Improved pharmacokinetic and pharmacodynamic profile of a novel PEGylated native Erwinia chrysanthemi L-Asparaginase

Abstract

SummaryIntroduction. Erwinase® (native Erwinia chrysanthemi L-Asparaginase (nErA)) is an approved second-line treatment for acute lymphoblastic leukaemia (ALL) in children and adolescents, who develop hypersensitivity or neutralising antibodies to E.coli derived L-Asparaginases (ASNases). However, nErA has a short in vivo half-life requiring frequent dosing schedules in patients. In this study, nErA was covalently conjugated to PEG molecules with the aim of extending its half-life in vivo. Methods. Firstly, efficacy of this novel product PEG-nErA was investigated on human ALL cell lines (Jurkat, CCRF-CEM and CCRF-HSB2), in vitro. Secondly, its pharmacokinetic (PK) and pharmacodynamic (PD) characteristics were determined, in vivo (12 rats in each group). Results. It was found that the specific activity (U/mg of enzyme) and the kinetic constant (KM) of nErA remained unaltered post PEGylation. PEG-nErA was shown to have similar cytotoxicity to nErA (IC50: 0.06–0.17 U/mL) on human ALL cell lines, in vitro. Further, when compared to nErA, PEG-nErA showed a significantly improved half-life in vivo, which meant that L-Asparagine (Asn) levels in plasma remained depleted for up to 25 days with a four-fold lower dose (100 U/kg) compared with 72 h for nErA at 400 U/kg dose. Conclusion. Overall, this next generation product PEG-nErA (with improved PK and PD characteristics compared to nErA) would bring a significant advantage to the therapeutic needs of ALL patients and should be further explored in clinical trials.

Polyoxazoline-Conjugated l-Asparaginase: An Antibody-Production-Free Therapeutic Agent for Acute Lymphoblastic Leukemia

“…SD rats (male; 6 weeks of age; 180–206 g weight; total n = 9) were obtained from Charles River Laboratories Japan, Inc. The protocol followed the procedures outlined in a previous report . Sample solutions (POx-ASNase, PEG-ASNase, ASNase) in saline were injected intravenously via the caudal vein without anesthesia ([ASNase] = 400 U/kg; dosage = 4.0 mL/kg).…”

“…The protocol followed the procedures outlined in a previous report. 38 Sample solutions (POx-ASNase, PEG-ASNase, ASNase) in saline were injected intravenously via the caudal vein without anesthesia ([ASNase] = 400 U/kg; dosage = 4.0 mL/ kg). Blood samples were collected from the caudal vein (0.1 mL) using a heparin-treated syringe at eight different time points: 0 (prior to sample injection), 1, 3, 5, 7, 14, 21, and 28 days after infusion.…”

Desirable L-asparaginases for treating cancer and current research trends

“…The primary treatment for most ALL patients is PEG-native E. coli L-ASNase (EcA); unfortunately, many patients experience hypersensitivity reactions. This hypersensitivity may result from either a negative immunological response to the enzyme or the formation of neutralizing antibodies (often known as silent inactivation; Modi and Gervais, 2022 ). Native E. chrysanthemi L-ASNase (ErA) differs immunologically from PEG-native EcA and does not react with PEG-nEcA-derived antibodies.…”

“…Native E. chrysanthemi L-ASNase (ErA) differs immunologically from PEG-native EcA and does not react with PEG-nEcA-derived antibodies. Therefore, patients who acquired an allergy to PEG-native EcA were administered native ErA (or, starting in July 2021, recombinant ErA) as second-line treatment ( Modi and Gervais, 2022 ).…”