Viral science news: A new preclinical strategy, termed in vivo antibody–ADC click, is reported to overcome resistance and expand the activity of antibody–drug conjugates (ADCs) beyond tumors with robust target expression. The approach uses two engineered components: an antibody carrying a trans-cyclooctene (TCO) handle and an ADC modified with a complementary tetrazine. When both bind near each other on the tumor cell surface, a rapid “click” reaction generates a potent increase in payload delivery.
In HER2-positive settings, the researchers first demonstrated that antibody–ADC click augments trastuzumab uptake and improves responses to T-DXd, an anti-HER2 ADC. They then asked whether the benefit extends to models that are typically nonresponsive to ADC therapy, including HER2-negative pancreatic tumors and HER2-low breast cancer mixed with low HER2 expression.
These low- or negative-target models were characterized using IHC and PET–CT imaging with radiolabeled trastuzumab, revealing only limited tumor uptake (around 9%ID g–1). Consistent with low HER2 engagement, T-DXd or T-DM1 alone produced minimal tumor effects, and combination regimens using panitumumab plus ADC without click chemistry also failed to significantly restrain growth.
By contrast, pairing panitumumab–TCO with T-DXd–tetrazine (enabling click ligation) produced a marked reduction in tumor volume and prolonged survival in mice bearing low/no HER2 tumors. The importance of temporal coordination was highlighted by an experiment in which excess tetrazine was administered 15 minutes before T-DXd–tetrazine delivery, diminishing the therapeutic benefit—supporting a mechanism reliant on proximity-driven ligation at the tumor.
To test whether the antibody’s targeting function is essential, the team used a non-targeted IgG–DM1–tetrazine control. Even when combined with panitumumab–TCO, the non-targeted click did not improve efficacy over saline or ADC-only groups, indicating that productive payload delivery requires antigen-directed tumor engagement rather than click chemistry in circulation.
The study also addresses adaptive resistance. In HER2+EGFRlow NCIN87 tumors treated with T-DXd monotherapy, some mice failed to respond, and PET imaging showed reduced trastuzumab uptake in non-responders. Western blotting revealed a 2.1-fold increase in EGFR protein in nonresponsive tumors compared with responders, aligning with EGFR upregulation as a resistance mechanism. When non-responders were switched to panitumumab–TCO plus T-DXd–tetrazine click therapy, tumor growth slowed in 5 of 9 mice.
Finally, the framework was extended to trastuzumab-resistant BT474 tumors. After stratifying T-DXd responders and non-responders, the resistant subgroup received pertuzumab–TCO plus T-DXd–tetrazine click therapy, achieving tumor suppression in 5 of 6 non-responding mice.
Overall, the researchers present antibody–ADC click as a modular platform to enhance ADC efficacy in tumors with low, heterogeneous, or therapy-adapted target expression—potentially broadening treatment options for refractory cancers.
Subject of Research: Modular in vivo antibody–ADC click to reverse drug resistance in tumours.
Article Title: Modular in vivo antibody–ADC click to reverse drug resistance in tumours.
Article References: Simó, C., Vanover, A.C., D’Oliveira Albanus, R. et al. Modular in vivo antibody–ADC click to reverse drug resistance in tumours. Nature (2026). https://doi.org/10.1038/s41586-026-10789-w
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-026-10789-w
Keywords: antibody–ADC click, TCO–tetrazine ligation, T-DXd, resistance, HER2-low, PET–CT, preclinical oncology
