Pre-clinical assessment of SAR442257, a CD38/CD3xCD28 trispecific T cell engager in treatment of relapsed/refractory multiple myeloma
Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different k...
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| Hauptverfasser: | , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
20 May 2024
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| In: |
Cells
Year: 2024, Jahrgang: 13, Heft: 10, Pages: 1-17 |
| ISSN: | 2073-4409 |
| DOI: | 10.3390/cells13100879 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.3390/cells13100879 Verlag, kostenfrei, Volltext: https://www.mdpi.com/2073-4409/13/10/879 
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| Verfasserangaben: | Anna Luise Grab, Peter S. Kim, Lukas John, Kamlesh Bisht, Hongfang Wang, Anja Baumann, Helgi Van de Velde, Irene Sarkar, Debarati Shome, Philipp Reichert, Calin Manta, Stefanie Gryzik, Rogier M. Reijmers, Niels Weinhold and Marc S. Raab |
MARC
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| 245 | 1 | 0 | |a Pre-clinical assessment of SAR442257, a CD38/CD3xCD28 trispecific T cell engager in treatment of relapsed/refractory multiple myeloma |c Anna Luise Grab, Peter S. Kim, Lukas John, Kamlesh Bisht, Hongfang Wang, Anja Baumann, Helgi Van de Velde, Irene Sarkar, Debarati Shome, Philipp Reichert, Calin Manta, Stefanie Gryzik, Rogier M. Reijmers, Niels Weinhold and Marc S. Raab |
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| 520 | |a Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson's r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-β (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-β inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells. | ||
| 650 | 4 | |a ADP-ribosyl Cyclase 1 | |
| 650 | 4 | |a BCC | |
| 650 | 4 | |a Antibodies, Bispecific | |
| 650 | 4 | |a CD28 Antigens | |
| 650 | 4 | |a CD3 Complex | |
| 650 | 4 | |a cell avidity | |
| 650 | 4 | |a Cell Line, Tumor | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a Membrane Glycoproteins | |
| 650 | 4 | |a microenvironment | |
| 650 | 4 | |a Multiple Myeloma | |
| 650 | 4 | |a Recurrence | |
| 650 | 4 | |a refractory multiple myeloma | |
| 650 | 4 | |a T cell engager | |
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