Menachem et al. showed that in the human and murine TME, IL18 is upregulated and primarily bound to similarly upregulated endogenous high-affinity binding proteins (IL18BP) at levels that activate T cells in vitro. A high-affinity anti-human IL18BP mAb that blocked IL18BP/IL18 interactions and released IL18 from preformed complexes was generated to enable IL18 stimulation of T and NK cell activity in vitro. In mouse models, (surrogate) anti-IL18BP treatment inhibited tumor growth, boosted survival, increased numbers and activity of polyfunctional non-exhausted T and NK cells selectively in the TME, induced immunologic memory, and was enhanced by anti-PD-L1 therapy.
Contributed by Paula Hochman
ABSTRACT: Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.
Author Info: (1) Preclinical Development, Compugen Ltd., Holon, Israel. (2) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (3) Computational Discovery, Compugen Ltd., Holon, Israel. (
Author Info: (1) Preclinical Development, Compugen Ltd., Holon, Israel. (2) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (3) Computational Discovery, Compugen Ltd., Holon, Israel. (4) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (5) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (6) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (7) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (8) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (9) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (10) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (11) Computational Discovery, Compugen Ltd., Holon, Israel. (12) Computational Discovery, Compugen Ltd., Holon, Israel. (13) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (14) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (15) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (16) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (17) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (18) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (19) Computational Discovery, Compugen Ltd., Holon, Israel. (20) Computational Discovery, Compugen Ltd., Holon, Israel. (21) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (22) Research & Drug Discovery, Compugen Ltd., Holon, Israel. (23) Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel. Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel. (24) Biobank, Department of pathology, Rabin Medical Center, Petah Tikva, Israel. (25) Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel. Department of Surgery, Rabin Medical Center, Petach Tikva, Israel. (26) Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel. Department of Pathology, Rabin Medical Center, Petah Tikva, Israel. (27) Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel. Gynecologic Oncology Division, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel. (28) Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel. Gynecologic Oncology Division, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel. (29) Department of Pathology, Rabin Medical Center, Petah Tikva, Israel. (30) Gynecologic Oncology Division, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel. (31) Compugen Ltd., Holon, Israel.
