BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone

Moreaux, Jérôme; Legouffe, Eric; Jourdan, Éric; Quittet, Philippe; Rème, Thierry; Lugagne, Cécile; Moine, Philippe; Rossi, Jean‐François; Klein, Bernard; Tarte, Karin

doi:10.1182/blood-2003-06-1984

Cited by 501 publications

(482 citation statements)

References 74 publications

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“…Soluble APRIL and BCMA have only a minor impact on BI 836909 activity Presence of soluble forms of APRIL 15 and BCMA 20 in the serum of MM patients have been described. A cytotoxicity assay with NCI-H929 and purified T cells in the presence and absence of pathological APRIL levels (100 ng/ml) showed that cytolytic activity of BI 836909 is not impacted in the presence of recombinant APRIL (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

“…13,14 BCMA is expressed on MM cell lines and malignant plasma cells with high prevalence and increased expression levels during disease progression from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma to active MM. [15][16][17][18][19][20][21] BCMA is also expressed on plasmacytoid dendritic cells, which promote MM cell growth, survival and drug resistance. [21][22][23] Expression levels on plasmacytoid dendritic cells are also elevated in MM patients versus normal donors.…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

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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“…Whether our present data can be extended to other myeloma growth factors is under active investigation in the laboratory. Two recent studies demonstrated that APRIL, a growth factor for myeloma cells (Moreaux et al, 2004), can bind HSPG (Hendriks et al, 2005;Ingold et al, 2005). One study reported that IL-6, the major known MMC growth factor (Klein et al, 1989), is a heparin-binding cytokine and that a heparin mimetic inhibits the biological activity of IL-6 and the binding to its receptors (Mummery and Rider, 2000).…”

Section: Discussionmentioning

confidence: 99%

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

et al. 2006

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The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro.To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-a were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) -neuregulin-1, amphiregulin, HB-EGF -promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10 5 molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.

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“…In multiple myeloma cells, Mcl-1 expression is highly regulated by IL-6 through the Janus kinase/signal transducersn and activators of transcription pathway (Puthier et al, 1999), although it could become IL-6 independent as disease progresses (Jourdan et al, 2003;Zhang et al, 2003). Mcl-1 expression is also upregulated by a interferon, vascular endothelial growth factor, Baff and April (Jourdan et al, 2000;Le Gouill et al, 2004;Moreaux et al, 2004). Mitochondrial Mcl-1 is mainly associated with Bim (Gomez-Bougie et al, 2005b), a BH3-only protein involved in cytokinedependent survival pathways (Opferman et al, 2003).…”

Section: Mitochondrial Changes Upon Malignant Transformationmentioning

confidence: 99%

Mitochondria in hematopoiesis and hematological diseases

et al. 2006

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BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone

Cited by 501 publications

References 74 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

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

Mitochondria in hematopoiesis and hematological diseases

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