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PMID: 16436662 Published · ppublish English Journal Article

A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys.

The American journal of pathology ·Vol. 168 ·No. 2 ·2006-02-00 ·Pages 476-89

Vugmeyster Y, Seshasayee D, Chang W, Storn A, Howell K, Sa S, Nelson T, Martin F, Grewal I, Gilkerson E, Wu B, Thompson J, Ehrenfels BN, Ren S, Song A, Gelzleichter TR, Danilenko DM

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.

MeSH Terms
Animals B-Cell Activating Factor B-Cell Activation Factor Receptor B-Lymphocytes/cytology,immunology,metabolism Cell Proliferation Cell Survival Female Flow Cytometry Humans Immunoglobulin Fc Fragments/genetics,pharmacology Immunoglobulin G/genetics,pharmacology Lymphoid Tissue/cytology,immunology,metabolism Macaca fascicularis Male Membrane Proteins/antagonists & inhibitors,genetics,metabolism,pharmacology Receptors, Tumor Necrosis Factor/antagonists & inhibitors,genetics,metabolism Recombinant Fusion Proteins/genetics,pharmacology Tumor Necrosis Factor-alpha/antagonists & inhibitors,metabolism
Chemicals
B-Cell Activating Factor B-Cell Activation Factor Receptor Immunoglobulin Fc Fragments Immunoglobulin G Membrane Proteins Receptors, Tumor Necrosis Factor Recombinant Fusion Proteins TNFRSF13C protein, human TNFSF13B protein, human Tumor Necrosis Factor-alpha
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Vugmeyster Yulia
Genentech, Inc, San Francisco, CA 94080, USA.
Seshasayee Dhaya
Chang Wesley
Storn Anahid
Howell Kathy
Sa Susan
Nelson Tenea
Martin Flavius
Grewal Iqbal
Gilkerson Ellen
Wu Ben
Thompson Jeff
Ehrenfels Barbara N
Ren Song
Song An
Gelzleichter Thomas R
Danilenko Dimitry M
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.2353/ajpath.2006.050600
Published
2006-02-00
Pages
476-89
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1606502
Subset
IM
External Links
PubMed source DOI: 10.2353/ajpath.2006.050600 PMC Full Text View journal details
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