Abstract 6079: Two is better than one: First in class anti-TIGIT IL-15 fusion antibody for enhanced tumor killing

Abstract Introduction: Immune checkpoint inhibitor therapies have revolutionised cancer treatment however, a portion of patients across malignancies become resistant or refractory to existing treatment. We have a first in class anti-TIGIT-IL-15 fusion antibody (MFA011) for treatment of solid tumors. Modes of action including superior tumor cell killing and increased immune effector function was observed in vitro. Significant inhibition of tumor growth and minimum toxicity was observed in 3 different hTIGIT knock-in mouse models. MFA011 has consistently outperformed competitor drugs when assessing pharmacokinetic activity providing a novel therapeutic option for cancer. Methods: Mechanism of action for TIGIT was measured using a CD155-TIGIT blocking luciferase bioassay platform (Promega). We assessed specificity of IL-15 binding by ELISA and IL-15R signalling by measuring pSTAT5 phospho-staining. Immunotoxicity was assessed by cytokine release assay and off-target effects of IL-15 was measured by flow cytometry. In vitro efficacy was assessed in human PBMC from healthy donors using cytotoxicity assays (IncuCyte, Sartorius), ELISA, and flow cytometry-based assays, including intracellular cytokine staining and immune cell proliferation. In vivo efficacy of MFA011 was assessed using CT26 and Renca bearing BALB/c-hTIGIT knock-in mouse models with i.v. dosing of MFA011. In addition, anti-tumor effects were also observed in Hepa1-6 bearing C57BL/6 hTIGIT knock-in mouse model. Results and discussion: MFA011 robustly bound and blocked CD155-TIGIT interactions and showed sustained signalling in comparison to unbound IL-15 cytokine alone. NK and CD8+ T cells showed increased proinflammatory cytokine production (IL-2 and IFNγ) and proliferation which led to improved anti-tumor killing observed in cancer derived cell lines. Conversely, regulatory T cells were depleted by antibody-dependent cellular cytotoxicity. Minimal immunotoxicity was observed and IL-15 bound specifically to cells that had been stimulated with MFA011. Reduction in tumor growth and stable biosafety profiles was observed in all mouse models after administration of MFA011. Conclusion: Dual targeting of TIGIT and IL-15 signalling through MFA011 effectively enhances anti-tumor immune responses while limiting the off-target effects of IL-15 signalling. Our combined in vitro and in vivo data provides strong evidence to pursue MFA011 to IND filing and to commence phase I clinical trials. Citation Format: Tejal Bhatt, Joyce Kim, Wondae Kang, Rachel Etherington, Seulki Cheon, Sabrina Nielsen, Christian Willberg, Hongseok Jo, Yu-Hoi Kang. Two is better than one: First in class anti-TIGIT IL-15 fusion antibody for enhanced tumor killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6079.