Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p<0.01; Fisher’s exact test). Two of 4 patients with pre-existing anti-PEG IgG and first-exposure hypersensitivity reactions were not switched to Erwinia ASNase and continued on PEG-ASNase with sufficient activities (≥100U/L).
Pre-existing anti-PEG antibodies were detected in a considerable proportion of patients with ALL, did not inhibit PEG-ASNase activity but were associated with lower serum PEGASNase activity levels. Patients with pre-existing antibodies may show mild to moderate signs of hypersensitivity reaction after their first PEG-ASNase, which may be successfully addressed by re-challenge.
Due to its favorable toxicity profile polyethylene glycol (PEG) is widely used in foods, cosmetics, and pharmaceuticals. 1 Pegylation can improve the therapeutic benefit of protein drugs. It prolongs their elimination by increasing the molecular mass and protecting them from enzymatic cleavage and it decreases their immunogenicity by shielding potential antigenic epitopes.2-4 Numerous pegylated drugs are currently marketed in the USA and Europe including pegylated uricase (KrystexxaTM), pegylated interferon (PegasysTM, PegIntronTM) and pegylated E. coli asparaginase (PEG-ASNase) (OncasparTM, calaspargase, AsparlasTM).5-8 The asparagine-hydrolyzing enzyme asparaginase (ASNase) is crucial for the successful treatment of acute lymphoblastic leukemia (ALL)9,10 and because of its favorable drug characteristics PEG-ASNase is increasingly replacing its unmodified native form in frontline treatment of ALL.11-13
While pegylated proteins, despite their higher molecular mass, tend to be less immunogenic than their non-pegylated forms of protein drugs, antibodies against PEG have been detected in patients treated with pegylated proteins as well as in healthy volunteers.14 The reported prevalence varies widely between studies (0.2-72%) which is partly due to the use of different detection methods and cutpoint definitions (Online Supplementary Tables S1 and S2). In animal studies anti-PEG antibodies, especially anti-PEG IgM, were considered responsible for the accelerated blood clearance of pegylated proteins, liposomes, and nanoparticles.15,16 In human studies, the reported effects of anti-PEG antibodies on the therapeutic efficacy of pegylated drugs have been ambiguous; no effects of antibodies against PEG have been observed for pegylated interferons to date,17 whereas in patients with gout anti-PEG IgM and anti-PEG IgG were associated with a faster elimination of PEG-uricase.18,19 Drug authorities now require evaluation of the relevance of anti-PEG antibodies during drug development and registration processes.20,21
Published data suggest that anti-PEG antibodies may have important effects on the efficacy of PEG-ASNase. Armstrong et al. detected anti-PEG antibodies in 12 of 15 patients with undetectable ASNase activities after PEGASNase administration and also in four of 12 patients before their first PEG-ASNase administration.22 Liu et al. recently showed that anti-PEG ASNase antibodies consisted mainly of antibodies against PEG rather than E. coli ASNase and were significantly associated with hypersensitivity reactions to PEG ASNase.23
Given the increasing use of PEG-ASNase in frontline treatment for ALL, the aims of this study were to: (i) evaluate the prevalence of anti-PEG antibodies in three cohorts of patients (children and adults with primary ALL and children with relapsed ALL) before and/or immediately after their first dose of PEG-ASNase during induction treatment, and (ii) investigate the effects of pre-existing anti-PEG antibodies on PEG-ASNase activities and hypersensitivity reactions.
Samples for anti-PEG antibody determination were obtained from children with primary ALL (ALL-cohort 1), children with relapsed ALL (ALL-cohort 2), adults with primary ALL (ALLcohort 3) and healthy infants, who served as the reference cohort. Patients in ALL-cohort 1 were treated according to the AIEOPBFM ALL 2009 trial (ClinicalTrials.gov identifier: NCT01117441) and a total of 673 plasma samples were collected from 673 pediatric patients (401 males, 272 females) prior to their first administration of PEG-ASNase. In addition, 646 patients provided one or two more serum samples (1,183 in total) taken within 15 days after the first PEG-ASNase dose on day 12 of induction.
Patients in ALL-cohort 2 were diagnosed with relapsed ALL and treated according to the protocol of the ALL-REZ BFM 2002 (ClinicalTrials.gov identifier: 00114348) or the ALL-REZ BFM Observational Study and Biobank study. Twenty-eight samples were collected from 28 patients (19 males, 9 females) 0 to 2 days after the first dose of PEG-ASNase
Patients in ALL-cohort 3 were treated according to the multicenter GMALL 07/2003 trial (ClinicalTrials.gov identifier: 00198991). A total of 188 samples from 120 males and 68 females were taken on the same day after the first administration of PEGASNase (n=16) or the following day (n=172). Further details on the ALL cohorts are provided in Table 1 and in the Online Supplementary Data.
