Adagene wins NMPA IND clearance for masked HER2xCD3 bispecific ADG138
Adagene has received investigational new drug clearance from China's National Medical Products Administration for ADG138, a HER2xCD3 bispecific T-cell engager built on the company's proprietary SAFEbody precision masking technology. A first-in-human Phase 1 study in patients with advanced solid tumours is now expected to begin in China before the end of 2026.
ADG138 applies Adagene's masking approach to both binding arms of the molecule simultaneously, shielding the HER2-targeting domain and the CD3-engaging domain in circulation. The company says the molecule becomes activated within the tumour microenvironment, where protease activity cleaves the masking peptides and allows selective T-cell recruitment to HER2-expressing cancer cells. This dual-masking design is intended to address one of the central challenges facing T-cell engager programmes in solid tumours: the on-target, off-tumour toxicity and cytokine-release syndrome that have historically limited dosing and therapeutic index.
Preclinical profile and the Enhertu-resistance angle
Preclinical data presented at AACR 2024 showed ADG138 achieving approximately 220-fold and greater than 1,000-fold reductions in HER2 and CD3 binding, respectively, in its masked state. Despite these binding reductions, Adagene says the activated molecule drove tumour regression in both HER2-high and HER2-low models, including a model refractory to AstraZeneca and Daiichi Sankyo's trastuzumab deruxtecan (Enhertu, DS-8201). ADG138 also showed synergistic activity in combination with anti-CTLA-4, anti-PD-1 and anti-CD137 antibodies in preclinical settings.
On tolerability, preclinical data suggested ADG138 was tolerated at doses more than 300-fold higher than an equivalent unmasked T-cell engager, with markedly reduced cytokine release and a longer apparent half-life. These figures are preclinical; clinical translation of tolerability gains for T-cell engagers has historically proved difficult, and investors will be watching the Phase 1 dose-escalation data closely.
Peter Luo, chairman and president of R&D at Adagene, said the NMPA's clearance "speaks to the strength of the preclinical package" and that the company expects ADG138 to demonstrate "a wider therapeutic window relative to an unmasked T-cell engager" in first-in-human studies.
Market context and competitive landscape
The HER2-targeted T-cell engager space is becoming increasingly competitive. Alongside antibody-drug conjugates such as Enhertu, which has reshaped treatment algorithms in HER2-positive breast, gastric and lung cancers, several companies are advancing bispecific T-cell engagers that redirect cytotoxic T cells to HER2-expressing tumours. The challenge of managing systemic toxicity in solid-tumour settings distinguishes this field from the haematological cancers where T-cell engagers, most notably Amgen's blinatumomab, first proved themselves. Conditional-activation approaches, including probody and masking strategies similar to Adagene's SAFEbody, have attracted significant investor interest precisely because they offer a potential route around these tolerability constraints.
Adagene's lead clinical programme, the masked anti-CTLA-4 antibody muzastotug (ADG126), already holds FDA Fast Track designation and is in Phase 1b/2 and Phase 2 studies, providing some platform validation ahead of ADG138's clinical debut. The Phase 1 study of ADG138 will evaluate safety, preliminary efficacy, and the recommended Phase 2 dose in patients with advanced solid tumours. No indication-specific cohorts were named in the announcement.
The NMPA clearance moves ADG138 from preclinical into the clinic at a time when China's regulatory authority has been working to accelerate oncology drug reviews. Whether data generated in a China-only Phase 1 will be sufficient to support a global development programme, or whether Adagene will seek a parallel IND with the FDA, remains to be seen.