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 A. Nordmaj, Thomas Mandel Clausen, Ann Skafte, Jan Oberkofler, Kaituo Wang, Mette Ø. Agerbæk, Caroline Løppke, Amalie M. Jørgensen, Daria Ropac, Joana Mujollari, Shona Caroline Willis, Agnès Garcias López, Rebecca L. Miller, Richard 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 Gögenür, Thor G. Theander, Nader Al-Nakouzi, Tobias Gustavsson, Mads Daugaard, Ali Salanti
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. Cancer cells often acquire molecular patterns of fast-growing embryonic tissues to enable propagation and invasion, which distinguish tumour tissues from their healthy adult counterpart. Here authors develop antibody fragments which specifically target oncofetal chondroitin sulphate on the cancer cell surface and in the tumour stroma, with the antibodies achieving therapeutic effect in multiple mouse models in antibody drug conjugate and bispecific immune cell engager formats.