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Crystal Structure Of Human Il-1beta In Complex With Antibody Binding Fragment Of IgG26
Structural highlights
Publication Abstract from PubMedInterleukin-1beta (IL-1beta) is a potent pleiotropic cytokine playing a central role in protecting cells from microbial pathogen infection or endogenous stress. After it binds to IL-1RI and recruits IL-1 receptor accessory protein (IL-1RAcP), signaling culminates in activation of NF-kappaB. Many pathophysiological diseases have been attributed to the derailment of IL-1beta regulation. Several blocking reagents have been developed based on two mechanisms: blocking the binding of IL-1beta to IL-1RI or inhibiting the recruitment of IL-1RAcP to the IL-1beta initial complex. In order to simultaneously fulfill these two actions, a human anti-IL-1beta neutralizing antibody IgG26 was screened from human genetic phage-display library and furthered structure-optimized to final version, IgG26AW. IgG26AW has a sub-nanomolar binding affinity for human IL-1beta. We validated IgG26AW-neutralizing antibodies specific for IL-1beta in vivo to prevent human IL-1beta-driving IL-6 elevation in C56BL/6 mice. Mice underwent treatments with IgG26AW in A549 and MDA-MB-231 xenograft mouse cancer models have also been observed with tumor shrank and inhibition of tumor metastasis. The region where IgG26 binds to IL-1beta also overlaps with the position where IL-1RI and IL-1RAcP bind, as revealed by the 26-Fab/IL-1beta complex structure. Meanwhile, SPR experiments showed that IL-1beta bound by IgG26AW prevented the further binding of IL-1RI and IL-1RAcP, which confirmed our inference from the result of protein structure. Therefore, the inhibitory mechanism of IgG26AW is to block the assembly of the IL-1beta/IL-1RI/IL-1RAcP ternary complex which further inhibits downstream signaling. Based on its high affinity, high neutralizing potency, and novel binding epitope simultaneously occupying both IL-1RI and IL-1RAcP residues that bind to IL-1beta, IgG26AW may be a new candidate for treatments of inflammation-related diseases or for complementary treatments of cancers in which the role of IL-1beta is critical to pathogenesis. Structure-based Development of Human Interleukin-1beta-Specific Antibody That Simultaneously Inhibits Binding to Both IL-1RI and IL-1RAcP.,Kuo WC, Lee CC, Chang YW, Pang W, Chen HS, Hou SC, Lo SY, Yang AS, Wang AH J Mol Biol. 2021 Feb 19;433(4):166766. doi: 10.1016/j.jmb.2020.166766. Epub 2020 , Dec 24. PMID:33359099[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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