Modular in vivo antibody–ADC click to reverse drug resistance in tumours
8 affiliations
- 1Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA
- 2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
- 3Cancer Biology Graduate Program, Washington University School of Medicine, St Louis, MO, USA
- 4Alvin J. Siteman Cancer Center, Washington University School of Medicine and Barnes-Jewish Hospital, St Louis, MO, USA
- 5Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
- 6Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA
- 7Alvin J. Siteman Cancer Center, Washington University School of Medicine and Barnes-Jewish Hospital, St Louis, MO, USA. [email protected]
- 8Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA. [email protected]
Abstract
Antibody–drug conjugates (ADCs) have significantly advanced cancer therapy by enabling the selective delivery of cytotoxic agents to tumour cells. However, ADC efficacy remains constrained by its dependence on a single target antigen, which limits tumour targeting and promotes resistance in heterogeneous tumours with variable and low antigen expression1–6. Here we introduce an in vivo bioorthogonal ligation strategy that generates functional antibody–ADC click constructs following systemic administration. This platform provides a modular and translatable approach for enhanced targeted drug delivery in heterogeneous tumours. We conjugate therapeutic antibodies and ADCs with trans-cyclooctene and tetrazine moieties for sequential administration to enable in vivo ligation of an antibody with an ADC after systemic delivery. The antibody–ADC click approach demonstrated improved antitumour activity relative to standard ADC monotherapy or antibody plus ADC combinations in preclinical models of HER2 and EGFR co-expression. These included tumours with low, ultralow, negative or heterogeneous HER2 expression and resistant or ineligible for conventional HER2-directed ADCs. This modular strategy leverages receptor biology and bioorthogonal chemistry for optimal therapeutic efficacy and does not require extensive antibody re-engineering. Moreover, the antibody–ADC click approach can be extended to other receptor pairs, which makes it a flexible modular platform to address heterogeneity and resistance to targeted therapies across different tumour types. In vivo ligation of clinically used therapeutic antibodies via bioorthogonal click chemistry to antibody–drug conjugates leads to enhanced antitumour activity in heterogeneous and treatment-resistant tumours.
Related
- Digestion and Orthogonal Click Conjugation Enables Nanopore Reading of Proteins
- The Copper(I)-catalyzed Alkyne-azide Cycloaddition “Click” Reaction in Water Requires the Formation of Two Distinct Mononuclear Copper(I) Complexes
- Ultrasound-Controlled Activation of Tetrazine-TCO Click-to-release Chemistry Through Sonochemical Oxidation of Dihydrotetrazine
- Auto‐Click Synthesis of a Copper(I) –N ‐Heterocyclic Carbene Porous Organic Polymer and Its Transmetalation to Palladium(II) for Azide–Alkyne Cycloaddition and Cross‐Coupling Reactions
- A sulfinate–azide hybrid reagent for sequential radical fluoroalkylation and click reaction†
BibTeX
@article{simo2026modular,
title = {{Modular in vivo antibody–ADC click to reverse drug resistance in tumours}},
author = {Cristina Simó and Alex Vanover and Ricardo D’Oliveira Albanus and Sandeep Surendra Panikar and Shayla Shmuel and Alex Benton and Jader Giraldo-Guzmán and José M. Luna and Yifei Xu and Na-Keysha Berry and Nai Keltee and Jingxia Liu and Farrokh Dehdashti and Patrícia M. R. Pereira},
journal = {Nature},
year = {2026},
month = jul,
doi = {10.1038/s41586-026-10789-w},
url = {https://doi.org/10.1038/s41586-026-10789-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Modular in vivo antibody–ADC click to reverse drug resistance in tumours
AU - Cristina Simó
AU - Alex Vanover
AU - Ricardo D’Oliveira Albanus
AU - Sandeep Surendra Panikar
AU - Shayla Shmuel
AU - Alex Benton
AU - Jader Giraldo-Guzmán
AU - José M. Luna
AU - Yifei Xu
AU - Na-Keysha Berry
AU - Nai Keltee
AU - Jingxia Liu
AU - Farrokh Dehdashti
AU - Patrícia M. R. Pereira
PY - 2026
DA - 2026/07/15
JO - Nature
DO - 10.1038/s41586-026-10789-w
UR - https://doi.org/10.1038/s41586-026-10789-w
AB - Antibody–drug conjugates (ADCs) have significantly advanced cancer therapy by enabling the selective delivery of cytotoxic agents to tumour cells. However, ADC efficacy remains constrained by its dependence on a single target antigen, which limits tumour targeting and promotes resistance in heterogeneous tumours with variable and low antigen expression1–6. Here we introduce an in vivo bioorthogonal ligation strategy that generates functional antibody–ADC click constructs following systemic administration. This platform provides a modular and translatable approach for enhanced targeted drug delivery in heterogeneous tumours. We conjugate therapeutic antibodies and ADCs with trans-cyclooctene and tetrazine moieties for sequential administration to enable in vivo ligation of an antibody with an ADC after systemic delivery. The antibody–ADC click approach demonstrated improved antitumour activity relative to standard ADC monotherapy or antibody plus ADC combinations in preclinical models of HER2 and EGFR co-expression. These included tumours with low, ultralow, negative or heterogeneous HER2 expression and resistant or ineligible for conventional HER2-directed ADCs. This modular strategy leverages receptor biology and bioorthogonal chemistry for optimal therapeutic efficacy and does not require extensive antibody re-engineering. Moreover, the antibody–ADC click approach can be extended to other receptor pairs, which makes it a flexible modular platform to address heterogeneity and resistance to targeted therapies across different tumour types. In vivo ligation of clinically used therapeutic antibodies via bioorthogonal click chemistry to antibody–drug conjugates leads to enhanced antitumour activity in heterogeneous and treatment-resistant tumours.
SN - 0028-0836
SN - 1476-4687
ER -