Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate

Elena Ethel Vidal-Calvo, Anne Martin-Salazar, Swati Choudhary, Robert Dagil, Sai Sundar Rajan Raghavan, Lara Duvnjak, Mie Anemone Nordmaj, Thomas Mandel Clausen, Ann Skafte, Jan Oberkofler, Kaituo Wang, Mette Ø Agerbæk, Caroline Løppke, Amalie Mundt Jørgensen, Daria Ropac, Joana Mujollari, Shona Willis, Agnès Garcias López, Rebecca Louise Miller, Richard Torbjörn Gustav KarlssonFelix Goerdeler, Yen-Hsi Chen, Ana R Colaço, Yong Wang, Thomas Lavstsen, Agnieszka Martowicz, Irina Nelepcu, Mona Marzban, Htoo Zarni Oo, Maj Sofie Ørum-Madsen, Yuzhuo Wang, Morten A Nielsen, Henrik Clausen, Michael Wierer, Dominik Wolf, Ismail Gögenur, Thor G Theander, Nader Al-Nakouzi, Tobias Gustavsson, Mads Daugaard, Ali Salanti

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Abstract

Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes. These antibody fragments show binding affinity to ofCS in the low nanomolar range across a broad selection of solid tumor types in vitro and in vivo with minimal binding to normal, inflamed, or benign tumor tissues. Anti-ofCS antibody drug conjugates and bispecific immune cell engagers based on these targeting moieties disrupt tumor progression in animal models of human and murine cancers. Thus, anti-ofCS antibody fragments hold promise for the development of broadly effective therapeutic and diagnostic applications targeting human malignancies.

Original languageEnglish
Article number7553
JournalNature Communications
Volume15
Issue number1
Number of pages20
ISSN2041-1723
DOIs
Publication statusPublished - 2024

Bibliographical note

© 2024. The Author(s).

Keywords

  • Animals
  • Humans
  • Chondroitin Sulfates/metabolism
  • Mice
  • Neoplasms/immunology
  • Cell Line, Tumor
  • Female
  • Epitopes/immunology
  • Antigens, Neoplasm/immunology
  • Xenograft Model Antitumor Assays
  • Immunoconjugates/therapeutic use
  • Peptide Library

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