Cytokines, such as interleukin-2, emerged decades ago as promising cancer treatments. After all, they were the first modern drugs to prove that the immune system could be targeted to treat cancer, says Aaron Ring, M.D., Ph.D., a professor of immunology at Yale University and founder of Simcha Therapeutics.
Problem is, cytokines evolved as signaling molecules and not to be cancer drugs.
“They evolved to be like Swiss army knives with many different functions,” Ring told Fierce Biotech. “Some functions can be useful, and others can be dangerous, toxic, or even oppose the function you are looking for.”
Native interleukins need to be given at high doses and can cause side effects like immunosuppression and vascular leak, where fluids and proteins leak from blood vessels into surrounding tissues, causing organ damage.
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Simcha wants to solve those problems, and others, by engineering cytokines with a deliberate therapeutic purpose—and it’s raised $25 million from WuXi AppTec, Sequoia Capital and Connecticut Innovations to do so.
Its lead program is a custom-built IL-18 that surmounts hurdles faced by the native protein. Other companies, like GlaxoSmithKline, had tried to develop IL-18 before, but ran into an unexpected problem.
“What they found was, for a cytokine, IL-18 was very well tolerated. It wasn’t limited by its toxicities,” Ring said. “Rather, what they found was, in a large trial of over 60 melanoma patients, there were absolutely no responses. That was shocking to us. How could this powerful cytokine acting on the right T cells not work?”
Ring looked for “counter-measures” that tumors might take to evade IL-18. His team learned of an IL-18 binding protein, a “decoy” receptor called IL-18BP, which binds to the drug and blocks it from its receptor.
“By no means were we the first people to describe this receptor … We had thought IL-18 might work but for this ‘decoy’ and if we could take it out of the equation, [IL-18] would be a very effective anti-tumor therapy,” Ring said.
He and his colleagues found that the “decoy” is “frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice,” in a paper published in the journal Nature.
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They used a protein engineering method called directed evolution to develop a “decoy-resistant” IL-18.
“You start by taking the molecule you want to evolve and diversity it: you make many hundreds of millions of different versions of that molecule,” Ring said. “Most are going to be complete garbage—you’ve broken the molecule. But within that, there will be ones where the mutations you made are beneficial.”
Out of the 300 million IL-18 variants Simcha screened, it landed on one that only bound the true IL-18 receptor and not the “decoy.”
In the Nature paper, the researchers showed that their designer IL-18 brought about anti-tumor effects in mouse tumor models, boosting the development of effector T cells and decreasing the prevalence of exhausted T cells. The drug also activated and expanded populations of natural killer cells, all of which could help more patients respond to immunotherapies like checkpoint inhibitors.
Other companies, like Synthorx—now part of Sanofi—and Nektar Therapeutics are working on other interleukins, including IL-2 and its cousin, IL-15.
“What other companies have done very successfully is alter the properties of cytokines … extending their half-life or modifying certain interfaces,” Ring said. “It works for many different cytokines, but not all of them. There’s no one-size-fits-all approach to improving them.”
With the $25 million in the bag, Simcha will build its executive team while pushing ST-067 toward an IND filing early next year.
“We are tremendously excited about IL-18 and the potential of our drug to be a game changer in immuno-oncology,” Ring said. “That, of course, is going to take a huge portion of our focus and effort, but there are dozens of cytokines in the body and many more cytokine-like molecules … We do plan to and we are starting to engage in additional campaigns on other cytokines.”