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-2Rß/? binding and attenuated but preserved IL-2Ra, 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. Overall design: 10x single cell on the tumor-infiltrating lymphocytes