Bispecific antibody CD73xEpCAM selectively inhibits the adenosine-mediated immunosuppressive activity of carcinoma-derived extracellular vesicles

Emily M Ploeg; Xiurong Ke; Isabel Britsch; Mark A J M Hendriks; Femke A Van der Zant; Schelto Kruijff; Douwe F Samplonius; Hao Zhang; Wijnand Helfrich

doi:10.1016/j.canlet.2021.08.037

Bispecific antibody CD73xEpCAM selectively inhibits the adenosine-mediated immunosuppressive activity of carcinoma-derived extracellular vesicles

Cancer Lett. 2021 Aug 28:521:109-118. doi: 10.1016/j.canlet.2021.08.037. Online ahead of print.

Authors

Emily M Ploeg¹, Xiurong Ke², Isabel Britsch¹, Mark A J M Hendriks¹, Femke A Van der Zant¹, Schelto Kruijff¹, Douwe F Samplonius¹, Hao Zhang³, Wijnand Helfrich⁴

Affiliations

¹ University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, the Netherlands.
² University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, the Netherlands; Shantou University Medical College, Shantou, Guangdong, China.
³ Institute of Precision Cancer and Pathology, Department of Pathology, School of Medicine, Department of General Surgery, First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China. Electronic address: haolabcancercenter@163.com.
⁴ University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, the Netherlands. Electronic address: w.helfrich@umcg.nl.

PMID: 34464670
DOI: 10.1016/j.canlet.2021.08.037

Abstract

Tumor-derived extracellular vesicles (EVs) carry potent immunosuppressive factors that affect the antitumor activities of immune cells. A significant part of the immunoinhibitory activity of EVs is attributable to CD73, a GPI-anchored ecto-5'-nucleotidase involved in the conversion of tumor-derived proinflammatory extracellular ATP (eATP) to immunosuppressive adenosine (ADO). The CD73-antagonist antibody oleclumab inhibits cell surface-exposed CD73 and is currently undergoing clinical testing for cancer immunotherapy. However, a strategy to selectively inhibit CD73 exposed on EVs is not available. Here, we present a novel bispecific antibody (bsAb) CD73xEpCAM designed to bind with high affinity the common EV surface marker EpCAM and concurrently inhibit CD73. Unlike oleclumab, bsAb CD73xEpCAM potently inhibited the immunosuppressive activity of EVs from CD73^pos/EpCAM^pos carcinoma cell lines and patient-derived colorectal cancer cells. Taken together, selective blockade of EV-exposed CD73 by bsAb CD73xEpCAM may be useful as an alternate or complementary targeted approach in cancer immunotherapy.

Keywords: Bifunctional antibody; Cancer immunotherapy; Ecto-5′-nucleotidase; Immune checkpoint; Tumor exosomes.