Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
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
_version_ 1785055114532225024
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
work_keys_str_mv AT sullivankathleenmc ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT vilaltamarta ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT ertllindas ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT wangyu ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT dunlapcarolyn ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT ebsworthkaren ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT zhaobinn ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT lishijie ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT zengyibin ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT miaozhenhua ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT fanpingchen ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT malivenkat ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT langechristopher ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT mcmurtriedarren ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT yangju ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT luirebecca ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT scampryan ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT chhinavicky ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT kumamotoalice ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT yausimon ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT dangton ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT easterdayashton ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT liushirley ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT miaoshichang ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT charoisrael ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT schallthomasj ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity
AT zhangpenglie ccx559isapotentorallyadministeredsmallmoleculepdl1inhibitorthatinducesantitumorimmunity