title: A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys.
abstract: BAFF (also known as BLyS), a member of the tumor necrosis factor superfamily, plays a critical role in the maturation and development of B cells. BAFF has three receptors on B cells, the most crucial of which is BR3. In this study, we demonstrate the biological outcome of BAFF blockade in cynomolgus monkeys using a soluble fusion protein consisting of human BR3 and human IgG1 Fc. In vitro, BR3-Fc blocked BAFF-mediated survival and proliferation of cynomolgus monkey B cells. Weekly treatment of cynomolgus monkeys with BR3-Fc for 13 to 18 weeks resulted in significant B-cell reduction in the peripheral blood and in lymphoid organs. CD21(high) B cells in lymphoid tissues, a subset analogous to human marginal zone B cells, expressed nearly twofold higher BR3 levels than did CD21(med) B cells. Lymphoid tissue flow cytometric analysis showed that BR3-Fc reduced this CD21(high) B-cell subset to a greater extent than it reduced CD21(med) B cells. Dual-label immunohistochemistry and morphometric image analysis supported these results by demonstrating that BR3-Fc reduced a significant proportion of the B cells within the splenic inner and outer marginal zones. These findings should prove very useful in guiding the desired therapeutic use of BR3-Fc for autoimmune diseases in the clinic.
authors.affiliation: Genentech, Inc, San Francisco, CA 94080, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Dhaya
authors.initials: D
authors.lastname: Seshasayee
authors.forename: Wesley
authors.initials: W
authors.lastname: Chang
authors.forename: Anahid
authors.initials: A
authors.lastname: Storn
authors.forename: Kathy
authors.initials: K
authors.lastname: Howell
authors.forename: Susan
authors.initials: S
authors.lastname: Sa
authors.forename: Tenea
authors.initials: T
authors.lastname: Nelson
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
authors.forename: Iqbal
authors.initials: I
authors.lastname: Grewal
authors.forename: Ellen
authors.initials: E
authors.lastname: Gilkerson
authors.forename: Ben
authors.initials: B
authors.lastname: Wu
authors.forename: Jeff
authors.initials: J
authors.lastname: Thompson
authors.forename: Barbara N
authors.initials: BN
authors.lastname: Ehrenfels
authors.forename: Song
authors.initials: S
authors.lastname: Ren
authors.forename: An
authors.initials: A
authors.lastname: Song
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gelzleichter
authors.forename: Dimitry M
authors.initials: DM
authors.lastname: Danilenko
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology*; D008221:Lymphoid Tissue / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C435926:TNFRSF13C protein, human; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha