Abstract P4-01-32: BAT8008, a novel Trop-2 ADC with strong bystander effect, for the treatment of Trop-2 positive cancer

Abstract

Abstract Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Elevated expression of TROP-2 is often associated with tumor invasion/aggression, progression, and metastasis. Efficacy of anti-TROP2 ADC have been demonstrated in clinical trials for both TNBC (triple negative breast cancer) and HR+/HER2- breast cancer. We have developed a novel Trop-2 ADC with strong bystander killing effect, BAT8008, which consists of an enzymatically cleavable linker and a topoisomerase I inhibitor as the payload, with DAR of 6. BAT8008 demonstrated potent in vitro cell growth inhibitory activity to Trop2-positive cells with IC50 values of < 1 nM. In an in vitro bystander killing assay, proliferation of Trop-2-negative cells was potently inhibited by addition/transfer of culture medium of BAT8008-treated Trop-2-positive cells, but not that of BAT8008-treated Trop-2-negative cells, indicating the bystander killing effect of the released payload in the culture medium. Less than 0.1% of the payload was released from BAT8008 when incubated with human or monkey plasma for 7 days in 37°C, suggesting the stability of BAT8008 in blood circulation. Single dose of BAT8008 at 1 and 2.5 mg/kg could inhibit 73% and 81% tumor growth in the Trop-2-positive MDA-MB-468 and MX-1 xenograft mice model, respectively. BAT8008 also demonstrated superior tumor inhibition activity than a modified ADC using Daiichi’s ADC technology or Trodelvy in a pancreatic BxPC-3 xenograft mice model. In addition, BAT8008 showed favorable pharmacokinetic and safety profiles in cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of at least 25 mg/kg when dosed once every two weeks for 3 times. Together these results indicate that BAT8008 could potentially provide a therapeutic benefit to treat TROP2-positive breast cancers in clinical trial. Citation Format: Xingxing Mei, Weijia Tang, Xin Zhou, Xuekang Qi, Siqi Mai, Zhi Zhong, Shuoxu Li, Jianjun Fan, Jirong Gan, Binghua Tan, Yao Qi, Yanling Guo, Jin-Chen Yu, Shengfeng Li. BAT8008, a novel Trop-2 ADC with strong bystander effect, for the treatment of Trop-2 positive cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-32.