Background Bispecific T cell engagers (TCEs) are designed with dual binding domains to target both cancer cells and T cells, enabling T cells to identify and eliminate cancer cells. However, the expression of most tumor-associated antigens (TAAs) on healthy cells often results in on-target toxicities in healthy tissues. TROP2, a transmembrane glycoprotein, is highly expressed in various devastating solid tumors, making it an attractive target for TCEs. The development of TROP2-specific TCEs is challenging due to its widespread expression in healthy tissues and organs. To address this, we developed the T-MATE® (Tumor Microenvironment Activated Therapeutics) platform, which exploits the acidic conditions of the tumor microenvironment. ABS-101, a novel acidic pH-dependent TCE targeting TROP2 and CD3, is engineered to be conditionally activated over a broad tumor-relevant pH range, while maintaining minimal activity in healthy tissues.

Methods We designed a 2+1 heterodimeric IgG1-based CD3xTROP2 T-MATE®TCE, which comprises one CD3 binding moiety and two TROP2 binding moieties. The binding activities of ABS-101 were evaluated under both physiologically relevant and tumor microenvironment-like conditions. The anti-tumor activities of ABS-101 were assessed through in vitro cell-based assays and in vivo tumor xenograft models using humanized NSG mice, including models of ovarian cancer (SKOV3), gastric cancer (NCI-N87), pancreatic cancer (HPAF-II), triple-negative breast cancers (HCC70, HCC1806), and non-small cell lung cancer (Calu-3). Safety and pharmacokinetic profiles were studied in non-human primates.

Results ABS-101 demonstrated exquisite pH-selectivity in target binding and tumor cell lysis. Under acidic tumor conditions, ABS-101 exhibited potent T cell-dependent cytotoxicity (EC50 ~1s-100s pM) across various type of cancer cell lines expressing low, intermediate, or high levels of TROP2, while showing little activity under physiologically relevant conditions. In preclinical xenografted tumor models, ABS-101 induced significant and robust antitumor activity at sub-mg/kg dose levels. Additionally, ABS-101 displayed excellent developability and was well tolerated in naïve non-human primates with a normal PK profile.

Conclusions Preclinical results indicate that ABS-101 achieves a superior balance of safety and efficacy for solid tumor treatment. The T-MATE® therapeutic platform can be extended to additional TCEs and other modalities, offering a powerful and safe therapeutic approach for solid cancer indications.

Acknowledgements Ms. Linrong Zhang for her vivarium support.