PO.IM01.13 · 免疫学

一种AI引导的双互补位DLL3靶向ADC展现出增强的临床前疗效

An AI-guided biparatopic DLL3-targeting ADC demonstrates enhanced preclinical efficacy

编号 6926 展板 7 时间 4/22 09:00–12:00 区域 Section 6 主讲 Liang Tian, PhD

分会场 Antibody-Drug Conjugates 2

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作者与单位 Authors & Affiliations

Chuan Chen, Yue Wu, Chenpeng Su, Zhaohui Chen, Dandan Liu, Jiyuan Tian, Xiaoqian Chen, Yang He, Yongxin Shang, Rongmei Yan, Liang Tian, Jian Peng, Zhenping Zhu

Earendil Labs, Wilmington, DE

摘要 Abstract

中文摘要

目的本研究旨在开发一种靶向delta样配体3（DLL3）的新型双互补位抗体药物偶联物（ADC），用于小细胞肺癌（SCLC）及其他神经内分泌肿瘤，以解决既往DLL3靶向疗法的局限性。方法利用我们的AI引导抗体开发平台，我们设计了一种具有优化结合和内化特性的双互补位抗DLL3抗体。该抗体与多种连接子-载荷组合进行偶联。使用DLL3表达细胞系评估ADC的体外细胞毒性，使用CDX小鼠模型评估其体内疗效。在转基因小鼠和非人灵长类动物中评估安全性。结果与相应的单克隆抗体相比，双互补位抗体展现出更高的内化效率。该ADC在多种DLL3表达细胞系中表现出强效的细胞毒性，并在CDX模型中实现了显著的肿瘤抑制。毒理学研究揭示其在转基因小鼠和非人灵长类动物中均具有良好的安全性特征。结论这种双互补位ADC代表了一种针对DLL3表达肿瘤的有前景的治疗候选物，与既往方法相比展现出增强的疗效和良好的临床前安全性。

查看英文原文 English abstract

Purpose This study aimed to develop a novel biparatopic antibody-drug conjugate (ADC) targeting delta-like ligand 3 (DLL3) for small cell lung cancer (SCLC) and other neuroendocrine neoplasms, addressing limitations of previous DLL3-targeted therapies. Methods Leveraging our AI-guided antibody development platform, we engineered a biparatopic anti-DLL3 antibody with optimized binding and internalization properties. The antibody was conjugated with various linker-payload combinations. In vitro cytotoxicity of the ADCs were evaluated using DLL3-expressing cell lines and in vivo efficacy were assessed using CDX mice models. Safety was assessed in transgenic mice and non-human primates. Results The biparatopic antibody demonstrated higher internalization efficiency compared to the monoclonal antibody counterparts. The ADC showed potent cytotoxicity across multiple DLL3-expressing cell lines and achieved significant tumor suppression in CDX models. Toxicological studies revealed a favorable safety profile in both transgenic mice and non-human primates. Conclusion This biparatopic ADC represents a promising therapeutic candidate for DLL3-expressing tumors, demonstrating enhanced efficacy and favorable preclinical safety compared to previous approaches.

利益披露 Disclosure

C. Chen, None.. Y. Wu, None.. C. Su, None.. Z. Chen, None.. D. Liu, None.. J. Tian, None.. X. Chen, None.. Y. He, None.. Y. Shang, None.. R. Yan, None.. L. Tian, None.. J. Peng, None.. Z. Zhu, None.

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