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CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity
The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies that block this pathway have been approved in multiple tumor indications. As a next generation therapy, small molecule inhibitors of PD-L1 have inherent dr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246841/ https://www.ncbi.nlm.nih.gov/pubmed/37285333 http://dx.doi.org/10.1371/journal.pone.0286724 |
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author | Sullivan, Kathleen M. C. Vilalta, Marta Ertl, Linda S. Wang, Yu Dunlap, Carolyn Ebsworth, Karen Zhao, Bin N. Li, Shijie Zeng, Yibin Miao, Zhenhua Fan, Pingchen Mali, Venkat Lange, Christopher McMurtrie, Darren Yang, Ju Lui, Rebecca Scamp, Ryan Chhina, Vicky Kumamoto, Alice Yau, Simon Dang, Ton Easterday, Ashton Liu, Shirley Miao, Shichang Charo, Israel Schall, Thomas J. Zhang, Penglie |
author_facet | Sullivan, Kathleen M. C. Vilalta, Marta Ertl, Linda S. Wang, Yu Dunlap, Carolyn Ebsworth, Karen Zhao, Bin N. Li, Shijie Zeng, Yibin Miao, Zhenhua Fan, Pingchen Mali, Venkat Lange, Christopher McMurtrie, Darren Yang, Ju Lui, Rebecca Scamp, Ryan Chhina, Vicky Kumamoto, Alice Yau, Simon Dang, Ton Easterday, Ashton Liu, Shirley Miao, Shichang Charo, Israel Schall, Thomas J. Zhang, Penglie |
author_sort | Sullivan, Kathleen M. C. |
collection | PubMed |
description | The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies that block this pathway have been approved in multiple tumor indications. As a next generation therapy, small molecule inhibitors of PD-L1 have inherent drug properties that may be advantageous for certain patient populations compared to antibody therapies. In this report we present the pharmacology of the orally-available, small molecule PD-L1 inhibitor CCX559 for cancer immunotherapy. CCX559 potently and selectively inhibited PD-L1 binding to PD-1 and CD80 in vitro, and increased activation of primary human T cells in a T cell receptor-dependent fashion. Oral administration of CCX559 demonstrated anti-tumor activity similar to an anti-human PD-L1 antibody in two murine tumor models. Treatment of cells with CCX559 induced PD-L1 dimer formation and internalization, which prevented interaction with PD-1. Cell surface PD-L1 expression recovered in MC38 tumors upon CCX559 clearance post dosing. In a cynomolgus monkey pharmacodynamic study, CCX559 increased plasma levels of soluble PD-L1. These results support the clinical development of CCX559 for solid tumors; CCX559 is currently in a Phase 1, first in patient, multicenter, open-label, dose-escalation study (ACTRN12621001342808). |
format | Online Article Text |
id | pubmed-10246841 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-102468412023-06-08 CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity Sullivan, Kathleen M. C. Vilalta, Marta Ertl, Linda S. Wang, Yu Dunlap, Carolyn Ebsworth, Karen Zhao, Bin N. Li, Shijie Zeng, Yibin Miao, Zhenhua Fan, Pingchen Mali, Venkat Lange, Christopher McMurtrie, Darren Yang, Ju Lui, Rebecca Scamp, Ryan Chhina, Vicky Kumamoto, Alice Yau, Simon Dang, Ton Easterday, Ashton Liu, Shirley Miao, Shichang Charo, Israel Schall, Thomas J. Zhang, Penglie PLoS One Research Article The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies that block this pathway have been approved in multiple tumor indications. As a next generation therapy, small molecule inhibitors of PD-L1 have inherent drug properties that may be advantageous for certain patient populations compared to antibody therapies. In this report we present the pharmacology of the orally-available, small molecule PD-L1 inhibitor CCX559 for cancer immunotherapy. CCX559 potently and selectively inhibited PD-L1 binding to PD-1 and CD80 in vitro, and increased activation of primary human T cells in a T cell receptor-dependent fashion. Oral administration of CCX559 demonstrated anti-tumor activity similar to an anti-human PD-L1 antibody in two murine tumor models. Treatment of cells with CCX559 induced PD-L1 dimer formation and internalization, which prevented interaction with PD-1. Cell surface PD-L1 expression recovered in MC38 tumors upon CCX559 clearance post dosing. In a cynomolgus monkey pharmacodynamic study, CCX559 increased plasma levels of soluble PD-L1. These results support the clinical development of CCX559 for solid tumors; CCX559 is currently in a Phase 1, first in patient, multicenter, open-label, dose-escalation study (ACTRN12621001342808). Public Library of Science 2023-06-07 /pmc/articles/PMC10246841/ /pubmed/37285333 http://dx.doi.org/10.1371/journal.pone.0286724 Text en © 2023 Sullivan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Sullivan, Kathleen M. C. Vilalta, Marta Ertl, Linda S. Wang, Yu Dunlap, Carolyn Ebsworth, Karen Zhao, Bin N. Li, Shijie Zeng, Yibin Miao, Zhenhua Fan, Pingchen Mali, Venkat Lange, Christopher McMurtrie, Darren Yang, Ju Lui, Rebecca Scamp, Ryan Chhina, Vicky Kumamoto, Alice Yau, Simon Dang, Ton Easterday, Ashton Liu, Shirley Miao, Shichang Charo, Israel Schall, Thomas J. Zhang, Penglie CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity |
title | CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity |
title_full | CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity |
title_fullStr | CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity |
title_full_unstemmed | CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity |
title_short | CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity |
title_sort | ccx559 is a potent, orally-administered small molecule pd-l1 inhibitor that induces anti-tumor immunity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246841/ https://www.ncbi.nlm.nih.gov/pubmed/37285333 http://dx.doi.org/10.1371/journal.pone.0286724 |
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