The respective ALL studies were approved by national and local review boards in accordance with the Helsinki Declaration and national laws. The approvals included monitoring antibodies against PEG-ASNase and determination of ASNase activity. Patients and/or their guardians gave their signed informed consent to participate in the monitoring of ASNase activities and antibodies against PEG-ASNase.
Serum samples from 58 infants <1 year, who were considered naïve to PEG were used as reference. The Central Laboratory of the University Hospital Muenster provided anonymized remainders of routine serum samples from infants. Only age in months was disclosed. Thus, these samples were considered as completely anonymized leftover material.
Determination of antibodies against PEG
For the detection of anti-PEG IgG and anti-PEG IgM the flow cytometry method described by Armstrong et al.22 was transferred to a 96-well format with fluorescent read-out. TentaGel M OCH3 particles (10 mm), to which methoxy-polyethylene glycol chains with a mean molecular weight of 5,000 Da were covalently bound, were used as the antigen (RAPP Polymere, Tuebingen, Germany). Mean fluorescent intensities (MFI) of duplicate determinations were calculated for anti-PEG IgG and IgM levels. Based on the MFI, determined in the reference cohort, cut-points of 8 (anti-PEG IgG) and 2 (anti-PEG IgM) were defined to classify samples as positive or negative. A detailed description of the method for the determination of anti-PEG antibodies and its performance characteristics is included in the Online Supplementary Data along with a description of the measurement of PEG-ASNase activity and total IgG and IgM.
Statistical analyses were performed using SAS® Version 9.4 (SAS Institute Inc., Cary, NC, USA) and RStudio Version 1.2.5033 (RStudio: Integrated Development for R. RStudio, Inc., Boston, MA, USA. URL: http://www.rstudio.com/). Kruskal-Wallis one way analysis of variance on ranks, all pairwise multiple comparison procedures (Dunn method, Holm-Sidak method), the Mann- Whitney rank sum test, Wilcoxon signed-rank test, χ2 test, McNemar χ2 test with continuity correction, Fisher exact test, Pearson correlation and logistic regression were used as indicated.
Anti-PEG IgG and anti-PEG IgM antibody levels
The MFI for anti-PEG IgG was between 0.65 and 67.4, whereas that for anti-PEG IgM was between 0.13 and 30.8. Overall, anti-PEG IgG levels correlated with anti-PEG IgM levels (r=0.68, P<0.005, Pearson correlation). However, high anti-PEG IgG levels did not necessarily coincide with high anti-PEG IgM levels and vice versa (Online Supplementary Tables S3 and S4). On average the lowest levels of anti-PEG IgG and IgM were determined in the reference cohort and the highest levels in children with primary ALL prior to their first dose of PEG-ASNase (ALLcohort 1) (Figure 1).
In ALL-cohort 1 anti-PEG IgG and IgM levels were significantly lower after the administration of PEG-ASNase. This difference was statistically significant in an unpaired analysis, when all samples available after the first administration were included (n=1,183, median days after administration: 13; range: 1-15; P<0.001, Mann-Whitney rank sum test) and in a paired analysis, when only the first sample taken after administration was chosen for the pairwise comparison (n=646, median days after administration: 7; range: 1-15; P<0.001, Wilcoxon signed-rank test). In addition, anti-PEG IgG and IgM levels were also significantly lower in ALL-cohorts 2 and 3, which were analyzed after PEG-ASNase administration (P<0.001, Kruskal-Wallis oneway analysis of variance on ranks, all pairwise multiple comparison procedures [Dunn method]) (Figure 1). The prevalence of anti-PEG antibodies was correspondingly lower in samples/patients analyzed after administration of PEG-ASNase (Figure 2C-E). In ALL-cohort 1 13.9% of samples were positive for anti-PEG IgG and 29.1% positive for anti-PEG IgM prior to the administration of PEG-ASNase. After administration of PEG-ASNase the prevalence dropped to 4.2% for anti-PEG IgG and 4.5% for anti-PEG IgM. This represented a significant reduction in prevalence by PEG-ASNase administration (P<0.0001, McNemar χ2 test with continuity correction) (Figure 2B, C). Among patients with pre-existing anti-PEG antibodies, the antibody levels decreased a mean of about 2.7-fold for anti- PEG IgG and about 4.1-fold for anti-PEG IgM.
