Abstract P6-20-16: BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer

Abstract

Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. These two characteristics make Trop-2 a potential drug target. An antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, has recently been demonstrated to be effective in treating triple negative breast cancer (TNBC) and gastric cancer patients. Here we present a Trop-2 ADC, BAT8003, which contains an uncleavable linker and a maytansine derivative as the payload. An A114C mutation on antibody heavy chain was introduced to BAT8003 for site-specific conjugation, in order to generate a more homogeneous product for a better pharmacokinetics profile. BAT8003 is also completely devoid of fucose modification, to allow for enhanced ADCC effect. We show that BAT8003 is effectively internalized upon binding to Trop-2, and inhibits proliferation of Trop2-overexpressed tumor cells with IC50s of ˜1 nM. In a TNBC (MDA-MB-468 cell) mouse xenograft model, BAT8003 strongly inhibits tumor growth at a dose level as low as 5 mg/kg. BAT8003 also demonstrates potent activity in another TNBC (MX-1 cell) mouse tumor model, in which it shows the same inhibition activity as the naked antibody conjugated heterogeneously with almost two fold payload (DAR 3.5), suggesting the effect caused by site-specific conjugation. We are currently developing BAT8003 for clinical evaluation in TNBC and other cancer indications. Citation Format: Tang W, Huang X, Ou Z, Yan H, Gan J, Dong Q, Tan B, Yang Y, Guo Y, Li S, Thomas B, Yu J-C. BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-16.