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The antibodies, cytotoxic drugs, and linkers of ADC are the key elements in ADC design. The linker is a bridge between antibody and cytotoxic drugs. The ideal coupling must be stable in vitro or in the blood circulation to prevent systemic toxicity caused by the early release of cytotoxic drugs, and at the same time can enter and kill the cancer cells by quickly releasing effective cytotoxic drugs .
The linker should be stable enough in the circulation so that the payload stays connected to the antibody when it is distributed to the tissue (including solid tumor tissue). Once the ADC enters into the cancer cell, it can effectively release the drug with cytocidal activity . At present, ADC drugs use chemical covalent bonds (disulfide bonds, peptide bonds, thioether bonds, etc.) to achieve the connection between antibodies and chemical drugs. These linkers can be divided into " cleavable linker " and " noncleavable linker" based on their dissociation properties.
(1) Cleavable linker: The linker may be cleavable. Here, a chemical bond (or multiple chemical bonds) between the payload and the antibody attachment site (usually an amino acid) will be cleaved intracellularly. The cleavable linker can be degraded under different pH values or the action of intracellular enzymes to achieve the separation of chemical drugs from antibodies. Adcetris uses this kind of linker. Since the chemical may escape from the target cell after the drug is released, the drug can also kill the adjacent tissue of the target cell. (2) Noncleavable linker: The noncleavable linker maintains the coupling integrity of the antibody and the chemical drug throughout the entire drug action process. The final active metabolite, released by ADC in the lysosome after complete hydrolysis by the protease, contains the payloads and all the constituent elements of the linker still connected to the amino acid residues of the antibody, which is usually lysine or cysteine residue. Kadcyla uses this kind of non-cleavable linker, so the drug will eventually degrade into a mixture of amino acids, antibodies, chemicals and other components after entering the target cells.
At an appropriate concentration, the antibody conjugates with the drug. There are various coupling methods, which can be combined by strong covalent bonds, or by scattered ionic and hydrophobic bonds. For ADC drugs, it is necessary to ensure stability in aqueous solutions and facilitate use. According to different target cells, the connection mode suitable for each drug is selected through in vivo and in vitro experiments. The antibody-acanthomycin conjugate generally uses acid-sensitive hydrazone linkage, the antibody-maytansinol conjugate uses disulfide or thioether linkage, and the antibody-auristatin conjugate uses enzyme-digested peptides linkage or unbreakable thioethers linkage.