Pharmacology, immunogenicity, and efficacy of a novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase.
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.
Université Claude Bernard Lyon 1, UMR 5239, CNRS, ENS, HCL, Faculté de Médecine Lyon Sud Equipe du Pr. Gilles Salles "Pathologie des cellules lymphoïdes" 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, France.
Wei-Wen
WW
Chien
Soraya
S
Allas
Nicolas
N
Rachinel
Pierre
P
Sahakian
Michel
M
Julien
Céline
C
Le Beux
Claire-Emmanuelle
CE
Lacroix
Thierry
T
Abribat
Gilles
G
Salles
D000818:Animals; D000906:Antibodies / Q000097:blood; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D001215:Asparaginase / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016974:Dickeya chrysanthemi; D005260:Female; D006801:Humans; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D001215:Asparaginase