TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignancies

JCI Insight
Mahiuddin AhmedNai-Kong V Cheung

Abstract

EBV infection is associated with a number of malignancies of clinical unmet need, including Hodgkin lymphoma, nasopharyngeal carcinoma, gastric cancer, and posttransplant lymphoproliferative disease (PTLD), all of which express the EBV protein latent membrane protein 2A (LMP2A), an antigen that is difficult to target by conventional antibody approaches. To overcome this, we utilized phage display technology and a structure-guided selection strategy to generate human T cell receptor-like (TCR-like) monoclonal antibodies with exquisite specificity for the LMP2A-derived nonamer peptide, C426LGGLLTMV434 (CLG), as presented on HLA-A*02:01. Our lead construct, clone 38, closely mimics the native binding mode of a TCR, recognizing residues at position P3-P8 of the CLG peptide. To enhance antitumor potency, we constructed dimeric T cell engaging bispecific antibodies (DiBsAb) of clone 38 and an affinity-matured version clone 38-2. Both DiBsAb showed potent antitumor properties in vitro and in immunodeficient mice implanted with EBV transformed B lymphoblastoid cell lines and human T cell effectors. Clone 38 DiBsAb showed a stronger safety profile compared with its affinity-matured variant, with no activity against EBV- tumor cell lines...Continue Reading

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Citations

Mar 14, 2020·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jeong A Park, Nai-Kong V Cheung
Jun 2, 2020·Biological & Pharmaceutical Bulletin·Tomohiro ShirayanagiKousei Ito
Sep 24, 2019·Antibodies·Lene Støkken HøydahlGeir Åge Løset
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Mar 3, 2021·Science·Jon Weidanz
Apr 27, 2021·Monoclonal Antibodies in Immunodiagnosis and Immunotherapy·Velizar Shivarov, Georgi Blazhev
Jan 21, 2019·Antibody Therapeutics·Yixiang XuZhiqiang An
May 15, 2021·Human Vaccines & Immunotherapeutics·Sylvia Annabel DassVenugopal Balakrishnan
Sep 28, 2021·Drug Discovery Today·John S SchardtPeter M Tessier

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Methods Mentioned

BETA
phage display
xenograft
FACS
size-exclusion chromatography
ELISA
electrophoresis
surface plasmon resonance
chips
flow cytometry

Software Mentioned

BIAevaluation
Living Image
Genewiz
Flowjo
Prism
GraphPad
Discovery Studio
CHARMM
Biovia

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