PEG-ASNase activities were determined in 1,183 samples from 646 patients of ALL-cohort 1. Samples were collected within 15 days of the first administration of 2,500 U/m2 PEG-ASNase (maximum 3,750 U per dose) on day 12 of induction. Of these samples, 95.5% were collected at the scheduled times (day 7±1 and day 14±1 after administration). The mean (± standard deviation) PEG-ASNase activities determined were 911±311 U/L on day 7±1 and 527±200 U/L on day 14±1.
PEG-ASNase activities were significantly lower among patients with elevated anti-PEG IgG (MFI ≥8) or anti-PEG IgM (MFI ≥2) prior to their first dose of PEG-ASNase (P<0.05, Kruskal-Wallis one way analysis of variance on ranks, all pairwise multiple comparison procedures [Holm- Sidak method]). In addition, the PEG-ASNase activities decreased with increasing anti-PEG antibody levels prior to administration (Figure 3). To evaluate the effect of anti- PEG antibodies on PEG-ASNase activities in individual patients, mean PEG-ASNase activities were calculated for the respective day after administration and individual PEGASNase activities were categorized as above or below the respective means. Pre-existing anti-PEG IgG (MFI ≥8) as well as pre-existing anti-PEG IgM (MFI ≥2) increased the risk of PEG-ASNase activities below average (anti-PEG IgG: odds ratio [OR]: 2.06, 95% confidence interval [95% CI]: 1.44-2.96; anti-PEG IgM: OR: 1.65; 95% CI: 1.27-2.15; P<0.001, χ2 test). No such associations were observed for anti-PEG IgG and IgM levels determined after PEG-ASNase administration. Pre-existing anti-PEG antibodies reduced but did not eliminate PEG-ASNase activities (Figure 3). Comparing the distribution of PEG-ASNase activities above and below 400 U/L, 100 U/L and the lower limit of quantitation (LLOQ = 5 U/L), significantly more samples with PEG-ASNase activities <400 U/L were found in patients with already existing anti-PEG antibodies (Table 2). No differences were observed for the distribution of PEG-ASNase activities above and below 100 U/L and the LLOQ (Table 2). Thus, silent inactivation of PEG-ASNase, which is defined by PEG-ASNase activities <100 U/L within 7±1 days and/or undetectable PEG-ASNase activities within 14±1 days after administration without signs of hypersensitivity reaction, was not affected by pre-existing anti-PEG antibodies.24,25 Anti-PEG antibodies did not inhibit the catalytic activity of PEG-ASNase and anti-PEG IgG and/or IgM had no effect on asparagine hydrolysis by PEGASNase (Online Supplementary Figure S4).
Anti-PEG antibodies prior to treatment with PEG-asparaginasese and hypersensitivity reactions to PEG-asparaginase
After initial exposure to PEG-ASNase, seven patients in ALL-cohort 1 (1.0%) showed hypersensitivity reactions (all Common Terminology Criteria for Adverse Events [CTCAE] grade 2) which were significantly associated with pre-existing anti-PEG IgG levels. Four of seven patients had pre-existing anti-PEG IgG (MFI ≥8) before their first PEG-ASNase dose (Table 3). No pre-existing anti- E. coli ASNase antibodies were detected in these patients. Four patients (2 with and 2 without pre-existing anti-PEG antibodies) were switched to Erwinia ASNase. Among the four patients with a first-exposure hypersensitivity reaction and pre-existing anti-PEG IgG no further boosts of anti-PEG IgG levels were observed. The two patients with pre-existing anti-PEG IgG, who continued on PEGASNase, completed the scheduled PEG-ASNase treatment without further signs of hypersensitivity. The relative risk of a hypersensitivity reaction upon first exposure to PEGASNase was 8 times higher for patients with anti-PEG IgG MFI ≥8 and 50 times higher for patients with anti-PEG IgG MFI ≥25 prior to their first PEG-ASNase (Table 3). This association was only observed for pre-existing anti-PEG IgG and not for pre-existing anti-PEG IgM.
We detected a high prevalence of anti-PEG IgG (13.9%) and IgM (29.1%) among children with primary ALL prior to their first PEG-ASNase.
Antibodies against PEG had already been detected in healthy volunteers of different ages and ethnicity and in patients who had never been treated with pegylated drugs before. The prevalence of anti-PEG antibodies in ALLcohort 1 was within the range of reported prevalences (0.2 to 72%).14,18,19,22,26–30 However, it must be acknowledged that it is difficult to compare the prevalence between different studies when different methods and cut-points were used (Online Supplementary Tables S1 and S2).
