Engineered Antibody Cytokine Chimera Synergizes with DNA-Launched Nanoparticle Vaccines to Potentiate Suppression of Melanoma Proliferation in vivo

Cancer immunotherapy has demonstrated great promise with the checkpoint inhibitors being approved as the first-line therapy for some types of cancer, and engineered cytokines like Neo2/15 being evaluated in many studies. In this work, we designed Antibody Cytokine Chimera (ACC) scaffolding cytokine mimetics with full-length tumor-specific antibody. We characterized the pharmacokinetic (PK) and pharmacodynamic (PD) properties of first-generation ACC TA99-Neo2/15, which synergized with DLnano-vaccines in suppressing in vivo melanoma proliferation but caused significant systemic cytokine activation. A novel second-generation ACC TA99-HL2-KOA1, with retained IL-2Rβ/γ binding and attenuated but preserved IL-2Rα, caused significantly lower systemic cytokine activation and non-inferior protection in murine tumor studies. Transcriptomic experiment demonstrated up-regulation of Type I interferon responsive genes, particularly ISG15, in dendritic cells, macrophages and monocytes following TA99-HL2-KOA1 treatment. Characterization of additional ACCs in combination with cancer vaccines will likely be an important area of research for treating melanoma and other types of cancer. 10x single cell on the tumor-infiltrating lymphocytes