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

Haematologica. 2022 Jan 1;107(1):49-57. doi: 10.3324/haematol.2020.258525.

Abstract

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.

MeSH terms

  • Adult
  • Antibodies
  • Antineoplastic Agents* / adverse effects
  • Asparaginase / therapeutic use
  • Child
  • Escherichia coli
  • Humans
  • Infant
  • Polyethylene Glycols / therapeutic use
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy

Substances

  • Antibodies
  • Antineoplastic Agents
  • Polyethylene Glycols
  • Asparaginase

Grants and funding

Funding: 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.