COM701 is a first-in-class therapeutic antibody targeting PVRIG, a novel immune checkpoint target candidate discovered computationally 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 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.
Preclinical studies have demonstrated that inhibition of PVRIG by COM701 results in increased activation of both normal and tumor derived T cells, consistent with in vitro activity demonstrated by other immune checkpoint inhibitors. Treatment of T cells with COM701 in combination with PD-1 or TIGIT inhibitors further increased T cell activation, demonstrating the combination potential of COM701 with other checkpoint inhibitors. The combination effect was particularly strong with TIGIT inhibitors, supporting the hypothesis that both inhibitory arms of the DNAM axis must be antagonized for full activation of DNAM costimulatory signaling.
Genetic ablation of the PVRIG gene in mice results in reduced tumor growth, which can be further enhanced by treatment with PD-1 pathway blockers. This combination effect is seen with antibody blockade of PVRIG together with PD-1 or TIGIT pathway inhibition, again supporting COM701 clinical combination with other checkpoint inhibitors.
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, colorectal, 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 ongoing in multiple medical centers the United States across two arms of the study: Arm A (monotherapy dose escalation and expansion cohorts) and Arm B (combination dose escalation). Additional Information on the COM701 Phase 1 clinical trial can be found here.
Preliminary results from the monotherapy dose escalation study were presented at SITC 2019 and AACR 2020. These data demonstrated that COM701 is well-tolerated and shows encouraging signals of anti-tumor activity as a monotherapy and in combination with Opdivo® in a highly refractory, all-comer patient population.
In February 2020, the Company announced plans to initiate a triple combination study to evaluate COM701 in combination Opdivo® and BMS-98620, Bristol-Myers Squibb’s investigational TIGIT inhibitor. The triple combination study is an open-label Phase 1/2 study in patients with advanced solid tumors. The study is designed to evaluate the safety and tolerability of escalating doses of COM701 in combination with fixed doses of Opdivo® and BMS-98620. Dose levels for Opdivo® and BMS-986207 combinations have already been determined through prior testing by Bristol-Myers Squibb. Additional endpoints include preliminary clinical activity in certain tumor types such as non-small cell lung, breast, ovarian and endometrial cancer. Preclinical data demonstrate that these tumor types express a high level of the biomarkers PVRIG and PVRL2.
The Phase 1/2 study is expected to commence in the second half of 2020. Compugen will be the study sponsor with Opdivo® and BMS-986207 supplied by Bristol-Myers Squibb.