Publications by authors named "Brandon Harder"

14 Publications

  • Page 1 of 1

Nonclinical safety assessment of a human interleukin-22FC IG fusion protein demonstrates in vitro to in vivo and cross-species translatability.

Pharmacol Res Perspect 2018 12 15;6(6):e00434. Epub 2018 Nov 15.

Genentech, Inc South San Francisco California USA.

Although Interleukin-22 (IL-22) is produced by various leukocytes, it preferentially targets cells with epithelial origins. IL-22 exerts essential roles in modulating various tissue epithelial functions, such as innate host defense against extracellular pathogens, barrier integrity, regeneration, and wound healing. Therefore, IL-22 is thought to have therapeutic potential in treating diseases associated with infection, tissue injury or chronic tissue damage. A number of in vitro and in vivo nonclinical studies were conducted to characterize the pharmacological activity and safety parameters of UTTR1147A, an IL-22 recombinant fusion protein that links the human cytokine IL-22 with the Fc portion of a human immunoglobulin. To assess the pharmacological activity of UTTR1147A, STAT3 activation was evaluated in primary hepatocytes isolated from human, cynomolgus monkey, minipig, rat, and mouse after incubation with UTTR1147A. UTTR1147A activated STAT3 in all species evaluated, demonstrating that all were appropriate nonclinical species for toxicology studies. The nonclinical safety profile of UTTR1147A was evaluated in rats, minipigs, and cynomolgus monkeys to establish a safe clinical starting dose for humans in Phase I trials and to support clinical intravenous, subcutaneous and/or topical administration treatment regimen. Results demonstrate the cross-species translatability of the biological response in activating the IL-22 pathway as well as the translatability of findings from in vitro to in vivo systems. UTTR1147A was well tolerated in all species tested and induced the expected pharmacologic effects of epidermal hyperplasia and a transient increase in on-target acute phase proteins. These effects were all considered to be clinically predictable, manageable, monitorable, and reversible.
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http://dx.doi.org/10.1002/prp2.434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238097PMC
December 2018

Best practice recommendations for the transfer of cell-based assays for the measurement of neutralizing anti-drug antibodies.

Bioanalysis 2016 Sep 15;8(17):1845-57. Epub 2016 Aug 15.

Amgen, Inc., Thousand Oaks, CA, USA.

We recommend the application of a strategically designed step-wise approach to transfer cell-based assays that includes assessing analytical performance (through a fit for purpose validation and/or design of experiment robustness characterization), clinical performance (i.e., concordance) and performance or proficiency testing for long-term method monitoring. Here we focus on the application of this strategy to cell-based assays for the measurement of neutralizing anti-drug antibodies. This application is unique in that it requires a custom cell-based assay to be used over a long period of time (potentially phase 1a through the life of a marketed product) with the confidence of consistent method performance and result reporting. But, the process is adaptable to a variety of assay types and applications. We present lessons learned from two cell-based assay transfers that met relevant challenges while implementing alternative permutations of the recommended method transfer process.
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http://dx.doi.org/10.4155/bio-2016-4998DOI Listing
September 2016

IL-31 receptor (IL-31RA) knockout mice exhibit elevated responsiveness to oncostatin M.

J Immunol 2010 Nov 18;185(10):6023-30. Epub 2010 Oct 18.

Department of Immunology, ZymoGenetics Inc., Seattle, WA 98102, USA.

IL-31 signals through the heterodimeric receptor IL-31RA and oncostatin M receptor (OSMR), and has been linked with the development of atopic dermatitis, a Th2 cytokine-associated disease in humans. However, recent studies of IL-31RA knockout (KO) mice have suggested that IL-31 signaling may be required to negatively regulate Th2 type responses rather than exacerbate them. Because those studies were performed on genetically modified mice, we examined whether neutralizing IL-31 with a specific mAb would give similar results to IL-31RA KO mice in two Th2 cytokine-associated immune models. We report no difference in lymphocyte Th2-type cytokine production after Ag immunization between IL-31RA KO mice, mice treated with the IL-31 mAb, or control animals. Second, we tested whether the absence of the IL-31RA subunit in IL-31RA KO mice may allow for increased pairing of the OSMR subunit with another cytokine receptor, gp130, resulting in overrepresentation of the heterodimeric receptor for OSM and increased responsiveness to OSM protein. We found that intranasal OSM challenge of IL-31RA KO mice resulted in increased IL-6 and vascular endothelial growth factor production in the lung compared with wild-type littermate control animals. Moreover, PBS-challenged IL-31RA KO mice already had increased levels of vascular endothelial growth factor, which were further increased by OSM challenge. These data imply that IL-31RA-deficient mice produce increased levels of OSM-inducible cytokines during airway sensitization and challenge, which may be the driving force behind the apparent exacerbation of Th2-type inflammatory responses previously observed in these mice.
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http://dx.doi.org/10.4049/jimmunol.0902769DOI Listing
November 2010

