COM701/Fc reduced Anti-PVRIG antibody

Compugen’s lead candidate, COM701, is a potentially first-in-class immunotherapy targeting PVRIG, a novel immune checkpoint that our team computationally discovered and validated in preclinical studies. Clinical data of COM701, as a monotherapy and in combination with PD-1 blockers, have demonstrated initial signs of antitumor activity, with encouraging disease control rate, durability of responses and safety and tolerability in patients that have progressed or failed on many prior lines of therapy. Learn more about the most recent clinical data on COM701 here.

 

COM701 is currently being studied in a targeted, science-driven clinical development program:

An adaptive platform trial to evaluate the safety and efficacy of COM701 as maintenance monotherapy or combination therapy in patients with relapsed platinum sensitive ovarian cancer. The purpose of sub-trial 1 is to assess if COM701 delays the progression of ovarian cancer in patients with relapsed platinum sensitive ovarian cancer and further assess its safety profile in this disease setting. The adaptive-platform design enables additional sub-trials. Sub-trial 1 is a double-blind, randomized placebo-controlled trial in which 60 patients will be randomized in a 2:1 ratio to COM701 or placebo. Subsequent sub-trials will evaluate COM701 in combination with other anticancer drugs.

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Proof-of-concept study evaluating the combination of COM701 with COM902 and pembrolizumab in up to 40 patients with platinum resistant ovarian cancer who have previously received up to 3 lines of therapy. The study includes patients with all histologies. The initiation of the study is based on Phase 1 cohort expansion data reported at ESMO-Immunology conference showing anti-tumor activity and potent immune modulation with the combination of COM701 and nivolumab with or without BMS-986207 in platinum resistant ovarian cancer patients.

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PVRIG

Through our computational discovery platform, we have identified PVRIG as a new immune checkpoint in the DNAM axis, an important signaling pathway in T and NK cell function.

PVRIG is located on the surface of T and NK cells. Our research exploring the PVRIG pathway show that when bound to its ligand, PVRL2, PVRIG inhibits T and NK cell activity. Working in parallel and in complement with PVRIG in the DNAM axis is TIGIT, which was computationally discovered by the Compugen team in 2009. When TIGIT binds its ligand, PVR, it also leads to inhibition of T and NK cell activity.

While PVRIG and TIGIT are complementary and part of the same biological axis, our research shows that they are in fact distinct. PVRIG and TIGIT bind to different ligands (PVRL2 and PVR, respectively), they are expressed on different immune cell types and their ligands have different expression patterns.

DNAM Axis

Furthermore, our data show that similar to TIGIT, PVRIG is expressed in stem-like memory T cells (TSCM) and PVRL2 is expressed in both dendritic cells and tertiary lymphoid structures, as well as in PD-L1low less inflamed tumors. TSCM cells, dendritic cells and tertiary lymphoid structures have all been shown to be important in clinical response to checkpoint inhibitors.

Extensive preclinical data as well as initial clinical results suggest that in tumor types where PVRIG is highly expressed, such as in breast, endometrial and ovarian cancers, it could serve as the dominant inhibitory pathway and therefore PVRIG blockade through COM701 has the potential to elicit a meaningful and durable anti-tumor immune response. Additional preclinical data indicate there is a synergistic effect on T cell activation following treatment with both COM701 and Compugen’s TIGIT inhibitor, COM902.

Triple pathway hypothesis: PVRIG, TIGIT, PD-1

In addition to the work that Compugen has done to understand the underlying biology of the DNAM axis, we along with others, have also found that there is an intersection between the two inhibitory pathways on the DNAM axis, PVRIG and TIGIT, and the inhibitory PD-1 pathway.


We hypothesize that the simultaneous blockade of PVRIG, TIGIT and PD-1 has the potential to synergistically enhance anti-tumor immune responses in selected patient populations that are not responsive or refractory to PD-1 blockers alone.

 

 

We believe that PVRIG is a critical component in enhancing treatment responses to cancer immunotherapies. We have seen preclinically that tumor response rates can vary depending on the relative dominance of each inhibitory checkpoint, PVRIG, TIGIT or PD-1, so simultaneous blockade of these three inhibitory pathways on T and NK cells may be key to improving anti-tumor immune responses. As the first company with a clinical PVRIG inhibitor, COM701, we aim to study whether PVRIG blockade will support synergistic effects with anti-PD-1 antibodies and/or TIGIT inhibitors.