Anti-BR3 antibodies: a new class of B-cell immunotherapy combining cellular depletion and survival blockade.
Removal of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)-BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.
Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
Wei Yu
WY
Lin
Qian
Q
Gong
Dhaya
D
Seshasayee
Zhonghua
Z
Lin
Qinglin
Q
Ou
Shiming
S
Ye
Eric
E
Suto
Jean
J
Shu
Wyne Pun
WP
Lee
Ching-Wei V
CW
Lee
Germaine
G
Fuh
Maya
M
Leabman
Suhasini
S
Iyer
Kathy
K
Howell
Thomas
T
Gelzleichter
Joseph
J
Beyer
Dimitry
D
Danilenko
Sherry
S
Yeh
Laura E
LE
DeForge
Allen
A
Ebens
Jeffrey S
JS
Thompson
Christine
C
Ambrose
Mercedesz
M
Balazs
Melissa A
MA
Starovasnik
Flavius
F
Martin
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D053265:B-Cell Activation Factor Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D007154:Immune System Diseases / Q000188:drug therapy* / Q000276:immunology; D007167:Immunotherapy; D008212:Lymphocyte Depletion; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology*; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C505720:Tnfsf13b protein, mouse