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ADC Linker

Antibody-drug conjugates (ADCs) consist of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker. An appropriate linker between the antibody and the cytotoxic drug provides a specific bridge, and thus helps the antibody to selectively deliver the cytotoxic drug to tumor cells and accurately releases the cytotoxic drug at tumor sites. In addition to conjugation, the linkers maintain ADCs’ stability during the preparation and storage stages of the ADCs and during the systemic circulation period.

The ADCs currently undergoing clinical evaluation contain linkers are mostly classified into two categories: cleavable and noncleavable. Cleavable linkers rely on processes inside the cell to liberate the toxin, such as reduction in the cytoplasm, exposure to acidic conditions in the lysosome, or cleavage by specific proteases within the cell. Noncleavable linkers require proteolytic degradation of the antibody portion of the ADC for release of the cytotoxic molecule, which will retain the linker and the amino acid by which it was attached to the antibody.

The selection of linker is target dependent, based on the knowledge of the internalization and degradation of the antibody-target antigen complex, and a preclinical in vitro and in vivo activity comparison of conjugates. Moreover, the choice of a linker is also influenced by which cytotoxin is used, as each molecule has different chemical constraints, and frequently the drug structure lends itself to a specific linker.

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