We are leveraging our core expertise in tumor biology and medicinal chemistry to develop small molecule selective arginase inhibitors.
Calithera’s program in metabolic immune-oncology is directed at developing inhibitors of the enzyme arginase and may provide a first-in-class therapeutic agent for this novel target. Arginase exerts its immunosuppressive effect by depleting the amino acid arginine in the tumor microenvironment and preventing the immune system’s cytotoxic T-cells and natural killer (NK) cells from proliferating and killing the tumor. Inhibition of arginase activity reverses this immunosuppressive block and restores T-cell function.
Calithera has discovered novel, orally active arginase inhibitors that have shown inhibition of tumor growth in immunocompetent syngeneic mice. This inhibition of tumor growth 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. This is similar to what happens when indoleamine 2,3-dioxygenase (IDO) inhibitors block the degradation of tryptophan by IDO, leading to restoration of tryptophan levels in the tumor and activation of tumor-associated T-cells. CB-1158 has the potential for anti-tumor 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.
In December 2014, Calithera entered into an exclusive license agreement with Mars Corporation’s Symbioscience Division, under which the company has been granted the exclusive, worldwide license rights to develop and commercialize Symbioscience’s portfolio of arginase inhibitors for use in human healthcare.
In July 2016, Calithera’s Investigational New Drug (IND) application was accepted by the FDA for the oral arginase inhibitor CB-1158. The Phase I clinical trial will enroll patients with advanced solid tumors. Patients will be treated with CB-1158 as a monotherapy, as well as in combination with an anti-PD1 antibody.