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Review
. 2015;15(7):828-36.
doi: 10.2174/1871520615666150302125448.

Advances in the Development of Site-Specific Antibody-Drug Conjugation

Qun Zhou  1 , Jennifer Kim
Affiliations
Review

Advances in the Development of Site-Specific Antibody-Drug Conjugation

Qun Zhou et al. Anticancer Agents Med Chem. 2015.

Abstract

Antibody-drug conjugates (ADCs) showed strong anticancer efficacy in the clinic. However, the current conventional technologies generate conjugates with undefined attachment sites and heterogeneous profiles containing different sub-populations, leading to potential off-target toxicity. In order to reduce the variability and heterogeneity associated with the ADCs generated using conventional technologies, several site-specific antibody-drug conjugation strategies were developed for the next generation of ADCs. These strategies include cysteine-targeted conjugation by engineering a free cysteine into the antibody or by placing a thiol bridge on cysteines in hinge disulfides. Glutamine-targeted conjugation was also demonstrated by coupling the drug-linker to glutamine residues through an engineered glutamine tag or a native glutamine, as well as an additionally introduced glutamine residue in aglycosylated antibody mutant using microbial transglutaminase. The site-specific conjugation of drug-linker to antibody carbohydrates was developed either through metabolic engineering or a chemo-enzymatic approach. Other amino acids, such as unnatural amino acids or amino acid derivatives introduced through protein engineering, have also been shown to be efficient targets for site-specific conjugation. The sitespecific ADCs with homogeneous profiles and well-defined conjugation sites were obtained using these second generation ADC methods and showed potent in vitro cytotoxicity and strong in vivo antitumor activity. These results suggest that newly developed site-specific conjugation technologies can potentially be applied in producing the next generation ADC for cancer treatment in the clinic with high therapeutic index.

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