People with pulmonary fibrosis have cells filled with excessive fat (lipids) within the lungs. These cells are known as “foam cells.” How foam cells contribute to pulmonary fibrosis is unknown.

The investigators, led by Ross Summer MD, Associate Professor in the department of Pulmonary and Critical Care Medicine at Thomas Jefferson University, examined a mouse model of lung fibrosis caused by a chemical called bleomycin. Bleomycin is known to cause pulmonary fibrosis and problems with lung functioning. Foam cells responded to the chemical by contributing excessive levels of fat within the lung airspaces. These levels of lipids exceeded the amount that is normally found in the lung. The fat accumulation also occurred prior to the formation of fibrosis, at around three days following bleomycin. Fibrosis began to form at approximately 14 days after the chemical was given, as measured by collagen, an indicator of scar tissue formation.

The scientists then tested whether foam cells and fat accumulation occur in response to other known inducers of lung fibrosis, silica exposure and radiation injury. With these two types of fibrosis-inducers they again observed that foam cells accumulate in the lungs, preceding the formation of fibrosis.

According to first author, Freddy Romero, PhD, “Both the initial damage to the cells lining the airway of the lung and the inflammation are important, but the thing that drives the damage is the unregulated excess lipids in the distal airspaces.”

The researchers used a substance called granulocyte macrophage colony-stimulating factor (GM-CSF) in mice treated with bleomycin, to reduce the secretion of lipids and to help promote lipid removal in the lungs. This protein is naturally secreted by cells known as macrophages. GM-CSF reduced lung fibrosis by over 50 percent, based on collagen levels.

Esbriet (pirfenidone), developed by InterMune (which is now owned by Roche), has been available in Europe for IPF since 2011, while Boehringer Ingelheim’s Ofev (nintedanib) will soon hit the market, having been backed by advisors to the European Medicines Agency last month.

Dr. Feghali-Bostwick’s study was published in Science Translational Medicine. “We designed short peptides, stretches of amino acids, that matched or corresponded to different regions of endostatin to try to find out which region is really responsible for the reduction of fibrosis,” she said. They produced an endostatin-like protein that they called E4. When the group studied the E4 in healthy human skin cells that had been given treatment that would normally make them fibrotic, E4 effectively blocked fibrosis. E4 also protected the skin and lungs of mice from fibrosis in a complementary mouse model. E4 was even able to reverse existing signs of fibrosis.

iBio now has an exclusive, worldwide license to patents and pending patents related to this technology and is developing a program to test and produce the active ingredient in IBIO-CFB03 using iBioLaunch™ technology. According the company’s website, “The iBioLaunch™ platform is a proprietary gene expression technology that causes non-transgenic plants to rapidly produce high levels of target proteins.” Plants can be grown and can produce proteins at lower cost than is required for producing proteins in animals or cells.

According to the company, preclinical animal studies have demonstrated efficacy and lack of toxicity, therefore the drug can now justifiably advance to human clinical trials. Phase 1 studies will evaluate safety in healthy participants and will also examine preliminary effectiveness in patients.

Researchers used a standard animal model that emulated pulmonary fibrosis in humans, demonstrating favorable outcomes for PBI-4050 compared to a recently approved drug as treatment for IPF. PBI-4050 significantly reduced scarring in the lungs when compared to non-treated animals. Scientists also found that PBI-4050 and Pirfenidone combined generated unprecedented reduction of fibrotic markers, which indicates that there is a possibility of stabilization and clinical improvement in lung function.