What are Antibody-drug Conjugates (ADCs)?

Antibody-drug conjugates or ADCs represent an innovative therapeutic application that combines the unique properties of monoclonal antibodies (mAbs) with the potent cell killing activity of cytotoxic small molecule drugs.  

The key components of antibody-drug conjugates include a monoclonal antibody (mAbs), a stable linkers and a cytotoxic (anticancer) agents.  Monoclonal antibodies are attached to biologically active drugs by chemical linkers with labile bonds.  By combining the unique targeting of mAbs with the cancer-killing ability of cytotoxic drugs, antibody-drug conjugates allow sensitive discrimination between healthy and diseased tissue.  Antibody-drug conjugates are part of a specialized and technically challenging type of therapy combining innovations from biotechnology and chemistry to form a new class of highly potent biopharmaceutical drugs.

The unique property of antibody-drug conjugates is that these so-called armed antibodies selectively dispatch highly potent cytotoxic anticancer chemotherapies directly to cancer cells while, at the same time, leaving healthy tissue unaffected. [1,2]

With the recent approvals of brentuximab vedotin (Adcetris; Seattle Genetics/Millennium Pharmaceuticals) and ado-trastuzumab emtansine (Kadcyla; Genentech/Roche) and more than 50 ADCs in clinical trials pipelines, ADCs are a new drug class. Owing to improved technology and appropriate targeting, the clinical application of ADCs is accelerating rapidly.[3]

Conventional chemotherapy is designed to eliminate fast -growing tumor cells. It can however, also harm healthy proliferating cells, which causes undesirable side effects [4]  In contrast, ADCs are designed to increase the efficacy of therapy and reduce systemic toxicity, often seen with small molecule drugs. 

Linker technology
Antibody-Drug Conjugates deliver highly potent cytotoxic anticancer agents to cancer cells by joining them to monoclonal antibodies by biodegradable linkers which are stable in the antibody-drug conjugates discriminate between cancer and normal tissue.  

Advances in linker technology needed to attach monoclonal antibodies to cytotoxic anticancer agents allow control over drug pharmacokinetics and significantly improve delivery of a cytotoxic agent to cancer cells.  

How they work
The antibody-drug conjugate is a three-component system including a potent cytotoxic anticancer agent linked via a biodegradable linker to an antibody. The antibody binds to specific markers (antigens or receptors) at the surface of the cancer cell. The whole antibody-drug conjugate is then internalized within the cancer cell, where the linker is degraded and the active drug released.

The focused delivery of the cytotoxic agent to the tumor cell is designed to maximize the anti-tumor effect of ADCs, while minimizing its normal tissue exposure, potentially leading to an improved therapeutic index. [1] 

For more information:
[1] DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, et al.  Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004 Mar 1;103(5):1807-14. Epub 2003 Nov 13
[2] Mullard A. Maturing antibody–drug conjugate pipeline hits 30. Nature Reviews Drug Discovery 12, 329–332 (May 2013) doi:10.1038/nrd4009
[3] Zolot RS, Basu S and Million RP. Antibody–drug conjugates. Nature Reviews Drug Discovery 12, 259-260 (April 2013) | doi:10.1038/nrd3980

Video provided by Genentech, a Member of the Roche Group. This page was last updated on May 12, 2013. Reviewed by Peter Hofland, PhD.

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