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A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes

The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to mAbs, improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in compar...

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Autores principales: Vukovic, Natasa, Halabi, Samer, Russo-Cabrera, Joan Salvador, Blokhuis, Bart, Berraondo, Pedro, Redegeld, Frank A.M., Zaiss, Dietmar M.W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293656/
https://www.ncbi.nlm.nih.gov/pubmed/35718062
http://dx.doi.org/10.1016/j.jbc.2022.102153
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author Vukovic, Natasa
Halabi, Samer
Russo-Cabrera, Joan Salvador
Blokhuis, Bart
Berraondo, Pedro
Redegeld, Frank A.M.
Zaiss, Dietmar M.W.
author_facet Vukovic, Natasa
Halabi, Samer
Russo-Cabrera, Joan Salvador
Blokhuis, Bart
Berraondo, Pedro
Redegeld, Frank A.M.
Zaiss, Dietmar M.W.
author_sort Vukovic, Natasa
collection PubMed
description The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to mAbs, improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in comparison to IgG isotypes, IgE has been shown to offer superior tumor control in preclinical models. Therefore, in order to combine the promising potential of IgE molecules with increased target selectivity of bsAbs, we developed dual tumor-associated antigen-targeting bispecific human IgE antibodies. As proof of principle, we used two different pairing approaches - knobs-into-holes and leucine zipper–mediated pairing. Our data show that both strategies were highly efficient in driving bispecific IgE formation, with no undesired pairings observed. Bispecific IgE antibodies also showed a dose-dependent binding to their target antigens, and cell bridging experiments demonstrated simultaneous binding of two different antigens. As antibodies mediate a major part of their effector functions through interaction with Fc receptors (FcRs) expressed on immune cells, we confirmed FcεR binding by inducing in vitro mast cell degranulation and demonstrating in vitro and in vivo monocyte-mediated cytotoxicity against target antigen-expressing Chinese hamster ovary cells. Moreover, we demonstrated that the IgE bsAb construct was significantly more efficient in mediating antibody-dependent cell toxicity than its IgG1 counterpart. In conclusion, we describe the successful development of first bispecific IgE antibodies with superior antibody-dependent cell toxicity–mediated cell killing in comparison to IgG bispecific antibodies. These findings highlight the relevance of IgE-based bispecific antibodies for clinical application.
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spelling pubmed-92936562022-07-20 A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes Vukovic, Natasa Halabi, Samer Russo-Cabrera, Joan Salvador Blokhuis, Bart Berraondo, Pedro Redegeld, Frank A.M. Zaiss, Dietmar M.W. J Biol Chem Research Article The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to mAbs, improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in comparison to IgG isotypes, IgE has been shown to offer superior tumor control in preclinical models. Therefore, in order to combine the promising potential of IgE molecules with increased target selectivity of bsAbs, we developed dual tumor-associated antigen-targeting bispecific human IgE antibodies. As proof of principle, we used two different pairing approaches - knobs-into-holes and leucine zipper–mediated pairing. Our data show that both strategies were highly efficient in driving bispecific IgE formation, with no undesired pairings observed. Bispecific IgE antibodies also showed a dose-dependent binding to their target antigens, and cell bridging experiments demonstrated simultaneous binding of two different antigens. As antibodies mediate a major part of their effector functions through interaction with Fc receptors (FcRs) expressed on immune cells, we confirmed FcεR binding by inducing in vitro mast cell degranulation and demonstrating in vitro and in vivo monocyte-mediated cytotoxicity against target antigen-expressing Chinese hamster ovary cells. Moreover, we demonstrated that the IgE bsAb construct was significantly more efficient in mediating antibody-dependent cell toxicity than its IgG1 counterpart. In conclusion, we describe the successful development of first bispecific IgE antibodies with superior antibody-dependent cell toxicity–mediated cell killing in comparison to IgG bispecific antibodies. These findings highlight the relevance of IgE-based bispecific antibodies for clinical application. American Society for Biochemistry and Molecular Biology 2022-06-16 /pmc/articles/PMC9293656/ /pubmed/35718062 http://dx.doi.org/10.1016/j.jbc.2022.102153 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Vukovic, Natasa
Halabi, Samer
Russo-Cabrera, Joan Salvador
Blokhuis, Bart
Berraondo, Pedro
Redegeld, Frank A.M.
Zaiss, Dietmar M.W.
A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes
title A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes
title_full A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes
title_fullStr A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes
title_full_unstemmed A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes
title_short A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes
title_sort human ige bispecific antibody shows potent cytotoxic capacity mediated by monocytes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293656/
https://www.ncbi.nlm.nih.gov/pubmed/35718062
http://dx.doi.org/10.1016/j.jbc.2022.102153
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