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Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

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Abstract

Increasing evidences suggest that the type I interferon α (IFNα) 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) AIFNα1bScFv01 and corresponding whole antibody AIFNα1bIgG01 to human interferon α1b (IFNα1b) with high specificity and high affinity. The IgG antibody could down-regulate the expression of ISG15 and IFIT-1 induced by either recombinant IFNα1b or naïve IFNα 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 AIFNα1bScFv01-IFNα1b complex solved to 2.8 Å resolution revealed that both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helix E of IFNα1b contribute to binding with AIFNα1bScFv01. Four residues of above two regions (Leu30, Asp32, Asp35 and Arg150) are critical for the formation of antigen–antibody complexes. AIFNα1bScFv01 shares partial epitopes of IFNα1b with its receptor IFNAR2 but with much higher binding affinity to IFNα1b than IFNAR2. Thus, AIFNα1bIgG01 exhibits its neutralizing activity through competition with IFNAR2 to bind with IFNα and prevents the activation of IFNα-mediated signaling pathway. Our results highlight the potential use of the human antibody for modulating the activity of IFNα in SLE.

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Acknowledgements

This work was funded by the Ministry of Science and Technology of China (grants 2009AA02Z109, 2009DFB30310 and 2009CB918803) and National Nature Science Foundation of China (grants 31070660, 31021062 and 81072449); Crystallographic data were collected at beamline 19-ID of APS (Argonne National Laboratory)

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The authors declare no conflict of interest in connection with the submitted material.

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Authors and Affiliations

  1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Songying Ouyang, Li-Xia Zhao, Wenguang Liang, Neil Shaw & Zhi-Jie Liu

  2. National Institute for Viral Diseases Control and Prevention, China CDC, Beijing, 102206, China

    Bin Gong, Wei Wu, Fu-Shun Zhang, Lina Sun, Chuan Li & Mifang Liang

  3. Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Jin-Zhi Li, Shu-Jun Wang & Ying Wang

  4. Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Meng Pan & Jie Zheng

  5. Shanghai-MOST Key Laboratory for Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, 201203, China

    Guo-Ping Zhao & Ying Wang

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  1. Songying Ouyang
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  2. Bin Gong
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Correspondence to Ying Wang, Zhi-Jie Liu or Mifang Liang.

Additional information

S. Ouyang, B. Gong, J. Z. Li and L. X. Zhao contributed equally to this work.

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Ouyang, S., Gong, B., Li, JZ. et al. Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus. J Mol Med 90, 837–846 (2012). https://doi.org/10.1007/s00109-012-0866-3

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  • DOI: https://doi.org/10.1007/s00109-012-0866-3

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