6wzm
LY3041658 Fab bound to CXCL8
Structural highlights
FunctionIL8_HUMAN IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to an inflammatory stimulus. IL-8(6-77) has a 5-10-fold higher activity on neutrophil activation, IL-8(5-77) has increased activity on neutrophil activation and IL-8(7-77) has a higher affinity to receptors CXCR1 and CXCR2 as compared to IL-8(1-77), respectively.[1] [2] [3] Publication Abstract from PubMedCXCR1 and CXCR2 signaling play a critical role in neutrophil migration, angiogenesis, and tumorigenesis and are therefore an attractive signaling axis to target in a variety of indications. In human, a total of seven chemokines signal through these receptors and comprise the ELR(+)CXC chemokine family, so named because of the conserved ELRCXC N-terminal motif. To fully antagonize CXCR1 and CXCR2 signaling, an effective therapeutic should block either both receptors or all seven ligands, yet neither approach has been fully realized clinically. In this work, we describe the generation and characterization of LY3041658, a humanized monoclonal antibody that binds and neutralizes all seven human and cynomolgus monkey ELR(+)CXC chemokines and three of five mouse and rat ELR(+)CXC chemokines with high affinity. LY3041658 is able to block ELR(+)CXC chemokine-induced Ca(2+) mobilization, CXCR2 internalization, and chemotaxis in vitro as well as neutrophil mobilization in vivo without affecting other neutrophil functions. In addition to the in vitro and in vivo activity, we characterized the epitope and structural basis for binding in detail through alanine scanning, crystallography, and mutagenesis. Together, these data provide a robust preclinical characterization of LY3041658 for which the efficacy and safety is being evaluated in human clinical trials for neutrophilic skin diseases. Discovery and characterization of a neutralizing pan-ELR+CXC chemokine monoclonal antibody.,Boyles JS, Beidler CB, Strifler BA, Girard DS, Druzina Z, Durbin JD, Swearingen ML, Lee LN, Kikly K, Chintharlapalli S, Witcher DR MAbs. 2020 Jan-Dec;12(1):1831880. doi: 10.1080/19420862.2020.1831880. PMID:33183151[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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