Can recombinant technology address asparaginase <i>Erwinia chrysanthemi</i> shortages?

Maese, Luke; Rizzari, Carmelo; Coleman, Russell; Power, Austin; Sluis, Inge van der; Rau, Rachel E.

doi:10.1002/pbc.29169

Cited by 25 publications

(26 citation statements)

References 30 publications

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“…However, Erwinase® has a limited supply issue, often leading to patient prioritisation [35]. Supposedly, recently approved JZP-458 (rErA produced in Pseudomonas fluorescens) potentially helps fulfil this unmet need by providing additional asparaginase preparation for those patients [3], however the hypersensitivity rate from this product is not yet understood or reported. Furthermore, PEG-nErA would also help resolve Erwinase® shortage problem, as clinically, it may be expected that PEG-nErA can be given at lower dosage and less frequently to patients compared with nErA or rErA, while achieving the same desired therapeutic outcome and improved patient experience.…”

Section: Discussionmentioning

confidence: 99%

“…For years, options for ASNase treatment have included native Escherichia coli ASNase (nEcA), native Erwinia chrysanthemi ASNase (nErA) and PEGylated Escherichia coli ASNase (PEG-nEcA). Recently, a recombinant version of Erwinia chrysanthemi ASNase has been approved by the US FDA [3]. However, to date no PEGylated Erwiniabased ASNase has been approved for clinical use in ALL treatment.…”

Section: Introductionmentioning

confidence: 99%

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

Modi¹,

Gervais²

2021

Invest New Drugs

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Modi¹,

Gervais²

2021

Invest New Drugs

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“…Five different L-ASNase preparations are currently used in the clinic. Two variants, Erwinase ® and Rylaze ® , are both of the same Erwinia chrysanthemi ansB gene product but differ in their bio-manufacturing process [ 23 , 24 ]. The three others are derived from the Escherichia coli Type 2 L-ASNase.…”

Section: Bacterial L-asnase Used In the Clinic For All Therapymentioning

confidence: 99%

“…Indeed, a new recombinant version of E. chrysanthemi L-ASNase, Rylaze ® , also known as JZP-458, has been developed and taken forward into a clinical trial (NCT04145531). Recently, it has been approved by the FDA as part of a treatment regimen for children and adults with ALL or lymphoblastic lymphoma [ 24 , 68 , 69 ]. Rylaze ® will help alleviate the shortage of additional L-ASNase for the treatment of ALL patients that develop hypersensitivity against PEG-L-ASNase [ 24 ].…”

Section: Bacterial L-asnase Used In the Clinic For All Therapymentioning

confidence: 99%

“…Recently, it has been approved by the FDA as part of a treatment regimen for children and adults with ALL or lymphoblastic lymphoma [ 24 , 68 , 69 ]. Rylaze ® will help alleviate the shortage of additional L-ASNase for the treatment of ALL patients that develop hypersensitivity against PEG-L-ASNase [ 24 ].…”

Section: Bacterial L-asnase Used In the Clinic For All Therapymentioning

confidence: 99%

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Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

Trimpont

Peeters

Visser

et al. 2022

Cancers

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L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.

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Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP‐458)

Lin

Dumas

Kaullen

et al. 2021

Clinical Pharm in Drug Dev

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JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme expected to lack immunologic cross-reactivity to Escherichia coli-derived asparaginases. It is being developed as part of a multiagent chemotherapeutic regimen to treat acute lymphoblastic leukemia or lymphoblastic lymphoma patients who develop E coli-derived asparaginase hypersensitivity. A population pharmacokinetic (PopPK) model was developed for JZP-458 using serum asparaginase activity (SAA) data from a phase 1, single-dose study (JZP458-101) in healthy adults. Effects of intrinsic covariates (body weight, body surface area, age, sex, and race) on JZP-458 PK were evaluated. The model included SAA data from 24 healthy adult participants from the phase 1 study who received JZP-458: intramuscular (IM) data at 12.5 mg/m 2 (N = 6) and 25 mg/m 2 (N = 6), and intravenous (IV) data at 25 mg/m 2 (N = 6) and 37.5 mg/m 2 (N = 6). Model simulations of adult and pediatric SAA profiles were performed to explore the likelihood of achieving a therapeutic target nadir SAA (NSAA) level ≥0.1 IU/mL based on different administration strategies. PopPK modeling and simulation suggest JZP-458 is expected to achieve 72-hour NSAA levels ≥0.1 IU/mL in 100% of adult or pediatric populations receiving IM administration at 25 mg/m 2 , and in 80.9% of adult and 94.5% of pediatric populations receiving IV administration at 37.5 mg/m 2 on a Monday/Wednesday/Friday (M/W/F) dosing schedule. Based on these results, the recommended starting dose for the phase 2/3 pivotal study is 25 mg/m 2 IM or 37.5 mg/m 2 IV on a M/W/F dosing schedule in pediatric and adult patients.

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Can recombinant technology address asparaginase Erwinia chrysanthemi shortages?

Cited by 25 publications

References 30 publications

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

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

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP‐458)

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