Development of a Versatile and Modular Linker for Antibody-Drug Conjugates Based on Oligonucleotide Strand Pairing

Bioconjug Chem. 2020 Jul 15;31(7):1804-1811. doi: 10.1021/acs.bioconjchem.0c00281. Epub 2020 Jun 25.

Abstract

Linker design is crucial to the success of antibody-drug conjugates (ADCs). In this work, we developed a modular linker format for attaching molecular cargos to antibodies based on strand pairing between complementary oligonucleotides. We prepared antibody-oligonucleotide conjugates (AOCs) by attaching 18-mer oligonucleotides to an anti-HER2 antibody through thiol-maleimide chemistry, a method generally applicable to any immunoglobulin with interchain disulfide bridges. The hybridization of drug-bearing complementary oligonucleotides to our AOCs was rapid, stoichiometric, and sequence-specific. AOCs loaded with cytotoxic payloads were able to selectively target HER2-overexpressing cell lines such as SK-BR-3 and N87, with in vitro potencies similar to that of the marketed ADC Kadcyla (T-DM1). Our results demonstrated the potential of utilizing AOCs as a highly versatile and modular platform, where a panel of well-characterized AOCs bearing DNA, RNA, or various nucleic acid analogs, such as peptide nucleic acids, could be easily paired with any cargo of choice for a wide range of diagnostic or therapeutic applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Antibody Complex
  • Antineoplastic Agents / chemistry
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoglobulin G / immunology
  • Maytansine / chemistry
  • Oligonucleotides / chemistry*
  • Receptor, ErbB-2 / immunology

Substances

  • Antigen-Antibody Complex
  • Antineoplastic Agents
  • Immunoconjugates
  • Immunoglobulin G
  • Oligonucleotides
  • Maytansine
  • ERBB2 protein, human
  • Receptor, ErbB-2