Antibodies against Poly(ethylene glycol) Activate Innate Immune Cells and Induce Hypersensitivity Reactions to PEGylated Nanomedicines

Abstract

Nanomedicines and macromolecular drugs can induce hypersensitivity reactions (HSRs) with symptoms ranging from flushing and breathing difficulties to hypothermia, hypotension, and death in the most severe cases. Because many normal individuals have pre-existing antibodies that bind to poly(ethylene glycol) (PEG), which is often present on the surface of nanomedicines and macromolecular drugs, we examined if and how anti-PEG antibodies induce HSRs to PEGylated liposomal doxorubicin (PLD). Anti-PEG IgG but not anti-PEG IgM induced symptoms of HSRs including hypothermia, altered lung function, and hypotension after PLD administration in C57BL/6 and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Hypothermia was significantly reduced by blocking FcγRII/III, by depleting basophils, monocytes, neutrophils, or mast cells, and by inhibiting secretion of histamine and platelet-activating factor. Anti-PEG IgG also induced hypothermia in mice after administration of other PEGylated liposomes, nanoparticles, or proteins. Humanized anti-PEG IgG promoted binding of PEGylated nanoparticles to human immune cells and induced secretion of histamine from human basophils in the presence of PLD. Anti-PEG IgE could also induce hypersensitivity reactions in mice after administration of PLD. Our results demonstrate an important role for IgG antibodies in induction of HSRs to PEGylated nanomedicines through interaction with Fcγ receptors on innate immune cells and provide a deeper understanding of HSRs to PEGylated nanoparticles and macromolecular drugs that may facilitate development of safer nanomedicines.

MRI Detection of Lymph Node Metastasis through Molecular Targeting of C–C Chemokine Receptor Type 2 and Monocyte Hitchhiking

“…Thus, the in vivo immunogenicity, plasma half-life, and biocompatibility of MCP1-Gd was characterized over the course of 4 weeks following weekly MCP1-Gd doses (Figure A). Recent literature has reported the development of anti-PEG immunogenic responses following repeated exposure of PEGylated biomaterials, resulting in accelerated blood clearance, reduced efficacy, and detrimental hypersensitivity reactions. − Hence, we tested the potential immunogenicity and characterized the plasma half-life of MCP1-Gd in mice before and after exposure to MCP1-Gd. As shown in Figure B, anti-PEG IgG and IgM titers remained unchanged over the duration of MCP1-Gd exposure, indicating that MCP1-Gd does not induce an immunogenic response against PEG.…”

Free PEG Suppresses Anaphylaxis to PEGylated Nanomedicine in Swine

“…There are recent reports of mouse models for assessing PEG-specific allergic response, primarily driven by anti-PEG IgG. , We elected to use the swine model due to its very high sensitivity, excellent inter/intra-animal reproducibility, rapid reaction, and a long history of characterization with nanomedicine-induced hypersensitivity. The existence of pulmonary intravascular macrophages in pigs can contribute to the acute drop in blood pressure.…”

Absence of Anaphylactic Reactions to Injection of Hemoglobin Vesicles (Artificial Red Cells) to Rodents

“…The mechanism of anaphylactic reaction after injection of PEG-conjugated materials in relation to the involvement of anti-PEG IgM, IgG, or IgE is still controversial. − The high incidence of complement activation by IgM should also be involved in the anaphylactic reaction, although HbV did not show complement activation. It is even more difficult to clarify the mechanism of the absence of anaphylactic reactions despite the induction of these antibodies.…”