Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma
Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma
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DOI：
10.1093/neuonc/noab133
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发表时间：
2021-05-29
期刊：
影响因子：
15.9
通讯作者：
Sarkaria, Jann N.
中科院分区：
文献类型：
--
作者：
Marin, Bianca-Maria;Porath, Kendra A.;Sarkaria, Jann N.
背景资料。针对表皮生长因子受体(EGFR)的抗体药物结合物(ADCs)，如Depatuxizumab mafodotin(Depatuxizumab mafodotin，Depatuxizumab mafodo了解这一有希望的策略失败的机制至关重要。采用PDX模型研究Depatux-M全身给药与颅内给药的疗效。用免疫荧光和MALDI-MSI检测脑内药物浓度。应用定量流式细胞术、Western blots、RNAseq、FISH和磷酸化蛋白质组学方法研究EGFR水平和代偿途径。在10个EGFR扩增的异位PDX中，9个系统给予Depatux-M是高效的，8个PDX的生存时间超过一年。两个PDX(GBM12和GBM46)的获得性耐药性是由抑制EGFR表达或出现缺乏Depatux-M抗体表位的新的EGFR短变异体引起的。与在异位肿瘤中观察到的深刻益处相反，七种内在敏感的PDX中只有两种对Depatux-M作为颅内肿瘤有效。Depatux-M在肿瘤组织中的分布有限且不均匀，人工阻断血脑屏障或直接向肿瘤内注射Depatux-M搭桥血脑屏障可显著提高药物治疗的疗效。尽管对Depatux-M具有深刻的内在敏感性，但有限的脑肿瘤药物输送可能是最近失败的临床试验中缺乏疗效的关键因素。
Background. Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important.Methods. PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics.Results. Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment.Conclusions. Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.