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Wang, Linya; Peterson, Sean M.; Lujan, Ana; Chan, Kara Y.; Hu, Cameron F.; Villalta, Mouna; Yuan, Tom Z.; Han, Zhen; Yang, Marisa; Prabhu, Vishwas; Htoy, Tammy; VanDyke, Paul; Holliday, Carson; Franco, Hector; Wadhwa, Hansika; Giang, Hoa; Stafford, Ryan; Axelrod, Fumiko; Sato, Aaron

Abstract 2649: Discovery of a potent, selective, and tumor-suppressing antibody antagonist of DKK1

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  • Medientyp: E-Artikel
  • Titel: Abstract 2649: Discovery of a potent, selective, and tumor-suppressing antibody antagonist of DKK1
  • Beteiligte: Wang, Linya; Peterson, Sean M.; Lujan, Ana; Chan, Kara Y.; Hu, Cameron F.; Villalta, Mouna; Yuan, Tom Z.; Han, Zhen; Yang, Marisa; Prabhu, Vishwas; Htoy, Tammy; VanDyke, Paul; Holliday, Carson; Franco, Hector; Wadhwa, Hansika; Giang, Hoa; Stafford, Ryan; Axelrod, Fumiko; Sato, Aaron
  • Erschienen: American Association for Cancer Research (AACR), 2023
  • Erschienen in: Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1538-7445.am2023-2649
  • ISSN: 1538-7445
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the β-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1) has been shown to be a potent inhibitor of Wnt signaling via competing Wnt binding to LRP5/6. DKK1 is tumorigenic in multiple cancer types and also immunosuppressive via MDSCs and NK cells. Emerging evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. With Twist’s precision DNA writing technologies, we have created phage display libraries with diversity greater than 1 × 1010, and utilized machine learning model for optimal discovery. In this study, we discovered anti-DKK1 antibodies blocking the binding of DKK1 to the receptor. The in vitro functional assays showed that the interaction of Wnt to its receptor was restored in the presence of anti-DKK1 antibodies, resulting in TCF/LEF signaling upregulation. Moreover, anti-DKK1 antibodies induced immune cell activation, and led to tumor cell cytotoxicity. In addition, anti-DKK1 antibodies binding to different domains of DKK1 led to different functional effect. In vivo study indicated anti-DKK1 antibodies is potent in tumor regression. Our anti-DKK1 leads shows promising efficacy in cancer immunotherapy.</jats:p> <jats:p>Citation Format: Linya Wang, Sean M. Peterson, Ana Lujan, Kara Y. Chan, Cameron F. Hu, Mouna Villalta, Tom Z. Yuan, Zhen Han, Marisa Yang, Vishwas Prabhu, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hansika Wadhwa, Hoa Giang, Ryan Stafford, Fumiko Axelrod, Aaron Sato. Discovery of a potent, selective, and tumor-suppressing antibody antagonist of DKK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2649.</jats:p>
  • Zugangsstatus: Freier Zugang