Abstract 3438: Enhanced NK and CD8+ T cell proliferation, tumor cytotoxicity and reversal of T cell exhaustion with IGM-7354, an anti-PD-L1 IgM antibody and IL-15 cytokine fusion
Authors: Giffon Thierry , Desbois Melanie , Yakkundi Poonam , Sekar Keerthana , Manlusoc Marigold , Rosete Rodnie , Machado Daniel , Calhoun Susan , Kothambawala Tasnim , Ng Dean , Tran Vu , Saini Avneesh , Jain Abhinav , Wang Beatrice , Kotturi Maya , Keyt Bruce , Sinclair Angus 
Published: June 2022

Abstract
Anti-PD-1/PD-L1 therapies are efficacious in certain cancer indications, but often patients relapse following a primary response Therefore rational combinations are needed to enhance initial and durable responses of anti-PD-1/PD-L1 therapies. Immunostimulatory cytokine, IL-15 is an attractive combination partner to enhance anti-tumor NK and memory CD8+ T cell expansion and survival. We are developing 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, designed to deliver IL-15 to PD-L1 expressing tumors for enhancing anti-tumor immune responses. IGM-7354 was generated by grafting heavy chain variable regions of a high affinity humanized anti-PD-L1 IgG onto the IgM heavy chain framework, co-expressed with the light chain and the J chain which included a single IL-15Rα and IL-15 fusion. Binding ELISAs were performed using recombinant antigens. IGM-7354 bound human and cynomolgus monkey PD-L1 with similar affinities but did not bind to rat or mouse PD-L1. In addition, the IL-15 component of IGM-7354 bound to human and cynomolgus β chain of the trimeric IL-15 receptor with similar affinities, but with weaker binding affinity to rodent IL-15Rβ. Using in vitro assays with human and cynomolgus monkey PBMCs, IGM-7354 dose-dependently enhanced the proliferation of NK and CD8+ T cells. Furthermore, in an in vitro MLR setting, IGM-7354 was able to reverse T cell exhaustion beyond that of an IL-15/IL15Rα complex or anti-PD-L1 IgM or IgG alone, as demonstrated by an increase in activation and effector cytokine secretion. In vitro cytotoxicity and ADCC assays were performed with luciferase-tagged human cancer cell lines and PBMCs. IGM-7354 enhanced in vitro killing of PD-L1-expressing cancer cells by human PBMCs in monotherapy and in combination with other therapeutic agents. Efficacy and pharmacodynamic studies in an MDA-MB-231 xenograft mouse model showed dose-dependent increases in circulating NK and CD8+ T cells and tumor-infiltrating lymphocytes, which correlated with tumor regression. In cynomolgus monkeys, IGM-7354 markedly induced the proliferation of NK and CD8+ T cells in a dose-dependent manner with a preferential expansion of effector memory CD8+ T cells and γδ T cells in the periphery. IGM-7354 stimulates NK and CD8+ T cell expansion in vitro and in vivo plus induces tumor regressions in mouse tumor models in monotherapy or combination with various agents. This approach may enhance tumor localization of the immunostimulatory cytokine IL-15 through high affinity and high avidity binding to PD-L1 thereby improving anti-tumor responses and minimizing toxicity.
Citation Format: Thierry Giffon, Melanie Desbois, Poonam Yakkundi, Keerthana Sekar, Marigold Manlusoc, Rodnie Rosete, Daniel Machado, Susan Calhoun, Tasnim Kothambawala, Dean Ng, Vu Tran, Avneesh Saini, Abhinav Jain, Beatrice Wang, Maya Kotturi, Bruce Keyt, Angus Sinclair. Enhanced NK and CD8+ T cell proliferation, tumor cytotoxicity and reversal of T cell exhaustion with IGM-7354, an anti-PD-L1 IgM antibody and IL-15 cytokine fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3438.