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

被引：99

作者：

Park, Jang-June ^{[1
]}

Thi, Emily P. ^{[1
]}

Carpio, Victor H. ^{[1
]}

Bi, Yingzhi ^{[1
]}

Cole, Andrew G. ^{[1
]}

Dorsey, Bruce D. ^{[1
]}

Fan, Kristi ^{[1
]}

Harasym, Troy ^{[1
]}

Iott, Christina L. ^{[1
]}

Kadhim, Salam ^{[1
]}

Kim, Jin Hyang ^{[1
]}

Lee, Amy C. H. ^{[1
]}

Nguyen, Duyan ^{[1
]}

Paratala, Bhavna S. ^{[1
]}

Qiu, Ruiqing ^{[1
]}

White, Andre ^{[2
]}

Lakshminarasimhan, Damodharan ^{[2
]}

Leo, Christopher ^{[2
]}

Suto, Robert K. ^{[2
]}

Rijnbrand, Rene ^{[1
]}

Tang, Sunny ^{[1
]}

Sofia, Michael J. ^{[1
]}

Moore, Chris B. ^{[1
]}

机构：

[1] Arbutus Biopharma Inc, Warminster, PA 18974 USA

[2] Xtal BioStruct Inc, Natick, MA USA

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

关键词：

T-CELL DYSFUNCTION; ANTI-PD-L1; ANTIBODY; CANCER-IMMUNOTHERAPY; HEPATITIS-B; IN-VIVO; SAFETY; B7-H1; PD-1; PD-1/PD-L1; BLOCKADE;

D O I：

10.1038/s41467-021-21410-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

共 53 条

[1] Restoring function in exhausted CD8 T cells during chronic viral infection [J].

Barber, DL ;

Wherry, EJ ;

Masopust, D ;

Zhu, BG ;

Allison, JP ;

Sharpe, AH ;

Freeman, GJ ;

Ahmed, R .

NATURE, 2006, 439 (7077) :682-687

[2] Design, Synthesis, Evaluation, and Structural Studies of C2-Symmetric Small Molecule Inhibitors of Programmed Cell Death1/Programmed Death-Ligand 1 Protein-Protein Interaction [J].

Basu, Subhadwip ;

Yang, Jeffrey ;

Xu, Bin ;

Magiera-Mularz, Katarzyna ;

Skalniak, Lukasz ;

Musielak, Bogdan ;

Kholodovych, Vladyslav ;

Holak, Tad A. ;

He, Longqin .

JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (15) :7250-7263

[3] Toward Small-molecule Inhibition of Protein-protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions [J].

Bojadzic, Damir ;

Buchwald, Peter .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2018, 18 (08) :674-699

[4] Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection [J].

Boni, Carolina ;

Fisicaro, Paola ;

Valdatta, Caterina ;

Amadei, Barbara ;

Di Vincenzo, Paola ;

Giuberti, Tiziana ;

Laccabue, Diletta ;

Zerbini, Alessandro ;

Cavalli, Albertina ;

Missale, Gabriele ;

Bertoletti, Antonio ;

Ferrari, Carlo .

JOURNAL OF VIROLOGY, 2007, 81 (08) :4215-4225

[5] Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer [J].

Brahmer, Julie R. ;

Tykodi, Scott S. ;

Chow, Laura Q. M. ;

Hwu, Wen-Jen ;

Topalian, Suzanne L. ;

Hwu, Patrick ;

Drake, Charles G. ;

Camacho, Luis H. ;

Kauh, John ;

Odunsi, Kunle ;

Pitot, Henry C. ;

Hamid, Omid ;

Bhatia, Shailender ;

Martins, Renato ;

Eaton, Keith ;

Chen, Shuming ;

Salay, Theresa M. ;

Alaparthy, Suresh ;

Grosso, Joseph F. ;

Korman, Alan J. ;

Parker, Susan M. ;

Agrawal, Shruti ;

Goldberg, Stacie M. ;

Pardoll, Drew M. ;

Gupta, Ashok ;

Wigginton, Jon M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (26) :2455-2465

[6] A Novel Anti-PD-L1 Vaccine for Cancer Immunotherapy and Immunoprevention [J].

Chen, Jie ;

Liu, Hui ;

Jehng, Tiffany ;

Li, Yanqing ;

Chen, Zhoushi ;

Lee, Kuan-Der ;

Shen, Hsieh-Tsung ;

Jones, Lindsey ;

Huang, Xue F. ;

Chen, Si-Yi .

CANCERS, 2019, 11 (12)

[7]

Dong HD, 1999, NAT MED, V5, P1365

[8]

Dong HD, 2002, NAT MED, V8, P793, DOI 10.1038/nm730

[9] Combined Blockade of Programmed Death-1 and Activation of CD137 Increase Responses of Human Liver T Cells Against HBV, But Not HCV [J].

Fisicaro, Paola ;

Valdatta, Caterina ;

Massari, Marco ;

Loggi, Elisabetta ;

Ravanetti, Lara ;

Urbani, Simona ;

Giuberti, Tiziana ;

Cavalli, Albertina ;

Vandelli, Carmen ;

Andreone, Pietro ;

Missale, Gabriele ;

Ferrari, Carlo .

GASTROENTEROLOGY, 2012, 143 (06) :1576-+

[10] Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation [J].

Freeman, GJ ;

Long, AJ ;

Iwai, Y ;

Bourque, K ;

Chernova, T ;

Nishimura, H ;

Fitz, LJ ;

Malenkovich, N ;

Okazaki, T ;

Byrne, MC ;

Horton, HF ;

Fouser, L ;

Carter, L ;

Ling, V ;

Bowman, MR ;

Carreno, BM ;

Collins, M ;

Wood, CR ;

Honjo, T .

JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 192 (07) :1027-1034

← 1 2 3 4 5 6 →