The principle and mode of action of ADC drugs

Antibody-drug conjugates or ADCs are an important class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of people with cancer. As the hottest research topic, ADC technology is intended to target and kill only the cancer cells and spare healthy cells . ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic (anticancer) payload or drug. Antibody-drug conjugates are examples of bioconjugates and immunoconjugates.

 

ADC drugs use specific linkers to connect antibodies and small molecule cytotoxic drugs, and its main components include antibodies, linkers and small molecule cytotoxic drugs (SM).

 

Antibody molecules mainly play a role in targeted delivery, and small molecule drugs play an effect. However, some antibodies also have anti-tumor pharmacodynamic effects, such as ado-trastuzumab (ado-trastuzumab) and maytansine (maitansine) in Kadcyla, which have synergistic effects.

 

A stable link between the antibody and the cytotoxic (anti-cancer) agent is a crucial aspect of an ADC conjugation. A highly stable ADC linker will ensure that less of the cytotoxic payload falls off in circulation, driving an improved safety profile, and will also ensure that more of the payload arrives at the cancer cell, driving enhanced efficacy. Linkers are based on chemical motifs including disulfides, hydrazones or peptides (cleavable), or thioethers (noncleavable) and control the distribution and delivery of the cytotoxic agent to the target cell.

 

Due to the complex structure of ADC drugs, and there are great differences between different ADC drug designs. Even for different drugs of the same target, the differences in toxicity are obvious due to the differences in recognition sites, attachment sites, linkers and small molecules to which they are attached. Therefore, before evaluating the toxicity of an ADC drug, it is necessary to understand the design of the ADC drug.

The ideal ADC drug design needs to be considered

①Antibody selection: clear target, high expression in tumor cells, low expression in normal tissues; support for drug loading, stability, and ability to internalize into cells; good PK properties; less non-specific binding;

②Connection site: generally there are lysine or cysteine ​​residues, which can be modified for directional coupling;

③Linker: stable in circulation and can be released in cells (such as release by enzyme cleavage in lysosome, or release after antibody degradation);

④Cytotoxic drugs: highly pharmacodynamic, non-immunogenic, can be combined with linkers through modification, and the mechanism is clear.

 

ADC drug mode of action

1. Circulation, ADC drugs are administered by systemic exposure, and first enter the blood system. Since the relative molecular mass of antibodies is about 150ku, and the relative molecular mass of cytotoxic drugs is about 1ku, the properties of ADC drug circulation are basically the same as "naked". Antibodies are the same.

2. Binding to the antigen, the antibody recognizes a specific antigenic site, and this process will determine the specificity of targeted delivery.

3. Internalization, after the antibody binds to the receptor on the cell membrane, endocytosis occurs.

4. Drug release, the linker is cleaved in the intracellular lysosome to release the small molecule cytotoxic drug.

5. Play the role of drugs, small molecule cytotoxic drugs play a role to kill tumor cells.

In addition to the above-mentioned common ADC drug designs, some ADC drug designs do not undergo internalization, but are released extracellularly and play a role in the local microenvironment.

 

AxisPharm provides the most comprehensive linker and payloads for conjugation research.

 

AxisPharm develops a broad range of Linkers and provide custom linker synthesis. Our current product catalog covers click chemistry tools such as DBCO, Tetrazine, TCO, BCN and Cycloprpene etc., biotin linkers, PEG linkers, peptide linkers, glucuronide linkers, photo cleavable linkers, Fluorescent Dye probe linkers and folic acid peg linkers.

 

As a customer-oriented contract research company, we offer flexible ADC Linker product kits and Bioconjugation services with competitive price.