Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, India.
Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India.
Pediatr Blood Cancer. 2021 Nov;68(11):e29046. doi: 10.1002/pbc.29046. Epub 2021 May 3.
The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli-derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low-middle-income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes.
Seven biogeneric EcASNases (P1-P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m /dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug-related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R).
In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high-risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch-to-batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory.
Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high-quality asparaginases remains an unmet therapeutic need.
生物治疗用的天冬酰胺酶是急性淋巴细胞白血病（ALL）治疗的基石。由于获得原始的天然大肠杆菌衍生的天冬酰胺酶（EcASNase）的途径有限，各种 EcASNase 生物仿制药在中低收入国家（LMICs）中使用。这些生物仿制药的质量差异可能会影响临床结果。
评估了在印度广泛销售的 7 种生物仿制药 EcASNases（P1-P7），以 P2 作为体内监测的代表。在诱导治疗期间监测 P2（10,000 IU/m/剂量，肌内，每 72 小时）的治疗活性，并记录药物相关毒性。使用多模式分析对 7 种生物仿制药的分子身份、纯度和体外药物活性进行了表征，并与参考 EcASNase（R）进行了比较。
在接受 P2 治疗的患者（N=62）中，在诱导期间，72 小时（给药后）的 66%（46/70）的时间点观察到亚治疗性天冬酰胺酶活性（<100 U/L）。12 名患者（19%），11 名患有高危 ALL，出现过敏反应。在所有 7 种生物仿制药中都鉴定出 EcASNase 的同工型。所有的通用产品都含有杂质，且具有批次间的可变性。这些杂质包括高水平的蛋白质聚集体和宿主细胞蛋白污染。体外 EcASNase 活性和白血病细胞系细胞毒性测定没有差异。
我们的研究结果证实了在中低收入国家销售的天然 EcASNase 生物仿制药质量和治疗活性令人不满意的广泛担忧。这些产品的适当使用需要进行监测研究，以确定临床适用性并确定适当的剂量和方案。对于世界上的大部分地区，确保获得高质量的天冬酰胺酶仍然是一个未满足的治疗需求。
