The role of complement activation in hypersensitivity to pegylated liposomal doxorubicin (DOXIL (R))

Liposomal formulations of some drugs, most importantly pegylated liposomal doxorubicin (Doxil(R)), have been reported to cause immediate hypersensitiv ity reactions that cannot be explained with the conventional paradigm of Ig E-mediated (type I) allergy. Here we present a rationale and experimental e vidence for the concept that these reactions represent a novel type of drug -induced hypersensitivity that can be called complement (C) activation-rela ted pseudoallergy (CARPA). The theoretical foundation includes the facts th at 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 act ivation by other activators; and 3) the C mechanism explains those manifest ations which are atypical for type 1 reactions. The experimental evidence i ncludes the observations that 1) Doxil caused massive C activation in a hig h ratio (4/10) of normal human sera, 2) high dose IgG attenuated Doxil-indu ced C activation in serum and prevented further C activation by amplificati on, 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 card iovascular manifestations of the human reaction and were shown to be trigge red by C activation. As for the question how Doxil, a long-circulating "ste alth" 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 th at PEG would interfere with CD11b/CD18-mediated phagocytosis by inhibiting the formation of its main ligand, iC3b.