After demonstrating in 2016 how its synthetic biology technology could produce new biologic drugs, San Diego’s Synthorx today revealed that its lead drug candidate is an improved version of interleukin-2, an anti-cancer drug of intense commercial interest in the 1980s.
Synthorx said its improved version of interleukin-2, known as Synthorin IL-2, is at the vanguard in a portfolio of enhanced cytokines the company plans to advance with $63 million in a Series C financing round disclosed today. Cytokines are small proteins that are important in cell signaling and play a key role in modulating the immune system. But these drugs can also cause serious side effects.
The new funding, which brings total fund-raising at Synthorx to roughly $79 million, was led by OrbiMed, the New York private equity firm, and joined by Medicxi and Osage University Partners. San Diego’s Avalon Ventures and Correlation Ventures, which were the founding investors, also joined the round, along with Boston’s RA Capital Management, an earlier investor.
The funding will be used to advance Synthorin IL-2 into early clinical studies by the first half of 2019, but is really intended to build the company and its overall ability to develop a suite of enhanced cytokine drugs, Synthorx CEO Laura Shawver (pictured above) said in a recent interview. The company currently has 17 employees, she added.
Interleukin-2, which regulates the activities of white blood cells responsible for immunity, was hailed as a breakthrough cancer drug in the 1980s. Cetus, a biotech then based in Emeryville, CA, used recombinant DNA techniques to create a proprietary version of the protein and advanced it through clinical trials at a cost of more than $100 million. But those studies showed interleukin-2 worked in only 10 to 20 percent of kidney cancer patients—and posed severe, life-threatening side effects, chiefly fluid buildup from leaking blood vessels.
The FDA refused to approve Cetus’ application to market IL-2 in the United States in mid-1990, a setback that led to Chiron’s acquisition of Cetus in 1991. Chiron continued development, and the FDA finally approved IL-2 (Proleukin) for metastatic renal carcinoma in 1992.
“It was the first immuno-oncology drug approved, even before we had the term immuno-oncology drug,” Shawver said. But the toxic side effects of IL-2 were problematic because IL-2 has both immune stimulating and immune repressing activities—depending on the type of receptor it binds to (the IL-2 receptor has three forms). The IL-2 molecule also breaks down relatively quickly, and is often administered in high doses—which can worsen the adverse effects.
Synthorx has set out to address the side effects in a two-step process. The first step is intended to ensure that the interleukin-2 acts only to boost the immune response by incorporating a synthetic amino acid to the protein in a specific location, Shawver said. Because interleukin-2 can bind to more than one receptor, this approach is intended to ensure that Synthorin IL-2 binds to the correct IL-receptor.
By using technology developed in Floyd Romesberg’s lab at The Scripps Research Institute, Synthorx has shown it can engineer E. coli bacteria to produce a variety of synthetic amino acids (as many as 152) by inserting a novel synthetic DNA base pair (X and Y) into the bacteria. (Their breakthrough in synthetic biology made the cover of the journal Nature when Romesberg’s lab reported the development in 2014.)
A second step extends the time that interleukin-2 can remain in the body by attaching polyethylene glycol to the protein, a technique known as pegylation that helps to keep the biologic drug from breaking down. The net effect is a biologic drug that is intended to act more precisely to boost the immune system, and is longer-lasting—so it can be administered in lower doses.
As Synthorx continues its pre-clinical studies, Shawver said, “We’ll need to demonstrate that we can selectively boost the immune-fighting ability without boosting those immune cells that are responsible for the side-effects.”
If Synthorx is successful, its approach could have wide-ranging applications as part of combination cancer treatments. The company says its enhanced cytokines could be used to boost the antitumor activity in a variety of leading immuno-oncology approaches, including checkpoint inhibitors, cancer vaccines, CAR-T therapies, and oncolytic viruses.
(Synthorx image of CEO Laura Shawver used with permission.)