CCL24 Blockade with Nebokitug Modulates Inflammation and Fibrosis Signatures in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation, fibrosis, and innate immune dysregulation, with no approved therapies. Nebokitug (CM-101), a humanized monoclonal antibody targeting CCL24, demonstrated anti-inflammatory, anti-fibrotic, and anti-cholestatic activity in a Phase 2 clinical trial in patients with PSC. We performed comprehensive serum proteomic analyses to characterize the mechanistic effects of the CCL24 blockade following treatment with nebokitug.

Serum samples from study patients treated with nebokitug 10 mg/kg (n = 21), 20 mg/kg (n = 27), or placebo (n = 18) were analyzed using the Olink Explore 3072 proximity extension assay. Differential protein expression, pathway enrichment, and liver-specific proteome analyses were performed. Proteins corresponding to four PSC-specific gene expression programs (GEPs), identified previously by single-cell liver transcriptomics, were evaluated. An Elastic Net machine learning model was trained to classify treatment response defined by changes in Enhanced Liver Fibrosis (ELF) scores, liver stiffness measurements, and PRO-C3 test results.

Nebokitug induced dose-dependent modulation of proteins involved in chemotaxis, leukocyte recruitment, extracellular matrix remodeling, cytokine signaling, and collagen organization. Proteins representing PSC-specific GEPs related to fibrosis, extracellular matrix remodeling, macrophage activation, myofibroblast biology, and immune activation and were reduced following nebokitug treatment, particularly in patients with moderate-to-advanced disease treated with the 20 mg/kg dose. A machine-learning model accurately identified responders (mean AUROC = 0.92), with liver-specific proteins representing the dominant predictive signature. Consistent with this finding, analysis of liver-specific proteins demonstrated clear separation between responders and non-responders in the 20 mg/kg group (p = 0.0001), further linking treatment response to modulation of liver-specific biology.

Comprehensive proteomic profiling demonstrates that a CCL24 blockade with nebokitug modulates key biological pathways driving PSC. These findings provide mechanistic support for nebokitug's effect in PSC and further validate CCL24 as a promising therapeutic target in this indication.