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Straightforward Glycoengineering Approach to Site-Specific Antibody–Pyrrolobenzodiazepine Conjugates
- Publication Year :
- 2016
- Publisher :
- American Chemical Society, 2016.
-
Abstract
- Antibody–drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively to cancer cells. ADCs have traditionally been prepared by stochastic conjugation of a cytotoxic drug using an antibody’s native cysteine or lysine residues. Through strategic selection of the mammalian expression host, we were able to introduce azide-functionalized glycans onto a homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with an alkyne-bearing pyrrolobenzodiazepine dimer payload (SG3364) using copper-catalyzed click chemistry yielded a site-specific ADC with a drug-to-antibody ratio (DAR) of four. This ADC was compared with a glycoengineered DAR two site-specific ADC, and both were found to be highly potent against EphA2-positive human prostate cancer cells in both an in vitro cytotoxicity assay and a murine tumor xenograft model.
- Subjects :
- 0301 basic medicine
Glycan
biology
010405 organic chemistry
medicine.drug_class
Organic Chemistry
Pyrrolobenzodiazepine
Monoclonal antibody
01 natural sciences
Biochemistry
0104 chemical sciences
body regions
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
chemistry
Drug Discovery
Cancer cell
biology.protein
medicine
Click chemistry
Antibody
Cytotoxicity
Conjugate
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....17a05cdfcb2e9de804b5da849e8a6140