Abstract 5660: IGM-7354, an immunocytokine with IL-15 fused to an anti-PD-L1 IgM, induces NK and CD8+ T cell mediated cytotoxicity of PD-L1-positive tumor cells
Authors: Giffon Thierry D. , Desbois Melanie , Yakkundi Poonam , Calhoun Susan , Sekar Keerthana , Denson Carolyn , Kothambawala Tasnim , Pearson Alexander , Pandey Sivani , Pandya Deepal , Rosete Rodnie , Machado Daniel , Raichlen Pat , Ng Dean , Jain Abhinav R. , Funke Roel , Humke Eric , Hinton Paul R. , Wang Beatrice , Keyt Bruce A. , Kotturi Maya F. , Sinclair Angus M. 
Published: April 2023

Abstract
Immunostimulatory cytokines are a promising immunotherapy for the treatment of advanced malignancies, but generally have been associated with severe toxicities when administered systemically. The recent development of antibody-cytokine fusion proteins, or immunocytokines, aims to localize cytokine activity to the tumor microenvironment and thus improve their therapeutic index. We have developed IGM-7354, a high affinity, high avidity anti-PD-L1 pentameric IgM antibody with an IL-15Rα chain and IL-15 fused to the joining (J) chain. The IGM-7354 immunocytokine was designed to deliver IL-15-mediated stimulation of NK and CD8+ T cells to PD-L1-expressing tumors and antigen-presenting cells, to enhance anti-tumor immune responses. The multivalent binding of IGM-7354 to PD-L1 provided a stronger binding avidity for human PD-L1 than the monovalent binding of IL-15 to IL-15Rb as confirmed in kinetic binding assays. In vitro IGM-7354 induced the proliferation of a cytotoxic T cell line responsive to IL-15 stimulation and enhanced the proliferation of NK and CD8+ T cells from healthy donor human PBMCs. In cytotoxicity assays with human PBMC and PD-L1+ cancer cell lines, IGM-7354 enhanced cancer cell killing through NK and CD8+ T cell expansion and cytotoxic activity, evidenced by Ki67 and Granzyme B upregulation in these cell populations. Next, in vivo pharmacodynamic studies were performed in two humanized mouse models: non-tumor-bearing BRGSF-HIS mice engrafted with human CD34+ cells, and PD-L1+ MDA-MB-231 tumor-bearing MHC-/- NSG mice engrafted with human PBMCs. In the BRGSF model, IGM-7354 increased NK cell activation and Granzyme B expression as well as NK and CD8+ T cell proliferation. In the tumor-bearing mouse model, IGM-7354 dose-dependently increased NK and CD8+ T cell proliferation in blood and infiltration of lymphocytes into the tumor. This pharmacodynamic activity correlated with IGM-7354 anti-tumor activity in the MDA-MB-231 model. Lastly, IGM-7354 increased the proliferation of NK and CD8+ T cells in cynomolgus monkeys and particularly induced the expansion of effector memory CD8+ T cells in the periphery. In summary, IGM-7354 induces NK and CD8+ T cell proliferation in both in vitro and in vivo preclinical models, resulting in the killing of PD-L1+ tumor cells. The strong avidity of IGM-7354 for PD-L1 may enhance IL-15 delivery to tumors and antigen-presenting cells and thus provide a more favorable safety profile. A Phase 1 clinical trial is planned.
Citation Format: Thierry D. Giffon, Melanie Desbois, Poonam Yakkundi, Susan Calhoun, Keerthana Sekar, Carolyn Denson, Tasnim Kothambawala, Alexander Pearson, Sivani Pandey, Deepal Pandya, Rodnie Rosete, Daniel Machado, Pat Raichlen, Dean Ng, Abhinav R. Jain, Roel Funke, Eric Humke, Paul R. Hinton, Beatrice Wang, Bruce A. Keyt, Maya F. Kotturi, Angus M. Sinclair. IGM-7354, an immunocytokine with IL-15 fused to an anti-PD-L1 IgM, induces NK and CD8+ T cell mediated cytotoxicity of PD-L1-positive tumor cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5660.