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Atacicept (TACI-Ig) Inhibits Growth of TACI High Primary Myeloma Cells in SCID-Hu Mice and in Coculture with Osteoclasts

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Atacicept (TACI-Ig) Inhibits Growth of TACI High Primary Myeloma Cells in SCID-Hu Mice and in Coculture with Osteoclasts Leukemia (2008) 22, 406–413 & 2008 Nature Publishing Group All rights reserved 0887-6924/08 $30.00 www.nature.com/leu ORIGINAL ARTICLE Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts S Yaccoby1, A Pennisi1,XLi1, SR Dillon2, F Zhan1, B Barlogie1 and JD Shaughnessy Jr1 1Myeloma Institute for Research and Therapy, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA and 2ZymoGenetics Inc., Seattle, WA, USA APRIL (a proliferation-inducing Ligand) and BLyS/BAFF activity in patients with myeloma results in partial or no (B-lymphocyte stimulator/B-cell-activating factor of the TNF response,9,10 suggesting that additional growth factors and/or (tumor necrosis factor) family have been shown to be the cell-to-cell interactions may be involved in the growth and survival factors for certain myeloma cells in vitro. BAFF binds to the TNF-related receptors such as B-cell maturation antigen survival of myeloma cells within the BM. (BCMA), transmembrane activator and CAML interactor (TACI) Two TNF (tumor necrosis factor) family members known to and BAFFR, whereas APRIL binds to TACI and BCMA and to play key roles in normal B-cell biology, BLyS/BAFF (B- heparan sulfate proteoglycans (HSPG) such as syndecan-1. lymphocyte stimulator/B cell activating factor of the TNF family) TACI gene expression in myeloma reportedly can distinguish and APRIL (A PRoliferation-Inducing Ligand), also promote tumors with a signature of microenvironment dependence high low the survival of various malignant B-cell types, including (TACI ) versus a plasmablastic signature (TACI ). We 11–13 tested the effect of atacicept (formerly TACI-Ig, which blocks myeloma. BAFF binds to three TNF-R-related receptors, BCMA APRIL and BAFF) and BAFFR-Ig (which blocks BAFF only) on (B-cell maturation antigen), TACI (transmembrane activator and primary myeloma growth in the SCID-hu model and in coculture CAML interactor), and BAFFR (BAFF-receptor), whereas APRIL with osteoclasts. With only few exceptions, atacicept and to a binds to TACI and BCMA and to heparan sulfate proteoglycans high lesser extent BAFFR-Ig, inhibited growth of TACI but not (HSPG) such as syndecan-1 (CD138).11–13 All myeloma cells low TACI myeloma samples in vivo and ex vivo, and the response express high levels of syndecan-1 and one or more of these three rate was inversely correlated with TACI expression. Most TACI high myeloma cells were molecularly classified as being TNF-R-related receptors. Culture of myeloma cells with BAFF low risk with our recently described 70-gene model. APRIL and and/or APRIL leads to enhanced survival of these malignant cells 14,15 16 BAFF were highly expressed by osteoclasts and were upregu- in vitro and promotes their adhesion to stromal cells. lated in myeloma cells after coculture with osteoclasts. Our APRIL and BAFF induce myeloma cell adhesion and survival findings suggest that APRIL plays an essential role in the through activation of nuclear factor-kB (NF-kB), phosphatidyli- high survival of TACI bone marrow-dependent myeloma cells and nositol-3 (PI-3) kinase/Akt and mitogen-activated protein kinase TACI gene expression may be a useful predictive marker for (MAPK) pathways and upregulation of the antiapoptotic factors patients who could benefit from atacicept treatment. 14,16 Leukemia (2008) 22, 406–413; doi:10.1038/sj.leu.2405048; MCL-1 and BCL-2 in myeloma cells. Although myeloma published online 29 November 2007 cells can express very low levels of BAFF and APRIL, circulating Keywords: myeloma; APRIL; BAFF; TACI; gene expression; levels of these cytokines in myeloma patients is higher than that microenvironment in normal individuals, suggesting that BM microenvironmental cells are a major source of these factors in myeloma patients.14,16 It has been shown that differences in TACI gene Introduction expression can distinguish tumors with a BM microenviron- ment-dependent signature (TACIhigh) from those with a plasma- In multiple myeloma, a plasma cell malignancy, a majority of blastic signature (TACIlow),17 suggesting that TACIhigh myeloma the tumor cells reside in the hematopoietic bone marrow (BM). cells may be more sensitive to growth factor withdrawal. As a consequence of interaction with certain microenviron- Inhibition of BAFF and APRIL using a soluble receptor, TACI-Ig, mental components, myeloma cells are protected from sponta- 1,2 in culture of L363 and RPMI8226 cell lines causes cultured neous and drug-induced apoptosis. In late-stage disease, myeloma cells to die rapidly.14 In coculture of certain myeloma myeloma cells become independent of BM