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Receptor-Mediated Endocytosis:
A Key Step in the Mechanism of Action of Antibody-Drug Conjugates (ADCs)

Receptor-mediated endocytosis is a process that transports extracellular molecules into a target cell.1

Receptor Mediated Endocytosis
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  1. Extracellular molecules bind with high specificity to their target receptor on the cell surface1
  2. These molecules and their receptors accumulate in coated pits and are internalized in clathrin-coated vesicles as molecule-receptor complexes1
  3. Once internalized, endocytosed molecules are delivered into intracellular vesicles known as endosomes1
  4. Endocytosed molecules are then transported into lysosomes where hydrolytic digestion begins1,2
    • Lysosomes are the main sites where intracellular digestion of the internalized molecules occurs1
    • They contain about 40 different hydrolytic enzymes known as acid hydrolases, including proteases, that are most active in an acidic environment (pH ~5)1

Receptor-mediated endocytosis is a critical process in the unique mechanism and activation of ADCs, an intensive area of research at Genentech.2-4

ADCs are composed of a monoclonal antibody that is connected to a potent cytotoxic agent with a stable linker.3 The specificity of the antibody and the stability of the linker allow ADCs to selectively target tumor-associated antigens (receptors) and limit systemic exposure to the cytotoxic agent.2-4 Once inside the tumor cell, the cytotoxic agent is free to exert its antitumor activity such as cell cycle arrest and subsequent apoptosis.2,3,5

Reference:
1.
Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Vesicular traffic in the secretory and endocytic pathways. In: Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing; 1994:599-651.
2.
Kovtun YV, Goldmacher VS. Cell killing by antibody–drug conjugates. Cancer Lett. 2007;255:232-240.
3.
Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.
4.
Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054.
5.
Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169.