Discovery of a potent, selective, and tumor-suppressing antibody antagonist of adenosine A 2A receptor

New immune checkpoints are emerging in a bid to improve response rates to immunotherapeutic drugs. The adenosine A 2A receptor (A 2A R) has been proposed as a target for immunotherapeutic development due to its participation in immunosuppression of the tumor microenvironment. Blockade of A 2A R coul...

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Bibliographic Details
Published in:PloS one 2024-06, Vol.19 (6)
Main Authors: Wang, Linya, Garg, Pankaj, Chan, Kara, Yuan, Tom, Lujan Hernandez, Ana, Han, Zhen, Peterson, Sean, Tuscano, Emily, Safavi, Crystal, Kwan, Eric, Villalta, Mouna, Mathur, Melina, Lai, Joyce, Axelrod, Fumiko, Souders, Colby, Emery, Chloe, Sato, Aaron
Format: Article
Language:English
Subjects:
Adenosine
Antibodies
Antigens
Binding
Cancer
Chromatography
Cloning
Cross-reactivity
Enzyme-linked immunosorbent assay
FDA approval
Immune checkpoint
Immunization
Immunoglobulin G
Immunosuppression
Immunosuppressive agents
Immunotherapy
Leukocytes (mononuclear)
Mutation
Peripheral blood mononuclear cells
Phage display
Proteins
Receptors
Success
Tumor microenvironment
Tumors
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Summary:New immune checkpoints are emerging in a bid to improve response rates to immunotherapeutic drugs. The adenosine A 2A receptor (A 2A R) has been proposed as a target for immunotherapeutic development due to its participation in immunosuppression of the tumor microenvironment. Blockade of A 2A R could restore tumor immunity and, consequently, improve patient outcomes. Here, we describe the discovery of a potent, selective, and tumor-suppressing antibody antagonist of human A 2A R (hA 2A R) by phage display. We constructed and screened four single-chain variable fragment (scFv) libraries—two synthetic and two immunized—against hA 2A R and antagonist-stabilized hA 2A R. After biopanning and ELISA screening, scFv hits were reformatted to human IgG and triaged in a series of cellular binding and functional assays to identify a lead candidate. Lead candidate TB206-001 displayed nanomolar binding of hA 2A R-overexpressing HEK293 cells; cross-reactivity with mouse and cynomolgus A 2A R but not human A 1 , A 2B , or A 3 receptors; functional antagonism of hA 2A R in hA 2A R-overexpressing HEK293 cells and peripheral blood mononuclear cells (PBMCs); and tumor-suppressing activity in colon tumor-bearing HuCD34-NCG mice. Given its therapeutic properties, TB206-001 is a good candidate for incorporation into next-generation bispecific immunotherapeutics.
ISSN:1932-6203
DOI:10.1371/journal.pone.0301223