CSL324, a granulocyte colony-stimulating factor receptor antagonist, blocks neutrophil migration markers that are upregulated in hidradenitis suppurativa

Abstract

Background Neutrophils have been shown to contribute to the pathophysiology of hidradenitis suppurativa (HS), a chronic, painful, and 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. Objectives We investigated the activation and migration of neutrophils in HS and the impact of blocking G-CSFR with CSL324. Methods Biopsy and peripheral blood samples were taken from participants of 2 studies: 2018.206, a non-interventional research study of systemic and dermal neutrophils and inflammatory markers in patients with neutrophilic skin diseases; and CSL324_1001 (ACTRN12616000846426), a single dose ascending and repeated dose, randomised, double-blind, placebo-controlled study to assess the safety, pharmacokinetics and pharmacodynamics of CSL324 in healthy adult subjects. Ex vivo experiments were performed, including neutrophil enumeration and immunophenotyping, migration, receptor occupancy and transcriptome analysis. Results The number of cells positive for the neutrophil markers myeloperoxidase (MPO) and neutrophil elastase (NE) was significantly higher in HS lesions compared with biopsies from healthy donors (HD) (p < 0.0001 and p = 0.0223, respectively). In peripheral blood samples, mean neutrophil counts were significantly higher in patients with HS than HD (2.98 versus 1.60 × 109/L, respectively; p = 8.8 × 10−4). Neutrophil migration pathways in peripheral blood 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 (24453.20 versus 20798.47 for HD; p = 0.03). 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 (mean 6.61 versus 3.84 pg/mL, respectively; p = 0.013). Administration of CSL324 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. Conclusions Data suggest 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.

Transcriptomic Analysis of Hidradenitis Suppurativa: A Unique Molecular Signature with Broad Immune Activation

“…Another approach to modulating the innate immune system involves targeting neutrophils. In agreement with our findings, neutrophils have been demonstrated to be involved in HS pathogenesis [13,16,25,34,35]. Anumigilimab, an antagonist of granulocytecolony-stimulating factor (G-CSF), blocking neutrophil migration and function, is under development for HS, but no clinical efficacy data have been published yet [35].…”

Emerging Treatments and the Clinical Trial Landscape for Hidradenitis Suppurativa Part I: Topical and Systemic Medical Therapies

“…CSL324 is a human recombinant GCSF receptor antagonist monoclonal antibody. Administration of systemic CSL324 decreased expression of genes associated with neutrophil migration in peripheral blood cells after stimulation in healthy participants [ 160 ]. An open-label phase 1 trial in 39 patients with HS or palmoplantar pustulosis was completed in October 2022 (NCT03972280).…”

Whole blood transcriptomics reveals granulocyte colony‐stimulating factor as a mediator of cardiopulmonary bypass‐induced systemic inflammatory response syndrome

“…To date, results show that blockade of endogenous G-CSFR is well tolerated, potently inhibits G-CSF-induced neutrophilia and counteracts the associated whole blood transcriptomic changes. 27,28 Importantly, treatment with the G-CSFR inhibitory antibody did not induce clinically significant neutropenia, or inhibit neutrophil effector functions. 27 Given the vast majority of CPB procedures are sterile, and patients are closely monitored during the perioperative period for infection, we suggest G-CSFR inhibition could provide a mechanism-based approach to limit neutrophil-mediated inflammation and organ damage.…”

“…More recently, an anti‐G‐CSFR antibody has undergone clinical trials for treatment of neutrophilic dermatoses (clinicaltrial.gov identified: NCT03972280, NCT04570267). To date, results show that blockade of endogenous G‐CSFR is well tolerated, potently inhibits G‐CSF‐induced neutrophilia and counteracts the associated whole blood transcriptomic changes 27,28 . Importantly, treatment with the G‐CSFR inhibitory antibody did not induce clinically significant neutropenia, or inhibit neutrophil effector functions 27 .…”