Research ADCs

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How are ADCs designed to work?

ADCs are designed to target antigens that are exclusively or preferentially expressed on the surface of cancer cells.^1,2 ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic.²

By combining the antigen-targeting precision and antitumor activity of monoclonal antibodies with the cell-killing potency of cytotoxic molecules, ADCs are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure.^3-5

See how ADCs are designed to work

Next Step:
Endocytosis Degradation Release Cell Death

The monoclonal antibody component of the ADC binds to the target antigen on the cell surface.⁵

The monoclonal antibody component of an ADC may possess its own anticancer activities, which may include⁶

Prevention of signaling
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Induction of apoptosis

Upon binding to the target antigen, the ADC/antigen complex may be internalized through a process known as receptor-mediated endocytosis.^3,5

The efficiency of internalization depends on which type of cell-surface molecule the antibody binds to³:

Those that are quickly internalized (eg, epidermal growth factor receptors)
Those that are internalized at a moderate rate
Those that are poorly internalized

Based on preclinical models, internalization of the ADC/antigen complex is followed by lysosomal degradation of the complex.⁷

Internalization of the ADC/antigen complex into endosomes is followed by delivery of the complex to the lysosomal compartment⁷
The lysosomes are both acidic and rich in proteolytic enzymes, and lysosomal degradation results in release of the cytotoxic^7,8

Based on preclinical models, lysosomal degradation of the ADC/antigen complex results in the intracellular release of the cytotoxic.⁷

Preclinical studies have shown that in order for the cytotoxic to be activated, the ADC/antigen complex must be internalized upon binding to its target antigen
Internalization and lysosomal degradation activate the release of the cytotoxic inside target tumor cells^3,5,8,9

In the proposed mechanism of action of an ADC, once the cytotoxic has been released, it then interacts with critical cellular machinery to elicit cell death.⁷

References:

1.: Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Molec Cell Biol. 2001;2:127-137.
2.: Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169.
3.: Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.
4.: Ducry L, Stump B. Antibody–drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5-13.
5.: Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054.
6.: Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180.
7.: Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66:4426-4433.
8.: Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.
9.: Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932.