mWTX-330, an IL-12 INDUKINE Molecule, Activates and Reshapes Tumor-Infiltrating CD8þ T and NK Cells to Generate Antitumor Immunity

Abstract

IL-12 is a pleotropic inflammatory cytokine, which has broad timulatory effects on various immune cell populations, making t an attractive target for cancer immunotherapy. However, espite generating robust antitumor activity in syngeneic murine tumor models, clinical administration of IL-12 has been imited by severe toxicity. mWTX-330 is a selectively inducible NDUKINE molecule comprised of a half-life extension domain nd an inactivation domain linked to chimeric IL-12 by tumor rotease–sensitive linkers. Systemic administration of mWTX-330 n mice was well tolerated, resulted in robust antitumor immuity in multiple tumor models, and preferentially activated umor-infiltrating immune cells rather than immune cells presnt in peripheral tissues. Antitumor activity was dependent on n vivo processing of the protease cleavable linkers and required CD8þ T cells for full efficacy. Within the tumor, mWTX-330 increased the frequency of cross-presenting dendritic cells (DC), activated natural killer (NK) cells, skewed conventional CD4þ T cells toward a T helper 1 (TH1) phenotype, drove regulatory T cells (Treg) fragility, and increased the frequency of polyfunctional CD8þ T cells. mWTX-330 treatment also increased the clonality of tumor-infiltrating T cells by expanding underrepresented T-cell receptor (TCR) clones, drove CD8þ T and NK cells towards increased mitochondrial respiration and fitness, and decreased the frequency of TOXþ exhausted CD8þ T cells within the tumor. A fully human version of this INDUKINE molecule was stable in human serum, was reliably and selectively processed by human tumor samples, and is currently in clinical development.