title: Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes.
abstract: The systemic application of nucleic acid drugs requires delivery systems that overcome the poor pharmacokinetics, limited biodistribution, and inefficient uptake of nucleic acids. PEGylated liposomes show considerable promise because of their intrinsic ability to accumulate at disease sites and facilitate transfection of target cells. Unlike many viral vectors, PEGylated liposomes are generally considered to be nonimmunogenic. We have developed a PEGylated liposome for the systemic administration of plasmid DNA that achieves high levels of selective gene expression at distal tumor sites. Here we report that the in vivo efficacy and safety of these systems can be severely compromised following repeat administration. This phenomenon is characterized by a loss of disease site targeting, accelerated clearance from the blood, and acute hypersensitivity. These effects are fully attributable to a surprisingly robust, long-lived antibody response generated against polyethylene glycol (PEG) that results from the strong adjuvant effect of the plasmid payload. Importantly, immunogenicity may be substantially reduced by modifying the alkyl chain of the PEG-lipid conjugate, thereby allowing successful repeat dosing of the modified plasmid formulations without adverse side effects. Immunogenicity is a relevant concern for a number of nonviral delivery systems given the potent immunostimulatory properties of many nucleic acid drugs.
authors.affiliation: Protiva Biotherapeutics, Burnaby, BC, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Judge
authors.forename: Kevin
authors.initials: K
authors.lastname: McClintock
authors.forename: Janet R
authors.initials: JR
authors.lastname: Phelps
authors.forename: Ian
authors.initials: I
authors.lastname: Maclachlan
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology*; D016503:Drug Delivery Systems / Q000379:methods; D006967:Hypersensitivity / Q000276:immunology*; D008081:Liposomes / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009374:Neoplasms, Experimental / Q000276:immunology*; D010972:Platelet Activating Factor / Q000502:physiology; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000378:metabolism*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*
chemical_list: D008081:Liposomes; D010972:Platelet Activating Factor; D019444:Vaccines, DNA; D011092:Polyethylene Glycols