{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:39:50Z","timestamp":1791434390784,"version":"4.3.3"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T00:00:00Z","timestamp":1716163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sanofi","award":["ExU 6.1.25"],"award-info":[{"award-number":["ExU 6.1.25"]}]},{"name":"Excellence Strategy of the Flagship Initiative Engineering Molecular Systems (University Heidelberg, Germany)","award":["ExU 6.1.25"],"award-info":[{"award-number":["ExU 6.1.25"]}]},{"name":"Dietmar-Hopp Foundation","award":["ExU 6.1.25"],"award-info":[{"award-number":["ExU 6.1.25"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2019s r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-\u03b2 (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-\u03b2 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.<\/jats:p>","DOI":"10.3390\/cells13100879","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T03:26:27Z","timestamp":1716261987000},"page":"879","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Pre-Clinical Assessment of SAR442257, a CD38\/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed\/Refractory Multiple Myeloma"],"prefix":"10.3390","volume":"13","author":[{"given":"Anna Luise","family":"Grab","sequence":"first","affiliation":[{"name":"Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"},{"name":"Clinical Cooperation Unit Molecular Hematology\/Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Sanofi Research and Development, Sanofi North America, Cambridge, MA 02141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8178-6890","authenticated-orcid":false,"given":"Lukas","family":"John","sequence":"additional","affiliation":[{"name":"Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"},{"name":"Clinical Cooperation Unit Molecular Hematology\/Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamlesh","family":"Bisht","sequence":"additional","affiliation":[{"name":"Sanofi Research and Development, Sanofi North America, Cambridge, MA 02141, 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Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc S.","family":"Raab","sequence":"additional","affiliation":[{"name":"Heidelberg Myeloma Center, Department of Medicine V, Medical Faculty Heidelberg and University Hospital, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"},{"name":"Clinical Cooperation Unit Molecular Hematology\/Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41408-023-00804-y","article-title":"Clinical evidence for immune-based strategies in early-line multiple myeloma: Current challenges in decision-making for subsequent therapy","volume":"13","author":"Raje","year":"2023","journal-title":"Blood Cancer 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