microenvironmental cell lines with the supporting osteoclasts or dendritic cells, signals and extramedullary disease is not uncommon. Recent TACI-Ig addition resulted in reduced myeloma cell growth and clinical studies indicate that using drugs that simultaneously diminished clonogenic potential.18,19 In the current study, we target myeloma cells and their supportive BM microenviron- further tested the involvement of APRIL and BAFF in myeloma ment (for example, thalidomide, bortezomib) provides a pathogenesis using two inhibitorsFatacicept (TACI-Ig) and promising approach to control disease progression and over- F 20,21 22,23 3,4 BAFFR-Ig in our in vivo and ex vivo experimental come drug resistance. Interaction of myeloma cells with systems for primary myeloma. Whereas atacicept binds and cellular and extracellular components results in upregulation of neutralizes both BAFF and APRIL, BAFFR-Ig blocks only BAFF y. growth factors such as interleukin (IL)-65–7 and vascular 8 For our in vivo model, SCID- (severe combined immunodefi- endothelial growth factor (VEGF). However, inhibiting their ciency) hu mice are constructed by implanting a human fetal bone into which primary human myeloma cells are directly Correspondence: Dr S Yaccoby, Myeloma Institute for Research and injected. Myeloma cells from the majority of patients interact Therapy, Department of Internal Medicine, University of Arkansas for with the human BM, grow exclusively in or on the implanted Medical Sciences, 4301 W. Markham, Slot 776, Little Rock, AR bone and produce myeloma manifestations, including stimula- 72205, USA. E-mail: [email protected] tion of osteoclastogenesis and angiogenesis of human origin, Received 23 August 2007; revised 23 October 2007; accepted 2 suppression of osteoblastogenesis and induction of severe November 2007; published online 29 November 2007 osteolytic bone disease. This SCID-hu system has been Atacicept inhibits TACIhigh myeloma S Yaccoby et al 407 successfully used to study the role of BM microenvironment in Corp., Piscataway, NJ, USA), and the proportion of myeloma myeloma.24–26 We also recently established a coculture system plasma cells in the light-density cell fractions was determined by for the growth of primary myeloma cells ex vivo using authentic CD38/CD45 flow cytometry. Aliquots of BM cells were taken for bone-resorbing osteoclasts, which are typically activated in in vivo studies. The rest of the BM cells were used for isolation of myelomatous BM. Cultured osteoclasts consistently support plasma cells by CD138 immunomagnetic bead selection long-term survival and proliferation and protect myeloma cells (Miltenyi-Biotec, Auburn, CA, USA).27 The isolated plasma cells from drug-induced apoptosis.22,23 Osteoclasts have been shown were subjected to global gene expression profiling as described to express high levels of APRIL and BAFF and thus may represent previously.27–29 an important paracrine source of these survival factors.17 Here, for the first time we demonstrate the association between TACI gene expression by myeloma cells and their response to Construction of primary myelomatous SCID-hu mice inhibitors of APRIL and BAFF in vivo and ex vivo. SCID-hu mice were constructed as described previously.20,21,24 Briefly, 6- to 8-week-old CB.17/Icr-SCID mice were obtained from Harlan Sprague Dawley (Indianapolis, IN, USA) and were Materials and methods housed and monitored in our animal facility. The University of Arkansas for Medical Sciences (UAMS) Institutional Animal Care Myeloma cells and Use Committee approved all experimental procedures and Myeloma cells were obtained from heparinized BM aspirates protocols. The human fetal bones were obtained from Advanced from 17 patients with active myeloma during scheduled clinic Bioscience Resources (ABR, Alameda, CA, USA). The bone visits. Signed Institutional Review Board-approved informed (femur or tibia) was inserted subcutaneously through a small consent forms are kept on record. Pertinent patient information (5 mm) incision. The incision was then closed with sterile used in animal experiments is provided in Table 1. The BM surgical staples, and engraftment of the bones was allowed to samples were separated by density centrifugation using Ficoll- take place for 6–8 weeks. For each experiment, 5–10 Â 106 Paque (specific gravity, 1.077 g mlÀ1; Amersham Biosciences mononuclear cells containing 415% plasma cells in 100 mlof Table 1 Patients’ characteristics, changes in hlg levels in control-, atacicept- and BAFFR-lg-treated SCID-hu mice, and myeloma cell response to atacicept in coculture with osteoclastsa In vivo studies hlg (% of pretreatment) g Patient Stageb Prior Isotype 70-gene 7-group TACI BAFFR BCMA PBS Atacicept BAFFR-lg therapy model c model d signal b signal e signal f 1 llla NO IgGk Low risk Low bone 2882 254 17 034 471 36 240 2 llla NO IgAk High risk
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