Abstract A054: Recruiting innate immune cells universally: Development of a novel universal innate cell engager for cancer-immunotherapy

Abstract Novel antibody-engineering approaches have enabled the development of targeted innate cell engagers which redirect innate immune cells to eliminate cancer or suppressive immune cells. These antibodies function through binding to surface antigens on target cells and engaging activating receptors on innate immune cells such as natural killer cells and macrophages. Although early innate cell engagers have shown promise in controlling various cancer types, several major challenges remain in the clinics, including high tumor heterogeneity, low tumor immunogenicity, and reduced efficacy in solid tumors. Here, we present a universal innate cell engager as part of a novel adaptor-based antibody platform. Our universal innate cell engager utilizes a two-step approach combining the power of an adaptor and an effector antibody. First, an Fc-silenced adaptor antibody comprising P329G LALA mutations is used to target the desired antigen in the tumor microenvironment. Then, as an effector antibody, a universal innate cell engager directed against the P329G mutation on the adaptor antibody is used. Innate immune cells are recruited by the universal innate cell engager through its active Fc, leading to antibody-dependent cellular cytotoxicity against the target cells. To maximize innate cell activation, the Fc portion of the universal innate cell engager can be glycoengineered for enhanced FcgRIII affinity.In vitro and in vivo assays showed that our universal innate cell engager is inducing innate immune cell activation and innate immune cell-mediated target cell killing when combined with different antigen-targeted adaptor antibodies. Ultimately, this approach may enable off-the-shelf personalization via combination of universal effector cell engagers and selected adaptor antibodies specific to the patient’s tumor profile. Citation Format: Idil Hutter-Karakoc, Marlena Surowka, Diana Darowski, Christina Klaus, Claudia Ferrara Koller, Thomas Hofer, Anne Freimoser-Grundschober, Ekkehard Mössner, Stephane Leclair, Pablo Umana, Christian Munz, Maria Amann, Christian Klein. Recruiting innate immune cells universally: Development of a novel universal innate cell engager for cancer-immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A054.