Clinical potential of SLAMF7 antibodies - focus on elotuzumab in multiple myeloma.
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SUBMITTER: Friend R
PROVIDER: S-EPMC5367738 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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Clinical potential of SLAMF7 antibodies - focus on elotuzumab in multiple myeloma.
Friend Reed R Bhutani Manisha M Voorhees Peter M PM Usmani Saad Z SZ
Drug design, development and therapy 20170320
Elotuzumab is one of the first monoclonal antibodies to be approved for the treatment of multiple myeloma. It is a humanized immunoglobulin G kappa (IgGκ) antibody that targets signaling lymphocytic activation molecule family member 7 (SLAMF7), a surface marker that is highly expressed on normal and malignant plasma cells. This review summarizes the preclinical and clinical data that led to the approval of elotuzumab, along with a discussion on the ongoing and future clinical investigations. ...[more]
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Project description:Elotuzumab is a humanized monoclonal antibody targeting the extracellular domain of signaling lymphocytic activation molecule F7 (SLAMF7) highly expressed in multiple myeloma cells. Upon binding to myeloma cells, elotuzumab exerts its cytotoxic effects through antibody-dependent cellular cytotoxicity, the antibody-induced selective lysis of tumor cells by activated natural killer (NK) cells. Furthermore, elotuzumab has been shown to directly induce NK-cell activation by binding to SLAMF7 expressed on NK cells and to indirectly modulate T-cell function by promoting the secretion of cytokines from NK cells. In combination with lenalidomide and low-dose dexamethasone, elotuzumab has shown remarkable effects in patients with relapsed or refractory multiple myeloma. In these patients, the risk of disease progression or death was significantly reduced by 30% on elotuzumab. Currently, elotuzumab is being evaluated in various myeloma patient populations and combination regimens. This review discusses the use of elotuzumab as an antimultiple myeloma agent and provides an update on the results of recent clinical trials evaluating the safety and efficacy of elotuzumab for the treatment of multiple myeloma.
| S-EPMC5026292 | biostudies-literature
Project description: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 Fc?RIIIA (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 PLC?, 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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Project description:Elotuzumab (Elo) is an IgG1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, and CD319), which is highly expressed on multiple myeloma (MM) cells, natural killer (NK) cells, and subsets of other leukocytes. By engaging with FcγRIIIA (CD16), Elo promotes potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) toward SLAMF7+ MM tumor cells. Relapsed/refractory MM patients treated with the combination of Elo, lenalidomide, and dexamethasone have improved progression-free survival. We previously showed that Elo enhances NK cell activity via a costimulation mechanism, independent of CD16 binding. Here, we further studied the effect of Elo on cytotoxicity of CD16-negative NK-92 cells. Elo, but not other SLAMF7 antibodies, uniquely enhanced cytotoxicity mediated by CD16-negative NK-92 cells toward SLAMF7+ target cells. Furthermore, this CD16-independent enhancement of cytotoxicity required expression of SLAMF7 containing the full cytoplasmic domain in the NK cells, implicating costimulatory signaling. The CD16-independent costimulation by Elo was associated with increased expression of NKG2D, ICAM-1, and activated LFA-1 on NK cells, and enhanced cytotoxicity was partially reduced by NKG2D blocking antibodies. In addition, an Fc mutant form of Elo that cannot bind CD16 promoted cytotoxicity of SLAMF7+ target cells by NK cells from most healthy donors, especially if previously cultured in IL2. We conclude that in addition to promoting NK cell-mediated ADCC (CD16-dependent) responses, Elo promoted SLAMF7-SLAMF7 interactions in a CD16-independent manner to enhance NK cytotoxicity toward MM cells.
| S-EPMC6774869 | biostudies-literature
Project description:The signaling lymphocytic activation molecule family (SLAMF7; also known as CS1 or CD319) is highly expressed on plasma cells from multiple myeloma (MM) as well as natural killer (NK) cells and is a well-known therapeutic target of elotuzumab. The objective of this study was to evaluate the clinical significance of serum soluble SLAMF7 (sSLAMF7) levels in patients with MM (n=103) and furthermore the impact of sSLMF7 on the antitumor activity of anti-SLAMF7 antibody. Thirty-one percent of MM patients, but not patients with monoclonal gammopathy of undetermined significance and healthy controls, had detectable levels of serum sSLAMF7, which were significantly increased in advanced MM patients. Further, MM in sSLAMF7-postive patients exhibited aggressive clinical characteristics with shorter progression-free survival times in comparison with sSLAMF7-negative patients. In responders to MM therapy, the levels of sSLAMF7 were undetectable or decreased compared with those before treatment. In addition, the anti-SLAMF7 antibody-mediated antibody-dependent cellular cytotoxicity of NK cells against MM cell lines was inhibited by recombinant SLAMF7 protein. Thus, our findings suggest that high concentrations of sSLAMF7, which could transiently suppress the therapeutic effects of elotuzumab, may be a useful indicator of disease progression in MM patients.
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Project description:Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.
