Interleukin-2 (IL-2) has been prescribed to treat metastatic renal cell carcinoma and melanoma, but high toxicities have limited its use. Scientists have been working on various strategies to improve it, and now a team at the University of Washington has used computer programs to design a new protein that looks like IL-2 but doesn’t trigger dangerous side effects.
The new protein, dubbed Neo-2/15, resembles both IL-2 and IL-15, which is also being studied as an anticancer therapy. In tests on animal models, the synthetic drug activated cancer-fighting T cells just as the naturally occurring IL-2 does, and it slowed tumor growth, but it didn’t cause toxic side effects, the team reported in the journal Nature.
“Neo-2/15 has therapeutic properties that are at least as good as or better than naturally occurring IL-2, but it was computationally designed to be much less toxic,” said the study’s co-lead author, Umut Ulge, in a statement.
IL-2 is an effective treatment for some cancer patients that have exhausted other options. However, despite being on the market for decades, it has never really gained popularity, partially due to its precarious safety profile. Because IL-2 has a short serum half-life, it is often given at a high dose to achieve optimal cancer-killing effect, and that only increases the likelihood of severe complications, including death.
So the pharma industry has been pulling back from the IL-2 class in recent years. Novartis sold Proleukin rights in the U.S. to Prometheus Laboratories in 2010 and ex-U.S. rights to Clinigen in 2018.
Natural IL-2 binds to three receptors: alpha, beta and gamma. While T-cell activation via beta and gamma receptors leads to therapeutic antitumor activity, IL-2’s binding to alpha receptor-expressing cells is believed to cause disastrous side effects as well as immunosuppression, the UW team explained in a statement.
To design their own protein, the researchers used a computer program called Rosetta that was developed in the lab of biochemist David Baker, the study’s leader. Using Rosetta, the team came up with Neo-2/15, which has surfaces that bind to IL-2 receptors beta and gamma but not the alpha receptor.
“This is the first example of a completely de novo designed protein which has very clear therapeutic anticancer potential. So this could be a first of many new drugs that have better properties than previous drugs,” said Baker in a recorded video interview.
Attempts to update IL-2 have seen their fair share of failures lately. Nektar Therapeutics’ long-acting IL-2 candidate NKTR-214, for example, had previously failed as a monotherapy. And top-line data from a phase 1/2 trial combining it with Bristol-Myers Squibb’s Opdivo also showed a reduced overall response rate from an earlier readout, prompting a bearish report from Plainview LLC.
Others are still pushing ahead with their IL-2 candidates. Alkermes is testing its ALKS 4230 in the monotherapy setting, and in September 2018 it expanded its ongoing phase 1 study to evaluate it in combination with Merck & Co.’s PD-1 inhibitor Keytruda. California biotech Synthorx recently got $131 million in an upsized IPO, and it’s looking to use the money to advance its lead molecule, Synthorin IL-2, into clinical trials this year.
There’s still a long way to go for Neo-2/15, but the UW team appears to be confident in its future.
“Neo-2/15 is very small and very stable. Because we designed it from scratch, we understand all its parts, and we can continue to improve it making it even more stable and active,” said the study’s co-lead author, Daniel-Adriano Silva, in a statement.
The next item on the team’s agenda is to enlarge the molecule to optimize it for use in people, said Baker. After further safety tests, a drug could be ready to enter clinical trials in a few years, the researchers reported.