The reported effects of pre-existing anti-PEG antibodies on the efficacy and tolerability of pegylated drugs vary.14,17– 19,31,32 Unexpectedly, the first administration of PEG-ASNase did not trigger the formation of further anti-PEG antibodies. Instead, anti-PEG antibody levels and their prevalence decreased, which was different from a typical hypersensitivity reaction to PEG-ASNase that developed after repeated administration of PEG-ASNase.23,33–35 We also observed no increase in anti-PEG antibodies in the seven patients with hypersensitivity reaction at first exposure to PEGASNase.
Four of these patients had pre-existing anti-PEG IgG (MFI ≥8) (Table 3). This association was significant and the risk for hypersensitivity reaction increased with increasing anti- PEG IgG levels prior to PEG-ASNase administration. A significant association between pre-existing anti-PEG antibodies and first-exposure hypersensitivity reaction was also documented in the RADAR phase IIb clinical trial, which evaluated pegnivacogin, a 2’-fluoropyrimidine-modified RNA aptamer, in patients with acute coronary syndrome.31 Among the six patients with the highest anti-PEG antibody levels prior to pegnivacogin administration, three suffered from a first-exposure hypersensitivity reaction. The firstexposure hypersensitivity reactions in the RADAR phase IIb clinical trial affected only 0.5% of patients but were considered serious and led to early termination of the trial.31 In ALL-cohort 1 the first-exposure hypersensitivity reactions to PEG-ASNase were, however, only moderate (CTCAE grade 2).
Symptoms of moderate hypersensitivity reactions (CTCAE grade ≤2) and infusion-related adverse events are often difficult to distinguish.36 Typically, hypersensitivity reactions occur after re-challenge to the antigen and are associated with an increase in antibodies, which can persist in the blood for up to several weeks.23,37 Since this was not the case in patients with first-exposure hypersensitivity reactions to PEG-ASNase and only moderate hypersensitivity reactions (CTCAE grade 2) occurred, one might conclude that pre-existing anti-PEG IgG simply predispose to mild hypersensitivity reactions for which re-challenge with PEG-ASNase may be possible. The two ALL patients with pre-existing anti-PEG IgG who developed first-exposure hypersensitivity reactions to PEG-ASNase and did not switch to Erwinia ASNase tolerated their subsequent PEG-ASNase administrations well.
Pre-existing anti-PEG antibodies are most likely triggered by repeated contact with PEG-containing products of daily life, such as cosmetics, pharmaceuticals and food. Depending on the nature of the PEG-containing compound, different immunological mechanisms are supposed to facilitate the anti-PEG antibody response.28,38,39 Experiments in nude mice showed that pegylated proteins induced the production of anti-PEG IgM in a T-celldependent manner, whereas the induction of anti-PEG IgM by pegylated liposomes was T-cell independent.39,40 Furthermore, studies in animals indicated that these different immunological processes may also lead to antibodies with different properties.40 Similar processes might also be feasible in humans and might explain why patients with pre-existing antibodies showed different antibody responses after their first PEG-ASNase dose than patients who developed a hypersensitivity reaction to the PEG-ASNase after repeated administrations and in whom the PEG covalently bound to the bacterial ASNase acted as a hapten.23,37 According to the “Consensus expert recommendations for identification and management of ASNase hypersensitivity and silent inactivation” discontinuation of treatment is recommended for grade ≥2 allergic reactions.24 Recently, the National Comprehensive Cancer Network clinical practice guidelines and other expert reviews on ASNase hypersensitivity recommended switching of ASNase preparations only in the event of grade ≥3, severe or life-threatening allergic or anaphylactic reactions.36,41–43 In addition, because of the repeated shortage of Erwinia ASNase, various strategies were evaluated in order to avoid or delay a switch to Erwinia ASNase as long as possible.36,44,45 Thus, PEG-ASNase was either generally administered under premedication or in the case of hypersensitivity reactions grade ≤2 under premedication at initially reduced infusion rates. In each case, PEG-ASNase activity was monitored to detect silent inactivation or premedication-masked hypersensitivity reactions.
