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...
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Veröffentlicht in: | PloS one 2023-06, Vol.18 (6), p.e0286724-e0286724 |
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creator | 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 |
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). |
doi_str_mv | 10.1371/journal.pone.0286724 |
format | Article |
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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).</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0286724</identifier><identifier>PMID: 37285333</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal models ; Animals ; Antibodies, Monoclonal ; Anticancer properties ; Antitumor agents ; B7-H1 Antigen - metabolism ; Biology and life sciences ; Cancer ; Cancer immunotherapy ; Care and treatment ; CD80 antigen ; Cell activation ; Cell culture ; Cell surface ; Complications and side effects ; Cytotoxicity ; Dendritic cells ; Dosage ; Drug dosages ; Engineering and Technology ; Health aspects ; Humans ; Immune checkpoint ; Immune Checkpoint Inhibitors ; Immune clearance ; Immunotherapy ; Immunotherapy - methods ; Inhibitors ; Internalization ; Ligands ; Lymphocytes ; Lymphocytes T ; Macaca fascicularis ; Medicine and Health Sciences ; Mice ; Monoclonal antibodies ; Neoplasms - drug therapy ; Oral administration ; Patient outcomes ; Patients ; PD-1 protein ; PD-L1 protein ; Pharmacodynamics ; Pharmacology ; Physical Sciences ; Plasma levels ; Programmed Cell Death 1 Receptor ; Research and Analysis Methods ; Solid tumors ; T cell receptors ; T cells ; T-cell receptor ; Tumors</subject><ispartof>PloS one, 2023-06, Vol.18 (6), p.e0286724-e0286724</ispartof><rights>Copyright: © 2023 Sullivan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Sullivan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Sullivan et al 2023 Sullivan et al</rights><rights>2023 Sullivan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c693t-88f88592f45bf31f0db149da69783c40ee361acefc6ec16fa63f2a99dd9583833</citedby><cites>FETCH-LOGICAL-c693t-88f88592f45bf31f0db149da69783c40ee361acefc6ec16fa63f2a99dd9583833</cites><orcidid>0000-0002-8690-6369</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246841/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246841/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37285333$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sullivan, Kathleen M C</creatorcontrib><creatorcontrib>Vilalta, Marta</creatorcontrib><creatorcontrib>Ertl, Linda S</creatorcontrib><creatorcontrib>Wang, Yu</creatorcontrib><creatorcontrib>Dunlap, Carolyn</creatorcontrib><creatorcontrib>Ebsworth, Karen</creatorcontrib><creatorcontrib>Zhao, Bin N</creatorcontrib><creatorcontrib>Li, Shijie</creatorcontrib><creatorcontrib>Zeng, Yibin</creatorcontrib><creatorcontrib>Miao, Zhenhua</creatorcontrib><creatorcontrib>Fan, Pingchen</creatorcontrib><creatorcontrib>Mali, Venkat</creatorcontrib><creatorcontrib>Lange, Christopher</creatorcontrib><creatorcontrib>McMurtrie, Darren</creatorcontrib><creatorcontrib>Yang, Ju</creatorcontrib><creatorcontrib>Lui, Rebecca</creatorcontrib><creatorcontrib>Scamp, Ryan</creatorcontrib><creatorcontrib>Chhina, Vicky</creatorcontrib><creatorcontrib>Kumamoto, Alice</creatorcontrib><creatorcontrib>Yau, Simon</creatorcontrib><creatorcontrib>Dang, Ton</creatorcontrib><creatorcontrib>Easterday, Ashton</creatorcontrib><creatorcontrib>Liu, Shirley</creatorcontrib><creatorcontrib>Miao, Shichang</creatorcontrib><creatorcontrib>Charo, Israel</creatorcontrib><creatorcontrib>Schall, Thomas J</creatorcontrib><creatorcontrib>Zhang, Penglie</creatorcontrib><title>CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity</title><title>PloS one</title><addtitle>PLoS One</addtitle><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).</description><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies, Monoclonal</subject><subject>Anticancer properties</subject><subject>Antitumor agents</subject><subject>B7-H1 Antigen - metabolism</subject><subject>Biology and life sciences</subject><subject>Cancer</subject><subject>Cancer immunotherapy</subject><subject>Care and treatment</subject><subject>CD80 antigen</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cell surface</subject><subject>Complications and side effects</subject><subject>Cytotoxicity</subject><subject>Dendritic cells</subject><subject>Dosage</subject><subject>Drug dosages</subject><subject>Engineering and Technology</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immune 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(ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sullivan, Kathleen M C</au><au>Vilalta, Marta</au><au>Ertl, Linda S</au><au>Wang, Yu</au><au>Dunlap, Carolyn</au><au>Ebsworth, Karen</au><au>Zhao, Bin N</au><au>Li, Shijie</au><au>Zeng, Yibin</au><au>Miao, Zhenhua</au><au>Fan, Pingchen</au><au>Mali, Venkat</au><au>Lange, Christopher</au><au>McMurtrie, Darren</au><au>Yang, Ju</au><au>Lui, Rebecca</au><au>Scamp, Ryan</au><au>Chhina, Vicky</au><au>Kumamoto, Alice</au><au>Yau, Simon</au><au>Dang, Ton</au><au>Easterday, Ashton</au><au>Liu, Shirley</au><au>Miao, Shichang</au><au>Charo, Israel</au><au>Schall, Thomas J</au><au>Zhang, Penglie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2023-06-07</date><risdate>2023</risdate><volume>18</volume><issue>6</issue><spage>e0286724</spage><epage>e0286724</epage><pages>e0286724-e0286724</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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).</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>37285333</pmid><doi>10.1371/journal.pone.0286724</doi><tpages>e0286724</tpages><orcidid>https://orcid.org/0000-0002-8690-6369</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2023-06, Vol.18 (6), p.e0286724-e0286724 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_2823477542 |
source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; PMC (PubMed Central); DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
subjects | Animal models Animals Antibodies, Monoclonal Anticancer properties Antitumor agents B7-H1 Antigen - metabolism Biology and life sciences Cancer Cancer immunotherapy Care and treatment CD80 antigen Cell activation Cell culture Cell surface Complications and side effects Cytotoxicity Dendritic cells Dosage Drug dosages Engineering and Technology Health aspects Humans Immune checkpoint Immune Checkpoint Inhibitors Immune clearance Immunotherapy Immunotherapy - methods Inhibitors Internalization Ligands Lymphocytes Lymphocytes T Macaca fascicularis Medicine and Health Sciences Mice Monoclonal antibodies Neoplasms - drug therapy Oral administration Patient outcomes Patients PD-1 protein PD-L1 protein Pharmacodynamics Pharmacology Physical Sciences Plasma levels Programmed Cell Death 1 Receptor Research and Analysis Methods Solid tumors T cell receptors T cells T-cell receptor Tumors |
title | CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity |
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