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Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory
Anna Luise Grab1,2, Peter S Kim3, Lukas John1,2
1Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Abstract:
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.
Insights
The novel trispecific antibody SAR442257 enhances T cell activity against relapsed/refractory multiple myeloma (RRMM) by targeting CD38 and CD28. It shows promise, especially when combined with TGF-β inhibition for refractory patients.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Multiple myeloma (MM) treatments are effective, but relapsed/refractory MM (RRMM) remains a challenge.
- Aberrant CD28 co-expression is frequent in RRMM, presenting a therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of the anti-CD38/CD3xCD28 trispecific antibody SAR442257 in RRMM.
- To investigate biomarkers of drug potency and identify resistance mechanisms.
Main Methods:
- Assessed T cell (TC) avidity, tumor killing, and biomarker expression in RRMM patient cohorts.
- Compared SAR442257 activity against bispecific knockout controls.
- Investigated the role of TGF-β and the efficacy of TGF-β inhibitor vactoserib.
Main Results:
- 86% of RRMM patients showed aberrant CD28 co-expression versus 19% of newly diagnosed MM (NDMM) patients.
- SAR442257 significantly enhanced TC activation and MM killing (Pearson's r = 0.7).
- Patients refractory to anti-CD38 therapy had elevated TGF-β, which was overcome by vactoserib.
Conclusions:
- SAR442257 demonstrates potential for enhancing T cell cytotoxicity in RRMM.
- Co-targeting CD38 and CD28 on MM cells and T cells offers a promising therapeutic strategy.
- TGF-β inhibition may be crucial for overcoming resistance to SAR442257 in specific patient populations.
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