3ux9

Publication Abstract from PubMed

Increasing evidences suggest that the type I interferon alpha (IFNalpha) 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) AIFNalpha1bScFv01 and corresponding whole antibody AIFNalpha1bIgG01 to human interferon alpha1b (IFNalpha1b) with high specificity and high affinity. The IgG antibody could down-regulate the expression of ISG15 and IFIT-1 induced by either recombinant IFNalpha1b or naive IFNalpha 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 AIFNalpha1bScFv01-IFNalpha1b complex solved to 2.8 A resolution revealed that both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helix E of IFNalpha1b contribute to binding with AIFNalpha1bScFv01. Four residues of above two regions (Leu30, Asp32, Asp35 and Arg150) are critical for the formation of antigen-antibody complexes. AIFNalpha1bScFv01 shares partial epitopes of IFNalpha1b with its receptor IFNAR2 but with much higher binding affinity to IFNalpha1b than IFNAR2. Thus, AIFNalpha1bIgG01 exhibits its neutralizing activity through competition with IFNAR2 to bind with IFNalpha and prevents the activation of IFNalpha-mediated signaling pathway. Our results highlight the potential use of the human antibody for modulating the activity of IFNalpha in SLE.

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus.,Ouyang S, Gong B, Li JZ, Zhao LX, Wu W, Zhang FS, Sun L, Wang SJ, Pan M, Li C, Liang W, Shaw N, Zheng J, Zhao GP, Wang Y, Liu ZJ, Liang M J Mol Med (Berl). 2012 Feb 4. PMID:22307521^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.