Department of Medical Oncology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310022, China.
Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
Adv Sci (Weinh). 2024 Aug;11(30):e2400203. doi: 10.1002/advs.202400203. Epub 2024 Jun 14.
Therapeutic benefits and underlying biomechanism(s) of antibody drug conjugates (ADC) in combination with other targeted therapeutics are largely unknown. Here, the synergy between ADC and epigenetic drug decitabine (DAC), a clinically approved DNA methylation inhibitor, in multiple preclinical models of melanoma specifically investigated. Mechanistically, the underlying biomechanisms of how DAC cooperatively worked with ICAM1 antibody conjugated DNA topoisomerase I inhibitor DXd (I1-DXd) is elucidated. DAC treatment significantly enhanced anti-tumor efficacy of I1-DXd by upregulating antigen expression, enhancing antibody internalization and potentiating tumor sensitivity by epigenetically reprogramming of melanoma. Meanwhile, I1-DXd/DAC combination also exerted regulatory effects on tumor microenvironment (TME) by enhancing tumor infiltration of innate and adaptive immune cells and improving penetration of ADCs with a boosted antitumor immunity. This study provides a rational ADC combination strategy for solid tumor treatment.
抗体药物偶联物（ADC）与其他靶向治疗联合的治疗益处和潜在的生物力学机制在很大程度上尚不清楚。在这里，专门研究了 ADC 与去甲基化药物地西他滨（DAC）在黑色素瘤的多种临床前模型中的协同作用。从机制上讲，阐明了 DAC 如何与 ICAM1 抗体偶联的 DNA 拓扑异构酶 I 抑制剂 DXd（I1-DXd）合作的潜在生物力学机制。DAC 治疗通过上调抗原表达、增强抗体内化以及通过对黑色素瘤进行表观遗传重编程来增强肿瘤敏感性，从而显著增强了 I1-DXd 的抗肿瘤疗效。同时，I1-DXd/DAC 联合还通过增强固有和适应性免疫细胞对肿瘤的浸润以及通过增强具有增强抗肿瘤免疫力的 ADC 的穿透性，对肿瘤微环境（TME）产生了调节作用。这项研究为实体瘤治疗提供了一种合理的 ADC 联合策略。
