A Soluble BAFF Antagonist, BR3-Fc, Decreases Peripheral Blood B Cells and Lymphoid Tissue Marginal Zone and Follicular B Cells in Cynomolgus Monkeys

Vugmeyster, Yulia; Seshasayee, Dhaya; Chang, Wesley; Storn, Anahid; Howell, Kathy; Sa, Susan; Nelson, Tenea; Martin, Flavius; Grewal, Iqbal S.; Gilkerson, Ellen; Wu, Ben; Thompson, Jeffrey P.; Ehrenfels, Barbara; Ren, Shifang; Song, An; Gelzleichter, Thomas; Danilenko, Dimitry M.

doi:10.2353/ajpath.2006.050600

Cited by 76 publications

(62 citation statements)

References 58 publications

(78 reference statements)

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“…BAFF blockade could result in B-cell reduction in animal models. 36,37 Recent clinical trials with BAFF blockade have shown clinical benefit in SLE and RA. 38,39 Treatment of lupus-prone New Zealand black/white F1 mice with both BR3-Fc and TACI-Ig significantly decreased the proteinuria and glomerular damage in these mice.…”

Section: Discussionmentioning

confidence: 99%

The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia

Zhu

Shi

Peng

et al. 2009

Blood

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IntroductionImmune thrombocytopenia (ITP) is an autoimmune disorder in which the patient's immune system is activated by platelet autoantigens resulting in immune-mediated platelet destruction and/or suppression of platelet production. 1 The autoantibodies produced by autoreactive B cells against self-antigens, specifically immunoglobulin G (IgG) antibodies against glycoprotein IIb (GPIIb)/IIIa and/or GPIb/IX, are considered to play a crucial role. 2 In addition, several abnormalities involving the cellular mechanisms of immune modulation, such as the T helper 1 (Th1) bias, 3,4 the decreased number or defective suppressive function of regulatory T cells, 5-7 and the platelet destruction by cytotoxic T cells (CTLs), [8][9][10] have been described. The cause for these abnormalities remains unknown. Moreover, the treatment regimens for ITP including glucorticosteroids, intravenous immunoglobulin G, anti-D, and splenectomy are not always effective, and only one-third of adult patients achieve long-term remission.B-cell activating factor (BAFF; also known as B-lymphocyte stimulator, tumor necrosis factor and apoptosis ligand-related leukocyte-expressed ligand 1, tumor necrosis factor homologue that activates apoptosis, nuclear factor B, and c-Jun NH 2 -terminal kinase, and tumor necrosis factor superfamily 13B) belonging to the family of tumor necrosis factor (TNF) ligands is critical for the maintenance of normal B-cell development, homeostasis, and autoreactivity 11,12 and T-cell costimulation. [13][14][15] In addition, BAFF also augments certain Th1-associated inflammatory responses. 16 BAFF binds to 3 receptors: B-cell maturation antigen (tumor necrosis factor receptor superfamily, member 17 [TNFRSF17]), transmembrane activator and calcium-modulating cyclophilin ligand (CAML) interactor (TACI; TNFRSF13B), and BAFF receptor (BR3/BAFF-R; TNFRSF13C). 17,18 BR3, identified as the crucial receptor for B-cell survival, is expressed on a wide range of B-cell subsets, including immature, transitional, mature, memory, and germinal center B cells, as well as on plasma cells. 19 Furthermore, BAFF binding to BR3 on T cells has been shown to costimulate T-cell proliferation both in vitro and in vivo. 15 Several lines of evidence suggested that BAFF may play an important role in autoimmunity. Autoantigen-binding B cells may have an increased dependence on the BAFF survival signal. 20 In addition, elevated BAFF plasma level was observed in many patients with autoimmune diseases such as rheumatoid arthritis (RA), 21 systemic lupus erythematosus (SLE), 22 Sjögren syndrome (SS), 23 and multiple sclerosis. 24 Inhibition of BAFF signaling is a potentially therapeutic option for treatment of B cell-mediated autoimmune conditions. Data from animal tests and clinical trials had proved that blockade of BAFF by blocking reagents (TACI-Ig, BAFF-R-Ig, BR3-Fc) was an effective therapeutic approach for some autoimmune diseases. [25][26][27] In our study, we focused on the effects of BAFF and BR3-Fc in ITP, and found recombinant human BAFF (r...

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Section: Discussionmentioning

confidence: 99%

The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia

Zhu

Shi

Peng

et al. 2009

Blood

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“…11,12 Several BAFF-targeted agents are currently being pursued in clinical development for both autoimmune disease and hematologic malignancies. [13][14][15] However, BR3 is the principal receptor responsible for mediating BAFF-dependent B-cell survival effects. [1][2][3]16 Thus, targeting BR3 directly with an antibody, unlike the ligand-directed approaches, would disrupt the BAFF/BR3 axis specifically and leave BAFF free to signal through its other receptors.…”

Section: Introductionmentioning

confidence: 99%

Synthetic anti-BR3 antibodies that mimic BAFF binding and target both human and murine B cells

Lee¹,

Hymowitz²,

Wallweber³

et al. 2006

Blood

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BR3, which is expressed on all mature B cells, is a specific receptor for the B-cell survival and maturation factor BAFF (Bcell-activating factor belonging to the tumor necrosis factor [TNF] family). In order to investigate the consequences of targeting BR3 in murine models and to assess the potential of BR3 antibodies as human therapeutics, synthetic antibody phage libraries were employed to identify BAFF-blocking antibodies cross-reactive to murine and human BR3, which share 52% identity in their extracellular domains. We found an antibody, CB1, which exhibits M affinity for murine BR3 and very weak affinity for the human receptor.

