Background Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods PubMed and ClinicalTrials.gov were searched for ADCs that are or were evaluated in clinical trials. Gene expression profiles of 18 055 patient-derived tumour samples representing 60 tumour (sub)types and 3520 healthy tissue samples were collected from the public domain. Next, we applied Functional Genomic mRNA-profiling to predict per tumour type the overexpression rate at the protein level of ADC targets with healthy tissue samples as a reference. Results We identified 87 ADCs directed against 59 unique targets. A predicted overexpression rate of ≥ 10% of samples for multiple ADC targets was observed for high-incidence tumour types like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumour types we observed, amongst others, a predicted overexpression rate of 55% of samples for CD22 and 55% for ENPP3 in adrenocortical carcinomas, 81% for CD74 and 81% for FGFR3 in osteosarcomas, and 95% for c-MET in uveal melanomas. Conclusion This study provides a data-driven prioritization of clinically available ADCs directed against 59 unique targets across 60 tumour (sub)types. This comprehensive ADC target landscape can guide clinicians and drug developers which ADC is of potential interest for further evaluation in which tumour (sub)type.

中文翻译：

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抗体-药物偶联物靶向范围广泛的肿瘤类型。

背景 抗体-药物偶联物 (ADC) 由一种针对细胞膜上特定靶标设计的抗体与细胞毒剂连接而成，是一类新兴的治疗剂。由于 ADC 肿瘤细胞靶点不一定是肿瘤生长的驱动因素，因此 ADC 可能与目前缺乏明确致癌驱动因素的广泛肿瘤相关。因此，我们的目标是在广泛的肿瘤中定义 ADC 目标的前景。材料和方法 PubMed 和 ClinicalTrials.gov 搜索了正在或正在临床试验中评估的 ADC。从公共领域收集了代表 60 种肿瘤（亚）类型的 18 055 个患者来源的肿瘤样本和 3520 个健康组织样本的基因表达谱。下一个，我们应用功能基因组 mRNA 分析来预测每种肿瘤类型在以健康组织样本为参考的 ADC 靶蛋白水平的过表达率。结果 我们确定了针对 59 个独特目标的 87 个 ADC。对于高发病率肿瘤类型，如乳腺癌（n = 31，三阴性乳腺癌中 n = 23）、结直肠癌（n = 18）、肺腺癌，观察到多个 ADC 靶标的预测样本过表达率≥ 10% (n = 18)、鳞状细胞肺癌 (n = 16) 和前列腺癌 (n = 5)。在罕见的肿瘤类型中，我们观察到，在肾上腺皮质癌中 CD22 和 ENPP3 的预测过表达率为 55%，在骨肉瘤中 CD74 为 81%，FGFR3 为 81%，c-MET 为 95%。葡萄膜黑色素瘤。结论 本研究提供了针对 60 种肿瘤（亚）类型的 59 个独特靶点的临床可用 ADC 的数据驱动优先级。这种全面的 ADC 目标环境可以指导临床医生和药物开发人员哪些 ADC 可能对进一步评估哪种肿瘤（亚）类型感兴趣。