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715 WTX-330 is an IL-12 pro-drug that is conditionally activated within the tumor microenvironment and induces regressions in mouse tumor models
  1. Kristin Morris1,
  2. Heather Brodkin1,
  3. Daniel Hicklin1,
  4. Nesreen Ismail1,
  5. Christopher Nirschl1,
  6. Andres Salmeron1,
  7. Philipp Steiner1,
  8. Zoe Steuert1,
  9. Jenna Sullivan2 and
  10. William Winston1
  1. 1Werewolf Therapeutics, Cambridge, MA, United States
  2., Cambridge, MA, United States


Background Systemic administration of proinflammatory cytokines is a promising approach to treat cancer. However, poor pharmacokinetic properties and dose-limiting toxicities after systemic administration of cytokines such as interleukin 12 (IL-12) renders this strategy impractical. WTX-330 is a novel therapy identified using the Predator™ discovery platform that is designed to selectively deliver active wild-type IL-12 to the tumor microenvironment.

Methods WTX-330 is an inducible polypeptide (INDUKINE™ molecule) that consists of wild-type IL-12 tethered to a high affinity antibody blockade domain and a half-life extension (HLE) domain via tumor protease-sensitive linkers.

Results WTX-330 shows favorable inducible activity in vitro. WTX-330 incubated ex vivo with various primary human tumors led to the release of active IL-12, while WTX-330 was stable in human serum and normal tissues. Intraperitoneal (i.p.) administration of mouse WTX-330 led to complete tumor regression in multiple syngeneic tumor models. Importantly, equimolar amounts of wild-type IL-12, while active, was not tolerated by the mice compared to the IL-12 INDUKINE™ molecule. Mouse surrogate WTX-330 led to increased activation and frequencies of cross-presenting dendritic cells, NK cells and tumor specific CD8 T cells in B16F10 tumors. Moreover, mouse WTX-330, but not wild type IL-12, led to increased T cell activation specifically within B16F10 tumors as compared to the periphery. WTX-330 was well tolerated in non-human primates at different dose levels and schedules with exposure levels which exceeded the levels needed for anti-tumor activity in mice. In addition, there was low systemic exposure of IL-12 in the plasma after dosing with WTX-330 as compared to levels observed after treatment with wild-type IL-12.

Conclusions Pharmacological and translational data obtained so far clearly support continued preclinical development with the goal of moving this innovative and differentiated engineered IL-12 therapy into human clinical testing.

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