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

Birley, K; Leboreiro-Babe, C; Rota, EM; Buschhaus, M; Gavriil, A; Vitali, A; Alonso-Ferrero, M; ... Anderson, J; + view all (2022) A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers. Molecular Therapy - Oncolytics , 26 pp. 429-443. 10.1016/j.omto.2022.08.008. Green open access

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Abstract

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.

Type: Article
Title: A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.omto.2022.08.008
Publisher version: https://doi.org/10.1016/j.omto.2022.08.008
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10156355
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