Background

Anti-disialoganglioside (anti-GD2) monoclonal antibodies are effective immunotherapeutic drugs for treating neuroblastoma, yet their toxicity spectrum is unclear.

Objective

This study aimed to assess the toxicity profiles of three anti-GD2 monoclonal antibodies (dinutuximab, dinutuximab β, and naxitamab) in clinical applications by mining and evaluating the adverse drug reaction (ADR) signals from the US Food and Drug Administration Adverse Event Reporting System.

Methods

Data in the US Food and Drug Administration Adverse Event Reporting System from the time anti-GD2 monoclonal antibodies became available in the market to the first quarter of 2023 were searched. The signals of anti-GD2 monoclonal antibody-associated ADRs were quantified using four types of algorithms, including the reporting odds ratio, the proportional reporting ratio, the combination of the proportional reporting ratio and χ² statistic method used by the UK Medicines and Healthcare Products Regulatory Agency, and the Bayesian confidence propagation neural network. The ADRs were categorized by System Organ Class based on the Medical Dictionary for Regulatory Activities, and were sorted according to the frequency and signal strength of ADRs.

Results

A total of 370 adverse drug event reports with anti-GD2 monoclonal antibodies listed as the ‘primary suspected drugs’ were identified, with 116 ADR signals detected, of which 22 were not in the drug labels. Among the adverse drug event reports, 276 reports concerned dinutuximab/dinutuximab β as primary suspected drugs with 90 ADR signals, involving 19 System Organ Classes, of which 21 signals were not in the label; 94 adverse drug event reports concerned naxitamab as the primary suspected drug with 26 ADR signals, involving 11 System Organ Classes, of which one was not in the label. For dinutuximab/dinutuximab β-related ADRs, the top five most frequent were “fever”, “abdominal pain”, “elevated aspartate aminotransferase (AST)”, “elevated alanine aminotransferase (ALT)” and “hypotension”; the top five most intensive signals were “hypoalbuminemia”, “elevated AST”, “capillary leakage syndrome”, “hypoxia” and “elevated ALT”. For naxitamab-related ADRs, the top five most frequent were “hypotension”, “pain”, “urticarial”, “hypertension” and “rash”; the top five most intensive signals were “hypotension”, “urticaria”, “hypoxemia”, “bronchospasm” and “hypertension”. Involved System Organ Classes included “investigations” and “respiratory, thoracic and mediastinal disorders” containing the most types of ADR signals in dinutuximab/dintuximab β-related ADRs and naxitamab-related ADRs, respectively.

Conclusions

Our study comprehensively analyzed the toxicity profiles of anti-GD2 monoclonal antibodies and provides an important reference for clinical monitoring and ADR identification of these drugs.

中文翻译：

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抗 GD2 免疫疗法的毒性谱：利用美国食品和药物管理局不良事件报告系统进行的真实世界研究

背景

抗二唾液酸神经节苷脂（抗GD2）单克隆抗体是治疗神经母细胞瘤的有效免疫治疗药物，但其毒性谱尚不清楚。

客观的

本研究旨在通过挖掘和评估美国食品药品监督管理局不良事件报告系统的药物不良反应（ADR）信号，评估三种抗GD2单克隆抗体（dinutuximab、dinutuximab β和naxitamab）在临床应用中的毒性特征。

方法

检索了美国食品药品监督管理局不良事件报告系统中抗GD2单克隆抗体上市至2023年第一季度的数据。使用英国药品和保健品公司使用的报告比值比、比例报告比、比例报告比和χ ²统计方法的组合等四种算法对抗GD2单克隆抗体相关ADR的信号进行量化监管机构和贝叶斯置信传播神经网络。ADR根据监管活动医学词典按系统器官类别进行分类，并根据ADR的频率和信号强度进行排序。

结果

共查出370份抗GD2单克隆抗体列为“首要疑似药物”的药品不良事件报告，检测到116个ADR信号，其中22个未出现在药品说明书中。药品不良事件报告中，以dinutuximab/dinutuximab β为主要疑似药物的报告有276份，有90个ADR信号，涉及19个系统器官类别，其中21个信号未在说明书中；94份药品不良事件报告涉及纳西他单抗作为主要可疑药物，共有26个ADR信号，涉及11个系统器官类别，其中一个未在标签中。对于dinutuximab/dinutuximab β相关ADR，最常见的前5位是“发烧”、“腹痛”、“天冬氨酸转氨酶（AST）升高”、“丙氨酸转氨酶（ALT）升高”和“低血压”；前五位最强烈的信号是“低白蛋白血症”、“AST升高”、“毛细血管渗漏综合征”、“缺氧”和“ALT升高”。对于纳西他单抗相关的不良反应，最常见的前五位是“低血压”、“疼痛”、“荨麻疹”、“高血压”和“皮疹”；前五位最强烈的信号是“低血压”、“荨麻疹”、“低氧血症”、“支气管痉挛”和“高血压”。涉及的系统器官类别包括“调查”和“呼吸、胸腔和纵隔疾病”，分别包含 Dinutuximab/dintuximab β 相关 ADR 和 naxitamab 相关 ADR 中最多类型的 ADR 信号。

结论

我们的研究全面分析了抗GD2单克隆抗体的毒性特征，为该类药物的临床监测和ADR鉴定提供了重要参考。