PO.CL06.03 · 临床研究
细胞黏附分子1(CADM1)-GGFG-Exatecan与CADM1-PEG3-VC-Exatecan在骨肉瘤临床前模型中的剂量反应疗效对比
Dose-response efficacy of cell adhesion molecule 1 (CADM1)-GGFG-Exatecan vs CADM1-PEG3-VC-Exatecan in preclinical osteosarcoma models
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摘要 Abstract
中文摘要
背景:骨肉瘤是儿童和青少年中最常见的原发性骨恶性肿瘤。尽管采用多模式治疗,自20世纪80年代以来生存率一直没有改变。靶向CADM1的抗体药物偶联物(ADC)作为靶向治疗显示出前景。本研究比较了两种CADM1靶向ADC制剂——CADM1-GGFG-Exatecan和CADM1-PEG3-VC-Exatecan——在骨肉瘤临床前模型中的剂量反应有效性。两种ADC均与Exatecan(一种强效拓扑异构酶I抑制剂)偶联,但其连接子结构不同(GGFG对比PEG3),这可能影响载荷释放和肿瘤穿透。
方法:我们评估了两种ADC在骨肉瘤细胞系(HOS、OS17、OS31)中的细胞毒性,以确定IC50值。内化研究比较了在相同细胞系中的摄取动力学。体内测试在六个患者来源异种移植(PDX)骨肉瘤模型(OS1、OS2、OS9、OS17、OS31、OS33)中评估了两种ADC,剂量为3 mg/kg和6 mg/kg。Human-IgG1-GGFG-Exatecan、Human-IgG1-PEG3-VC-Exatecan和PBS作为同型对照和载体对照。测量了肿瘤生长抑制和无事件生存期(EFS)。
结果:CADM1-GGFG-Exatecan显示出显著优于CADM1-PEG3-VC-Exatecan的抗肿瘤活性,IC50值更低,在表达CADM1的细胞中内化更高。CADM1-GGFG-Exatecan的内化在第4天达到稳定平台,而CADM1-PEG3-VC-Exatecan的摄取极少。在体内,两种ADC均耐受良好(体重减轻≤10%)。CADM1-GGFG-Exatecan在所有六个PDX模型中均显著延长EFS(P<0.05),在OS1、OS31和OS33中诱导持续完全缓解(MCR),在OS2中诱导部分缓解(PR),在OS9和OS17中为疾病进展(PD)。相比之下,PEG3-VC-Exatecan和所有对照在所有模型中均导致PD。
结论:CADM1-GGFG-Exatecan在体外和体内骨肉瘤模型中均显示出优于CADM1-PEG3-VC-Exatecan的剂量反应疗效。其增强的抗肿瘤活性可能由改善的内化和效力驱动,支持在表达CADM1的骨肉瘤中进一步开发,包括药代动力学的优化和联合策略。
查看英文原文 English abstract
Background: Osteosarcoma is the most common primary bone malignancy in children and young adults. Despite multimodal therapy, survival rates have remained unchanged since the 1980s. Antibody-drug conjugates (ADCs) targeting CADM1 show promise as targeted treatments. This study compares the dose-response effectiveness of two CADM1-targeted ADC formulations, CADM1-GGFG-Exatecan and CADM1-PEG3-VC-Exatecan, in preclinical osteosarcoma models. Both ADCs are conjugated with Exatecan, a potent topoisomerase I inhibitor, but differ in their linker structures (GGFG vs PEG3), which may affect payload release and tumor penetration.
Methods: We assessed the cytotoxicity of both ADCs in osteosarcoma cell lines (HOS, OS17, OS31) to determine IC 50 values. Internalization studies compared uptake kinetics in the same lines. In vivo testing evaluated both ADCs in six patient-derived xenograft (PDX) osteosarcoma models (OS1, OS2, OS9, OS17, OS31, OS33) at doses of 3 mg/kg and 6 mg/kg. Human-IgG1-GGFG-Exatecan, Human-IgG1-PEG3-VC-Exatecan, and PBS served as isotype and vehicle controls. Tumor growth inhibition and event-free survival (EFS) were measured.
Results: CADM1-GGFG-Exatecan showed significantly greater anti-tumor activity than CADM1-PEG3-VC-Exatecan, with lower IC 50 values and higher internalization in CADM1-expressing cells. Internalization of CADM1-GGFG-Exatecan reached a steady plateau by day 4, whereas CADM1-PEG3-VC-Exatecan showed minimal uptake. In vivo, both ADCs were well tolerated (≤10% body weight loss). CADM1-GGFG-Exatecan significantly prolonged EFS across all six PDX models (P < 0.05), inducing maintained complete responses (MCR) in OS1, OS31, and OS33, a partial response (PR) in OS2, and progressive disease (PD) in OS9 and OS17. In contrast, PEG3-VC-Exatecan and all controls resulted in PD in all models.
Conclusion: CADM1-GGFG-Exatecan demonstrates superior dose-response efficacy versus CADM1-PEG3-VC-Exatecan in both in vitro and in vivo osteosarcoma models. Its enhanced anti-tumor activity, likely driven by improved internalization and potency, supports further development in CADM1-expressing osteosarcoma, including optimization of pharmacokinetics and combination strategies.
利益披露 Disclosure
Z. Zhang, None..
C. Longo, None..
W. Zhang, None..
Y. Wang, None..
Y. Yi, None..
Z. Xu, None..
X. Zhou, None..
A. Bahadir, None..
M. Roth, None..
J. Gill, None..
R. Gorlick, None.