Purpose: Antibody-drug conjugates (ADCs) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given the molecular heterogeneity of GBM, bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), with similar auristatin toxins, were compared in GBM patient-derived xenografts (PDXs) and normal murine brain following direct infusion by convection enhanced delivery (CED). Methods: EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Non-tumor bearing mice were used to evaluate pharmacokinetics and toxicity of ADCs using LC-MS/MS and immunohistochemistry. Results: CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to >300 days vs 20-49 days with isotype-control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221, with the cell-permeable MMAE, as compared to Depatux-M, with the cell-impermeant MMAF. CED infusion of ABBV-221 into brain or incubation of ABBV-221 with normal brain homogenate resulted in significant release of MMAE, which is consistent with linker instability in the brain microenvironment. Conclusion: EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intra-tumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.

中文翻译：

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胶质母细胞瘤模型中 EGFR 靶向抗体药物缀合物 Losatuxizumab vedotin 和 Depatux-M 的旁观者效应、药代动力学和接头有效负载稳定性

目的：抗体药物偶联物 (ADC) 是对实体癌具有强大疗效的靶向疗法，人们对使用 EGFR 特异性 ADC 来靶向 EGFR 扩增的胶质母细胞瘤 (GBM) 产生了浓厚的兴趣。鉴于 GBM 的分子异质性，ADC 的旁观者活性对于确定治疗效果可能很重要。在这项研究中，比较了两种 EGFR 靶向 ADC，Losatuxizumab vedotin (ABBV-221) 和 Depatuxizumab mafodotin (Depatux-M) 以及类似的 auristatin 毒素，在 GBM 患者来源的异种移植物 (PDX) 和正常小鼠中的活性和毒性。通过对流增强输送（CED）直接输注后的大脑。方法：使用 EGFRviii 扩增和未扩增的 GBM PDX 来确定 ABBV-221 和 Depatux-M 的体外细胞毒性、体内功效和旁观者活性。使用非荷瘤小鼠通过 LC-MS/MS 和免疫组织化学评估 ADC 的药代动力学和毒性。结果：CED 在三种 EGFRviii 扩增的 GBM PDX 模型中改善了 Depatux-M 和 ABBV-221 的颅内疗效（中位生存期：125 至 > 300 天，而同种型对照 AB095 为 20-49 天）。两种 ADC 的体外和体内功效相当。然而，与具有细胞非渗透性 MMAF 的 Depatux-M 相比，在注入 ABBV-221 且具有细胞渗透性 MMAE 的大脑中，神经元毒性和 CD68+ 小胶质细胞/巨噬细胞浸润明显更高。 CED 将 ABBV-221 输注到大脑中或将 ABBV-221 与正常脑匀浆一起孵育会导致 MMAE 显着释放，这与大脑微环境中接头的不稳定性一致。结论：通过 CED 进行肿瘤内递送时，EGFR 靶向 ADC 是 GBM 有前途的治疗选择。然而，必须仔细考虑 ADC 的连接器和有效负载，以最大化治疗窗口。