Engineered antibody cytokine chimera synergizes with DNA-launched nanoparticle vaccines to potentiate melanoma suppression in vivo

• DOI: 10.3389/fimmu.2023.1072810
• Publication Date: 2023-02-23T13:31:42Z
• Authors: Nicholas J. Tursi; Ziyang Xu; Michaela Helble; Susanne Walker; Kevin Liaw; Neethu Chokkalingam; Toshitha Kannan; Yuanhan Wu; Edgar Tello-Ruiz; Daniel H. Park; Xizhou Zhu; Megan C. Wise; Trevor R. F. Smith; Sonali Majumdar; Andrew Kossenkov; Daniel W. Kulp; David B. Weiner
• Keywords: 0301 basic medicine; cancer immunotherapy; Immunology; DNA; antibody cytokine chimera; RC581-607; Antibodies; 3. Good health; DNA vaccines; Mice; 03 medical and health sciences; melanoma; Vaccines, DNA; Animals; Cytokines; Nanoparticles; nanoparticle vaccines; Immunologic diseases. Allergy; Melanoma

Cancer immunotherapy has demonstrated great promise with several checkpoint inhibitors being approved as the first-line therapy for some types of cancer, and new engineered cytokines such as Neo2/15 now being evaluated in many studies. In this work, we designed antibody-cytokine chimera (ACC) scaffolding cytokine mimetics on a 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 to suppress in vivo melanoma proliferation and induced significant systemic cytokine activation. A novel second-generation ACC TA99-HL2-KOA1, with retained IL-2Rβ/γ binding and attenuated but preserved IL-2Rα binding, induced lower systemic cytokine activation with non-inferior protection in murine tumor studies. Transcriptomic analyses demonstrated an upregulation 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.