CLD-401, an IL-15 superagonist gene medicine via redtail virotherapy, achieves sustained tumor eradication

RedTail is a next-generation gene therapy platform engineered for systemic delivery and tumor selectivity. It uses a tumor-specific replication form of extracellular enveloped vaccinia virus (EEV) with chimeric CD55 expression to resist complement and neutralizing antibodies, enabling robust systemic administration. CLD-401, the lead candidate, converts tumors into factories producing IL-15(N72D)-IL-15RalphaSushi (IL-15 superagonist, IL-15 SA), a clinically validated cytokine that potently activates NK and CD8⁺ T cells. Methods Resistance to humoral immunity was assessed via plaque assays. Tumor cytotoxicity was measured by real-time impedance analysis. CLD-401 was administered systemically in multiple syngeneic models to evaluate tumor selectivity and IL-15 SA expression. Biodistribution and pharmacokinetics were quantified by dPCR. Flow cytometry and IHC characterized immune infiltration. Results To enable effective systemic delivery, CLD-401 was manufactured using an optimized host cell line that supports high production of EEV. These CD55 expressing EEV particles e were resistant to complement-mediated lysis and neutralizing antibodies in both syngeneic models and in ex vivo experiments using human serum. This immune evasion mechanism enables CLD-401 to selectively target tumors while maintaining robust systemic activity. In tumor-bearing preclinical models, but not in non-tumor-bearing controls, systemic administration resulted in tumor-specific viral amplification, which correlated with in situ IL-15 SA expression at levels comparable to clinically validated efficacy in bladder cancer reported with the approved IL-15-SA-Fc. IL-15 SA and viral expression peaked in tumors and plasma around day 6 and declined by day 17, coinciding with 80% tumor complete responses and tumor clearance, while remaining undetectable in other organs. Data confirmed strong local IL-15 SA production after systemic virotherapy, promoting antitumor immune cell infiltration and activation. Tumor amplification of CLD-401 and IL-15 SA expression also drove changes in peripheral cytokine profiles and immune cell populations, observed significantly in tumor-bearing animals but not in disease-free models suggesting a remodeling of the tumor microenvironment. CLD-401 supported repeat dosing, achieving superior efficacy compared to single-dose regimens indicating a lack of a neutralizing response. Conclusions Systemic CLD-401 enables tumor-specific amplification and high-level IL-15 SA expression, achieving durable regression without off-target toxicity. These findings support IND-enabling studies for CLD-401 and highlight the potential of the RedTail platforms as a next-generation systemic virotherapy with targeted and efficient delivery of genetic payloads.