Ethynylphosphonamidates for the Rapid and Cysteine-Selective Generation of Efficacious Antibody-Drug Conjugates

Angew Chem Int Ed Engl. 2019 Aug 19;58(34):11631-11636. doi: 10.1002/anie.201904193. Epub 2019 Jul 18.


Requirements for novel bioconjugation reactions for the synthesis of antibody-drug conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as the stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. We report Cys-selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non-engineered monoclonal antibodies through a simple one-pot reduction and alkylation. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties. We demonstrate that ethynylphosphonamidate-linked ADCs have excellent properties for next-generation antibody therapeutics in terms of serum stability and in vivo antitumor activity.

Keywords: ADCs; antibodies; bioconjugation; bioorganic chemistry; drug delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Immunological / chemistry*
  • Antineoplastic Agents, Immunological / immunology
  • Cysteine / chemistry*
  • Ethylene Glycol / chemistry*
  • Humans
  • Immunoconjugates / chemistry
  • Immunoconjugates / metabolism*
  • Organophosphonates / chemistry*
  • Receptor, ErbB-2 / immunology*
  • Trastuzumab / chemistry*
  • Trastuzumab / immunology
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Immunological
  • Immunoconjugates
  • Organophosphonates
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Ethylene Glycol
  • Cysteine
  • Trastuzumab