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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274796/
https://www.ncbi.nlm.nih.gov/pubmed/34263144
http://dx.doi.org/10.1097/HS9.0000000000000620
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author 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
author_facet 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
author_sort Bewarder, Moritz
collection PubMed
description 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.
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spelling pubmed-82747962021-07-13 The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells 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 Hemasphere Article 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. Lippincott Williams & Wilkins 2021-07-13 /pmc/articles/PMC8274796/ /pubmed/34263144 http://dx.doi.org/10.1097/HS9.0000000000000620 Text en Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC) (https://creativecommons.org/licenses/by-nc/4.0/) , where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
spellingShingle Article
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
The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
title The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
title_full The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
title_fullStr The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
title_full_unstemmed The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
title_short The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
title_sort b-cell receptor autoantigen lrpap1 can replace variable antibody regions to target mantle cell lymphoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274796/
https://www.ncbi.nlm.nih.gov/pubmed/34263144
http://dx.doi.org/10.1097/HS9.0000000000000620
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