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

Autor:	Birley K; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Leboreiro-Babe C; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Rota EM; The Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Buschhaus M; The Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Gavriil A; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Vitali A; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Alonso-Ferrero M; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Hopwood L; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Parienti L; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Ferry G; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Flutter B; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Himoudi N; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK., Chester K; The Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Anderson J; Zayed Centre for Research, University College London, 20c Guildford Street, London WC1N 1DZ, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy oncolytics [Mol Ther Oncolytics] 2022 Aug 25; Vol. 26, pp. 429-443. Date of Electronic Publication: 2022 Aug 25 (Print Publication: 2022).
DOI:	10.1016/j.omto.2022.08.008
Abstrakt:	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. Competing Interests: John Anderson declares founder shares in Autolus Ltd and collaborations with Roche and ALX-Oncology. (© 2022 The Author(s).)
Databáze:	MEDLINE
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