Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions.

Autor:	Kozma GT; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary.; SeroScience Ltd. , Budapest 1125, Hungary, and Cambridge , Massachusetts 02138 , United States., Mészáros T; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary., Vashegyi I; SeroScience Ltd. , Budapest 1125, Hungary, and Cambridge , Massachusetts 02138 , United States., Fülöp T; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary., Örfi E; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary., Dézsi L; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary., Rosivall L; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary.; SeroScience Ltd. , Budapest 1125, Hungary, and Cambridge , Massachusetts 02138 , United States.; Department of Pathophysiology, International Nephrology Research and Training Center , Semmelweis University , Budapest 1089 , Hungary., Bavli Y; Laboratory of Membrane and Liposome Research, IMRIC , Hebrew University-Hadassah Medical School , Jerusalem 9112102 , Israel., Urbanics R; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary.; SeroScience Ltd. , Budapest 1125, Hungary, and Cambridge , Massachusetts 02138 , United States., Mollnes TE; Department of Immunology , Oslo University Hospital , Rikshospitalet , Oslo 0372 , Norway.; Research Laboratory, Nordland Hospital Bodø, and Faculty of Health Sciences and TREC , University of Tromsø , Tromsø 9019 , Norway.; Centre of Molecular Inflammation Research , Norwegian University of Science and Technology , Trondheim 7012 , Norway., Barenholz Y; Laboratory of Membrane and Liposome Research, IMRIC , Hebrew University-Hadassah Medical School , Jerusalem 9112102 , Israel., Szebeni J; Nanomedicine Research and Education Center , Semmelweis University , Budapest 1089 , Hungary.; SeroScience Ltd. , Budapest 1125, Hungary, and Cambridge , Massachusetts 02138 , United States.; Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health , Miskolc University , Miskolc 3515 , Hungary.
Jazyk:	angličtina
Zdroj:	ACS nano [ACS Nano] 2019 Aug 27; Vol. 13 (8), pp. 9315-9324. Date of Electronic Publication: 2019 Aug 06.
DOI:	10.1021/acsnano.9b03942
Abstrakt:	Polyethylene glycol (PEG)-coated nanopharmaceuticals can cause mild to severe hypersensitivity reactions (HSRs), which can occasionally be life threatening or even lethal. The phenomenon represents an unsolved immune barrier to the use of these drugs, yet its mechanism is poorly understood. This study showed that a single i.v. injection in pigs of a low dose of PEGylated liposomes (Doxebo) induced a massive rise of anti-PEG IgM in blood, peaking at days 7-9 and declining over 6 weeks. Bolus injections of PEG-liposomes during seroconversion resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2-3 min, although similar treatments of naı̈ve animals led to only mild hemodynamic disturbance. Parallel measurement of pulmonary arterial pressure (PAP) and sC5b-9 in blood, taken as measures of HSR and complement activation, respectively, showed a concordant rise of the two variables within 3 min and a decline within 15 min, suggesting a causal relationship between complement activation and pulmonary hypertension. We also observed a rapid decline of anti-PEG IgM in the blood within minutes, increased binding of PEGylated liposomes to IgM + B cells in the spleen of immunized animals compared to control, and increased C3 conversion by PEGylated liposomes in the serum of immunized pigs. These observations taken together suggest rapid binding of anti-PEG IgM to PEGylated liposomes, leading to complement activation via the classical pathway, entailing anaphylactoid shock and accelerated blood clearance of liposome-IgM complexes. These data suggest that complement activation plays a causal role in severe HSRs to PEGylated nanomedicines and that pigs can be used as a hazard identification model to assess the risk of HSRs in preclinical safety studies.
Databáze:	MEDLINE
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