SOUTH SAN FRANCISCO, Calif.—Arginase, a critical immunosuppressive enzyme responsible for T cell suppression, depletes arginine, a nutrient that is critical for the activation, growth and survival of the body’s cancer-fighting immune cells, known as cytotoxic T cells. Arginase inhibitors can restore arginine levels and reverse the immunosuppressive effect of myeloid-derived suppressor cells (MDSCs). Myeloid cells, which are present in many human tumors, are correlated with poor prognosis.
Arginase inhibitors are also found in chocolate, and the Mars Corp.—yes, the candy company—wanted to understand their role in cardiovascular health. In December 2014, Calithera Biosciences Inc., a clinical-stage biotechnology company focused on the development of novel cancer therapeutics, entered into an exclusive license agreement with Mars’ Symbioscience division. Under the agreement, Calithera has been granted the exclusive, worldwide license rights to develop and commercialize Symbioscience’s portfolio of arginase inhibitors for use in human healthcare. The company licensed the compounds to use in immuno-oncology and other applications, according to Dr. Susan Molineaux, president and CEO of Calithera.
Calithera’s lead preclinical program in tumor immunology is directed at developing inhibitors of the enzyme arginase and may provide a first-in-class therapeutic agent for this novel target, according to a paper presented at the American Association for Cancer Research (AACR).
“Arginine gets co-opted into working in tumors,” according to Molineaux. “The body is trying to fight the tumor, but it can’t. It’s necessary to disrupt this activity.”
Calithera has developed novel, orally active arginase inhibitors that have shown inhibition of tumor growth in immunocompetent syngeneic mice. This inhibition is accompanied by a rapid increase in the local concentration of arginine, resulting in a rise in the number of CD3+ T cells within the tumor. Calithera’s CB-1158 has the potential for antitumor activity in renal cell cancer, breast cancer, non-small cell lung cancer, acute myeloid leukemia and other tumor types where arginase-secreting MDSCs are known to play an immunosuppressive role. CB-1158 may also have the ability to combine with other immuno-oncology therapies that target T cell activation, such as CTLA-4 and PD-1 antibodies.
While the role of MDSCs has become increasingly recognized as an important mechanism of tumor immune evasion, there has been no effective way to antagonize the immunosuppressive activity of these cells in patients. MDSCs suppress cytotoxic T cells and natural killer cells through the secretion of the enzyme arginase, which depletes local arginine concentrations. The depletion of arginine in the tumor microenvironment keeps cytotoxic T cells from proliferating and effectively mounting an antitumor attack. M2 macrophages and polymorphonuclear cells express high levels of arginase and may contribute to the local suppression of immune responses.
The restoration of arginine levels in the tumor microenvironment via arginase inhibition enables T cell activation and proliferation, resulting in T cell-mediated antitumor responses. Calithera’s novel, potent and specific inhibitor of arginase, CB-1158, has shown high oral bioavailability in mice and rats. The pharmacodynamic effect of arginase inhibition in tumors was sustained throughout a 24-hour period using a twice-daily oral dosing schedule and has been observed in multiple syngeneic models.
Systemic plasma arginine levels are significantly increased in mice following dosing with CB-1158. Importantly, oral dosing with CB-1158 results in single agent antitumor efficacy in the mice.
CB-1158, a first-in-class arginase inhibitor, targets the immunosuppressive effects of myeloid cells in the tumor microenvironment and is currently in development as a novel immuno-oncology strategy. There is also a potential for enhanced therapeutic benefit by combining CB-1158 with other immune checkpoint inhibitors.
Molineaux summarizes: “We believe that drugs targeting metabolic checkpoints have the potential to be transformational in the treatment of cancer. We are dedicated to researching and developing first-in-class therapies that could significantly advance the field of oncology. We have made significant progress on our CB-1158 program and remain on track to file an Investigational New Drug application in the first half of 2016.”