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DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies
Tetraspanin CD37 has recently received renewed interest as a therapeutic target for B-cell malignancies. Although complement-dependent cytotoxicity (CDC) is a powerful Fc-mediated effector function for killing hematological cancer cells, CD37-specific antibodies are generally poor inducers of CDC. T...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186228/ https://www.ncbi.nlm.nih.gov/pubmed/32341336 http://dx.doi.org/10.1038/s41408-020-0292-7 |
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author | Oostindie, Simone C. van der Horst, Hilma J. Kil, Laurens P. Strumane, Kristin Overdijk, Marije B. van den Brink, Edward N. van den Brakel, Jeroen H. N. Rademaker, Hendrik J. van Kessel, Berris van den Noort, Juliette Chamuleau, Martine E. D. Mutis, Tuna Lindorfer, Margaret A. Taylor, Ronald P. Schuurman, Janine Parren, Paul W. H. I. Beurskens, Frank J. Breij, Esther C. W. |
author_facet | Oostindie, Simone C. van der Horst, Hilma J. Kil, Laurens P. Strumane, Kristin Overdijk, Marije B. van den Brink, Edward N. van den Brakel, Jeroen H. N. Rademaker, Hendrik J. van Kessel, Berris van den Noort, Juliette Chamuleau, Martine E. D. Mutis, Tuna Lindorfer, Margaret A. Taylor, Ronald P. Schuurman, Janine Parren, Paul W. H. I. Beurskens, Frank J. Breij, Esther C. W. |
author_sort | Oostindie, Simone C. |
collection | PubMed |
description | Tetraspanin CD37 has recently received renewed interest as a therapeutic target for B-cell malignancies. Although complement-dependent cytotoxicity (CDC) is a powerful Fc-mediated effector function for killing hematological cancer cells, CD37-specific antibodies are generally poor inducers of CDC. To enhance CDC, the E430G mutation was introduced into humanized CD37 monoclonal IgG1 antibodies to drive more efficient IgG hexamer formation through intermolecular Fc-Fc interactions after cell surface antigen binding. DuoHexaBody-CD37, a bispecific CD37 antibody with the E430G hexamerization-enhancing mutation targeting two non-overlapping epitopes on CD37 (biparatopic), demonstrated potent and superior CDC activity compared to other CD37 antibody variants evaluated, in particular ex vivo in patient-derived chronic lymphocytic leukemia cells. The superior CDC potency was attributed to enhanced IgG hexamerization mediated by the E430G mutation in combination with dual epitope targeting. The mechanism of action of DuoHexaBody-CD37 was shown to be multifaceted, as it was additionally capable of inducing efficient antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro. Finally, potent anti-tumor activity in vivo was observed in cell line- and patient-derived xenograft models from different B-cell malignancy subtypes. These encouraging preclinical results suggest that DuoHexaBody-CD37 (GEN3009) may serve as a potential therapeutic antibody for the treatment of human B-cell malignancies. |
format | Online Article Text |
id | pubmed-7186228 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-71862282020-04-29 DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies Oostindie, Simone C. van der Horst, Hilma J. Kil, Laurens P. Strumane, Kristin Overdijk, Marije B. van den Brink, Edward N. van den Brakel, Jeroen H. N. Rademaker, Hendrik J. van Kessel, Berris van den Noort, Juliette Chamuleau, Martine E. D. Mutis, Tuna Lindorfer, Margaret A. Taylor, Ronald P. Schuurman, Janine Parren, Paul W. H. I. Beurskens, Frank J. Breij, Esther C. W. Blood Cancer J Article Tetraspanin CD37 has recently received renewed interest as a therapeutic target for B-cell malignancies. Although complement-dependent cytotoxicity (CDC) is a powerful Fc-mediated effector function for killing hematological cancer cells, CD37-specific antibodies are generally poor inducers of CDC. To enhance CDC, the E430G mutation was introduced into humanized CD37 monoclonal IgG1 antibodies to drive more efficient IgG hexamer formation through intermolecular Fc-Fc interactions after cell surface antigen binding. DuoHexaBody-CD37, a bispecific CD37 antibody with the E430G hexamerization-enhancing mutation targeting two non-overlapping epitopes on CD37 (biparatopic), demonstrated potent and superior CDC activity compared to other CD37 antibody variants evaluated, in particular ex vivo in patient-derived chronic lymphocytic leukemia cells. The superior CDC potency was attributed to enhanced IgG hexamerization mediated by the E430G mutation in combination with dual epitope targeting. The mechanism of action of DuoHexaBody-CD37 was shown to be multifaceted, as it was additionally capable of inducing efficient antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro. Finally, potent anti-tumor activity in vivo was observed in cell line- and patient-derived xenograft models from different B-cell malignancy subtypes. These encouraging preclinical results suggest that DuoHexaBody-CD37 (GEN3009) may serve as a potential therapeutic antibody for the treatment of human B-cell malignancies. Nature Publishing Group UK 2020-04-28 /pmc/articles/PMC7186228/ /pubmed/32341336 http://dx.doi.org/10.1038/s41408-020-0292-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Oostindie, Simone C. van der Horst, Hilma J. Kil, Laurens P. Strumane, Kristin Overdijk, Marije B. van den Brink, Edward N. van den Brakel, Jeroen H. N. Rademaker, Hendrik J. van Kessel, Berris van den Noort, Juliette Chamuleau, Martine E. D. Mutis, Tuna Lindorfer, Margaret A. Taylor, Ronald P. Schuurman, Janine Parren, Paul W. H. I. Beurskens, Frank J. Breij, Esther C. W. DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies |
title | DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies |
title_full | DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies |
title_fullStr | DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies |
title_full_unstemmed | DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies |
title_short | DuoHexaBody-CD37(®), a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies |
title_sort | duohexabody-cd37(®), a novel biparatopic cd37 antibody with enhanced fc-mediated hexamerization as a potential therapy for b-cell malignancies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186228/ https://www.ncbi.nlm.nih.gov/pubmed/32341336 http://dx.doi.org/10.1038/s41408-020-0292-7 |
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