Abstract 4821: Development of a potent Trop-2 antibody-drug conjugate, BAT8003, for the treatment of Trop-2 positive gastric tumors

Abstract

Abstract Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas while having low levels of expression on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. Trop-2 is overexpressed in ~60% of gastric cancer, which causes more than 500,000 mortalities every year in China. We have developed a Trop-2 antibody-drug conjugate (ADC), BAT8003, that utilizes an anti-Trop-2 IgG1 antibody, engineered for site-specific conjugation, a novel uncleavable linker, and a potent maytansine derivative as the payload. Site-specific conjugation allows for a more controllable drug-antibody ratio (DAR), resulting in a more homogenous product. BAT8003 also incorporates increased ADCC effects through afucosylation to further enhance potency. Here we show that BAT8003 is internalized in Trop-2 positive cells. It inhibits proliferation of a number of different Trop2-overexpressed tumor cells with IC50s of ~1 nM. In a gastric cancer (NCI-N87) mouse xenograft model, BAT8003 demonstrates strong inhibition activity on tumor growth at doses of 5 mg/kg and 15 mg/kg. A multiple dose toxicity study in monkey reveals that the highest non-severely toxic dose (HNSTD) of BAT8003 is 20 mg/kg when dose once every 3 weeks. The preclinical profile of BAT8003 warrants further clinical development for the treatment of gastric cancer as well as other Trop-2 over-expressing cancers. Citation Format: Weijia Tang, Xingxing Mei, Ziqiang Ou, Jirong Gan, Shengfeng Li, Jin-Chen Yu. Development of a potent Trop-2 antibody-drug conjugate, BAT8003, for the treatment of Trop-2 positive gastric tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4821.