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

Barry W. Neun, Yechezkel Barenholz, J. Szebeni, Marina A. Dobrovolskaia

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalMolecules (Basel, Switzerland)
Volume23
Issue number7
DOIs
Publication statusPublished - Jul 12 2018

Fingerprint

Complement Activation
antibodies
complement
glycols
polyethylenes
Chemical activation
activation
Nanomedicine
Medical nanotechnology
Antibodies
Plasma (human)
mice
affinity
Complement Factor I
Plasmas
Complement Factor H
Nanotechnology
Knowledge Bases
Immunoglobulin Isotypes
Inbred C57BL Mouse

Keywords

  • anti-PEG antibody
  • CARPA
  • complement activation
  • hypersensitivity
  • immunotoxicity
  • infusion reaction
  • liposomes
  • nanoparticles

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro. / Neun, Barry W.; Barenholz, Yechezkel; Szebeni, J.; Dobrovolskaia, Marina A.

In: Molecules (Basel, Switzerland), Vol. 23, No. 7, 12.07.2018.

Research output: Contribution to journalArticle

Neun, Barry W. ; Barenholz, Yechezkel ; Szebeni, J. ; Dobrovolskaia, Marina A. / Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro. In: Molecules (Basel, Switzerland). 2018 ; Vol. 23, No. 7.
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