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

Background and aims: 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.

Methods

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.