B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin.

Arthritis Res Ther 2010 19;12(2):R48. Epub 2010 Mar 19.

Preclinical Research and Development, ZymoGenetics, Inc, 1201 Eastlake Ave East, Seattle, WA 98102, USA.

Introduction: B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are members of the tumor necrosis factor (TNF) family that regulate B-cell maturation, survival, and function. They are overexpressed in a variety of autoimmune diseases and reportedly exist in vivo not only as homotrimers, but also as BLyS/APRIL heterotrimers.

Methods: A proprietary N-terminal trimerization domain was used to produce recombinant BLyS/APRIL heterotrimers. Heterotrimer biologic activity was compared with that of BLyS and APRIL in a 4-hour signaling assay by using transmembrane activator and CAML interactor (TACI)-transfected Jurkat cells and in a 4-day primary human B-cell proliferation assay. A bead-based immunoassay was developed to quantify native heterotrimers in human sera from healthy donors (n = 89) and patients with systemic lupus erythematosus (SLE; n = 89) or rheumatoid arthritis (RA; n = 30). Heterotrimer levels were compared with BLyS and APRIL homotrimer levels in a subset of these samples.

Results: The recombinant heterotrimers consisted mostly of one BLyS and two APRIL molecules. Heterotrimer signaling did not show any significant difference compared with APRIL in the TACI-Jurkat assay. Heterotrimers were less-potent inducers of B-cell proliferation than were homotrimeric BLyS or APRIL (EC(50), nMol/L: BLyS, 0.02; APRIL, 0.17; heterotrimers, 4.06). The soluble receptor fusion proteins atacicept and B-cell maturation antigen (BCMA)-immunoglobulin (Ig) neutralized the activity of BLyS, APRIL, and heterotrimers in both cellular assays, whereas B-cell activating factor belonging to the TNF family receptor (BAFF-R)-Ig neutralized only the activity of BLyS. In human sera, significantly more patients with SLE had detectable BLyS (67% versus 18%; P < 0.0001), APRIL (38% versus 3%; P < 0.0002), and heterotrimer (27% versus 8%; P = 0.0013) levels compared with healthy donors. Significantly more patients with RA had detectable APRIL, but not BLyS or heterotrimer, levels compared with healthy donors (83% versus 3%; P < 0.0001). Heterotrimer levels weakly correlated with BLyS, but not APRIL, levels.

Conclusions: Recombinant BLyS/APRIL heterotrimers have biologic activity and are inhibited by atacicept and BCMA-Ig, but not by BAFF-R-Ig. A novel immunoassay demonstrated that native BLyS/APRIL heterotrimers, as well as BLyS and APRIL homotrimers, are elevated in patients with autoimmune diseases.
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http://dx.doi.org/10.1186/ar2959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888197PMC
September 2010

Generation of a high-affinity Fcgamma receptor by Ig-domain swapping between human CD64A and CD16A.

Protein Eng Des Sel 2010 Apr 11;23(4):299-309. Epub 2010 Feb 11.

Department of Immunology, ZymoGenetics, Inc., Seattle, WA 98102, USA.

