstin
Wiegering, Armin
Otto, Christoph
Wajant, Harald
Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
title Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
title_full Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
title_fullStr Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
title_full_unstemmed Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
title_short Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
title_sort antibody-based soluble and membrane-bound tweak mimicking agonists with fcγr-independent activity
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402896/
https://www.ncbi.nlm.nih.gov/pubmed/37545514
http://dx.doi.org/10.3389/fimmu.2023.1194610
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