Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myeloma
Abstract Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti‐MM activity of engineered toxin body MT‐0169, a next‐generation immunotox...
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| Format: | Article |
| Language: | English |
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Wiley
2024-11-01
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| Series: | HemaSphere |
| Online Access: | https://doi.org/10.1002/hem3.70039 |
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| author | Wassilis S. C. Bruins Rosa Rentenaar John Newcomb Wenrou Zheng Ruud W. J. Ruiter Thomas Baardemans Eric Poma Chris Moore Garrett L. Robinson Anya Lublinsky Yuhong Zhang Sakeena Syed Michael Milhollen Ajeeta B. Dash Niels W. C. J. van deDonk Richard W. J. Groen Sonja Zweegman Tuna Mutis |
| author_facet | Wassilis S. C. Bruins Rosa Rentenaar John Newcomb Wenrou Zheng Ruud W. J. Ruiter Thomas Baardemans Eric Poma Chris Moore Garrett L. Robinson Anya Lublinsky Yuhong Zhang Sakeena Syed Michael Milhollen Ajeeta B. Dash Niels W. C. J. van deDonk Richard W. J. Groen Sonja Zweegman Tuna Mutis |
| author_sort | Wassilis S. C. Bruins |
| collection | DOAJ |
| description | Abstract Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti‐MM activity of engineered toxin body MT‐0169, a next‐generation immunotoxin comprising a CD38‐specific antibody fragment linked to a de‐immunized Shiga‐like toxin A subunit (SLTA) payload. We show that specific binding of MT‐0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co‐culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT‐0169. In the preclinical setting, MT‐0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT‐0169 showed efficient in vivo anti‐MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow‐like niche. These findings support clinical investigation of MT‐0169 in relapsed/refractory MM patients, including those refractory to CD38‐targeting immunotherapies. |
| format | Article |
| id | doaj-art-a8979c0c00ea435fb33c791621bce91e |
| institution | Kabale University |
| issn | 2572-9241 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj-art-a8979c0c00ea435fb33c791621bce91e2024-11-26T10:54:29ZengWileyHemaSphere2572-92412024-11-01811n/an/a10.1002/hem3.70039Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myelomaWassilis S. C. Bruins0Rosa Rentenaar1John Newcomb2Wenrou Zheng3Ruud W. J. Ruiter4Thomas Baardemans5Eric Poma6Chris Moore7Garrett L. Robinson8Anya Lublinsky9Yuhong Zhang10Sakeena Syed11Michael Milhollen12Ajeeta B. Dash13Niels W. C. J. van deDonk14Richard W. J. Groen15Sonja Zweegman16Tuna Mutis17Amsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsTakeda Development Center Americas, Inc. Cambridge Massachusetts USAAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsMolecular Templates, Inc. Austin Texas USAMolecular Templates, Inc. Austin Texas USAMolecular Templates, Inc. Austin Texas USATakeda Development Center Americas, Inc. Cambridge Massachusetts USATakeda Development Center Americas, Inc. Cambridge Massachusetts USATakeda Development Center Americas, Inc. Cambridge Massachusetts USATakeda Development Center Americas, Inc. Cambridge Massachusetts USATakeda Development Center Americas, Inc. Cambridge Massachusetts USAAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsAmsterdam UMC location Vrije Universiteit Amsterdam, Hematology Amsterdam NetherlandsAbstract Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti‐MM activity of engineered toxin body MT‐0169, a next‐generation immunotoxin comprising a CD38‐specific antibody fragment linked to a de‐immunized Shiga‐like toxin A subunit (SLTA) payload. We show that specific binding of MT‐0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co‐culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT‐0169. In the preclinical setting, MT‐0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT‐0169 showed efficient in vivo anti‐MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow‐like niche. These findings support clinical investigation of MT‐0169 in relapsed/refractory MM patients, including those refractory to CD38‐targeting immunotherapies.https://doi.org/10.1002/hem3.70039 |
| spellingShingle | Wassilis S. C. Bruins Rosa Rentenaar John Newcomb Wenrou Zheng Ruud W. J. Ruiter Thomas Baardemans Eric Poma Chris Moore Garrett L. Robinson Anya Lublinsky Yuhong Zhang Sakeena Syed Michael Milhollen Ajeeta B. Dash Niels W. C. J. van deDonk Richard W. J. Groen Sonja Zweegman Tuna Mutis Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myeloma HemaSphere |
| title | Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myeloma |
| title_full | Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myeloma |
| title_fullStr | Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myeloma |
| title_full_unstemmed | Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myeloma |
| title_short | Preclinical evaluation of the CD38‐targeting engineered toxin body MT‐0169 against multiple myeloma |
| title_sort | preclinical evaluation of the cd38 targeting engineered toxin body mt 0169 against multiple myeloma |
| url | https://doi.org/10.1002/hem3.70039 |
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