Pre-existing anti-PEG antibodies reduced the PEGASNase activity levels as a function of concentration, but did not reduce the PEG-ASNase activity levels to such an extent that the criteria of silent inactivation were fulfilled. Silent inactivation (or subclinical hypersensitivity reaction) is characterized by the development of antibodies without overt symptoms of a hypersensitivity reaction. 24,25 According to the “Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation” silent inactivation of PEG-ASNase is defined by PEG-ASNase activities ≤100 U/L within 7 days and undetectable PEGASNase activities within 14 days after administration.24 Neutralizing antibodies but also an accelerated elimination of antigen-antibody complexes are being discussed as the underlying cause for the rapid decrease in ASNase activity.24,25 We could not detect any inhibition of asparagine hydrolysis by anti-PEG antibodies (Online Supplementary Figure S4). Animal studies have shown an increased clearance of pegylated proteins, liposomes and nanoparticles in the presence of anti-PEG IgM and anti- PEG IgG.15,16 In nude mice, anti-PEG IgM induced a rapid clearance of pegylated protein from serum with simultaneous accumulation in the liver. Similar processes could also be conceivable in humans. The increased clearance of PEG uricase in gout patients was associated with an increase in anti-PEG IgG and IgM levels.18,19 The lower PEG-ASNase activity levels in patients with pre-existing antibodies might have been caused by an increased clearance of PEG-ASNase.
When comparing the distribution of PEG-ASNase activities above and below 400 U/L, 100 U/L and the LLOQ (5 U/L), we found a significant difference between patients with and without pre-existing anti-PEG antibodies only at 400 U/L. The 400 U/L value was chosen in addition to the generally accepted target activity of 100 U/L and the LLOQ because 400 U/L have been shown to result in deeper asparagine depletion.46,47 This higher activity level and its associated glutaminase activity have been suggested to increase the effectiveness of ASNase against leukemic blasts with residual asparagine synthetase activity. 48 Several studies have recently shown that PEGASNase clearance in a patient can vary significantly between different parts of the protocol.49,50 Thus, the effect of increased PEG-ASNase clearance due to preexisting antibodies on the intensity of ASNase therapy would depend on the dose and concomitant ALL treatment. Therefore, the effects of pre-existing anti-PEG antibodies on the pharmacokinetics of PEG-ASNase must be determined separately for each protocol.
In summary, we observed a considerable number of patients with pre-existing antibodies against PEG. Anti- PEG antibody kinetics after PEG-ASNase administration were not the same in patients with pre-existing antibodies as in patients with hypersensitivity reactions after repeated PEG-ASNase administration.23,37 Pre-existing anti-PEG antibodies may cause mild to moderate symptoms of hypersensitivity reaction with the first administration of PEG-ASNase, which might be addressed by rechallenge. They do not inhibit PEG-ASNase activity but lower PEG-ASNase activity levels, which, depending on the dose and protocol, may interfere with the targeted PEG-ASNase treatment intensity.
- Received May 19, 2020
- Accepted November 25, 2020
MS and the ALL-BFM Study Center have received funding from medac, Shire, SigmaTau, Servier, and Jazz Pharmaceuticals for research, and MS has participated in advisory boards. CR received institutional grants for PEG-asparaginase pharmacological studies aimed at the therapeutic monitoring of asparaginase activity within the AIEOP-BFM ALL 2009 study, as well as fees for participation in advisory boards and invited lectures for the companies involved in marketing different asparaginase products, medac GmbH, Sigma-Tau, Baxalta, Shire, Servier. CLK has held invited talks for Sigma tau, Erytech and Jazz Pharmaceuticals, received honoraria for consultancy from Erytech and travel expenses from Erytech and Servier. AA has consulting and advisory roles for Jazz Pharmaceuticals, and has also received travel and accommodation fees and expenses from Jazz Pharmaceuticals. AM has received honoraria from Baxter. JB has served personally as a consultant and participated in advisory as well as in safety boards for medac GmbH; he has received support for travel from Eusa Pharma, Jazz Pharmaceuticals, Baxalta Shire and Servier; has held invited lectures for medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Servier, Shire and Sigma-Tau; and, in addition, he has received institutional grants in the context of ASNase drug monitoring from more or less all ASNase providers contributing to the therapeutic drug monitoring program, including medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Servier, Shire, and Sigma-Tau (all representing the varying marketing authorization holders of E. coli ASNase, PEG-ASNase and Erwinase). NG has received research support from Jazz Pharmaceuticals and honoraria as an advisory board member from Jazz Pharmaceuticals and Baxalta. The other authors declare that they have no potential conflicts of interest.
AK, CLK, GW and JB designed the research. CR, MZu, VC, CN, AA, AM, MS, JB, AvS and NG collected data. AA, CN, MZu, MF, CLK, GH and JB analyzed and interpreted the data. AK, GW, JG, MZi, AM and CLK performed the statistical analysis. AK and CLK wrote the manuscript.
