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Antibody-drug conjugate (ADC) is a humanized or human monoclonal antibody conjugated to highly cytotoxic small molecules (payloads) through a chemical linker. It is a novel form of treatment with great potential to make a paradigm shift in cancer chemotherapy. Compared with traditional chemotherapy, this new antibody-based molecular platform can selectively deliver effective cytotoxic payloads to target cancer cells, thereby improving efficacy, reducing systemic toxicity, and having better pharmacokinetics (PK)/Pharmacodynamics (PD) and biodistribution. So far, 8 ADC drugs have been approved by the FDA, and about 164 ADCs are in clinical trials.
The difficulty of ADC technology development lies in linker technology. At present, the site-specific ADC technology generally conjugates antibodies with drug molecules specifically through the engineering of cysteine sites, unnatural amino acids, selenocysteine, and enzyme (glutamine, glycoengineering, FGE) coupling technologies.
Figure 1. Antibody binding methods means that (a) cysteine-reactive and (b) lysine-reactive chemicals will produce a heterogeneous mixture of drug-antibody ratios (DAR). And (c) site-specific conjugation method can provide a more homogeneous product with defined DAR using engineered residues, modified glycans, enzymatic ligations, and chemical crosslinkers. (Donmienne Leung. 2020)
BOS Sciences has its own site-specific linker technology platform. Site-specific linker technology can ensure that a certain number of drug molecules are site-specifically coupled to specific sites of antibodies, to ensure drug homogeneity and mass production stability to a large extent. In addition, the DAR value can also be accurately controlled at 2 or 4.
Table 1: ADCs conjugation technologies (Kyoji Tsuchikama. 2018).
| Strategy | DARs | Advantages | Disadvantages | |
| Chemical conjugation | Lysine coupling | 0-7 | Simple process Used in FDA-approved and clinically tested ADCs | Heterogeneous mixtures of products Potential reduction of antigen binding |
| Cysteine coupling | 0, 2, 4, 6, 8 | Simple process Used in FDA-approved and clinically tested ADCs | Heterogeneous mixtures of products Increased clearance rate with high DAR Requires genetic engineering | |
| THIOMAB | 2 | Defined DAR Homogeneity | Requires genetic engineering | |
| Cysteine rebridging | 4 | Defined DAR Homogeneity High structural stability | Potential disulfide scrambling | |
| Non-natural amino acid | 2 | Defined DAR Homogeneity | Requires special techniques and biological agents Potential immunogenicity | |
| Sortase | 3-4 | Tightly-controlled DAR No adverse effect on antibody binding | Requires incorporation of LPETG motif on the heavy chain | |
| (Chemo) enzymatic conjugation | Microbial transglutaminase | 2 | Defined DARs Homogeneity | Requires removal of N-glycan on N297 |
| Glycan engineering (GlycoConnect) | 2 | Defined DARs Homogeneity | Requires multiple steps (i.e., N-glycan trimming, glycosylation, and conjugation | |
| Hydrazone | pH-responsive cleavage | Premature cleavage during circulation | ||
| Val-Citb-PABCc | Stability during circulation | Hydrophobicity | ||
| Val-Ala-PABCc | Traceless release of payload | |||
| Cleavable linker | Disulfide | Intracellular release of payload | Potential premature cleavage during circulation | |
| Pyrophosphate diester | Stability during circulation Hydrophilicity Traceless release of payload | Unknown mechanism of lysosomal cleavage | ||
| Non-cleavable linker | Stable linker without cleavage mechanism | Stability during circulation | An amino acid residue attached on the released payload |
Site-specific ADCs technology not only makes it possible to study the effects of coupling on ADC pharmacodynamics at different sites but also can be widely used in the coupling of other molecules such as nuclides, immunotoxins, proteins, precursor enzymes with antibodies. The therapeutic effect and application of these conjugated drugs in drug development have been greatly improved.
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