Cytokines are small proteins that enable cells to communicate with each other, particularly to modulate the immune system—an increasingly popular target in drug development for immunology, virology, and cancer. But the challenge of using cytokines as therapeutics is that they are pleiotropic and promiscuous. The same cytokine has biological functions on many immune cells, stimulating and suppressing the immune system in different contexts. Promiscuity is far from an ideal drug characteristic, making it challenging to develop cytokine-based therapeutics, which need to be selective with their target and function.
Based in Menlo Park, California, Synthekine is an engineered cytokine therapeutics company developing disease-optimized treatments. The company uses immunological insights to guide targeted protein engineering to generate transformative medicines for cancer and autoimmune disorders. These various distinct cytokine engineering platforms all aim to generate selective cytokine therapeutics.
The company is developing selective agonists across several families of cytokines receptors and is marching forward with two lead clinical candidates. The most advanced program relies on their cytokine partial agonist platform. STK-012, an IL-2 partial agonist, is designed to selectively stimulate T cells that recognize tumor antigens and has demonstrated single-agent activity in preclinical tumor models. STK-009, an orthogonal IL-2, is designed to selectively activate CAR-Ts in vivo to selectively harness the potent anti-tumoral T-cell effector functions of IL-2 and improve the efficacy, durability, and manufacturability of CAR-T cell therapy.
Synthekine’s scientific advisory board is led by its founder, Stanford University School of Medicine Professor and HHMI Investigator K. Christopher Garcia, PhD, who has trailblazed research on the interaction between cytokines and their receptors. Garcia’s work has enabled the engineering of modified cytokines to deliver selective activity to particular cell types of therapeutic interest, giving them the potential for optimized efficacy, a larger therapeutic window, and improved patient safety.
GEN Edge spoke with Synthekine CEO Debanjan Ray, previously chief financial officer and head of business development at CytomX Therapeutics, about how the company is growing an initial set of licensed cytokine programs and platforms from Stanford into a clinical-stage pipeline and proprietary combinatorial engineering platform.
GEN Edge: What was the foundation for Synthekine’s launch?
Ray: We’re a company with ambitions to be the category-defining cytokine company in the industry. We build more selective cytokines using different platform technologies across autoimmune diseases and cancer.
The company was founded about three years ago by licensing a broad portfolio of cytokine programs (molecules or assets) and platforms (engineering technologies) from Dr. Chris Garcia’s lab at Stanford, which focuses on structure-based protein engineering to understand receptor-ligand interactions. He has been responsible for resolving the structure-function relationship of more than a dozen cytokines, starting with IL-2 back in the 2000s to, most recently, IL-12, IL-10, and IL-22. In 2019, Synthekine licensed several programs and a couple of platforms with the Garcia lab. That was the foundation for building Synthekine and motivated people to join and investors to put in capital.
GEN Edge: How is Synthekine developing the initial licensing into new medicines?
Ray: We’re developing three different engineering technologies to make selective cytokine drugs. The first engineering technology is what we call partial agonists. These are essentially modified wildtype cytokines mutated to bias the activity of specific receptors and cell types. Typically, a cytokine binds onto a cell via two or three receptors, and it’s the dimerization of those receptors that drives the downstream signaling. We can decipher where the cytokine binds the receptors and the mutations in and around those binding sites to change the cytokine’s affinity to a given receptor. That’s what a partial agonist is. The partial agonist is a cytokine that looks like the wildtype, with a few mutations that bias the activity towards specific receptors.
Our most advanced partial agonist program is STK-012, which targets IL-2. IL-2 is one of the most promiscuous cytokines, activating anti-inflammatory regulatory T-cells, pro-inflammatory T-cells, and NK cells. We think that the real driver of IL-2 efficacy is the stimulation of antigen-activated T cells, while stimulation of broader lymphocytes, such as NK cells, drives IL-2 toxicity. So, we’ve engineered a highly biased protein towards antigen-activated T-cells and biased away from NK cells. Each of these cells has a different expression of IL-2 receptors on its surface. Understanding which receptors are expressed and when on these different cells and then engineering a molecule that biases towards antigen-activated T-cells allowed us to build those unique molecules that so far preclinically have shown an excellent therapeutic index that’s better than wildtype IL-2 and the next generation IL-2 programs in the industry, known as non-alpha IL-2s.
We’re using that same partial agonist platform around other important but promiscuous cytokine targets. We’ve got a program against IL-12, a cytokine that has the promise to be very effective in cancer but has suffered from significant toxicities. We’re also using that platform for autoimmunity with IL-10, which is also very promiscuous.
Platform 2 is our orthogonal IL-2 platform. Cell therapies like CAR-Ts are powerful and have made significant inroads, particularly in hematological cancers. But in the end, a CAR-T is nothing more than a modified T-cell, and to drive the activation and persistence of these therapies, we need to feed them with cytokines. So, we’ve built a lock and key system, putting a modified orthogonal cytokine receptor on the surface of the CAR-T, and then we use a modified orthogonal cytokine (STK-009) that only binds through that modified receptor.
