Technical development trend of ADC drug

Technical development trend of ADC drug

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  DARsAdvantagesDisadvantages
Chemical conjugationLysine coupling0-7Simple process
Used in FDA-approved and clinically tested ADCs
Heterogeneous mixtures of products      
Potential reduction of antigen binding
Cysteine coupling0, 2, 4, 6, 8Simple process  
Used in FDA-approved and clinically tested ADCs
Heterogeneous mixtures of products
Increased clearance rate with high DAR
Requires genetic engineering
THIOMAB2Defined DAR HomogeneityRequires genetic engineering
Cysteine rebridging4Defined DAR
High structural stability
Potential disulfide scrambling
Non-natural amino acid2Defined DAR
Requires special techniques and biological agents
Potential immunogenicity
Sortase3-4Tightly-controlled DAR
No adverse effect on antibody binding
Requires incorporation of LPETG motif on the heavy chain
(Chemo) enzymatic   conjugationMicrobial transglutaminase2Defined DARs
Requires removal of N-glycan on N297
Glycan engineering (GlycoConnect)2Defined DARs
Requires multiple steps (i.e., N-glycan trimming, glycosylation, and conjugation
HydrazonepH-responsive cleavagePremature cleavage during circulation
Val-Citb-PABCcStability during circulationHydrophobicity
Val-Ala-PABCcTraceless release of payload
Cleavable linkerDisulfide Intracellular release of payloadPotential premature cleavage during circulation
Pyrophosphate diester Stability during circulation
Traceless release of payload
Unknown mechanism of lysosomal cleavage
Non-cleavable linkerStable linker without cleavage mechanism Stability during circulationAn 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.


  1. Kyoji Tsuchikama, Zhiqiang An. Antibody-drugconjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018; 9(1):33-46.
  2. Donmienne Leung, Jacqueline M. Wurst, Tao Liu,Ruben M. Martinez,Amita Datta-Mannan, and Yiqing Feng. Antibody Conjugates-Recent Advances and Future Innovations. Antibodies. 2020, Jau.; 9(1):2.
  3. Pengxuan Zhao, et al. Recent advances of antibody drug conjugates for clinical applications. Acta Pharmaceutica Sinica B. Available online 24 April 2020.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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