3UX9

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

Summary for 3UX9

• Entry DOI: 10.2210/pdb3ux9/pdb
• Descriptor: Interferon alpha-1/13, ScFv antibody (3 entities in total)
• Functional Keywords: five helices, long loop connecting helix, hydrophobic interactions, cytokine-immune system complex, cytokine/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01562
• Total number of polymer chains: 4
• Total formula weight: 93994.74

Authors

Ouyang, S.,Zhao, L.X.,Liang, W.,Shaw, N.,Liu, Z.-J.,Liang, M.-F. (deposition date: 2011-12-04, release date: 2012-02-29, Last modification date: 2024-11-13)

Primary citation

Ouyang, S.,Gong, B.,Li, J.-Z.,Zhao, L.-X.,Wu, W.,Zhang, F.-S.,Sun, L.,Wang, S.-J.,Pan, M.,Li, C.,Liang, W.,Shaw, N.,Zheng, J.,Zhao, G.-P.,Wang, Y.,Liu, Z.-J.,Liang, M.-F.
Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus
J.Mol.Med., 2012

PubMed Abstract: 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.

PubMed: 22307521
DOI: 10.1007/s00109-012-0866-3

Experimental method

X-RAY DIFFRACTION (2.8 Å)