类器官加速ADC大分子新药研发

12.13 2023

类器官加速ADC大分子新药研发

类器官加速ADC大分子新药研发

Antibody-exatecan conjugates with a novel self-immolative moiety overcome resistance in colon and lung cancer

Cancer Discov. 2023 Apr 3;13(4):950-973. doi: 10.1158/2159-8290.CD-22-1368.

Antibody-drug conjugates (ADCs) using DNA Topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent Topoisomerase I inhibitor with less sensitivity to multidrug (MDR) resistance. Characterized by enhanced therapeutic indices, higher stability and improved intra-tumoral pharmacodynamic response, antibody-T moietyexatecan conjugates targeting HER2, HER3, TROP2 overcome intrinsic or treatmentresistance of equivalent DXd/SN-38 ADCs in low-target expression, large-size and MDR+ tumors. T moiety-exatecan ADCs display durable antitumor activity in PDX and organoid models representative of unmet clinical needs including EGFR-del19/T790M/C797S triple mutation lung cancer and BRAF/KRAS–TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti-PD-1 treatment. High tolerability of T moiety-exatecan ADC class in non-human primate supports its potential to expand responding patient population and tumor types beyond current ADCs.

这项研究中设计了一种ADC类药物(MTX-1000),通过一种新型的自裂解T部分,用于exatecan的无踪偶联和释放,以此克服ADC药物在结直肠癌和肺癌中的耐药性。这一发现有望在提高ADC效力,克服肿瘤耐药性的同时,不增加药物毒副作用,为目前ADC治疗选择尚未触达的患者造福。

该药物靶向HER2、HER3、TROP2,克服了ADC药物DXd/SN-38在靶点蛋白表达水平低,肿瘤体积大和MDR+肿瘤中的耐药性,具有治疗指标增强、稳定性提高和肿瘤内药效反应改善等特点。药物在PDX和类器官模型中表现出持久的抗肿瘤活性,包括EGFR-del19/T790M/C797S三突变肺癌和BRAF/ KRAS-TP53双突变结肠癌,并显示出与PARP/ATR抑制剂和抗PD -1治疗的协同作用。该研究表明T moiet -exatecan ADC类药物在非人灵长类动物中具有高耐受性,可能克服耐药机制,在更多的患者群体和更广泛的肿瘤中获得响应。


原文链接:https://doi.org/10.1158/2159-8290.CD-22-1368


上一篇:Advanced Science | 结直肠癌肝转移患者来源的类器官模型助力临床肿瘤精准治疗 下一篇:SCIENCE TRANSLATIONAL MEDICINE|肝癌类器官模型库实现药物精准筛查
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