PO.ET01.03 · 实验与分子治疗
TRO-02：一种整合 TROCAD™ 和 TROSIG™ 平台的条件激活型 EGFR 靶向 ADC，显示出增强的肿瘤选择性和强效疗效
TRO-02, a conditionally activated EGFR-targeting ADC incorporating TROCAD TM and TROSIG TM platforms, shows enhanced tumor selectivity and potent efficacy
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摘要 Abstract
中文摘要
表皮生长因子受体（EGFR）是多种实体瘤适应症（包括非小细胞肺癌、头颈部鳞状细胞癌和结直肠癌）中经验证的治疗靶点。然而，EGFR 在正常上皮组织（尤其是皮肤）中的表达限制了 EGFR 靶向疗法的治疗窗口，常引起剂量限制性毒性从而损害临床疗效。为克服这一挑战，我们开发了 TRO-02，一种新型条件激活型 EGFR 靶向抗体药物偶联物（ADC），它在肿瘤微环境中选择性激活，而在健康组织中保持屏蔽状态。TRO-02 是一种 DAR8 型 ADC，通过可切割、稳定且亲水的 TROSIG™ 连接子将一种强效拓扑异构酶 I 抑制剂偶联至 panitumumab 而生成。此外，它整合了我们专有的 TROCAD™ 平台，该平台具有双重功能：（1）屏蔽 panitumumab，在被肿瘤相关蛋白酶蛋白水解切割之前防止其与 EGFR 结合；（2）通过靶向膜联蛋白 A1（annexin A1，在肿瘤血管系统上高度表达并促进胞吞转运）引导 ADC 前往肿瘤。这一双重机制使 TRO-02 既能在肿瘤微环境内特异性激活，又能实现选择性的肿瘤递送。在体外，屏蔽状态的 TRO-02 与 EGFR 的结合约比激活的 ADC 弱 100 倍，证实了对靶点结合的有效抑制。去屏蔽的 TRO-02 对表达 EGFR 的肿瘤细胞表现出亚纳摩尔级的细胞毒性，而屏蔽形式显示出显著降低的细胞毒性，视细胞类型不同，其效力比去屏蔽形式低 30 至 100 倍。在 MDA-MB-231 异种移植模型中，单次给药 0.3 和 1 mg/kg 分别实现了 65% 和 98% 的肿瘤生长抑制。大鼠血浆稳定性研究显示出高稳定性，孵育 7 天后仍有 >85% 的完整 ADC 保留。此外，大鼠药代动力学分析显示出良好的 PK 特性（在 4 mg/kg 时 t1/2 = 4.47 天，AUC = 163.52 天·μg/mL，CL = 25.05 mL/天/kg，Vd = 0.08 L/kg），表明高体内稳定性和低清除率。总之，这些发现表明 TRO-02 是一种具有改善治疗指数的条件激活型 EGFR 靶向 ADC，在实现强效抗肿瘤疗效的同时，最大程度地减少了靶向/脱靶肿瘤（on-target/off-tumor）毒性。
查看英文原文 English abstract
Epidermal growth factor receptor (EGFR) represents a validated therapeutic target across multiple solid tumor indications, including non-small cell lung cancer, head and neck squamous cell carcinoma, and colorectal cancer. However, EGFR expression in normal epithelial tissues, particularly skin, has limited the therapeutic window of EGFR-targeted therapies, often causing dose-limiting toxicities that impair clinical efficacy. To overcome this challenge, we developed TRO-02, a novel conditionally activated EGFR-targeting antibody-drug conjugate (ADC) that selectively activates in the tumor microenvironment while remaining masked in healthy tissues. TRO-02 is a DAR8-type ADC generated by conjugating a potent topoisomerase I inhibitor to panitumumab via a cleavable, stable, and hydrophilic TROSIG TM linker. Furthermore, it incorporates our proprietary TROCAD TM platform, which provides dual functions: (1) masking the panitumumab to prevent EGFR binding until proteolytic cleavage by tumor-associated proteases, and (2) guiding the ADC to the tumors by targeting annexin A1, which is highly expressed on tumor vasculature and facilitates transcytosis. This dual mechanism allows TRO-02 achieve both specific activation within the tumor microenvironment and selective tumor delivery. In vitro, the masked TRO-02 exhibited approximately 100-fold weaker binding to EGFR than the activated ADC, confirming effective suppression of target engagement. The unmasked TRO-02 displayed sub-nanomolar cytotoxicity against EGFR-expressing tumor cells, whereas the masked form showed markedly reduced cytotoxicity, with 30- to 100-fold lower potency depending on the cell type compared with the unmasked form. In MDA-MB-231 xenograft model, a single dose of 0.3 and 1 mg/kg achieved 65% and 98 % tumor growth inhibition, respectively. Rat plasma stability studies showed high stability, with >85% of intact ADC remaining after 7 days of incubation. Furthermore, pharmacokinetic analysis in rats demonstrated favorable PK properties (t 1/2 = 4.47 days, AUC = 163.52 day·μg/mL, CL = 25.05 mL/day/kg, Vd = 0.08 L/kg at 4 mg/kg), indicating high in vivo stability and low clearance. Collectively, these findings demonstrate that TRO-02 is a conditionally activated EGFR-targeting ADC with improved therapeutic index, achieving potent antitumor efficacy while minimizing on-target/off-tumor toxicity.
利益披露 Disclosure
Y. Lee, None..
D. Kim, None..
E. Shim, None..
E. Choi, None..
J. Cho, None..
M. Baek, None..
S. Woo, None.