CGEN-15029 is the internal designation for PVRIG, a novel B7/CD28-like immune checkpoint target candidate discovered by Compugen.
Validation studies show that expression of PVRIG in T cells inhibits their activation by melanoma cells, consistent with an immune suppressive role of the target in the tumor microenvironment. The target possesses signature immune-checkpoint receptor characteristics, including expression in relevant subsets of T- and NK-cells, with particularly high expression in lymphocytes that populate the tumor microenvironment (known as tumor infiltrating lymphocytes or TILs). PVRL2 was identified as the binding partner for PVRIG, placing it in the immune regulatory TIGIT/DNAM-1 signaling axis on T-cells. Expression analysis of PVRL2 shows it to be highly expressed in a number of cancer indications, including breast, ovarian, and endometrial tumors, suggesting that the PVRIG/PVRL2 signaling pathway way be a dominant mechanism of immune suppression in those patient populations.
In June 2016, COM701 was selected as the lead therapeutic candidate for PVRIG. COM701 is undergoing preclinical development activities in preparation for advancement to clinical trials. The selected humanized lead antibody demonstrated potent, reproducible enhancement of T cell activation, consistent with the desired mechanism of action of activating T cells in the tumor microenvironment to generate anti-tumor immune responses.
PVRIG immune checkpoint represents a new inhibitory component of the known TIGIT axis. Consistent with the placement of PVRIG in the TIGIT axis, antibody blockade of both TIGIT and PVRIG had a synergistic effect on human T cell stimulation, indicating the potential of the two to generate enhanced immune response against the cancer. Moreover, antibodies targeting the mouse PVRIG developed by the Company were assessed in vivo for effects on tumor growth inhibition in mouse models, commonly used to study immune checkpoint inhibitors. In these studies, antibodies that block the mouse PVRIG/PVRL2 interaction, similar to those generated against the human target, were shown to inhibit tumor growth when used in combination with PD1 pathway blockade. These results were further reinforced when tumor growth was tested in knock-out (KO) mice. Tumor growth was significantly reduced in KO mice, where the PVRIG gene was removed. Consistent with the antibody combination data, this effect was even further enhanced in the KO mice when they were treated with anti-PDL1 blocking antibodies.
COM701 is currently being evaluated in a Phase 1 study in patients with advanced solid tumors. The study is designed to evaluate the safety and tolerability of COM701 as monotherapy and in combination with a PD-1 inhibitor. Additional endpoints include evaluation of PK/PD and preliminary clinical activity in certain tumor types such as NSCLC, breast, ovarian and endometrial cancer. Preclinical data demonstrate that these tumor types express a high level of the biomarkers PVRIG and PVRL2.
The Phase 1 study is currently enrolling patients in the United States. Additional Information on the COM701 Phase 1 clinical trial can be found here.