PO.IM01.13 · 免疫学
一种靶向CEACAM5和CDH17的新型双特异性抗体-药物偶联物展现出强效抗肿瘤活性和增强的肿瘤选择性
A novel bispecific antibody-drug conjugate targeting CEACAM5 and CDH17 exhibits potent anti-tumor activity and enhanced tumor-selectivity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
CEACAM5和CDH17在胃肠道肿瘤中优先表达，包括超过95%的结直肠癌、80%的胃癌和胰腺癌以及70%的胆管癌。此外，这两种分子在胃肠道癌症中常常共表达。CEACAM5和CDH17研究的最新进展揭示了它们作为开发新型癌症治疗药物有前景靶点的潜力。在此，我们构建了一种能够同时结合CEACAM5和CDH17的双特异性抗体（bsAb）。使用多种结直肠癌和胰腺癌细胞系，将该bsAb的细胞结合和内化活性与一组单克隆抗体进行比较，包括M9140类似物（一种抗CEACAM5单克隆抗体）和TORL-3-600类似物（一种抗CDH17单克隆抗体）。该bsAb与多种拓扑异构酶I抑制剂载荷偶联，以生成多个双特异性ADC分子（bsADC）。在体外肿瘤细胞杀伤试验及体内多种胃肠道恶性肿瘤CDX模型中研究了这些bsADC的活性。我们进一步考察了bsADC在人和食蟹猴血浆中三周期间的稳定性、其药代动力学特征以及在SD大鼠和食蟹猴中的耐受性。结果表明，该bsAb表现出优异的可开发性，且所得bsADC在与不同连接子-载荷偶联后保持高纯度。先导bsADC候选物表现出卓越的旁观者杀伤活性。在CEACAM5/CDH17表达水平各异的胃肠道癌CDX模型中，其肿瘤抑制作用与M9140a和TORL-3-600a相当或更优，提示其在胃肠道癌患者中具有广泛应用前景。此外，该候选物在人/食蟹猴血浆中表现出良好稳定性，并在SD大鼠和食蟹猴中表现出良好的药代动力学特征和耐受性。综上所述，这些数据支持该bsADC用于胃肠道癌治疗的进一步开发和广泛应用。
查看英文原文 English abstract
CEACAM5 and CDH17 are preferentially expressed in gastrointestinal tumors, including more than 95% of colorectal cancers, 80% of gastric and pancreatic cancers, and 70% of cholangiocarcinomas. Moreover, these two molecules are frequently co-expressed in gastrointestinal cancers. Recent advancements in CEACAM5 and CDH17 research have unveiled their potential as the promising targets for developing novel cancer therapeutics. Here we engineered a bispecific antibody (bsAb) capable of simultaneously binding to both CEACAM5 and CDH17. The cell binding and internalization activities of the bsAb were compared to a panel of monoclonal antibodies, including M9140 analog (an anti-CEACAM5 monoclonal antibody) and TORL-3-600 analog (an anti-CDH17 monoclonal antibody), using multiple colorectal and pancreatic cancer cell lines, The bsAb was conjugated to various topoisomerase I inhibitor payloads to generate several bispecific ADC molecules (bsADCs). The activity of these bsADC was studied in vitro in tumor cell-killing assay, and in vivo in multiple CDX models of GI malignancies. We further investigated the bsADC stability in human and cynomolgus monkey plasma over a three-week period, its pharmacokinetic profile and tolerability in both SD rats and cynomolgus monkeys. The results demonstrated that the bsAb exhibits excellent developability, and the resulting bsADCs maintained high purity after conjugation with different linker-payloads. The lead bsADC candidate showed superior bystander killing activity. In GI cancer CDX models with varying CEACAM5/CDH17 expression levels, it showed tumor inhibition comparable or superior to M9140a and TORL-3-600a, suggesting a broad application in GI cancer patients. Furthermore, the candidate exhibited favorable stability in human/cynomolgus plasma and good pharmacokinetic profile and tolerability in SD rats and cynomolgus monkeys. Taken together, these data support further development and broad utility of this bsADC for GI cancer treatment.
利益披露 Disclosure
J. Hou, None..
T. Gu, None..
L. Dong, None..
J. Tian, None..
X. Chen, None..
D. Liu, None..
Y. Shang, None..
R. Yan, None..
K. Ye, None..
L. Tian, None..
J. Peng, None..
Z. Zhu, None.