Site-specific antibody drug conjugates for cancer therapy
Top Cited Papers
Open Access
- 20 November 2013
- journal article
- review article
- Published by Informa UK Limited in mAbs
- Vol. 6 (1), 34-45
- https://doi.org/10.4161/mabs.27022
Abstract
Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors—target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0–8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics.Keywords
This publication has 76 references indexed in Scilit:
- Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugatesmAbs, 2013
- Synthesis of site-specific antibody-drug conjugates using unnatural amino acidsProceedings of the National Academy of Sciences of the United States of America, 2012
- Site-specific chemical protein conjugation using genetically encoded aldehyde tagsNature Protocols, 2012
- Monoclonal antibodies for the treatment of cancerSeminars in Cancer Biology, 2012
- World Bispecific Antibody Summit, September 27–28, 2011, Boston, MAmAbs, 2012
- Molecularly Defined Antibody Conjugation through a Selenocysteine InterfaceBiochemistry, 2009
- Site Specific Conjugation of Fluoroprobes to the Remodeled Fc N-Glycans of Monoclonal Antibodies Using Mutant Glycosyltransferases: Application for Cell Surface Antigen DetectionBioconjugate Chemistry, 2009
- Targeted antimicrobial activity of a specific IgG–SMAP28 conjugate against Porphyromonas gingivalis in a mixed cultureInternational Journal of Antimicrobial Agents, 2008
- shRNA and siRNA delivery to the brainAdvanced Drug Delivery Reviews, 2007
- Structural characterization of the maytansinoid–monoclonal antibody immunoconjugate, huN901–DM1, by mass spectrometryProtein Science, 2005