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

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

doi:10.1097/HS9.0000000000000620

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

Hemasphere. 2021 Jul 13;5(8):e620. doi: 10.1097/HS9.0000000000000620. eCollection 2021 Aug.

Authors

Moritz Bewarder^{1

2}, Maximilian Kiefer^{1

2}, Helene Will¹, Kathrin Olesch¹, Clara Moelle¹, Stephan Stilgenbauer^{1

2}, Konstantinos Christofyllakis^{1

2}, Dominic Kaddu-Mulindwa², Joerg Thomas Bittenbring^{1

2}, Natalie Fadle¹, Evi Regitz¹, Lea Kaschek³, Markus Hoth³, Frank Neumann¹, Klaus-Dieter Preuss¹, Michael Pfreundschuh^{1

2}, Lorenz Thurner^{1

2}

Affiliations

¹ José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical Center, Homburg, Germany.
² Internal Medicine I, Saarland University Medical Center, Homburg, Germany.
³ Biophysics, CIPMM, Saarland University, Homburg, Germany.

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.