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 Karlsson, Felix 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 () and Ali Salanti ()
Additional contact information
Elena Ethel Vidal-Calvo: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Anne Martin-Salazar: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Swati Choudhary: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Robert Dagil: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Sai Sundar Rajan Raghavan: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Lara Duvnjak: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Mie Anemone Nordmaj: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Thomas Mandel Clausen: VAR2 Pharmaceuticals ApS
Ann Skafte: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Jan Oberkofler: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Kaituo Wang: Faculty of Health and Medical Sciences, University of Copenhagen
Mette Ø Agerbæk: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Caroline Løppke: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Amalie Mundt Jørgensen: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Daria Ropac: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Joana Mujollari: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Shona Willis: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Agnès Garcias López: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Rebecca Louise Miller: Faculty of Health and Medical Sciences, University of Copenhagen
Richard Torbjörn Gustav Karlsson: Faculty of Health and Medical Sciences, University of Copenhagen
Felix Goerdeler: Faculty of Health and Medical Sciences, University of Copenhagen
Yen-Hsi Chen: GlycoDisplay ApS
Ana R. Colaço: University of Copenhagen
Yong Wang: Zhejiang University
Thomas Lavstsen: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Agnieszka Martowicz: Comprehensive Cancer Center Innsbruck (CCCI) and Tyrolean Cancer Research Institute (TKFI), Medical University of Innsbruck
Irina Nelepcu: Vancouver Coastal Health Research Institutes
Mona Marzban: Vancouver Coastal Health Research Institutes
Htoo Zarni Oo: Vancouver Coastal Health Research Institutes
Maj Sofie Ørum-Madsen: Vancouver Coastal Health Research Institutes
Yuzhuo Wang: Vancouver Coastal Health Research Institutes
Morten A. Nielsen: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Henrik Clausen: Faculty of Health and Medical Sciences, University of Copenhagen
Michael Wierer: University of Copenhagen
Dominik Wolf: Comprehensive Cancer Center Innsbruck (CCCI) and Tyrolean Cancer Research Institute (TKFI), Medical University of Innsbruck
Ismail Gögenur: Zealand University Hospital Køge
Thor G. Theander: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Nader Al-Nakouzi: VAR2 Pharmaceuticals ApS
Tobias Gustavsson: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital
Mads Daugaard: VAR2 Pharmaceuticals ApS
Ali Salanti: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51781-0

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