SAR-442257

T cell–engaging antibodies (TCEs) are showing promising efficacy in relapsed/refractory multiple myeloma, even in patients that relapsed after B-cell maturation antigen (BCMA)-targeted therapy. Patients with multiple myeloma may have compromised T-cell health unaccounted for by preclinical models. Here, we use Myeloma Drug Sensitivity Testing (My-DST) for ex vivo measurement of anti-multiple myeloma cytotoxicity for the trispecific CD38/CD28xCD3 TCE SAR442257 through activation of the patients’ own endogenous T cells to inform clinical development of the compound in multiple myeloma. My-DST incubates primary mononuclear cells in humanized media for 48 hours followed by flow cytometry for multiple myeloma cell viability with or without drug treatment. SAR442257 was tested on 34 samples from patients with multiple myeloma across disease settings. Potential biomarkers, T-cell dependence, and degranulation were assessed. SAR442257 was effective at low dose in My-DST cultures. High ex vivo response rates were observed in primary aspirates taken from patients with multiple myeloma at diagnosis, with modestly reduced response in multiple myeloma recently treated with anti-CD38 mAbs. SAR442257 was highly effective in patients relapsing after BCMA therapy. The CD38/CD28xCD3 trispecific format was substantially more effective than a conventional bispecific CD38/CD3 antibody format and CD38 mAbs. Anti-multiple myeloma cell cytotoxicity was dependent on the presence of endogenous T cells. Surface CD38 expression was the strongest biomarker of TCE response. My-DST is capable of measuring T cell–dependent killing using the multiple myeloma patient's own bone marrow–derived T cells. SAR442257 shows promise for multiple myeloma and may be best suited for patients declared resistant to both CD38 mAbs and BCMA-targeted therapy.

This study introduces the use of My-DST to measure and characterize sensitivity to anti-CD38 T-cell engager SAR442257 in primary samples using matched endogenous T cells. Preclinical testing in samples from patients with diverse treatment history supports further testing in post-chimeric antigen receptor T-cell 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 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.