Abstract B017: CLD-401, a Systemic Gene Medicine for In Situ IL-15 Superagonist Delivery: Driving NK and γδ T Cell-Mediated Tumor Killing

Abstract

RedTail is a next-generation gene medicine platform based on a tumor-selective extracellular enveloped vaccinia virus (EEV) expressing chimeric CD55 for complement and antibody resistance, enabling systemic delivery. Our lead candidate, CLD-401, delivers an IL-15 superagonist (IL-15[N72D]-IL-15Rα sushi domain), a potent cytokine that induces NK, γδ T and CD8+ T cell responses in the tumor microenvironment (TME), driving robust antitumor immunity. Because IL-15 SA is produced locally within the tumor, it eliminates the need for a stabilizing Fc region, reducing systemic and off-tumor exposure. CLD-401 is currently in IND-enabling studies, with IND submission targeted by end of 2026. CLD-401 was administered systemically in syngeneic tumor-bearing mice. IL-15 SA was quantified by ELISA, immune infiltration by flow cytometry, viral biodistribution by qPCR, and complement resistance using human serum. Tumor selectivity and immune activity were confirmed on human and murine cells. CLD-401 produced EEVs with CD55-mediated resistance to complement and neutralizing antibodies, enabling systemic delivery without immune clearance. CLD-401 selectively amplified in tumor cells with no detectable replication in normal human primary cells or tissues, confirming tumor-restricted amplification. Secreted IL-15 SA demonstrated functional activity on both human and murine immune cells, validating the mouse as a pharmacologically relevant model. Importantly, the viral vector alone induced substantial TME remodeling, including significant T cell infiltration; these changes were further enhanced by IL-15 SA expression, driving marked increases in NK, NKT, and γδ T cell populations and reduction of regulatory T cells. Within tumors, CLD-401 reprogrammed infected cells to produce high levels of IL-15 SA (No Fc) at concentrations comparable to clinically validated IL-15 SA-Fc therapies, with expression confined exclusively to tumor tissue. IL-15 SA and viral expression peaked around day 6 and declined by day 17, coinciding with tumor clearance, ultimately resulting in complete tumor regression in murine breast cancer models. Dose escalation identified an optimal regimen, with a single intravenous dose achieving 80% complete responses in a bilateral EMT6 model. CLD-401 combines tumor-selective amplification with localized in situ cytokine expression, achieving potent antitumor immunity while minimizing systemic toxicity. The self-limiting pharmacokinetic profile supports a favorable safety profile. The tumor-restricted amplification and TME remodeling established by CLD-401 provide the foundation for additional payloads, including tumor-targeted T cell engagers (CLD-501). These findings support IND submission (CLD-401) by end of 2026 and clinical trial initiation in H1 2027, positioning RedTail as a next-generation gene medicine platform. Yunyi Kang, Duong H. Nguyen, Stephanie Songco, Trevor Smith, David Nguyen, Yan Pang, Lina Schulte, Hongli Zhang, Sinje Tigges, Fabian Kortum, Daniela Kleinholz, Susan Tamraz, Ivelina Minev, Robert Porter, Evan Cassavaugh, Thomas Herrmann, G. Travis Clifton, Barbara Haertl, Eric Poma, Antonio F. Santidrian. CLD-401, a Systemic Gene Medicine for In Situ IL-15 Superagonist Delivery: Driving NK and γδ T Cell-Mediated Tumor Killing [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B017.