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PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer
Targeting immune checkpoint molecules such as programmed death ligand-1 (PDL1) is an emerging strategy for anti-cancer therapy. However, transient expression of PDL1 and difficulty in tumor stroma penetration has limited the utility of anti-PDL1 therapy. To overcome these limitations, we report a ne...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406713/ https://www.ncbi.nlm.nih.gov/pubmed/30781490 http://dx.doi.org/10.3390/cancers11020232 |
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author | Sau, Samaresh Petrovici, Alex Alsaab, Hashem O. Bhise, Ketki Iyer, Arun K. |
author_facet | Sau, Samaresh Petrovici, Alex Alsaab, Hashem O. Bhise, Ketki Iyer, Arun K. |
author_sort | Sau, Samaresh |
collection | PubMed |
description | Targeting immune checkpoint molecules such as programmed death ligand-1 (PDL1) is an emerging strategy for anti-cancer therapy. However, transient expression of PDL1 and difficulty in tumor stroma penetration has limited the utility of anti-PDL1 therapy. To overcome these limitations, we report a new conjugate between the clinically approved PDL1 antibody (PDL1 AB) and drug Doxorubicin (Dox), named PDL1-Dox. We conjugated PDL1-Dox through a hydrazone linker containing a polyethylene glycol (PEG) spacer, which allows it to dissociate in a tumor environment and improves solubility. The purpose of using Dox is to disrupt the tumor extracellular environment so that PDL-1 antibody can penetrate the tumor core. PDL1-Dox demonstrates significant cell killing, disruption of tumor spheroid and induction of apoptosis in a breast cancer cell line. Significant release of IFN-γ suggests PDL1-Dox can upmodulate T cell activation. Optical imaging of dye conjugate supports the selective tumor targeting ability and core penetration of the construct. |
format | Online Article Text |
id | pubmed-6406713 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64067132019-03-21 PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer Sau, Samaresh Petrovici, Alex Alsaab, Hashem O. Bhise, Ketki Iyer, Arun K. Cancers (Basel) Article Targeting immune checkpoint molecules such as programmed death ligand-1 (PDL1) is an emerging strategy for anti-cancer therapy. However, transient expression of PDL1 and difficulty in tumor stroma penetration has limited the utility of anti-PDL1 therapy. To overcome these limitations, we report a new conjugate between the clinically approved PDL1 antibody (PDL1 AB) and drug Doxorubicin (Dox), named PDL1-Dox. We conjugated PDL1-Dox through a hydrazone linker containing a polyethylene glycol (PEG) spacer, which allows it to dissociate in a tumor environment and improves solubility. The purpose of using Dox is to disrupt the tumor extracellular environment so that PDL-1 antibody can penetrate the tumor core. PDL1-Dox demonstrates significant cell killing, disruption of tumor spheroid and induction of apoptosis in a breast cancer cell line. Significant release of IFN-γ suggests PDL1-Dox can upmodulate T cell activation. Optical imaging of dye conjugate supports the selective tumor targeting ability and core penetration of the construct. MDPI 2019-02-16 /pmc/articles/PMC6406713/ /pubmed/30781490 http://dx.doi.org/10.3390/cancers11020232 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sau, Samaresh Petrovici, Alex Alsaab, Hashem O. Bhise, Ketki Iyer, Arun K. PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer |
title | PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer |
title_full | PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer |
title_fullStr | PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer |
title_full_unstemmed | PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer |
title_short | PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer |
title_sort | pdl-1 antibody drug conjugate for selective chemo-guided immune modulation of cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406713/ https://www.ncbi.nlm.nih.gov/pubmed/30781490 http://dx.doi.org/10.3390/cancers11020232 |
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