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

Author(s): Qun Zhou, Jennifer Kim

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 15 , Issue 7 , 2015

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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.

Keywords: Antibody-drug conjugate; conjugation through unnatural amino acids or amino acid derivatives, glutamine conjugation, glycoconjugation, lysine conjugation, site-specific conjugation, cysteine conjugation.

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Article Details

Year: 2015
Published on: 12 July, 2015
Page: [828 - 836]
Pages: 9
DOI: 10.2174/1871520615666150302125448
Price: $65

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