Parthanatos-inducing zinc agent C010DS-Zn elicits anti-tumor immune responses involving T cells and macrophages in vivo

• Published in: bioRxiv
• Main Authors: Jinhyuk Fred Chung, Her, Zhisheng, Kong, Wai Mun, Chen, Qingfeng
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 19.03.2021; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Apoptosis; Bioavailability; Cancer; Cancer therapies; Cell death; COVID-19; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA fragmentation; DNA repair; Immune checkpoint inhibitors; Immunogenicity; Inflammation; Intellectual property; Intravenous administration; Lymphocytes T; Macromolecules; Macrophages; Pharmacokinetics; Pharmacology and Toxicology; Poly(ADP-ribose) polymerase; Stockholders; Zinc
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2021.03.18.433812

Abstract Immune checkpoint inhibitors opened a new horizon in cancer therapy by enabling durable and complete responses in patients, but their wider application against general solid cancers has been hampered by the lack of a broadly acting anti-cancer immune response initiating agents. Parthanatos is a previously unexplored immunogenic programmed necrosis mechanism that is triggered by the hyperactivation of PARP DNA repair and executed by an efficient DNA-fragmentation mechanism. We developed a proprietary macromolecular zinc complex agent C010DS-Zn that efficiently induced parthanatos against 4T1 murine cancer cells in vitro, which was characterized as PARP-mediated necrotic death with massive DNA damages. Ex vivo screening of its cytotoxicity against a panel of 53 low-passage human solid cancer PDX tumor fragments demonstrated its consistent delivery of characteristically DNA-damaging cell death that was unseen in the corresponding apoptosis positive controls. Further characterization of its in vivo treatment effects versus the immunosuppressive 4T1-Balb/c and immunogenic CT26-Balb/c syngeneic cancer models showed that sufficiently high intravenous C010DS-Zn treatments led to robust initiation of the tumor-suppressed antitumor immune compartments such as T cells and macrophages. At lower non-anticancer doses, C010DS-Zn treatment still led to significantly reduced macrophage content and inflammation in the 4T1 tumor, suggesting its potential utility against macrophage-mediated inflammations such as those seen in MIS-C or COVID19. Given the observation of its low serum bioavailability in a rat pharmacokinetic study, these results suggest potential development opportunities for C010DS-Zn to become a widely applicable immune initiation agent with chemo-like broad applicability upon its pharmacokinetic improvements. Competing Interest Statement QC is a shareholder of Invivocue. JFC is an executive director of Xylonix and is a shareholder of the same. Xylonix claims multiple intellectual property rights and patents filed on subjects relating, and not limited to, C005D-Zn and C010DS-Zn.