AD-114 for IPF Reduces Disease Progression in Patient-derived Cells and Mice, Study Shows
An Australian study showed that AD-114, an investigative therapy for idiopathic pulmonary fibrosis (IPF) developed by AdAlta, prevented the infiltration of immune cells and collagen build-up in lung cells from IPF patients. AD-114 also reduced fibrotic injury in a mouse model.
The study, “Anti-fibrotic Effects of CXCR4-Targeting i-body AD-114 in Preclinical Models of Pulmonary Fibrosis,” was published in the journal Scientific Reports.
Although Esbriet (pirfenidone, Genentech) and Ofev (nintedanib, Boehringer Ingelheim), the only currently approved therapies for IPF, are able to slow down disease progression, there’s no existing therapy that stops IPF from worsening.
The processes that cause progression of fibrosis, or scarring, in IPF remain controversial. Among the proposed pathways is the invasion of cells called fibroblasts (which produce collagen and are involved in wound healing) from fibrotic to normal lung areas.
Pro-inflammatory cytokines and chemokines, which are molecules produced by immune cells, are known promoters of cellular invasion in processes including fibrosis. In particular, the involvement of the CXC chemokine receptor 4 (CXCR4) is described in several types of cancer cells and in pulmonary and kidney fibrosis.
In preclinical studies, blocking CXCR4 resulted in anti-fibrotic effects. AD-114 binds to CXCR4 with high affinity, blocking its activity.
AD-114 is an unusually small protein that belongs to a class called i-bodies, which means it combines features of small molecules and antibodies. It is engineered on the scaffold of a human protein, but has the two-loop shape of shark antibodies for improved specificity.
Earlier studies reported that AD-114 binding to CXCR4 results in anti-inflammatory and anti-fibrotic effects.
The research team now reported that CXCR4 is expressed by different types of cells in the lung, and that its production is elevated in IPF patients, particularly those with rapid, progressing disease.
Researchers found that administration of AD-114 prevented invasive wound healing and secretion of type I collagen (the most abundant type of collagen) by fibroblasts collected from IPF patients — mainly from those with slow, progressive decline of lung function — but not by non-IPF lung fibroblasts.
In a mouse model of pulmonary fibrosis, AD-114 decreased the degree of fibrotic injury and the loss of body weight, which the researchers attributed to the reduced migration of fibroblasts to the injured lung, and to the inhibition of collagen production.
AD-114 also led to a greater reduction in the number of immune cells in mouse lungs compared to AMD3100 and Esbriet.
“Our data add to the small but robust and growing body of literature showing that CXCR4 is an important alternative target for treating IPF and other fibrotic diseases,” Kate Griffiths, a study co-author, said in a press release.
But “more research is warranted to better understand the role of CXCR4 signaling on these cells and in the overall fibrotic process,” the researchers wrote.
The team is now evaluating the specific cell types involved in the fibrotic effect of CXCR4 in the lung.
In 2017, the U.S. Food and Drug Administration granted orphan drug status to AD-114 as a potential IPF treatment, a designation that is intended to accelerate its development.