Next-gen antibody shows promise as lung fibrosis treatment

Australian and US researchers have found that a locally developed molecule called an ‘i-body’ serves as a powerful inhibitor of fibroblast migration in human lungs, providing promising evidence for a new treatment of lung fibrosis. Their work has been published in the journal Scientific Reports.

Lung fibrosis, also referred to as idiopathic pulmonary fibrosis (IPF), is a debilitating and life-limiting disease that causes irreversible scarring of lung tissue. The cause is unknown and the scarring continues to worsen over time, making it difficult to breathe. Prognosis is very poor, with a median survival of only three to five years.

Currently, there are just two treatments for IPF — pirfenidone and nintedanib — approved for use in Australia. These drugs are not curative but slow the disease progression, and patients tend to discontinue use due to severe side effects.

Unlike these existing treatments, the i-body known as AD-114 is designed to mimic the shape of the antigen-binding domain of shark antibodies and their key stability features. Developed by Australian biotech company AdAlta based on an antibody found in Wobbegong sharks, it can carry out the functional role of recognising and binding to other molecules/antigens, including disease targets, to produce a therapeutic effect.

In preclinical research conducted by AdAlta (based at La Trobe University), The Alfred Hospital and Cedars-Sinai, AD-114 was found to selectively target and bind to CXCR4, a protein expressed at higher levels in patients with lung fibrosis. CXCR4 is believed to play a role in the recruitment of fibrotic cells to the lung, which is thought to contribute to the progression of lung fibrosis.

The study also demonstrated that AD-114 slows the migration of diseased fibroblasts but has no effect on healthy cells. It additionally reduces the overproduction of collagen, a protein that is known to contribute to the disease pathology of IPF.

“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,” said La Trobe researcher Dr Kate Griffiths, a co-author on the paper. “We have been able to show that the i-body AD-114 binds to lung tissue from IPF patients, and that the i-body blocks migration of some of the cells that are implicated in fibrosis without influencing or impacting the healthy cells. In an animal model, we have shown that the i-body has a protective effect on an artificially induced form of lung fibrosis.

“Unfortunately there is no cure for IPF as the scarring of the lung tissue is irreversible. With limited therapeutic options available to patients worldwide, there is a significant unmet medical need in the treatment of this rare lung disease. Our data, however, clearly demonstrate the therapeutic potential of the i-body in the case of IPF and show strong promise as a future therapeutic option.”

AdAlta Chief Scientific Officer Associate Professor Mick Foley, a co-author on the paper and co-inventor of AD-114, said the i-bodies are “remarkable” due to their “incredible specificity and affinity with their target”.

“Unlike existing treatments for IPF, which have an unknown or very broad mode of action, the mechanism of action AD-114 is exquisitely specific and well understood,” he said. “The new drug could potentially bring the progression of the disease to a grinding halt.”

AD-114 has already received orphan drug status by the US FDA, enabling its approval to potentially be fast-tracked. The first human trials of the drug will begin in Australia later this year.

Image credit: ©stock.adobe.com/au/Minerva Studio