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The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells

Authors :
Moritz Bewarder
Maximilian Kiefer
Helene Will
Kathrin Olesch
Clara Moelle
Stephan Stilgenbauer
Konstantinos Christofyllakis
Dominic Kaddu-Mulindwa
Joerg Thomas Bittenbring
Natalie Fadle
Evi Regitz
Lea Kaschek
Markus Hoth
Frank Neumann
Klaus-Dieter Preuss
Michael Pfreundschuh
Lorenz Thurner
Source :
HemaSphere, Vol 5, Iss 8, p e620 (2021)
Publication Year :
2021
Publisher :
Wiley, 2021.

Abstract

Mantle cell lymphoma (MCL) accounts for 5%–10% of all lymphomas. The disease’s genetic hallmark is the t(11; 14)(q13; q32) translocation. In younger patients, the first-line treatment is chemoimmunotherapy followed by autologous stem cell transplantation. Upon disease progression, novel and targeted agents such as the BTK inhibitor ibrutinib, the BCL-2 inhibitor venetoclax, or the combination of both are increasingly used, but even after allogeneic stem cell transplantation or CAR T-cell therapy, MCL remains incurable for most patients. Chronic antigenic stimulation of the B-cell receptor (BCR) is thought to be essential for the pathogenesis of many B-cell lymphomas. LRPAP1 has been identified as the autoantigenic BCR target in about 1/3 of all MCLs. Thus, LRPAP1 could be used to target MCL cells, however, there is currently no optimal therapeutic format to integrate LRPAP1. We have therefore integrated LRPAP1 into a concept termed BAR, for B-cell receptor antigens for reverse targeting. A bispecific BAR body was synthesized consisting of the lymphoma-BCR binding epitope of LRPAP1 and a single chain fragment targeting CD3 or CD16 to recruit/engage T or NK cells. In addition, a BAR body consisting of an IgG1 antibody and the lymphoma-BCR binding epitope of LRPAP1 replacing the variable regions was synthesized. Both BAR bodies mediated highly specific cytotoxic effects against MCL cells in a dose-dependent manner at 1–20 µg/mL. In conclusion, LRPAP1 can substitute variable antibody regions in different formats to function in a new therapeutic approach to treat MCL.

Details

Language :
English
ISSN :
25729241 and 00000000
Volume :
5
Issue :
8
Database :
Directory of Open Access Journals
Journal :
HemaSphere
Publication Type :
Academic Journal
Accession number :
edsdoj.5324ddacc5804349809eddbf248c6384
Document Type :
article
Full Text :
https://doi.org/10.1097/HS9.0000000000000620