Case study: complement activation related hypersensitivity reactions to pegylated liposomal doxorubicin - experimental and clinical evidence, mechanisms and approaches to inhibition

PEGylated liposomal doxorubicin (Doxil®) is the fi rst FDA-approved nanomedicine (1995); it has been successfully used for cancer therapy for nearly 20 years. Despite its "stealth" properties, Doxil activates the complement system, which leads to a hypersensitivity reaction (HSR) known as Complement Activation Related Pseudoallergy (CARPA). Herein we provide a comprehensive overview of both in vitro and in vivo aspects of this phenomenon, and review recent clinical experience with Doxil and its generic formulations. We discuss the complexity of the mechanism of CARPA, which, in addition to the engagement of different complement activation pathways, may include triggering of mast cells, macrophages and other allergy-mediating secretory cells, leading to the liberation of multiple vasoactive mediators and a variety of effects on the cardiovascular and other organs. We describe furthermore the approaches of inhibiting Doxil-induced CARPA in vivo in experimental animals and humans. The case study of Doxil is likely applicable to many other reactogenic nanomedicines that share common toxicities related to complement activation and for which CARPA represents an immune barrier to successful clinical use.