Abstract B291: Identification of novel immune checkpoints and their implementation as mAb targets for cancer immunotherapy.

Immune checkpoints, such as CTLA4 and PD-1, have emerged as promising drug targets for cancer immunotherapy. We hypothesize that additional novel members of the B7/CD28 family play a role in T cell regulation and thus may serve as targets for therapeutic mAbs. However, the discovery of novel family members is challenging since proteins of the immune system, including proteins of the B7 protein In order to identify novel members of the B7/CD28 protein family, Compugen has developed a discovery approach integrating gene and protein information with extensive expression data, and has identified nine novel membrane proteins that possess characteristics of the B7/CD28 protein family members and are therefore predicted to play a role in T cell co-stimulation. In order to validate our predictive discovery findings, we evaluated the effect of our proteins on immune cells, particularly T cells. For that goal, we expressed the proteins on the cell surface upon ectopic expression, and also produced fusion proteins consisting of the extracellular domain of the predicted proteins, fused to an IgG Fc domain. Here we present results obtained for two of our novel proteins, CGEN-15001T and CGEN-15022. Both display robust inhibition of T cell activation. Interestingly, CGEN-15001, one of the Fc-fused proteins, leads to increased levels of anti-inflammatory cytokines such as IL-4 and IL5, while reducing pro-inflammatory cytokines such as IFN-γ and IL-17. In addition, CGEN-15001 was found to enhance iTregs differentiation. Furthermore, these molecules showed therapeutic efficacy in mouse models of multiple sclerosis and rheumatoid arthritis. To investigate the potential of these membrane proteins as drug targets for treatment of cancer we have performed extensive IHC studies, on a variety of healthy and malignant tissues. Both CGEN-15001T and CGEN-15022 were found to be expressed in numerous types of cancers, each showing a unique pattern of expression. CGEN-15001T, in addition to its expression on tumor cells, was found to be expressed on tumor infiltrating immune cells, especially on Macrophages and Mast cells. Based on the immunomodulatory activities and the expression pattern on malignant and immune cells, CGEN15001T and CGEN15022 may serve as mAb targets for cancer immunotherapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B291. Citation Format: Gady Cojocaru, Ofer Levy, Amir Toporik, Liat Dassa, Iris Hecht, Ilan Vaknin, Sergey Nemzer, Tania Pergan, Amit Novik, Shirley Sameah-Greenwald, Anat Oren, Zohar Tiran, Peter Steinberger, Joseph Podojil, Nora Tarcic, Eyal Neria, Galit Rotman, Zurit Levine. Identification of novel immune checkpoints and their implementation as mAb targets for cancer immunotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B291.