Tumor Cell-Surface Binding of Immune Stimulating Polymeric Glyco-Adjuvant via Cysteine-Reactive Pyridyl Disulfide Promotes Antitumor Immunity
Anna J. Slezak, Aslan Mansurov, Michal M. Raczy, Kevin Chang, Aaron T. Alpar, Abigail L. Lauterbach, Rachel P. Wallace, Rachel K. Weathered, Jorge Emiliano Gomez Medellin, Claudia Battistella, Laura Gray, Tiffany M. Marchell, Suzana Gomes, Melody A. Swartz, Jeffrey A. Hubbell
Abstract
vaccine. The metabolic and enzymatic dysregulation in the tumor microenvironment produces these exofacial free thiols, which can undergo efficient disulfide exchange with thiol-reactive pyridyl disulfide moieties upon intratumoral injection. These functional monomers are incorporated into a copolymer with pendant mannose groups and TLR7 agonists to target both antigen and adjuvant to antigen presenting cells. When tethered in the tumor, the polymeric glyco-adjuvant induces a robust antitumor response and prolongs survival of tumor-bearing mice, including in checkpoint-resistant B16F10 melanoma. The construct additionally reduces systemic toxicity associated with clinically relevant small molecule TLR7 agonists.