Elements of an Antibody-Drug Conjugate (ADC)
Click to enlarge
References: 1. Carter PJ et al. Cancer J. 2008;14(3):154-169. 2. Senter PD. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG et al. Cancer Res. 2009;69(6):2358-2364.
Primary Mechanism of Action of ADCs:
Targeted Delivery of a Cytotoxic Agent
Click to enlarge
Reference: Carter PJ et al. Cancer J. 2008;14(3):154-169.
Source: Antibody-drug conjugates (ADCs): empowering monoclonal antibodies to fight cancer. Seattle Genetics website. seagen.com. Published June 2011. Accessed May 29, 2012. Reprinted with permission.
Antibodies directed against tumor cell antigens or overexpressed proteins are currently the fastest-growing class of targeted cancer therapeutics. However, their success has been tempered by their limited efficacy as single agents. They are often combined with chemotherapeutic agents, which are much more effective at killing cells, but lack the selectivity of antibodies and, as a result, often have side effects as the drugs attack both normal and cancerous cells indiscriminately.
The concept of combining the two approaches in the hope of achieving the best of both worlds is not novel, but has proved more difficult than expected to put into practice. The first generation of so-called antibody-drug conjugates (ADCs) met with disappointing results, and the first FDA-approved agent, Mylotarg (gemtuzumab ozogamicin; Pfizer) was withdrawn from the market in mid-2010.
In recent years, we have come to appreciate the complexity of these molecules, and further research has led to the development of increasingly refined ADCs. These second- and even third-generation molecules are showing great promise. Last year, the FDA approved brentuximab vedotin (Adcetris; Seattle Genetics) for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Positive phase III trial results for trastuzumab emtansine (T-DM1; Genentech) for the treatment of HER2-positive metastatic breast cancer were recently announced, and many other new agents are entering clinical trials. (Table Below
What Are Antibody-Drug Conjugates?
ADCs are therapeutic agents designed to target the delivery of chemotherapy to tumor cells. ADCs link cytotoxic agents to monoclonal antibodies that bind to tumor cell-specific antigens or to antigens that are overexpressed on the surface of tumor cells. The antibody acts as a sort of GPS system, and the theory is that this should increase delivery of potent cell-killing drugs to the tumor, while reducing the exposure of normal cells.
ADCs are made up of three parts: a monoclonal antibody, a cytotoxic drug, and a linker that joins the two together. The antibody guides the ADC to target tumor cells, where it binds to cell surface antigens. The ADC is then taken into the cell and the cytotoxic drug is released to perform its cell-killing function.
An important factor in the successful development of ADCs is the selection of wellcharacterized antigens to serve as the target for the antibody. The full expression pattern of the antigen throughout the body and on both healthy and tumor cells must be taken into consideration in order to avoid unwanted toxic side effects. Likewise, the expression of tumor-specific antigens within the tumor itself may be heterogeneous, with some cells displaying the antigen and others not, and this can affect the efficacy of the ADC.
A number of tumor-associated antigens have been investigated as potential targets for the antibody component of ADCs. Blood cell cancers, including leukemia, lymphoma, and multiple myeloma are often chosen as cancer types in which to study ADCs, since malignant blood cells are more accessible to antibodies than solid tumors. As such, B- and T-cell surface proteins are frequently chosen as target antigens since they are widely expressed on the surface of malignant B and T cells in these types of cancer.