Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator.
OBJECTIVE
To identify and characterize a fully human antibody directed against B lymphocyte stimulator (BLyS), a tumor necrosis factor-related cytokine that plays a critical role in the regulation of B cell maturation and development. Elevated levels of BLyS have been implicated in the pathogenesis of autoimmune diseases.


METHODS
A human phage display library was screened for antibodies against human BLyS. A human monoclonal antibody, LymphoStat-B, specific for human BLyS was obtained from the library screening and subsequent affinity optimization mutagenesis. The antibody was tested for inhibition of human BLyS in vitro and in an in vivo murine model. Additionally, the consequences of BLyS inhibition were tested in vivo by administration of LymphoStat-B to cynomolgus monkeys.


RESULTS
LymphoStat-B bound with high affinity to human BLyS and inhibited the binding of BLyS to its 3 receptors, TACI, BCMA, and BLyS receptor 3/BAFF-R. LymphoStat-B potently inhibited BLyS-induced proliferation of B cells in vitro, and administration of LymphoStat-B to mice prevented human BLyS-induced increases in splenic B cell numbers and IgA titers. In cynomolgus monkeys, administration of LymphoStat-B resulted in decreased B cell representation in both spleen and mesenteric lymph nodes.


CONCLUSIONS
A fully human monoclonal antibody has been isolated that binds to BLyS with high affinity and neutralizes human BLyS bioactivity in vitro and in vivo. Administration of this antibody to cynomolgus monkeys resulted in B cell depletion in spleen and lymph node. This antibody may prove therapeutically useful in the treatment of autoimmune diseases in humans.
Baker
Kevin P
KP
Human Genome Sciences, Inc., Rockville, Maryland 20850, USA. kevin_baker@hgsi.com
Edwards
Bryan M
BM
Main
Sarah H
SH
Choi
Gil H
GH
Wager
Ruth E
RE
Halpern
Wendy G
WG
Lappin
Patrick B
PB
Riccobene
Todd
T
Abramian
Donara
D
Sekut
Les
L
Sturm
Bonnie
B
Poortman
Carol
C
Minter
Ralph R
RR
Dobson
Claire L
CL
Williams
Elizabeth
E
Carmen
Sara
S
Smith
Rodger
R
Roschke
Viktor
V
Hilbert
David M
DM
Vaughan
Tristan J
TJ
Albert
Vivian R
VR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000096:biosynthesis* / Q000276:immunology; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D053303:Transmembrane Activator and CAML Interactor Protein
D000911:Antibodies, Monoclonal; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; C120197:BLyS receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C086966:TNFRSF17 protein, human; C486361:Tnfrsf13b protein, mouse; C486662:Tnfrsf13c protein, mouse; C490176:Tnfrsf17 protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein