PO.IM01.13 · 免疫学
一种靶向5T4和MUC1的新型双特异性抗体-药物偶联物BCG016展现出强劲的临床前抗肿瘤活性
A novel bispecific antibody-drug conjugate, BCG016, that targets 5T4 and MUC1, demonstrates robust preclinical antitumor activity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：滋养层糖蛋白（5T4）在多种癌症中显著过表达，包括乳腺癌、肺癌、卵巢癌、子宫内膜癌、膀胱癌、胰腺癌、食管癌和结直肠癌，而在正常组织中表达极少。其在癌症干细胞中的存在与不良预后相关，可能促进转移、耐药和复发。MUC1是跨膜黏蛋白家族中一种高度糖基化的成员，也在一系列实体瘤中过表达。癌症中MUC1表达和糖基化的异常可激活多条驱动肿瘤迁移、侵袭和加速生长的通路。重要的是，5T4和MUC1在多种实体瘤中常常共表达，如肺癌、乳腺癌、卵巢癌、结直肠癌和胰腺癌。
结果：在我们的研究中，我们使用全人源共同轻链RenLite小鼠生成并评价了靶向5T4和MUC1的抗体。5T4亲本抗体在体内表现出比基准更强且特异性的结合以及更高的疗效。我们此前生成了MUC1-C亲本抗体，其被鉴定为靶向癌细胞上膜结合型MUC1。抗5T4×MUC1 bsAb对具有不同5T4和MUC1表达水平的肿瘤细胞表现出良好结合，在5T4和MUC1均高表达的情况下观察到结合增强。该bsAb在5T4/MUC1共表达细胞系中表现出高效内化活性，表现与基准抗体相当或更优。值得注意的是，抗5T4×MUC1-vcMMAE相比亲本ADC表现出改善的疗效，在患者来源异种移植（PDX）模型中优于基准ADC。BCG016与TOP1抑制剂连接子-载荷（BLD1102）联用时，相比亲本ADC在PDX模型中表现出增强的疗效，显著优于靶向5T4和MUC1的基准ADC。
结论：总之，我们开发了一种同时靶向5T4和膜结合型MUC1-C的新型双特异性ADC。BCG016在PDX模型中表现出卓越的抗肿瘤疗效，凸显了其作为5T4和MUC1共表达肿瘤新型治疗选择的潜力。
查看英文原文 English abstract
Background Trophoblast glycoprotein (5T4) is significantly overexpressed in a variety of cancers, including breast, lung, ovarian, endometrial, bladder, pancreatic, esophageal, and colorectal cancers, while demonstrating minimal expression in normal tissues. Its presence in cancer stem cells is correlated with poor prognoses, possibly contributing to metastasis, resistance, and recurrence. MUC1, a highly glycosylated member of the transmembrane mucin family, is also overexpressed across a range of solid cancers. Abnormalities in MUC1 expression and glycosylation in cancer activate multiple pathways that drive tumor migration, invasion, and accelerated growth. Importantly, 5T4 and MUC1 are frequently co-expressed in various solid tumors, such as lung, breast, ovarian, colorectal, and pancreatic cancers.
Results In our study, we generated and evaluated antibodies targeting 5T4 and MUC1 using fully human common light chain RenLite mice. The 5T4 parental antibody demonstrated stronger and specific binding and greater efficacy than the benchmark in vivo. We previously generated the MUC1-C parental antibody, which was identified as targeting membrane-bound MUC1 on cancer cells. The anti-5T4×MUC1 bsAb demonstrated good binding to tumor cells with varying levels of 5T4 and MUC1 expression, with enhanced binding observed in cases of high expression of both 5T4 and MUC1. The bsAb demonstrated efficient internalization activity in the 5T4/MUC1 co-expression cell line, performing either as well as or better than benchmark antibodies. Notably, the anti-5T4×MUC1-vcMMAE demonstrated improved efficacy compared to parental ADCs, outperforming benchmark ADCs in patient-derived xenograft (PDX) models. BCG016, in combination with a TOP1 inhibitor linker-payload (BLD1102), exhibited enhanced efficacy in PDX models compared to parental ADCs, significantly outperforming benchmark ADCs targeting 5T4 and MUC1.
Conclusion In summary, we have developed a novel bispecific ADC that targets both 5T4 and the membrane-bound MUC1-C. BCG016 showed superior anti-tumor efficacy in PDX models, underscoring its potential as a new therapeutic option for tumors that co-express 5T4 and MUC1.
利益披露 Disclosure
Z. Zeng, None..
Y. Xu, None..
C. Shang, None..
Y. Yang, None.