Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs that modulate powerful cytokine pathways, launched today with $25 million in Series A financing and a mission to harness the precision and power of the immune system through the use of directed evolution.

Simcha's lead program involves a customized variant of interleukin-18 (IL-18), a cytokine with potent antitumor effects, developed in the lab of Scientific Founder Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The biology and preclinical profile of this molecule, which Simcha expects to advance to the clinic in the first half of 2021, is described in detail in a scientific paper published today in the journal Nature.

Cytokine therapies heralded the immuno-oncology revolution more than 30 years ago with the discovery that interleukin-2 (IL-2) could promote rare, but dramatic, responses in melanoma and kidney cancer patients. However, they have not lived up to their promise as a class due to substantial toxicities and limited efficacy. Simcha was founded to overcome those obstacles by using directed evolution to engineer a new generation of cytokines with improved properties relative to those of their native variants. Simcha's molecules are purpose-built to control immune cell activation, differentiation and proliferation - and to reverse the immunosuppressive tumor microenvironment that is a barrier to effective eradication of the cancer.

"Cytokines represent a compelling therapeutic class because they tap into pathways that are hard-wired into immune cells. The challenge is that nature didn't design them to be anti-cancer therapies; they're signaling molecules, so their activity can be hard to specifically direct," Dr. Ring said. "At Simcha, we set out to improve on nature's design by engineering custom-built proteins that can precisely activate and expand populations of crucial immune responders, such as natural killer (NK) cells and T cells. Too many cancer patients do not respond to the immunotherapies available today. We're hopeful that our approach will provide new options and potential benefits to these patients."

Evading a "Decoy" Receptor

Simcha's lead asset, ST-067, activates the IL-18 receptor, triggering potent inflammatory signaling in antitumor immune cells of both the adaptive and innate branches of the immune system.

Early efforts by leading pharmaceutical companies to develop IL-18 into a drug failed. Dr. Ring's lab broke new ground by identifying the reason for that failure: The tumor microenvironment is teeming with a "decoy" called IL-18BP, which binds IL-18 and blocks it from activating its receptor. When infused as a drug, IL-18 is drawn to the decoy and fails to reach its true target. As described in the Nature paper, the decoy receptor is a "major barrier to IL-18 immunotherapy."

To overcome that barrier, Dr. Ring's lab used directed evolution to create a version of the cytokine that would evade the decoy and bind only to the true IL-18 receptor. This was a difficult task, since IL-18 normally binds its decoy 10,000 times tighter than it does to the IL-18 receptor. The designer version of IL-18 made in Ring's lab has dramatic alterations in its receptor binding properties, biasing binding towards the IL-18 receptor and away from the decoy by more than one million-fold. This "decoy-resistant" property enables the custom-built cytokine to work effectively in the immunosuppressive tumor microenvironment.

Potent Single-agent Antitumor Effects

When Ring's lab tested the decoy-resistant IL-18 and compared it to natural IL-18 in mice, they found that - just as in human patients - natural IL-18 had little to no antitumor activity. By contrast, the decoy-resistant IL-18 had potent single-agent activity that inhibited tumor growth and even produced complete tumor regression in many animals, including in tumor types that are refractory to checkpoint inhibitors.

Ring's lab also examined the effect of decoy-resistant IL-18 on the tumor microenvironment. A key finding: The engineered IL-18 acted on a crucial population of "stem-like" T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. In checkpoint-resistant tumors, the engineered IL-18 also acted on innate NK cells, increasing their numbers and maturation to promote antitumor activity.

"The mechanism of action of decoy-resistant IL-18 is unique and distinct from immunotherapeutic agents that are being developed for other pathways. For this reason, we are hopeful it could be effective in tumors that have not otherwise responded to immune-based treatments, as well as enhance the activity of standard cancer immunotherapies," said Dr. Ring.

Founder's Strong Record in IO Drug Discovery

Dr. Ring has a strong track record in immuno-oncology drug discovery. He co-invented the first described CD122-biased IL-2 variant, originally detailed in Nature in 2012, which is now advancing through preclinical studies at Medicenna Therapeutics. He also developed a high-affinity SIRPα antagonist, featured in Science in 2013, that is now in clinical development at ALX Oncology as ALX-148. For these and other discoveries, Ring was named to Forbes '30 under 30' list of rising stars in health care in 2016 and has been honored with an NIH Director's Early Independence Award and recognition as a Pew-Stewart Scholar in Cancer Research.

Simcha plans to build out a full executive team as the company prepares to move ST-067 into the clinic next year.

The company's investors include WuXi AppTec's Corporate Venture Fund, Sequoia Capital China and Connecticut Innovations.

About Simcha Therapeutics

Simcha Therapeutics uses directed evolution to engineer novel cytokines designed to unlock the precision and power of the immune system. Simcha's lead program, ST-067, is a designer IL-18 cytokine that has shown potent antitumor effects in animal models, both as a monotherapy and when combined with anti-PD-1 checkpoint inhibitors, as described in Nature in June 2020. A Phase 1 trial is expected to be launched in the first half of 2021. Simcha was founded by Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The company has received $25 million in funding to date and is based in New Haven, Conn.