China's NMPA Clears IND for Adagene's Double-Masked HER2×CD3 T-Cell Engager ADG138
核心洞察
China's NMPA has approved Adagene's IND application for ADG138, a double-masked HER2 (搜索)×CD3 (搜索) bispecific T-cell engager built on the company's SAFEbody precision masking technology.
Adagene plans to begin a first-in-human Phase 1 study of ADG138 in patients with advanced solid tumors (搜索) in China in the fourth quarter of 2026.
Preclinical data showed ADG138 drove tumor regression in HER2 (搜索)-high and HER2-low models, including tumors refractory or resistant to Enhertu (DS-8201).
China's National Medical Products Administration (搜索) (NMPA) has approved Adagene's investigational new drug (IND) application for ADG138, a double-masked HER2 (搜索)×CD3 (搜索) bispecific T-cell engager built on the company's proprietary SAFEbody precision masking technology. Adagene expects to initiate a first-in-human Phase 1 study of ADG138 in patients with advanced solid tumors (搜索) in the fourth quarter of 2026.
"The NMPA's rapid approval of our IND application for ADG138 speaks to the strength of the preclinical package and allows us to bring a differentiated, double-masked T-cell engager into the clinic for patients with HER2 (搜索)-expressing solid tumors," said Peter Luo, Ph.D., Chairman and President of R&D at Adagene.
Masking Both Arms of the Molecule
ADG138 is designed with masking peptides covalently linked to both the HER2 (搜索)- and CD3 (搜索)-binding arms of the molecule. In its inactivated state, the construct is intended to minimally bind HER2-expressing cancer cells and T cells. The molecule becomes activated within the tumor microenvironment, where it engages T cells to selectively kill HER2-expressing tumor cells while limiting off-target toxicity.
Preclinical data presented at the American Association for Cancer Research (AACR) Annual Meeting in 2022 showed that double-masked ADG138 achieved approximately 220-fold and greater than 1,000-fold reductions in binding to HER2 (搜索) and CD3 (搜索), respectively, while retaining high efficiency in T cell-mediated tumor cell killing and T cell activation.
Preclinical Activity in Enhertu-Resistant Models
ADG138 drove regression in both HER2 (搜索)-high and HER2-low tumor models, including a model refractory and/or resistant to Enhertu (DS-8201). The program also showed synergistic anti-tumor activity in combination with anti-CTLA-4 (搜索), anti-PD-1 (搜索), or anti-CD137 (搜索) antibodies.
In preclinical testing, ADG138 was tolerated at doses over 300-fold higher than an unmasked T-cell engager, with markedly reduced cytokine release and a favorable pharmacokinetic profile, including a longer apparent half-life and higher systemic exposure than the parental molecule. Luo said ADG138 achieved potent, T-cell mediated anti-tumor activity in Enhertu-resistant tumor models while retaining a substantial reduction in cytokine release and a wider therapeutic window relative to an unmasked T-cell engager.
Phase 1 Design
The planned Phase 1, first-in-human, open-label study is designed to evaluate the safety and preliminary efficacy of ADG138 in patients with advanced solid tumors (搜索) and to determine the recommended dose for Phase 2.
Platform Context
Adagene's SAFEbody technology is designed to address safety and tolerability challenges associated with many antibody therapeutics by using precision masking to shield the binding domain of the biologic therapy. Activation in the tumor microenvironment allows tumor-specific targeting while minimizing on-target off-tumor toxicity in healthy tissues.
The company's lead clinical program, muzastotug (ADG126), is a masked anti-CTLA-4 (搜索) SAFEbody with FDA Fast Track designation that targets a unique epitope of CTLA-4 in regulatory T cells (Tregs) in the tumor microenvironment. Muzastotug is in Phase 1b/2 and Phase 2 studies in combination with anti-PD-1 (搜索) therapy, with a focus on microsatellite stable (MSS) metastatic colorectal cancer (搜索). According to Adagene, the SAFEbody platform can be applied across antibody-based modalities including Fc empowered antibodies, antibody-drug conjugates, and bi/multi-specific T-cell engagers.