Researchers reported an in vivo “click” method that sequentially links antibodies and antibody-drug conjugates after injection, boosting antitumor activity versus standard ADC monotherapy or simple antibody-plus-ADC combinations in heterogeneous and resistant tumors.
The approach uses TCO and tetrazine tags to join approved HER2 and EGFR-targeting drugs inside the body, improving internalization and extending HER2-directed payload delivery to tumors with low, ultralow or even negative HER2 expression.
In mice, the strategy raised trastuzumab uptake 3.2-fold in HER2-ultralow A431 tumors and produced complete remission in 100% of treated HER2-positive NCIN87 tumors with clicked T-DXd, while 50% of mice responded in an immunocompetent HER2-low model.
The platform also shrank pancreatic and breast tumors that were minimally responsive to T-DXd or T-DM1 alone, and rescued responses in 5 of 9 T-DXd non-responders and 5 of 6 trastuzumab-resistant tumors.
A site-specific version cut liver accumulation about twofold while preserving efficacy, suggesting a more reproducible and potentially translatable platform for overcoming ADC resistance across tumor types.
Could this mix-and-match drug strategy make creating personalized cancer treatments significantly cheaper and faster?
What are the risks if these 'clickable' cancer drugs assemble incorrectly or in the wrong place inside the body?
2026 Nature-Validated Modular ADCs: In Vivo Click Chemistry Revolutionizes Targeted Cancer Treatment
Overview
Traditional Antibody-Drug Conjugates (ADCs) often struggle to fully eliminate tumors because of tumor heterogeneity—meaning tumors contain diverse cell populations, and not all cancer cells display the same target antigen. This leads to incomplete tumor eradication and possible relapse. Additionally, traditional ADCs can cause severe side effects due to non-specific binding to healthy cells and the premature release of toxic drugs into the bloodstream, which limits their safe use. The report highlights how these challenges have driven the development of new modular ADC strategies that aim to improve targeting, reduce side effects, and better address the complexity of cancer.