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

Bioconjugate Chemistry
Nai-Shu HsuAndrew H-J Wang

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.

References

May 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·S L LokeL M Neckers
May 1, 1992·Trends in Cell Biology·S Akhtar, R L Juliano
Jul 20, 2010·Current Opinion in Biotechnology·Brian J GallettaJohn A Cooper
Apr 27, 2011·Journal of Medicinal Chemistry·Robert Y ZhaoRavi V J Chari
Feb 22, 2012·Proceedings of the National Academy of Sciences of the United States of America·Stephanie A KazaneVaughn V Smider
Jan 18, 2014·ACS Chemical Biology·Kathrin Lang, Jason W Chin
Aug 6, 2014·Molecular Therapy. Nucleic Acids·Hongguang SunYouli Zu
Mar 12, 2015·Pharmaceutical Research·Nareshkumar JainBruce Tomczuk
Jan 9, 2016·Journal of the American Chemical Society·Jeffrey C KernRobert M Garbaccio
Jan 23, 2016·Nature Chemistry·Vijay ChudasamaStephen Caddick
Mar 8, 2016·Scientific Reports·Jessie A G L van BuggenumKlaas W Mulder
Oct 11, 2016·Chemical Society Reviews·Malay PatraGilles Gasser
Oct 16, 2016·Protein & Cell·Kyoji Tsuchikama, Zhiqiang An
Mar 18, 2017·Nature Reviews. Drug Discovery·Alain BeckNathalie Corvaïa
Dec 20, 2017·Nature Chemistry·Jinny X ZhangDavid Yu Zhang
Jul 25, 2019·Bioconjugate Chemistry·Igor DovganAlain Wagner
Mar 21, 2020·SLAS Discovery·Laurence Gauzy-LazoMarie-Priscille Brun

❮ Previous
Next ❯

Citations

Mar 7, 2021·Journal of Clinical Medicine·Julien Dugal-TessierNareshkumar Jain
Mar 17, 2021·Scientific Reports·Victor LehotAlain Wagner
May 20, 2021·Journal of Agricultural and Food Chemistry·Panting SangHe Qian
Aug 21, 2021·Bioconjugate Chemistry·Christopher J AddonizioMatthew J Webber

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Journal of Clinical Medicine
Julien Dugal-TessierNareshkumar Jain
European Journal of Anaesthesiology
T FrietschK F Waschke
Journal of Anxiety Disorders
Hans-Christoph SteinhausenChrista Winkler Metzke
© 2022 Meta ULC. All rights reserved