Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

Aneel Paulus, Alak Manna, Sharoon Akhtar, Shumail M. Paulus, Mayank Sharma, Marie V. Coignet, Liuyan Jiang, Vivek Roy, Thomas Elmer Witzig, Stephen Maxted Ansell, John Allan, Richard Furman, Sonikpreet Aulakh, Rami Manochakian, Sikander Ailawadhi, Asher A Chanan Khan, Taimur Sher

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalBritish Journal of Haematology
DOIs
StateAccepted/In press - Jan 1 2018

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Waldenstrom Macroglobulinemia
Cytophagocytosis
Antibodies
B-Lymphocytes
Cell Death
Apoptosis
S 6
daratumumab
PCI 32765
Monoclonal Antibodies
Cell Line

Keywords

  • Bruton tyrosine kinase
  • CD38
  • daratumumab
  • ibrutinib
  • Waldenström macroglobulinaemia

ASJC Scopus subject areas

  • Hematology

Cite this

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells. / Paulus, Aneel; Manna, Alak; Akhtar, Sharoon; Paulus, Shumail M.; Sharma, Mayank; Coignet, Marie V.; Jiang, Liuyan; Roy, Vivek; Witzig, Thomas Elmer; Ansell, Stephen Maxted; Allan, John; Furman, Richard; Aulakh, Sonikpreet; Manochakian, Rami; Ailawadhi, Sikander; Chanan Khan, Asher A; Sher, Taimur.

In: British Journal of Haematology, 01.01.2018.

Research output: Contribution to journalArticle

Paulus, Aneel ; Manna, Alak ; Akhtar, Sharoon ; Paulus, Shumail M. ; Sharma, Mayank ; Coignet, Marie V. ; Jiang, Liuyan ; Roy, Vivek ; Witzig, Thomas Elmer ; Ansell, Stephen Maxted ; Allan, John ; Furman, Richard ; Aulakh, Sonikpreet ; Manochakian, Rami ; Ailawadhi, Sikander ; Chanan Khan, Asher A ; Sher, Taimur. / Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells. In: British Journal of Haematology. 2018.
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abstract = "CD38 is expressed on Waldenstr{\"o}m 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.",
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AU - Paulus, Aneel

AU - Manna, Alak

AU - Akhtar, Sharoon

AU - Paulus, Shumail M.

AU - Sharma, Mayank

AU - Coignet, Marie V.

AU - Jiang, Liuyan

AU - Roy, Vivek

AU - Witzig, Thomas Elmer

AU - Ansell, Stephen Maxted

AU - Allan, John

AU - Furman, Richard

AU - Aulakh, Sonikpreet

AU - Manochakian, Rami

AU - Ailawadhi, Sikander

AU - Chanan Khan, Asher A

AU - Sher, Taimur

PY - 2018/1/1

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N2 - 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.

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