Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma
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,
Marc S. Raab
Affiliations
Anna Luise Grab
Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Peter S. Kim
Sanofi Research and Development, Sanofi North America, Cambridge, MA 02141, USA
Lukas John
Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Kamlesh Bisht
Sanofi Research and Development, Sanofi North America, Cambridge, MA 02141, USA
Hongfang Wang
Sanofi Research and Development, Sanofi North America, Cambridge, MA 02141, USA
Anja Baumann
Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Helgi Van de Velde
Sanofi Research and Development, Sanofi North America, Cambridge, MA 02141, USA
Irene Sarkar
LUMICKS, 1059 CM Amsterdam, The Netherlands
Debarati Shome
LUMICKS, 1059 CM Amsterdam, The Netherlands
Philipp Reichert
GMMG Central Study Lab, Biobank, University Hospital Heidelberg, 69120 Heidelberg, Germany
Calin Manta
Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Stefanie Gryzik
Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Rogier M. Reijmers
LUMICKS, 1059 CM Amsterdam, The Netherlands
Niels Weinhold
Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Marc S. Raab
Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
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.