This work was supported by the Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLSR 13/01). The monitoring of PEG-ASNase activities and of antibodies against PEG-ASNase and native E. coli ASNase was supported by Servier (Suresnes, France), Shire (Lexington, USA), Baxalta (Westlake Village, USA), Sigma Tau Pharmaceuticals (Zofingen, Switzerland) and medac GmbH (Wedel, Germany). In Australia, ASNase monitoring and the collection of samples for antibody determination for the AIEOP-BFM ALL 2009 trial were funded by the Kids Cancer Alliance (KCA), a Translational Cancer Research Center of the Cancer Institute of New South Wales (15/TRC/1-04). CN is supported by the Leukemia Research and Support Fund at The Children’s Hospital at Westmead (Australia). In Austria monitoring of ASNase activity and collection of samples for antibody determination for the AIEOP-BFM ALL 2009 trial were funded by the St. Anna Kinderkrebsforschung (BFM-Austria). The work is part of the thesis of AK.
The authors would like to thank Ms Schulze Westhoff, Ms Hoogestraat and Ms Günter for their excellent technical assistance. We acknowledge support from the Open Access Publication Fund of the University of Muenster.
- Fruijtier-Pölloth C. Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products. Toxicology. 2005; 214(1-2):1-38. https://doi.org/10.1016/j.tox.2005.06.001PubMedGoogle Scholar
- Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2003; 55(10):1261-1277. https://doi.org/10.1016/S0169-409X(03)00108-XGoogle Scholar
- Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003; 2(3):214-221. https://doi.org/10.1038/nrd1033PubMedGoogle Scholar
- Werle M, Bernkop-Schnürch A.. Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids. 2006; 30(4):351-367. https://doi.org/10.1007/s00726-005-0289-3PubMedGoogle Scholar
- Sherman MR, Saifer MGP, Perez-Ruiz F.. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev. 2008; 60(1):59-68. https://doi.org/10.1016/j.addr.2007.06.011PubMedGoogle Scholar
- Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R.. FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist. 2007; 12(8):991-998. https://doi.org/10.1634/theoncologist.12-8-991PubMedGoogle Scholar
- Barnard DL. Pegasys (Hoffmann-La Roche). Curr Opin Investig Drugs. 2001; 2(11):1530-1538. Google Scholar
- Graham ML. Pegaspargase: a review of clinical studies. Adv Drug Deliv Rev. 2003; 55(10):1293-1302. https://doi.org/10.1016/S0169-409X(03)00110-8Google Scholar
- Pieters R, Hunger SP, Boos J. L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer. 2011; 117(2):238-249. https://doi.org/10.1002/cncr.25489PubMedPubMed CentralGoogle Scholar
- Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015; 373(16):1541-1552. https://doi.org/10.1056/NEJMra1400972PubMedGoogle Scholar
- Place AE, Stevenson KE, Vrooman LM. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli Lasparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015; 16(16):1677-1690. https://doi.org/10.1016/S1470-2045(15)00363-0Google Scholar
- Zeidan A, Wang ES, Wetzler M.. Pegasparaginase: where do we stand?. Expert Opin Biol Ther. 2009; 9(1):111-119. https://doi.org/10.1517/14712590802586058PubMedGoogle Scholar
- Rytting M. Peg-asparaginase for acute lymphoblastic leukemia. Expert Opin Biol Ther. 2010; 10(5):833-839. https://doi.org/10.1517/14712591003769808PubMedGoogle Scholar
- Yang Q, Lai SK. Anti-PEG immunity: emergence, characteristics, and unaddressed questions. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015; 7(5):655-677. https://doi.org/10.1002/wnan.1339PubMedPubMed CentralGoogle Scholar
- Poppenborg SM, Wittmann J, Walther W. Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice. Eur J Pharm Sci. 2016; 91:122-130. https://doi.org/10.1016/j.ejps.2016.06.007PubMedGoogle Scholar
- Ishida T, Kashima S, Kiwada H.. The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats. J Control Release. 2008; 126(2):162-165. https://doi.org/10.1016/j.jconrel.2007.11.009PubMedGoogle Scholar
