SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma
| العنوان: | SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma |
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| المؤلفون: | Alain Fournier, Marielle Chiron, Nadège Carrié, Sukhvinder Sidhu, Marine Cuisinier, Sahar Kassem, Dmitri Wiederschain, Hélène Bonnevaux, Jean-Luc Teillaud, Ludovic Martinet, Helgi van de Velde, Jill Corre, Isabelle Arnould, Béré K. Diallo, Nizar El-Murr, Céline Nicolazzi, Angela Virone-Oddos, Hervé Avet-Loiseau, Alexandre Tang |
| المصدر: | Blood. 139:1160-1176 |
| بيانات النشر: | American Society of Hematology, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | medicine.drug_class, Immunology, Bone Marrow Cells, Mice, Transgenic, CD38, Monoclonal antibody, Biochemistry, Antineoplastic Agents, Immunological, Cell Line, Tumor, medicine, Animals, Humans, Receptor, Isatuximab, Antibody-dependent cell-mediated cytotoxicity, Membrane Glycoproteins, biology, Chemistry, Degranulation, Daratumumab, Cell Biology, Hematology, ADP-ribosyl Cyclase 1, Xenograft Model Antitumor Assays, Neoplasm Proteins, HEK293 Cells, Cancer research, biology.protein, Antibody, Multiple Myeloma |
| الوصف: | Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients’ primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients’ primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM. |
| تدمد: | 1528-0020 0006-4971 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ed0517bb90aadd5eef0a42bc69ee4141 https://doi.org/10.1182/blood.2021012448 |
| رقم الأكسشن: | edsair.doi.dedup.....ed0517bb90aadd5eef0a42bc69ee4141 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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