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
Hauptverfasser: 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
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container_issue 6
container_start_page e0286724
container_title PloS one
container_volume 18
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
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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. 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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. 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Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content (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>
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1932-6203
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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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