Comparison of soluble decoy IgG fusion proteins of BAFF-R and BCMA as antagonists for BAFF.
BAFF is considered a therapeutic target because dysregulated production of BAFF can induce systemic lupus erythematosus-like phenotype in mice, and elevated levels of BAFF are associated with disease severity in systemic lupus erythematosus and rheumatoid arthritis patients. Fc fusion decoy receptors, BCMA-Fc and BAFF-R-Fc, are therapeutic candidates for blocking BAFF. While studying their interactions with BAFF, we found that BAFF-R-Fc is more effective than BCMA-Fc for blocking BAFF binding to its receptors. We also found that a trimeric BAFF can bind more than one BAFF-R-Fc but only one BCMA-Fc. Moreover, we show that, in contrast to monovalent BAFF-R-Fc, monovalent BCMA does not form stable complexes with BAFF. Differences in their interaction with BAFF predict BAFF-R-Fc would be a better inhibitor. Indeed, we show BAFF-R-Fc is 10-fold more efficacious than BCMA-Fc for blocking BAFF-induced B cell proliferation in vitro and for blocking BAFF-mediated survival of mouse splenic B lymphocytes in vivo.
Pelletier
Marc
M
Department of Protein Engineering, Biogen Inc., Cambridge, Massachusetts 02142, USA.
Thompson
Jeffrey S
JS
Qian
Fang
F
Bixler
Sarah A
SA
Gong
Dahai
D
Cachero
Teresa
T
Gilbride
Kevin
K
Day
Eric
E
Zafari
Mohammad
M
Benjamin
Chris
C
Gorelik
Leonid
L
Whitty
Adrian
A
Kalled
Susan L
SL
Ambrose
Christine
C
Hsu
Yen-Ming
YM
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D001216:Asparagine / Q000737:chemistry; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D001402:B-Lymphocytes / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D002470:Cell Survival; D006224:Cricetinae; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000737:chemistry*; D007930:Leucine / Q000737:chemistry; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry*; D014633:Valine / Q000737:chemistry
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D007074:Immunoglobulin G; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C486662:Tnfrsf13c protein, mouse; C490176:Tnfrsf17 protein, mouse; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D001216:Asparagine; D011392:Proline; D007930:Leucine; D014633:Valine