Antibody-Drug Conjugate Efficacy in Neuroblastoma: Role of Payload, Resistance Mechanisms, Target Density, and Antibody Internalization.
Antibody-Drug Conjugate Efficacy in Neuroblastoma: Role of Payload, Resistance Mechanisms, Target Density, and Antibody Internalization.
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DOI：
10.1158/1535-7163.mct-20-1034
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发表时间：
2021-11
影响因子：
5.7
通讯作者：
Bosse KR
中科院分区：
文献类型：
--
作者：
Buongervino S;Lane MV;Garrigan E;Zhelev DV;Dimitrov DS;Bosse KR
抗体药物偶联物（ADC）是一种靶向癌症疗法，利用抗体的特异性选择性地将有效药物递送至肿瘤。在这里，我们通过在不同的神经母细胞瘤细胞系中测试一组全面的 ADC 有效负载，并利用磷脂酰肌醇蛋白聚糖 2 (GPC2) 靶向 D3-GPC2-PBD ADC 来研究目标抗原密度和抗体内化在神经母细胞瘤中 ADC 功效中的作用，从而定义决定 ADC 在神经母细胞瘤中功效的因素之间的复杂相互作用。我们首先发现 DNA 结合药物对神经母细胞瘤的细胞毒性明显高于结合微管蛋白或抑制 DNA 拓扑异构酶 1 的有效负载。我们还表明，ABCB1 药物转运蛋白高表达或含有 TP53 突变的神经母细胞瘤分别对微管蛋白和 DNA/DNA 拓扑异构酶 1 结合有效负载显着更强的抵抗力。接下来，我们利用 GPC2 特异性 D3-GPC2-IgG1 抗体来证明神经母细胞瘤以显着不同的速率内化该抗体/GPC2 复合物，并且这些抗体内化动力学与 GPC2 细胞表面密度显着相关。然而，对吡咯苯并二氮杂卓 (PBD) 二聚体的敏感性主要决定了对相应 D3-GPC2-PBD ADC 的敏感性，总体而言，与 GPC2 细胞表面密度或抗体内化相比，对 ADC 功效的影响更大。最后，我们利用具有不同细胞表面 GPC2 表达水平的 GPC2 同基因 Kelly 神经母细胞瘤细胞来定义 ADC 功效所需的目标密度阈值。综上所述，鉴于 DNA 结合 ADC 有效负载的优越功效，并考虑到 ADC 有效负载敏感性是 ADC 功效的主要决定因素，应优先开发神经母细胞瘤药物。
Antibody–drug conjugates (ADC) are a targeted cancer therapy that utilize the specificity of antibodies to deliver potent drugs selectively to tumors. Here we define the complex interaction among factors that dictate ADC efficacy in neuroblastoma by testing both a comprehensive panel of ADC payloads in a diverse set of neuroblastoma cell lines and utilizing the glypican 2 (GPC2)-targeting D3-GPC2-PBD ADC to study the role of target antigen density and antibody internalization in ADC efficacy in neuroblastoma. We first find that DNA binding drugs are significantly more cytotoxic to neuroblastomas than payloads that bind tubulin or inhibit DNA topoisomerase 1. We additionally show that neuroblastomas with high expression of the ABCB1 drug transporter or that harbor a TP53 mutation are significantly more resistant to tubulin and DNA/DNA topoisomerase 1 binding payloads, respectively. Next, we utilized the GPC2-specific D3-GPC2-IgG1 antibody to show that neuroblastomas internalize this antibody/GPC2 complex at significantly different rates and that these antibody internalization kinetics correlate significantly with GPC2 cell surface density. However, sensitivity to pyrrolobenzodiazepine (PBD) dimers primarily dictated sensitivity to the corresponding D3-GPC2-PBD ADC, overall having a larger influence on ADC efficacy than GPC2 cell surface density or antibody internalization. Finally, we utilized GPC2 isogenic Kelly neuroblastoma cells with different levels of cell surface GPC2 expression to define the threshold of target density required for ADC efficacy. Taken together, DNA binding ADC payloads should be prioritized for development for neuroblastoma given their superior efficacy and considering that ADC payload sensitivity is a major determinant of ADC efficacy.