Abstract 581: Discovery and development of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG

Abstract

Background: While blockade of the CTLA4 and PD1 pathways has emerged as an effective treatment of cancer, the majority of patients do not derive long term benefit. This provides a rationale for identifying and targeting additional checkpoints. Employing our unique computational algorithms, we identified PVRIG, a new member of the B7/CD28 family. We report here the expression pattern, functional characterization, and anti-tumor activity of blocking antibodies targeting PVRIG as well as characterization of PVRIG KO mice. Materials and Methods: PVRIG is expressed by T and NK cells within the tumor microenvironment. We identified PVRL2 as its counterpart and characterized the PVRIG-PVRL2 interaction. Antibody discovery was carried out with phage display and hybridoma platforms and antibodies against the human protein were screened for their ability to enhance T-cell activity in vitro, while surrogate antibodies targeting the mouse protein were assessed in syngeneic models for effects on tumor growth. PVRIG -/- KO mice were generated and characterized including phenotyping and anti-tumor immune response. Results: PVRIG is expressed on different T cell subsets and on NK, NKT and γδ T-cells. Within T cells, memory subsets possess the highest level of PVRIG and its expression is induced upon long term activation with different stimuli. Within tumor microenvironment, PVRIG was found to be expressed on NK and CD8+ T cells in multiple cancers. A high affinity lead Ab was selected, COM701, for further clinical development and demonstrated blockade of the interaction of PVRIG with PVRL2 as well as enhancement of activation of both primary and tumor-derived effector immune cells through a PVRL2-dependent mechanism. Moreover, COM-701 showed notable enhancement of T cell function in-vitro when combined with PD1 or TIGIT Ab blockade. The lead antibody, COM-701, is currently in preclinical development. A surrogate antibody, that blocks PVRIG-PVRL2 interaction, was shown to inhibit growth of colon carcinoma and melanoma in syngeneic models upon combined treatment with anti-PDL1 antibody. Comparative analysis of PVRIG KO versus WT derived T cells revealed enhanced reactivity of PVRIG null T cells upon polyclonal activation in presence of PVRL2-Ig. Accordingly, MC38 tumors grew slower in PVRIG KO than in WT mice and ex vivo analysis pointed to the quantitative and functional differences in anticancer immunity developed in these mice. Conclusion: We describe the identification of PVRIG as a novel T cell immune checkpoint. We further demonstrate that antibody blockade of the PVRIG-PVRL2 interaction has the potential to be efficiently combined with PD1 or TIGIT blockade for enhancing anti-tumor immunity. COM-701 is a high affinity antagonistic antibody that is currently in preclinical development. Taken together, these data demonstrate the utility of targeting PVRIG in addition to other B7 family checkpoints for the treatment of cancer. Citation Format: Ofer Levy, Chris Chan, Gady Cojocaru, Spencer Liang, Eran Ophir, Sudipto Ganguly, Maya Kotturi, Tal Friedman, Benjamin Murter, Liat Dassa, Ling Leung, Shirley Greenwald, Meir Azulay, Sandeep Kumar, Zoya Alteber, Xiaoyu Pan, Andy Drake, Ran Salomon, Arthur Machlenkin, John Hunter, Zurit Levine, Drew Pardoll, Mark White. Discovery and development of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 581. doi:10.1158/1538-7445.AM2017-581

TIGIT as an emerging immune checkpoint

“…Five clinical trials are currently evaluating the safety of TIGIT/PD‐1 co‐blockade in cancer patients. Other promising combination targets for TIGIT include TIM‐3 , CD112R or CD96 . Interestingly, while most efforts are focused on blocking TIGIT inhibitory activity through mAbs, a recent study considered TIGIT in the context of T cell engineering .…”

“…However, the TIGIT/CD96/DNAM‐1 pathway appears even more complex than the CTLA‐4/CD28 pathway. Indeed, TIGIT and DNAM‐1 also share CD112 as a ligand , and CD112R (PVRIG), a recently discovered immune checkpoint receptor expressed mainly on T cells and NK cells, competes with DNAM‐1 and TIGIT for the binding of CD112 .…”

Peptidomic analysis reveals multiple protection of human breast milk on infants during different stages

“…PKD1 was related to sclerotin development (Xiao et al, 2010), MX1 was also related to immunocompetence (Haller, Arnheiter, Gresser, & Lindenmann, 1981;Pichlmair et al, 2004), GRIN3B and HCFC1 were related to brain development (Hornig et al, 2017;Jolly et al, 2015), RANBP9 was related to neurodevelopment, RICTOR was related to muscle development (Suryawan et al, 2007), as well as WDR81 was related to heart, eyes, and neurodevelopment (Doldur-Balli et al, 2015;Traka et al, 2013). In transitional milk, a total of six peptides derived from four proteins were both located in domains and predicted to be related to neonatal immunity and organ development such as CSN2 and PVRIG were related to immunocompetence and development (Cui et al, 2016;Levy et al, 2017), HNRNPK was related to lung development (Yang et al, 2013), PRDM13 was related to eyes development and lipid metabolism (Manes et al, 2017;Satoh, Brace, Rensing, & Imai, 2015). In mature milk, we found 18 peptides derived from 12 proteins were both located in domains and predicted to be related to neonatal immunity, energy metabolism, and tissues and organs development.…”

Immune checkpoint inhibitors for PD-1/PD-L1 axis in combination with other immunotherapies and targeted therapies for non-small cell lung cancer

“…These mechanisms, however, are more complex and have more than one ligand/receptor combination. Recently, TIGIT and DNAM-1 have been found to bind to a ligand called CD112, which also binds to the immune-cell receptor CD112R (PVRIG) causing DNAM-1 and TIGIT to compete for the binding of CD112 ( 121 – 123 ). The DNAM-1/TIGIT/CD96 pathways offer new ways to improve immune-cell anti-tumor response.…”