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Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy

Cancer immunotherapy has already shown significant improvements by combining different antibodies specific for distinct immune checkpoints, such as Ipilimumab and Nivolumab. Here, we tested combinatorial treatments of immunomodulatory antibodies, previously generated in our laboratory, for their eff...

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Autores principales: Passariello, Margherita, Yoshioka, Asami, Takahashi, Kota, Hashimoto, Shu-ichi, Rapuano Lembo, Rosa, Manna, Lorenzo, Nakamura, Koji, De Lorenzo, Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998846/
https://www.ncbi.nlm.nih.gov/pubmed/35408827
http://dx.doi.org/10.3390/ijms23073466
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author Passariello, Margherita
Yoshioka, Asami
Takahashi, Kota
Hashimoto, Shu-ichi
Rapuano Lembo, Rosa
Manna, Lorenzo
Nakamura, Koji
De Lorenzo, Claudia
author_facet Passariello, Margherita
Yoshioka, Asami
Takahashi, Kota
Hashimoto, Shu-ichi
Rapuano Lembo, Rosa
Manna, Lorenzo
Nakamura, Koji
De Lorenzo, Claudia
author_sort Passariello, Margherita
collection PubMed
description Cancer immunotherapy has already shown significant improvements by combining different antibodies specific for distinct immune checkpoints, such as Ipilimumab and Nivolumab. Here, we tested combinatorial treatments of immunomodulatory antibodies, previously generated in our laboratory, for their effects on hPBMC activation, either upon stimulation with SEB or in co-cultures with tumor cells by cytokine secretion assays. We found that some of them showed additive or synergistic effects, and on the basis of these observations, we constructed, for the first time, four novel bispecific tribodies (TR), made up of a Fab derived from one anti-IC mAb and two scFvs derived from another mAb targeting a different IC. All four TRs cotargeting either programmed cell death protein 1 (PD-1) and Lymphocyte Activating 3 (LAG-3) or programmed death-ligand 1 (PD-L1) and LAG-3 retained binding affinity for their targets and the antagonistic effects of their parental mAbs, but some of them also showed an increased ability to induce lymphocyte activation and increased in vitro cytotoxicity against tumor cells compared to parental antibodies used either alone or in combinatorial treatments. Furthermore, none of the tribodies showed significant increased cytotoxicity on human cardiomyocytes. Considering that the tribody format reduces production costs (as only one construct provides the inhibitory effects of two antibodies), has an intermediate molecular size (100 kDa) which is well suited for both tumor penetration and an acceptable half-life, we think that these novel immunomodulatory TRBs have the potential to become precious tools for therapeutic applications, particularly in monotherapy-resistant cancer patients.
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spelling pubmed-89988462022-04-12 Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy Passariello, Margherita Yoshioka, Asami Takahashi, Kota Hashimoto, Shu-ichi Rapuano Lembo, Rosa Manna, Lorenzo Nakamura, Koji De Lorenzo, Claudia Int J Mol Sci Article Cancer immunotherapy has already shown significant improvements by combining different antibodies specific for distinct immune checkpoints, such as Ipilimumab and Nivolumab. Here, we tested combinatorial treatments of immunomodulatory antibodies, previously generated in our laboratory, for their effects on hPBMC activation, either upon stimulation with SEB or in co-cultures with tumor cells by cytokine secretion assays. We found that some of them showed additive or synergistic effects, and on the basis of these observations, we constructed, for the first time, four novel bispecific tribodies (TR), made up of a Fab derived from one anti-IC mAb and two scFvs derived from another mAb targeting a different IC. All four TRs cotargeting either programmed cell death protein 1 (PD-1) and Lymphocyte Activating 3 (LAG-3) or programmed death-ligand 1 (PD-L1) and LAG-3 retained binding affinity for their targets and the antagonistic effects of their parental mAbs, but some of them also showed an increased ability to induce lymphocyte activation and increased in vitro cytotoxicity against tumor cells compared to parental antibodies used either alone or in combinatorial treatments. Furthermore, none of the tribodies showed significant increased cytotoxicity on human cardiomyocytes. Considering that the tribody format reduces production costs (as only one construct provides the inhibitory effects of two antibodies), has an intermediate molecular size (100 kDa) which is well suited for both tumor penetration and an acceptable half-life, we think that these novel immunomodulatory TRBs have the potential to become precious tools for therapeutic applications, particularly in monotherapy-resistant cancer patients. MDPI 2022-03-23 /pmc/articles/PMC8998846/ /pubmed/35408827 http://dx.doi.org/10.3390/ijms23073466 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Passariello, Margherita
Yoshioka, Asami
Takahashi, Kota
Hashimoto, Shu-ichi
Rapuano Lembo, Rosa
Manna, Lorenzo
Nakamura, Koji
De Lorenzo, Claudia
Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy
title Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy
title_full Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy
title_fullStr Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy
title_full_unstemmed Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy
title_short Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy
title_sort novel bi-specific immuno-modulatory tribodies potentiate t cell activation and increase anti-tumor efficacy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998846/
https://www.ncbi.nlm.nih.gov/pubmed/35408827
http://dx.doi.org/10.3390/ijms23073466
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