Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors.
Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors.
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DOI：
10.1016/j.celrep.2022.110839
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发表时间：
2022-05-24
期刊：
影响因子：
8.8
通讯作者：
Tsuchikama, Kyoji
中科院分区：
文献类型：
--
作者：
Anami, Yasuaki;Otani, Yoshihiro;Xiong, Wei;Ha, Summer Y. Y.;Yamaguchi, Aiko;Rivera-Caraballo, Kimberly A.;Zhang, Ningyan;An, Zhiqiang;Kaur, Balveen;Tsuchikama, Kyoji
多形性胶质母细胞瘤（GBM）是所有脑肿瘤类型中最具侵袭性和致命性的疾病。大多数疗法很少能在 GBM 的治疗中提供具有临床意义的结果。尽管抗体药物偶联物 (ADC) 是有前景的抗癌药物，但目前还没有 ADC 在治疗 GBM 方面获得成功，这主要是因为血脑屏障 (BBB) 渗透性较差。在此，我们报告 ADC 均匀性和有效负载加载率是造成这种差异的关键参数。尽管同质和异质缀合物都表现出相当的体外效力和药代动力学特征，但前者显示出增强的对脑肿瘤的有效负载递送。我们的均质 ADC 可在原位脑肿瘤模型中提供改善的抗肿瘤效果和生存益处。我们还证明，异质缀合物中载药过多的物质穿过血脑屏障的能力特别差，导致整体脑肿瘤靶向性恶化。我们的研究结果表明，均匀结合与最佳有效负载对于生成有效的 ADC 来治疗顽固性脑肿瘤非常重要。大多数疗法很少对多形性胶质母细胞瘤 (GBM) 治疗产生具有临床意义的改善。阿纳米等人。报道称，静脉注射均质抗体药物偶联物 (ADC) 可以有效地将有效负载递送至脑肿瘤，从而显着改善肿瘤生长抑制。他们的研究结果为有效治疗顽固性脑肿瘤（包括 GBM）提供了合理的 ADC 设计。
Glioblastoma multiforme (GBM) is the most aggressive and fatal disease of all brain tumor types. Most therapies rarely provide clinically meaningful outcomes in the treatment of GBM. Although antibody-drug conjugates (ADCs) are promising anticancer drugs, no ADCs have been clinically successful for GBM, primarily because of poor blood-brain barrier (BBB) penetration. Here, we report that ADC homogeneity and payload loading rate are critical parameters contributing to this discrepancy. Although both homogeneous and heterogeneous conjugates exhibit comparable in vitro potency and pharmacokinetic profiles, the former shows enhanced payload delivery to brain tumors. Our homogeneous ADCs provide improved antitumor effects and survival benefits in orthotopic brain tumor models. We also demonstrate that overly drug-loaded species in heterogeneous conjugates are particularly poor at crossing the BBB, leading to deteriorated overall brain tumor targeting. Our findings indicate the importance of homogeneous conjugation with optimal payload loading in generating effective ADCs for intractable brain tumors. Most therapies rarely provide clinically meaningful improvements in glioblastoma multiforme (GBM) treatment. Anami et al. report that intravenous administration of homogeneous antibody-drug conjugates (ADCs) efficiently delivers payloads to brain tumors, leading to substantially improved tumor growth suppression. Their findings provide rational ADC design for effectively treating intractable brain tumors, including GBM.
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