Abstract P6-17-39: BAT8001, a potent anti-HER2 antibody-drug conjugate with a novel stable linker for the treatment of HER2-positive breast cancer

Abstract

Abstract Overexpression of HER2 occurs in approximately 20% of breast cancers and is associated with shortened survival. Trastuzumab emtansine (T-DM1), an anti-HER2 ADC, has shown efficacy in HER2-positive breast cancer patients and was approved by the FDA and EMA for advanced HER2-positive breast cancer. However T-DM1 causes grade 3 and 4 thrombocytopenia in up to 14.5% of patients as its major toxicity. The thrombocytopenia is likely caused by one of T-DM1's catabolites and payload, DM1, indicating T-DM1's linker can be cleaved. Here we adopted a novel noncleavable linker and created an anti-HER2 ADC, BAT8001, which is expected be efficacious in HER2-positive breast cancer and have a better side effect profile relative to T-DM1 due to the stability of BAT8001's noncleavable linker. BAT8001 is internalized in HER2-positive cancer cells. It inhibits proliferation of HER2-positive tumor cells with IC50s of ˜0.1 nM, similar to the potency of T-DM1. BAT8001 also induces apoptosis in HER2-positive cancer cells. In both cell-line and patient-derived mouse xenograft (PDX) models, BAT8001 demonstrates strong inhibition activity on tumor growth. For example, in a cell-line model of breast cancer (BT474), BAT8001 demonstrates potent activity with complete responses in all animals tested at the 15mg/kg dose level. Pharmacokinetics studies in monkey reveals BAT8001 has similar Cmax, AUC, and t1/2 as T-DM1. The major catabolite of BAT8001 is the Cys-linker-payload containing product. No free payload is observed. This compares favorably with T-DM1 where free DM1, T-DM1's payload, is one of the major catabolites. In a multiple dose toxicity study, BAT8001 had a NOAEL of 15 mg/kg versus 10 mg/kg for T-DM1. BAT8001 exhibits similar potency to T-DM1 on inhibiting HER2-positive cell proliferation and tumor growth, yet demonstrates better multiple dose toxicity than T-DM1. The improved toxicity profile of BAT8001 suggests that the novel noncleavable linker utilized in BAT8001 is more stable than the linker utilized in T-DM1. BAT8001 is very efficacious in cell-line xenograft models of breast cancer. The preclinical profile of BAT8001 warrants further development for the treatment of breast cancer and other HER2-positive cancers. Citation Format: Tang W, Deng X, Ou Z, Gan J, Dong Q, Tan B, Lu L, Chen B, Bao C, Li S, Thomas B, Yu J-C. BAT8001, a potent anti-HER2 antibody-drug conjugate with a novel stable linker for the treatment of HER2-positive 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 P6-17-39.