PO.CL05.12 · 临床研究

一种新型AI工程化的双互补位DLL3/CD3 T细胞衔接器表现出强效的临床前疗效和良好的安全性特征

A novel AI-engineered biparatopic DLL3/CD3 T cell engager demonstrates potent preclinical efficacy and a promising safety profile

编号 5406 展板 19 时间 4/21 09:00–12:00 区域 Section 48 主讲 Liang Tian, PhD

分会场 Redefining Targeted Therapy: Bispecific T-Cell Engagers and Antibody-Drug Conjugates 2

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作者与单位 Authors & Affiliations

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

Earendil Labs, Wilmington, DE

摘要 Abstract

中文摘要

目的：本研究旨在开发并表征一种新型靶向DLL3的双互补位T细胞衔接器（TCE），用于治疗小细胞肺癌（SCLC）及其他神经内分泌癌（NECs）。方法：利用AI工程化的多特异性抗体平台，我们构建了一种双互补位DLL3/CD3 TCE，使其结合DLL3上的两个不同表位，同时衔接T细胞上的CD3。系统性地优化了结合亲和力，以增强肿瘤靶向并最大限度减少非T细胞激活。该分子在体外评估了T细胞依赖性细胞毒性、T细胞激活和细胞因子释放活性，并使用源自人SCLC细胞系的异种移植模型评估了体内疗效。安全性在转基因小鼠和食蟹猴中进行了评估。结果：该双互补位DLL3/CD3 TCE对表达DLL3的细胞系表现出强效且特异的细胞毒性，同时限制了T细胞激活和细胞因子释放。在小鼠模型中，其以低于基准TCE（tarlatamab类似物）的剂量实现了显著的肿瘤生长抑制。该分子在转基因小鼠中剂量高达30 mpk、在猴中剂量达10 mpk（经阶梯给药方式给药）时表现出良好的耐受性，未见显著不良反应。结论：该双互补位DLL3/CD3 TCE表现出强大的临床前疗效和良好的安全性特征，支持其作为针对DLL3阳性SCLC和NECs的靶向免疫疗法进一步开发。

查看英文原文 English abstract

Purpose: This study aimed to develop and characterize a novel biparatopic T-cell engager (TCE) targeting DLL3 for the treatment of small cell lung cancer (SCLC) and other neuroendocrine carcinomas (NECs). Methods: Using an AI-engineered multispecific antibody platform, we engineered a biparatopic DLL3/CD3 TCE to bind two distinct epitopes on DLL3 while engaging CD3 on T cells. Binding affinities were systematically optimized to enhance tumor targeting and minimize off-T cell activation. The molecule was evaluated in vitro activity for T cell-dependent cytotoxicity, T cell activation, and cytokine release and in vivo efficacy using human SCLC cell lines-derived xenograft models. Safety was assessed in transgenic mice and cynomolgus monkeys. Results: The biparatopic DLL3/CD3 TCE demonstrated potent and specific cytotoxicity against DLL3-expressing cell lines, while limiting T cell activation and cytokine release. In murine models, it achieved significant tumor growth inhibition at lower doses than a benchmark TCE (tarlatamab analog). The molecule exhibited good tolerability at doses up to 30 mpk in transgenic mice and 10 mpk (administered via step-dosing) in monkeys, without significant adverse effects. Conclusion: The biparatopic DLL3/CD3 TCE exhibits robust preclinical efficacy and a favorable safety profile, supporting its further development as a targeted immunotherapy for DLL3-positive SCLC and NECs.

利益披露 Disclosure

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

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