{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA",
    "Department of Neurology, Washington University School of Medicine, St Louis, MO, USA",
    "Cancer Biology Graduate Program, Washington University School of Medicine, St Louis, MO, USA",
    "Alvin J. Siteman Cancer Center, Washington University School of Medicine and Barnes-Jewish Hospital, St Louis, MO, USA",
    "Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA",
    "Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA",
    "Alvin J. Siteman Cancer Center, Washington University School of Medicine and Barnes-Jewish Hospital, St Louis, MO, USA. ribeiropereirap@wustl.edu",
    "Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA. ribeiropereirap@wustl.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Cristina Simó",
      "orcid": "0000-0002-5980-9379"
    },
    {
      "affs": [
        0
      ],
      "name": "Alex Vanover",
      "orcid": "0000-0002-1275-1202"
    },
    {
      "affs": [
        1
      ],
      "name": "Ricardo D’Oliveira Albanus",
      "orcid": "0000-0003-3651-0136"
    },
    {
      "affs": [
        0
      ],
      "name": "Sandeep Surendra Panikar",
      "orcid": "0000-0002-1275-1069"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Shayla Shmuel"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Alex Benton",
      "orcid": "0000-0002-4421-0179"
    },
    {
      "affs": [
        0
      ],
      "name": "Jader Giraldo-Guzmán",
      "orcid": "0000-0001-6365-689X"
    },
    {
      "affs": [
        3,
        0
      ],
      "name": "José M. Luna",
      "orcid": "0000-0002-5513-022X"
    },
    {
      "affs": [
        4
      ],
      "name": "Yifei Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Na-Keysha Berry"
    },
    {
      "affs": [
        0
      ],
      "name": "Nai Keltee"
    },
    {
      "affs": [
        5,
        4
      ],
      "name": "Jingxia Liu",
      "orcid": "0000-0002-9434-7907"
    },
    {
      "affs": [
        3,
        0
      ],
      "name": "Farrokh Dehdashti",
      "orcid": "0000-0002-6019-3997"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Patrícia M. R. Pereira",
      "orcid": "0000-0002-4772-9339"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/660sxxc0b57zh.bib",
  "cited_by": 6,
  "doi": "10.1038/s41586-026-10789-w",
  "fulltext_url": null,
  "id": "660sxxc0b57zh",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10789-w",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Click Chemistry and Applications"
    ]
  ],
  "openalex": "W7168424393",
  "pdf_url": null,
  "pmcid": "PMC13538031",
  "pmid": "42457957",
  "published": "2026-07-15",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/660sxxc0b57zh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:44Z",
      "native_id": "W7168424393",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10789-w"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Click Chemistry and Applications",
      "subfield": "organic"
    }
  ],
  "title": "Modular in vivo antibody–ADC click to reverse drug resistance in tumours",
  "title_text": "Modular in vivo antibody–ADC click to reverse drug resistance in tumours",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:04Z",
  "url": "https://research.draconitic.com/paper/660sxxc0b57zh",
  "venue": "Nature",
  "versions": []
}