A novel AI-engineered biparatopic DLL3/CD3 T cell engager demonstrates potent preclinical efficacy and a promising safety profile
Presenter: Liang Tian, PhD Session: Redefining Targeted Therapy: Bispecific T-Cell Engagers and Antibody-Drug Conjugates 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
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
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.
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.
Cited in
Control: 8252 · Presentation Id: 9677 · Meeting 21436