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Welcoming the fourth wave of drug discovery
THOUSAND OAKS, Calif.—Dr. Ray Deshaies, senior vice president of global research at Amgen, believes he has identified the “fourth wave” of drug discovery: the advent of multispecific drugs that induce proximity to enable targeted cell degradation. Advancements in this concept will radically transform how scientists understand how drugs work and how new methodology can be applied to targeting disease. In a paper and an accompanying perspective piece recently published in Nature, he explored the potential of this trajectory and what it could mean for the future of drug development.
Induced proximity is already utilized in the body, as ubiquitin-tagged proteins can be absorbed by a proteasome and destroyed. Some viruses have been able to override a cell’s antiviral proteins by linking to those proteins and tricking the cell into trashing its own defenses. Proteolysis targeting chimera (PROTAC) molecules use the same playbook, initiating the degradation process by utilizing two classes of multispecific drugs, with one end “tethering” to the target needing to be altered while the other end binds to the cellular effector that acts on the target, like a matchmaker of sorts. This approach frees drugs from the strictures that require the target to have an active site, and the need for individual specificity based on the kinase differentials in different molecules. These matchmaker multispecifics have the potential to target the roughly 85 percent of proteins currently believed to be “undruggable.”
“In the future, medicines could function very differently than conventional medicines do today. In biopharma pipelines across the industry, we’re seeing more and more multispecific drugs that can form connections with two or more proteins,” said Deshaies. “They include some highly sophisticated structures that function as molecular matchmakers. By inducing proximity between their targets and natural enzymes or even cells, multispecifics can harness the awesome power of biology to go well beyond what conventional drugs can accomplish. This isn’t an incremental improvement in drug design, it’s a sea change.”
Last year, Deshaies reviewed the Amgen portfolio and realized that nearly two-thirds of the pipeline were already multispecific, recognizing that the concept was already pervasive. He then engaged with his process development colleagues to start planning for the future—developing classes of molecules specifically for biologics that lend themselves to multispecificity. They are seeking to create a “scaffold” for antibody protein fusions where this tether body will work in multiple instances. This would help to systematize that scaffold, enabling the establishment of a topology of placement and conjugation of cytokines and antibodies.
“A lot of people have written reviews of antibody drug conjugates (ADCs), bispecific T cell engagers (BiTE molecules) and PROTACs, but this is something bigger. All of these are different types of multispecifics, and if Amgen’s portfolio is any reflection [of the rest of the industry], this is a movement. This is not just a one-off here or there, this is a movement. It’s going to change our whole industry,” asserted Deshaies.
Looking down the road at future potential to develop this wave, Deshaies hopes for a day when researchers might be able to completely replace the cytokine with a synthetic protein that would allow for more effective control of antibodies, or even to make an antibody that would mimic the actions of a cytokine receptor. Deshaies says that would be revolutionary because one could get rid of cytokines altogether and just have bispecific antibodies.
According to Deshaies, “Multispecific molecules have the potential to expand the universe of druggable proteins from just 15 percent to nearly 100 percent. This new wave of innovation makes it possible to imagine a day when many more diseases can be treated or even cured.”
The most likely initial application of multispecifics will be in oncology, when even the most promising drugs may max out at 50-percent effectiveness and the need for protein degradation is very high. Science’s detailed understanding of cancer genomics, its lethality and its many undruggable targets make it a guaranteed application, though certainly not the only one. Deshaies does caution that just as the path to success with monoclonal antibodies, PROTACs or immunotherapy took decades, this too will be a long road from discovery to approval to market success. While there may be pressure to get the benefits to patients quickly, this is a new wave that will not happen overnight.
“We are developing a whole new modality,” he remarks. “We will have some molecules come out early that may not be the most effective or successful molecules, but meanwhile we will be accumulating learning just like we did with antibodies. They went through generations before reaching widespread success, and I expect it will be the same with PROTACs. We will invest the time to really understand the platform and answer the relevant questions to maximize it. I believe there will be a huge payoff over time—the potential payoff is enormous.”