Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.
Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.
复制标题
DOI：
10.1093/noajnl/vdac130
复制
发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
EGFR靶向抗体-药物偶联物（adc）对EGFR扩增的肿瘤非常有效，但在血脑屏障（BBB）上的不良分布限制了它们在系统给药时对胶质母细胞瘤（GBM）的疗效。我们研究了对流增强输注（CED）是否可以用于安全地将adc输注到EGFRvIII突变GBM的原位患者源异种移植（PDX）模型中。体外和体内评价egfr靶向adc depatuzumab mafodotin （Depatux-M）和Serclutamab talirine （Ser-T）的疗效。在非肿瘤小鼠和荷瘤小鼠中进行CED。免疫染色用于评估ADC分布、药效学效应和正常细胞毒性。原位GBM6的剂量研究发现，单次输注2 μg Ser-T和60 μg Depatux-M安全有效，可延长生存期（分别为300天和95天）。然而，每21天连续输注一次，4次Ser-T剂量控制肿瘤生长，但在最后一次输注后约7天出现致命毒性。限制剂量至两次输注GBM108提供了超过200天的显着中位生存延长。相比之下，四剂Depatux-M CED耐受性良好，并显著延长了GBM6（158天）和GBM108（310天）的生存期。在毒性分析中，Ser-T导致NeuN+细胞的严重损失和GFAP染色显著升高，而Depatux-M仅与GFAP染色轻微升高相关。Depatux-M的CED耐受性良好，可延长原位GBM pdx的生存期。相比之下，Ser-T的CED与更窄的治疗窗口相关。
EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood–brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We studied whether convection-enhanced delivery (CED) can be used to safely infuse ADCs into orthotopic patient-derived xenograft (PDX) models of EGFRvIII mutant GBM. The efficacy of the EGFR-targeted ADCs depatuxizumab mafodotin (Depatux-M) and Serclutamab talirine (Ser-T) was evaluated in vitro and in vivo. CED was performed in nontumor and tumor-bearing mice. Immunostaining was used to evaluate ADC distribution, pharmacodynamic effects, and normal cell toxicity. Dose-finding studies in orthotopic GBM6 identified single infusion of 2 μg Ser-T and 60 μg Depatux-M as safe and effective associated with extended survival prolongation (>300 days and 95 days, respectively). However, with serial infusions every 21 days, four Ser-T doses controlled tumor growth but was associated with lethal toxicity approximately 7 days after the final infusion. Limiting dosing to two infusions in GBM108 provided profound median survival extension of over 200 days. In contrast, four Depatux-M CED doses were well tolerated and significantly extended survival in both GBM6 (158 days) and GBM108 (310 days). In a toxicity analysis, Ser-T resulted in a profound loss in NeuN+ cells and markedly elevated GFAP staining, while Depatux-M was associated only with modest elevation in GFAP staining. CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.