Physician Awareness of Immune Responses to Polyethylene Glycol‐Drug Conjugates

McSweeney, Morgan D.; Versfeld, Zina; Carpenter, Delesha M.; Lai, Samuel K.

doi:10.1111/cts.12537

Cited by 41 publications

(26 citation statements)

References 17 publications

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“…We are mindful of the concerns surrounding anti‐PEG immunity, and that its relevance to human patients are still in the infant stage . There is still debate as to why some patients mount a robust immune response to PEG while others do not, and clarification is needed as to why administering PEG‐modified products only sometimes generates clinically observable outcomes.…”

Section: Discussionmentioning

confidence: 99%

Architectural Modification of Conformal PEG‐Bottlebrush Coatings Minimizes Anti‐PEG Antigenicity While Preserving Stealth Properties

Joh

Zimmers

Avlani

et al. 2019

Adv Healthcare Materials

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Poly(ethylene glycol) (PEG), a linear polymer known for its “stealth” properties, is commonly used to passivate the surface of biomedical implants and devices, and it is conjugated to biologic drugs to improve their pharmacokinetics. However, its antigenicity is a growing concern. Here, the antigenicity of PEG is investigated when assembled in a poly(oligoethylene glycol) methacrylate (POEGMA) “bottlebrush” configuration on a planar surface. Using ethylene glycol (EG) repeat lengths of the POEGMA sidechains as a tunable parameter for optimization, POEGMA brushes with sidechain lengths of two and three EG repeats are identified as the optimal polymer architecture to minimize binding of anti‐PEG antibodies (APAs), while retaining resistance to nonspecific binding by bovine serum albumin and cultured cells. Binding of backbone‐ versus endgroup‐selective APAs to POEGMA brushes is further investigated, and finally the antigenicity of POEGMA coatings is assessed against APA‐positive clinical plasma samples. These results are applied toward fabricating immunoassays on POEGMA surfaces with minimal reactivity toward APAs while retaining a low limit‐of‐detection for the analyte. Taken together, these results offer useful design concepts to reduce the antigenicity of polymer brush‐based surface coatings used in applications involving human or animal matrices.

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Section: Discussionmentioning

confidence: 99%

Architectural Modification of Conformal PEG‐Bottlebrush Coatings Minimizes Anti‐PEG Antigenicity While Preserving Stealth Properties

Joh

Zimmers

Avlani

et al. 2019

Adv Healthcare Materials

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“…Furthermore, it will be important for physicians who regularly prescribe APA-sensitive drugs (such as pegloticase, pegaspargase, and investigational PEGylated compounds) to be aware of the issue of APA. We recently found that only roughly one quarter of physicians who regularly prescribe PEGylated therapeutics are aware that 1) PEG is part of those drugs, and 2) that patients can form antibodies against PEG [53]. Addressing this knowledge gap will be necessary to ensure the continued safe and efficacious use of PEGylated therapeutics.…”

Section: Discussionmentioning

confidence: 99%

A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse

McSweeney

Wessler

Price

et al. 2018

Journal of Controlled Release

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Circulating antibodies that specifically bind polyethylene glycol (PEG), a polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy and increased adverse reactions to some PEGylated therapeutics. In addition to acute induction of anti-PEG antibodies (APA) by PEGylated drugs, typically low but detectable levels of APA are also found in up to 70% of the general population. Despite the broad implications of APA, the dynamics of APA-mediated clearance of PEGylated drugs, and why many patients continue to respond to PEGylated drugs despite the presence of pre-existing APA, remains not well understood. Here, we developed a minimal physiologically based pharmacokinetic (mPBPK) model that incorporates various properties of APA and PEGylated drugs. Our mPBPK model reproduced clinical PK data of APA-mediated accelerated blood clearance of pegloticase, as well as APA-dependent elimination of PEGyated liposomes in mice. Our model predicts that the prolonged circulation of PEGylated drugs will be compromised only at APA concentrations greater than ~500 ng/mL, providing a quantitative explanation to why the effects of APA on PEGylated treatments appear to be limited in most patients. This mPBPK model is readily adaptable to other PEGylated drugs and particles to predict the precise levels of APA that could render them ineffective, providing a powerful tool to support the development and interpretation of preclinical and clinical studies of various PEGylated therapeutics.

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“…A brief report by McSweeney et al. 54 disclosed that PEG-modified therapeutics can induce specific PEG-binding antibodies, leading to rapid elimination of drugs and a significantly increased risk of serious adverse events.…”

Section: Main Textmentioning

confidence: 99%

Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy

Liu

Zhang

Zhu

et al. 2020

Molecular Therapy - Methods & Clinical Development

147

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Cationic liposomes (CLs) have been regarded as the most promising gene delivery vectors for decades with the advantages of excellent biodegradability, biocompatibility, and high nucleic acid encapsulation efficiency. However, the clinical use of CLs in cancer gene therapy is limited because of many uncertain factors in vivo . Extracellular barriers such as opsonization, rapid clearance by the reticuloendothelial system and poor tumor penetration, and intracellular barriers, including endosomal/lysosomal entrapped network and restricted diffusion to the nucleus, make CLs not the ideal vector for transferring extrinsic genes in the body. However, the obstacles in achieving productive therapeutic effects of nucleic acids can be addressed by tailoring the properties of CLs, which are influenced by lipid compositions and surface modification. This review focuses on the physiological barriers of CLs against cancer gene therapy and the effects of lipid compositions on governing transfection efficiency, and it briefly discusses the impacts of particle size, membrane charge density, and surface modification on the fate of CLs in vivo , which may provide guidance for their preclinical studies.

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Physician Awareness of Immune Responses to Polyethylene Glycol‐Drug Conjugates

Cited by 41 publications

References 17 publications

Architectural Modification of Conformal PEG‐Bottlebrush Coatings Minimizes Anti‐PEG Antigenicity While Preserving Stealth Properties

Architectural Modification of Conformal PEG‐Bottlebrush Coatings Minimizes Anti‐PEG Antigenicity While Preserving Stealth Properties

A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse

Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy

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