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Review
. 2023 Jan 17;28(3):917.
doi: 10.3390/molecules28030917.

Site-Specific Antibody Conjugation with Payloads beyond Cytotoxins

Qun Zhou  1
Affiliations
Review

Site-Specific Antibody Conjugation with Payloads beyond Cytotoxins

Qun Zhou. Molecules. .

Abstract

As antibody-drug conjugates have become a very important modality for cancer therapy, many site-specific conjugation approaches have been developed for generating homogenous molecules. The selective antibody coupling is achieved through antibody engineering by introducing specific amino acid or unnatural amino acid residues, peptides, and glycans. In addition to the use of synthetic cytotoxins, these novel methods have been applied for the conjugation of other payloads, including non-cytotoxic compounds, proteins/peptides, glycans, lipids, and nucleic acids. The non-cytotoxic compounds include polyethylene glycol, antibiotics, protein degraders (PROTAC and LYTAC), immunomodulating agents, enzyme inhibitors and protein ligands. Different small proteins or peptides have been selectively conjugated through unnatural amino acid using click chemistry, engineered C-terminal formylglycine for oxime or click chemistry, or specific ligation or transpeptidation with or without enzymes. Although the antibody protamine peptide fusions have been extensively used for siRNA coupling during early studies, direct conjugations through engineered cysteine or lysine residues have been demonstrated later. These site-specific antibody conjugates containing these payloads other than cytotoxic compounds can be used in proof-of-concept studies and in developing new therapeutics for unmet medical needs.

Keywords: degraders; engineering; payloads; peptides/proteins; siRNA; site-specific antibody conjugation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The site-specific antibody conjugation using payloads other than synthetic cytotoxins. The monoclonal antibody on the left is engineered by introducing different sites for selective coupling including specific amino acids, unnatural amino acids, short peptide tags, or modified glycans (middle). Different payloads, including non-cytotoxic compounds, proteins and peptides, nucleic acids, as well as glycans and lipids (right), are used for conjugation.
Figure 2
Figure 2
Target protein degradation through proteolysis-targeting chimeras (PROTAC). A bifunctional small molecule PROTAC compound is consist of ligand (circle in orange color) that binds the protein of interest (POI, light blue) and ligand (circle in green) for an E3 ubiquitin ligase (E3, rectangle in dark blue). Both ligands are connected by a linker. The binding of PROTAC compound to both POI and E3 ubiquitin ligase results in ternary complex formation, leading to addition of ubiquitin (circle in red) to POI that is degraded by proteasome inside the cells.
Figure 3
Figure 3
The mechanism of action of antibody conjugated with short interfering RNA (siRNA). Antibody–siRNA–conjugate (ARC) containing Fab and siRNA binds to the receptor on cell surface and is endocytosed into endosome inside the cells, where the siRNA is released and escaped into cytoplasm. The siRNA is then loaded into RISC, resulting in degradation of particular mRNA.
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Grants and funding

This work was supported by Sanofi.