A positron emission tomography (PET) tracer that recognizes a potential protein biomarker of fibrotic interstitial lung diseases can be used to detect idiopathic pulmonary fibrosis (IPF) and several cancers in PET scans, a pilot clinical study suggests.
The research, “Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis,” was published recently in the journal Nature Communications.
Interstitial lung diseases (ILDs) comprise more than 200 disorders, including pulmonary fibrosis (PF), collectively characterized by progressive scarring (fibrosis) and impaired function of the lungs.
Integrins are cell surface proteins that mediate the adhesion to the extracellular matrix (ECM) — the network that surrounds and supports cells as they grow. Specifically, integrin αvβ6 stimulates the production of other ECM proteins by fibroblasts (connective tissue cells) during wound healing and tissue scarring.
Previous studies indicated that integrin αvβ6 could be used as a biomarker of ILD progression, since its levels are directly correlated with IPF mortality.
In addition to fibrotic ILDs, integrin αvβ6 also has been studied as a biomarker for several types of cancer, including colon, gastric, and non-small cell lung cancer, because it is overproduced by certain tumor cells.
Researchers from Pliant Therapeutics now have described the development of a new PET tracer — an imaging agent used during a PET scan — that specifically recognizes human integrin αvβ6.
Their main goal was to assess if this new PET tracer could be used to identify fibrotic lesions in the lungs of IPF patients, and to detect different types of cancer.
“Despite significant study in this field, biomarkers are urgently needed to monitor and assess treatment responses in clinical trials in IPF,” Scott Turner, PhD, Pliant’s vice president of translational sciences, said in a press release. “The lack of adequate tools necessitates large and lengthy clinical trials that slow the pace at which new therapies can be evaluated and potentially brought to market.”
To create the new PET imaging agent, investigators from Pliant collaborated with Sanjiv Gambhir, MD, PhD, professor of radiology at Stanford University. Together, they engineered a cystine knot peptide (knottin) to increase the tracer’s stability and specifically recognize integrin αvβ6.
First, they assessed the safety and pharmacokinetic properties of the new PET tracer in five healthy volunteers. (Pharmacokinetics is the study of how a compound is absorbed, distributed, metabolized, and eliminated from the body.)
No adverse side effects were reported following intravenous injection (into the vein) of the compound, indicating that the new PET tracer was safe to use in patients.
Next, researchers administered the PET tracer to six individuals who had been diagnosed with pancreatic, cervical, or lung cancer. They found that the imaging agent correctly labeled tumors in PET scans.
Then, the team administered the αvβ6 PET tracer to six IPF patients (mean age 72.5 years) diagnosed after a computed tomography (CT) scan. Compared to healthy volunteers, PET scans revealed that the tracer accumulated at fibrotic lesions with high levels of αvβ6, a molecular signature of the disease.
“The study results suggest that the PET tracers may have broad clinical application in detecting and diagnosing multiple indications, monitoring the efficacy of various therapeutics, as well as in staging diseases,” Gambhir said.
Pliant is now planning to take advantage of the new tracer to assess the effectiveness of PLN-74809, its lead candidate for the treatment of IPF, in an open-label, Phase 2a clinical trial (NCT04072315) that is currently recruiting participants at Stanford Medical Center.
Results of a prior Phase 1b trial in healthy volunteers showed that PLN-74809, a selective inhibitor of the αvβ6 and αvβ1 integrins, can prevent the activation of the pro-fibrotic protein TGF-beta by up to 70%. This experimental therapy already has received orphan drug designation by the U.S. Food and Drug Administration for treating IPF.
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