Abstract
Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. These methods couple cytotoxins or chemotherapeutic drugs to specifically defined sites in antibody molecules including cysteine, glutamine, unnatural amino acids, short peptide tags, and glycans. The ADCs produced showed high homogeneity, increased therapeutic index, and strong antitumor activities in vitro and in vivo. Moreover, there are recent trends in using these next generation technologies beyond the cytotoxin-conjugated ADC. These site-specific conjugations have been applied for the generation of many different immunoconjugates including bispecific Fab or small molecule–antibody conjugates, immunosuppressive antibodies, and antibody–antibiotic conjugates. Thus, it is likely that additional technologies and related site-specific conjugates will emerge in the near future, with various chemicals or small molecular weight proteins in addition to cytotoxin for better treatment of many challenging diseases.
Highlights
Therapeutic antibodies have become a major class of biologics in treating many challenging diseases, including cancer
The coupling of drug-linker to unnatural amino acid residues in the antibody is another approach for site-specific conjugation [36]
There are several site-specific conjugation methods being developed through coupling of cytotoxin to specific short peptide tags that contain four to six amino acid residues
Summary
Therapeutic antibodies have become a major class of biologics in treating many challenging diseases, including cancer. As one of the targeted therapies or the “magic bullet” proposed by Paul Ehrlich more than a century ago [12], the concept of ADCs is the targeted delivery of a highly cytotoxic drug for selective (as opposed to systemic) chemotherapy, resulting in improved therapeutic index and enhanced efficacy relative to traditional chemotherapies or naked monoclonal antibodies. This unique format would allow the use of certain chemotherapeutic drugs which are too potent or toxic to be applied systemically.
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