Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus.
Increasing evidences suggest that the type I interferon α (IFN α) plays a critical role in the etiopathogenesis of systemic lupus erythematosus (SLE), which makes it a promising therapeutic target for the treatment of the disease. By screening a large size non-immune human antibody library, we have developed a human single-chain antibody (ScFv) AIFN α 1bScFv01 and corresponding whole antibody AIFN α 1bIgG01 to human interferon α 1b (IFN α 1b) with high specificity and high affinity. The IgG antibody could down-regulate the expression of ISG15 and IFIT-1 induced by either recombinant IFN α 1b or naïve IFN α from SLE patients' sera, and reduced total serum IgG and IgM antibodies level in a pristane-primed lupus-like mouse model. The crystal structure of AIFN α 1bScFv01-IFN α 1b complex solved to 2.8 Å resolution revealed that both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helix E of IFN α 1b contribute to binding with AIFN α 1bScFv01. Four residues of above two regions (Leu30, Asp32, Asp35 and Arg150) are critical for the formation of antigen-antibody complexes. AIFN α 1bScFv01 shares partial epitopes of IFN α 1b with its receptor IFNAR2 but with much higher binding affinity to IFN α 1b than IFNAR2. Thus, AIFN α 1bIgG01 exhibits its neutralizing activity through competition with IFNAR2 to bind with IFN α and prevents the activation of IFN α-mediated signaling pathway. Our results highlight the potential use of the human antibody for modulating the activity of IFN α in SLE.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Songying
S
Ouyang
Bin
B
Gong
Jin-Zhi
JZ
Li
Li-Xia
LX
Zhao
Wei
W
Wu
Fu-Shun
FS
Zhang
Lina
L
Sun
Shu-Jun
SJ
Wang
Meng
M
Pan
Chuan
C
Li
Wenguang
W
Liang
Neil
N
Shaw
Jie
J
Zheng
Guo-Ping
GP
Zhao
Ying
Y
Wang
Zhi-Jie
ZJ
Liu
Mifang
M
Liang
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use; D000915:Antibody Affinity; D000936:Antigen-Antibody Complex / Q000737:chemistry; D004195:Disease Models, Animal; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry* / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D015398:Signal Transduction; D057127:Single-Chain Antibodies / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use
D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; D016898:Interferon-alpha; D057127:Single-Chain Antibodies