Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells
Abstract Despite recent advances in the therapy of diffuse large B‐cell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after first‐line treatment. Recently, Ars2 was reported as the auto‐antigenic target of the B‐cell receptor (BCR) in approxi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-02-01
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| Series: | eJHaem |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jha2.635 |
| _version_ | 1797263317759164416 |
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| author | Maximilian Kiefer Lorenz Thurner Theresa Bock Onur Cetin Igor Kos Vadim Lesan Dominic Kaddu‐Mulindwa Joerg Thomas Bittenbring Natalie Fadle Evi Regitz Markus Hoth Frank Neumann Klaus‐Dieter Preuss Michael Pfreundschuh Konstantinos Christofyllakis Moritz Bewarder |
| author_facet | Maximilian Kiefer Lorenz Thurner Theresa Bock Onur Cetin Igor Kos Vadim Lesan Dominic Kaddu‐Mulindwa Joerg Thomas Bittenbring Natalie Fadle Evi Regitz Markus Hoth Frank Neumann Klaus‐Dieter Preuss Michael Pfreundschuh Konstantinos Christofyllakis Moritz Bewarder |
| author_sort | Maximilian Kiefer |
| collection | DOAJ |
| description | Abstract Despite recent advances in the therapy of diffuse large B‐cell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after first‐line treatment. Recently, Ars2 was reported as the auto‐antigenic target of the B‐cell receptor (BCR) in approximately 25% of activated B‐cell DLBCL cases. Ars2 could be used to specifically target B cells expressing Ars2‐reactive BCRs. However, the optimal therapeutic format to integrate Ars2 into has yet to be determined. To mimic therapeutic antibody formats, Ars2‐containing bispecific and IgG1‐like constructs (BCR antigens for reverse [BAR]‐bodies) were developed. Two bispecific BAR‐bodies connecting single‐chain antibodies against CD16 or CD3 to the BCR‐binding epitope of Ars2 were constructed. Both constructs showed strong binding to U2932 cells and induced effector cell‐dependent and selective cytotoxicity against U2932 cells of up to 44% at concentrations of 20 μg/ml. Additionally, IgG1‐format Ars2 BAR‐bodies were constructed by replacing the variable heavy‐ and light‐chain regions of a full‐length antibody with the Ars2 epitope. IgG1‐format Ars2 BAR‐bodies also bound selectively to U2932 and OCI‐Ly3 cells and induced selective cytotoxicity of up to 60% at 10 μg/ml. In conclusion, Ars2‐containing bispecific and IgG1‐format BAR‐bodies both are new therapeutic formats to target DLBCL cells. |
| first_indexed | 2024-03-12T14:06:30Z |
| format | Article |
| id | doaj.art-3a0abd5820a6499887da9e481226713c |
| institution | Directory Open Access Journal |
| issn | 2688-6146 |
| language | English |
| last_indexed | 2024-04-25T00:11:05Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj.art-3a0abd5820a6499887da9e481226713c2024-03-13T13:30:47ZengWileyeJHaem2688-61462023-02-014112513410.1002/jha2.635Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cellsMaximilian Kiefer0Lorenz Thurner1Theresa Bock2Onur Cetin3Igor Kos4Vadim Lesan5Dominic Kaddu‐Mulindwa6Joerg Thomas Bittenbring7Natalie Fadle8Evi Regitz9Markus Hoth10Frank Neumann11Klaus‐Dieter Preuss12Michael Pfreundschuh13Konstantinos Christofyllakis14Moritz Bewarder15Internal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyBiophysics, CIPMM Saarland University Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyInternal Medicine I Saarland University Medical Center Homburg GermanyAbstract Despite recent advances in the therapy of diffuse large B‐cell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after first‐line treatment. Recently, Ars2 was reported as the auto‐antigenic target of the B‐cell receptor (BCR) in approximately 25% of activated B‐cell DLBCL cases. Ars2 could be used to specifically target B cells expressing Ars2‐reactive BCRs. However, the optimal therapeutic format to integrate Ars2 into has yet to be determined. To mimic therapeutic antibody formats, Ars2‐containing bispecific and IgG1‐like constructs (BCR antigens for reverse [BAR]‐bodies) were developed. Two bispecific BAR‐bodies connecting single‐chain antibodies against CD16 or CD3 to the BCR‐binding epitope of Ars2 were constructed. Both constructs showed strong binding to U2932 cells and induced effector cell‐dependent and selective cytotoxicity against U2932 cells of up to 44% at concentrations of 20 μg/ml. Additionally, IgG1‐format Ars2 BAR‐bodies were constructed by replacing the variable heavy‐ and light‐chain regions of a full‐length antibody with the Ars2 epitope. IgG1‐format Ars2 BAR‐bodies also bound selectively to U2932 and OCI‐Ly3 cells and induced selective cytotoxicity of up to 60% at 10 μg/ml. In conclusion, Ars2‐containing bispecific and IgG1‐format BAR‐bodies both are new therapeutic formats to target DLBCL cells.https://doi.org/10.1002/jha2.635autoantigenBAR‐bodiesB cellsB‐cell receptorlymphoid malignancies |
| spellingShingle | Maximilian Kiefer Lorenz Thurner Theresa Bock Onur Cetin Igor Kos Vadim Lesan Dominic Kaddu‐Mulindwa Joerg Thomas Bittenbring Natalie Fadle Evi Regitz Markus Hoth Frank Neumann Klaus‐Dieter Preuss Michael Pfreundschuh Konstantinos Christofyllakis Moritz Bewarder Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells eJHaem autoantigen BAR‐bodies B cells B‐cell receptor lymphoid malignancies |
| title | Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells |
| title_full | Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells |
| title_fullStr | Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells |
| title_full_unstemmed | Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells |
| title_short | Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells |
| title_sort | ars2 containing bispecific fab and igg1 format bar bodies to target dlbcl cells |
| topic | autoantigen BAR‐bodies B cells B‐cell receptor lymphoid malignancies |
| url | https://doi.org/10.1002/jha2.635 |
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