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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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 CD73pos/EpCAMpos 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.

Original language	English
Pages (from-to)	109-118
Number of pages	10
Journal	Cancer letters
Volume	521
Early online date	28-Aug-2021
DOIs	https://doi.org/10.1016/j.canlet.2021.08.037
Publication status	Published - 28-Nov-2021

Keywords

Bifunctional antibody
Tumor exosomes
Ecto-5 '-nucleotidase
Immune checkpoint
Cancer immunotherapy
T-CELLS
EXOSOMES
TARGET
CD73

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10.1016/j.canlet.2021.08.037

Bispecific antibody CD73xEpCAM selectively inhibits the adenosine-mediated immunosuppressive activity of carcinoma-derived extracellular vesiclesFinal publisher's version, 6.83 MBLicence: Taverne

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@article{18d88ee5a0154e738f93c635b01f8f28,

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

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 CD73pos/EpCAMpos 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, Tumor exosomes, Ecto-5 '-nucleotidase, Immune checkpoint, Cancer immunotherapy, T-CELLS, EXOSOMES, TARGET, CD73",

author = "Ploeg, {Emily M} and Xiurong Ke and Isabel Britsch and Hendriks, {Mark A J M} and {Van der Zant}, {Femke A} and Schelto Kruijff and Samplonius, {Douwe F} and Hao Zhang and Wijnand Helfrich",

note = "Copyright {\textcopyright} 2021. Published by Elsevier B.V.",

year = "2021",

month = nov,

day = "28",

doi = "10.1016/j.canlet.2021.08.037",

language = "English",

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T1 - Bispecific antibody CD73xEpCAM selectively inhibits the adenosine-mediated immunosuppressive activity of carcinoma-derived extracellular vesicles

AU - Ploeg, Emily M

AU - Ke, Xiurong

AU - Britsch, Isabel

AU - Hendriks, Mark A J M

AU - Van der Zant, Femke A

AU - Kruijff, Schelto

AU - Samplonius, Douwe F

AU - Zhang, Hao

AU - Helfrich, Wijnand

PY - 2021/11/28

Y1 - 2021/11/28

N2 - 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 CD73pos/EpCAMpos 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.

AB - 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 CD73pos/EpCAMpos 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.

KW - Bifunctional antibody

KW - Tumor exosomes

KW - Ecto-5 '-nucleotidase

KW - Immune checkpoint

KW - Cancer immunotherapy

KW - T-CELLS

KW - EXOSOMES

KW - TARGET

KW - CD73

U2 - 10.1016/j.canlet.2021.08.037

DO - 10.1016/j.canlet.2021.08.037

M3 - Article

C2 - 34464670

SN - 0304-3835

VL - 521

SP - 109

EP - 118

JO - Cancer letters

JF - Cancer letters

ER -