PO.ET01.06 · 实验与分子治疗
SCR-A019：一种靶向MSLN的首创双互补位ADC，搭载新型拓扑异构酶I抑制剂，在临床前模型中显示出令人鼓舞的疗效
SCR-A019, a first-in-class biparatopic ADC targeting MSLN, with a novel topoisomerase I inhibitor demonstrates encouraging efficacy in preclinical models
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摘要 Abstract
中文摘要
背景：间皮素（MSLN）是一种GPI锚定糖蛋白，在多种癌症中表达，而在正常组织中表达有限，因此成为基于抗体的癌症治疗的理想靶点。然而，MSLN会通过在其近膜C端区域切割的蛋白酶从细胞表面高水平脱落。脱落的MSLN在患者体液和肿瘤中蓄积，可阻断抗MSLN抗体对癌细胞的杀伤。为克服MSLN脱落带来的挑战，我们开发了一种新型双互补位ADC，其优先结合膜结合型MSLN而非可溶性MSLN。
方法与结果：双互补位ADC SCR-A019通过亲水性可切割连接子偶联新型拓扑异构酶1抑制剂（CPT116），DAR为6。SCR-A019以高亲和力特异性识别人MSLN，在多种肿瘤细胞系中相比亲本单克隆抗体ADC及基准ADC表现出更强的内化和结合能力。体外细胞毒性实验表明SCR-A019可诱导肿瘤细胞裂解。与基准ADC相比，SCR-A019在可溶性MSLN存在下仍能驱动强效细胞毒性。在体内，SCR-A019对MSLN阳性肿瘤异种移植物（包括肺癌和卵巢癌细胞）表现出特异性、剂量依赖性的抗肿瘤疗效。此外，SCR-A019表现出比其亲本单抗ADC或基准ADC更强的抗肿瘤活性。SCR-A019还具有很好的稳定性和良好的可开发性。
结论：这些临床前数据表明，SCR-A019可能成为一种首创双互补位BsADC，以克服基于抗体的MSLN靶向癌症治疗中的障碍。
查看英文原文 English abstract
Background: Mesothelin (MSLN) is a GPI-anchored glycoprotein that is expressed on many cancers but limited in normal tissues, which makes it an attractive target for antibody-based cancer therapy. However, MSLN is shed from surface of cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patient fluids and tumors and can block anti-MSLN antibodies from killing cancer cells. To overcome the challenge of MSLN shedding, we developed a novel biparatopic ADC which prefers binding to membrane MSLN rather than soluble MSLN.
Method & Results: The biparatopic ADC SCR-A019 is conjugated with novel topoisomerase 1 inhibitor (CPT116) via a hydrophilic cleavable linker at DAR 6. SCR-A019 specifically recognizes human MSLN with high affinity and showed enhanced internalization and binding capacity compared to parental monoclonal antibody ADC and benchmark ADC in multiple tumor cell lines. In vitro cytotoxicity experiment demonstrated that SCR-A019 induced tumor cell lysis. Compared to benchmark ADC, SCR-A019 drived potent cytotoxicity in the presence of soluble MSLN. In vivo, SCR-A019 showed specific, dose-dependent anti-tumor efficacy toward MSLN positive tumor xenografts including lung and ovary cancer cells. Besides, SCR-A019 exhibited stronger anti-tumor activity than their parental monoclonal-ADC or benchmark ADC. SCR-A019 also have very good stability and favorable developability.
Conclusion: These preclinical data demonstrated SCR-A019 could be a potential first-in-class biparatopic BsADC to overcome the obstacles in antibody-based MSLN-targeting cancer therapy.
利益披露 Disclosure
Q. Wang, None..
Y. Fu, None..
Q. Deng, None..
C. Xia, None..
H. Zheng, None..
Y. Chu, None..
R. Tang, None.