A recombinant soluble version of the human high-affinity receptor for IgG, rh-FcgammaRIA or CD64A, was expressed in mammalian cells and purified from their conditioned media. As assessed by circular dichroism, size exclusion chromatography and dynamic light scattering, incubation of rh-FcgammaRIA at 37 degrees C resulted in time-dependent formation of soluble aggregates caused by protein unfolding and loss of native structure. Aggregate formation was irreversible, temperature-dependent and was independent of rh-FcgammaRIA concentration. Aggregated rh-FcgammaRIA lost its ability to inhibit immune complex precipitation and failed to bind to IgG-Sepharose. Addition of human IgG1 to rh-FcgammaRIA prior to incubation at 37 degrees C blocked the formation of rh-FcgammaRIA aggregates. Production of soluble monomeric rh-FcgammaRIA was limited by aggregate formation during cell culture. Substitution of the membrane distal D1 Ig domain of FcgammaRIA with the D1 Ig domain of FcgammaRIIIA or CD16A resulted in a chimeric receptor, FcgammaR3A1A, with enhanced temperature stability. Relative to native rh-FcgammaRIA, FcgammaR3A1A exhibited less aggregation in Chinese hamster ovary cell-conditioned media or when purified receptor was incubated for up to 24 h at 37 degrees C. Both receptors bound to immobilized human IgG1 with high affinity and were equipotent at blockade of immune complex-mediated cytokine production from cultured mast cells. Equivalent dose-dependent reductions in edema and neutrophil infiltration in the cutaneous Arthus reaction in mice were noted for rh-FcgammaRIA and FcgammaR3A1A. These data demonstrate that the D1 Ig domains of FcgammaRIA and FcgammaRIIIA are functionally interchangeable and further suggest that the chimeric receptor FcgammaR3A1A is an effective inhibitor of type III hypersensitivity in mice.
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http://dx.doi.org/10.1093/protein/gzq007DOI Listing
April 2010

Recombinant soluble human FcgammaR1A (CD64A) reduces inflammation in murine collagen-induced arthritis.

J Immunol 2009 Jun;182(11):7272-9

Department of Immunology, Zymo-Genetics, Seattle, WA 98102, USA.

Binding of immune complexes to cellular FcgammaRs can promote cell activation and inflammation. In previous studies, a recombinant human (rh) soluble FcgammaR, rh-FcgammaRIA (CD64A), was shown to block inflammation in passive transfer models of immune complex-mediated disease. To assess whether rh-FcgammaRIA could block inflammation in a T cell- and B cell-dependent model of immune complex-mediated disease, the efficacy of rh-FcgammaRIA in collagen-induced arthritis was evaluated. Mice with established arthritis were treated with a single s.c. injection of rh-FcgammaRIA (0.2-2.0 mg/dose) given every other day for 11 days. Relative to mice injected with vehicle alone, mice treated with rh-FcgammaRIA exhibited lower serum concentrations of IL-6, anti-type II collagen Abs, and total IgG2a. These changes were correlated with lower levels of paw swelling and joint damage in the rh-FcgammaRIA-treated mice and occurred in the presence of a significant murine Ab response to rh-FcgammaRIA. Comparison of the serum rh-FcgammaRIA concentration vs time profiles for rh-FcgammaRIA administered at two dose levels by i.v. and s.c. injection revealed that the bioavailabilty of s.c. administered rh-FcgammaRIA was 27-37%. Taken together, these data show that rh-FcgammaRIA is an effective inhibitor of inflammation in a model of established arthritis in mice.
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http://dx.doi.org/10.4049/jimmunol.0803497DOI Listing
June 2009

Targeting immune complex-mediated hypersensitivity with recombinant soluble human FcgammaRIA (CD64A).

J Immunol 2008 Jan;180(1):580-9

Department of Autoimmunity and Inflammation, ZymoGenetics, Seattle, WA 98102, USA.

Binding of Ag-Ab immune complexes to cellular FcgammaR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcgammaR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcgammaRIA, FcgammaRIIA, and FcgammaRIIIA were prepared. Binding of rh-FcgammaRIA to IgG was of high affinity (KD=1.7x10(-10) M), whereas rh-FcgammaRIIA and rh-FcgammaRIIIA bound with low affinity (KD=0.6-1.9x10(-6) M). All rh-FcgammaR reduced immune complex precipitation, blocked complement-mediated lysis of Ab-sensitized RBC, and inhibited immune complex-mediated production of IL-6, IL-13, MCP-1, and TNF-alpha by cultured mast cells. Local or systemic delivery only of rh-FcgammaRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. 125I-labeled rh-FcgammaRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with a t1/2gamma of approximately 130 h. The highest percentage of injected radioactivity accumulated in blood approximately liver approximately carcass>kidney. s.c. dosing of rh-FcgammaRIA resulted in lower serum levels of inflammatory cytokines and prevented paw swelling and joint damage in a murine model of collagen Ab-induced arthritis. These data demonstrate that rh-FcgammaRIA is an effective inhibitor of type III hypersensitivity.
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http://dx.doi.org/10.4049/jimmunol.180.1.580DOI Listing
January 2008

Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.

