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

• Published in: Frontiers in immunology Vol. 14; p. 1072810
• Main Authors: Tursi, Nicholas J, Xu, Ziyang, Helble, Michaela, Walker, Susanne, Liaw, Kevin, Chokkalingam, Neethu, Kannan, Toshitha, Wu, Yuanhan, Tello-Ruiz, Edgar, Park, Daniel H, Zhu, Xizhou, Wise, Megan C, Smith, Trevor R F, Majumdar, Sonali, Kossenkov, Andrew, Kulp, Daniel W, Weiner, David B
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23.02.2023
• Subjects: Animals; Antibodies; antibody cytokine chimera; cancer immunotherapy; Cytokines; DNA; DNA vaccines; Immunology; Melanoma; Mice; nanoparticle vaccines; Nanoparticles; Vaccines, DNA; antibody cytokine chimera; nanoparticle vaccines; melanoma; DNA vaccines; cancer immunotherapy
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1072810

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 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.