Abstract LB261: ProTCE-PSMA, a novel therapeutic PSMA/CD3 prodrug for prostate cancer

作者：Pu Pu, Le Huang, Xiaoning Li, Ting Zhang, Huaixin Dang, Xiaoying Yang, Qiuchen Zheng, Weiyun Wen, Zhendong Xue, Yuchang Mao, Limin Zhang, Ce Wang, Hanxiao Ying, Emily Wu, Jun Feng, Min Hu, Feng He · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-lb261 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Prostate Cancer Treatment and Research、CAR-T cell therapy research

Abstract Over the past decade, T-cell engagers (TCEs) have demonstrated impressive efficacies and reshaped the therapeutic landscape for blood cancers. However, the application of TCEs in solid tumors is still facing hurdles, such as CRS, on-target off-tumor toxicity and immunogenicity. JANX007, a phase Ib stage PSMA/CD3 prodrug, achieved the first clinical PoC of conditionally activated TCE, yet its CRS profile and clinical efficacy were still not satisfying. In order to overcome these limitations, we have established a tumor microenvironment (TME) conditionally activated TCE prodrug platform. And a PSMA/CD3 prodrug (ProTCE-PSMA) was designed with the building blocks including a high affinity VHH antibody for PSMA, a proprietary CD3 binder, a CD3 masking peptide, a cleavable linker, and anti-HSA sdAb for PK switch. The scFv-free format of ProTCE-PSMA provided a smaller steric hindrance from the PSMA side, resulting a higher binding affinity compared with HRP358 (Janx-007 analog synthesized in-house). The CD3 binder exhibits rapid on and off kinetics, while the linker can be cleaved by multiple enzymes enriched in TME with high efficiency and selectivity. These characteristics enabled ProTCE-PSMA to demonstrate superior efficacy in CDX models with various levels of PSMA expression, compared with HRP358. ProTCE-PSMA showed a favorable PK profile in cyno monkeys, with t1/2 of approximately 5 days, while the active form has t1/2 of only 1 day. This favorable PK switch property c...