Tag Technology Helps Drugmakers Assess If ‘The Juice Is Worth The Squeeze’
By Deborah Borfitz
June 15, 2022 | While the field of targeted protein degradation (TPD) continues its rapid expansion, with multiple TPD drugs now in clinical trials, researchers in Australia are jumping in at an earlier stage with “tag technology” to ensure the disease protein is worth designing a drug against in the first place. Their work—an extension of other tag-targeting protein degradation technologies—gives researchers the wherewithal to ask if, “the juice is worth the squeeze,” according to Rebecca Feltham, Ph.D., laboratory head in the Ubiquitin Signalling Division of the Walter and Eliza Hall Institute (WEHI).
As she rightly points out, most drugs that make it to the clinical trial stage ultimately fail, which is “extremely disappointing” given the hefty investment of time and money required for their development. Almost 95% of biomedical projects never enter human trials at all. The average cost of bringing a new drug to market is now estimated to be around $1.8 billion, and a key issue is the difficulty in assessing a drug’s true safety and effectiveness in preclinical studies.
Tag-targeted protein degradation is changing the game when it comes to target validation, Feltham says. Unlike conventional drug development that aims to inhibit the activity of disease-causing proteins, protein degrader technology looks to destroy those proteins, with precision targeting, leaving healthy parts of the body untouched.
“[TPD] technology allows us to mimic what would happen in real drug treatment scenarios to determine whether removal of that protein is beneficial to reducing disease, and safe for the patient,” says Feltham. “Validating targets robustly before entering into a large drug discovery study to design the therapeutic counterpart—the drug that will be given to patients—is critical to reducing drug failure rates.”
As described in a study recently published in Nature Communications (DOI: 10.1038/s41467-022-29670-1), Feltham and her colleagues developed and characterized a new tagging system using the NanoLuc luciferase technology of U.S. biotech company Promega. Luciferase is a light-producing enzyme naturally found in fireflies.
The technology, “expands the current [proteolysis targeting chimera or PROTAC] toolbox to give researchers more flexibility to validate their targets,” says Charlene Magtoto, Ph.D., a WEHI postdoctoral researcher. “We also, for the first time, benchmarked our new system to the existing technologies to compressively characterize the advantages and disadvantages of each tool in the tag-degrader toolbox.”
Consequently, the drugging of virtually any protein in the proteome can be modelled to allow robust validation to be performed,” Magtoto says. “We can do this because the tag we use is a generic entity that can be attached to any protein. After [it] is attached to our protein of interest, we use drugs that bind the tag to destroy the protein.”
Importantly, she adds, to truly mimic what happens when patients in a clinical trial receive a TPD-based drug, researchers need a system that allows for “reversible removal” of the target protein. This is because when patients stop taking a TPD drug, the targeted protein will restore to normal levels. Other commonly used validation technologies (notably CRISPR) instead “terminally remove the protein and don’t allow for reversible depletion.”
Focus On Cancer
The WEHI research team collaborated on the study with Promega and the University of Dundee to develop the new tag-targeted degradation system and benchmark existing systems against each other, says Feltham. “Dundee had previously developed a tag system that we wanted to compare to our system and [others].” The tag-drugs being used have two arms and Promega had already developed half of it.
Separately, Feltham says, her lab has been working with other Australian labs and institutes to apply its knowledge and expertise in tag-degradation systems to validate numerous potential cancer targets in a project funded by the Australian Medical Research Future Fund. The group has used tag-targeting TPD technology to investigate 24 potential drug targets, 19 of which are linked to cancer.
The lack of effective new drugs is a particular barrier for cancer researchers, with as few as 1 in 15 developmental drugs progressing into the clinic. “Most of the 150,000 Australians diagnosed with cancer each year are still treated with drugs that came onto the market over 25 years ago, which can cause significant side effects,” she notes.
Many labs and companies (mainly in the U.S.) are working in the TPD field and developing degrader drugs against different proteins, says Feltham. Although the focus currently is on cancer, progress is being made in other therapeutic areas, including neurodegenerative diseases. Outside of Australia, only a handful of labs in the U.S., U.K., and Vienna are concentrating on tag-degraders using Promega’s luciferase technology.