J Immunol 2007 Oct;179(8):5462-73

Department of Molecular and Cell Based Discovery, ZymoGenetics Incroporated, Seattle, WA 98102, USA.

The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849293PMC
http://dx.doi.org/10.4049/jimmunol.179.8.5462DOI Listing
October 2007

IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis.

J Allergy Clin Immunol 2006 Feb;117(2):418-25

Department of Autoimmunity and Inflammation, ZymoGenetics, Inc., Seattle, WA 98102, USA.

Background: IL-31 is a newly discovered T-cell cytokine that, when overexpressed in mice, results in pruritus and skin dermatitis resembling human atopic dermatitis (AD).

Objective: We sought to investigate the expression of IL-31 and IL-31 receptor A (IL-31RA) in skin biopsy specimens and peripheral blood cells from patients with AD and healthy individuals.

Methods: Expression of IL-31 and IL-31RA was evaluated in skin biopsy specimens from patients with AD and healthy individuals by means of immunohistochemistry and RT-PCR. IL-31 protein production by skin-homing cutaneous lymphocyte antigen (CLA)-positive T cells was also assessed.

Results: IL-31RA protein was expressed by keratinocytes and infiltrating macrophages in skin biopsy specimens from patients with AD. Comparisons between skin from patients with AD and healthy skin showed IL-31RA expression at higher levels on epidermal keratinocytes in AD samples. Infiltrating cells, more numerous in skin from patients with AD compared with that of healthy individuals, expressed IL31 mRNA. Histomorphometric analysis of these cells indicated they were of the lymphocytic lineage, with the majority of cells staining positive for CLA and CD3. IL31 mRNA and protein expression is largely restricted to CD45RO(+) (memory) CLA(+) T cells in peripheral blood of patients with AD and healthy volunteers. Moreover, circulating CLA(+) T cells from patients with AD, but not from patients with psoriasis, are capable of producing higher levels of IL-31 compared with CLA(+) T cells from healthy individuals. However, the average levels of IL-31 were not significantly different between patients with AD and healthy individuals.

Conclusion: We provide evidence that IL-31 expression is associated with CLA(+) T cells and might contribute to the development of AD-induced skin inflammation and pruritus.
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http://dx.doi.org/10.1016/j.jaci.2005.10.046DOI Listing
February 2006

Elevated serum B-lymphocyte stimulator levels in patients with familial lymphoproliferative disorders.

J Clin Oncol 2006 Feb 23;24(6):983-7. Epub 2006 Jan 23.

Division of Hematology and Internal Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Purpose: Serum B-lymphocyte stimulator (BLyS) levels have been found to be elevated in a number of immune disease models. Therefore, we sought to establish whether BLyS levels were elevated in patients with B-cell lymphoproliferative disorders and to determine whether elevated BLyS levels correlated with clinical characteristics of the disease.

Patients And Methods: Specimens were collected from the peripheral blood of individuals diagnosed with B-cell chronic lymphocytic leukemia (B-CLL; n = 70) or from age- and sex-matched patients seen at the same institution (n = 41). Serum BLyS levels were determined by enzyme-linked immunosorbent assay, and sequencing of the BLyS promoter was performed by conventional methods and confirmed by restriction fragment length polymorphism analysis.

Results: We found that elevated BLyS levels were more common in patients with familial B-CLL than individuals with sporadic B-CLL or normal controls. Because of this association, we sequenced the BLyS promoter in patients with B-CLL and normal controls and identified a polymorphic site, -871 C/T. We found that the wild-type sequence was significantly underrepresented in patients with familial B-CLL (4%) compared with patients with sporadic B-CLL (30%; P = .01) or controls (24%; P = .04). Furthermore, using a luciferase reporter under control of the BLyS promoter containing either a C or a T at position -871, we found that the reporter construct containing a T at -871 had a 2.6-fold increase in activity (P = .004).

