Biotechnology plays a key role in bringing new treatments to market, whether it’s early research that provides a foundation for developing future medicines or tools to make that development process more efficient. As covered in a previous Lab Manager Big Picture series, drug discovery and development is a long and expensive process that often ends in failure. As such, many researchers and companies are focusing their efforts on identifying which potential treatments are most likely to succeed at the very earliest stages. However, this work comes with challenges of its own.
Rather than providing a broad overview of how biotech as a whole is affecting the creation of new treatments, this article will provide a narrow focus on one recently published proof-of-concept project as well as recent developments in an emerging tool for drug discovery researchers, along with the challenges faced and how scientists solved them.
Most drugs today are based on compounds that either stop or otherwise interfere with the activity of proteins known to cause disease, but what if we could get rid of those disease-causing proteins altogether? This is basically what small molecules called proteolysis targeting chimeras (PROTACs) do, essentially tagging proteins that cause disease so they can be degraded by cells’ proteasomes. Once considered far-fetched, research on PROTACs is growing quickly and has shown that using these molecules in treatments may not be as out-there as initially thought. In fact, cancer treatments based on PROTACs are now entering clinical trials to be tested in humans. The first PROTACs entered clinical trials in 2019 and, as of January 2022, there were 21 degraders being tested in clinical trials—of that total, 15 included PROTACs.
Recently-published proof-of-concept research led by Alessio Ciulli, from the University of Dundee’s Centre for Targeted Protein Degradation, and Danette Daniels, former senior research scientist at Promega Corporation, now vice president of the protein degrader platform at Foghorn Therapeutics, could eventually help other researchers make such treatments more effective. While traditional PROTACs have a two-headed, or bivalent, design, Ciulli, Daniels, and their colleagues created PROTACs with a three-headed, or trivalent design. Though initially not even sure their design would work, their research showed that not only did the trivalent PROTACs work, they worked much better—degrading target proteins more effectively—than the traditional design.
“We couldn't anticipate they would work so well, that they were so potent, that they were so remarkable in their activity,” said Ciulli in an interview with Lab Manager in December 2021. Once the team had surpassed the initial challenge of determining if their design would even work, the next challenge was to find out how it worked and what made their PROTACs so special. Ciulli said a whole range of methods and reaching out to external labs was the key to answering these questions.
Next, the team needed to prove that it was the molecule’s three heads “engaging” at the same time that made it so effective, which they were able to prove by adding some extra controls during the revision process of the research. Ciulli said this stage of research is often challenging with big projects as key players may leave at different points and then come back with more work. “We were very fortunate that we were able to address this challenge, because we had great people in our labs that could step up to that challenge,” he said.
The building blocks of innovation
While Daniels, speaking in the same December 2021 interview, said their compound is unlikely to be used in actual treatments, it shows a trivalent design is possible, providing an important foundation for future work. And, while reviewers of their research were at first skeptical that their PROTACs could even be used in mice or cells for preclinical research, the team’s later experiments showed the molecules could be.
“Without that foundation, you can't get to this later stage of therapeutics,” Daniels said. “I think it seeds the idea for what could be next for therapeutics, and opens more possibilities.”
Currently, most research on PROTACs focuses on monovalent (one head) vs bivalent and which has an advantage over the other, the two researchers said. The trivalent design gives researchers another option to think about, which may help drive further innovation in the field.
“There's a lot of things that you could do with that scaffold of the trivalent complex that I think people are starting to consider,” Daniels said.
Both researchers had worked together previously and made significant contributions to PROTACs research, which led to the initial idea of making a trivalent molecule, so while they took a risk with the trivalent PROTACs research, it was one they felt comfortable taking. Both said strong collaboration was critical to tackling that risk and the other challenges of the project.
“The best science is truly collaborative,” Ciulli said. “If you can find that fantastic collaborator, you can take your science in a different direction, but not only that, you can also see how your science informs them.”
