6WZM

LY3041658 Fab bound to CXCL8

Summary for 6WZM

• Entry DOI: 10.2210/pdb6wzm/pdb
• Related: 6WZJ 6WZK 6WZL
• Descriptor: LY3041658 Fab heavy chain, LY3041658 Fab light chain, Interleukin-8, ... (6 entities in total)
• Functional Keywords: cxcr1, cxcr2, neutrophil, interleukin-8, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 111056.30

Authors

Durbin, J.D.,Druzina, Z. (deposition date: 2020-05-14, release date: 2020-11-25, Last modification date: 2024-10-30)

Primary citation

Boyles, J.S.,Beidler, C.B.,Strifler, B.A.,Girard, D.S.,Druzina, Z.,Durbin, J.D.,Swearingen, M.L.,Lee, L.N.,Kikly, K.,Chintharlapalli, S.,Witcher, D.R.
Discovery and characterization of a neutralizing pan-ELR+CXC chemokine monoclonal antibody.
Mabs, 12:1831880-1831880,

PubMed Abstract: CXCR1 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 ELRCXC 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 ELRCXC chemokines and three of five mouse and rat ELRCXC chemokines with high affinity. LY3041658 is able to block ELRCXC chemokine-induced Ca mobilization, CXCR2 internalization, and chemotaxis as well as neutrophil mobilization without affecting other neutrophil functions. In addition to the and 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.

PubMed: 33183151
DOI: 10.1080/19420862.2020.1831880

Experimental method

X-RAY DIFFRACTION (2.28 Å)