164: CSL324, a humanised anti G-CSFR antibody, can inhibit neutrophil migration while not impaction on neutrophil number or effector functions

Abstract

Neutrophils are the most abundant white blood cells (40–60%) and play an essential role in initiating the clearance of bacterial and fungal infections and maintaining inflammation. Tight regulation of both neutrophil number and recruitment to sites of inflammation is critical in maintaining a balanced immune response. Granulocyte Colony-Stimulating Factor (G-CSF) is the major cytokine regulator of neutrophils, controlling various aspects of neutrophil development and activity including neutrophil mobilization from the bone arrow into the blood and recruitment to inflamed tissue sites. G-CSF acts via binding the homodimeric G-CSF receptor (G-CSFR) resulting in the activation of Jak1 and Jak2 protein tyrosine kinases, and in turn Stat-3. Animal studies demonstrate that Stat-3 signaling is critical for controlling GCSF induced mobilization via increased expression of the chemokine receptor CXCR2. In various inflammatory conditions, such as rheumatoid arthritis, vascilulitis, cystic fibrosis and inflammatory bowel disease, there is an increase in serum G-CSF which correlates to an increase in the ability of activated neutrophils to infiltrate tissues which can contribute to the pathogenesis of disease. We hypothesise that blocking the activity of G-CSF with an anti-G-CSFR antibody will reduce G-CSF-driven mobilization and recruitment and will assist in reducing inflammation in these patients. CSL324 is a fully human antibody that binds to the G-CSFR, and neutralises the activity of G-CSF in various in vitro assays. CSL324 inhibits the G-CSF mediated expression of CXCR1 and CXCR2 on neutrophils which correlates with reduced migratory potential to various chemo-attractants. In vivo NHP studies demonstrate that administration of CSL324 is well tolerated and does not result in neutropenia supporting the development of this antibody for indications where neutrophils contribute to the disease pathogenesis.