Findings supporting novel approaches to inhibit or enhance immune responses for treating autoimmunity and cancer published in Nature Chemical Biology.
ANN ARBOR, Mich. – Jan 5, 2015 – Lycera Corp., a biopharmaceutical company developing breakthrough medicines to treat autoimmune diseases and cancer, today announced publication of research showing that sterols and sterol sulfates formed during cholesterol biosynthesis and processing are potent endogenous ligands for the retinoic acid receptor-related orphan receptor RORγ. The findings, which are published online today in the journalNature Chemical Biology, demonstrate how sterol metabolism controls effector T helper 17 cell (Th17) differentiation and point the way toward novel approaches to treat autoimmunity and cancer.
Previous studies have shown that IL-17 producing Th17 cells are critical in driving the pathogenesis of autoimmune diseases while in other settings these cells provide durable anti-tumor immune responses. “Other researchers have concluded that RORγ alone was sufficient to induce Th17 cell differentiation. Our results show that Th17 differentiation actually requires two sets of signals, one to induce the expression of RORγ and the other to induce formation of agonist ligands,” said Gary Glick, Ph.D., founder and chief scientific officer, Lycera Corp.
According to the research, during Th17 cell differentiation, cholesterol biosynthesis and uptake pathways along with enzymes that convert sterols to sterol sulfates are induced while genes controlling their metabolism and efflux are suppressed. These changes result in the accumulation of desmosterol sulfate, which functions as a potent, endogenous RORγ agonist. Other proliferating T cells upregulate cholesterol biosynthesis, however Lycera’s data show that this effect is selectively important in Th17 cells by providing endogenous ligands for RORγ, thus enforcing commitment of naïve T cells to the Th17 lineage. Importantly, inhibition of relevant steps in cholesterol biosynthesis in vitro and in vivo decreases IL-17 production.
“With these insights, we can now consider a range of new approaches to inhibit Th17 cells for treating autoimmune diseases and that enhance Th17 function to target cancer,” said Dr. Glick, adding, “Based on these findings, Lycera is continuing development of synthetic RORγ agonists possessing robust anti-tumor properties in preclinical models as potential first-in-class oral immunotherapies for cancer.”
The Nature Chemical Biology paper, titled “Sterol metabolism controls Th17 differentiation by generating endogenous RORγ agonists,” is available at http://www.nature.com/nchembio/ and will also appear in an upcoming print edition of the journal.
About RORgamma agonists
RORgamma is a nuclear receptor transcription factor that drives the activation and differentiation of immune cells including Th17 (helper T-cells) and Tc17 (cytotoxic) T cells. These polyfunctional cells boost the immune response to cancer cells by direct immune system activation as well as by decreasing immune suppression. Selective agonists have been shown to activate multiple anti-tumor mechanisms, resulting in increased immune function, durable tumor killing activity, decreases in checkpoint pathways and decreases in regulatory immune cells. Lycera has developed potent, oral RORγ agonists that demonstrate anti-cancer activity in animal models. RORγ agonists represent a potential new class of immune therapy either as a stand-alone agent or in combination with standard of care approaches.
Lycera is a privately held biopharmaceutical company that seeks to uncover new small molecule therapies for the treatment of autoimmune diseases and cancer. Our approach builds on an in-depth understanding of the immune response in disease progression.
Lycera product development programs are enhanced by our established global relationships with leading scientists and clinical researchers. We are currently advancing novel small molecule compounds from distinct, yet complementary, areas of research, including immune metabolism, cell signaling and immune cell differentiation. In addition to a robust proprietary pipeline, the company has an established research collaboration with Merck to discover, develop and commercialize small-molecule therapies for autoimmune disorders.