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Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.

ABSTRACT: Immune responses against polyethylene glycol (PEG) can lead to the rapid clearance of PEGylated drugs and are associated with increased risk of serious adverse events such as infusion reactions and anaphylaxis. Although select PEGylated therapeutics can induce anti-PEG antibodies (APA), there is currently no readily deployable strategy to mitigate their negative effects. Given the large number of PEGylated therapeutics that are either FDA-approved or in clinical development, methods that suppress APA induction to ensure the safety and efficacy of PEGylated drugs in patients would be a valuable clinical tool. We previously showed that infusion of high molecular weight (MW) free PEG can safely and effectively restore the circulation of PEG liposomes in animals with high pre-existing titers of APA, without stimulating additional APA production. Here, we explored the effectiveness of prophylaxis with free PEG or tolerogenic PEGylated liposomes as a strategy to reduce the amount of APA induced by subsequently administered PEGylated liposomes. Surprisingly, we found that a single administration of free PEG alone was capable of markedly reducing the APA response to PEG-liposomes for ~2 months; the effectiveness was comparable to, and frequently exceeded, interventions with different tolerogenic PEG-liposomes. These results support further investigations of free PEG prophylaxis as a potential strategy to ameliorate the APA response to sensitizing PEGylated therapeutics.

SUBMITTER: McSweeney MD

PROVIDER: S-EPMC7904660 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.

McSweeney Morgan D MD Shen Limei L DeWalle Alexander C AC Joiner Jordan B JB Ciociola Elizabeth C EC Raghuwanshi Dharmendra D Macauley Matthew S MS Lai Samuel K SK

Journal of controlled release : official journal of the Controlled Release Society 20201007

Immune responses against polyethylene glycol (PEG) can lead to the rapid clearance of PEGylated drugs and are associated with increased risk of serious adverse events such as infusion reactions and anaphylaxis. Although select PEGylated therapeutics can induce anti-PEG antibodies (APA), there is currently no readily deployable strategy to mitigate their negative effects. Given the large number of PEGylated therapeutics that are either FDA-approved or in clinical development, methods that suppres ...[more]

PMID: 33038448

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Project description:L-asparaginase (ASNase) is an important biological drug used to treat Acute Lymphoblastic Leukemia (ALL). It catalyzes the hydrolysis of L-asparagine (Asn) in the bloodstream and, since ALL cells cannot synthesize Asn, protein synthesis is impaired leading to apoptosis. Despite its therapeutic importance, ASNase treatment is associated to side effects, mainly hypersensitivity and immunogenicity. Furthermore, degradation by plasma proteases and immunogenicity shortens the enzyme half-life. Encapsulation of ASNase in liposomes, nanostructures formed by the self-aggregation of phospholipids, is an attractive alternative to protect the enzyme from plasma proteases and enhance pharmacokinetics profile. In addition, PEGylation might prolong the in vivo circulation of liposomes owing to the spherical shielding conferred by the polyethylene (PEG) corona around the nanostructures. In this paper, ASNase was encapsulated in liposomal formulations composed by 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) containing or not different concentrations of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy (polyethylene glycol)-2000] (DSPE-PEG). Nanostructures of approximately 142-202 nm of diameter and polydispersity index (PDI) of 0.069 to 0.190 were obtained and the vesicular shape confirmed by Transmission Electron Microscopy (TEM and cryo-TEM). The encapsulation efficiency (%EE) varied from 10% to 16%. All formulations presented activity in contact with ASNase substrate, indicating the liposomes permeability to Asn and/or enzyme adsorption at the nanostructures' surface; the highest activity was observed for DMPC/DSPE-PEG 10%. Finally, we investigated the activity against the Molt 4 leukemic cell line and found a lower IC50 for the DMPC/DSPE-PEG 10% formulation in comparison to the free enzyme, indicating our system could provide in vivo activity while protecting the enzyme from immune system recognition and proteases degradation.

Dataset Information

Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.

Publications

Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.

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