Blocking Specific ‘Signaling Molecule’ Seen to Ease Inflammation, Scarring in Early Study
Targeting a signaling molecule called CCL24 with a new antibody was seen to lessen inflammation and scarring (fibrosis) in a mouse model of systemic sclerosis (SSc), research shows.
The study, “Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis,” was published in journal Annals of the Rheumatic Diseases.
Chemokines are molecules involved in inflammation that act as chemical attractants of immune cells, regulating cell trafficking, the formation of new blood vessels (angiogenesis), and the production of collagen, whose accumulation in tissues is a hallmark of fibrosis.
Research has suggested that chemokines play an important role in SSc by promoting the activation of fibroblasts into myofibroblasts — the cells responsible for the synthesis and buildup of scar tissue — by stimulating the activation of inflammatory cells, and by dysregulating angiogenesis.
Here researchers show, for the first time, that a chemokine called CCL24 is involved in the development of SSc, and that blocking this molecule has clinical benefits.
They first discovered that the levels of CCL24 were increased in blood samples from SSc patients, compared to healthy controls, with an average of 1,003 and 262 picograms per milliliter (pg/mL), respectively. Additionally, the levels of CCL24 and its binding partner, called CCR3, were higher in skin biopsies of patients with early diffuse SSc.
Then, to confirm the importance of CCL24, the team used an animal model of the disease. In mice that lacked the CCL24 gene, markers of the disease — including skin thickness and immune cell infiltration into bronchoalveolar lavage fluid — were reduced.
Researchers then tested if blocking CCL24 with a newly developed antibody, called CM-101, affected the transition of fibroblasts into damaging myofibroblasts. Results showed that fibroblasts exposed to blood serum from SSc patients and treated with CM-101 underwent a 50% decrease in their ability to transform into myofibroblasts compared to control cells.
Treating the SSc mouse model with two different concentrations of CM-101, 0.5 or 2.5 mg/kg, significantly reduced skin thickness by 31 and 57 percent, respectively. Collagen deposition and fibroblasts’ activation also lessened with treatment.
The team also evaluated whether CM-101 had an effect on lung fibrosis. Quantification analysis showed this antibody reduced lung fibrosis by 40% compared with control mice.
“Our findings provide the first evidence that an anti-inflammatory, antifibrotic approach selectively targeting the CCL24 pathway robustly attenuates experimental skin and lung inflammation, and fibrosis,” the researchers wrote.
“These preclinical data may support the translation to clinic of an anti-CCL24 antibody to attenuate the progression of fibrosis in SSc” patients, they concluded.