As well as research that provides more insight to drive innovation, biotech also provides drug discovery researchers with tools that help solve other key challenges in the field, for example drug attrition rates. Most drugs never make it to market after billions in investment because the current toolbox of in vitro and in vivo animal tests fail to predict human effects.
Organ-on-a-chip (OOC) also known as microphysiological system (MPS) represents one such tool. The purpose of OOC is to improve the translatability of data between the laboratory and the clinic by enabling users to grow tiny three-dimensional human organs and tissues in the lab. With fluid circulating through them to recapitulate blood flow, these healthy or diseased organ mimics function and respond to drugs in the same way as in humans. At the field’s cutting edge are multi-organ models which recreate the interaction and communication of a complex human system. Currently, only animal studies enable such insights. There’s much debate about whether OOC can replace animal testing, to address the data accuracy and ethical concerns surrounding its use. Time will tell, however, OOC provides a unique path for new gene and cellular therapies where species differences render animal models unsuitable.
According to Dr. Audrey Dubourg, product manager for organ-on-a-chip provider CN Bio, “OOC is not a technology to keep an eye on, it is implementable now. The human-relevant insights OOC provides are being used to cross-validate and supplement data derived from traditional methodologies for better informed decision-making earlier in the drug development process. By allowing researchers to rule out drug candidates that are unlikely to be successful in humans before they reach clinical trials, OOC’s potential to deliver safer and more efficacious therapeutics has piqued the interest of many, including the regulators who are working with providers to support its widespread adoption into drug discovery workflows.”
Challenges with OOC
However, she added that challenges remain to OOC gaining that widespread adoption, with the main one being regulatory acceptance as new gold standards need to be established. This means OOC have to be evaluated against current methods. “Very few investigational new drug (IND) submissions currently use OOC data to support clinical development, with regulators still expecting studies to use data from animal models,” Dubourg said. “Lack of standardization is a related issue, as companies that develop and produce OOC all have different methods of mimicking organs. Standardization will allow for better comparison and translating of OOC data to in vivo/clinical data,” Dubourg says. However, she explains, OOC as they are now are being used alongside current gold-standard methods to better inform the drug discovery process.
One final challenge includes the lack of a human-relevant cell supply for some organs, such as the gut, as some cells are difficult to isolate and grow in vitro, Dubourg explains. That, along with restrictions on the use and import of certain cells by some countries, makes it difficult for OOC technology to fully move away from immortalized cell lines, she says.
As with Ciulli and Daniels in their PROTACs research, Dubourg said collaboration has been the key for her company as they work to solve these challenges. They’ve been working with various regulators, including the FDA, stakeholders within industry and academia, plus consortiums such as the IQ MPS to standardize endpoint assays, readouts, and the models themselves.
When it comes to cell supply, “unfortunately there is no shortcut,” Dubourg said, adding strong partnerships with a wide range of suppliers are essential to ensure access to large donor stocks and high-quality cells for 3D culture at a reasonable cost. For labs looking to adopt OOC technology, she recommends making sure they understand all the options available as there’s such a huge variety, as well as looking for companies that offer strong expertise and customer service.
According to Dubourg, the OOC space is expected to see healthy market growth, estimated to expand at a compound annual growth rate of 39.9 percent to reach a value of $220 million USD by 2025.
In addition to addressing the challenges above, Dubourg cites “factors driving innovation in the OOC space are mostly focused on driving improved data translatability throughout the drug discovery and development workflow. These include the need for new or more physiologically relevant OOC models, more complex models made up of multiple interconnected organs that mimic human systems and processes, and addressing the demand for high-throughput OOC systems.”
Based on these two examples of work being done in the PROTACs and OOC spaces, collaboration and partnerships are critical to solving key challenges in biotechnology, whether that’s taking a risk to try out a seemingly impossible idea, or gaining a more widespread adoption of new approach methodologies (NAMs), helping to eventually achieve the end goal of better, successfully-approved treatments for patients.