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Activation of distinct antiviral T-cell immunity: A comparison of bi- and trispecific T-cell engager antibodies with a chimeric antigen receptor targeting HBV envelope proteins
Bilge Debelec-Butuner 1 2 , Oliver Quitt 1 , Sophia Schreiber 1 , Frank Momburg 3 , Karin Wisskirchen 1 4 , Ulrike Protzer 1 4
Affiliations
Affiliations
1
Institute of Virology, School of Medicine, Technical University of Munich/Helmholtz Centre Munich, Munich, Germany.
2
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Izmir, Turkey.
3
Antigen Presentation and T/NK Cell Activation Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Centre, Heidelberg, Germany.
4
German Centre for Infection Research (DZIF), Munich partner site, Munich, Germany.
PMID: 36405686 PMCID: PMC9670976 DOI: 10.3389/fimmu.2022.1029214
Abstract
Despite the availability of an effective prophylactic vaccine, 820,000 people die annually of hepatitis B virus (HBV)-related liver disease according to WHO. Since current antiviral therapies do not provide a curative treatment for the 296 million HBV carriers around the globe, novel strategies to cure HBV are urgently needed. A promising approach is the redirection of T cells towards HBV-infected hepatocytes employing chimeric antigen receptors or T-cell engager antibodies. We recently described the effective redirection of T cells employing a second-generation chimeric antigen receptor directed against the envelope protein of hepatitis B virus on the surface of infected cells (S-CAR) as well as bispecific antibodies that engage CD3 or CD28 on T cells employing the identical HBV envelope protein (HBVenv) binder. In this study, we added a trispecific antibody comprising all three moieties to the tool-box. Cytotoxic and non-cytolytic antiviral activities of these bi- and trispecific T-cell engager antibodies were assessed in co-cultures of human PBMC with HBV-positive hepatoma cells, and compared to that of S-CAR-grafted T cells. Activation of T cells via the S-CAR or by either a combination of the CD3- and CD28-targeting bispecific antibodies or the trispecific antibody allowed for specific elimination of HBV-positive target cells. While S-CAR-grafted effector T cells displayed faster killing kinetics, combinatory treatment with the bispecific antibodies or single treatment with the trispecific antibody was associated with a more pronounced cytokine release. Clearance of viral antigens and elimination of the HBV persistence form, the covalently closed circular (ccc) DNA, through cytolytic as well as cytokine-mediated activity was observed in all three settings with the combination of bispecific antibodies showing the strongest non-cytolytic, cytokine-mediated antiviral effect. Taken together, we demonstrate that bi- and trispecific T-cell engager antibodies can serve as a potent, off-the-shelf alternative to S-CAR-grafted T cells to cure HBV.
Keywords: HBV cure; T-cell engager antibody; adoptive T-cell therapy; chimeric antigen receptor; chronic hepatitis B; drug development; immunotherapy.
Copyright © 2022 Debelec-Butuner, Quitt, Schreiber, Momburg, Wisskirchen and Protzer.
Conflict of interest statement
UP and FM are named as inventors on the patent WO 2015/036606 held by HMGU and DKFZ. UP, FM, and OQ are named as inventors on the patent WO 2016/146702 held by HMGU, DKFZ and TUM. UP serves as ad hoc advisor for Abbott, Aligos, Arbutus, Gilead, GSK, Merck, Sanofi, Roche and VirBiotech. UP is co-founder and share-holder of SCG Cell Therapy who licensed patents WO 2015/036606 and WO 2016/146702. KW is Managing Director/Head of Research and share-holder of SCG Cell Therapy Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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发表于 2022-11-22 12:33