Antibody targeting of B-cell maturation antigen on malignant plasma cells

Ryan, Maureen C.; Hering, Michelle A.; Peckham, D. W.; McDonagh, Charlotte F.; Brown, Lindsay L.; Kim, Kristine M.; Meyer, Damon L.; Zabinski, Roger F.; Grewal, Iqbal S.; Carter, Paul J.

doi:10.1158/1535-7163.mct-07-0464

Cited by 80 publications

(55 citation statements)

References 54 publications

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“…Biotechnology companies are devoting intense efforts to develop therapeutic molecules that target autoreactive or malignant B cells through the neutralization of APRIL or its partner Blys in autoimmune diseases, non-Hodgkin's lymphoma, multiple myeloma and B-CLL. 8,14 In xenograft models of lung and colon cancer, intratumoral delivery of soluble BCMA was able to significantly reduce tumor growth. 8 The increased cell death induced by chemotherapeutic drugs in AML cells upon inhibition of the APRIL circuit suggests that pharmacological strategies aimed at blocking of APRIL activity may considerably improve the efficacy of chemotherapeutic drugs in myeloid leukemia.…”

Section: Resultsmentioning

confidence: 99%

Blocking the APRIL circuit enhances acute myeloid leukemia cell chemosensitivity

Bonci¹,

Musumeci²,

Coppola³

et al. 2008

Haematologica

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Resistance to chemotherapy-induced cell death represents a major obstacle in the treatment of acute myeloid leukemia. APRIL (A Proliferation Inducing Ligand) is a member of the tumor necrosis factor superfamily that plays a key role in normal B-cell development, while promoting survival and proliferation of malignant B cells. We investigated APRIL expression and activity in acute myeloid leukemia. We found that APRIL mRNA and protein, including the secreted form, are expressed in leukemic cells of patients with M0, M2 and M4 acute myeloid leukemia subtypes but not in normal hematopoietic progenitors. Retrovirus-mediated APRIL expression in normal hematopoietic progenitors confers resistance to chemotherapeutic drugs-induced apoptosis. Conversely, blocking APRIL function by recombinant soluble APRIL receptors increased chemotherapeutic drugs-induced cell adeath in acute myeloid leukemia cells. These results indicate that APRIL acts in an autocrine fashion to protect acute myeloid leukemia cells from drug-induced death and foresee a therapeutic potential of APRIL antagonists in the treatment of acute myeloid leukemia.

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Section: Resultsmentioning

confidence: 99%

Blocking the APRIL circuit enhances acute myeloid leukemia cell chemosensitivity

Bonci¹,

Musumeci²,

Coppola³

et al. 2008

Haematologica

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“…37 However, point mutations in the Fc could potentially result in undesired effects such as increased immunogenicity or decreased stability. In contrast, removal of fucose does not affect mAb stability and is unlikely to change the immunogenicity in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The in vivo efficacy of SG1-vcMMAF is unknown because no in vivo study was reported. 37 On the other hand, because BCMA is absent in memory B cells, any possible immunosuppressive effects by J6M0-mcMMAF would be likely to be transient and reversible.…”

Section: Discussionmentioning

confidence: 99%

Novel anti–B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma

Tai

Mayes

Acharya

et al. 2014

Blood

386

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• Selective myeloma cell killing and enhanced effector function of a novel anti-BCMA antibody conjugated with MMAF via noncleavable linker.• Specific multiple myeloma antigen for monoclonal antibody-based immunotherapy.B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G 2 /M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer. (Blood. 2014;123(20):3128-3138) IntroductionAlthough there is no monoclonal antibody (mAb)-based targeted therapy approved to treat patients with multiple myeloma (MM), many mAbs targeting different antigens have been preclinically and clinically evaluated. ) were either moved toward or remain in clinical development based on encouraging results from preclinical studies. However, these antigens still lack specificity and are also expressed in other normal tissues including natural killer (NK) or other effectors, which could limit their clinical utility. Therefore, novel therapeutic mAbs to achieve improved MM selectivity, simultaneously targeting cytotoxic drugs to MM cells, are urgently needed.B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), is selectively induced during plasma cell differentiation and is nearly absent on naive and memory B cells. 13,14 Upon binding to its ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), the survival of bone marrow (BM) plasma cells and plasmablasts is promoted.15,16 BCMA does not maintain normal B-cell homeostasis, but is required for the survival of long-lived plasma cells. 17 In MM, BCMA messenger RNA (mRNA) is commonly expressed at high levels in malignant plasma...

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“…We showed that enzastaurin may affect interactions between plasma cells and the bone marrow microenvironment and pathways that are mainly involved in the pathogenesis and progression of MM. Some molecules involved in these pathways and highlighted in our study, such as BCMA, BAFF and APRIL, have already been identified as potential therapeutic targets [16][17][18]. Noteworthy is the downregulation of IRF4 following enzastaurin treatment, on the light of the recent evidence of the crucial pathogenetic role of IRF4 in malignant plasma cells [14].…”

Section: Amo1 Kms-18 and Mm1s Cell Lines (mentioning

confidence: 59%

Molecular targeting of the PKC‐β inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression

Verdelli

Nobili

Todoerti

et al. 2008

Hematological Oncology

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The protein kinase C (PKC) pathway has been shown to play a role in the regulation of cell proliferation in several haematological malignancies, including multiple myeloma (MM). Recent data have shown that a PKC inhibitor, enzastaurin, has antiproliferative and proapoptotic activity in a large panel of human myeloma cell lines (HMCLs). In order to further characterise the effect of enzastaurin in MM, we performed gene expression profiling of enzastaurin-treated KMS-26 cell line. We identified 62 upregulated and 32 downregulated genes that are mainly involved in cellular adhesion (CXCL12, CXCR4), apoptosis (CTSB, TRAF5, BCL2L1), cell proliferation (IGF1, GADD45A, BCMA (B-cell maturation antigen), CDC20), transcription regulation (MYC, MX11, IRF4), immune and defence responses. Subsequent validation by Western blotting of selected genes in four enzastaurin-treated HMCLs was consistent with our microarray analysis. Our data indicate that enzastaurin may affect important processes involved in the proliferation and survival of malignant plasma cells as well as in their interactions with the bone marrow microenvironment and provide a preclinical rationale for the potential role of this drug in the treatment of MM.

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Antibody targeting of B-cell maturation antigen on malignant plasma cells

Cited by 80 publications

References 54 publications

Blocking the APRIL circuit enhances acute myeloid leukemia cell chemosensitivity

Blocking the APRIL circuit enhances acute myeloid leukemia cell chemosensitivity

Novel anti–B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma

Molecular targeting of the PKC‐β inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression

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