1. Engineered antibody cytokine chimera synergizes with DNA-launched nanoparticle vaccines to potentiate melanoma suppression in vivo
- Author
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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, and David B. Weiner
- Subjects
cancer immunotherapy ,antibody cytokine chimera ,DNA vaccines ,nanoparticle vaccines ,melanoma ,Immunologic diseases. Allergy ,RC581-607 - Abstract
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.
- Published
- 2023
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