Abstract 348: Development of an anti-TF ADC with a potentially improved therapeutic index

Abstract Tissue factor (TF) plays important roles in the hemostasis process. Through forming complex with factor (F) VII/VIIa, TF helps to initiate the blood coagulation process that protects vital organs from excessive bleeding. Under pathological conditions TF could also be involved in thrombosis. Furthermore, TF has functions beyond hemostasis such as signaling. TF is involved in many aspects of cancer transformation such as aberrant signaling, metastasis, and tumor angiogenesis. TF has been found to overexpress in multiple cancers including cervical, pancreatic, lung, head and neck, and prostate cancers, etc. Therapeutics targeting TF has achieved success with most notably the recent approval of Tisotumab Vedotin against cervical cancer. We report here the early phase development of an anti-TF ADC. Our in-house phage display library was employed to isolate a panel of fully human anti-TF antibodies. They vary in binding epitope and affinity allowing the opportunity to evaluate the optimum combination of both to achieve superior efficacy and safety. We found that the binding epitope plays a significant role in the antibody-mediated internalization, whereas within the same binding bin, antibody affinity and internalization may not have a direct correlation. One such antibody, 1E11, has a similar epitope to Tisotumab. It has a modest binding affinity (KD=68 nM) compared to other internal candidates as well as Tisotumab, yet it displayed similar or superior internalization efficiency and ADC mediated cell killing against multiple TF positive cell lines in vitro. In several CDX in vivo models tested so far, 1E11 based ADC showed comparable or superior activities to Tisotumab carrying the same linker/payload. Significantly, while Tisotumab displayed significant disruption of TF/factor VII interaction, a potential cause for excessive bleeding observed in clinics using Tisotumab Vedotin, 1E11 showed little or no such activities. These highly relevant function and safety features of 1E11-based ADC plus its excellent developability profile suggest that it is a promising candidate for further development into various ADC based therapeutics either used alone or in combination with other therapeutics. Citation Format: Xiaodong Xiao, Zhidi Pan, Zhangyi Song, Haiyang Yin, Hua Jiang, Yueqing Xie, Jianwei Zhu. Development of an anti-TF ADC with a potentially improved therapeutic index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 348.