Abstract 6014: A new generation of Tumor Microenvironment Activated Therapeutic (T-MATE) targeting solid tumors

Abstract T-cell engagers (TCEs) have emerged as potent immuno-therapies, demonstrating significant success in treating hematologic cancers and showing promising clinical benefits in solid tumors. However, their therapeutic potential is often limited by severe side effects, primarily due to cytokine release syndrome and on-target/off-tumor toxicities. To address these challenges, we leveraged Amberstone’s Tumor-Microenvironment Activated ThErapeutic (T-MATE) technology to develop bispecific and multispecific TCE antibodies with strong potency in diseased tissues, specifically in the acidic tumor microenvironment, while exhibiting minimal activity in healthy tissue under normal physiological conditions. We have discovered and engineered a set of proprietary pH-dependent CD3 antibodies with varying affinities and binding kinetics. Due to the pH-induced conformational change, TCE T-MATEs offer a wide therapeutic index when paired with antibodies targeting several well-studied tumor associated antigens. Here, we demonstrate the potential of the T-MATE platform by targeting clinically validated tumor associated antigens that are widely expressed in healthy tissues, such as TROP2, FOLR1 and EGFR. All T-MATE TCEs were tested in vitro through various cell-based assays, including pH-dependent binding and T-cell-dependent cytotoxicity, and in vivo using xenograft models in humanized NSG mice, across several cancer indications (ovarian, endometrial, colon, gastric, pancreatic, breast, and non-small cell lung cancers). All TROP2, FOLR1 and EGFR-targeting TCEs showed robust pH-selectivity in target binding and exhibited potent T cell-dependent cytotoxicity (EC50 ∼ 1-100 pM) against antigen-expressing tumor cells under acidic tumor conditions, while with minimal activity under physiological conditions. In preclinical xenografted tumor models, these TCE T-MATEs induced significant tumor regression. In Non-Human Primate pharmacology and toxicology studies, TCE T-MATEs exhibited exposure comparable to clinically validated TCEs, with negligible cytokine release and a favorable toxicity profile. These preclinical results confirm that the T-MATE platform offers a superior therapeutic margin, enabling the targeting of widely expressed tumor antigens that were previously considered intractable. Beyond oncology, the T-MATE platform holds promise for a broad range of indications, offering an optimal balance of safety and potency for patients with unmet medical needs. Acknowledgements: Ms. Lingrong Zhang for her vivarium support. Citation Format: Xiaoya Ma, Yang Zhou, Xianzhi Jiang, Juy-Yi Chen, Rodrigo Rivera, Randall Bettman, Thanthar Aye, Ashley Navarro, Daniel Tong, Ricky Cheng, George Wu, Aude Segaliny, Yonglei Shang. A new generation of Tumor Microenvironment Activated Therapeutic (T-MATE) targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6014.