Abstract 4414: A bispecific antibody-drug conjugate targeting protein tyrosine kinase 7 and fibroblast activation protein alpha simultaneously acts on tumor cells and the tumor microenvironment

Abstract Bispecific antibody-drug conjugates (Bs-ADCs) represent a significant advancement over traditional ADCs by addressing key limitations, including tumor selectivity, on-target/off-tumor toxicity, tumor heterogeneity, antigen escape, inefficient internalization, and low payload delivery efficiency. By simultaneously targeting tumor cells and cancer-associated fibroblasts (CAFs), Bs-ADCs not only enrich drug concentration at the tumor site but also disrupt the tumor's supportive stroma, thereby improving drug penetration. We have developed a Bs-ADC, HB0085, which targets tumor cells through protein tyrosine kinase 7 (PTK7) and CAFs through fibroblast activation protein (FAP), delivering a topoisomerase I inhibitor (TOP1i) payload to tumor. HB0085 has demonstrated potent antitumor activities both in vitro and in vivo. In multiple patient-derived xenograft (PDX) experiments, HB0085 achieved a tumor growth inhibition (TGI) rate greater than 70% in 42.9% (3/7) of lung cancer models and 83.3% (5/6) of pancreatic cancer models. Notably, HB0085 exhibited superior efficacy compared to combination therapy with individual monospecific ADCs targeting PTK7 and FAP in PDX models. Furthermore, when combined with the bispecific antibody HB0025 (targeting PD-L1/VEGF), the antitumor activity of HB0085 was significantly enhanced. These results position HB0085 as a promising therapeutic candidate for a range of solid tumors. Citation Format: Yifan Zhan, Shi Chen, Jingen Xu, Xiaofang Chen, Changping Zheng, Xianfei Pan, Shaojie Wang, Simin Xia, Haijia Yu, Yujie Feng, Guoyuan Peng, Huifeng Jia, Xiaopei Cui, Xiangyang Zhu. A bispecific antibody-drug conjugate targeting protein tyrosine kinase 7 and fibroblast activation protein alpha simultaneously acts on tumor cells and the tumor microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4414.