有效负载多样化克服了抵抗,并指导了乳腺癌的序列抗体-药物结合疗法
Dileep Reddy Rampa1, Minji Seo2, Nanae Ogata1
1University of Hawaii Cancer Center honolulu, Hawaii United States.
概括
转移性乳腺癌 (MBC) 的耐药性通常是由于有效载荷机制,而不是目标损失. 切换到具有不同有效载荷的抗体-药物联合体 (ADC),如微管抑制剂,可以克服耐药性并改善治疗策略.
科学领域:
- 在瘤学瘤学.
- 药理学 药理学是指药理学的学科.
- 癌症治疗方法 癌症治疗方法
背景情况:
- 抗体与药物联合体 (ADC) 已经彻底改变了乳腺癌的治疗方法.
- 像T-DXd和SG这样的批准的ADC提供临床益处,但在转移性环境中面临获得的耐药性.
- 在最初的ADC治疗中进展后,没有明确的策略来测序ADCs.
研究的目的:
- 阐明乳腺癌中对ADCs获得的耐药性机制.
- 在转移性环境中评估ADC的合理测序策略.
- 确定克服ADC耐药性的治疗方法.
主要方法:
- 生成的抗T-DXd (TDXd-R) 和抗SG (SG-R) 的乳腺癌细胞系.
- 评估了抗原表达,内化和抵抗通路,包括流出输送器.
- 在体外和体内测试了非拓酶1 (Topo1) 有效载荷的ADC的有效性.
主要成果:
- 阻力主要是由有效载荷特定的因素介导的,例如流量输送器上调,而不是抗原损失.
- 切换到具有不同有效载荷的ADC (例如微管抑制剂) 恢复了抗瘤活性.
- 交叉阻力与共享有效载荷机制有关,而不是目标表达.
结论:
- 序列ADC的有效性受到共享有效载荷机制的限制,特别是基于Topo1的药物.
- 切换到具有非交叉耐药有效载荷的ADC是克服转移性乳腺癌耐药性的可行策略.
- 有效载荷多样化是ADC测序的临床可行的策略.
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