- Myler H, Hruska MW, Srinivasan S. Anti-PEG antibody bioanalysis: a clinical case study with PEG-IFN-g-1a and PEG-IFNa2a in naive patients. Bioanalysis. 2015; 7(9):1093-1106. https://doi.org/10.4155/bio.15.36PubMedGoogle Scholar
- Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther. 2006; 8(1):R12. https://doi.org/10.1186/ar1861PubMedPubMed CentralGoogle Scholar
- Hershfield MS, Ganson NJ, Kelly SJ, Scarlett EL, Jaggers DA, Sundy JS. Induced and preexisting anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res Ther. 2014; 16(2):R63. https://doi.org/10.1186/ar4500PubMedPubMed CentralGoogle Scholar
- U.S. Department of Health and Human Services Food and Drug Administration. Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products.Publisher Full TextGoogle Scholar
- Parenky A, Myler H, Amaravadi L. New FDA draft guidance on immunogenicity. AAPS J. 2014; 16(3):499-503. https://doi.org/10.1208/s12248-014-9587-6PubMedPubMed CentralGoogle Scholar
- Armstrong JK, Hempel G, Koling S. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer. 2007; 110(1):103-111. https://doi.org/10.1002/cncr.22739PubMedGoogle Scholar
- Liu Y, Smith CA, Panetta JC. Antibodies predict pegaspargase allergic reactions and failure of rechallenge. J Clin Oncol. 2019; 37(23):2051-2061. https://doi.org/10.1200/JCO.18.02439PubMedPubMed CentralGoogle Scholar
- van der Sluis IM, Vrooman LM, Pieters R. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016; 101(3):279-285. https://doi.org/10.3324/haematol.2015.137380PubMedPubMed CentralGoogle Scholar
- Asselin B, Rizzari C.. Asparaginase pharmacokinetics and implications of therapeutic drug monitoring. Leuk Lymphoma. 2015; 56(8):2273-2280. https://doi.org/10.3109/10428194.2014.1003056PubMedPubMed CentralGoogle Scholar
- Richter AW, Akerblom E.. Polyethylene glycol reactive antibodies in man: titer distribution in allergic patients treated with monomethoxy polyethylene glycol modified allergens or placebo, and in healthy blood donors. Int Arch Allergy Appl Immunol. 1984; 74(1):36-39. https://doi.org/10.1159/000233512PubMedGoogle Scholar
- Liu Y, Reidler H, Pan J. A double antigen bridging immunogenicity ELISA for the detection of antibodies to polyethylene glycol polymers. J Pharmacol Toxicol Methods. 2011; 64(3):238-245. https://doi.org/10.1016/j.vascn.2011.07.003PubMedGoogle Scholar
- Lubich C, Allacher P, de la Rosa M. The mystery of antibodies against polyethylene glycol (PEG) - what do we know?. Pharm Res. 2016; 33(9):2239-2249. https://doi.org/10.1007/s11095-016-1961-xPubMedGoogle Scholar
- Chen B-M, Su Y-C, Chang C-J. Measurement of pre-existing IgG and IgM antibodies against polyethylene glycol in healthy individuals. Anal Chem. 2016; 88(21):10661-10666. https://doi.org/10.1021/acs.analchem.6b03109PubMedGoogle Scholar
- Yang Q, Jacobs TM, McCallen JD. Analysis of pre-existing IgG and IgM antibodies against polyethylene glycol (PEG) in the general population. Anal Chem. 2016; 88(23):11804-11812. https://doi.org/10.1021/acs.analchem.6b03437PubMedPubMed CentralGoogle Scholar
- Ganson NJ, Povsic TJ, Sullenger BA. Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer. J Allergy Clin Immunol. 2016; 137(5):1610-1613. https://doi.org/10.1016/j.jaci.2015.10.034PubMedPubMed CentralGoogle Scholar
- Tillmann H, Ganson NJ, Patel K. High prevalence of pre-existing antibodies against polyethylene glycol (PEG) in hepatitis C (HCV) patients which is not associated with impaired response to PEG-interferon. J Hepatol. 2010; 52:S129. https://doi.org/10.1016/S0168-8278(10)60309-1Google Scholar
- Henriksen LT, Nersting J, Raja RA. Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia. Br J Haematol. 2014; 166(2):213-220. https://doi.org/10.1111/bjh.12865PubMedGoogle Scholar
- Henriksen LT, Harila-Saari A, Ruud E. PEG-asparaginase allergy in children with acute lymphoblastic leukemia in the NOPHO ALL2008 protocol. Pediatr Blood Cancer. 2015; 62(3):427-433. https://doi.org/10.1002/pbc.25319PubMedGoogle Scholar
