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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2021
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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. |
format | Online Article Text |
id | pubmed-8274796 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
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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