TY - JOUR
T1 - Development of a Versatile and Modular Linker for Antibody-Drug Conjugates Based on Oligonucleotide Strand Pairing
AU - Hsu, Nai Shu
AU - Lee, Cheng Chung
AU - Kuo, Wen Chih
AU - Chang, Ya Wen
AU - Lo, Shin Yi
AU - Wang, Andrew H.J.
N1 - Funding Information:
We thank the Ministry of Science and Technology [MOST 108-3114-Y-001-002], and the Technology Supporting Platform Axis [AS-KPQ-106-TSPA] for funding. We thank Cheng-Hsilin Hsieh for technical assistance in MALDI-TOF/TOF mass spectrometry from Genomic Core at the Institute of Molecular Biology, Academia Sinica. We thank Tzung-Jie Yang at the Development Center for Biotechnology for obtaining mass spectra of the AOC conjugates. We thank Chin-Chun Hung at The Bioimaging and Cell Biology Facility for acquiring confocal microscopy images.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.bioconjchem.0c00281
DO - 10.1021/acs.bioconjchem.0c00281
M3 - Article
C2 - 32526138
AN - SCOPUS:85088180235
SN - 1043-1802
VL - 31
SP - 1804
EP - 1811
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 7
ER -