China's National Medical Products Administration (NMPA) has cleared an investigational new drug application for ADG138, a HER2×CD3 bispecific T-cell engager developed by Adagene Inc. (Nasdaq: ADAG), allowing the San Diego and Suzhou-based company to initiate a first-in-human Phase I study in patients with advanced solid tumors in China. The trial is expected to begin in Q4 2026.
ADG138 applies Adagene's SAFEbody precision masking technology to both binding arms of the molecule — simultaneously masking the HER2-targeting domain and the CD3-engaging domain. In its inactivated state, the molecule is designed to minimally bind either target; proteolytic cleavage within the tumor microenvironment unmasks both sites, redirecting cytotoxic T cells to HER2-expressing tumor cells while the company says limiting off-target activity in healthy tissue. The dual-masking approach may differentiate ADG138 from conventional HER2×CD3 bispecific T-cell engagers, which carry unmasked CD3-binding domains that can trigger systemic cytokine release at lower doses.
Preclinical data presented at the American Association for Cancer Research (AACR) Annual Meeting in 2022 showed approximately 220-fold and greater than 1,000-fold reductions in HER2 and CD3 binding, respectively, in the masked state, while retaining T cell-mediated tumor cell killing. Adagene reported that ADG138 drove regression in HER2-high and HER2-low tumor models, including models described as refractory or resistant to trastuzumab deruxtecan (Enhertu), and was tolerated at doses more than 300-fold higher than an unmasked comparator T-cell engager, with reduced cytokine release and a longer apparent half-life. The company attributed these findings to the dual-masking configuration.
The planned Phase I study is open-label and designed to evaluate safety and preliminary efficacy in advanced solid tumors, with determination of a recommended Phase II dose as a secondary objective.