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A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers

B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role as a driver of tumor immune inhibition. Recent studies have reported B7-H3 to be a suitable target for chimeric antigen...

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Autores principales: Birley, Kathleen, Leboreiro-Babe, Clara, Rota, Enrique Miranda, Buschhaus, Magdalena, Gavriil, Artemis, Vitali, Alice, Alonso-Ferrero, Maria, Hopwood, Lee, Parienti, Lara, Ferry, Gabrielle, Flutter, Barry, Himoudi, Nourredine, Chester, Kerry, Anderson, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467911/
https://www.ncbi.nlm.nih.gov/pubmed/36159778
http://dx.doi.org/10.1016/j.omto.2022.08.008
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author Birley, Kathleen
Leboreiro-Babe, Clara
Rota, Enrique Miranda
Buschhaus, Magdalena
Gavriil, Artemis
Vitali, Alice
Alonso-Ferrero, Maria
Hopwood, Lee
Parienti, Lara
Ferry, Gabrielle
Flutter, Barry
Himoudi, Nourredine
Chester, Kerry
Anderson, John
author_facet Birley, Kathleen
Leboreiro-Babe, Clara
Rota, Enrique Miranda
Buschhaus, Magdalena
Gavriil, Artemis
Vitali, Alice
Alonso-Ferrero, Maria
Hopwood, Lee
Parienti, Lara
Ferry, Gabrielle
Flutter, Barry
Himoudi, Nourredine
Chester, Kerry
Anderson, John
author_sort Birley, Kathleen
collection PubMed
description B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role as a driver of tumor immune inhibition. Recent studies have reported B7-H3 to be a suitable target for chimeric antigen receptor-modified T cell (CAR-T) therapy using CARs constructed from established anti-B7-H3 antibodies converted into single-chain Fv format (scFv). We constructed and screened binders in an scFv library to generate a new anti-B7-H3 CAR-T with favorable properties. This allowed access to numerous specificities ready formatted for CAR evaluation. Selected anti-human B7-H3 scFvs were readily cloned into CAR-T and evaluated for anti-tumor reactivity in cytotoxicity, cytokine, and proliferation assays. Two binders with divergent complementarity determining regions were found to show optimal antigen-specific cytotoxicity and cytokine secretion. One binder in second-generation CD28-CD3ζ CAR format induced sustained in vitro proliferation on repeat antigen challenge. The lead candidate CAR-T also demonstrated in vivo activity in a resistant neuroblastoma model. An empirical approach to B7-H3 CAR-T discovery through screening of novel scFv sequences in CAR-T format has led to the identification of a new construct with sustained proliferative capacity warranting further evaluation.
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spelling pubmed-94679112022-09-22 A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers Birley, Kathleen Leboreiro-Babe, Clara Rota, Enrique Miranda Buschhaus, Magdalena Gavriil, Artemis Vitali, Alice Alonso-Ferrero, Maria Hopwood, Lee Parienti, Lara Ferry, Gabrielle Flutter, Barry Himoudi, Nourredine Chester, Kerry Anderson, John Mol Ther Oncolytics Original Article B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role as a driver of tumor immune inhibition. Recent studies have reported B7-H3 to be a suitable target for chimeric antigen receptor-modified T cell (CAR-T) therapy using CARs constructed from established anti-B7-H3 antibodies converted into single-chain Fv format (scFv). We constructed and screened binders in an scFv library to generate a new anti-B7-H3 CAR-T with favorable properties. This allowed access to numerous specificities ready formatted for CAR evaluation. Selected anti-human B7-H3 scFvs were readily cloned into CAR-T and evaluated for anti-tumor reactivity in cytotoxicity, cytokine, and proliferation assays. Two binders with divergent complementarity determining regions were found to show optimal antigen-specific cytotoxicity and cytokine secretion. One binder in second-generation CD28-CD3ζ CAR format induced sustained in vitro proliferation on repeat antigen challenge. The lead candidate CAR-T also demonstrated in vivo activity in a resistant neuroblastoma model. An empirical approach to B7-H3 CAR-T discovery through screening of novel scFv sequences in CAR-T format has led to the identification of a new construct with sustained proliferative capacity warranting further evaluation. American Society of Gene & Cell Therapy 2022-08-25 /pmc/articles/PMC9467911/ /pubmed/36159778 http://dx.doi.org/10.1016/j.omto.2022.08.008 Text en © 2022 The Author(s) 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 Original Article
Birley, Kathleen
Leboreiro-Babe, Clara
Rota, Enrique Miranda
Buschhaus, Magdalena
Gavriil, Artemis
Vitali, Alice
Alonso-Ferrero, Maria
Hopwood, Lee
Parienti, Lara
Ferry, Gabrielle
Flutter, Barry
Himoudi, Nourredine
Chester, Kerry
Anderson, John
A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
title A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
title_full A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
title_fullStr A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
title_full_unstemmed A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
title_short A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
title_sort novel anti-b7-h3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467911/
https://www.ncbi.nlm.nih.gov/pubmed/36159778
http://dx.doi.org/10.1016/j.omto.2022.08.008
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