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Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro

Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement...

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Autores principales: Neun, Barry W., Barenholz, Yechezkel, Szebeni, Janos, Dobrovolskaia, Marina A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100003/
https://www.ncbi.nlm.nih.gov/pubmed/30002298
http://dx.doi.org/10.3390/molecules23071700
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author Neun, Barry W.
Barenholz, Yechezkel
Szebeni, Janos
Dobrovolskaia, Marina A.
author_facet Neun, Barry W.
Barenholz, Yechezkel
Szebeni, Janos
Dobrovolskaia, Marina A.
author_sort Neun, Barry W.
collection PubMed
description Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety.
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spelling pubmed-61000032018-11-13 Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro Neun, Barry W. Barenholz, Yechezkel Szebeni, Janos Dobrovolskaia, Marina A. Molecules Article Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety. MDPI 2018-07-12 /pmc/articles/PMC6100003/ /pubmed/30002298 http://dx.doi.org/10.3390/molecules23071700 Text en © 2018 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
Neun, Barry W.
Barenholz, Yechezkel
Szebeni, Janos
Dobrovolskaia, Marina A.
Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
title Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
title_full Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
title_fullStr Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
title_full_unstemmed Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
title_short Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
title_sort understanding the role of anti-peg antibodies in the complement activation by doxil in vitro
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100003/
https://www.ncbi.nlm.nih.gov/pubmed/30002298
http://dx.doi.org/10.3390/molecules23071700
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