Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1

Jang-June Park, Emily P. Thi, Victor H. Carpio, Yingzhi Bi, Andrew G. Cole, Bruce D. Dorsey, Kristi Fan, Troy Harasym, Christina L. Iott, Salam Kadhim, Jin Hyang Kim, Amy C. H. Lee, Duyan Nguyen, Bhavna S. Paratala, Ruiqing Qiu, Andre White, Damodharan Lakshminarasimhan, Christopher Leo, Robert K. Suto, Rene Rijnbrand, Sunny Tang, Michael J. Sofia and Chris B. Moore ()
Additional contact information
Jang-June Park: Arbutus Biopharma Inc
Emily P. Thi: Arbutus Biopharma Inc
Victor H. Carpio: Arbutus Biopharma Inc
Yingzhi Bi: Arbutus Biopharma Inc
Andrew G. Cole: Arbutus Biopharma Inc
Bruce D. Dorsey: Arbutus Biopharma Inc
Kristi Fan: Arbutus Biopharma Inc
Troy Harasym: Arbutus Biopharma Inc
Christina L. Iott: Arbutus Biopharma Inc
Salam Kadhim: Arbutus Biopharma Inc
Jin Hyang Kim: Arbutus Biopharma Inc
Amy C. H. Lee: Arbutus Biopharma Inc
Duyan Nguyen: Arbutus Biopharma Inc
Bhavna S. Paratala: Arbutus Biopharma Inc
Ruiqing Qiu: Arbutus Biopharma Inc
Andre White: Xtal BioStructures Inc.
Damodharan Lakshminarasimhan: Xtal BioStructures Inc.
Christopher Leo: Xtal BioStructures Inc.
Robert K. Suto: Xtal BioStructures Inc.
Rene Rijnbrand: Arbutus Biopharma Inc
Sunny Tang: Arbutus Biopharma Inc
Michael J. Sofia: Arbutus Biopharma Inc
Chris B. Moore: Arbutus Biopharma Inc

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21410-1

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DOI: 10.1038/s41467-021-21410-1

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