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Project description:Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone (ELd) for relapsed/refractory multiple myeloma (MM) based on the findings of the phase III randomized trial ELOQUENT-2 (NCT01239797). Four-year follow-up analyses of ELOQUENT-2 have demonstrated that progression-free survival was 21% in ELd versus 14% in Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of action: natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and enhancement of NK cell activity. The ADCC is mediated through engagement between Fc portion of elotuzumab and FcgRIIIa/CD16 on NK cells. Enhanced NK cell cytotoxicity results from phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) that is induced via elotuzumab binding and recruits the SLAM-associated adaptor protein EAT-2. The coupling of EAT-2 to the phospholipase Cg enzymes SH2 domain leads to enhanced Ca2+ influx and MAPK/Erk pathway activation, resulting in granule polarization and enhanced exocytosis in NK cells. Elotuzumab does not stimulate the proliferation of MM cells due to a lack of EAT-2. The inhibitory effects of elotuzumab on MM cell growth are not induced by the lack of CD45, even though SHP-2, SHP-1, SHIP-1, and Csk may be recruited to phosphorylated ITSM of SLAMF7. ELd improves PFS in patients with high-risk cytogenetics, i.e. t(4;14), del(17p), and 1q21 gain/amplification. Since the immune state is paralytic in advanced MM, the efficacy of ELd with minimal toxicity may bring forward for consideration of its use in the early stages of the disease.
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Project description:Although the introduction of novel drugs has improved outcome significantly in multiple myeloma (MM), many patients still eventually relapse. Monoclonal antibodies (mAbs) targeting MM-related antigens can complement currently available therapies. CS1 (also known as CD2 subunit 1, SLAMF7, CD319, and CRACC), a cell surface glycoprotein receptor that is a member of the signaling lymphocytic activation molecule (SLAM) family, is highly and nearly uniformly expressed in myeloma cells at the gene and protein level, but not expressed in other tissues, including hematopoietic stem cells, making CS1 a compelling target for the design of immunotherapies directed at MM. Elotuzumab (formerly HuLuc63), which is a humanized IgG1 mAb recognizing the extracellular region of human CS1, has been shown to be effective in preclinical and early stage clinical investigations, and its efficacy and safety will be further validated in ongoing Phase III trials. Integration of elotuzumab into multidrug therapeutic paradigms seems logical, as elotuzumab is more effective when combined with other agents, such as immunomodulatory drugs or proteasome inhibitors. The functional role of CS1 in MM pathogenesis and the consequences of elotuzumab on normal immune cells should be further investigated. Identification of potential biomarkers and exploration of resistance mechanisms are important issues for elotuzumab-based therapies, as is determining the best clinical placement of elotuzumab, not only in the relapsed/refractory setting but also in upfront therapy for high-risk frank MM, smoldering MM at high-risk of progression, and in maintenance regimens. This review will cover the biological characteristics of CS1 in normal immune cells and MM cells, the efficacy profile and mechanisms of action of elotuzumab from preclinical and clinical investigations, and its potential impact on the treatment of MM.
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Project description:Elotuzumab is one of the first two monoclonal antibodies that gained FDA approval for the treatment of multiple myeloma (MM). It targets SLAMF7, which is highly expressed in normal plasma and MM cells as well as natural killer (NK) cells. Elotuzumab demonstrated significant anti-myeloma activity in preclinical studies, and its mechanisms of action include mediating antibody-dependent cell-mediated cytotoxicity, enhancing cytotoxicity of NK cells, and inhibiting MM cell interaction with bone marrow stromal cells. In clinical trials, elotuzumab in combination with immunomodulatory drugs and proteasome inhibitors has demonstrated an excellent efficacy and safety profile in treating MM.
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Project description:Elotuzumab is a monoclonal antibody directed against the SLAMF7 receptor, expressed on normal and malignant plasma cells with a lower expression on other lymphoid cells such as natural killer (NK) cells. Elotuzumab has no significant antimyeloma activity when given as a single agent to patients with relapsed or refractory multiple myeloma (RRMM). However, when combined with other antimyeloma agents, it results in improved response and outcome. Owing to the results from the landmark ELOQUENT-2 phase III clinical trial, which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab in combination with lenalidomide and dexamethasone was approved by the American Food and Drug Administration (FDA) in November 2015 for multiple myeloma (MM) patients who received one to three prior lines of therapy. This review will give a brief description of the signaling lymphocytic activation molecule (SLAM) family receptors, the unique SLAMF7 receptor and the mechanism of action of elotuzumab. Thereafter, we will give an overview on its antimyeloma activity in preclinical and clinical trials, including its toxicity profile and management thereof.
| S-EPMC4959642 | biostudies-literature
Project description:Multiple myeloma is a common plasma cell malignancy with a median overall survival of fewer than 10 years. Proteasome inhibitors comprise an important part of the treatment regimen for this disease. The present study reports the case of a 57-year-old man who experienced a second relapse of multiple myeloma 6 years after initial treatment with bortezomib, lenalidomide, dexamethasone (VRD) followed by autologous hematopoietic cell transplant. The first relapse had been successfully treated with VRD, but this approach failed to control his second relapse. Given the lack of response to VRD therapy and relapse while on bortezomib maintenance, the patient was deemed proteasome inhibitor-refractory and received a new treatment of elotuzumab, lenalidomide, and dexamethasone. Four and a half cycles were completed before the treatment was stopped due to grade 4 cytopenias. The patient received a novel combination of elotuzumab, bortezomib, nelfinavir, and dexamethasone. After six cycles, the serum M-protein level was improved to 0.6 g/dL and the kappa light chains dropped from 3.49 to 1.04 mg/dL. A bone marrow biopsy conducted after five treatment cycles demonstrated < 1% plasma cells by immunohistochemistry and achievement of minimal residual disease status. Overall, this case study suggests that proteasome inhibitor-refractory multiple myeloma may be successfully re-treated with proteasome inhibitors when co-administered with nelfinavir.
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