Cytokines such as interleukin-2 have long held great promise as cancer treatments, but they can cause nasty side effects that have limited their use. They’re not very good drugs because they haven’t evolved as drugs, but rather as signaling molecules, says Debanjan Ray, CEO of Synthekine, a biotech with a two-pronged plan to develop better cytokine treatments for cancer and autoimmune disease. It aims to deliver the pros of cytokines without the cons, both as standalone treatments and in combination with other approaches, such as CAR-T.
The company uncloaks with $82 million from Canaan Partners, Samsara BioCapital and The Column Group, with research and technology out of Stanford University. The funding will propel two programs into the clinic in 2021 as well as expand Synthekine’s discovery work and further develop its cytokine engineering platforms.
Its lead programs are cytokines engineered by making small changes to the wild-type proteins, Ray said, but the company is also pursuing synthetic cytokines, dubbed synthekines, that are built from the ground up.
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This way, Synthekine wants to improve upon treatments like Proleukin, a recombinant version of native IL-2.
“Proleukin is a great example—it has encouraging efficacy with deep and durable responses in a subset of patients. But it’s not used very much because of the toxicity that it drives,” Ray said. That toxicity includes immunosuppression and vascular leak, where fluids and proteins leak from blood vessels into surrounding tissues, causing organ damage.
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Synthekine’s pipeline is based on the work of K. Christopher Garcia, Ph.D., whose lab studies cell surface receptors and the ligands they bind to, including cytokines. The binding of cytokines to cell surface receptors drives signaling processes that can stimulate or suppress the immune system. Garcia’s lab has determined the 3D structures of many cytokine-receptor complexes, including interleukins 1, 2, 4, 6, 13, 17 and 23.
“He takes it a step beyond that, modifying the cytokine to see if it can deliver a selective activity to a particular cell type,” Ray said. Synthekine’s team of immunologists, cytokine biologists and protein engineers came together to pursue this work.
They’re working on STK-012, a partial IL-2 agonist designed to activate T cells that recognize tumor antigens, and STK-009, an orthogonal IL-2 ligand designed to activate CAR-T cells and other adoptive cell therapies inside a patient’s body.
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Although CAR-T therapies have transformed the treatment of certain blood cancers, they face challenges in solid tumors. Another big hurdle comes when the modified T cells are infused back into the patient’s body.
“Once they’re delivered, the physician has lost all control of the cells. They may or may not engraft. They may or may not expand. They may go into the tumor microenvironment and get exhausted,” Ray said. “One way to effectively signal T cells is through IL-2, but the wild-type is not a tenable mechanism for long-term dosing because of toxicity concerns.”
Synthekine is developing STK-009 for use with SYNCAR-001, a CD-19-targeting CAR-T therapy that has a mutated IL-2 receptor so that wild-type IL-2 can’t signal through it. STK-009 is designed to signal only through that mutated receptor and not through wild-type IL-2 receptor.
Ray likens the duo to a private lock-and-key system: “We deliver the CAR-T that works like you would expect, except it has this mutated receptor on it. We can deliver the IL-2 ligand to very selectively proliferate, activate and impact those CAR-T cells and avoid activity on wild-type T cells and wild-type NK cells. It’s a unique system we hope gives physicians control of CAR-Ts once they’ve bene dosed.”
Synthekine is starting with CD-19 CAR-T cells “because so much is known about that CAR-T,” Ray said. But the company is looking at other CAR-T targets, including those in solid tumors, and it thinks the approach could also work with regulatory T cells or tumor-infiltrating lymphocytes. While it plans to push forward its own pipeline, the company hopes to partner with other companies to explore other targets and cell types.
Beyond its two lead programs, both of which are based on wild-type IL-2, Synthekine is checking out different combinations of cytokines and receptors, including pairs that don’t naturally come together. This could lead to “brand new biology, brand new signaling” that can’t be found with wild-type cytokines.