SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma

• Published in: Blood Vol. 139; no. 8; pp. 1160 - 1176
• Main Authors: Kassem, Sahar, Diallo, Béré K., El-Murr, Nizar, Carrié, Nadège, Tang, Alexandre, Fournier, Alain, Bonnevaux, Hélène, Nicolazzi, Céline, Cuisinier, Marine, Arnould, Isabelle, Sidhu, Sukhvinder S., Corre, Jill, Avet-Loiseau, Hervé, Teillaud, Jean-Luc, van de Velde, Helgi, Wiederschain, Dmitri, Chiron, Marielle, Martinet, Ludovic, Virone-Oddos, Angela
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24-02-2022; American Society of Hematology
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - metabolism; Animals; Antineoplastic Agents, Immunological - pharmacology; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cell Line, Tumor; HEK293 Cells; Humans; Life Sciences; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - metabolism; Mice, Transgenic; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021012448

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.
•SAR442085 is a novel Fc-engineered anti-CD38 monoclonal antibody with enhanced affinity for FcγRIIa and FcγRIIIa receptors.•SAR442085 has higher NK cell-dependent in vitro and in vivo antimyeloma efficacy than standard-of-care daratumumab and isatuximab.
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