Antibody-drug conjugate (ADC) connects a biologically active small molecule drug to a monoclonal antibody through a chemical link. The monoclonal antibody acts as a carrier to target the small molecule drug to the target cell.
Antibody-drug conjugate (ADC) research can be traced back to 1980s, but it was not until 2000 that the first antibody conjugate drug (trade name Mylotarg, developed by Pfizer) was approved by the FDA for the treatment of acute myeloid leukemia, but Due to limitations in coupling technology, targeting and effectiveness, complete antibody-conjugated drugs are unstable in the blood, leading to lethal toxicity, and they were withdrawn from the market in 2010. This has cast a shadow over the otherwise unclear ADC drug research.
However, as Takeda/SeattleGenetics improved the original technology and used its own new antibody coupling technology to develop a new antibody conjugate drug brentuximabvedotin (SGN-35, trade name Adcetris,), which was approved by the FDA for use in 2011 Treatment of Hodgkin's lymphoma and systemic anaplastic large cell lymphoma. In 2013, another breakthrough was made in antibody conjugate drugs. Ado-trastuzumabemtansine (T-DM1, trade name Kadcyla) jointly developed by Genentech/ImmunoGen was approved by the FDA for HER2-positive breast cancer. This is the first antibody conjugate drug for solid tumor. With the successful development of these two drugs, ADC drugs have once again entered people's research horizons in a fiery state.
ADC drugs use specific linkers to connect antibodies and small molecule cytotoxic drugs. Its main components include antibodies, linkers, and small molecular cytotoxic drugs (SM). Antibody molecules mainly play the role of targeted delivery, and small molecule drugs play an effect. However, some antibodies also have anti-tumor pharmacodynamic effects. For example, Kadcyla has a synergistic effect between ado-trastuzumab and maitansine (maytansine).
Because the structure of ADC drugs is more complex, and there are big differences between different ADC drug designs. Even for different drugs with the same target, the difference in toxicity is obvious due to the difference in recognition sites, connection sites, linkers and small molecules connected. Therefore, before evaluating the toxicity of ADC drugs, it is necessary to understand the design of the ADC drugs. Ideal ADC drug design needs to consider ① The choice of antibody: clear target, high expression in tumor cells, low expression in normal tissues; support drug loading, stability, and internalization into cells; good PK characteristics; less non-specific binding; ② connection Site: Generally, there are lysine or cysteine residues, which can be reconfigured for directional coupling; ③ Linker: stable in the circulation, and can be released in the cell (such as lysosomal enzyme digestion release, or antibody Released after degradation); ④ Cytotoxic drugs: High pharmacodynamic effects, no immunogenicity, can be combined with the linker through modification, the mechanism is clear
3. 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 150 ku, and the relative molecular mass of cytotoxic drugs is about 1 ku, the nature of ADC drugs in circulation is basically the same as “The "naked" antibody is consistent.
2. Binding antigen, antibody recognizes specific antigenic site, 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. When the drug is released, the linker is cleaved in the intracellular lysosome to release small molecule cytotoxic drugs.
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 are not internalized, but are released outside the cell and play a role in the local microenvironment.
BOC Sciences is a life sciences group with its headquarters in the NY. BOC Sciences provides the most complete set of solutions in antibody-drug conjugate (ADC) drug development services in the pharmaceutical industry. Working with companies and academic groups all over the world, including most of the top biopharmaceutical companies, BOC Sciences supports the development and manufacture of antibody drug conjugates.such as: mmaf, adc linker products, pab linker, adc technology companies.