PO.ET09.08 · 实验与分子治疗
针对 CDH17 的双互补位抗体-药物偶联物的设计与开发
Design and development of a biparatopic antibody-drug conjugate against CDH17
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
CDH17 在多种腺癌中过表达，包括结直肠癌、胃癌和胰腺癌。高水平的 CDH17 与这些恶性肿瘤患者的转移性疾病和不良预后相关。在正常组织中，CDH17 的表达有限。目前，多种基于 CDH17 的疗法，包括双特异性抗体、ADC 和 CAR-T，正处于治疗 CRC 的临床研究中。在此，我们描述了一种新型双互补位抗 CDH17 抗体的发现与优化。该双互补位抗体表现出高效的 CDH17 导向细胞结合，并以远高于单表位靶向 ADC 的效率促进快速内化。接下来，我们将该双互补位抗体与多种细胞毒性载荷偶联。这些 ADC 在体外对具有不同 CDH17 表达水平的多种肿瘤细胞系表现出选择性细胞毒性，并在动物模型中强效抑制表达 CDH17 的肿瘤异种移植物的生长。总之，这些发现表明我们的先导双互补位抗 CDH17 ADC 是治疗过表达 CDH17 癌症的一个有前景的候选药物。
查看英文原文 English abstract
CDH17 is overexpressed in various adenocarcinomas, including colorectal, gastric, and pancreatic cancers. High levels of CDH17 are associated with metastatic disease and poor prognosis in patients with these malignancies, In normal tissues, the expression of CDH17 is limited. Currently, various CDH17-based therapeutics, including bispecific antibodies, ADCs, and CAR-T, are under clinical investigation for treating CRC. Here, we describe the discovery and optimization of a novel biparatopic anti-CDH17 antibody. The biparatopic antibody exhibits efficient CDH17-directed cell binding and promotes rapid internalization at a much higher efficiency than the mono-epitope targeting ADCs. Next, we conjugated the biparatopic antibody to various cytotoxic payloads. The ADCs showed selective cytotoxicity towards multiple tumor cell lines with varying levels of CDH17 expression in vitro, and potently inhibited the growth of CDH17-expressing tumor xenografts in animal models. Together, these findings indicate that our lead biparatopic anti-CDH17 ADC is a promising candidate for the treatment of cancers that overexpress CDH17.
利益披露 Disclosure
J. Hou, None..
L. Dong, None..
T. Gu, None..
J. Tian, None..
D. Liu, None..
Y. Shang, None..
R. Yan, None..
L. Pan, None..
L. Tian, None..
J. Peng, None..
Z. Zhu, None.