Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma

Palumbo, Antônio; Sonneveld, Pieter

doi:10.1586/17474086.2015.1053866

Cited by 28 publications

(17 citation statements)

References 67 publications

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“…MM is characterized by uncontrolled proliferation of monoclonal plasma cells in the bone marrow, resulting in the over-production of monoclonal immunoglobulin and immunosuppression, as well as osteolysis and end-organ damage. 1 Treatment advances in the past decade have significantly improved survival of MM patients, and recently the first two monoclonal antibodies have been approved, daratumumab and elotuzumab, targeting CD38 and CS-1/SLAMF7, [2][3][4] respectively. Nonetheless, there is still unmet medical need for more effective treatments, in particular, for relapsed/refractory patients who are resistant to current therapies.…”

Section: Introductionmentioning

confidence: 99%

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

et al. 2016

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B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ε (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMApositive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/ refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

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Section: Introductionmentioning

confidence: 99%

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

et al. 2016

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“…[1][2][3][4] Most recently, elotuzumab and daratumumab targeting cell surface antigens SLAMF7 and CD38, respectively, have been US Food and Drug Administration approved to treat relapsed and refractory MM. 1,2,5 Ongoing efforts are focusing on developing more effective immunotherapies targeting selective tumor antigens while simultaneously enhancing immune function in patients. One such selective antigen is B-cell maturation antigen (BCMA), a cell surface glycoprotein 6 and non-tyrosine kinase receptor exclusively expressed on all MM cell lines and patient MM cells at high levels.…”

Section: Introductionmentioning

confidence: 99%

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Tai

Acharya

et al. 2016

Blood

277

242

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Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM

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“…CD38 is a cell surface glycoprotein, highly expressed on PCs in the bone marrow and is involved in activating signal transduction and calcium-based signaling [34]. Similarly, SLAMF7 is a glycoprotein expressed on most clonal PCs in MM and NK cells but not on normal tissues that enables selective killing of myeloma cells with minimal effects on healthy tissue [35]. The various clinical trials evaluating the efficacy of both monoclonal antibodies are listed in Table 5.…”

Section: • Monoclonal Antibodiesmentioning

confidence: 99%

The next generation of novel therapies for the management of relapsed multiple myeloma

Gonsalves

Milani

Derudas³

et al. 2016

Future Oncol.

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The advent of various novel therapies such as immunomodulators and proteasome inhibitors has transformed the treatment paradigm for patients with multiple myeloma (MM). As a result, the overall survival has improved dramatically over the last decade. Despite these advances, MM remains mostly incurable and most patients experience disease relapse after enjoying a period of disease control or remission. Fortunately, the scientific community continues to make strides in developing ‘next-generation’ therapies for the management of patients with relapsed MM. This review will summarize the efficacy of some of the newest therapeutic agents available for the treatment of patients with relapsed MM after their upfront treatment with the original novel agents such as thalidomide, lenalidomide and bortezomib.

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Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma

Cited by 28 publications

References 67 publications

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

The next generation of novel therapies for the management of relapsed multiple myeloma

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