Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia

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.

[1]  R. Mathôt,et al.  Individualized dosing guidelines for PEGasparaginase and factors influencing the clearance: a population pharmacokinetic model , 2020, Haematologica.

[2]  C. Lanvers-Kaminsky,et al.  Asparaginase activities during intensified treatment with pegylated E. coli asparaginase in adults with newly-diagnosed acute lymphoblastic leukemia , 2020, Leukemia & lymphoma.

[3]  M. Zucchetti,et al.  Incidence of Hypersensitivity Reactions (HSR) Reactions (HSR) to Peg-Asparaginase (PEG-ASP) in 6136 Patients Treated in the AIEOP-BFM ALL 2009 Study Protocol , 2019, Blood.

[4]  David J. Young,et al.  Universal premedication and therapeutic drug monitoring for asparaginase‐based therapy prevents infusion‐associated acute adverse events and drug substitutions , 2019, Pediatric blood & cancer.

[5]  M. Relling,et al.  Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  R. Hutchinson,et al.  A single-center multidisciplinary approach to managing the global Erwinia asparaginase shortage , 2019, Leukemia & lymphoma.

[7]  Karin Chen,et al.  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 , 2018, Pediatric hematology and oncology.

[8]  D. Bixby,et al.  Catalyzing improvements in ALL therapy with asparaginase. , 2017, Blood reviews.

[9]  S. Rheingold,et al.  Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia , 2017, Leukemia & lymphoma.

[10]  Samuel K Lai,et al.  Analysis of Pre-existing IgG and IgM Antibodies against Polyethylene Glycol (PEG) in the General Population. , 2016, Analytical chemistry.

[11]  Yu-Cheng Su,et al.  Measurement of Pre-Existing IgG and IgM Antibodies against Polyethylene Glycol in Healthy Individuals. , 2016, Analytical chemistry.

[12]  W. Walther,et al.  Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[13]  C. Lubich,et al.  The Mystery of Antibodies Against Polyethylene Glycol (PEG) - What do we Know? , 2016, Pharmaceutical Research.

[14]  J. Coligan,et al.  Emerging Functions of Natural IgM and Its Fc Receptor FCMR in Immune Homeostasis , 2016, Front. Immunol..

[15]  A. Baruchel,et al.  Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation , 2016, Haematologica.

[16]  Jeffrey M. Sailstad,et al.  Pre-existing anti–polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer , 2015, The Journal of allergy and clinical immunology.

[17]  Traci M. Blonquist,et al.  Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. , 2015, The Lancet. Oncology.

[18]  C. Mullighan,et al.  Acute Lymphoblastic Leukemia in Children. , 2015, The New England journal of medicine.

[19]  S. Lai,et al.  Anti-PEG immunity: emergence, characteristics, and unaddressed questions. , 2015, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[20]  T. Ishida,et al.  Anti-PEG IgM Is a Major Contributor to the Accelerated Blood Clearance of Polyethylene Glycol-Conjugated Protein. , 2015, Molecular pharmaceutics.

[21]  R. Dodge,et al.  Anti-PEG antibody bioanalysis: a clinical case study with PEG-IFN-λ-1a and PEG-IFN-α2a in naive patients. , 2015, Bioanalysis.

[22]  Anthony J. Perissinotti,et al.  Pharmacokinetic and clinical considerations for monitoring asparaginase activity levels during pegaspargase therapy , 2015, Pediatric blood & cancer.

[23]  K. Schmiegelow,et al.  PEG‐asparaginase allergy in children with acute lymphoblastic leukemia in the NOPHO ALL2008 protocol , 2015, Pediatric blood & cancer.

[24]  B. Asselin,et al.  Asparaginase pharmacokinetics and implications of therapeutic drug monitoring , 2015, Leukemia & lymphoma.

[25]  M. Loh,et al.  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. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  H. Schrøder,et al.  Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia , 2014, British journal of haematology.

[27]  A. Rosenberg,et al.  New FDA Draft Guidance on Immunogenicity , 2014, The AAPS Journal.

[28]  M. Hershfield,et al.  Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients , 2014, Arthritis Research & Therapy.

[29]  J. Weinstein,et al.  The glutaminase activity of L-asparaginase is not required for anticancer activity against ASNS-negative cells. , 2013, Blood.

[30]  W. Tissing,et al.  A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. , 2013, Blood.

[31]  J. Gerss,et al.  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. , 2011, Blood.

[32]  Ray Yin,et al.  A double antigen bridging immunogenicity ELISA for the detection of antibodies to polyethylene glycol polymers. , 2011, Journal of pharmacological and toxicological methods.

[33]  C. Pui,et al.  L‐asparaginase treatment in acute lymphoblastic leukemia , 2011, Cancer.

[34]  M. Rytting Peg-asparaginase for acute lymphoblastic leukemia , 2010, Expert opinion on biological therapy.

[35]  H. Tillmann,et al.  307 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 , 2010 .

[36]  M. Wetzler,et al.  Pegasparaginase: where do we stand? , 2009, Expert opinion on biological therapy.

[37]  Viswanath Devanarayan,et al.  Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. , 2008, Journal of pharmaceutical and biomedical analysis.

[38]  T. Ishida,et al.  The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[39]  F. Perez-Ruiz,et al.  PEG-uricase in the management of treatment-resistant gout and hyperuricemia. , 2008, Advanced drug delivery reviews.

[40]  Taro Shimizu,et al.  PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[41]  P. Keegan,et al.  FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). , 2007, The oncologist.

[42]  Herbert J Meiselman,et al.  Antibody against poly(ethylene glycol) adversely affects PEG‐asparaginase therapy in acute lymphoblastic leukemia patients , 2007, Cancer.

[43]  A. Bernkop‐Schnürch,et al.  Strategies to improve plasma half life time of peptide and protein drugs , 2006, Amino Acids.

[44]  M. Hershfield,et al.  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 , 2005, Arthritis research & therapy.

[45]  Claudia Fruijtier-Pölloth Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products. , 2005, Toxicology.

[46]  George Scott,et al.  Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. , 2004, Journal of immunological methods.

[47]  P. Caliceti,et al.  Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. , 2003, Advanced drug delivery reviews.

[48]  M. Graham Pegaspargase: a review of clinical studies. , 2003, Advanced drug delivery reviews.

[49]  J. M. Harris,et al.  Effect of pegylation on pharmaceuticals , 2003, Nature Reviews Drug Discovery.

[50]  G. Hempel,et al.  Analytical validation of a microplate reader-based method for the therapeutic drug monitoring of L-asparaginase in human serum. , 2002, Analytical biochemistry.

[51]  D. Barnard Pegasys (Hoffmann-La Roche). , 2001, Current opinion in investigational drugs.

[52]  Vinod P. Shah,et al.  Bioanalytical Method Validation—A Revisit with a Decade of Progress , 2000, Pharmaceutical Research.

[53]  H. Jürgens,et al.  Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations. , 1996, European journal of cancer.

[54]  E. Panosyan,et al.  Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations , 2005, Clinical pharmacokinetics.

[55]  C. Snapper,et al.  T cell independent antigens. , 1995, Current opinion in immunology.

[56]  E. Åkerblom,et al.  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. , 1984, International archives of allergy and applied immunology.

[57]  E. Åkerblom,et al.  Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins. , 1983, International archives of allergy and applied immunology.