Abstract
The use of antibody drug conjugates (ADCs) as targeted chemotherapies has successfully entered clinical practice and holds great promise. ADCs consist of an antibody and toxin-drug combined together via a chemical linker. While the antibody and drug are of vital importance in the direct elimination of cancer cells, more advanced linker technology was instrumental in the delivery of more potent drugs with fewer side effects. Here, we discuss the preclinical experience as well as clinical trials, with a specific emphasis on the clinical outcomes and side effects, in addition to linker strategies for five different ADCs, in order to describe different approaches in the development of this new class of anticancer agents. Brentuximab vedotin is approved for use in Hodgkin's lymphoma and Trastuzumab emtansine is approved for breast cancer. Combotox, Inotuzumab Ozogamicin, and Moxetumomab Pasudotox are in various stages of clinical development and are showing significant efficacy in lymphoid malignancies. These ADCs illustrate the promise and future potential of targeted therapy for presently incurable malignancies.
Highlights
The concept of linking an antibody to a toxin to create a safe and effective agent against cancer cells is not a new one
This review describes in detail the development of five unique antibody drug conjugates (ADCs), each using a different combination of linker technology and toxin
This study showed that SGN-35 might be more effective at a weekly dosing, and had increased adverse events, especially related to peripheral neuropathy.[35]
Summary
The concept of linking an antibody to a toxin to create a safe and effective agent against cancer cells is not a new one. The magic bullet concept of Paul Ehrlich is over 100 years old,[1] while the first credible experiments linking chemotherapeutic agents to antibodies were performed almost 55 years ago).[2] At this point, despite all the years of research, there have only been four antibody drug conjugates (ADCs) approved by the FDA (Figure 1).[3,4,5,6] Brentuximab vedotin (SGN35; AdcetrisTM) and Trastuzumab emtansine (T-DM1; KadcyclaTM) were recently approved Both revolutionized treatment for their respective indication (relapsed Hodgkin’s lymphoma (HL)/systemic anaplastic large cell lymphoma (sALC), and Her2-positive breast cancer), while denileukin difitox (OntakTM) and, gemtuzumab ozogamicin (GO; MylotargTM) have seen limited clinical use. These examples demonstrate that various components of an ADC are important in determining its efficacy and relative safety (Table 1).[10,11,12,13]
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