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“…The PD marker measured in this study was absolute peripheral blood B cell counts because by neutralizing BAFF, we expect B cell counts to be reduced (Vugmeyster et al, 2006;Lin et al, 2007). CD19 is expressed on mouse B-lineage cells throughout their development from the early pro-B cell stages onward and was used to gate B cells from the lymphocyte population.…”

Section: Resultsmentioning

confidence: 99%

“…BR3-BAFF interaction seems to be particularly important for the regulation of B cell survival and maturation in the spleen (Ng et al, 2004). Prevention of BAFF binding to BR3 on B cells by neutralizing BAFF via BR3-Fc results in notable peripheral and tissue B cell reduction in rodents and monkeys due to apoptosis (Vugmeyster et al, 2006;Lin et al, 2007). BR3-Fc consists of two polypeptide chains, each containing 299 amino acids, with sequences from the extracellular domain of the human BAFF receptor BR3 and the Fc domain of human IgG1.…”

mentioning

confidence: 99%

Evidence for an Asialoglycoprotein Receptor on Nonparenchymal Cells forO-Linked Glycoproteins

Stefanich¹,

Ren²,

Danilenko³

et al. 2008

J Pharmacol Exp Ther

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B cell-activating factor receptor 3 (BR3)-Fc is an IgG1-receptor dimeric fusion protein that has multiple O-linked glycosylation sites and sialylation levels that can vary in the manufacturing process. Increased sialic acid levels resulted from increased site occupancy with the O-linked N-acetylgalactosamine (GalNAc-Gal), but because the ratio of sialic acid per mole of oligosaccharide remained approximately 1, this led to increased asialo terminal GalNAc. Previous studies have demonstrated an effect of terminal asialo Gal or GalNAc on the clearance of glycoproteins due to uptake and degradation by lectin receptors in the liver. However, the previous studies examined N-linked oligosaccharides, and there are less data regarding O-linked oligosaccharides. The objective of these studies was to determine the effects on the pharmacokinetics and distribution of the asialo terminal GalNAc and varying amounts of sialic acid residues on BR3-Fc. The results of the data presented here suggest that exposed Gal on the desialylated BR3-Fc led to rapid clearance due to uptake and degradation in the liver that was associated with nonparenchymal cells. It is interesting to note that the data indicated a decreased clearance and increased exposure of BR3-Fc as the sialic acid levels increased, even though increased sialic acid was associated with increased asialo GalNAc. Therefore, the exposed GalNAc did not seem to play a role in the clearance of BR3-Fc; although the Gal linked to the hydroxyl group at position 3 may have prevented an interaction. Because we did not see uptake of desialylated BR3-Fc in hepatocytes where the asialoglycoprotein receptor is localized, this nonparenchymal cell lectin may have preference for O-linked glycoproteins.B cell-activating factor receptor 3 (BR3)-Fc is an IgG1-receptor dimeric fusion protein that is directed against B cell-activating factor (BAFF of the tumor necrosis factor ligand superfamily) (Gordon et al., 2003;Mackay and Ambrose, 2003;. BR3-BAFF interaction seems to be particularly important for the regulation of B cell survival and maturation in the spleen (Ng et al., 2004). Prevention of BAFF binding to BR3 on B cells by neutralizing BAFF via BR3-Fc results in notable peripheral and tissue B cell reduction in rodents and monkeys due to apoptosis (Vugmeyster et al., 2006;Lin et al., 2007). BR3-Fc consists of two polypeptide chains, each containing 299 amino acids, with sequences from the extracellular domain of the human BAFF receptor BR3 and the Fc domain of human IgG1. The two chains are joined by two disulfide bonds located in the IgG1 Fc domain near the junction between the BR3 extracellular domain and the IgG1 Fc region.In addition, BR3-Fc has multiple O-linked glycosylation sites with sialylation on the glycoproteins that can vary in the manufacturing process. There are six potential sites per BR3 domain and two BR3 domains per molecule. The monosaccharide analyses of BR3-Fc lots indicate that, on average, less than half of the identified O-linked sites are occupied and th...

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A Soluble BAFF Antagonist, BR3-Fc, Decreases Peripheral Blood B Cells and Lymphoid Tissue Marginal Zone and Follicular B Cells in Cynomolgus Monkeys

Cited by 76 publications

References 58 publications

The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia

The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia

Synthetic anti-BR3 antibodies that mimic BAFF binding and target both human and murine B cells

Evidence for an Asialoglycoprotein Receptor on Nonparenchymal Cells forO-Linked Glycoproteins

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