Pre-existing anti–polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer

Ganson, Nancy J.; Povsic, Thomas J.; Sullenger, Bruce A.; Alexander, John H.; Zelenkofske, Steven L.; Sailstad, Jeffrey; Rusconi, Christopher P.; Hershfield, Michael S.

doi:10.1016/j.jaci.2015.10.034

Cited by 230 publications

(254 citation statements)

References 12 publications

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“…Recently, a phase III clinical study testing a PEG-aptamer was halted because one patient died from an anaphylactic reaction. Researchers postulated that high levels of pre-existing anti-PEG found in this patient was a major, although not the sole, factor necessary for triggering the "firstexposure" allergic reaction (Ganson et al 2015).…”

Section: Immunogenicity Testing Of Hep-g-csf In Ratsmentioning

confidence: 93%

“…PEG lacks a natural, efficient degradation system and thus has been associated with the accumulation of intracellular vacuoles in animals (Bendele et al 1998;Rudmann et al 2013), which could become a concern for long-term pediatric or genetic disease treatments. PEG has also been reported to induce anti-PEG antibodies (Armstrong et al 2007;Hershfield et al 2014;Garay et al 2012;Richter and Akerblom 1984;Ganson et al 2015;Veronese 2001). Studies correlate the existence of pre-existing or induced anti-PEG with poor or non-responsiveness to some PEGylated drugs.…”

Section: Immunogenicity Testing Of Hep-g-csf In Ratsmentioning

confidence: 99%

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Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia

Wei¹,

Roberts²,

Green

et al. 2017

Glycobiology

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Many injectable drugs require delivery strategies for enhancing their pharmacokinetics due to rapid loss via renal filtration if possess low molecular weight (<60-70 kDa) and/or clearance by the body"s components (e.g., proteases, antibodies, high-efficiency receptors) in their native form. FDA-approved polyethylene glycol [PEG] is a vehicle for improving therapeutics, but artificial polymers have potential biocompatibility and immunogenicity liabilities. Here we utilized a natural vertebrate carbohydrate, heparosan [HEP], the biosynthetic precursor of heparan sulfate and heparin, to enhance performance of a biologic drug. The heparosan polysaccharide was stable with a long half-life (~8 days for 99-kDa chain) in the non-human primate bloodstream, but was efficiently degraded to very short oligosaccharides when internalized by cells, and then excreted into urine and feces. Several heparosanmodified human granulocyte-colony stimulating factor [G-CSF] conjugates were synthesized with defined quasi-monodisperse HEP polysaccharide chains. Single dosing of 55-or 99-kDa HEP-G-CSF in rats increased blood neutrophil levels comparable to PEG-G-CSF conjugates. Repeated dosing of HEP-G-CSF or heparosan alone for 2 weeks did not cause heparosan-specific toxic effects in rats. Heparosan did not possess the anticoagulant behavior of its daughter, heparin, based on testing in rats or clinical diagnostic assays with human plasma. Neither anti-heparosan IgG nor IgM antibodies were detected in a long-term (9 doses over 7 months) immunogenicity study of the HEP-drug conjugate with rats. These proof-of-concept experiments with HEP-G-CSF indicate that it is a valid drug candidate for neutropenia and suggest the potential of this HEP-based platform as a safe alternative delivery vehicle for other therapeutics.

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Section: Immunogenicity Testing Of Hep-g-csf In Ratsmentioning

confidence: 93%

Section: Immunogenicity Testing Of Hep-g-csf In Ratsmentioning

confidence: 99%

Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia

Wei¹,

Roberts²,

Green

et al. 2017

Glycobiology

View full text Add to dashboard Cite

show abstract

“…While a high prevalence of anti-PEG preexisting antibodies was not associated with impaired response to PEG-interferon in hepatitis C patients, increased drug clearance, reduced efficacy, and increased infusion reactions have been reported for pegloticase (PEG-porcine uricase) in patients with refractory chronic gout (14,40). Additionally, pre-existing anti-PEG antibodies were associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer in a phase 2b clinical trial in patients with acute coronary syndrome (41,42). Monitoring of the clinical impact of anti-PEG pre-existing antibodies is warranted on a case by case basis.…”

Section: Pre-existing Antibodies To Pegylated Drugsmentioning

confidence: 99%

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Xue

Clements-Egan

Amaravadi

et al. 2017

AAPS J

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Abstract.Anti-drug antibodies (ADA) pose a potential risk to patient safety and efficacy and are routinely monitored during clinical trials. Pre-existing drug-reactive antibodies are present in patients without prior drug exposure and are defined by their ability to bind to a component of the drug. These pre-existing drug-reactive antibodies are frequently observed and could represent an adaptive immune response of an individual who has been previously exposed to antigens with structural similarities to the biotherapeutic. Clinical consequences of these antibodies can vary from no impact to adverse effects on patient safety, exposure, and efficacy, and are highly dependent on biotherapeutic modality, disease indications, and patient demographics. This paper describes how the immunogenicity risk assessment of a biotherapeutic integrates the existence of pre-existing drug-reactive antibodies, and provides recommendations for risk-based strategies to evaluate treatment-emergent ADA responses.

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“…In one clinical trial, 36% of enrolled patients were positive for anti-PEG antibodies before treatment and three of them then suffered severe allergic reactions minutes after the injection of the PEGylated therapeutic [16]. Other researchers have detected PEG-specific antibodies in the blood of healthy donors, anywhere from 25% to 63% of unique samples tested, and have hypothesized that the incidence may be due to exposure to increasing amount of commercial products that contain PEG, such as cosmetics and food additives [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Zwitterionic polymer-protein conjugates reduce polymer-specific antibody response

Liu

Jiang

2016

Nano Today

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Proteins are promising therapeutics with several design challenges, such as their inherent immunogenicity due to their exogenous source or short circulation time. The common solution to such issues is the chemical conjugation of the amphiphilic polymer poly(ethylene glycol) (PEG), a process known as PEGylation. However, several studies demonstrated a decrease in protein bioactivity or an increase in the presence of specific antibodies post PEGylation, highlighting the importance of an alternative strategy. Here we compare the performance of a superhydrophilic zwitterionic polymer in protecting an immunogenic protein to PEG in (i) the maintenance of enzyme activity and stability post modification, (ii) mitigation of the antibody response elicited by the polymer and any subsequent effect on pharmacokinetics, and (iii) minimization of host response toward the underlying protein. In contrast to PEG, zwitterionic conjugation decreases host antibody response without sacrificing bioactivity or generating polymer-specific antibodies.

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Pre-existing anti–polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer

Cited by 230 publications

References 12 publications

Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia

Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Zwitterionic polymer-protein conjugates reduce polymer-specific antibody response

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