Neuroblastoma is the most common extracranial solid tumor of childhood and is associated with poor survival in high risk patients. Recently, dinutuximab (DNX) has emerged as an effective immunotherapy to treat patients with high risk neuroblastoma. DNX works through the induction of cell lysis via complement-dependent cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC). However, one third of patients who undergo DNX treatment exhibit tumor relapse and the therapy is dose limited by side effects such as severe pain. To overcome delivery challenges of DNX, including large size and dose limiting side effects, we fabricated a delivery system capable of sustained local delivery of bioactive DNX utilizing silk fibroin. We evaluated the impact of silk properties (MW, crystallinity, and concentration) on release properties and confirmed the bioactivity of the release product. Additionally, we observed that the effectiveness of CDC induction by DNX could be correlated to the GD2 expression level of the target cells, with both the intravenous DNX formulation and the released DNX. Collectively, these data highlights a strategy to overcome delivery challenges and potentially improve therapeutic efficacy in cells expressing heterogenous levels of GD2.

中文翻译：

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使用丝泡沫开发用于 GD2 靶向神经母细胞瘤细胞死亡的 dinutuximab 递送系统

神经母细胞瘤是儿童期最常见的颅外实体瘤，与高危患者的生存率低有关。最近，dinutuximab (DNX) 已成为治疗高危神经母细胞瘤患者的有效免疫疗法。DNX 通过补体依赖性细胞毒性 (CDC) 或抗体依赖性细胞毒性 (ADCC) 诱导细胞裂解起作用。然而，接受 DNX 治疗的患者中有三分之一表现出肿瘤复发，并且治疗剂量受到严重疼痛等副作用的限制。为了克服 DNX 的递送挑战，包括大尺寸和剂量限制的副作用，我们制造了一种能够利用丝素蛋白持续局部递送生物活性 DNX 的递送系统。我们评估了丝绸特性的影响（分子量、结晶度、和浓度）的释放特性，并确认释放产品的生物活性。此外，我们观察到 DNX 诱导 CDC 的有效性可能与靶细胞的 GD2 表达水平相关，包括静脉内 DNX 制剂和释放的 DNX。总的来说，这些数据强调了克服递送挑战并可能提高表达异质 GD2 水平的细胞的治疗效果的策略。