Targeting the recently identified immune checkpoint PVRIG may hold promise in combination with current immune checkpoint inhibitors in a large number of solid tumors, according to recent data presented by Compugen.
In the presentation, “Computational identification, functional characterization and antibody blockade of a new immune checkpoint in the TIGIT family of interacting molecules,” John Hunter, PhD, site head and vice president, Antibody R&D, Compugen USA, included extensive data from PVRIG in the context of cancer, showing that inhibiting this pathway activates CD4 T-cells and CD8 T-cells and inhibits tumor growth when used in combination with PD1/PD-L1 inhibitors.
“While antibody blockade of the CTLA4 and PD1 pathways has emerged as an effective treatment modality for certain types of cancer, the majority of patients do not derive long-term benefits, suggesting a need for additional approaches such as new immune checkpoints targeting new pathways and providing new mechanisms to activate the immune response against the tumor,” Anat Cohen-Dayag, PhD, CEO and president of Compugen, said in a press release. “Employing our unique predictive infrastructure to define new immune checkpoint targets, we identified PVRIG, among other novel immune checkpoint target candidates in our target pipeline.”
PVRIG was recently discovered by Compugen using its computational predictive discovery infrastructure, and is believed to be linked to another recently discovered immune checkpoint, called TIGIT. The company has been studying PVRIG in its preclinical CGEN-15029 program.
Hunter’s presentation revealed that PVRIG, which binds to the ligand PVRL2, is expressed in tumor-killing immune cells, such as T-cells and natural killer cells.
Antibodies designed to block the interaction between PVRIG and PVRL2, developed by Compugen, were shown to enhance the activity of both primary CD4 T-cells and tumor-derived CD8 T-cells.
Compugen researchers also found that blocking both PVRIG and TIGIT had a synergistic effect on T-cell stimulation, suggesting that inhibitors of both immune checkpoints might be combined to enhance anti-tumor immune responses.
In mice, the combination of PYRIG inhibitors with blockers of the PD1 pathway also showed promise, revealing reduced tumor growth. Genetically engineered mice that lacked PVRIG gene also confirmed the importance of this pathway in immune surveillance. Indeed, these mice had significantly reduced tumor growth, which was even further enhanced upon treatment with PD-1 blocking antibodies.
In June, the Company selected COM701 as its lead PVRIG inhibitor. COM701 is currently in preclinical development and Compugen is planning to file an Investigational New Drug application in 2017 to test COM701 in clinical studies.
“We are very pleased to see the rapidly increasing amount of preclinical data demonstrating the potential utility of COM701, an antibody targeting PVRIG, as a new cancer immunotherapy treatment,” said Cohen-Dayag. “These results highlight, once more, the power and uniqueness of our computational predictive approach — from computer prediction of novel drug targets to preclinical validation.”