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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...

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Detalles Bibliográficos
Autores principales: Sau, Samaresh, Petrovici, Alex, Alsaab, Hashem O., Bhise, Ketki, Iyer, Arun K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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.
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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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