ROLE OF COMPLEMENT ACTIVATION IN HYPERSENSITIVITY REACTIONS TO DOXIL AND HYNIC PEG LIPOSOMES: EXPERIMENTAL AND CLINICAL STUDIES

J. Szebeni Walter Reed Army Institute of Research, Silver Spring, MD, U.S.A.

L. Baranyi Walter Reed Army Institute of Research, Silver Spring, MD, U.S.A.

S. Savay Walter Reed Army Institute of Research, Silver Spring, MD, U.S.A.

J. Milosevits Walter Reed Army Institute of Research, Silver Spring, MD, U.S.A.

R. Bunger Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, U.S.A.

P. Laverman Department of Nuclear Medicine, University Medical Center, Nijmegen, The Netherlands

J. M. Metselaar Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands

G. Storm Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands

A. Chanan-Khan Kaplan Comprehensive Cancer Center, New York University Medical Center, New YorkUSA

L. Liebes Kaplan Comprehensive Cancer Center, New York University Medical Center, New YorkUSA

F. M. Muggia Kaplan Comprehensive Cancer Center, New York University Medical Center, New YorkUSA

R. Cohen Laboratory of Membrane and Liposome Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel

Y. Barenholz Laboratory of Membrane and Liposome Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel

C. R. Alving Walter Reed Army Institute of Research, Silver Spring, MD, U.S.A.

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ABSTRACT

Pegylated liposomal doxorubicin (Doxil) and ^99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles.

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ROLE OF COMPLEMENT ACTIVATION IN HYPERSENSITIVITY REACTIONS TO DOXIL AND HYNIC PEG LIPOSOMES: EXPERIMENTAL AND CLINICAL STUDIES

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ROLE OF COMPLEMENT ACTIVATION IN HYPERSENSITIVITY REACTIONS TO DOXIL AND HYNIC PEG LIPOSOMES: EXPERIMENTAL AND CLINICAL STUDIES

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