'Click' chemistry assembles cancer drug conjugates in the body, bypassing tumour resistance
Scientists have developed a "modular" strategy that assembles cancer-fighting antibody–drug conjugates inside the body, a step they say could overcome the drug resistance that leaves many tumour patients ineligible for existing therapies. The approach, detailed in Nature, uses a rapid in vivo chemical reaction to build the conjugates from separately administered antibody components, rather than relying on a single pre-made molecule. (Nature: https://www.nature.com/articles/s41586-026-10789-w)
By Source Reporters Newsdesk
Sat, 18 July 2026 · 2 min read
Scientists have developed a "modular" strategy that assembles cancer-fighting antibody–drug conjugates inside the body, a step they say could overcome the drug resistance that leaves many tumour patients ineligible for existing therapies. The approach, detailed in Nature, uses a rapid in vivo chemical reaction to build the conjugates from separately administered antibody components, rather than relying on a single pre-made molecule. (Nature: https://www.nature.com/articles/s41586-026-10789-w)
About a dozen antibody–drug conjugates (ADCs) approved by the US Food and Drug Administration have shown clinical success, but their effectiveness depends on tumours displaying high, uniform levels of a target protein and on the cell efficiently absorbing the drug. Tumour heterogeneity, compensatory signalling and loss of the target antigen drive resistance, leaving many patients refractory or ineligible, the authors write.
The team's method, which they call "antibody–ADC click," uses bioorthogonal click chemistry — a selective reaction between trans-cyclooctene (TCO) and tetrazine — to link antibody components in vivo after they are given sequentially. Using the clinically validated targets HER2 and EGFR, they showed the technique could deliver HER2-directed ADCs such as trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) into cancer cells across the full range of HER2 expression, including EGFR-high or EGFR-low tumours that conventional ADCs struggle to treat.
In mouse models, the click-assembled conjugates increased tumour uptake (about 22.4 ± 6.4 %ID/g) and improved internalisation and trafficking of the drug into lysosomes compared with non-clicked antibody combinations, and enhanced therapeutic efficacy. The modular design, the authors argue, could be extended to other receptor pairs and to tumours that currently benefit little from approved ADCs.
The findings are confined to laboratory cell lines and animal models and have not yet been tested in people, so any clinical benefit remains unproven. But the researchers say the platform addresses a key limitation of existing ADCs — the need for uniform target expression — and could widen the pool of patients who respond to the drugs.
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