Conclusion: Our data suggest serum BLyS levels are elevated in patients with familial B-CLL and that elevated BLyS levels correlate with the presence of a T at -871 in the BLyS promoter.
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http://dx.doi.org/10.1200/JCO.2005.02.7938DOI Listing
February 2006

B-lymphocyte stimulator (BLyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenstrom macroglobulinemia.

Blood 2006 Apr 22;107(7):2882-8. Epub 2005 Nov 22.

Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Waldenström macroglobulinemia (WM) is a serious and frequently fatal B-cell malignancy associated with an elevated monoclonal IgM protein in the serum. Many of the mechanisms leading to this disease are not yet known. B-lymphocyte stimulator (BLyS) is a TNF family member that is critical for maintenance of normal B-cell development and homeostasis. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B cells. It also regulates immunoglobulin secretion by normal B cells. To determine the relevance of BLyS in WM, we examined the role of BLyS in WM patient samples. Malignant B cells were found to bind soluble BLyS and variably express the receptors BAFF-R, TACI, and BCMA. We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM. BLyS, alone or in combination with cytokines that induce immunoglobulin production, was found to increase IgM secretion by malignant B cells. Furthermore, BLyS was found to increase the viability and proliferation of malignant B cells from WM patients. Due to the role of BLyS in WM, strategies to inhibit BLyS may potentially have therapeutic efficacy in these patients.
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http://dx.doi.org/10.1182/blood-2005-09-3552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895377PMC
April 2006

Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome.

Blood 2004 Oct 13;104(8):2247-53. Epub 2004 Jul 13.

Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

BLyS, recently shown to be critical for survival of normal B cells, has been found to be elevated in a number of immune disease models. A role for BLyS in the survival of malignant B cells has also been revealed and we therefore sought to identify a role for BLyS and its receptors in non-Hodgkin lymphoma (NHL). We found that tumor cells from all NHL histologic subtypes expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern of expression was variable. We provide evidence that BLyS is expressed in tumors from patients with NHL and that BLyS levels increase as tumors transform to a more aggressive phenotype. Additionally, we provide evidence that serum BLyS levels are elevated in a subgroup of patients with NHL. In patients with de novo large B-cell lymphoma, a high BLyS level correlated with a poorer median overall survival, the presence of constitutional symptoms, and elevated values of lactic dehydrogenase. When BLyS levels were correlated with response to therapy in all patients, responding patients had a significantly lower BLyS level than those with progressive disease. In summary, we found that BLyS and its receptors represent a potentially important therapeutic target in B-cell lymphoma.
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http://dx.doi.org/10.1182/blood-2004-02-0762DOI Listing
October 2004

Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.

Nat Immunol 2004 Jul 6;5(7):752-60. Epub 2004 Jun 6.

Department of Immunology, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, Washington 98102, USA.

T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.
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http://dx.doi.org/10.1038/ni1084DOI Listing
July 2004

Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.

Blood 2004 Jan 25;103(2):689-94. Epub 2003 Sep 25.

Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905.

Multiple myeloma (MM) is a progressive disease that is thought to result from multiple genetic insults to the precursor plasma cell that ultimately affords the tumor cell with proliferative potential despite its differentiated phenotype and resistance to undergoing apoptosis. Altered expression of antiapoptotic factors as well as growth factors have been described in a significant number of patients. However, the key regulatory elements that control myeloma development and progression remain largely undefined. Because of the knowledge that B-lymphocyte stimulator (BLyS), a tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis, promotes the survival of malignant B cells, we began a coordinated study of BLyS and its receptors in MM. All MM cells studied expressed one or more of 3 known receptors (B-cell maturation antigen [BCMA], transmembrane activator and CAML interactor [TACI], and B-cell activating factor receptor [BAFF-R]) for BLyS; however, the pattern of expression was variable. Additionally, we provide evidence that BLyS can modulate the proliferative capacity and survival of MM cells. Finally, we provide evidence that BLyS is expressed by MM cells and is present in the bone marrow of patients with MM. Expression of BCMA, TACI, and BAFF-R by MM taken together with the ability of BLyS to support MM cell growth and survival has exciting implications because they may be potential therapeutic targets.
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http://dx.doi.org/10.1182/blood-2003-06-2043DOI Listing
January 2004