Investigational New Drugs

, Volume 32, Issue 5, pp 795–805 | Cite as

Pharmacology, immunogenicity, and efficacy of a novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase

  • Wei-Wen Chien
  • Soraya Allas
  • Nicolas Rachinel
  • Pierre Sahakian
  • Michel Julien
  • Céline Le Beux
  • Claire-Emmanuelle Lacroix
  • Thierry Abribat
  • Gilles SallesEmail author


Bacterial L-asparaginase (ASNase), hydrolyzing L-asparagine (Asn), is an indispensable component used in the treatment of acute lymphoblastic leukemia (ALL) and certain lymphoma entities. Native Erwinia chrysanthemi-derived ASNase (n-crisantaspase) has been approved as a second-line drug for treating patients exhibiting allergy syndromes to native and pegylated Escherichia coli-derived ASNase (EC-ASNase). However, it still induces hypersensitivity in at least 17 % of treated patients. In the present study, we investigated the pharmacological activity, immunogenicity and anti-leukemic activity of a new pegylated recombinant crisantaspase (PEG-r-crisantaspase). The results demonstrate that when compared to n-crisantaspase in vivo, PEG-r-crisantaspase maintains a complete depletion of plasma Asn for up to 72 h with a 50-fold lower dose. In mice receiving PEG-r-crisantaspase, specific antibodies against the enzyme were undetectable, indicating a lower immunogenicity of the pegylated enzyme. In vitro, PEG-r-crisantaspase exhibits similar cytotoxic effects (EC50 < 5 × 10−4 U/mL for the most sensitive cell lines) to n-crisantaspase on various leukemia and lymphoma cells and was shown to be more efficient than EC-ASNase. Three repeated PEG-r-crisantaspase injections (2–20 U/Kg) prevented leukemia development in leukemia-bearing mice for 17 days and significantly prolonged animal survival to 7–12 days. Therefore, PEG-r-crisantaspase appears to be a promising drug candidate for ALL treatment and should be further explored in experimental and clinical trials.


Acute lymphoblastic leukemia Lymphoma L-asparaginase Erwinia chrysanthemi pegylation 



Special thanks to Dr. Philippe Gaulard (INSERM U955, France), Dr. Paul Coppo (Hôpital Saint-Antoine, Paris, France), and Dr. Hiroshi Kimura (Department of Virology, Japan) for providing MEC04 and KHYG1 cells lines, respectively. Sincere thanks to Dr. Christine Saban for amino acid measurement, Patrick Manas for his help in animal experiments, Martine Ffrench and Aline Billoud for patient samples, Lucile Baseggio for the immunocytochemistry technique, and to the ALL patients who donated blood samples for our studies. The project received partial financial support with a refundable grant from Oséo (Maisons Alfort, France) and an FUI (Fonds Unique Interministériel) grant contributed by both the European Regional Development Fund (ERDF), and the Grand Lyon and Rhône Alpes regions.

Conflict of interest

SA PS, MJ, and TA are employees, and TA is a shareholder of Alizé Pharma II. The remaining authors declare no competing financial interests.

Supplementary material

10637_2014_102_MOESM1_ESM.doc (54 kb)
Supplemental Table 1 (DOC 54 kb)
10637_2014_102_MOESM2_ESM.doc (764 kb)
Supplemental Figure 1 (DOC 764 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Wei-Wen Chien
    • 1
  • Soraya Allas
    • 2
  • Nicolas Rachinel
    • 1
  • Pierre Sahakian
    • 2
  • Michel Julien
    • 2
  • Céline Le Beux
    • 1
  • Claire-Emmanuelle Lacroix
    • 1
  • Thierry Abribat
    • 2
  • Gilles Salles
    • 1
    • 3
    Email author
  1. 1.Université Claude Bernard Lyon 1, UMR 5239, CNRS, ENS, HCLOullinsFrance
  2. 2.Alizé PharmaEcullyFrance
  3. 3.Hospices Civils de Lyon, Service d’HématologiePierre-BéniteFrance

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