The idea is to engineer the modified cytokine receptor (the lock) into a CAR-T and then dose it with STK-009 (the key), which will bind to the lock to activate and proliferate only the CAR-T cells specifically. Preclinically, we have shown that we can significantly lower the dose of CAR-Ts using STK-009 to proliferate those CAR-Ts in vivo. Clinically, we hope to reduce the dose of CAR-Ts as well, which might help from a toxicity perspective.
From an efficacy perspective, STK-009 proliferates and activates those CAR-Ts and keeps them at a high level, which preclinically has shown deep and more durable responses than traditional CAR-Ts.
Our first program with this second platform technology we call SYNCAR-001, which is a CD19 CAR that includes the orthogonal receptor. We expect to file an IND on that program this year. The next step with this platform will be extending it to solid tumors. Our first orthogonal solid tumor CAR-T program is against a target called GPC3, which is a target expressed at high levels of some liver cancers. We recently presented data at AACR showing deep responses preclinical responses with our GPC3 CAR + STK-009.
Platform 3 is our surrogate cytokine platform. A cytokine is designed by nature to dimerize a pair of cytokine receptors on the cell’s surface to drive the downstream signaling. Cytokines evolved to fit into the binding pocket of two or three receptors to bring them together and drive the downstream signaling.
Our focus with the surrogate cytokine platform is on using antibody-like molecules that bind to each cytokine receptor. Those molecules pull together those cytokine receptors without reliance on the wildtype cytokine, and extracellular conversations drive the signal downstream. This is an entirely different way to engineer cytokines or generate biased cytokine signals. We are a leader in this field.
GEN Edge: How has Synthekine used a licensing portfolio of programs and platforms in the past three years?
Ray: The initial license from the Garcia lab included several partial agonists and the orthogonal and surrogate agonist platforms. But we have extended our efforts beyond these initial licenses. For example, the CD19 and GPC3 applications for our orthogonal IL-2 program were initiated at Synthekine.
The depth of the science we licensed from the Garcia lab at Stanford gave us a very fast start. Everything translated well in our hands, which sped up the company’s development. Over the past three years, we’ve built a deep pipeline of cytokine therapeutics both in the autoimmune and cancer spaces. In January 2022, we put our first program in the clinic with the first patient dosed with our IL-2 partial agonist, STK-012. We’re about to file the IND on our second program, a unique program where we’re combining cytokines with cell therapy.
We’ve accomplished a lot. We built a solid team. We’ve supplemented Chris’s expertise with a team with deep experience in cytokine discovery, development, and optimization. The leaders in this organization have spent decades working on cytokines. We’ve got a knowledgeable team about how human cytokines stimulate different cell types and what cell types we want to promote or avoid to expand their therapeutic index.
GEN Edge: How is Synthekine organized?
Ray: Synthekine is being built into a fully integrated company. We’re still early, but it’s important to have all the capabilities in-house. We’ve got strong discovery, protein engineering, and preclinical teams with a vivarium for in-house initial efficacy experiments. We’ve built a very strong Chemistry, manufacturing, and controls (CMC) team, but we don’t have the GMP manufacturing capabilities of the company, so we’re outsourcing that. Ultimately, contractors will generate the CAR-Ts being put into the patients for the cell therapy work. Still, our manufacturing team does the process development and transfers to our contractors, who will get us there.
In terms of the company’s integrated research capabilities, we design all the cytokines, whether partial agonists or surrogate agonists, at Synthekine. We do the in vitro validation and the in vivo efficacy studies here. We’re making the proteins for the non-human primate studies and then using outside parties for that preclinical work. That’s a pretty wide range of capabilities for a company of our size. And we’ve built a strong clinical team executing the clinical studies.
It’s a unique company in that we’ve got these three very different platforms, which requires quite a bit of strength across all of those different capabilities that we built. As we move forward, we will continue integrating, especially those development capabilities that can take molecules from phase one to phase two and hopefully phase three over time. We’ve consciously built a multi-prong pipeline, and the multiple programs are based on different technologies that don’t have fundamentally correlated risks. That is an important vision of this company. This is a competitive space, and there’s lots of innovation, especially in oncology. We ensure that we are keeping up with that innovation and thinking about the cytokines to target and drive the proper biology.
GEN Edge: What milestones does Synthekine have in its sights?
Ray: Near term, an important goal is clinical validation of the STK-012 and the orthogonal IL-2 programs and building a pipeline and advancing more of these biased cytokine and cell therapy programs. We’re excited about our breadth of programs. Many of these are in the preclinical stages of validation. Hopefully, we can move those into the clinic and generate some meaningful clinical data on the more mature programs in the near term.
We want to keep building that clinical pipeline as a midterm goal. I’d love to take one of our products through registration right across the finish. Longer-term, I want to build a truly fully integrated company with multiple products with a commercial focus and ultimately get our products to help patients with cancer and autoimmune disease.
