Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

• Published in: British journal of haematology Vol. 183; no. 2; pp. 196 - 211
• Main Authors: Paulus, Aneel, Manna, Alak, Akhtar, Sharoon, Paulus, Shumail M., Sharma, Mayank, Coignet, Marie V., Jiang, Liuyan, Roy, Vivek, Witzig, Thomas E., Ansell, Stephen M., Allan, John, Furman, Richard, Aulakh, Sonikpreet, Manochakian, Rami, Ailawadhi, Sikander, Chanan‐Khan, Asher A., Sher, Taimur
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2018
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; AKT protein; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Bruton tyrosine kinase; CD38; CD38 antigen; Cell death; Cell Line, Tumor; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; daratumumab; Hematology; Humans; ibrutinib; Lymphocytes B; Mice, Inbred NOD; Monoclonal antibodies; Phagocytosis; Phagocytosis - drug effects; Pyrazoles - administration & dosage; Pyrimidines - administration & dosage; Syk protein; Therapeutic applications; TOR protein; Tumor Cells, Cultured - drug effects; Tumors; Waldenstrom Macroglobulinemia - immunology; Waldenstrom Macroglobulinemia - pathology; Waldenstrom Macroglobulinemia - prevention & control; Waldenström macroglobulinaemia; Xenograft Model Antitumor Assays; Xenografts; ibrutinib; CD38; Bruton tyrosine kinase; daratumumab; Waldenström macroglobulinaemia
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.15515

Summary CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti‐CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib‐resistant lines) elicited antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), antibody‐dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI‐WM1‐xenografted mice. CD38 is reported to augment B‐cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib‐resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single‐agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti‐WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co‐targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.