SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide.
The anti-CD38 monoclonal antibody SAR650984 (SAR) is showing promising clinical activity in treatment of relapsed and refractory multiple myeloma (MM). Besides effector-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, we here define molecular mechanisms of SAR-directed MM cell death and enhanced anti-MM activity triggered by SAR with Pomalidomide (Pom). Without Fc-cross-linking agents or effector cells, SAR specifically induces homotypic aggregation (HA)-associated cell death in MM cells dependent on the level of cell surface CD38 expression, actin cytoskeleton and membrane lipid raft. SAR and its F(ab)'2 fragments trigger caspase 3/7-dependent apoptosis in MM cells highly expressing CD38, even with p53 mutation. Importantly, SAR specifically induces lysosome-dependent cell death (LCD) by enlarging lysosomes and increasing lysosomal membrane permeabilization associated with leakage of cathepsin B and LAMP-1, regardless of the presence of interleukin-6 or bone marrow stromal cells. Conversely, the lysosomal vacuolar H+-ATPase inhibitor blocks SAR-induced LCD. SAR further upregulates reactive oxygen species. Pom enhances SAR-induced direct and indirect killing even in MM cells resistant to Pom/Len. Taken together, SAR is the first therapeutic monoclonal antibody mediating direct cytotoxicity against MM cells via multiple mechanisms of action. Our data show that Pom augments both direct and effector cell-mediated MM cytotoxicity of SAR, providing the framework for combination clinical trials.
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Myeloma and Lymphoma Centre, Department of Hematology, Chang Zheng Hospital, The Second Military Medical University, Shanghai, China.
H
H
Jiang
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
C
C
Acharya
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
G
G
An
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
M
M
Zhong
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
X
X
Feng
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
L
L
Wang
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
N
N
Dasilva
Sanofi Oncology, Cambridge, MA, USA.
Z
Z
Song
Sanofi Oncology, Cambridge, MA, USA.
G
G
Yang
Sanofi Oncology, Cambridge, MA, USA.
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F
Adrian
Institute of Hematology, CAMS & PUMC, Tianjin, China.
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L
Qiu
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
P
P
Richardson
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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NC
Munshi
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Y-T
YT
Tai
LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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KC
Anderson
D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000199:Actins / Q000737:chemistry; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D021962:Membrane Microdomains / Q000502:physiology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
D000199:Actins; D061067:Antibodies, Monoclonal, Humanized; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D013792:Thalidomide; C467566:pomalidomide; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; C000599209:isatuximab