1556 CSL324, a G-CSF receptor antagonist, blocks neutrophil migration markers that are upregulated in hidradenitis suppurativa

Neutrophils contribute to the pathophysiology of hidradenitis suppurativa (HS), a chronic debilitating inflammatory skin disease, yet their exact role remains to be fully defined. Granulocyte colony-stimulating factor (G-CSF), a major regulator of neutrophil development and survival, can be blocked by the novel, fully human anti-G-CSF receptor (G-CSFR) monoclonal antibody CSL324. We investigated the activation and migration of neutrophils in HS and the impact of blocking G-CSFR with CSL324. Neutrophil numbers were significantly higher in HS lesions compared with biopsies from healthy donors (HD)(p<0.0001). In peripheral blood samples, mean neutrophil counts were significantly higher in patients with HS than HD. Neutrophil migration pathways were increased in patients with HS and their neutrophils demonstrated an increased migration phenotype, with higher mean CXCR1 on the surface of neutrophils in patients with HS. G-CSF was a key driver of the transcriptomic changes in the peripheral blood of patients with HS and was elevated in serum from patients with HS compared with HD (p=0.013). Administration of CSL324 in a randomized, double-blind, placebo-controlled study CSL324_1001 inhibited G-CSF-induced similar transcriptional changes in HD to those observed in the HS cohort, as highlighted by expression changes in genes related to neutrophil migratory capacity. Our data suggests that neutrophils contribute to HS pathophysiology and that neutrophils are increased in lesions due to an increase in G-CSF-driven migration. CSL324 counteracted G-CSF-induced transcriptomic changes and blocked neutrophil migration by reducing cell surface levels of chemokine receptors.