Porath Kendra A, Regan Michael S, Griffith Jessica I, Jain Sonia, Stopka Sylwia A, Burgenske Danielle M, Bakken Katrina K, Carlson Brett L, Decker Paul A, Vaubel Rachael A, Dragojevic Sonja, Mladek Ann C, Connors Margaret A, Hu Zeng, He Lihong, Kitange Gaspar J, Gupta Shiv K, Feldsien Thomas M, Lefebvre Didier R, Agar Nathalie Y R, Eckel-Passow Jeanette E, Reilly Edward B, Elmquist William F, Sarkaria Jann N
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Neurooncol Adv. 2022 Aug 24;4(1):vdac130. doi: 10.1093/noajnl/vdac130. eCollection 2022 Jan-Dec.
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 and . 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.
表皮生长因子受体（EGFR）靶向抗体药物偶联物（ADC）对EGFR扩增的肿瘤具有高效性，但全身给药时，其在血脑屏障（BBB）中的分布不佳限制了它们在胶质母细胞瘤（GBM）中的疗效。我们研究了对流增强递送（CED）是否可用于将ADC安全输注到EGFRvIII突变型GBM的原位患者来源异种移植（PDX）模型中。
评估了EGFR靶向ADC药物地帕妥昔单抗莫福汀（Depatux-M）和塞鲁他单抗他利林（Ser-T）的疗效。在无肿瘤和荷瘤小鼠中进行了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的剂量探索研究确定，单次输注2μg Ser-T和60μg Depatux-M是安全有效的，可延长生存期（分别超过300天和95天）。然而，每21天进行连续输注时，四个Ser-T剂量可控制肿瘤生长，但在最后一次输注后约7天与致命毒性相关。在GBM108中将给药次数限制为两次可使中位生存期显著延长超过200天。相比之下，四个Depatux-M CED剂量耐受性良好，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+细胞大量损失，胶质纤维酸性蛋白（GFAP）染色显著升高，而Depatux-M仅与GFAP染色适度升高相关。
Depatux-M的CED耐受性良好，并可延长原位GBM PDX模型的生存期。相比之下，Ser-T的CED治疗窗口要窄得多。
