PO.ET02.01 · 实验与分子治疗
位点特异性双载荷抗体偶联增强抗肿瘤疗效
Site-specific dual-payload antibody conjugation enhances antitumor efficacy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
我们开发了一种位点特异性偶联平台，能够在抗体上实现受控的双载荷递送。该抗体经酶促修剪和修饰，以允许两种载荷的顺序生物正交连接。该方法可精确控制载荷类型和DAR数量，实现在较低载荷剂量下改善体内肿瘤抑制的组合。此处我们展示双载荷HER2 ADC作为概念验证。一种基于trastuzumab、携带DM1(DAR 2)和seco-DUBA(DAR 2)的ADC，对JIMT-1异种移植肿瘤(一种已知对T-DM1耐药的模型)表现出强效抑制。此外，一种双载荷MMAE/exatecan ADC(DAR 2+2)实现了与T-DXd(DAR 8)相当的抗肿瘤活性，尽管其使用的总载荷显著更低。这些结果显示了我们双载荷位点特异性偶联策略的多功能性和治疗潜力。该平台为克服耐药性和扩大新一代ADC治疗窗提供了一种方法。
查看英文原文 English abstract
We have developed a site-specific conjugation platform enabling controlled dual-payload delivery on antibodies. The antibody is enzymatically trimmed and modified to allow sequential bioorthogonal attachment of two payloads. This approach permits precise control of payload type and DAR number, enabling combinations that improve in vivo tumor suppression at lower payload doses. Here we present dual-payload HER2 ADCs as a proof-of-concept. A trastuzumab-based ADC carrying DM1 (DAR 2) and seco-DUBA (DAR 2) demonstrated potent inhibition of JIMT-1 xenograft tumors, a model known to be resistant to T-DM1. Additionally, a dual-payload MMAE/exatecan ADC (DAR 2+2) achieved antitumor activity comparable to T-DXd (DAR 8), despite using substantially lower total payload. These results show the versatility and therapeutic potential of our dual-payload site-specific conjugation strategy. The platform provides a method to overcoming drug resistance and expanding therapeutic windows for next-generation ADCs.
利益披露 Disclosure
W. Sun, None..
S. Chuang, None..
S. Tsai, None..
C. Yu, None.