Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab.
Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab.
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DOI：
10.1136/jitc-2022-005660
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发表时间：
2022-12
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
抗体-药物结合物(ADC)是治疗实体肿瘤和血液病的基本选择。抗表皮生长因子受体(EGFR)抗体西妥昔单抗(CET)用于结直肠癌的治疗。氨基双膦酸唑来膦酸(ZA)可诱导肿瘤细胞产生抗结直肠癌病毒δ-2细胞毒性T淋巴细胞，然后通过BTN家族成员如BTN-3A1和BTN-2A1递呈异戊烯焦磷酸。影响ZA靶向结直肠癌的一个主要缺点是氨基二膦酸盐的趋骨性。在咪唑存在下，ZA的磷酸基团被连接到CET的游离氨基上，然后DNA的磷酸基团被标记到蛋白质的氨基上。基质辅助激光解吸电离质谱仪和电感耦合等离子体质谱分析证实了CET-ZA模数转换器的生成。在Geltrex穹顶中，用化学定义的无血清培养液获得了13个CRC有机化合物。用流式细胞仪、结晶紫、细胞毒探针和图像分析等方法检测V-δ-2T细胞对结直肠癌有机物的增殖和杀伤活性。采用全自动免疫组织化学染色、全切片扫描和计算机数字病理图像分析等方法，对结直肠癌组织中BTN3A1或BTN2A1的表达和肿瘤浸润性V-δ-2T细胞进行免疫组织化学染色和定量。新型ADCcet-ZA的药物抗体比为4.3，具有与未结合抗体相似的反应性。更重要的是，患者来源的结直肠癌有机化合物，或结直肠癌细胞悬液，当用CET-ZA启动时，可以触发来自外周血和肿瘤浸润性淋巴细胞的Vδ2T细胞的扩张。此外，CET-ZA还可触发Vδ2T细胞介导的对结直肠癌有机物的杀伤作用.BTN3A1和BTN2A1不仅在结直肠癌组织中有表达，而且在结直肠癌标本中也有表达，并有大量的肿瘤浸润性V-δ-2T细胞。这些发现证明了CET-ZA ADC可用于靶向特定的CRC有机化合物，并可能建议一种新的实验方法来将氨基二磷酸盐输送到EGFR+的实体瘤中。
Antibody-drug conjugates (ADC) are essential therapeutic options to treat solid and hematological cancers. The anti-epidermal growth factor-receptor (EGFR) antibody cetuximab (Cet) is used for the therapy of colorectal carcinoma (CRC). Anti-CRC Vδ2 cytolytic T lymphocytes can be elicited by the priming of tumor cells with the aminobisphosphonate zoledronic acid (ZA) and consequent presentation of isopentenyl pyrophosphates through butyrophilin (BTN) family members such as BTN3A1 and BTN2A1. A major drawback that impairs the targeting of ZA to CRC is the bone tropism of aminobisphosphonates. The phosphoric group of ZA was linked to free amino groups of Cet in the presence of imidazole following the labeling of phosphoric groups of DNA to amino groups of proteins. The generation of Cet-ZA ADC was confirmed by matrix assisted laser desorption ionization mass spectrometry and inductively coupled plasma-mass spectrometry analysis. Thirteen CRC organoids were obtained with a chemically defined serum-free medium in Geltrex domes. Proliferation and activation of cytolytic activity against CRC organoids by Vδ2 T cells was detected with flow cytometry, crystal violet and cytotoxic probe assays and image analysis. Immunohistochemistry and quantification of BTN3A1 or BTN2A1 expression and the number of tumor infiltrating Vδ2 T cells in CRC were performed by automatic immunostaining, whole slide scanning and computerized analysis of digital pathology imaging. The novel ADC Cet-ZA was generated with a drug antibody ratio of 4.3 and displayed a reactivity similar to the unconjugated antibody. More importantly, patient-derived CRC organoids, or CRC tumor cell suspensions, could trigger the expansion of Vδ2 T cells from peripheral blood and tumor infiltrating lymphocytes when primed with Cet-ZA. Furthermore, Cet-ZA triggered Vδ2 T cell-mediated killing of CRC organoids. The expression of BTN3A1 and BTN2A1 was detected not only in CRC organoids but also in CRC specimens, together with a considerable amount of tumor infiltrating Vδ2 T cells. These findings are proof of concept that the Cet-ZA ADC can be used to target specifically CRC organoids and may suggest a new experimental approach to deliver aminobisphosphonates to EGFR+ solid tumors.
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影响因子：
4.7
作者：
Ghosh, Sournitra S.;Kao, Philip M.;Chappelle, Hugh L.
通讯作者：
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作者：
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通过胆固醇封存增强 EGFR 靶向抗体西妥昔单抗和抗体药物缀合物的肿瘤摄取和治疗功效。
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