The role of complement activation in hypersensitivity to pegylated liposomal Doxorubicin (Doxil®)

J. Szebeni, L. Baranyi, S. Savay, H. U. Lutz, E. Jelezarova, R. Bunger, C. R. Alving

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Liposomal formulations of some drugs, most importantly pegylated liposomal doxorubicin (Doxil®), have been reported to cause immediate hypersensitivity reactions that cannot be explained with the conventional paradigm of IgE-mediated (type I) allergy. Here we present a rationale and experimental evidence for the concept that these reactions represent a novel type of drug-induced hypersensitivity that can be called complement (C) activation-related pseudoallergy (CARPA). The theoretical foundation includes the facts that 1) some liposomes have been known to activate C, 2) most of the clinical symptoms of liposome-induced reactions coincide with those caused by C activation by other activators, and 3) the C mechanism explains those manifestations which are atypical for type 1 reactions. The experimental evidence includes the observations that 1) Doxil caused massive C activation in a high ratio (4/10) of normal human sera, 2) high dose IgG attenuated Doxil-induced C activation in serum and prevented further C activation by amplification, and 3) intravenous injection of therapeutically relevant doses of Doxil in pigs caused significant pulmonary hypertension with consequent systemic hypotension and decline of cardiac output, which changes mimicked the cardiovascular manifestations of the human reaction and were shown to be triggered by C activation. As for the question how Doxil, a long-circulating "stealth" liposome formulation, avoids phagocytic uptake by macrophages despite its potential opsonization by C3b, we demonstrated efficient inactivation of Doxil-bound and free C3b to iC3b in human serum. Thus, it is unlikely that PEG would interfere with CD11b/CD18-mediated phagocytosis by inhibiting the formation of its main ligand, iC3b.

Original languageEnglish
Pages (from-to)467-481
Number of pages15
JournalJournal of Liposome Research
Volume10
Issue number4
DOIs
Publication statusPublished - Jan 1 2000

Keywords

  • Anaphylatoxins
  • Complement
  • Hemodynamics
  • Hypersensitivity reactions
  • Liposome

ASJC Scopus subject areas

  • Pharmaceutical Science

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