Werewolf Therapeutics presents preclinical data on PREDATOR Platform

Werewolf Therapeutics (HOWL) shared preclinical data at the 2025 Society for Immunotherapy of Cancer’s 40th Annual Meeting, taking place November 5-9, 2025, in National Harbor, Maryland. Werewolf’s proprietary PREDATOR platform uses clinically validated protease-cleavable linkers for tumor-selective activation to improve the therapeutic index. This technology has already produced three clinical-stage INDUKINE candidates. The new preclinical data presented at SITC expand on this foundation by demonstrating two novel therapeutic strategies: a sequential regimen designed to safely harness the complementary immune mechanisms of IL-12 and IL-2, and the development of masked, conditional T cell engagers designed to mitigate systemic toxicities. These strategies are supported by first-in-kind pharmacokinetic data that provided a real-time assessment of WTX-124’s selective activation and immune engagement within the tumor. Key findings include: INDUCER Platform mitigated T Cell Engager toxicity with a novel masking strategy Abstract # 964 INDUCER molecules use a differentiated masking approach on the anti-CD3 domain that prevents systemic T cell activation and cytokine release in preclinical models. The mask was efficiently removed only in the presence of human tumor tissue, unleashing potent T cell activation and anti-tumor activity, demonstrating the platform’s potential to improve the safety and efficacy of this powerful class of cancer drugs. Sequential IL-12 and IL-2 dosing enhanced antitumor activity with improved tolerability Abstract # 861 In mice bearing poorly immunogenic EMT6 tumors, a sequential regimen of mWTX-330 followed by WTX-124 was well tolerated and demonstrated superior tumor-killing ability compared to either drug alone. These data suggest that mWTX-330 primes the immune response, and WTX-124 subsequently amplifies it, leveraging their complementary mechanisms of action to create a potent and translatable therapeutic strategy. Real-time spatiotemporal dynamics confirmed WTX-124’s tumor-selective activity Abstract # 862 Using microdialysis in live animals to monitor IL-2 INDUKINE pharmacology in a syngeneic murine model, WTX-124 was shown to release active IL-2 selectively in the tumor, with minimal active cytokine released in the plasma, validating the prodrug design. This localized IL-2 release drove a robust immune response, increasing the infiltration of NK and CD8+ T cells in the tumor, as well as selective production of effector cytokines like IFNg.