The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells. Issue 8 (13th August 2021)

• Record Type: Journal Article
• Authors: Bewarder, Moritz; Kiefer, Maximilian; Will, Helene; Olesch, Kathrin; Moelle, Clara; Stilgenbauer, Stephan; Christofyllakis, Konstantinos; Kaddu-Mulindwa, Dominic; Bittenbring, Joerg Thomas; Fadle, Natalie; Regitz, Evi; Kaschek, Lea; Hoth, Markus; Neumann, Frank; Preuss, Klaus-Dieter; Pfreundschuh, Michael; Thurner, Lorenz
• Is Part Of: HemaSphere. Volume 5:Issue 8(2021)
• Page Start: e620
• Publication Date: 2021-08-13
• Subjects: Hematology -- Periodicals; 616.15005
• DOI: 10.1097/HS9.0000000000000620
• Languages: English
• ISSNs: 2572-9241

Abstract

Abstract : Supplemental Digital Content is available in the text. 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.