- Tong WH, Pieters R, Kaspers GJL. A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood. 2014; 123(13):2026-2033. https://doi.org/10.1182/blood-2013-10-534347PubMedPubMed CentralGoogle Scholar
- Burke MJ, Rheingold SR. Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia. Leuk Lymphoma. 2017; 58(3):540-551. https://doi.org/10.1080/10428194.2016.1213826PubMedGoogle Scholar
- Willer A, Gerss J, König T. Anti- Escherichia coli asparaginase antibody levels determine the activity of second-line treatment with pegylated E coli asparaginase: a retrospective analysis within the ALL-BFM trials. Blood. 2011; 118(22):5774-5782. https://doi.org/10.1182/blood-2011-07-367904PubMedGoogle Scholar
- Mond JJ, Vos Q, Lees A, Snapper CM. T cell independent antigens. Curr Opin Immunol. 1995; 7(3):349-354. https://doi.org/10.1016/0952-7915(95)80109-XGoogle Scholar
- Ishida T, Wang X, Shimizu T, Nawata K, Kiwada H.. PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner. J Control Release. 2007; 122(3):349-355. https://doi.org/10.1016/j.jconrel.2007.05.015PubMedGoogle Scholar
- Mima Y, Hashimoto Y, Shimizu T, Kiwada H, Ishida T.. Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein. Mol Pharm. 2015; 12(7):2429-2435. https://doi.org/10.1021/acs.molpharmaceut.5b00144PubMedGoogle Scholar
- Marini BL, Perissinotti AJ, Bixby DL, Brown J, Burke PW. Catalyzing improvements in ALL therapy with asparaginase. Blood Rev. 2017; 31(5):328-338. https://doi.org/10.1016/j.blre.2017.06.002PubMedGoogle Scholar
- Benitez L, Perissinotti AJ, Santarossa M, Marini BL. Pharmacokinetic and clinical considerations for monitoring asparaginase activity levels during pegaspargase therapy. Pediatr Blood Cancer. 2015; 62(6):1115. https://doi.org/10.1002/pbc.25426PubMedGoogle Scholar
- Verma A, Chen K, Bender C, Gorney N, Leonard W, Barnette P.. PEGylated E. coli asparaginase desensitization: an effective and feasible option for pediatric patients with acute lymphoblastic leukemia who have developed hypersensitivity to pegaspargase in the absence of asparaginase Erwinia chrysanthemi availability. Pediatr Hematol Oncol. 2019; 36(5):277-286. https://doi.org/10.1080/08880018.2019.1634778PubMedGoogle Scholar
- Marini BL, Brown J, Benitez L. A singlecenter multidisciplinary approach to managing the global Erwinia asparaginase shortage. Leuk Lymphoma. 2019; 60(12):2854-2868. https://doi.org/10.1080/10428194.2019.1608530PubMedGoogle Scholar
- Cooper SL, Young DJ, Bowen CJ, Arwood NM, Poggi SG, Brown PA. Universal premedication and therapeutic drug monitoring for asparaginase-based therapy prevents infusion-associated acute adverse events and drug substitutions. Pediatr Blood Cancer. 2019; 66(8):e27797. https://doi.org/10.1002/pbc.27797PubMedGoogle Scholar
- Angiolillo AL, Schore RJ, Devidas M. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014; 32(34):3874-3882. https://doi.org/10.1200/JCO.2014.55.5763PubMedPubMed CentralGoogle Scholar
- Avramis VI, Panosyan EH. Pharmacokinetic/ pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet. 2005; 44(4):367-393. https://doi.org/10.2165/00003088-200544040-00003PubMedGoogle Scholar
- Chan WK, Lorenzi PL, Anishkin A. The glutaminase activity of L-asparaginase is not required for anticancer activity against ASNS-negative cells. Blood. 2014; 123(23):3596-3606. https://doi.org/10.1182/blood-2013-10-535112PubMedPubMed CentralGoogle Scholar
- Kloos RQH, Mathôt R, Pieters R, van der Sluis IM. Individualized dosing guidelines for PEGasparaginase and factors influencing the clearance: a population pharmacokinetic model. Haematologica. 2021; 106(5):1254-1261. https://doi.org/10.3324/haematol.2019.242289PubMedGoogle Scholar
- Lanvers-Kaminsky C, Niemann A, Eveslage M. Asparaginase activities during intensified treatment with pegylated E. coli asparaginase in adults with newly-diagnosed acute lymphoblastic leukemia. Leuk Lymphoma. 2020; 61(1):138-145. https://doi.org/10.1080/10428194.2019.1658099PubMedGoogle Scholar
Figures & Tables
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.