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A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes

Immune checkpoint blockades prescribed in the neoadjuvant setting are now under active investigation for many types of tumors, and many have shown early success. The primary tumor (PT) and tumor-draining lymph node (TDLN) immune factors, along with adequate therapeutic antibody distributions to the...

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Detalles Bibliográficos
Autores principales: Salgado, Eric, Cao, Yanguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036243/
https://www.ncbi.nlm.nih.gov/pubmed/35466281
http://dx.doi.org/10.3390/antib11020028
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author Salgado, Eric
Cao, Yanguang
author_facet Salgado, Eric
Cao, Yanguang
author_sort Salgado, Eric
collection PubMed
description Immune checkpoint blockades prescribed in the neoadjuvant setting are now under active investigation for many types of tumors, and many have shown early success. The primary tumor (PT) and tumor-draining lymph node (TDLN) immune factors, along with adequate therapeutic antibody distributions to the PT and TDLN, are critical for optimal immune activation and anti-tumor efficacy in neoadjuvant immunotherapy. However, it remains largely unknown how much of the antibody can be distributed into the PT-TDLN axis at different clinical scenarios. The goal of the current work is to build a physiologically based pharmacokinetic (PBPK) model framework capable of characterizing antibody distribution gradients in the PT-TDLN axis across various clinical and pathophysiological scenarios. The model was calibrated using clinical data from immuno-PET antibody-imaging studies quantifying antibody pharmacokinetics (PK) in the blood, PTs, and TDLNs. The effects of metastatic lesion location, tumor-induced compression, and inflammation, as well as surgery, on antibody concentration gradients in the PT-TDLN axis were characterized. The PBPK model serves as a valuable tool to predict antibody exposures in various types of tumors, metastases, and the associated lymph node, supporting effective immunotherapy.
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spelling pubmed-90362432022-04-26 A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes Salgado, Eric Cao, Yanguang Antibodies (Basel) Article Immune checkpoint blockades prescribed in the neoadjuvant setting are now under active investigation for many types of tumors, and many have shown early success. The primary tumor (PT) and tumor-draining lymph node (TDLN) immune factors, along with adequate therapeutic antibody distributions to the PT and TDLN, are critical for optimal immune activation and anti-tumor efficacy in neoadjuvant immunotherapy. However, it remains largely unknown how much of the antibody can be distributed into the PT-TDLN axis at different clinical scenarios. The goal of the current work is to build a physiologically based pharmacokinetic (PBPK) model framework capable of characterizing antibody distribution gradients in the PT-TDLN axis across various clinical and pathophysiological scenarios. The model was calibrated using clinical data from immuno-PET antibody-imaging studies quantifying antibody pharmacokinetics (PK) in the blood, PTs, and TDLNs. The effects of metastatic lesion location, tumor-induced compression, and inflammation, as well as surgery, on antibody concentration gradients in the PT-TDLN axis were characterized. The PBPK model serves as a valuable tool to predict antibody exposures in various types of tumors, metastases, and the associated lymph node, supporting effective immunotherapy. MDPI 2022-04-14 /pmc/articles/PMC9036243/ /pubmed/35466281 http://dx.doi.org/10.3390/antib11020028 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Salgado, Eric
Cao, Yanguang
A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes
title A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes
title_full A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes
title_fullStr A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes
title_full_unstemmed A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes
title_short A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes
title_sort physiologically based pharmacokinetic framework for quantifying antibody distribution gradients from tumors to tumor-draining lymph nodes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036243/
https://www.ncbi.nlm.nih.gov/pubmed/35466281
http://dx.doi.org/10.3390/antib11020028
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