The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and –independent mechanisms

Pazina, Tatiana; James, Ashley M.; Macfarlane, Alexander W.; Bezman, Natalie; Henning, Karla A.; Bee, Christine; Graziano, Robert F.; Robbins, Michael; Cohen, Adam D.; Campbell, Kerry S.

doi:10.1080/2162402x.2017.1339853

Cited by 66 publications

(83 citation statements)

References 49 publications

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“…HuLuc63 was also shown to induce similar lysis of patient myeloma cells by NK cells from allogeneic healthy donors as compared to NK cells from the same MM patient, even in patients who were resistant to conventional therapy ( 18 ). Furthermore, HuLuc63 was significantly more effective in inducing ADCC responses by NK cells than another chimerized SLAMF7 antibody (human IgG1-human Fc/mouse variable regions) named ChLuc90 ( 18 , 19 , 39 ). Tai et al also demonstrated that HuLuc63 stimulated ADCC responses by NK cells from healthy donors to a variety of myeloma cell lines, and they further showed strong ADCC of autologous myeloma cells by NK cells from MM patients, even if patients were resistant to conventional therapies ( 19 ).…”

Section: Elotuzumab As a New Therapeutic To Target Multiple Myelomamentioning

confidence: 99%

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

2018

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Multiple myeloma (MM) is a bone marrow plasma cell neoplasm and is the second most-common hematologic malignancy. Despite advances in therapy, MM remains largely incurable. Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7, which is highly expressed on myeloma cells, and the antibody is approved for the treatment of relapsed and/or refractory (RR) MM in combination with lenalidomide and dexamethasone. Elotuzumab can stimulate robust antibody-dependent cellular cytotoxicity (ADCC) through engaging with FcγRIIIA (CD16) on NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Interestingly, SLAMF7 is also expressed on cytolytic NK cells, which also express the requisite adaptor protein, EAT-2, to mediate activation signaling. Accumulating evidence indicates that antibody crosslinking of SLAMF7 on human and mouse NK cells can stimulate EAT-2-dependent activation of PLCγ, ERK, and intracellular calcium mobilization. The binding of SLAMF7 by elotuzumab can directly induce signal transduction in human NK cells, including co-stimulation of the calcium signaling triggered through other surface receptors, such as NKp46 and NKG2D. In RRMM patients, elotuzumab monotherapy did not produce objective responses, but did enhance the activity of approved standard of care therapies, including lenalidomide or bortezomib, which are known to enhance anti-tumor responses by NK cells. Taken together, these preclinical results and accumulating experience in the clinic provide compelling evidence that the mechanism of action of elotuzumab in MM patients involves the activation of NK cells through both CD16-mediated ADCC and direct co-stimulation via engagement with SLAMF7, as well as promoting ADCP by macrophages. We review the current understanding of how elotuzumab utilizes multiple mechanisms to facilitate immune-mediated attack of myeloma cells, as well as outline goals for future research.

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Section: Elotuzumab As a New Therapeutic To Target Multiple Myelomamentioning

confidence: 99%

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

2018

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“…Since SLAMF7 is also expressed on NK cells, the cross-linking of SLAMF7 on NK cells by a treatment with elotuzumab induces NK cell activation via immunoreceptor tyrosine-based switch motifs (ITSM)-mediated signaling. These ITSM-mediated signaling enhances calcium signaling from ITAM-linked activating receptor, through an interaction between NKp46 and NKG2D and their ligands expressed on myeloma cells [142] or stimulates macrophage-mediated ADCP [143]. The phase III ELOQUENT-2 study (elotuzumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone) reported a 29% reduction in risk of death or disease progression at 4 years in the elotuzumab arm of the trial [144] (Table S1).…”

Section: Inkt and Nk Cell-mediated Immunotherapymentioning

confidence: 99%

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.

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“…Elotuzumab is a humanized IgG-1 monoclonal antibody targeting SLAMF7 that promotes NK-mediated ADCC, directly activates NK cells and interferes with the MM cell adhesion to the bone marrow stromal cells [63][64][65]. Elotuzumab showed no clinically meaningful activity when administered as a single agent-in a phase I dose-escalating study, the best response achieved by RRMM patients treated at different doses of elotuzumab was stable disease (SD, 26%) [66] (Table 3).…”

Section: Clinical Developmentmentioning

confidence: 99%

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Bonello

Mina

Boccadoro

2019

Cancers

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Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs ® ), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.Cancers 2020, 12, 15 2 of 24 Cancers 2020, 12, 15 3 of 24 (Bregs, which promote tumor growth and immune escape), as well as a subset of regulatory T cells (Tregs) express CD38, and their levels are reduced after daratumumab exposure. Conversely, daratumumab results in significant expansion of CD8+ cytotoxic and CD4+ helper T cells, likely following the depletion of regulatory cells. Remarkably, expanded effector T cells also show increased killing capacity due to augmented levels of granzyme B, which activates caspases and triggers cell apoptosis [23][24][25]. In addition, among the activities promoted by CD38, there is a nicotinamide adenine dinucleotide (NAD)-ase activity, which results in reduced levels of NAD+ in T cells, responsible for the loss of their effector functions (exhausted T cells). In murine models, anti-CD38 mAbs administration induced higher levels of NAD+ in T effector cells, thus enhancing their antitumor activity [23]. The main mechanisms of action of anti-CD38 monoclonal antibodies are summarized in Figure 1.

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The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and –independent mechanisms

Cited by 66 publications

References 49 publications

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

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