Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Multiple Myeloma*/drug therapy ; Multiple Myeloma*/pathology ; Multiple Myeloma*/immunology ; ADP-ribosyl Cyclase 1*/metabolism ; ADP-ribosyl Cyclase 1*/antagonists & inhibitors ; T-Lymphocytes*/immunology ; T-Lymphocytes*/metabolism ; T-Lymphocytes*/drug effects; Humans ; CD3 Complex/metabolism ; CD28 Antigens/metabolism ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; Cell Line, Tumor ; Recurrence

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.

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ExU 6.1.25 Flagship initiative for engineering molecular systems, University Heidelberg, Germany

Keywords: T cell engager; cell avidity; microenvironment; refractory multiple myeloma

EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
0 (CD3 Complex)
0 (CD28 Antigens)
0 (Antibodies, Bispecific)

Date Created: 20240524 Date Completed: 20240524 Latest Revision: 20240526

20240526

PMC11120574

10.3390/cells13100879

38786100