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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2021
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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 |
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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 |
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