Abstract
B lymphocyte stimulator (BLyS) antagonists are new therapeutic reagents for treating the autoimmune diseases. Peptibodies can inhibit the bioactivity of BLyS, the same as other BLyS antagonists: decoyed BLyS receptors and anti-BLyS antibodies. In this study, a new optimized BLyS antagonist peptide was designed according to our previous work by the computer-aided homology modeling. Competitive ELISA showed that the peptide at 100 μg/ml could inhibit 54 % of the BCMA-Fc binding to BLyS. To maintain its stability and spatial conformation, the peptide was fused to human IgG1 Fc to form a peptide-Fc fusion protein—a novel peptibody by gene engineering. ELISA indicated that the peptibody could bind with BLyS in dosage-dependent manner as BCMA-Fc did. This study highlights the possibility of designing and optimizing BLyS antagonist peptides with high biopotency by the computer-aided design. Thus, these peptides could neutralize BLyS activity and be potential antagonists to treat autoimmune diseases related with BLyS overexpression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Avery DT, Kalled SL, Ellyard JI, Ambrose C, Bixler SA, Thien M, Brink R, Mackay F, Hodgkin PD, Tangye SG (2003) BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Invest 112:286–297
Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, Sanchez-Guerrero J, Schwarting A, Merrill JT, Chatham WW, Stohl W, Ginzler EM, Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF, BLISS-76 Study Group (2011) A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 63:3918–3930
Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404:995–999
Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, Roque R, Rixon M, Schou O, Foley KP, Haugen H, McMillen S, Waggie K, Schreckhise RW, Shoemaker K, Vu T, Moore M, Grossman A, Clegg CH (2001) TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS. Immunity 15:289–302
Hsu H, Khare SD, Lee F, Miner K, Hu YL, Stolina M, Hawkins N, Chen Q, Ho SY, Min H, Xiong F, Boone T, Zack DJ (2012) A novel modality of BAFF-specific inhibitor AMG623 peptibody reduces B-cell number and improves outcomes in murine models of autoimmune disease. Clin Exp Rheumatol 30:197–201
Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285:260–263
O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ, Noelle RJ (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199:91–98
Pelletier M, Thompson JS, Qian F, Bixler SA, Gong D, Cachero T, Gilbride K, Day E, Zafari M, Benjamin C, Gorelik L, Whitty A, Kalled SL, Ambrose C, Hsu YM (2003) Comparison of soluble decoy IgG fusion proteins of BAFF-R and BCMA as antagonists for BAFF. J Biol Chem 278:33127–33133
Ramanujam M, Bethunaickan R, Huang W, Tao H, Madaio MP, Davidson A (2010) Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 mice. Arthritis Rheum 62:1457–1468
Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, Scott ML (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111–2114
Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J (1999) BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189:1747–1756
Shu HB, Hu WH, Johnson H (1999) TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol 65:680–683
Sun J, Feng J, Li Y, Shen B (2006) A novel BLyS antagonist peptide designed based on the 3-D complex structure of BCMA and BLyS. Biochem Biophys Res Commun 346:1158–1162
Sun J, Lin Z, Feng J, Li Y, Shen B (2008) BAFF-targeting therapy, a promising strategy for treating autoimmune diseases. Eur J Pharmacol 597:1–5
Thompson JS, Bixler SA, Qian F, Vora K, Scott ML, Cachero TG, Hession C, Schneider P, Sizing ID, Mullen C, Strauch K, Zafari M, Benjamin CD, Tschopp J, Browning JL, Ambrose C (2001) BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293:2108–2111
Wang H, Marsters SA, Baker T, Chan B, Lee WP, Fu L, Tumas D, Yan M, Dixit VM, Ashkenazi A, Grewal IS (2001) TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice. Nat Immunol 2:632–637
Acknowledgments
This study was supported by the National Natural Science Foundation of China (Grant No. 81273308) to Jian Sun.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tian, Y., Zhu, Yf., Wu, Z. et al. An optimized B lymphocyte stimulator (BLyS) antagonist peptide inhibits the interaction of BLyS with BCMA. Biotechnol Lett 35, 523–528 (2013). https://doi.org/10.1007/s10529-012-1117-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10529-012-1117-y