RETRACTED ARTICLE: SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide

Abstract

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.

The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor–Mediated Cross-Linking

“…However, on the Burkitt's lymphoma cell line Ramos we did show caspase-3 activation upon cross-linking of DARA with secondary Ab (8). The homotypic aggregation-related caspase-independent and -dependent PCD was also shown for SAR650984, a chimeric CD38 Ab (40,41), in the absence of secondary cross-linking. Nonetheless, we have previously shown that the direct effect of SAR650984 to induce PCD is comparable to DARA-induced PCD in the presence of a secondary Ab (8).…”

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

“…CD38, which is frequently expressed in MM cells, is also induced during OC formation, as analyzed by immunoblotting ( Figure 1C and 6A) and flow cytometry ( Figure 6B). Because anti-CD38 mAbs recently showed a clinical benefit in relapsed and refractory MM patients, 29,30 we further addressed whether an anti-CD38 mAb SAR650984 (SAR) 31 has any impact on OCs. We cultured CD14…”

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“…Isa, like dara, induces MM cell lysis via multiple effector cell-dependent mechanisms including antibody-dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and antibody-dependent phagocytosis (ADCP). In contrast to dara, isa directly kills MM cells via lysosomemediated cell death and apoptosis in the absence of Fc cross-linking agents or effector cells [3]. Furthermore, this direct toxicity is preferentially seen in myeloma cells expressing elevated levels of CD38 regardless of p53 mutations, which are common in the setting of RRMM.…”