BOC Sciences established advanced high throughput ADCs linkers production platform to meet the increasing demand for ADC linkers researches. Antibody-Drug Conjugates (ADCs) is a novel generation of antibody-targeted therapeutic drug, mainly applied for tumors and cancer treatment. Structurally, ADCs are composed of 3 components, the payload, antibody and linker. Mechanistically, ADCs act by binding to the target antigen on the cell surface, internalization via antigen-mediated endocytosis trafficking into the lysosome, and payload release through the proteolytic degradation of the antibody moiety/or cleavage of the linker. The rationale for developing ADCs is that linking a cytotoxic agent to a tumor-targeting antibody will enable selective targeting to cancer cells, leading to their eradication while sparing cells in normal tissues. Optimal ADCs achieving maximum efficacy with minimal toxicity require the appropriate combination of each of these components.
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J. Med. Chem. 2014, 57, 16, 6949–6964.
The most essential role of antibody-drug conjugates (ADCs) is the release of cytotoxic molecules in the cytoplasm, which is achieved by destroying the chemical linker between the antibody and the cytotoxic molecule. Thus, choosing a suitable linker is highly critical to ADCs. The ideal ADCs linker must satisfy the following conditions: it must be stable enough in the peripheral blood circulation to avoid the toxicity caused by the release of cytotoxic molecules. Thus, it can effectively release small cytotoxins after ADCs internalization. The key to ADCs therapeutic effect is to select a suitable linker and couple with the appropriate number of cytotoxins at the reaction site. The linkers can be divided into cleavable linkers and non-cleavable linkers based on their dissociation properties.
Non-cleavable linkers stabilized in the blood circulation system and tumor cells, such as thioethers linkers and amides linkers. After being engulfed by tumor cells, antibody-drug conjugates (ADCs) monoclonal antibodies (mAbs) are degraded in lysosomes, releasing small-molecule cytotoxic from the linker to exert antitumor effects. With this mechanism, differences between parent drugs and potential ADCs metabolites must be taken into consideration. For example, MMAE, a protein-based anti-mitotic drug, is most potent in its native form and is therefore poorly suited for derivatization with non-cleavable linkers. Conversely, MMAF retained its potency even when linked with a simple alkyl chain in vitro and in vivo. One proposed mechanism for the decreased efficacy of non-cleavable linked ADCs is that drugs bearing charged amino acids suffer from decreased membrane permeability, limiting their ability to kill nearby cells. Several non-cleavable alkyl and polymeric linkers have been explored in ADCs development. A notable example is the MCC amine-to-sulfhydryl bifunctional cross-linker featured in T-DM, this linker is especially useful as the cyclohexane ring provides a steric hindrance that decreases the hydrolysis of the resulting thioether.
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