Cargando…

Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents

Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody pr...

Descripción completa

Detalles Bibliográficos
Autores principales: Assi, Hikmat H., Wong, Chihunt, Tipton, Kimberly A., Mei, Li, Wong, Ken, Razo, Jennifer, Chan, Chanty, Howng, Bruce, Sagert, Jason, Krimm, Michael, Diep, Linnea, Jang, Andrew, Nguyen, Margaret T., Lapuyade, Nicole, Singson, Victoria, Villanueva, Ruth, Paidhungat, Madan, Liu, Shouchun, Rangan, Vangipuram, Vasiljeva, Olga, West, James W., Richardson, Jennifer H., Irving, Bryan, Daniel, Dylan, Belvin, Marcia, Kavanaugh, W. Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414278/
https://www.ncbi.nlm.nih.gov/pubmed/34635485
http://dx.doi.org/10.1158/2326-6066.CIR-21-0031
_version_ 1784775951104606208
author Assi, Hikmat H.
Wong, Chihunt
Tipton, Kimberly A.
Mei, Li
Wong, Ken
Razo, Jennifer
Chan, Chanty
Howng, Bruce
Sagert, Jason
Krimm, Michael
Diep, Linnea
Jang, Andrew
Nguyen, Margaret T.
Lapuyade, Nicole
Singson, Victoria
Villanueva, Ruth
Paidhungat, Madan
Liu, Shouchun
Rangan, Vangipuram
Vasiljeva, Olga
West, James W.
Richardson, Jennifer H.
Irving, Bryan
Daniel, Dylan
Belvin, Marcia
Kavanaugh, W. Michael
author_facet Assi, Hikmat H.
Wong, Chihunt
Tipton, Kimberly A.
Mei, Li
Wong, Ken
Razo, Jennifer
Chan, Chanty
Howng, Bruce
Sagert, Jason
Krimm, Michael
Diep, Linnea
Jang, Andrew
Nguyen, Margaret T.
Lapuyade, Nicole
Singson, Victoria
Villanueva, Ruth
Paidhungat, Madan
Liu, Shouchun
Rangan, Vangipuram
Vasiljeva, Olga
West, James W.
Richardson, Jennifer H.
Irving, Bryan
Daniel, Dylan
Belvin, Marcia
Kavanaugh, W. Michael
author_sort Assi, Hikmat H.
collection PubMed
description Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody prodrugs, known as Probody therapeutics (Pb-Tx), localize antibody activity by attenuating capacity to bind antigen until protease activation in the tumor microenvironment. Herein, we show that systemic administration of anti–programmed cell death ligand 1 (anti–PD-L1) and anti–programmed cell death protein 1 (anti–PD-1) Pb-Tx to tumor-bearing mice elicited antitumor activity similar to that of traditional PD-1/PD-L1–targeted antibodies. Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile, with markedly reduced target occupancy on peripheral T cells and reduced incidence of early-onset autoimmune diabetes in nonobese diabetic mice. Our results confirm that localized PD-1/PD-L1 inhibition by Pb-Tx can elicit robust antitumor immunity and minimize systemic immune-mediated toxicity. These data provide further preclinical rationale to support the ongoing development of the anti–PD-L1 Pb-Tx CX-072, which is currently in clinical trials.
format Online
Article
Text
id pubmed-9414278
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher American Association for Cancer Research
record_format MEDLINE/PubMed
spelling pubmed-94142782023-01-05 Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents Assi, Hikmat H. Wong, Chihunt Tipton, Kimberly A. Mei, Li Wong, Ken Razo, Jennifer Chan, Chanty Howng, Bruce Sagert, Jason Krimm, Michael Diep, Linnea Jang, Andrew Nguyen, Margaret T. Lapuyade, Nicole Singson, Victoria Villanueva, Ruth Paidhungat, Madan Liu, Shouchun Rangan, Vangipuram Vasiljeva, Olga West, James W. Richardson, Jennifer H. Irving, Bryan Daniel, Dylan Belvin, Marcia Kavanaugh, W. Michael Cancer Immunol Res Research Articles Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody prodrugs, known as Probody therapeutics (Pb-Tx), localize antibody activity by attenuating capacity to bind antigen until protease activation in the tumor microenvironment. Herein, we show that systemic administration of anti–programmed cell death ligand 1 (anti–PD-L1) and anti–programmed cell death protein 1 (anti–PD-1) Pb-Tx to tumor-bearing mice elicited antitumor activity similar to that of traditional PD-1/PD-L1–targeted antibodies. Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile, with markedly reduced target occupancy on peripheral T cells and reduced incidence of early-onset autoimmune diabetes in nonobese diabetic mice. Our results confirm that localized PD-1/PD-L1 inhibition by Pb-Tx can elicit robust antitumor immunity and minimize systemic immune-mediated toxicity. These data provide further preclinical rationale to support the ongoing development of the anti–PD-L1 Pb-Tx CX-072, which is currently in clinical trials. American Association for Cancer Research 2021-12-01 2021-10-11 /pmc/articles/PMC9414278/ /pubmed/34635485 http://dx.doi.org/10.1158/2326-6066.CIR-21-0031 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Research Articles
Assi, Hikmat H.
Wong, Chihunt
Tipton, Kimberly A.
Mei, Li
Wong, Ken
Razo, Jennifer
Chan, Chanty
Howng, Bruce
Sagert, Jason
Krimm, Michael
Diep, Linnea
Jang, Andrew
Nguyen, Margaret T.
Lapuyade, Nicole
Singson, Victoria
Villanueva, Ruth
Paidhungat, Madan
Liu, Shouchun
Rangan, Vangipuram
Vasiljeva, Olga
West, James W.
Richardson, Jennifer H.
Irving, Bryan
Daniel, Dylan
Belvin, Marcia
Kavanaugh, W. Michael
Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents
title Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents
title_full Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents
title_fullStr Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents
title_full_unstemmed Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents
title_short Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents
title_sort conditional pd-1/pd-l1 probody therapeutics induce comparable antitumor immunity but reduced systemic toxicity compared with traditional anti–pd-1/pd-l1 agents
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414278/
https://www.ncbi.nlm.nih.gov/pubmed/34635485
http://dx.doi.org/10.1158/2326-6066.CIR-21-0031
work_keys_str_mv AT assihikmath conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT wongchihunt conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT tiptonkimberlya conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT meili conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT wongken conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT razojennifer conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT chanchanty conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT howngbruce conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT sagertjason conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT krimmmichael conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT dieplinnea conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT jangandrew conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT nguyenmargarett conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT lapuyadenicole conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT singsonvictoria conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT villanuevaruth conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT paidhungatmadan conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT liushouchun conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT ranganvangipuram conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT vasiljevaolga conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT westjamesw conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT richardsonjenniferh conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT irvingbryan conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT danieldylan conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT belvinmarcia conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents
AT kavanaughwmichael conditionalpd1pdl1probodytherapeuticsinducecomparableantitumorimmunitybutreducedsystemictoxicitycomparedwithtraditionalantipd1pdl1agents