Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer.

Media type: E-Article

Title: Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer

Contributor: Liang, Spencer; Levy, Ofer; Ganguly, Sudipto; Kotturi, Maya; Vaknin, Ilan; Dassa, Liat; Azulay, Meir; Alteber, Zoya; Hansen, Kyle; Chan, Chris; Leung, Ling; Kumar, Sandeep; Levin, Doron; Safyon, Einav; Friedman, Tal; Greenwald, Shirley; Salomon, Ran; Pardoll, Drew M.; White, Mark; Ophir, Eran

imprint: American Society of Clinical Oncology (ASCO), 2017

Language: English

DOI: 10.1200/jco.2017.35.15_suppl.3074

ISSN: 0732-183X; 1527-7755

Origination:

Footnote:

Description: 3074 Background: While inhibitors of CTLA4 and PD1 have emerged as effective cancer therapies, the majority of treated patients do not derive long term benefit. Employing our computational discovery platform, we discovered PVRIG as an immune suppressive molecule expressed on T and NK cells and identified COM701, an antibody (Ab) targeting human PVRIG that enhances T cell function and anti-tumor responses. Methods: Anti-human PVRIG Ab COM701 was identified as an antagonistic Ab that enhanced T cell function in multiple assays. Antagonistic anti-mouse PVRIG Abs and PVRIG deficient (PVRIG-/-) mice were generated and characterized using syngeneic tumor models. Results: PVRIG was induced upon T cell activation, with long term activation leading to the highest expression. PVRL2 was identified as the ligand for PVRIG, placing PVRIG in the DNAM/TIGIT immunoreceptor axis. Compared to normal adjacent tissues, PVRIG and PVRL2 were both induced in the tumor microenvironment of several human cancers. To target PVRIG for therapeutic intervention, we identified COM701, a high affinity Ab that disrupts the interaction of PVRIG with PVRL2. COM701 enhanced CD8 T cell proliferation and IFN-g production in vitro and had an additive or synergistic effect on T cell activation when further combined with an anti-PD1 or anti-TIGIT Ab. Consistent with a checkpoint function for human PVRIG, mouse PVRIG-/- T cells showed increased function compared to wild type T cells. A surrogate antagonistic anti-mPVRIG Ab reduced growth of CT26 and B16 tumors when combined with an anti-PDL1 Ab in vivo. MC38 tumors also grew slower in PVRIG-/- mice compared to wild type mice and ex vivo analysis pointed to functional differences in anti-cancer immunity. Conclusions: We demonstrated that targeting PVRIG with COM701, a high affinity antagonistic Ab, increased human T cell function. We further showed that PVRIG was induced in the tumor microenvironment and that disruption of PVRIG/PVRL2 interaction resulted in reduced tumor growth in preclinical models. These data demonstrate that PVRIG is a promising target for the treatment of cancer and provide the rationale for COM701 as a potential cancer immunotherapy.

Access State: Open Access

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