The endocytosis mechanism of ADC drugs: Part I
Posted by beauty33 on December 16th, 2021
Antibody-drug conjugates (ADCs) have made great progress in the past 10 years, which are a complex that has cytotoxic small-molecule drug coupled to a monoclonal antibody (mAb) through a reasonably placed linker. It can selectively deliver effective cytotoxic drugs into the tumor.
In 2009, gemtuzumab ozogamicin (Mylotarg) was the first ADC drug approved by the US Food and Drug Administration (FDA). By now, there are 11 ADC drugs already approved on the market, with hundreds of candidates in the clinical research phase.
In addition to the over-expression of these antigens in the selection of drug targets for ADC, another important factor to be considered is the efficiency of endocytosis, or ADC internalization, which is necessary for drug release activity. In fact, the efficacy of ADC is highly affected by the efficiency of target-mediated internalization to deliver payloads in tumor cells.
The way and efficiency of ADC internalization are also closely related to the efficacy and design of ADC drugs as it is an important factor in the choice of cleavable, non-cleavable, or pH/reduction sensitive type of linker, whether the payload (or its active metabolite) can diffuse on the cell membrane to provide a \"bystander effect\", whether it improves tumor killing rate, or whether it may help limit toxicity. Therefore, it is necessary to deeply understand the endocytosis and mechanism of ADC, because it is an extremely important initial step for the ADC to take effect in the body.
ADC related endocytic pathways
Generally speaking, normal endocytosis can be divided into three stages:
2.Membrane bending and vesicle maturation
3.Membrane breakage and release into the cytoplasm
Multiple endocytosis pathways have overlapping aspects, so the general process of endocytosis is highly flexible and complex.
Clathrin-mediated endocytosis (CME)
CME is conceptually a simple process consisting of several consecutive and partially overlapping steps, which can be activated structurally by certain receptors on the plasma membrane, or requires ligand and/or antibody binding. CME begins when the endocytic capsid proteins in the cytoplasm begin to accumulate on the inner lobules of the plasma membrane. Capsid proteins continue to assemble and grow by recruiting from the cytoplasm and interacting with additional protein adaptors. The key adaptor protein bends the membrane, thus concentrating the internalized receptor/ligand into a clathrin coating pit (CCP). As the CCP invagination increases, when the CCP neck narrows, it separates from the plasma membrane through a fracture process. The actin polymerization helps to pull the CCP inward into the cytoplasm until the rupture is complete and the CCP is released and becomes a clathrin-coated vesicle (CCV). Finally, the outer shell of CCV is broken down, and CCV is fused with endosomes to be transported to specific subcellular locations, or recycled to the cell surface.
Clathrin is a key component of CME and consists of heavy and light chains. The three clathrin heavy and light chains form a trimer that interacts with other trimers and forms a polygonal lattice around the emerging CCP. Adaptor protein 2 (AP-2) is a heterotetrameric complex that mediates the contraction of the CCP neck. Dynamin is a GTPase that forms a spiral polymer in the neck of mature vesicles, which, after GTP hydrolysis, induces vesicles to split from the plasma membrane.
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About the Authorbeauty33
Joined: July 10th, 2017
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